tituted l'I-Sub Functionalization of · Reaction of B-lactams bearing activating substituents at exocyclic carbon adjacent to nitrogen with N-bromosuccinimide resulted in regioselective

\b' 3'43

Regioselective

Functionalization of l'I-Sub s tituted

p- and y-Lactams

A thesis submitted for the

degree of

Doctor of Philosophy

rn the

Department of Organic Chemistry,The University of Adelaide

Michael Joseph Pitt B.Sc. (Hons.)

by

November 1992

RegioselectiveFunctionali zation of N-Sub stituted

B- and y-Lactams

CoNTENTS

Ansrnacr

SransMhlT

PusucanoN

ACTqNOWLSDGEMENTS

Irrm<opuctoN . .

TTESULTS AND DISCUSSION - I . . . .

Exocyclic Functionalization of N-Substituted B-LactamsPreparation of the 2-azetidinonesT2 -76 .

Reactions of the 2-azetidinones 72 - 76 .

RESULTS AND DISCUSSIoN - II . . .

Elaboration of Functionalized N-Substituted p-Lactams

RUSUITS AND DISCUSSION - III . .

Functionalization of N-Substituted ylactamsPreparation of the 2-pyrrolidinones L41 and 142 . .

Functionalization of the 2-pyrrolidinones 141 and L42 . .

Rnsurrs AND DISCUSSIoN - TV .

Endocyclic Functionalization and Elaboration of y-Lactams

Preparation of the 2-pyrrolidinones L71 and 772 . .

Functionalization of the 2-pyrrolidinones 769 -L72 . .

CoNcrusroN

ÐcgRn¡rnrneL

RPpgRH\rCES

24

31

tlt

ía

7)

.1

24

48

66

66

70

83

83

115

717

766

86

I

AeSTRACT

With the aim of developing methodology for direct regioselective

functionalization of N-substituted p-lactams at exocyclic carbon adjacent to

lactam nitrogen, free radical bromination of N-substituted p-lactams bearing

activating substituents at that carbon has been investigated.

Reaction of B-lactams bearing activating substituents at exocyclic carbon

adjacent to nitrogen with N-bromosuccinimide resulted in regioselective

bromination at the exocyclic carbon adjacent to nitrogen. The resultant

product bromides are suitable for elaboration and the simplicity of this

procedure points to its potential for use in synthesis. In particular, the direct

exocyclic bromination of N-substituted p-lactams aíø this methodology

provides a novel attractive alternative route to the synthesis of N-(a-halo-

alkyl)-substituted lactams, which are of interest in the synthesis of p-lactam

antibiotics.

To demonstrate the synthetic utility of the direct exocyclic

functionalization of N-substituted B-lactams, the elaboration of N-(cr-bromo-

alkyl)-substituted p-lactams thus obtained was investigated.

Reaction of ethyl cr-bromo-2-oxo-L-azetidineacetate with allyltributyltin

afforded the corresponding allylated derivative oia radical carbon-carbon bond

formation at the exocyclic carbon adjacent to nitrogen. Ionic carbon-carbon

bond formation at the exocyclic carbon was achieved in a Wittig reaction and

Lewis acid catalysed allylation and arylation reactions of this bromide.

tl

To examine the possibility of directing functionalization to the exocyclic

carbon adjacent to lactam nitrogen in y-lactams, the regioselectivity of free

radical bromination of N-substituted y-lactams bearing activating substituents

at the exoryclic carbon adjacent to nitrogen was investigated.

Whereas analogous p-lactams gave products of reaction at the exocyclic

carbon only, N-substituted y-lactams bearing activating substituents at the

exocyclic carbon reacted with N-bromosuccinimide to give both products of

reaction at the exocyclic carbon adjacent to nitrogen and of competing reaction

at the endocyclic carbon adjacent to nitrogen. The endocyclic methylenes

adjacent to nitrogen in the y-lactams are presumably more reactive towards

hydrogen atom abstraction than those in the corresponding p-tactams due to

the relative degrees of ring strain in the product radicals.

The contribution of activating substituents at the exocyclic carbon

adjacent to nitrogen to the regioselectivity of free radical bromination of

y-lactams was examined. N-Substituted y-lactams not bearing activating

substituents at the exocyclic carbon adjacent to nitrogen reacted with

N-bromosuccinimide to give predominantly products resulting from initial

bromination at the endocyclic carbon adjacent to lactam nitrogen.

Endocyclic free radical bromination of n¡lactams leads to the production

of 4,S-dibromopyrrolidinones and as such provides novel methodology for the

regioselective difunctionalization of y-lactams at C4 and C5. The difunction-

alized y-lactams thus obtained are amenable to further regioselective

elaboration and their utility in synthesis is demonstrated by conversion to the

bicyclic tetrahydrofuropyrrolidinone system.

111

SrarnMENT

This thesis contains no material which has been accepted for the award

of any other degree or diploma in any university or other tertiary institution

and, to the best of my knowledge and belief, this thesis contains no material

previously published or written by another person, except where due reference

has been made in the text.

I consent to this copy of my thesis being made available for

photocopying and loan, if applicable, if accepted for the award of the degree for

which it is presented.

November '1.992

ta

PueucATroN

Part of the work described in this thesis has been published in the

following paper:

"Exocyclic Bromination of N-Substituted p- and llactams"

Easton, C. J.; Pitt, M.l. Tetrøhedron Lett.1990,31-, 347'1..

a

AcTNoWLEDGEMENTS

I would like to foremost thank my supervisor Dr. Chris Easton for his

guidance, encouragement and enthusiasm throughout the course of this work.

I would also like to thank all my friends and colleagues within the

Department of Organic Chemistry for providing an intellectually stimulating

environment from which I gained both support and criticism.

I thank my fiancée Lina for her understanding, encouragement,

unending support and patience, the least of which exemplified by her typing of

the majority of this manuscript.

The continuing support and encouragement of my family is, as will

always be, greatly appreciated.

INrnoDUCTroN

In 1928 Flemingl observed the antibiotic activity of penicillíum notatum

and gave the name penicillin to the active component produced by this fungal

strain. Penicillin (1) was first isolated some ten years later by Chain, Florey and

co-workers,2 who demonstrated its marked biologicat activity and therapeutic

value. It was 1945 before the structure of penicillin (1) was fully established,3,4

being the first example of a p-lactam found in nature. The first total synthesis

of a penicillin, penicillin V (1 : R = PhOCHz) was reported by Sheehan and

Henry-Logan5 in 1957.

CHs

CHao

The B-lactam ring plays a crucial role in the antibacterial activity of

penicillin (1) and a large number of antibiotics with this structural feature are

now known.6 These include the penicillins 1, cephalosporins 2, cephamycins

3, l-oxacephems 4, clavulanic acids 5, penems 6, carbapenems 7, norcardicins 8

and monobactams 9.

HSRlCONH

2R2

CO2H

SH

N

H=RCONH

CO2HH

L

SHH

N

2

co2H

p2

R

3

INTRODUCTION

2

R1

Rl

o

H:

N

5

H

N

R2

R3

H

N

4

H

N

H

R2

CHR

co2H

c02H

cH2R2

OH

o

R1

H CO2H

co2H

so3

SR3

o o

H

7

¡¡32RR

H

co2HH

I

6

RCONH

N No

9

Although the majority of these antibiotics in clinical use are naturally

occurring, being produced commercially from fermentation cultures,T the

requirement for antibiotics with greater antibacterial activities as a

consequence of drug resistänce by certain bacteriaS has lead to the development

of many semi- or totally-synthetic p-lactam antibiotics.6

A common approach to the synthesis of p-lactam antibiotics involves

completion of the molecular backbone by annelation of non-fused p-lactams

bearing appropriate substitus¡¡s.9,lO In such a manner, the first total synthesis

of the carbapenem antibiotic thienamycin (12) was accomplis¡"¿.11,12 The key

step in this synthesis was the intramolecular alkylation of a malonate anion.

INTRODUCT/ON

3

Thus, treatment of the malonic acid derivative 10 with bromine followed by

triethylamine in dimethylformamide gave the carbapenam 11, which was

subsequently converted to (+)-thienamycin (12) and (t)-8-epithienamycin (13)

(Scheme 1).

gS-rr'^-

BrLIHH

H¡CHeC NHCO2R

7. Br2

2. Et3N / DMFRqC

10

OHH H

HsCS1,'NHz ,1-NH2

co2H

13

B = p-nitrobenzyl

Scheme L

Following the same approach as that above, the intramolecular reaction

of a stabilized phosphorane with an aldehyde, ketone or thioester has been

widely used in the synthesis of a variety of bicyclic p-lactam antibiotics.l3:18

Woodward and co-workersl9 have thus described the total synthesis of several

penem antibiotics 18 in this manner, as depicted in Scheme 2. The

acylthioazetidinones L4 were converted to the required phosphoranes 17 in

three steps aia a previously established proc"¿,r.".13,20 Condensation of the

azetidinones 1-4 with the hydrate of a gyloxylic ester gave the carbinolamines 15

which were converted to the corresponding chlorides 16 through treatment

with thionyl chloride in the presence of a base. The crude chlorides 16 were

Sl,.NHCO2R

lL

OH

=

+

H

N

H

N

co2H

12

INTRODUCT/ON

4

treated in dioxane solution with triphenylphosphine in the presence of a base

and afforded the desired phosphoranes 17. The phosphorane thioesters 17

cyclized uPon heating in toluene at 90C to give the penems 18 in good yield.

(HO)2CHCO2R2 soc12N base N

corR2

15 16

/ base

HS

toluene

olt

oHll

oI

1H=

H

NH

L4

1

Yo"co2R2

A¡1r

H

N

1

oil

SCR

18 17

Scheme 2

With the high susceptibility of B-lactam antibiotics to nucleophilic

reagents2l as a consideration, Bachi and co-worker s22,23 have used free radical

carbon-carbon bond forming reactions rather than ionic reactions to complete

the molecular backbone of some fused bicyclic B-lactams. For example, the

oxabicyclo-p-lactams 20 and 21 were obtained by the action of tri-z-butyltin

hydride on the appropriately substituted non-fused azetidinone L9 (Scheme 3).

The mixture of products obtained in the reaction of 19 arises from competitive

exo and endo cyclization of the initially formed radical 22 to give 20 and 21,

respectively. The relative stability of the radicals 23 and 24, produced during

the ring closure of 22, is an important factor in determining the relative extent

of the exo and endo modes of cyclizatíon (Scheme 4). When R1 = H, the

/NTRODUCTION

5

secondary radical 24 is more stable than the primary radical 23 and the reaction

occurs in the endo rnode, but when R1 = Ph or CO2CH3, the radical 23 is more

stable than the radical 24 and. exo additton is favoured. rt

'

t3

pr

tt-Bu3SnH

Scheme 3

+

endo

N

Yt'cqR2

N ¡1r

19 20 21

R1

exo

¡¡t N

co2R2

23

R

Scheme 4

Methods for the synthesis of fused bicyclic 1-lactams are of interest in the

synthesis of certain alkaloids.24 The pyrrolizidine alkaloids are a large class of

naturally occurring compounds isolated from a variety of plant sources.2S

These alkaloids exhibit diverse biological activities and various members of

this family, possessing the common azabicyclol3.3.0]octane ring system, have

been reported to act as antitumour, hypotensive, local anaesthetic,

N

24

INTRODUCTION

6

antispasmotic, antiinflammatory, mutogenic or hepatotoxic agents.26-28

Pyrrolizidine alkaloids are commonly isolated as esters, diesters or macrocyclic

bislactones of the basic ring system, although the free pyrrolizidine or "necine"

bases themselves have been isolated from natural sources.29 The most

common examples are the saturated diols, hastenecine (25a), turneforcidine

(25b), dihydroxyheliotridane (zøa) and platynecine (26b) and the 1,2-

unsaturated diols, heliotridine (27a) and retronecine (27b). The antitumour

agent indicine N-oxide (ZA)SO is then derived in nature from retronecine (27b).

R=

2 CH.'OH ¡12 H=

N

H=

N5

1

3

26

R1¡1.2

o

o

28

a: Rl =H,R2=OHb:R1 =OFI,R2=H

A synthetic approach analogous to that outlined above for the synthesis

of B-lactam antibiotics, but based on completion of the molecular backbone by

annelation of y-lactams bearing appropriate substituents, has found widespread

use in the synthesis of pyrrolizidine alkaloi¿5.31,32 A notable illustration of

this approach is provided by the work of Speckamp and co-workers,33 6ur"O

25

H

H:

N

H=

N

27

INTRODUCTION

7

upon the acid-catalysed cyclization of N-acyliminium ions. For example, the

alkaloids 33 and 34 were obtained aía cyclization of the S-ethoxypyrrolidinone

3034 as depicted in Scheme 5. Thus, reduction of the imide 29 with sodium

borohydride in ethanol3S afforded the S-ethoxylactam 30 which was cyclizedby

treatment with formic acid. After subsequent acid hydrolysis the thioesters 31

SPh

oEtNaBHa / EIOH

N

29 30

SPh

1. HCO2H2. HCI

SPhH

N

g

N

o

+

LiAlH4

31 32

H2OHC

T

N+

LI:

N

33

Scheme 5

34

INTRODUCT/ON

8

and 32 were obtained in an approximately 4 : 1 mixture. Lithium aluminium

hydride reduction at 70"C in tetrahydrofuran then furnished the pyrrolizidine

alkaloids (+)-trachelanthamidine (33) ur,¿ (+)-isoretronecanol (34), from 31 and

32 respectively.

It is noteworthy in this example that the products 31 and 32 obtained are

attributable to exo cyclization of the N-acyliminium ion 35 derived from 30,

with no products attributable to endo cyclization of 35 being detected. The

regioselectivity of. cyclization thus displayed in this example is due to the

presence of the phenylthio substituent on the alkenyl sidechain which may

mesomerically stabilize the exocyclic vinyl cation 36 formed upon exo

cyclization of the N-acyliminium ion 35 (Scheme 6). In this way, the normally

unfavourable ringstrain effects associated with the intermediacy of.36, thereby

favouring endo cyclization to give 37, are adequately compensated and exo

cyclization to 36 therefore predominates.

exo endoSPh

+ SPh

+

N

o

N+

35

N

3736

Scheme 6

INTROD UCTION

9

In a variation of this approach to the synthesis of pyrrolizidine

alkaloids, Flart and co-worke¡536-38 have utilized o-acylamino radical

cyclizations in construction of the molecular backbone. Thus treatment of the

S-phenylthiopyrrolidinone 38 with tri-n-butyltin hydride in the presence of

azobisisobutyronitrile (AIBN) gave an LL:5 mixture of the pyrrolizidinone 39

and the indolizidinone 40 (Scheme 7), presumably aiø competing exo and

endo cyclization respectively, of the cr-acylamino radical 4L (R =H) (Scheme 8)

formed upon initial phenylthiyl radical abstraction from 38. As for the case of

the N-acyliminium ion cyclization described above, the ratio of

z-Bu3SnH +AIBN

39

Scheme 7

39

N

o

NN

38

o40

R

N

oexo 4L endo

R R

a

N N

4342

Scheme B

/NTRODUCTION

10

Pyrrolizidinone 39 to indolizidinone 40 formation in this reaction may be

increased by introduction of appropriate substituents R on the alkenyl side-

chain. Thus, when R = Cozf-Bu or CN the radical 42 formed upon exo

cyclization of the cr-acylamino radical 4l is more stable than the radical 43

resulting from endo cyclization and pyrrolizidinone formation consequently

predominates to the extent that indolizidinone formation is not observed.3S

Radical cyclizations of silylated alkenyl and allenyl derivatives have also been

reported to proceed with high regioselectivity.39,ar

Common to all of the syntheses described above is that each involves

construction of lactams bearing functional groups, appropriate to cyclizanon, at

the endocyclic and exocyclic carbons adjacent to lactam nitrogen. In each case

the lactam is constructed or substituents are introduced onto nitrogen of the

lactam with this required functionality already in place. As such, these

syntheses require the somewhat elaborate synthesis of specific, and often

unstable, precursors to cyclization, and so are limited in their applicability as

general methods. For this reason, an alternative strategy based upon the later

introduction of functionality directly at carbon adjacent to lactam nitrogen of

non-functionalized N-substituted p- and y-lactam systems presents an

attractive proposition. In view of the aforesaid susceptibility of fused bicyclic

p-lactams to nucleophilic reagents2l it is preferable to investigate the utility of

free radical rather than ionic reactions as methodology for direct

functionalization of such B- and y-lactam systems.

The electrochemical oxidation of amides is a free radical process

involving an initial one electron removal from nitrogen,4l and results in

substitution at carbon adjacent to amide nitrogen.42 Electrochemical oxidation

of 2-azetidinones has been reported to similarly result in functionalization at

carbon adjacent to amide nitrogen.43-45 For example, Ban and co-workers44

have reported that electrolysis of the N-substituted azetidinone 44 in methanol

INTRODUCTION

77

affords a mixture of the endocyclic and exocyclic substitution products 45 and

46 (Scheme 9). As the products 45 and 46, thus obtained, were inseparable by

ocH3-e

cH3oH Nv"\ +CO2Me CO2Me

44ocH3

4546

Scheme 9

chromatography, their ratio of formation was estimated by 1H n.m.r. analysis

as ca.2:5. Thus, this example serves to illustrate that although electrochemical

oxidation of N-substituted azetidinones provides methodology for direct

functionalization at carbon adjacent to nitrogen, the non-regioselectivity of

reaction is manifest in competing reaction at both endocyclic and exocyclic

carbon adjacent to amide nitrogen.4S

A radical on carbon adjacent to amide nitrogen is stabilized through

interaction of the radical's semi-occupied p-orbital with the rc-orbitals of the

amide, and as such may forrn selectively by l'rydrogen atom transfer. Easton

and co-workers46,47 have reported use of hydrogen atom transfer reactions as

methodology for the direct functionalization of N-substituted 2-azetidinones.

Treatment of the N-methylazetidinone 47 with f-butyl perbenzoate, in the

presence of a copper I catalyst in benzene, resulted in reaction at the exocyclic

carbon adjacent to nitrogen, with competing reaction at the corresponding

endocyclic position.46 Thus, the exocyclic and endocyclic substitution products

48 and 49 were obtained as the primary products of reaction in the ratio of cø.

2:7 (Scheme L0). The mechanism of oxidation of organic substrates with ú-butyl

perbenzoate has been investigated48 and a free radical chain process is

F-o'

INTRODUCTION

72

HsCOCOPh

H¡C HeCÍ-BuO2COPh +

CuI

47

Scheme L0

proposed involving generation of ú-butoxy radical by one.electron reduction of

the perester (Scheme 1.1.). Hydrogen atom transfer from the substrate 50 to

ú-butoxy radical affords the substrate radical 51 which, upon incorporation of

benzoate at the site of abstraction, yields the benzoyloxylated product 52 and

regenerated copper I catalyst. The ratio of formation of the benzoyloxylated

ú-BuOOCOPh + Cu* f-BuO'+-OCOPh+Cu2*

f-BuO' + RH R' + ú-BuOH

+ -ocoPh + cu2* ROCOPh + CU*

Scheme 1.1.

products 48 and 49 in the present example may then be attributed to the

relative ease of formation of their free radical precursors. It is presumable that

the preference for exocyclic benzoyloxylation of the azetidinone 47 reflects that

the degree of ring strain engendered upon formation of the endocyclic radical

precursor to 49 outweighs the normal thermodynamic preference for the

production of secondary radicals over that of primary radicals.49

'a",NN

o

4948

'a*t,

5150

52

R

51

INTRODUCTION

13

With the exocyclic position blocked to reaction, Easton and Love46 have

demonstrated use of the free radical benzoyloxylation procedure for endocyclic

functionalization of azetidinones at carbon adjacent to lactam nitrogen.

Treatment of the 2-azetidinones 53 with ú-butyl perbenzoate afforded the

corresponding 4-benzoyloxy substituted Z-azetidinones 54 (Scheme L2). That

f-BuO2COPh

CLJR

R = f-Bu, Ph

Scheme 12

the benzoyloxy substituent is incorporated at C4 of the azetidinones 53, in this

example, is indicative of the greater reactivity of the C4 methylene protons to

hydrogen atom abstraction by f-butoxy radical over that of the methylene+6

protons of C3. This reflects the activating effect of the adjacent amide nitrogen,

whereby a radical generatecl at C4 of the azetidinones 53 would be resonance

stabilized through interaction of the radical's semi-occupied p-orbital with the

æ-orbitals of the lactam amide.

Through functionalization of azètidinones bearing a removable

protecting group on nitrogen, Easton and co-workers4T have further extended

this benzoyloxylation procedure to synthesis of N-unsubstituted -benzoyloxy-

azetidinones. Similarly, electrochemical oxidation has been applied to the

synthesis of N-unsubstituted 4-alkoxyazetidinones aia direct endocyclic

functionalization of N-unsubstituted azetidinones.4S

,n NR

5453

TNTRODUCT/ON

74

The above examples illustrate that free radical oxidation reactions

provide effective methodology for the direct functionalization at carbon

adjacent to lactam nitrogen in Z-azetidinones, and whilst functionalization

solely at the endocyclic carbon adjacent to nitrogen may be acheived simply

through blocking the corresponding exocyclic position to reaction,

functionalization at the exocyclic carbon adjacent to nitrogen in N-substituted

azetidinones is complicated by competing reaction at the corresponding

endocyclic position. There therefore exists a need in such methodology for a

procedure enabling the direct regioselective functionalization at exocyclic

carbon adjacent to lactam nitrogen in N-substituted 2-azetidinones. Prior to

the outset of the work presented in this thesis, such a procedure had not been

reported. The development of methodology for the direct regioselective

functionalization at exocyclic carbon adjacent to nitrogen in N-substituted 2-

azetidinones then forms the main aim of the work described in Chapter I of

this thesis.

The course of a free radical reaction is often affected by the stability of the

free radical intermediates involved and, as has been illustrated in the

examples discussed above in Schemes 3 and 7, radical stabilizing substituents

may be employed to control the regioselectivity of these reactions. As

discussed above, a radical on carbon adjacent to lactam nitrogen is stabilized

through resonance by interaction of the radical's semi-occupied p-orbital with

the æ-orbitals of the electron-donating amido substituent. Enhanced

stabilization of such a radical may be gained through the combined

participation of an electron-withdrawing substituent at the radical centre. For

example, the cr-centred radicals 55 and 56, generated from N-acetylglycine and

glycylglycine respectively, both having an electron-donating amido and an

electron-withdrawing carboxy substituent at the radical centre, possess an

inherent stability arising from extensive delocalization of unpaired spin

INTRODUCT/ON

density through resonance. The electron spin resonance spectra of the radicals

55 and 56 show that there is extensive conjugation in these radicals with only

70 - 75Vo of the unpaired spin density at the respective cr-carbons.50,51 In

o oH3NI

NH

56

addition, molecular orbital calculationsS2 also indicate that unpaired spin

density in the radical 55 is distributed over the molecule, the major

contribution being from from the c¿-carbon with contributions from both the

amido and carboxyl moieties (Figure 1.).

o-{.03H

0.10

+ aa

15

HgC

55

HsC-o.004

Fígure 1. Distribution of unpaired electron spin density in the c,-centred radical derivedby hydrogen atom transfer from N-acetylglycine.52'

Radicals of the type 55 have been classified by Veihe and co-workerss3 as

captodative radicals. The captodative effect was postulated as the combined

resonance effect of an electron-withdrawing (cøpto) and an electron-donating

(datiae) substituent on a radical centre, leading to an enhanced stabilization of

the radical. The theoretical basis of the combined stabilizing effect of an

electron-donor and an electron-acceptor substituent on a radical centre was

INTRODUCTION

76

originally formulated by Dewar54 in 7952. This concept was later observed

experimentally and termed "push-pull stabilization" by Balaban55 and in

independent observations by Katritzky and co-workersS6 the term

"merostabilization" was introduced. Although it remains debatable as to

whether or not a synergistic radical stabilizing effect is realized,ST-62 when a

radical is substituted by both electron-donor and electron-acceptor moieties, it

is clear that stabilization of the radical results from the combined but not

necessarily synergistic action of both substituents.

Thus, the present proposal was to attempt to direct the free radical

functionalization of N-substituted 2-azetidinones to the exocyclic carbon

adjacent to nitrogen through the use of electron-withdrawing substituents, as

radical stabilizing groups, at that position. N-Bromosuccinimide was chosen

as the reagent for functionalization in this investigation, as hydrogen atom

abstractions in reactions with N-bromosuccinimide are selective for formation

of the most stable product radical.63

The generally accepted mechanism for bromination by N-bromo-

succinimide, postulated by Goldfinger and co-workers& in 1953, is as depicted

in Scheme 1.3. Hydrogen atom abstraction from the substrate 57 by bromine

atom forms hydrogen bromide and the substrate radical 58. Reaction of

N-bromosuccinimide with hydrogen bromide produces a steady but very low

concentration of molecular bromine'in the reaction mixture. Bromine atom

transfer from molecular bromine to the substrate radical 58 then affords the

brominated product 59 and bromine atom, which propagates the chain. The

proposed mechanism is supported by the fact that allylic bromination can be

achieved either with N-bromosuccinimide or by slow introduction of

molecular bromine into an irradiated solution of olefin.65 Furthermore,

investigations by Walling and co-workers66 and Russell and co-workers6T have

INTRODUCTION

77

+ Br'

NBr + HBr

R.

58

+ Brz

R'+58

RIT

57

HBr

NH + Btz

RBr + Br'59

o

o

confirmed that reactivities of benzylic hydrogens with N-bromosuccinimide

are indentical to those with molecular bromine. Thus, the initial reaction of

reactive substrates with N-bromosuccinimide involves hydrogen atom

abstraction by bromine atom, a reaction in which there is relatively extensive

C-H bond homolysis and, consequently, much development of radical

character in the transition s¡¿1s.49,63 As such, this reaction is relatively

sensitive to the stability of the product radial.

The sensitivity of free radical bromination with N-bromosuccinimide to

radical stability effects is exemplified by the selectivity displayed in reactions

with amino acid derivatives.6S-72 For example, Lidert and GronowitzT3 have

reported treatment of the N-acylglycine derivative 60a with N-bromo-

succinimide in carbon tetrachloride, in the presence of benzoyl peroxide as

radical initiator, to give the cr-bromoglycine derivative 67a (Scheme 14).

Subsequently, Easton and Hay68 have demonstrated that the reaction with

N-bromosuccinimide is selective for monobromination of the glycine

derivative 60b. As the rate determining step of this reaction was shown to be

ø-hydrogen atom transfer, the selectivity for monobromination exhibited may

be attributed to the relative ease of formation of the o-centred radical 62,

TA/TRODUCTION

18

Broo

nrAruH^corRz ,\ **rÅNBS

¡¡1 co2R2

60 6L

a: R1 =Me,R2=Etb: R1 =Ph,R2:Me

generated upon hydrogen atom abstraction from 60b, with respect to that of the

radical 63, similarly derived from the bromide 61b. Thus it was proposed that

62 forms in preference to 63 as a result of greater stability. The greater stability

of 62 results as the radical may adopt a planar conformation, relatively free of

non-bonding interactions, in which there is maximum delocalization of the

unpaired electron aia overlap of the semi-occupied p-orbital with the

n-orbitals of the amido and methoxycarbonyl substituents (Figure 2). Severe

non-bonding interactions within the analogous conformation of 63 would,

however, distort this radical out of planarity, resulting in reduced orbital

overlap and, consequently, a much reduced stabilization of the radical. This

rationale is supported by the relative rates of reaction of several N-acylamino

acid derivatives with N-bromosuccini¡nids.68,71

Ph,/c

62

Fígure 2. Non-bonding interactions in planar conformations of the radicals 62 and 63

3

o

/.OCF{s\*

I

H

63

INTRODUCTION

79

Although a radical on carbon adjacent to an electron-withdrawing

group such as an alkoxycarbonyl substituent may be stabilized through

resonance, the formation of such a radical by hydrogen atom transfer to

bromine atom is often disfavoured.49,63,74 This is due to a polar effect

resulting from the inductive interaction between the electron deficient centre

of the substituent and that developing in the transition state at the site of

hydrogen abstraction by bromine atom. FIowever, Easton and co-workersT2

have demonstrated the proactive effect of an alkoxycarbonyl substituent

toward hydrogen atom abstraction at the adjacent carbon, when in cooperation

with an amido substituent at the same carbon. In this situation the charge

developing in the transition state of hydrogen atom abstraction by bromine

atom may be delocalized by the adjacent amido group (Figure 3), leading to a

lessening of the deactivating polar effect of the alkoxycarbonyl substituent to

the extent that radical stabilization factors dominate and an enhanced rate of

õ* õ*

RCONRI -CH-

CO2R2 RCONR1 ----CH-CO2R2

Figure 3 Delocalization of developing positive charge by an amido substituentin the transition state of hydrogen atom abstraction by bromine atom.

hydrogen atom abstraction results. On this basis, it was envisaged that

electron-withdrawing substituents at the exocyclic carbon adjacent to lactam

nitrogen in 2-azetidinones would activate that position to free radical

bromination.

ÒÒBr

IIIa

I

H

BrIIIa

I

HIII¡I

INTRODUCTION

20

The choice of N-bromosuccinimide as the reagent for regioselective

functionalization of azetidinones is attractive from a synthetic standpoint, as it

was expected that the product bromides thus obtained would be amenable to

further elaboration. The choice of electron-withdrawing substituents to

activate the exocyclic carbon adjacent to nitrogen of azetidinones towards

bromination provides for the use of alkoxycarbonyl or cyano substituents as

masked carboxylate functionality. This aspect is envisaged as advantageous

in syntheses toward mono- and bicyclic p-lactam antibiotics, which bear

carboxylate functionality at this position. In particular, the direct free radical

bromination at exocyclic carbon adjacent to amide nitrogen of an azetidinone

bearing an alkoxycarbonyl substituent at that position would provide

an alternative route to the synthesis of N-(ø-haloalkyl)-substituted

azetidinonesl3,lg such as 15, illustrated in Scheme 2 above.

The investigation of regioselective free radical bromination of

2-azetidinones bearing activating substituents at the exocyclic carbon adjacent

to lactam nitrogen is described in Chapter I of this thesis. The work presented

in Chapter II is then based upon an investigation into the synthetic utility of

methodology developed in Chapter I.

Free radical reactions have been employed as methodology for the

direct functionalization of Z-pyrrolidinones at carbon adjacent to lactam

nitrogen.42,43,75-79 Ban and co-workersT5 have reported that anodic oxidation

of N-alkylpyrrolidinones occurs regioselectively at the endocyclic carbon

adjacent to nitrogen. Controlled potential electrolysis of the pyrrolidinones 64,

in an electrolyte solution containing water, gave the corresponding S-hydroxy-

pyrrolidinones 65 as the major products, with minor amounts of the

respective imides 66 (Scheme L5).

INTRODUCTION

27

Electrochemical oxidation of N-unsubstituted 2-pyrrolidinones has

similarly been reported to result in functionalization at the endocyclic carbon

adjacent to nitrogen,43,76 and photochemical oxidations of Z-pyrrolidinones to

their corresponding imides have also been repofted.77,78

H

-e +Hzo

o64 65 66

R=Me,Et

Scheme L5

Easton and co-workersT9 have reported that free radical benzoyloxyl-

ation of the N-methylpyrrolidinone 67 results in reaction at both the

endocyclic and exocyclic carbons adjacent to lactam nitrogen (Scheme L6).

OCOPh

H¡C N

ú-BuO2COPh HsC

Hsc-c", CuICHa

69

*-o*-o*'*

o

N-..

H¡C

Hgc+HeC

oo

67 68

H¡CHsC

H¡C

o

HaC N-a",

7L

Scheme L6

70

/NTROD UCTION

22

Treatment of 67 with f-butyl perbenzoate in the presence of a copper I catalyst

gave both the exocyclic and endocyclic substitution products 68 and 69, isolated

upon hydrolysis during chromatography as the corresponding alcohols 70 and

7L. The ratio of formation of the benzoyloxylated products 68 and 69 was

determined by tg n.m.r. spectroscopic analysis of crude reaction mixtures as ca.

1:3 and may be attributed to the relative ease of formation of their free radical

precursors.

In each of the examples presented above, reaction at the endocyclic

carbon adjacent to nitrogen of the pyrrolidinones 64 and 67 exhibits preference

over reaction at the corresponding exocyclic carbon. In the case of free radical

benzoyloxylation of 67 this preference presumably reflects a greater reactivity of

the endocyclic carbon toward hydrogen atom abstraction, than that of the

corresponding exocyclic carbon. This may be attributed to the relief of ring

strain, as a result of the release of steric interactions between the C4 and C5

protons, upon hydrogen atom abstraction from the endocyclic carb6¡.80,81 1¡ ig

further possible that hydrogen atom abstraction from the endocyclic position is

favoured entropically by the inflexibility of the lactam ring of 67 maintaining

the amido group in the planar orientation required for stabilization of the

product radical.Tl

With the aim of directing functionalization to the exocyclic carbon

adjacent to nitrogen in 2-pyrrolidinones, the work presented in Chapter III of

this thesis is based upon application of methodology developed in Chapter I,

for exocyclic functionalization of azetidinones, to analogous pyrrolidinone

systems. Thus, an investigation of the regioselectivity of free radical

bromination of 2-pyrrolidinones bearing activating substituents at the exocyclic

carbon adjacent to nitrogen is described

INTRODUCT/ON

23

In the investigation of free radical bromination of pyrrolidinones

bearing activating substituents at the exocyclic carbon adjacent to nitrogen, as

presented in Chapter III, two factors were employed to direct the regio-

selectivity of reaction, in common with the work described in Chapter I.

Namely, the choice of a reagent for functionalization that is selective for

formation of the most stable product radical, and the choice of substituents at

the exocyclic carbon that in cooperation with the lactam amide substituent

activate this position to hydrogen atom abstraction. In work described in

Chapter IV of this thesis an assessment of the individual contributions of each

of these factors was made, through an investigation of the regioselectivity of

free radical bromination of pyrrolidinones not bearing activating substituents

at the exocyclic carbon adjacent to nitrogen. From a consideration of the

regioselectivity displayed in free radical benzoyloxylation of the N-methyl

pyrrolidinone 67, as discussed in Scheme 16 above, it was expected that free

radical bromination would occur with a high degree of regioselectivity at the

endocyclic carbon adjacent to nitrogen in pyrrolidinones not bearing activating

substituents at the corresponding exocyclic position. A subsequent aim of the

work presented in Chapter IV was the elaboration of the functionalized

pyrrolidinones obtained in this investigation, toward the synthesis of bicyclic

pyrrolidinones.

INTRODUCTION

RpsuLTS AND DrscussroN - I

Exocyclic Functionalization of N-Substitutedp-Lactams

Preparation of t}lre Z-azetidinones 72 - 76

T}:.e Z-azetidinones 72 - 76 were required for the investigation of their

possible functionalization each at the exocyclic carbon adjacent to amide

nitrogen. They were synthesized uiø cyclization of the corresponding

24

COzEtCNPhCH=CHzCOzCHzPh

72 R = COzEt73 R = Cl.J74 R=Ph75 R = CH=CHz76 R = COzCH2Ph

3-bromopropionamides 77 - 81, prepared by Schotten-Baumann coupling of

3-bromopropionyl chloride (8a) with the corresponding amines 83,86,88,89,

and 91. Details of the syntheses of the azetidinones 72 -76 are given below.

,n-ì

R

Br

NH

77 f{=78 f{=79 f{=80 f{=81. R-

R

RESULTS AND D/SCUSSION - I

25

Ethyl 2-oxo-7-azetidineacetate (72) was synthesized from glycine (82) as

shown in Scheme 17. Glycine ethyl ester hydrochloride (83), obtained by

esterification of glycine (82) with ethanol that had been pretreated with thionyl

chloride, was treated with 3-bromopropionyl chloride (8a) in the presence of

excess aqueous sodium bicarbonate to give the bromopropionamide 77 . Using

this procedure, 77 was obtained in 56To yield from the acid chloride 84 and

had physical and spectral characteristics in accord with those previously

reported.32

HCI.NH2CFI2CO2Et

83

/ EIOr{ +NH3CH2CO2

Br

/ aq. NaHCO3

CI

KOH / Bu4NBr +N NH

CO2Et co2Et77 72

Scheme L7

The cyclization of 3-halopropionamides to azetidinones is complicated

by the readiness with which these compounds undergo elimination to give

acrylamides.S3 However, Wasserman and co-workersS3 have reported that

high dilution and a slow rate of addition of propionamide to base favour the

desired cyclization over the competing elimination reaction. These

observations have also been made by Takahata and co-workers,82 who

82

84

Br

co2Et85

RESULTS AND DISCUSSION - 1

26

reported a convenient cyclization of 3-halopropionamides with potassium

hydroxide utilizing a phase transfer catalyst in a solid-liquid two phase system.

Using this methodolgy, the cyclization of 77 to give 72 has been previously

reported.S2 Accordingly, the propionamide 77 was cyclized by its slow

addition in dilute solution to a stirred suspension of powdered potassium

hydroxide and tetra-n-butylammonium bromide in a 1,9:7 mixture of

dichloromethane and acetonitrile. Chromatography of the reaction mixture

followed by distillation to separate the small amount of the acrylamide 85

formed, gave ethyl 2-oxo-L-azetidineacetate (72) in 61,Vo yield from the

propionamide 77. The lactam and ester carbonyl groups in 72 gave rise to

characteristic absorptions in the infrared spectrum at 7744 and 1758 cm-l

respectively. Other spectral characteristics were in accord with those

previously reported82 for the azetidinone 72.

2-Oxo-L-azetidineacetonitrile (73) was prepared as outlined in Scheme

18. Aminoacetonitrile bisulphate (86) was treated with 3-bromopropionyl

chloride (84) in the presence of excess aqueous sodium bicarbonate to give the

bromopropionamide 78 in 79Vo yîeld. The product exhibited physical and

spectral characteristics consistent with the structure of 78 and was fully

characterized. In particular, formation of the amide in 78 was confirmed by

the observation of a characteristic absorption at 1655 cm-1 in the infrared

spectrum. Treatment of the propionamide 78 with a suspension of powdered

potassium hydroxide and tetra-n-butylammonium bromide in

dichloromethane and acetonitrile, as for the cyclization of 77 above, afforded

the desired azetidinone 73 in 62Vo yield, with negligible formation of the

acrylamide 87. The lactam 73 was fully characterized, exhibiting satisfactory

spectroscopic properties and elemental analyses. It was distinguished by the

observation of a strong infrared absorption at 7754 cm-1, characteristic of the

lactam carbonyl group.


27

Br

H2SO4.NH2CH2C\I +

86

84

aq. NaHCO3

KOH / Bu4NBr

NH N + NH

78 73 87

Scheme 1-8

1-Benzyl-2-oxoazetidine (74) was synthesized as shown in Scheme 1-9.

Thus, treatment of 3-bromopropionyl chloride (84) with excess benzylamine

(88) in dichloromethane gave the bromopropionamide 79 in 67Vo yield, with

physicat and spectral properties in accord. with those previously reported.S2

Takahata and co-workersS2 have reported the cyclization of the propionamide

79 to give the lactam 74, using the methodology described above in the

synthesis of 72. Accordingly, Tg was treated with a suspension of powdered

potassium hydroxide and tetra-n -butylammonium bromide indichloromethane, affording the lactam 74in70% yield. Spectral characteristics

of the product 74 were consistent with those reported,S2 with the lactam

carbonyl giving rise to a characteristic absorption in the infrared spectrum

at 1734 cm-1.

Br

ìCNCNCN

RESULTS AND DISCUSSION - I

28

Br

NH2CH2Ph +CI

KOH / Bu4NBr

NH

79 74

Scheme L9

1-Allyt-2-oxoazetidineacetate (75) was synthesized from allylamine

(8e), similarly to the above synthesis of. 74, as shown in Scheme 20. N-411y1-3-

bromopropionamide (80) was obtained in 697o yield by treatment of 3-bromo-

propionyl chloride (8a) with excess allylamine (89) in dichloromethane.

The propionamide 80 was fully characterized exhibiting satisfactory

spectroscopic properties and elemental analyses. In particular, the amide

carbonyl of 80 gave rise to a characteristic infrared absorption at 1640 cm-1.

Treatment of the propionamide 80 with a suspension of powdered potassium

hydroxide and tetra-n-butylammonium bromide gave a mixture of 1.-allyl-Z-

oxoazetidine (75) and the by-product acrylamide 90, as judged by 1H n.m.r.

spectroscopic analysis. The methylene protons of the allylic carbon in 80

resonate as a doublet of doublets at ô 3.90 with / = 6.0 and 5.0 FIz. In the crude

product mixture obtained from 80 as above, a doublet resonance at õ 3.83

with I : 6.7 FIz was observed, consistent with the methylene protons of

88

84

Br

Ph Ph


29

Br

+HzNCI

Br

KOH / Bu4NBr+

\,,^

80 75 90

Scheme 20

the allylic carbon of the azetidinone 75. The presence of the acrylamide 90

in the same product mixture was evident from the observation of a signal at

ô 6.33, indicative of the methine proton adjacent to the amide carbon. The

lactam 75 was readily isolated from the crude product mixture in 30Vo yield by

chromatography and subsequent distillation. The azetidinone 75 exhibited

consistent spectroscopic properties, with the observation of an infrared

absorption at 7744 cm-1 characteristic of the lactam carbonyl grouP.

Benzyl 2-oxo-1-azetidineacetate (76) was synthesized from glycine (82)

as shown in Scheme 21-. Glycine benzyl ester hydrochloride (91), obtained by

esterification of glycine (02¡ with benzyl alcohol which had been

pretreated with thionyl chloride, was treated with 3-bromopropionyl chloride

(84) under basic conditions and gave the bromopropionamide 81 in 77o yield.

The propionamide 81 was fully characterized, with the observation of an

infrared absorption at 1652 cm-1 confirming the presence of the amide

8984

Ão o

RESULTS AND DÌSCUSSION - /

30

group. The propionamide 81- was cyclized by treatment with powdered

potassium hydroxide and tetra-í -butylammonium bromide indichloromethane and acetonitrile affording benzyl 2-oxo-L-azetidineacetate

(76) in a yield of. 22Vo. The lactarn 76 was fully characterized, the lactam

carbonyl group giving rise to a characteristic infrared absorption at 7742 cm-1.

HCt.NH2CH2CO2CH2Phsocl2 / PhcH2oH +

NH3CH2CO2

9Í

Br

/ aq. NaHCO3

84

KOF{ / Bu4NBr + PhcH2oHNH N

CO2CH2Ph co2cH2Ph8L 76

Scheme 21

The low yield of the azetidinone 76 obtained was reasoned as due to hydrolysis

of the benzyl ester moiety of 81 under the basic conditions of cyclization.

Accordingly, a substantial amount of benzyl alcohol was observed in crude

product mixtures obtained upon cyclization of the propionamide 81.

82

Br


37

Reactions of the 2-azetidínones 72-76

Reactions of the }-azetidinones 72 - 76 with N-bromosuccinimide were

studied in order to investigate free radical bromination at the exocyclic carbon

adjacent to nitrogen in B-lactams bearing activating substituents at that

position. The azetidinone 72 bearing an ethoxycarbonyl substituent at the

exocyclic carbon adjacent to the lactam nitrogen was chosen for intial study.

On the basis that an alkoxycarbonyl substituent exhibits a proactive effect

toward hydrogen atom abstraction at the adjacent carbon, when in cooperation

with an amido substituent at the same carbon,7z it was envisaged that the

ethoxycarbonyl substituent would facilitate free radical bromination at the

cr-carbon of 72. In addition, the choice of the ethoxycarbonyl substituent in

72 was attractive from a view to the synthesis of naturally occurring mono-

and bicyclic p-lactam antibiotics which bear a carboxylate functionality at the

same position relative to the lactam nitrogen.

Ethyl 2-oxo-7-azetidineacetate (72) was initially treated with one mole

equivalent of N-bromosuccinimide in carbon tetrachloride, at reflux under

nitrogen for 15 minutes, with reaction initiated by irradiation with a 300 W

mercury lamp. The cooled, filtered reaction mixture yielded, upon

evaporation of the solvent, a brown tarry residue containing the bromide 92

as the only identifiable product of reaction, as determined by 1H n.m.r.

spectroscopic analysis. Thus, although the bromide 92 was obtained in this

reaction, its production was accompanied by considerable decomposition of the

reaction mixture. This decomposition was reasoned as due to inadequate

solubility of the lactam 72 in the reaction solvent.

Tan and co-workersTO have reported the use of dichloromethane as a

suitable solvent for bromination of reactive amino acid derivatives with

N-bromosuccinimide, where the high rate of bromination of the substrate

RESULTS AND DISCUSSION - 1

32

presumably overcomes competing solvent reactions. However, when the

azetidinone 72 was treated with one mole equivalent of N-bromosuccinimide

as above, but in dichloromethane, lFI n.m.r. analysis of the crude reaction

mixture revealed the presence of the starting material 72 only. The lack of

reactivity of the azetidinone 72 with N-bromosuccinimide, in this instance,

was concluded as being due to the reduction in temperature uPon using

dichloromethane as the solvent. In order to elevate the temperature of the

reaction mixture whilst maintaining solubility of the substrate 72,

bromination in mixtures of carbon tetrachloride and dichloromethane was

investigated.

When the azetidinone 72 was treated with N-bromosuccinimide in a

mixture of carbon tetrachloride and dichloromethane containing just

sufficient dichloromethane to dissolve the substrate, bromination of 7 2

proceeded readily, without decomposition. Thus, ethyl 2-oxo-'l'-

azetidineacetate (72) was treated with one mole equivalent of

N-bromosuccinimide in a 5:1 mixture of carbon tetrachloride and

dichloromethane, at reflux under nitrogen for L5 minutes, with reaction

initiated by irradiation with a 300 W mercury lamp. The reaction mixture was

cooled, filtered and concentrated to give cr-bromo-2-oxo-L-azetidineacetate

(SZ¡ as the only product of reaction (Scheme 22). Production of the

NBS

hv

co2Et CO2Et92

^

o'Br

72

Scheme 22

RESULTS ,AND D/SCUSS/ON - I

33

bromide 92 in this reaction was determined on the basis of 1H n.m.r.

spectroscopic analysis of the crude reaction mixture after evaporation of the

solvent. The methylene protons of the cr-carbon in 72 give rise to a singlet

resonance at ô 3.99. With the crude product mixture obtained from the

bromination of 72, a singlet resonance at ò 6.3k was observed, consistent with

the methine proton of the cr-carbon in 92.

The substitution of bromine at the cr-carbon of 92 also induces

magnetic non-equivalence of the four methylene protons of the azetidinone

ring such that each gives rise to a distinct 1FI n.m.r. signal. The coupling

constants associated with the C3 and C4 methylene protons are in accord with

those reported. for related systems. Barrow and Spotswood& have reported 1H

n.m.r. data for some C3 and C4 substituted Z-azetidinones, wherein the

substituent at C3 or C4 induces magnetic non-equivalence in the protons of the

neighbouring methylene group. For methylene protons at C3 the geminal

coupling constants (lgg,), in the systems studied, ranged from -l'4.3 to L5.0 ÉIz in

magnitude and for methylene protons at C4 the geminal coupling constants

(l++,) ranged from 5.5 to 5.6 Hz in magnitude. Ttre trans vicinal coupling

constants (lg+tron) ranged from 2.2 to 2.8 ÍIz, whilst the cis vicinal coupling

constants (lgk¡), of greater magnitude, were in the range of 4.9 to 5.9 Hz.

,. It is on the basis of the data reported by Barrow and SpotswoodS4 that

assignments for the coupling constants associated with the lactam methylene

protons of the bromide 92 were made (Figure 4).

RËSULTS AND DISCUSSION - I

34

FI'FI'H

Vicinal:

t

H

CO2Et

3 4

N

co2Er

92

Geminal: 133'=15.6Í12 144'=6$Í12

o

Fígure 4. 1H r,.^.r. coupling constants observed for C3 and C4 methylene protons

of cr-bromo -2-oxo -L -azetidineacetate (92).

The bromide 92 was not sufficiently stable for complete characterization,

and so was converted to the corresponding ethyl ether 92 through the addition

of two mole equivalents each of ethanol and 2,6-lutidine directly to the

crude reaction mixture after cooling to room temperature. After purification

by chromatography on silica, the ether 93 was isolated in 57Vo yield,

based on 72, and was fully characterized, exhibiting consistent spectral

]satit = 6.2EIzI3'4'rit = 5'9 Í12

N

I3'4t ors = 3.9 Hz]34't ont = 3.5}j2

93

properties and elemental analyses. In the 1H n.m.r. spectrum of the ether 93,

a characteristic singlet resonance at õ 5.35 was observed for the methine proton

of the cr-carbon. The presence of the ethoxy substituent in 93 was confirmed by

a characteristic triplet resonance al õ 7.27 (l = 7.0 FIz) arising from the methyl

protons, and two doublet of quartet resonances, at õ 3.59 (l = 9.5,7.0 Hz) and


35

3.68 (l =9.5, 7.0Il2), corresponding to the two non-equivalent methylene

protons. Due to the presence of the ethoxy substituent at the cr-carbon in 93,

magnetic non-equivalence of the lactam methylene protons was observed, as

with the bromide 92. For the C3 methylene protons the geminal coupling

constant was 1.3.4 Hz, with a 5.4}12 geminal coupling constant observed for the

methylene protons of C4. The trans vicinal coupling constants observed were

of 3.3 and 3.9 Hz, while the cis vicinal coupling constants were both 4.9 fIz.

The mechanism proposed for the production of the ether 93 is as shown

in Scheme 23. The bromide 92 may be considered to be in equilibrium

with the N-acyliminium species 94. Ethanol readily adds to the electrophilic

cr-carbon of 94 giving 95 initially, with subsequent deprotonation to afford

the ether 93.

tr-oBr tr-o

tr-o

CO2Et

Br

ì

CO2Et92 93

-H*

,nH

IEtOH

Y?'t

-BaCO2Et co2Et

94 95

Scheme 23

Formation of the bromide 9 2 in the above reaction of

N-bromosuccinimide with 72, indicates reaction aiø initial hydrogen atom

RESUTTS ,AND DISCUSS/ON - I

36

abstraction from the exocyclic methylene adjacent to the amide nitrogen to

form the cr-centred intermediate radical 96, stabilized by the combined

resonance effects of the electron-donating amido and electron-withdrawing

ethoxycarbonyl substituents. This result in turn indicates that with the

ethoxycarbonyl substituent at the exocyclic methylene adjacent to nitrogen,

radical formation at the cr-carbon of 72 is facilitated.

o

oEt

The reaction of 2-oxo-L-azetidineacetonitrile (73) with N-bromo-

succinimide was studied in order to investigate the possible activating effect of

the cyano substituent in concert with the amido substituent toward free radical

bromination at the exocyclic carbon adjacent to the amide nitrogen. A cyano

substituent stabilizes, through resonance, a radical formed at the adjacent

carbon, but formation of such a radical by hydrogen atom transfer to bromine

may be disfavoured by the operation of a polar effect in the transition

s¡v¡s.49,63,74 Flowever, following the rationale for the proactive effect of an

alkoxycarbonyl substituent in cooperation with an amido substituent toward

hydrogen atom abstraction,T2 as discussed in the Introduction of this thesis, it

was envisaged that the cyano substituent would exhibit a similar activating

effect toward free radical bromination at the cr-carbon of 73 to that of the

ethoxycarbonyl substituent of 72. In addition, the choice of 73 was appealing

from a synthetic standpoint as the cyano substituent was considered a masked

carboxylate functionality, since nitriles may be readily hydrolysed by a variety

of reagents to give carboxylic acids.8S

,n96


J/

As with the azetidinone 72, bromination of the nitrile analogue 73

required use of a mixture of carbon tetrachloride and dichloromethane as

solvent in order to maintain substrate solubility and reactivity. Thus, 2-oxo-'1.-

azetidineacetonitrile (73) was treated with one mole equivalent of N-bromo-

succinimide in a 2;'l., mixture of carbon tetrachloride and dichloromethane at

reflux under nitrogen, whilst irradiating with a 300 W mercury lamp for 30

minutes. cr-Bromo-2-oxo-1-azetidineacetonitrile (97) was obtained as the only

product of reaction (Scheme 24), as determined by lH n.m.r spectroscopic

analysis of the crude reaction mixture after solvent evaporation. The

methylene protons of the q-carbon in 73 give rise to a singlet resonance at

õ 4.23. With the crude product mixture obtained from the bromination of 73,t?

a singlet resonance at ô 6.Sþ was observed, indicative of the methine proton of

the a-carbon in 97.

NBS

hv

97

Scheme 24

As with 92, the substitution of bromine at the o-carbon of 97 induces

magnetic non-equivalence of the lactam methylene protons and the associated

coupling constants are in accord with those observed for the bromide 92. For

the C3 methylene protons of 97 the geminal coupling constant is 15.7 Hz, with

a 6.'l,Hz geminal coupling constant observed for the methylene protons at C4.

The trøns vicinal coupling constants observed are 4.0 and 4.1. FIz, while the cis

vicinal coupling constants are 5.9 and 6.0 FIz.

-l Br

CNCN

rnY73


38

The bromide 97 was not sufficiently stable for complete characterization,

and so was converted to the corresponding ethyl ether 98 in the same manner

as for the bromide 92 above. Addition of two mole equivalents each of

ethanol and 2,6-Iutidine directly to the crude reaction mixture of 73 with

N-bromosuccinimide after cooling to room temperature, afforded 9I

Tn 41,Vo yield, based on 73. The ether 98 was fully characterized, exhibiting

tnyo,t

CN

98

consistent spectroscopic properties and elemental analyses. In the 1H n.m.r.

spectrum of the ether 98, the methine proton of the o-carbon gave rise to

a characteristic singlet resonance at ô 5.68. The presence of the ethoxy

substituent in 98 was confirmed by the observation of a characteristic triplet

resonance at õ 7.27 (] = 7.0 FIz) corresponding to the methyl protons, and two

doublet of quartet resonances, at ô 3.63 (l = 9.3, 7 .0 flz) and 3.67 (l = 9.3, 7 .0 F{z)

arising from the two non-equivalent methylene protons. As for the ether 93,

the four lactam methylene protons of 98 show non-equivalence due to the

presence of the ethoxy substituent at the cr-carbon. The mech4nism for the

formation of 98 from 97 is proposed as analogous to that depicted in

Scheme 23, above.

The formation of the bromide 97 in the above reaction of

N-bromosuccinimide with 73 is consistent with reaction aia initial hydrogen

atom abstraction to give the cr-centred intermediate radical 99. Consequently,

this indicates that the cyano substituent facilitates free radical formation at the

exocyclic carbon adjacent to the amide nitrogen of 73.

RËSULTS AND DISCUSSION - I

39

The N-benzylazetidinone 74 was chosen for investigation to compare

the activating effect of the phenyl substituent toward free radical bromination

at the cr-carbon to that of the ethoxycarbonyl substituent of 72. A phenyl

substituent may stabilize a radical at the adjacent carbon through resonance

and formation of such a radical by hydrogen atom transfer to bromine is not

influenced by the operation of a polar effect as, unlike the ethoxycarbonyl or

cyano substituents of 72 and 73 respectively, a phenyl substituent does not

possess an electron deficient centre adjacent to the site of hydrogen abstraction.

On this basis, it was envisaged that the phenyl substituent would facilitate free

radical bromination at the cr-carbon of 74 to a greater extent than the

ethoxycarbonyl substituent of 72.

When L-benzyl-2-oxoazetidine (74) was treated with one mole

equivalent of N-bromosuccinimide in a 5:1 mixture of carbon tetrachloride

and dichloromethane at reflux under nitrogen, whilst irradiating with a 300 W

mercury lamp for 15 minutes, a complex mixture of products, containing a

minor amount of unreacted starting material 74, was obtained. 1H n.m.r.

spectroscopic analysis of the crude reaction mixture gave no evidence for the

presence of the bromide L00, but the observation of a singlet resonance at

õ 10.03 in particular, was indicative of the production of benzaldehyde (101).

The presence of benzaldehyde (101) in the reaction mixture was confirmed by

comparative thin layer chromatography against an authentic sample of the

aldehyde 10L.

,n N2C

99


40

The production of benzaldehyde (fOf) in the reaction of 74 with

N-bromosuccinimide can be rationalized as resulting from a subsequent

reaction of any initially formed bromide 100 with adventitious water (Scheme

25). The N-acyliminium species 102, in equlilibrium with the bromide 100, is

readily attacked at the electrophilic a-carbon by nucleophiles, leading to the

subsequent formation of benzaldehyde (101) aia tli.e alcohol 103 in the case

where water is the nucleophile. Thus, the bromide 100 is unstable to the

extent that only products of its decomposition are obtained from the reaction

of the lactam 74wlth N-bromosuccinimide.

NBSBr

PhPh

hv ÃoPhCHO +

101

otherproducts

ì

74 L00

,n H- HBr

Ph1.02

Scheme 25

That the bromide 100 derived from 74 is markedly unstable in

comparison to the bromides 92 and 97 derived from the respective

azetidinones 72 and 73 may be rationalized in terms of the relative stabilities

of the corresponding N-acyliminium species 102,94 and 104 in equilibrium

with these bromides. The phenyl substituent of 102 may act to delocalize

ìPh

103

RESULTS AND D/SCUSSION - /

the positive charge over the phenyl ring through resonance, whereas such

delocalization by the ethoxycarbonyl substituent of 94 or the cyano

substituent of 104 involves less favourable interaction between adjacent

electron deficient centres and is therefore less efficient (Fígure 5). Thus the

iminium species 102, being more stable than either 94 or L04, forms more

readily through dissociation of its bromide precursor 100. In turn, this

results in a greater degree of instability of the bromide 100 with respect to the

bromides 92 and97.

47

++

!02

NN

94

<->Ã,

o'<+N

+

o o

+++ Et

+ v'cd !c 7N

104

Figure 5. Resonance contributors forLO2,94 and 104.

In order to ascertain the relative reactivity of the N-benzylazetidinone

74 and the azetidinone 72 a competitive bromination between the two

substrates was conducted. Thus a 1:1:1 mixture of 72,74 and N-bromo-

succinimide in a 5:1 mixture of carbon tetrachloride and dichloromethane was

heated at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp

"Æ

+

RESULTS .AND D/SCUSSION - I

42

for 15 minutes. 1H n.m.r. spectroscopic analysis of the crude reaction mixture

revealed a complex mixture of products containing benzaldehyde (101), a

minor amount of unreacted 74 and a major amount of unreacted 72. In

particular, the absence of the bromide 92 ín this product mixture was noted.

This result indicated that 74)i.ad reacted preferentially to 72 and consequently,

that the reactivity of 74 toward free radical bromination is greater than

that of 72.

The relative reactivity of 72 and 74 toward free radical bromination

reflects the relative rate of formation of the corresponding q,-centred radicals

96 and 105. It then follows that the phenyl substituent of 74 is more

activating towards hydrogen atom abstraction at the c-carbon than is the

ethoxycarbonyl substituent of 72. This is consistent with expectations based on

the absence of a polar effect in the fransition state of hydrogen atom abstraction

from the benzylic cr-carbon of 74.

,n1.05

The N-allylazetidinone 75 was chosen for investigation as the N-allyl

substituent was considered as a further example of an activating substituent for

hydrogen atom abstraction at the o-carbon. A radical formed at an allylic

carbon is resonance stabilized by the adjacent olefinic moiety and its formation

by hydrogen atom abstraction is not influenced by the operation of polar

effects, as the olefinic moiety does not possess an electron deficient centre

adjacent to the site of abstraction. Accordingly, it was envisaged that free

radical bromination could be affected readily at the cr-carbon of 104.

RESUTTS ,AND D/SCUSSION - I

43

In order to ensure solubility of the substrate, the bromination of 1-allyl-

Z-oxoazetidine (75) was initially investigated by treatment of the lactam 75

with one mole equivalent of N-bromosuccinimide in a L:1. mixture of carbon

tetrachloride and dichloromethane as solvent. The mixture was heated at

reflux under nitrogen whilst irradiating with a 300 W mercury lamp, for 15

minutes and 1H n.m.r. spectroscopic analysis of the crude reaction mixture

revealed a major amount of unreacted starting material 75. The azetidinone

75 was subsequently found to be soluble in neat carbon tetrachloride, and so in

order to increase the rate of reaction the reaction temperature was increased by

investigating the bromination of 75 in this solvent. When the azetidinone 75

was treated with one mole equivalent of N-bromosuccinimide as above, but

using carbon tetrachloride as the solvent, 1H n.m.r. spectroscopic analysis of

the crude reaction mixture indicated that a complex mixture of products

containing some of the unreacted starting material 75 was obtained.

In an attempt to derivatize and isolate any possible bromination

products of 75, a crude bromination mixture in carbon tetrachloride was

treated with ethanol and 2,6-lutidne as described above for the preparation of

the ethers 93 and 98. Upon chromatography of the crude reaction mixture thus

obtained however, no discrete identifiable products could be isolated. It is

presumable that the complex mixtures of products obtained in the reaction of

75 with N-bromosuccinimide result from the ready decomposition of any

intially formed bromide 106. As was postulated for the bromide 100, 106 may

readily dissociate to give the conjugated acyliminium species L07 which being

susceptible to attack by nucleophiles at the electrophilic cr-carbon reacts to give

various decomposition products (Scft¿me 26).

RESULTS ,AND DISCUSS/ON - 1

N

M

decompositionproducts

+ \^

106

Br-

107

Scheme 26

In order to ascertain the relative reactivity of the N-allylazetidinone 75

and the azetidinone 72 a competitive bromination between the two was

investigated. Thus, a 1.:1.:1. mixture of 72,75 and N-bromosuccinimide in a 5:1

mixture of carbon tetrachloride and dichloromethane was heated at reflux

under nitrogen whilst irradiating with a 300 W mercury lamp for 15 minutes.

lH n.m.r. spectroscopic analysis of the crude reaction mixture revealed a

complex mixture of products containing a minor amount of unreacted 75 and

a major amount of unreacted 72. In addition, the absence of the bromide 92 in

this product mixture was evident. This result indicated that 75 had reacted

preferentially to 101 and consequently that the reactivity of 75 toward free

radical bromination is greater than that of 72.

To the extent that it may be assumed that 75 reacts in free radical

bromination reactions oia hydrogen abstraction from the cr-carbon, the relative

reactivity of 72 and 75 then reflects the relative rate of formation of the

corresponding cr-centred radicals 96 and L08. This result in turn indicates that

the olefinic moiety at the c-carbon of 75 is more activating towards hydrogen

atom abstraction at the cr-carbon than is the ethoxycarbonyl substituent of 72,

consistent with the absence of polar effects in the transition state of hydrogen

atom abstraction from the allylic s-carbon of 75.


,n a

45

CO,CHPh-l

,n\/^

hv

a

108

The reaction of benzyl 2-oxo-'1.-azetidineacetate (76) with N-bromo-

succinimide was studied in order to investigate the applicability of the

bromination procedure to functionalization of the cr -carbon in

oxoazetidineacetate systems bearing removable protecting groups for the

carboxyl group. Benzyl esters are readily cleaved by a variety of methods86

including hydrogenolysis8T,SS and mild alkaline hydrolysis,S9 and as

such have found wide application as protecting groups in p-lactam

chemistrY .88,89,90

The azetidinone 76 was treated with one mole equivalent of N-bromo-

succinimide in a 2:'l., mixture of carbon tetrachloride and dichloromethane

at reflux under nitrogen for 15 minutes, with reaction initiated by irradiation

with a 300 W mercury lamp. 1H n.m.r. spectroscopic analysis of the crude

reaction mixture after filtration and evaporation of the solvent gave evidence

for the production of two bromides, L09 and 110, in an approximately

3:1 ratio (Scheme 27). The methylene protons of the cr-carbon in 7 6

resonate as a singlet at ô 4.07, with the benzylic methylene protons

Ão

NBS tr-o+ ,nBr

ì IBrL09

co2cH2Ph 2Ph

11076

Scheme 27

RËSULTS AND D/SCUSS/ON - I

46

giving rise to a singlet resonance at õ 5.L2. In the crude product mixture

obtained from the bromination oÍ 76, a singlet resonance at ô 6.36 was

observed, indicative of the methine proton of the cr-carbon in 109. In

addition, a resonance observed at ô 5.18 with twice the peak area was consistent

with the downfield shift expected for the benzylic methylene protons of 109.

Evidence for the formation of the bromobenzyl ester 110 was given by a singlet

resonance at õ 7.49, corresponding to the methine proton of the benzylic carbon

and a singlet resonance of twice the peak area at ô 4.11, corresponding to the

methylene protons of the cx,-carbon.

Production of the bromide 109 in the above reaction is consistent with

reaction oia initial hydrogen atom abstraction from the exocylic methylene

adjacent to nitrogen to form the cr-centred intermediate radical 11-1-, stabiltzed

by the combined resonance effects of the electron-donating amido and

electron-withdrawing benzyloxycarbonyl substituents. Formation of the

bromobenzyl ester 110 would result from reaction aia initial hydrogen atom

abstraction from the benzylic carbon of 76, affording the intermediate benzylic

o

Ph Pho

oa

Na

11L L72

radical L12. The observed ratio of formation of the bromides 109 and 110

from the lactam 7 6 then reflects the relative rate of formation of the

corresponding intermediate radicals 111, and 112. Thus, since formation of the

benzylic radical L12 competes with that of the ct-centred radical L1-1 in the free

radical bromination of the azetidinone 76, ít is concluded that this procedure

RESULTS AND DTSCUSSION - I

47

may be unsuitable for regioselective functionalization of benzyl 2-oxo-

azetidineacetates.

Whilst the azetidinones 74-76 each gave mixtures of products, the free

radical bromination of the azetidinones 72 and 73 described in this chapter

demonstrates methodology for direct regioselective exocyclic functionalization

of these systems. In particular, the procedure provides an attractive alternative

method for the synthesis of N-(a-haloalkyl)-substituted azetidinones, to that

described in the Introduction of this ¡þssis.13,19 The simplicity of the

procedure and the relatively high conversion to product in the case of the

azetidinones 72 and 73 indicate the potential for use of this method in

synthesis. As such, an investigation of the synthetic utility of this

methodology is presented in the next chapter of this thesis

RESULTS ,4ND D/SCUSSION - I

48

REsuLrs AND DrscussloN - II

Elaboration of Functionalized N-Substituted

B-Lactams

In Chapter I of this thesis a procedure for selective bromination at the

exocyclic carbon adjacent to nitrogen in oxoazetidineacetate systems was

established. The study described in this chapter was aimed at an investigation

of the applicability of this procedure as a key step in the synthesis of bicyclic

and monocyclic p-lactam antibiotics. To this end, methods for the elaboration

of the bromide 92, obtained from the azetidinone 72, were investigated.

Bachi and co-workers23 have reported the conversion of N-(cr-chloro-

alkyl)-substituted azetidinones, analogous to the bromide 92, to the

corresponding phenylthioethers by treatment with thiophenol and sodium

hydroxide in benzene in the presence of a phase transfer catalyst. They

demonstrated use of these thioethers as free radical precursors in radical

cyclization reactions having the advantage of greater stability than the

corresponding chlorides. Conversion of the bromide 92 to the corresponding

thioether 113 was investigated aiø an analogous procedure to that of the

preparation of the ether 93 described in Chapter I.

The bromide 92, prepared from 72 by treatment with N-bromo-

succinimide in a 5:1 mixture of carbon tetrachloride and dichloromethane as

described in Chapter I, was treated in situ with two mole equivalents each of

thiophenol and 2,6-lutidine, Chromatography of the crude product mixture

thus obtained afforded the phenylthioether L13 in 64Vo yield, based on 72. The

RESULTS AND DISCUSSION - II

49

phenylthioether LL3 was fully characterized, exhibiting consistent spectral

properties and elemental analyses. In the 1H n.m.r. spectrum of the thioether

113 a singlet resonance observed at ô 5.82 was characteristic of the methine

proton of the o-carbon. The presence of the phenylthio substituent in 113 was

confirmed by the observation of multiplet resonances centred at ô 7.33 and 7.49

of three and two protons integration respectively. As noted for the ethers 93

and 98 and their corresponding bromides 92 and97, the four lactam methylene

protons of 113 each gave rise to distinct 1H n.m.r. resonances due to non-

equivalence, in this case arising from the presence of the phenylthio

substituent at the cr-carbon.

N SPh

CO2Et

113

The mechanism for the formation of L13 from the bromide 92 is

proposed as analogous to that of the ether 93 depicted in Scheme 23 above,

whereby the electrophilic cr-carbon of the iminium species 96 would in this

case be attacked by thiophenoxide anion. That the phenylthioether 113 was

obtained in greater yield from the azetidinone 72 than was the ether 93, may

reflect a greater reactivity of the iminium species 96 with thiophenoxide

anion than with ethanol. It should be noted that the yield of the

phenylthioether 113 obtained from the azetidinone 72, oia the bromide 92,

compares favourably with the yietds reported by Bachi and co-workers23

for the production of the analogous phenylthioethers from their

corresponding N-(cr-chloroalkyl)-substituted azetidinones. As such, synthesis

of the phenylthioether 113 provides good illustration of the free radical

RESULTS ,AND DISCUSSION - I1

50

bromination procedure as an attractive alternative to the use of N-(a-chloro-

alkyl)-substituted azetidinones.

N-(a-Chloroalkyl)-substituted azetidinones have enjoyed widespread

use in the synthesis of B-lactam antibiotics.2O Their use has chiefly centred

upon their role as the precursors to phosphoranes used in a Wittig reaction to

complete the molecular backbonel3-19, as described in the Introduction of this

thesis. The application of the analogous bromides, obtained aía tÞ.e

methodology established in Chapter I, to this synthetic procedure was studied.

Thus, conversion of the bromide 92 to the corresponding phosphorane L14 was

investigated using methodology previously reported9l for preparation of

phosphoranes from the analogous chlorides.

Accordingly, a sample of the crude bromide 92 was dissolved in dry

L,4-dioxane and treated with two mole equivalents each of triphenylphosphine

and 2,6-lutidine, at room temperature under nitrogen. Flowever, upon

chromatography of the crude product mixture, none of the desired

phosphorane L1.4 was obtained. The maleate derivative 115 was isolated as the

only identifiable product of reaction in 30% yield, based on the amount of the

azetidinone 72 used in preparation of the bromide 92.

N CO2Et

CO2Et

174 11s

The 1H n.m.r. spectrum of the maleate derivative 115 exhibited a singlet

resonance at ô 6.31 attributable to the single vinylic proton, whereas triplet

resonances at ô 3.10 (/ = 4.9 FIz) and 3.92 (l = 4.9 Hz) were indicative of the C3


51

and C4 methylene protons, respectively. The presence of two ethoxy

substituents in the molecule was indicated by a triplet resonance at ô 1.31 (/ =

7.1,IJ2) and a quartet resonance at E 4.23 (l = 7.1, Hz) being attributable to one

ethoxy substituent, with the other giving rise to a triplet and a quartet

resonance at ô 1.34 and 4.30 respectively, each with ,Ivic = 7.7FJ2. The

assignments for the two ethoxy substituents of 115 were enabled by

homonuclear decoupling of resonances in the lH n.m.r. spectrum. The

presence of the alkenyl moiety in 115 was indicated by an infrared absorption at

1.628 cm-1 with resonances at õ 133.19 and 115.50 in the 13C n¡pT n.m.r.

spectrum being characteristic of the quaternary and tertiary alkenyl carbons

respectively. The Electron Impact (EI) mass spectrum of 115 exhibited a

molecular ion at mlz 247 and in addition elemental analyses were consistent

with the structure.

Formation of the maleate derivative 115 in the above reaction of the

bromide 92 may be rationalized as due to reaction of the phosphorane 1-L4,

upon its formation, with the bromide 92 as outlined in Scheme 28. Thus,

reaction of the bromide 92 with triphenylphosphine initially gives the

phosphonium salt 116 which, upon deprotonation from the cr-carbon, affords

the phosphorane L14, stabilized by resonance delocalization of the charge on

carbon over the ester carbonyl moiety. Attack by the phosphorane 114 at the

electrophilic ø-carbon of the N-acyliminium species 94, in equilibrium with

the bromide 92, yields the intermediate LL7, which then eliminates L18 to give

the maleate derivative 115. The by-product 1,18 was not observed in the crude

product mixture as it is presumably unstable, hydrolysing upon workup to

give triphenylphosphine oxide.

RESUTTS AND D/SCUSSION - I1

52

BrPPh3

CO2Et

CO2Et

+N PPh3

co2Et

CO2Et

92 1L6

+

^Ro

94 174

co2Et

+Br CO2EtN

)+

EtO2C co2Et

177r*-PPh3

118

Scheme 28

In support of the above rationale for the production of the maleate

derivative 115, Sharma and Stoodley92 have reported reaction of the

phosphorane 120 with the N-(a-chloroalkyl)-substituted azetidinone 119 to

tr-o

115

Br

RESULTS ,4ND DISCUSSION - II

53

give the substituted phosphorane 12'1, (Scheme 29). The reaction of

phosphoranes with imines at elevated temperatures has also been reported.93

+ Ph3P:CHCO2EI

120

Scheme 29

Whereas reaction of the phosphorane 1,T4 with the bromide 9 2

competes with its formation from the bromide 92, the similar reaction is not

observed in the preparation of phosphoranes from N-(cr-chloroalkyl)-

substituted azetidinones.13-19 This is consistent with expectations of a greater

electrophilicity of the cr-carbon of the bromide 92 over that of corresponding

chlorides. Although the phosphorane 114 was not isolated, the reaction of the

bromide 92 with triphenylphosphine to give the maleate derivative 115

nevertheless illustrates that the phosphorane LL4 can be formed from the

bromide 92. Furthermore, formation of the maleate derivative 115 in this

reaction illustrates use of the bromide 92 in a Wittig reaction, achieving

carbon-carbon bond formation at the ü-carbon. Other methods for elaboration

of the bromide 92 aia carbon-carbon bond formation at the g-carbon were

subsequently investigated.

Keck and co-workers94 have reported the use of allyltributyltin for the

synthesis of carbon-carbon bonds aia addition reactions with alkyl radicals

derived from alkyl halides. Subsequently allylstannanes have been shown to

be amenable to the elaboration of s-bromoglycine derivatives,70,95,96 which

bear functional similarity to the bromide 92. The proposed mechanism of

lttco2R

t

co2R

727lT9

RESULTS AND D/SCUSSION - II

54

reaction of allytributyltingT is as depicted in Scheme 30. Bromine atom

abstraction from the substrate 122 by tributyltin radical forms the substrate

RBr

122

+ BurSn' R' + BurSnBr

123

R1,r\ + Bu3sn'

123

Scheme 30

radical L23. Homolytic allyl group transfer from allytributyltin to the

substrate radical 123 affords the allylated product L24 and tributyltin radical,

which propagates the chain. Allylation of the bromide 92 with allyltributyltin

was investigated as a method for functionalization uia free radical carbon-

carbon bond formation, at the cr-carbon of oxoazetidineacetates. The

incorporation of an allyl substituent at the cr-carbon of 72 was considered an

attractive proposition from a synthetic standpoint as an allyl substituent has

the potential for further elaboration. As an example, Kametani and Honda9S

have previously reported intramolecular cyclization of an allyl substituent at

the cr-carbon of an oxoazetidineacetate system onto C4 of the lactam as

methodology for the synthesis of bicyclic B-lactams.

?xThe bromide % was initially treated with two mole equivalents of

allyltributyltin in the presence of a catalytic amount of AIBN as radical

initiator, in dry benzene heated at reflux under nitrogen, for five hours.

However, upon chromatography of the crude product mixture, no product

identifiable as the desired allylated compound 125 was isolated. Indeed, no

discrete identifiable products could be isolated from the crude product mixturel^

and this was attributed to decomposition of the bromide :t3å under the

"'^\73ftnBu3L24

RESULTS AND DISCUSS/ON - 1I

55

reaction conditions employed. Thus, milder reaction conditions were applied

to the allylation of the bromide 72.

Ethyl c-bromo-2-oxo-L-azetidineacetate (72) was treated with two and

a half mole equivalents of allyltributyltin in the presence of a catalytic amount

of AIBN in dry benzene at room temperature, under nitrogen overnight.

Chromatography of the crude product mixture thus obtained afforded ethyl cr-

allyl-2-oxo-1-azetidineacetate (125) (Scheme 31) in 25Vo yíeld, based on the

amount of 7|used in the preparation of the brom ¡a" b. On a subsequent

occasion a minor amount of the alcohol 126 was also obtained.

,n 4/SnBu3AIBN

t co2Et co2Er

92 125 126

Scheme 31

The 1H n.m.r. spectrum of 725 exhibited a doublet of doublets resonance

at õ 4.49 (] = 5.2,9.7 }jlz) attributable to the methine proton of the cr-carbon and

distinct resonances were observed, attributable to each of the four non-

equivalent methylene protons of the lactam ring. The presence of the allyl

substituent in 125 was indicated by resonances characteristic of the olefinic

protons observed at õ 5.17 (2H) and 5.76 (7H). The allylic methylene protons

of L25 were non-equivalent, giving rise to multiplet resonances centred at

õ 2.50 and 2.66. Further evidence of the allyl substituent ol 725 was given by

an infrared absorption at 1640 cm-1. A molecular ion was observed at mlz 197

in the EI mass spectrum and other spectroscopic properties were in accord with

the structure of L25.

tr-oBrI

co2E

+ ,n

RESULTS ,AND DISCUSSION - 11

56

The alcohol 126 was identified on the basis of 1H n.m.r. spectroscopic

evidence whereby a singlet resonance observed at ô 5.49 was attributable to the

methine proton of the o-carbon with a broad resonance at õ 4.86 being

consistent with the hydroxyl proton. A broad infrared absorption at 3350 cm-1

was further evidence of the hydroxyl group ín'126. Production of the alcohol

126 presumably results from reaction of the bromide 92 aia the iminium

species 94, with adventitious water.

Whilst production of the altyl derivative 126 in the above reaction of

the bromide 92 with allyltributyltin illustrates methodology for free radical

carbon-carbon bond formation at the cr-carbon of 92, the relatively low yield of

product L25 obtained in this reaction prompted an investigation of alternative

methodology for allylation of the bromide 92. Castelhano and co-workers99

have reported ionic allylation of an cr-methoxyglycine derivative in high yield

by treatment with allyltrimethylsilane under Lewis acid conditions. The use of

this methodology to effect allylation of the bromide 92 was investigated as an

alternative to free radical allylation.

The crude bromide 92 was treated in situ at 0 - 5'C with four mole

equivalents each of allytrimethylsilane and boron trifluoride etherate and the

reaction mixture was allowed to warm to room temperature overnight. Upon

workup, chromatography of the crude product mixture afforded the allyl

derivative '1.25 in 347o yield based on 72. The product 125 obtained in this

reaction bore identical spectroscopic properties to that previously obtained pia

the free radical allylation of the bromide 92. It was considered that the greater

yield of the allyt derivative 125 aia this procedure over that obtained oiø free

radical allylation was in part due to the greater ease of chromatographic

separation of the product from the crude reaction mixture.

RESULTS AND DISCUSS/ON - II

57

The reactions of the bromide 92 described above exemplify methods for

its elaboration and serve to illustrate the synthetic utility of the selective

bromination procedure described in Chapter I of this thesis. Whilst this

methodology may then be considered applicable to the synthesis of bicyclic

p-lactams, the selective bromination at the cr-carbon of 72 to give the bromide

92 was further considered as a basis for an approach to the synthesis of

analogues of the norcardicins (8), monocyclic p-lactam antibiotics. Thus a

method for the substitution of bromine in 92 with a suitable aryl group would

provide a route to the synthesis of norcardicin analogues. Williams and

Hendrixl00 have reported arylation of an cr-bromoglycine derivative with

electron rich aromatic compounds such as furan under Friedel-Crafts

conditions, and it was considered that this methodology might be amenable to

arylation of the bromide 92. Accordingly, arylation of the bromide 92 with

furan in the presence of a Lewis acid was investigated.

The bromide 92 was treated with a twenty-fold excess of furan, in the

presence of two mole equivalents of zinc chloride in dry tetrahydrofuran, and

afforded ethyl cr-(2-furyt)-2-oxo-1-azetidineacetate (L27) (Scheme 32) in 62Vo

yield, based on the amount of 72 used in preparation of the bromide 92.

o(}N

ZnCl2

co2Et CO2Et

92 127

Scheme 32

The furyl derivative L27 was characterized by 1H n.m.r. spectroscopic

evidence. A singlet resonance observed at ô 5.62 was attributable to the

methine proton of the cx,-carbon and the presence of the 2-substituted furyl

Br ,n

RESULTS AND DISCUSSION - 1I

58

group was confirmed by resonances observed at ô 6.31 (d,l = 3.2LIz), 6.34 (dd,

I = 3.2, 7.9 }lz) and 7.37 (d, I = 7.9IIz), that were characteristic of the aromatic

protons of C3', C4' and C5', respectively. In addition, the four lactam

metþlene protons of 127 showed non-equivalence due to the presence of the

furyl substituent at the G-carbon, each giving rise to distinct resonances. A

molecular ion was observed at mlz 223 in the EI mass spectrum and other

spectroscopic properties were in accord with the structure of !27.

Production of the furyl derivative 127 from the bromide 92 illustrates

the viability of the procedure for direct exocyclic bromination of

oxoazetidineacetates as a route to the synthesis of norcardicin analogues. In

extending this approach, ultimately to the synthesis of analogues of

3-aminonorcardicinic acid (728), the structural element common to all

members of the norcardicin family (8),ror an investigation of the free radical

bromination of a protected 3-aminosubstituted oxoazetidineacetate was

warranted. A phthalimide group provides a convenient protecting

group for an amino substituent, being readily removable by

aminolysislO2 6¡ borohydride reduction,103 under mild conditions. Thus the

3-phthaloylazetidinone 1.29 was subsequently chosen for investigation, the

H NH o

H CO2Me

L29128

co2H

RESUTTS AND DTSCUSSION - II

59

synthesis of which has previously been reported by Miller and Mattingly.loa

Accordingly, synthesis of 129 aia cyclization of N-phthaloylserylglycine methyl

ester (136) was investigated as described below.

N-Phthaloylserylglycine methyl ester (136) was synthesized from

N-phthaloylserine (133), prepared according to the method of Nefkens and co-

workers,105 ¿s outlined in Scheme J3. Thus, phthalimide (L30) was treated

with excess ethyl chloroformate in the presence of triethylamine in

dimethylformamide and afforded N-carboethoxyphthalimide (131) in 92%

yield after recrystallization. Treatment of an aqueous solution of serine (132)

with a slight excess of N-carboethoxyphthalimide (131) under basic conditions

then afforded N-phthaloylserine (133) in 86% yield after recrystallization from

ethyl acetate / Iight petroleum, bearing consistent physical and spectroscopic

properties.

The dipeptide 136 was synthesized oia the Schotten-Baumann

procedure, in preference to the dicyclohexylcarbodiimide (DCC) coupling

procedure employed by Milter and Mattingly,704 as it was found in practice to

provide comparable yields of the product from reaction mixtures affording a

greater ease of chromatographic separation. Thus, N-phthaloylserine (133)

was treated with thionyl chloride to give N-phthaloylseryl chloride (134).

Glycine methyl ester hydrochloride (135), prepared by esterification of glycine

(S2) by treatment with methanol that had been pretreated with thionyl

chloride, was then treated with the crude acid chloride 134 in dichloromethane

in the presence of excess aqueous sodium bicarbonate, and gave the dipeptide

136 in 57Vo yield. The product L36 thus obtained exhibited spectroscopic

properties in accord with those previously reported.lO4

RESULTS ,AND DISCUSS/ON - 1I

60

NHCICO2Et

Er3N

socl2

HCI.NH2CHTCOTMe

135

MeOH / ÐCl2 I 'NH3CH2CO2

82

N

o

+HsNt

130 132131

Na2C03

OH

134 L33

aq. NaHCO3

Phth = N-NH

o136

Scheme 33

Cyclization of the dipeptide 136 was investigated under Mitsunobu

conditionsl06-108 as reported by Miller and Mattingly.l04 Thus, a solution of

L36 in tetrahydrofuran was treated with one mole equivalent of

diethylazidodicarboxylate (DEAD) and a slight excess of triphenylphosphine

o

RESUTTS ,4ND DISCUSS/ON - 1I

67

(Scheme 34). Chromatography of the crude product mixture afforded the

dehydrop"plilÊry_ ll 13,t", li.'t$ rhe 3-phthaloylazetidinone 12e w as isolated

in only 3Vo yield after further chromatography of the crude product

NH

L36

DEAD / PPh3

Phth

-CO.'Me\./

L

-lo

CO2Me

129137

Scheme 34

mixture and subsequent selective recrystallization to remove dicarboethoxy-

hydrazine, the by-product of reaction of DEAp.108 The 3-phthaloylazetidinone

129 thus obtained bore physical and spectroscopic properties in accord with

those previously reporte 6.213 In the 1H n.m.r. spectrum of 729 a doublet of

doublets resonance at õ 5.56 (/ = 5.5, 2.9 }lz) was attributable to the C3 methine

proton, with doublet of doublets resonances at õ 3.U (l = 5.3, 2.9ffò and 3.91

(/ = 5.5, 5.3 Hz) being consistent with the non-equivalent methylene protons of

C4. The methylene protons of the cr-carbon of 129 were non-equivalent, giving

rise to doublet resonances at ô 4.02 and 4.58 each with /t"* = 18.0 FIz.

Ph

o

+

RESULTS AND DISCUSSÌON - II

62

Owing to the low irreproducible yield of the 3-phthaloylazetidinone

L29 from the above treatment of the dipeptide 136, concomitant with the

inherent difficulty of isolation of this product from the reaction mixture/ an

alternative method for the synthesis of 129 was sought. To this end,

conversion of the seryl dipeptide 136 to the p-chloroalanyl dipeptide 138 was

investigated. Treatment of the dipeptide L36 with 1.2 mole equivalents of

phosphorous pentachloride in the presence of one mole equivalent of calcium

.ut6on¿¡s218 in dry tetrahydrofuran solution afforded N-phthaloyt-p-

chloroalanylglycine methyl ester (138), in 69Vo yield after chromatography and

subsequent recrystallization (Scheme 35). The p-chloroalanyl dipeptide 138

Phth* .. CO2Me

CaCO3NH

o136 L38

Scheme 35

thus obtained was fully characterized, exhibiting satisfactory spectroscopic

properties and elemental analyses. It was distinguished by the observation of

two molecular ions in the EI mass spectrum at mlz 324 and 326 in the ratio of

3:1,, thus confirming the presence of chlorine in the molecuie.

Cyclization of the chloride 138 using the methodology of Takahata and

co-workersS2 as described in Chapter I was subsequently investigated, where in

this case, tetra-n-butylammonium chloride was the catalyst of choice.

Accordingly, the chloride L38 was added slowly in dilute solution to a stirred

suspension of powdered potassium hydroxide and tetra-n-butylammonium

chloride in a 19:1 mixture of dichloromethane and acetonitrile. Flowever,

PCls

o

RESULTS AND DTSCUSS,TON - II

63

PhPh

oo

upon chromatography of the crude product mixture, none of the desired

3-phthaloylazetidinone 129 was obtained. The dehydropeptide 137 was the

only product of reaction, isolated in 57% yield, with 797o of the starting

material 138 being recovered unreacted (scheme 36). Owing to the lack of

azetidinone 129 obtained in this reaction, synthesis oÍ L29 aia cyclization of the

chloride 138 was not investigated further.

KOH / BuaNCl NH Me

138 137

Scheme 36

Although it would appear from the investigations described above that

the 3-phthaloylazetidinone 129 does not provide a viable target for synthesis,

an initial investigation of the free radical bromination of 729 was

nevertheless conducted on the limited amount of this azetidinone 'l'29

obtained aiø qclization of the seryl dipeptide L36.

Bromination of the 3-phthaloylazetidinone L29 was investigated by

treatment with N-bromosuccinimide under the conditions employed

previously in the bromination of the azetidinone 72. Thus, methyl

3-phthaloyl-2-oxo-1-azetidineacetate (129) was treated with one mole

equivalent of N-bromosuccinimide in a 5:1 mixture of carbon tetrachloride

and dichloromethane at reflux under nitrogen, whilst irradiating with a 300 W

mercury lamp for 15 minutes. Methyl cr-bromo-3-phthaloyl-2-oxo-1-

azetidineacetate (139) was obtained as the only product of reaction as a 3:2

mixture of diastereomers (Scheme 37), as determined by 1g n.m.r.

spectroscopic analysis of the crude reaction mixture, after solvent evaporation.


64

Phrh

NBS

CO2Me CO2Me

139

Scheme 37

The 1H n.m.r. spectrum of the crude bromide 139 exhibited two singlet

resonances at õ 3.83 and 3.84 in a 3:2 ratio, attributable to the methyl ester

protons of the major and minor diastereomers respectively. Two doublet

resonances in a 3:2 ratio at õ 6.44 and 6.46, each with / : 0.8H2, were

attributable to the methine proton at the cr-carbon of each diastereomer of 139,

wherein the observed multiplicity of these resonances was due to long range

coupling to the corresponding methine proton at C3. Accordingly, doublet of

doubtet of doublets resonances were observed at ô 5.56 (l = 6.0,3.8, 0.8 FIz) and

5.M (] = 6.5,3.5, 0.8 }Jz) for the methine proton at C3 of the major and minor

diastereomers, respectively. In addition, the non-equivalent methylene

protons of C4 each gave rise to distinct resonances attributable to the major and

minor diastereomers of 139.

The above reaction of the azetidinone 729 with N-bromosuccinimide to

give the bromide 139 is consistent with reaction oía inittal hydrogen atom

abstraction from the a-carbon of '1.29 to give the cr-centred intermediate radical

L40. Formation of the bromide 139 in this reaction illustrates the viability

Phrh

CO2Me

Ph

BrNhv-l

729

140


65

of the free radical bromination procedure for direct regioselective exocyclic

functionalization of a protected 3-amino substituted oxoazetidineacetate

system. As such, use of this methodology holds promise as a possible route to

analogues of the norcardicins (8) through synthesis of analogues of 3-amino-

norcardicinic acid (128).


66

REsuLrs AND DrscussloN - III

Functionalization of N-Substituted y-Lactams

Preparation of the 2-pyrrolidinones L41 and L42

The 2-pyrrolidinones L4L and L42 were required for the investigation

described in this chapter, of the regioselectivity of functionalization of

y-lactams bearing activating substituents at the exocyclic carbon adjacent to

amide nitrogen. They were synthesized in an analogous manner to the

f{=R-NI

R

L4L142

COzMeCN

2-azetidinones 72-76 prepared in Chapter I of this thesis,uia cyclization of

the corresponding 4-chlorobutyramides 143 and 144. This route to the

preparation of the pyrrolidinones 14L and L42 was chosen for its simplicity and

convenience over that of methods involving N-alkylation of 2-pyrrolidinone

reported previously.ll'0' 111 Ths butyramides 143 and L44 were readily obtained

743 R: COzMeL44 R=CN

Ro NH

RËSULTS AND DISCUSSION - //I

67

by Schotten-Baumann coupling of 4-chlorobutyryl chloride (145) with the

corresponding amines 135 and 146. Details of the syntheses of the

pyrrolidinones L41 and L42 are given below.

Methyl 2-oxo-1-pyrrolidineacetate (141) was synthesized from glycine

(82) as shown in Scheme 38. Glycine methyl ester hydrochloride (135),

obtained by esterification of glycine (SZ¡ with methanol that had been

pretreated with thionyl chloride, was treated with 4-chlorobutyryl chloride

(145) in the presence of excess aqueous sodium bicarbonate, affording the

chlorobutyramide L43 in 477o yield. The product 143 thus obtained was fully

characterized, exhibiting spectral properties and elemental analyses consistent

with its structure. In particular, the amide carbonyl of L43 gave rise to a

characteristic infrared absorption at 1656 cm-1 and further evidence for the

production of the amide in L43 was given by the observation of a resonance at

õ 172.71, in the 13C n.m.r spectrum.

HCI.NH2CH2COTMe

L35

MeOH / SOCII

æÇz

C1

/ aq. NaHCO3

745

KOH / BuaNClN

NHCO2Me

L4t

o

o143

Scheme 38

RESULTS AND D/SCUSS/ON - 1II

68

Cyclization of the butyramide 743 was achieved using the methodology

of Takahata and co-workers,82 ¿"r.ribed in Chapter I, with the choice of phase

transfer catalyst in this case being tetra-n-butylammonium chloride.

Accordingly, 143 was added slowly in dilute solution to a stirred suspension of

powdered potassium hydroxide and tetra-r-butylammonium chloride in a 19:1

mixture of dichloromethane and acetonitrile, affording the desired

pyrrolidinone 141 in 55Vo yield after purification by chromatography and

subsequent distillation. Spectral characteristics of the product 141 were

consistent with those previously reported,Tlz with the lactam carbonyl giving

rise to a characteristic infrared absorption at 1685 cm-1, and in addition the

amide carbon giving rise to a resonance at ô 175.32 in the 13C n.m.r. spectrum.

2-Oxo-L-pyrrolidineacetonitrile (L42) was synthesized as outlined in

Scheme 39. 4-Chlorobutyryl chloride (145) was treated with aminoacetonitrile

hydrochloride (146) in the presence of excess aqueous sodium bicarbonate to

give the chlorobutyramide 1,44 ín 54Vo yield. The butyramide 144 was fully

characterized, exhibiting consistent spectroscopic properties and elemental

analyses. In particular, the observation of an infrared absorption at 1645 cm-1

and the further observation of a resonance at õ 172.24 in the 13C n.m.r.

spectrum, both confirmed the presence of the amide in 144. Treatment of the

butyramide L44 with a suspension of powdered potassium hydroxide and tetra-

n-butylammonium chloride in dichloromethane and acetonitrile, as for the

cyclization of 143 above, afforded the pyrrolidinone L42 in 67Vo yield af.ter

purification by chromatography and distillation. The white crystalline

pyrrolidinone 142 thus obtained was unstable, discolouring at room

temperature over a period of days. However, minimal decomposition of the

pyrrolidinone L42 occurred in storage under refrigeration in a sealed vial. The

RESULTS .AND DISCUSSION - III

69

HCI.NH2CH2CN +L46

145

aq. NaHCO3

C1

KOH / BuaNCl

NH

144CT\,I

1l2

Scheme 39

pyrrolidinone L42 was fully characterized, exhibiting satisfactory spectroscopic

properties and elemental analyses. The lactam carbonyl in L42 gave rise to a

characteristic infrared absorption at 1685 cm-1 with a resonance observed in

the 13C n.m.r spectrum at õ 174.41, corresponding to the amide carbon.

ì

RESULTS AND D/SCUSSION - IIl

70

Functionalization of the 2-pyrrolidinones '1.41 and L42

The investigation described in Chapter I of this thesis established that

free radical bromination may be affected regioselectively at the exocyclic carbon

adjacent to nitrogen in p-lactams bearing activating substituents at that

position. The study described in this chapter was based upon an investigation

of the regioselectivity of free radical bromination of analogous y-lactams, with

the aim of directing functionalization to the exocyclic carbon adjacent to

nitrogen. The pyrrolidinones 141 and L42, bearing methoxycarbonyl and cyano

substituents respectively at the exocyclic carbon adjacent to nitrogen, were tltus

chosen for study.

To ensure the solubility of the substrate in the reaction mixture, the

bromination of the pyrrolidinone 141 was initially investigated in a mixture of

carbon tetrachloride and dichloromethane as solvent. Methyl 2-oxo-1-

pyrrolidineacetate (14L) was treated with one mole equivalent of N-bromo-

succinimide in a 1:1 mixture of carbon tetrachloride and dichloromethane at

reflux under nitrogen for 10 minutes, with reaction initiated by irradiation

with a 300 W mercury lamp. 1H n.m.r. spectroscopic analysis of the cooled

crude reaction mixture revealed a mixture of products containing unreacted

starting material 141.

The extent of reaction was increased when the pyrrolidinone 141 was

treated with a slight excess of N-bromosuccinimid.e in neat carbon

tetrachloride, heating at reflux under nitrogen whilst irradiating as above, for

10 minutes. In this instance, 1H n.m.r. spectroscopic analysis of the crude

reaction mixture revealed the absence of starting material 141 and in addition

gave evidence for the production of the bromide L47 and t}:re trans-dibromide

148+ in an approximately 3:1 ratio (Scheme 40). The methylene protons of the

t Otrly one enantiomer of each racemic mixhrre is shown.

RESULTS,4ND DISCUSSION - lII

77

o-carbon of L4'/.. give rise to a singlet resonance at õ 4.08, with a triplet

resonance at ô3.50 (l =7.1H2) arising from the methylene protons of C5. In

the 1H n.m.r. spectrum of the crude product mixture obtained from the

bromination of 14l a singlet resonance at õ 6.76 was observed, consistent with

the methine proton of the cr-carbon of the bromide 1-47. The presence of the

trøns-dibromide 148 in the same reaction mixture was indicated

Br

--+

N Br+

Nì

hv N

CO2Me CO2Me117 747 148

Scheme 40

by an observed singlet resonance at ô 6.34 attributable to the methine proton of

C5, with an observed doublet resonance of equal peak area at ô 4.90 (l = 6.1flz)

being attributable to the methine proton of C4. That the resonance observed

for the C5 methine proton of 148 appeared as a singlet is consistent with a

minimal vicinal coupling constant for the C4 and C5 protons. On the basis of

the Karplus equation,113,114 this is in accord with a dihedrat angle for the C4

and C5 methine protons of approximately 90 degrees, thus indicating that these

protons are in a trans geometry. This in turn is consistent with expectations of

a trans geometry based on the proposed mechanism of formation of the

dibromide 148 from L3L, as described in Scheme 43 below. The observed

doublet resonance attributed to the C4 methine proton of L48 may be

rationalized in terms of a very small vicinal coupling to the trans methylene

proton of C3, such that the observed vicinal coupling constant of 6.\ Hz is due

to coupling to the cis methylene proton of C3 only.

Br

SNB

o

RESUTTS AND D/SCUSSION - III

72

The bromides L47 and 1.48 were insufficiently stable for isolation and so

conversion of these products to stable derivatives for isolation and

characterization was necessary to further ascertain the course of reaction of the

pyrrotidinone 141 with N-bromosuccinimide. Accordingly, methyl 2-oxo-L-

pyrrolidineacetate (141) was treated with N-bromosuccinimide in carbon

tetrachloride as described above and this was followed by treatment of the

cooled crude reaction mixture with two mole equivalents each of ethanol and

2,6-lutidine. Chromatography of the crude product mixture thus obtained

afforded the ether 149 and the 4-bromo-5-ethoxypyrrolidinone 150 in yields

of 37 artd 9% respectively, based on 141 (Scheme 41). On a subsequent occasion

the 4-bromo-5-hydroxypyrrolidinone 151 was also obtained as a minor

product.

N

CO2MeL47

1. NBS / hv2. EIOH / 2,6-lutidine

Et

+N -l

CO2Meo

CO2Me

1,50 15L

Br=

Bra.

N*ì+

749

CO2Me

Scheme 41

RESUITS,4ND DISCUSSION - lII

73

Identification of the ether 149 was made initially on the basis of

1H n.m.r. spectroscopic evidence. A singlet resonance observed at õ 5.75 was

attributable to the methine proton of the cr-carbon. The presence of the ethoxy

substituent in 149 was confirmed by the observation of a characteristic triplet

resonance at õ 1.26 (] = 7.0 Hz), corresponding to the methyl protons, and a

quartet resonance at õ 3.57 (l =7.0 FIz) arising from the methylene protons. In

addition, two doublet of doublet of doublets resonances at õ 3.37 and 3.47 were

indicative of the two non-equivalent methylene protons of C5, with the

associated geminal coupling constant being,l55' = 9.8F{2. The non-equivalence

of the C5 methylene protons is consistent with the presence of the cr-ethoxy

substituent at the cr-carbon of 149. Although the ether 149 was insufficiently

stable for elemental analyses, a molecular ion at mlz 207 was observed by Fast

Atom Bombardment (FAB) mass spectrometry, and in addition, an ion

observed at mlz '1.42 corresponded to the fragmentation M+ - CO2Me. Other

spectral properties were consistent with the structure of L49.

The 4-bromo-5-ethoxypyrrolidinone 150 was fully characterized,

exhibiting consistent spectral characteristics and elemental analyses. The

presence of bromine in 150 was confirmed by the observation of two ions of

equal abundance at mfz 280 and 282in the FAB mass spectrum, corresponding

to M+ + H. The high field 1H n.m.r. spectrum of this compound was

particularly characteristic. The ethoxy substituent of 150 gave rise to a

characteristic triplet resonance at õ1..24 with /rriç = 7.0F{2 for the methyl

protons, and two doublet of quartets resonances at õ 3.61 and 3.70 each with

,Igem = 9.4TIz and /yi¡ = 7.0 FIz being due to the two non-equivalent methylene

protons. A doublet resonance at õ 5.21 (/ = 1.5 Hz) was attributable to the

methine proton of C5 and a doublet of doublet of doublets resonance at õ 4.24

Çz+ = 7.4,Il,q - 2.9, Iqs = 1.5tlz) was consistent with the methine proton of C4.

Further, two distinct resonances at õ 2J6 (dd, ¡33' = 78.2,12't = 2.9 ÍIz) and 3.23

RESULTS .AND DISCUSS.ION - II1

74

(ddd, Igz' = 1.8.2, lga = 7.4,lgo = 0.9 HÐ were attributable to the non-equivalent

methylene protons of C3. The methylene protons of the cr-carbon of 150 also

exhibited non-equivalence, giving rise to distinct resonances at ô 3.81 (dd,

I c¡a' = 77.6, lgs = 0.9 flz) and 4.43 (d, /cra' = 77.6 ÍIz).

The vicinal coupling constant of 1.5 Hz observed for the C4 and C5

methine protons of 150 is of the magnitude expected for these protons when in

a trøns orientation, where the dihedral angle would approximate 90 degrees.

From an application of the Karplus equation,773,7\4 it can be seen that for such

protons in a cis orientation, where the dihedral angle would be less than that

for the trans orientation, a larger vicinal coupling constant would be expected.

It is on this basis, that a trans geometry was assigned to the substituents at C4

and C5 of the 4-bromo-5-ethoxypyrrolidinone L50 (Fígure 6).

H BrEt

F{',.r,, ,,,rIfr

N

ì

L50

Figure 6. Numbering of methyl trans-A-bromo-5-ethoxy-2-oxo-1-pyrrolidineacetate (150).

The alcohol 151 was identified by 1H n.m.r. spectral characteristics that

were similar to those of the 4-bromo-5-ethoxypyrrolidinone 150, with a doublet

resonance at õ 5.40 with / = 1.5 Hz, attributable to the methine proton of C5 and

a broad resonance at õ 5.11, consistent with the hydroxyl proton. Further

indication of the hydroxyl group in 15L was given by a broad infrared

absorption at 3400 cm-1. As for the ether 1,50, a trøns geometry was assigned to

H

CO2Me

RESULTS AND DISCUSSION - III

75

the substituents at C4 and C5 of the alcohol 151, on the basis of the observed

vicinal coupling constant for the methine protons of C4 and C5.

Production of the ether 149 above is consistent with formation of the

bromide 147 in the reaction of the pyrrolidinone 141 with N-bromo-

succinimide. The mechanism for formation of L49 is proposed as analogous

to that of the formation of the ethers 93 and 98 discussed in Chapter I

above. The N-acyliminium species 152, in equilibrium with the bromide 747,

is attacked at the electrophilic cr-carbon by ethanol thus giving the ether 149

(Scheme 42).

EtOH

-

Br- tI - HBr

CO2Me CO2Me CO2Me

.wtv7

752 749

Scheme 42

Formation of the endocyclic substitution product 150 may be attributed

to bromination of t47 at the endocyclic carbon adjacent to nitrogen to give the

corresponding intermediate S-bromopyrrolidinone 153, which undergoes

subsequent reaction during treatment with N-bromosuccinimide as shown

in Scheme 43. Elimination of hydrogen bromide from the S-bromo-

pyrrolidinone L53 aiø the N-acyliminium species 154 gives 155, with

which molecular bromine present in the reaction mixture, reacts aia anti

addition, to give the trans-dibromide 148. Reaction of the N-acyliminium

species 156, in equilibrium with the dibromide 148, with ethanol then affords

the ether l-50. TÌr.e trans geometry of the C4 and C5 substituents of 150 is

consistent with intermediacy of the iminium species 156 in the conversion of

NBrNo

RESULTS .AND DISCUSSION - 1I1

76

Br Br-- HBr

N-ì

CO2Me CO2Me CO2Me

L53 \54

Br-

EtOHN

+- HBr NI

CO2Me CO2Me148

Hzo- HBr

N-ì

CO2Me151

Scheme 43

the dibromide 148 to the ether 150. Attack at the planar S-position of the

iminium species 156 by ethanol occurs from the opposite face of the lactam

ring to that occupied by the bromo substituent of C4. The minor product L51

then presumably results from the similar reaction of any unreacted dibromide

148, aiø the iminium species 156, with adventitious water.

N tì

Btz

I+

Br=.

BrBr-z

*l+

t

150 156

Br

RESULTS AND D/SCUSSION - III

77

As for the pyrrolidinone 14L, the bromination of the nitrile analogue

142 was initially investigated in a L:1 mixture of carbon tetrachloride and

dichloromethane in order to ensure the solubility of the substrate. ÉIowever,

1H n.m.r. spectroscopic analysis of the crude reaction mixture obtained upon

treatment of 2-oxo-L-pyrrolidineacetonitrile (tlz) with a slight excess of

N-bromosuccinimide in this solvent mixture revealed the presence of a

substantial amount of unreacted starting material 142. The extent of reaction

was increased when 2-oxo-1-pyrrolidineacetonitrile (142) was treated with a

slight excess of N-bromosuccinimide in a.2:'1, mixture of carbon tetrachloride

and dichloromethane, heated at reflux under nitrogen whilst irradiating with

a 300 W mercury lamp, for 10 minutes. 1H n.m.r. spectroscopic analysis

revealed the absence of unreacted starting material L42 in the crude reaction

mixture and gave evidence for the production of the two bromides 1-57 and

L58 in an approximately 3:L ratio (Scheme 44). The methylene protons of the

Br

NBSN hv

Bri

NBr+

CN CN1.42 157 158

Scheme 44

cr-carbon in 142 give rise to a singlet resonance at õ 4.26 with the methylene

protons of C5 giving rise to a triplet resonance at ô 3.53. In the 1H n.m.r.

spectrum of the crude product mixture obtained from the bromination of 142,

a singlet resonance at õ 6.76 was attributable to the methine proton of the

cr-carbon in the bromide 157. A singlet resonance observed at ô 6.13 was

RESULTS AND DISCUSS/ON - III

78

indicative of the methine proton at C5 of the trans-dibromide 1,58. As for the

case of the dibromide 148 above, the observed singlet resonance attributed to

the methine proton at C5 of 158 is consistent with a minimal vicinal couping

constant for the C4 and C5 protons, thus indicating a trans geometry for the

bromo substituents at C4 and C5.

The bromides 157 and 158 were not stable for isolation and

characterization and so were converted to the corresponding ethers 159 and

160, in the same manner as for the case of the bromides L47 and 148 above.

Addition of two mole equivalents each of ethanol and 2,6-lutidine directly to

the crude reaction mixture of 742 with N-bromosuccinimide after cooling to

room temperature afforded, after chromatography, the ether 159 and the

4-bromo-5-ethoxypyrrolidinone 160 in yields of 26 and 8Vo respectively, based

onL42. In addition, the 3,4-didehydro-5-ethoxypyrrolidinone 161 was obtained

as a minor product on one occasion.

Br

CNCNCN

t

N t N

o

1s9 160 t6t

The ether 159 was fully characterized, being identified initially by u

singlet resonance at ô 6.02 in its 1H n.m.r. spectrum, attributable to the methine

proton of the cr-carbon. The ethoxy substituent of 159 gave rise to a triplet

resonance at õ 1.25 (l =7.0 Hz), however the resonance arising from the

methylene protons of this substituent was coincident with that arising from

the methylene protons of C5 and as such was not distinct. Additionally, a

*ì


79

molecular ion was observed at mlz 168 in the EI mass spectrum, with a further

fragment ion at mlz 142 corresponding to M+ - CN. All other spectroscopic

properties were in accord with the structure of 159.

The 4-bromo-5-ethoxypyrrolidinone 160 was fully characterized,

exhibiting spectral characteristics and elemental analyses consistent with its

structure. The observation of two ions of equal abundance in the FAB mass

spectrum at mlz 247 and249, that were consistent with M+ + H, confirmed the

presence of bromine in 160. The high field 1H n.m.r. spectrum of 160 was

particularly characteristic. The ethoxy substituent gave rise to a characteristic

triplet resonance at õ 1.29 with/.,0¡. =7.0Ílzfor the methyl protons and two

doublet of quartet resonances at õ 3.77 and 3.76, each with /g"- = 9.4 FIz and

/vic : 7.0H2, due to the two non-equivalent methylene protons. A doublet

resonance at õ 5.15 (l = 7.1H2) was attributable to the methine proton of C5 and

a doublet of doublet of doublets resonance at õ4'25 (l =7'2,2'1',1"7 Hz) was

consistent with the methine proton of C4. Two resonances at õ 2.76 (dd,

I = 18.4,2.1, }lz) and 3.24 (ddd, I = 78.4, 7.2, 0.8 Hz) were consistent with the two

non-equivalent methylene protons of C3. The methylene protons of the

cr-carbon, being non-equivalent, gave rise to resonances at E 4.07 (dd, ¡ = 17.5,

0.8 Hz) and 4.51 (d, I = 77.5H2). With the vicinal coupling constant observed

for the C4 and C5 methine protons being 1,.7H2, a trans geometry was assigned

to the substituents at C4 and C5 of L60, as for the analogous case of L50 above.

The 3,4-didehydropyrrotidinone L61 was identified by characteristic

resonances in its 1H n.m.r. spectrum. A doublet resonance at õ 5.53 with

I = 7.5 ÍIz was attributed to the methine proton of C5 and further resonances at

õ 7.07 (dd, ¡ = 6.1,7.5}12) and 6.30 (d, I = 6.7F{2) were consistent with the

olefinic methine protons of CLand C3 respectively. In addition, the methylene

protons of the cr-carbon were non-equivalent, giving rise to doublet resonances

atõ 4.77 and 4.46 with a geminal coupling constant of 77.5fI2. The presence of

RËSULTS AND DISCUSS/ON - IlI

80

the olefinic moiety in 161 was confirmed by the observation of an infrared

absorption at 1598 cm-1 and a molecular ion at mlz 766 was also observed in

the EI mass spectrum. All other spectroscopic properties were consistent with

the structure of L61.

Formation of the ethers 159 and 160 in the above reaction of the

pyrrolidinone 142 with N-bromosuccinimide and ethanol confirms the

production of the corresponding bromides 157 and 158 in the reaction of 142

with N-bromosuccinimide. The mechanisms for the production of the ethers

1"59 and 160 from the respective bromides L57 and 158 are proposed as being

analogous to those depicted in Schemes 42 and 43, respectively. Formation of

the minor product 16L may be attributed to subsequent elimination of

hydrogen bromide from the 4-bromo-5-ethoxypyrrolidinone 161.

In the reactions of the pyrrolidinones 141 and'1,42 with N-bromo-

succinimide, production of the respective bromides L47 and 157 is consistent

with reaction aia initial hydrogen atom abstraction from the exoryclic carbon

adjacent to nitrogen, to form the corresponding cr-centred intermediate

radicals 162 and 163. Formation of the dibromides 148 and 158 from the

corresponding pyrrolidinones 141 and 142 indicates initial formation of

the S-bromopyrrolidinones 153 and 164, which in turn is consistent with

reaction uia initial hydrogen atom abstraction from the endocyclic carbon

adjacent to nitrogen, to form the corresponding endocyclic intermediate

radicals 165 and L66.


81

Br

ìRCN

N*ì*ì'

R

162 R = COzMe163 R=CN

164 165 R = COzMe166 R = Cl.J

To the extent that the observed ratios of formation of the bromides 147

and L57 to the respective dibromides 148 and 158 from the corresponding

pyrrolidinones 1-4L and L42 are indicative of the relative rates of formation of

the ¡adicals 762 and L63 to 165 and 166 respectively, it follows that formation of

the endocyclic radicals L65 and L66 competes with formation of the

corresponding exocyclic radicals L62 and763. The exocyclic radicals 162 and

163 are stabilized by the combined resonance effects of the electron-donating

amido and electron-withdrawing methoxycarbonyl or cyano substituents,

whereas the endocyclic radicals L65 and L66 are resonance stabilized by the

electron-donating amido group only. However hydrogen atom abstraction

from the endocyclic methylene adjacent to nitrogen in the pyrrolidinones 141

and 142 is favoured by the relief of ring strain due to the release of steric

interactions between the C4 and C5 protons upon formation of the

corresponding radicals 165 ¿n¿ 15,5.80,81 Further, it is possible that formation of

the radicals 165 and.166 is favoured entropically by the inflexibility of the

lactam ring in each of 141 and L42, maintaining the amido group in the planar

orientation required for stabilization of the radicals.Tl

Whereas free radical bromination of the pyrrolidinones 141. and 142

gave both products of reaction at the exocyclic methylene adjacent to nitrogen

and of competing reaction at the endocyclic methylene adjacent to nitrogen,

the azetidinones 72 and 73 investigated in Chapter I, gave products resulting

from reaction at the exocyclic methylene adjacent to nitrogen exclusively.

RESUTTS ,4ND DTSCUSSION - III

82

Thus the relative reactivity of the endocyclic methylenes adjacent to nitrogen

compared to the exocyclic methylenes adjacent to nitrogen is greater for the

pyrrolidinones 141 and 142 than for the corresponding azetidinones 72 and

73. Presumably the endocyclic methylenes adjacent to nitrogen in the

pyrrolidinones 741 and 142 are more reactive towards hydrogen atom

abstraction than those in the corresponding azetidinones 72 and 73 due to the

relative degrees of ring strain in the product radicals 165 - 168 resulting from

hydrogen atom abstraction from the pyrrolidinones 141 and 142 and the

azetidinones 72 and 73 respectively. The change in hybridization from sp3 to

sp2 accompanying radical formation will engender greater strain in the

endocyclic azetidinone radicals 167 and L68 than in the corresponding

pyrrolidinone radicals 165 and 166.

L67 R = COzEt168 R=CN

a

R

RESULTS ,AND DISCUSSION - III

83

RESULTS AND DrscussroN - IV

E ndo cyclic Functio nalization and EIab orationof y-Lactams

Preparation of the 2-pyrrolidinon es 17L and 172

The 2-pyrrolidinones 769 - 172 were required for the investigation

described in this chapter, of the endocyclic functionalization of y-lactams.

1,3,3-Trimethyl-2-oxopyrrolidine (169), prepared according to the method of

Gassman and Fox,115 was the generous donation of Ms. C. Ward116 and

1-methyl-2-oxopyrrolidine (770), a common HPLC solvent, was commercially

¿rr¿i1¿61s.117 The syntheses of the pyrrolidinones 17L and 772 are detailed

below.

Ntat,

R

RN

o771

169 R = CHs170 R=H

172

Following a method reported by Mazzocchi and co-workers118 for the

synthesis of 1-(2-methylbutyl)-2-oxopyrrolidine, 1-(3-butenyl)-2-oxopyrrolidine

(l7L) was prepared aiø N-alkylation of 2-pyrrolidinone (773) as shown in

Scheme 45. Thus, treatment of Z-pyrcolidinone (773) with a slight excess of

sodium hydride in xylene at 110'C for one hour followed by treatment of the

resulting salt with excess 4-bromo-1-butene, whilst heating at reflux overnight,

RESULTS ,AND DISCUSSION - IY

u

1. NaHNH N

2.Bré173 L7L

Scheme 45

afforded the N-butenylpyrrolidinone l7l in'1.47o yíeld after distillation. The

product 171 thus obtained exhibited spectral characteristics consistent with its

structure. In the lH n.m.r. spectrum of L7L, the methylene protons of the

exocyclic and endocylic carbons adjacent to nitrogen gave rise to triplet

resonances at õ 3.36 (l =7.2H2) and 3.39 (l = 7.']-. FIz) respectively, with the

olefinic protons of the butenyl moiety giving rise to characteristic resonances at

õ 5.07 (2H) and 5.77 (7H). The amide carbon of 171gave rise to a characteristic

resonance at õ 774.64 in the 13C n.m.r. spectrum, with resonances at õ 1,34.84

and L16.53 being due to the two alkenyl carbons. In addition, a molecular ion

was observed at mlz 739 in the EI mass spectrum.

1-(p-Methoxyphenyl)-2-oxopyrrolidine'/..72 was synthesized in an

analogous manner to the pyrrolidinones 14L and 1.42 prepared in Chapter III,

aia cyclízation of the corresponding 4-chlorobutyramide L75 as depicted in

Scheme 46. Thus, 4-chlorobutyryl chloride (146) was treated with an excess of

freshly recrystallized p-anisidine (1,74) in dichloromethane, affording the

chlorobutyramide 1,75 in 547o yield. The butyramide 175 thus obtained was

fully characterized, exhibiting spectral properties and elemental analyses

consistent with its structure. In particular, the amide carbonyl of 775 gave rise

to a characteristic infrared absorption at 7662 cm-1 and further evidence for the

production of the amide in 175 was given by the observation of a resonance at

ô 169.84 in the 13C n.m.r. spectrum. The butyramide 175 was added slowly in

dilute solution to a stirred suspension of powdered potassium hydroxide and

RESULTS AND DISCUSSION - IY

85

tetra-n-butylammonium chloride in dichloromethane, to give the

pyrrolidinone 172 in 637o yield after chromatography and subsequent

recrystallization. The pyrrolidinone L72 was fully characterized, exhibiting

satisfactory spectroscopic properties and elemental analyses. The lactam

carbonyl in L72 gave rise to a characteristic infrared absorption at1,682 cm-l,

and the amide carbon gave rise to a resonance at õ 173.90 in the 13C n.m.r.

spectrum.

+ HzN ocH3

L46 L74

KOH / BuaNCl

NH

L75 \72

Scheme 46

ocH3

RESULTS AND DTSCUSSION - IV

86

Functionalization of the 2-pyrcolidinones L69 - L72

The investigation described in Chapter trI of this thesis established that

substitution at the endocyclic carbon adjacent to nitrogen competes with

substitution at the corresponding exocyclic carbon in the free radical

bromination of pyrrolidinones bearing activating substituents at the exocyclic

carbon adjacent to nitrogen. The study described in this chapter was aimed at

assessment of the separate contributions of the brominating reagent and

exocyclic activating substituent to the regioselectivity of reaction, based on an

investigation of the regioselectivity of free radical bromination of

pyrrolidinones not bearing activating substituents at the exocyclic carbon

adjacent to nitrogen.

The trimethylpyrrolidinone 169 was chosen for initial investigation as it

was reasoned that the methyl substituents at C3 would block this position to

possible side reactions leading to formation of unidentifiable decomposition

products. Free radical bromination of 769 was investigated by treaûnent with

two mole equivalents of N-bromosuccinimide in carbon tetrachloride at reflux

under nitrogen for 10 minutes, with reaction initiated by irradiation with a

300 W mercury lamp. The crude reaction mixture thus obtained was not

analysed directly but the products of reaction were converted to stable

derivatives for isolation and characterization. Accordingly, the crude reaction

mixture of the pyrrolidinone L69 with N-bromosuccinimide was treated with

two mole equivalents of ethanol and one mole equivalent of 2,6-Iutidine and

afforded, after chromatography, the 4-bromo-5-ethoxypyrrolidinone 176 and

the 4,4-dibromo-5-ethoxypyrrolidinone 777 (Scheme 47) in yields of 9 and'1.47o

respectively, based on L69.


87

H¡C

t69

1. NBS / hv2. EIOH / 2,6lutidine

Br Br

OEt

HsC HeCtc",

176 \77

Scheme 47

The 4-bromo-5-ethoxypyrrolidinone 176 was identified on the basis of

characteristic resonances in its 1H n.m.r. spectrum. Two doublet resonances at

õ 3.98 and 4.89 each with -lvic = 3.8Í12 were attributable to the methine protons

of C4 and C5 respectively. The presence of the ethoxy substituent in L76 was

confirmed by the observation of a characteristic triplet resonance at õ'1,.29

(l = 7 .0 ÍIz) for the methyl protons, with doublet of quartets resonance s at õ 3 .7 4

and 3.80, each with /t"^ = 9.4FIz and /vic = 7.0H2, being due to the two

methylene protons. The EI mass spectrum of L76 exhibited two molecular ions

of equal abundance at mfz249 and 251, confirming the presence of bromine in

the molecule. In addition, other spectral characteristics were in accord with the

structure of L76. Whilst the vicinal coupling constant observed for the C4 and

C5 methine protons of 176 was not diagnostic, it was nevertheless consistent

with the assignment of a trans geometry for the substituents at C4 and C5,

made on the basis of mechanistic considerations presented below.

N'ct,

Br-i

+Ntct,

RESULTS .AND D/SCUSS/ON - /Y

88

The 4,4-dibromo-5-ethoxypyrrolidinone 177 was identified on the basis

of mass spectrometric and 1H n.m.r. spectroscopic evidence. Three molecular

ions observed at mlz 327, 329 and 331 in the ratio of 1.:2:7 in its EI mass

spectrum confirmed the presence of two bromine atoms in 177. The 1H n.m.r.

spectrum exhibited characteristic triplet and two doublet of quartets resonances

due to the ethoxy substituent, with the three methyl substituents of 777 each

giving rise to distinct singlet resonances. A singlet resonance at ô 5.02,

attributable to the methine proton of C5 was the only other signal observed in

the 1H n.m.r. spectrum. Other spectroscopic properties were consistent with

the structure of 177.

Production of the 4-bromo-5-ethoxypyrrolidinone '1,7 6 and the

4,4-dibromo-5-ethoxypyrrolidinone 777 in the above reaction of the

pyrrolidinone 169 indicates formation of the corresponding dibromide 179 and

tribromide 182 respectively, in the reaction of 169 with N-bromosuccinimide.

The mechanism of formation of the ether 176 frorn the pyrrolidinone L69, ttia

the dibromide 179,is proposed as analogous to that of the formation of the

4-bromo-5-ethoxypyrrolidinone 150, from 14L, depicted in Scheme 43 of

Chapter trI. Thus, initial bromination of 169 at the endocyclic carbon adjacent

to nitrogen affords the intermediate S-bromopyrrolidinone L78 which

undergoes subsequent reaction during treatment with N-bromosuccinimide,

as described'for the analogous prod.uction of 148 above, to give tlne trans-

dibromide L79. The N-acyliminium species 180, in equilibrium with the

dibromide 179 is then attacked by ethanol from the least hindered face to give

the trans-4-bromo-5-ethoxypyrrolidinone 176 (Scheme 48). Formation of the

4,4-dibromo-5-ethoxypyrrolidinone 177 may be attributed to subsequent

reaction of the dibromide L79 during treatment with N-bromosuccinimide as

shown in Scheme 48. Thus elimination of hydrogen bromide from L79 pia


89

BriBr BrH¡C

o

H¡C ......+€ HsC

N Ntct, tct,

L78 L79

Br BrBr

- HBr 'T:ç EtOHtr lagu

Br- Et

HsC

tct, tat,o

tct,

L80 176

Btz

Br Br Br Br B Br

Br HsC Br- HeC

+ H¡CNN tat, tct,tct,

L82 1.83

Scheme 48

the iminium species 180 gives L81,, which upon reaction with molecular

bromine present in the reaction mixture, affords the tribromide 182. Reaction

of the N-acyliminium species L83, in equilibrium with L82, with ethanol then

affords the ether 177.

N

L8L

o

tHsC

H¡C

177

RESULTS .AND DISCUSSION - IY

90

No products attributable to bromination at the exocyclic carbon adjacent

to nitrogen were observed in the above reaction of the pyrrolidinone L69, the

products 176 and L77 obtained being due to initial bromination at the

endocyclic carbon adjacent to nitrogen. Given that this result indicates that

exocyclic bromination is not a major reaction pathway of the pyrrolidinone

169, it was considered to test the generality of the bromination procedure for

endocyclic functionalization of pyrrolidinones not bearing blocking

substituents at C3. The pyrrolidinone L70, not bearing substituents at C3, was

readily availablellT and was therefore next chosen for investigation.

l-Methyl-2-oxopyrrolidine (170)'t17 was treated with two mole

equivalents of N-bromosuccinimide in carbon tetrachloride at reflux under

nitrogen for 10 minutes, with reaction initiated by irradiation with a 300 W

mercury lamp. 1H n.m.r. spectroscopic analysis of the crude reaction mixture,

after filtration and evaporation of the solvent, revealed a mixture of products

and gave evidence for the production of a major amount of the trøns-

dibromide 184 and the tribromide 185 in an approximately 5:2 ratio (Scheme

49). The methylene protons of C5 in 170 resonate as a triplet at õ 3.47

Br Br Br

3

Br

SNB____+ +hv

'at,L70

Scheme 49

U = 7.7 FIz), with the methylene protons of C4 giving rise to a triplet of triplets

resonance at õ 2.04 (l - 7.7, 8.7FJ2), whereas the protons of the methyl

N'at,

N

L85L84


97

substituent give rise to a singlet resonance at ô 2.84. In the 1H n.m.r. spectrum

of the crude product mixture obtained from the bromination of 170, an

observed singlet resonance at ð 6.12 was attributable to the methine proton of

C5 in t}rre trans-dibromide 184 with the observation of a doublet resonance of

equal peak area at õ 4.87 being consistent with the methine proton of C4. A

singlet resonance of three times the peak area at õ 2.90 was then due to the

methyl substituent of 184. Evidence for the production of the tribromide 185

in the same reaction mixture was given by the observation of a singlet

resonance at õ 6.34 indicative of the methine proton of C5 with two doublet

resonances at ô 3.39 (l = 77.5 FIz) and 3.47 (l = 77.5 fU) being consistent with the

non-equivalent methylene protons of C3. In addition, a singlet resonance

observed at ô 2.95 was consistent with the methyl substituent of 185.

The bromides 184 and 185 were insufficiently stable for isolation and

characterization and so were converted to the corresponding ethers 186 and

187, through the addition of two mole equivalents of ethanol and one mole

equivalent of 2,6-lutidine directly to the cooled crude reaction mixture of L70

with two mole equivalents of N-bromosuccinimide. Chromatography of

the crude product mixture thus obtained afforded the 4-bromo-S-

ethoxypyrrolidinone 186 and the 4,4-dibromo-5-ethoxypyrrolidinone 187 in

yields of 9 and 177o respectively, based on 170.

Br BrBr

t Et

N Ntat.

187186

tcH3

RESULTS ,AND D/SCUSSION - IV

92

Identification of the ether 186 was made initially on the basis of lH

n.m.r. spectral characteristics that were similar to those of the 4-bromo-5-

ethoxypyrrolidinones 1-50 and 160 of Chapter III, above. A doublet resonance at

õ 4.97 (l : 0.9 FIz) was attributable to the methine proton of C5 and a doublet of

doublet of doublets resonance at ô 4.24 (l = 6.8,'1.4, 0.9 FIz) was then consistent

with the methine proton of C4. In addition, two doublet of doublets

resonances at õ 2.65 (] = 17.9,1,.48fò and 3.21 (l = 17.9, 6.8Hò were attributable

to -the non-equivalent methylene protons of C3. The ethoxy substituent oftc661# Eave rise to a characteristic triplet resonance at õ L.26 (l =7.0 Hz) and two

doublet of quartets resonances at õ 3.63 and 3.68, each with .Igem = 9.2IJ2 and

,Ivic = 7.0H2. The presence of bromine in 186 was confirmed by the observation

of two molecular ions of equal abundance at mfz 221 and223 in the EI mass

spectrum. Other spectral properties were in accord with the structure of 186.

On the basis of the vicinal coupling constant observed for the C4 and C5

methine protons being 0.9 ÍIz a trans geometry was assigned to the substituents

at C4 and C5 of L86.

The 4,4-dibromo-5-ethoxypyrrolidinone 787 exhibited characteristic lH

n.m.r. spectroscopic properties enabling its identification. A singlet resonance

at ô 5.02 was attributable to the methine proton of C5 with a singlet resonance

of three times the peak area at ô 2.93 corresponding to the methyl substituent.

Two doublet resonances observed at ô 3.36 urrA a.St each with /g"- = 77.6]H2

were indicative of the methylene protons of C3 and the ethoxy substituent of

187 gave rise to a characteristic triplet resonance at õ 1.32 and two doublet of

quartets resonances at ô 3.80 and 4.07. Although the ether 187 w a s

insufficiently stable for elemental analyses, three molecular ions at mf z 299,

30L and 303 were observed in the ratio of. 7:2:7 in the EI mass spectrum,

confirming the presence of two bromine atoms in the molecule. In addition,

other spectral properties were consistent with the structure of 1.87.

RESU¿TS .AND DISCUSSION - IV

93

Production of the 4-bromo-5-ethoxypyrrolidinone 186 and the

4,4-dlbromo-5-ethoxypyrrolidinone L87 above, confirms formation of the

dibromide 184 and the tribromide L85 respectively, in the reaction of the

pyrrolidinone 170 withN-bromosuccinimide, consistent with subsequent

reaction of the initially formed S-bromopyrrolidinone 188. The mechanisms

for the formation of 186 and 187 from 184 and 185 respectively, are proposed as

analogous to those of the formation of the ethers L76 and 177 from the

pyrrolidinone 169, depicted in Scheme 48 above.

Ntat,

188

The yields of the ethers 186 and L87 from the pyrrolidinone 170 quoted

above were not optimized, but given the ready availability of the starting

material L70, they nevertheless serve to illustrate the accessibility of

functionalized pyrrolidinones uía t)i.e free radical bromination procedure.

From a consideration of the synthetic potential of this procedure for endocyclic

difunctionalization of pyrrolidinones it was sought to optimize production of

the 4-bromo-5-ethoxypyrrolidinone 186 with respect to that of the 4,4-dibromo-

S-ethoxypyrrolidinone 187. In an initial attempt to limit subsequent reaction

of the dibromide 184 leading to the production of the tribromide 185, the

pyrrolidinone L7 0 was treated with only one mole equivalent of

N-bromosuccinimide and subsequently with ethanol and 2,6-lutidine, as

above. Flowever, upon chromatography of the product mixture thus obtained,

the 4-bromo-5-ethoxypyrrolidinone L86 and the 4,4-dibromo-5-ethoxy-

Br

RESULTS ,4ND DISCUSSION - IY

pyrrolidinone 187 were obtained in yields of 2 and 6Vo respectively, based on

170. In addition, the 3,4-didehydropyrrolidinone 189 was obtained in 27o yield

and a minor amount of the alcohol 190 was also obtained.

94

Br Br

t

189 190

The didehydropyrrolidinone 189 was identified by characteristic

resonances in its 1H n.m.r. spectrum. In addition to characteristic resonances

arising from the ethoxy substituent, a singlet resonance observed at õ 5.21 was

attributable to the methine proton of C5, with a singlet resonance at õ 6.42 then

being consistent with the olefinic methine proton of C3. The presence of the

olefinic moiety in 189 was confirmed by an infrared absorption at 1638 cm-1

and the observation of two molecular ions of equal abundance at mfz 219 and

22'1, in the EI mass spectrum confirmed the presence of bromine in the

molecule.

NN tat,'at,


were similar to those of the 4,4-dibromo-5-ethoxypyrrolidinone 1-87. A singlet

resonance observed at ô 5.29 was attributable to the methine proton of C5 and a

broad resonance at ô 4.69 with equal peak area was consistent with the hydroxyl

proton of 190. Further evidence of the hydroxyl group of 190 was given by a

broad infrared absorption at 3380 cm-1.

RESULTS AND D/SCUSSION - IV

95

Formation of the didehydropyrrolidinone L89 above may be attributed

to a subsequent elimination of hydrogen bromide from the 4,4-dibromo-5-

ethoxypyrrolidinone 787 during chromatography and the alcohol 190

presumably results from the reaction of the tribromide 185 with adventitious

water.

As for the pyrrolidinone 169, no products attributable to brornination at

the exocyclic carbon adjacent to nitrogen were observed in the above reactions

of the pyrrolidinone 170, the products obtained each resulting from initial

bromination at the endocyclic methylene adjacent to nitrogen. In the case of

the reactions of each of the pyrrolidinones 169 and 170, the 4,4-dibromo-5-

ethoxypyrrolidinones L77 and 187 were obtained in greater yields than those of

the respective 4-bromo-5-ethoxypyrrolidinones L76 and L86. This presumably

indicates the facility with which the initially formed S-bromopyrrolidinones

L78 and 188 undergo subsequent ionic reaction during bromination to give the

corresponding tribromides 182 and 185.

It was reasoned that in order to ensure a high rate of formation of the

dibromopyrrolidinone 184 with respect to the tribromopyrrolidinone 185 from

the pyrrolidinone 170, an increase in the efficiency of hydrogen atom

abstraction leading to the initial production of the S-bromopyrrolidinone 188

was necessitated. Free radical bromination reactions with N-bromo-

succinimide are known to be accelerated by chemical intiatorsll9 and to this

extent bromination of the pyrrolidinone 170 was investigated as before, but in

the presence of a catalytic amount of AIBN. Coincidently, conversion of the

products of bron.ination of 170 in this manner, to their corresponding

phenylthioethers through reaction with thiophenol was investigated. The

preparation of such phenythioethers was considered attractive from a synthetic

standpoint as S-phenylthiopyrrolidinones have previously been shown to

RËSULTS AND D,ISCUSSION - IV

96

provide stable precursors for site specific generation of o-acylamino radicals in

the synthesis of pyrrolizidine alkaloi¿s.36-38

The pyrrotidinone 770 was treated with two mole equivalents of

N-bromosuccinimide in the presence of a catalytic amount of AIBN in carbon

tetrachloride at reflux under nitrogen for 6 minutes, whilst irradiating with a

300 W mercury lamp. The cooled crude reaction mixture was subsequently

treated with two mole equivalents each of thiophenol and 2,6-lutidine.

Chromatography of the product mixture thus obtained afforded the 4-bromo-5-

phenylthiopyrrolidinone L9L in 25% yield, based on 170. In addition the

exocyclic substitution product 192 was obtained in 3% yield.

SPh

N SPh-.rí79L

The 4-bromo-5-phenylthiopyrrolidinone 191 was identifiable on the

basis of 1H n.m.r spectral characteristics that were similar to those of its ethoxy

analogue 186' A doublet resonance observed at õ 4'98 (l = 7'1Hz) was

attributable to the methine proton of C5, with a doublet of doublet of doublets

resonance at ô 4.53 (] = 6.5, 1,.2, 1,.7 Hz) being consistent with the methine

proton of C4. The presence of the phenylthio substituent in 191 was confirmed

by the observation of a multiplet resonance centred atõ7.37. Two molecular

ions of equal abundance in the EI mass spectrum at mf z 285 and 287 confirmed

the presence of bromine in 1,9L, and in addition other spectroscopic properties

Br

'at,L92


97

were in accord with the structure. As for the ether 186 above, a trans-geometry

was assigned to the substituents at C4 and C5 of L91,, on the basis of the

magnitude of the observed vicinal coupling constant for C4 and C5 methine

protons.

The exoryclic substitution product 192 was identifiable on the basis of its

1H n.m.r. spectral characteristics. The protons of the methyl substituent of 170

give rise to a singlet resonance at õ 2.85. A singlet resonance observed at õ 4J7

in the lH n.m.r. spectrum of 792 was then attributable to the methylene

protons of the phenylthiomethyl substituent. The presence of the phenylthio

moiety in 192 was confirmed by the observation of multiplet resonances

centred at õ 7.27 and ô 7.44 of three and two protons integration respectively.

The EI mass spectrum of 792 gave rise to a molecular ion at mf z 207 and in

addition the compound exhibited consistent elemental analyses confirming its

structure.

Formation of the 4-bromo-5-phenylthiopyrrolidinone 19L in the above

reaction of the pyrrolidinone 170 with N-bromosuccinimide and thiophenol is

consistent with reaction uia the dibromide L84 as for the analogous reaction to

give the ether 186 above, whereas formation of the exocyclic substitution

product 192 provides evidence for the production of the exocyclic bromide

193 in the reaction of 170 with N-bromosuccinimide. The N-acyliminium

species 194, in equilibrium with the exocyclic bromide 193, is presumably

attacked at the electrophilic imine carbon, thus affording the thioether L92

(Scheme 50).

RESULTS AND DISCUSS/ON - IY

98

Br:

uå

NBS / hv

N .........'................-

PhSH.*

- HBr

Br

NBS / hvBr

+

N

170

tcH,N'cH,

N

184

'cH,

791

NBrPhSH

- HBr N SPhCHzo

\CHz CHz

193 \94

Scheme 50

Formation of the exocyclic bromide 193 from the pyrrolidinone 170 is

consistent with reaction oíø initial hydrogen atom abstraction from the

exocyclic carbon adjacent to nitrogen to form the corresponding primary

exocyclic radical 195, whereas formation of the dibromide 184 indicates

initial formation of the S-bromopyrrolidinone L80, consistent with reaction aiø

initial hydrogen atom abstraction from the endocyclic carbon adjacent to

nitrogen to form the corresponding endocyclic radical 196. To the extent that

the observed ratio of formation of the thioethers 791 and L92 from the

pyrrolidinone 170 reflects the relative rate of formation of the radicals 195 and

196, it follows that the endocyclic methylene adjacent to nitrogen in 170 is

more reactive towards free radical bromination than is the exocyclic methyl

substituent on nitrogen. In comparison with the results of Chapter III, it may

be concluded that in the absence of an activating substituent at the exocyclic

carbon adjacent to nitrogen, free radical bromination at the endocyclic carbon

L92

RESULTS AND DTSCUSS/ON - ,rY

99

adjacent to nitrogen in 2-pyrrolidinones predominates over that at the

corresponding exocyclic carbon.

a

NNtéH2

ta",

195 L96

Production of the 4-bromo-5-phenylthiopyrrolidinone 191 from the

pyrrolidinone 170 illustrates methodology for the synthesis of 4,S-disubstituted

pyrrolidinones which may be utilized as cr-acylamino radical precursors in

subsequent reactions. On this basis it was considered an attractive proposition

to investigate application of the endocyclic functionalization procedure to the

synthesis of bicyclic pyrrolidinones aia functionalization of a pyrrolidinone

bearing a substituent on nitrogen suitable for further elaboration. To this end,

reaction of the N-butenylpyrrolidinone 171 with N-bromosuccinimide was

investigated.

1-(3-Butenyl)-2-oxopyrrolidine (771) was treated with two mole

equivalents of N-bromosuccinimide in the presence of a catalytic amount of

AIBN in a 4:1 mixture of carbon tetrachloride and dichloromethane at reflux

under nitrogen, whilst irradiating with a 300 W mercury lamp for 1,0 minutes.

Chromatography of the crude product mixture, following removal of by-

product succinimide aia a brine wash, afforded three products L97,L98 and

199, in yields of 1.0, 21 and 57o respectively, based on 17L. The structural

elucidation of each of the bromides 197 - 199 is presented below.

RESULTS AND D^TSCUSSION - /Y

100

Br

N

Br

197

NBr Br

Br Br

199

Br

Br

N

OH

Both the FAB and EI mass spectra of L97 exhibited five molecular ions

at mlz 453, 455, 457, 459 and 461 in the ratio of 1,:4:6;4;7, indicating the presence

of four bromine atoms in the molecule. From this mass spectral evidence the

molecular formula of L97 was deduced as CaHrrNOBr¿. Whilst the

tetrabromide 197 was insufficiently stable to afford elemental analyses within

the usual limits of acceptability, the analyses obtained were nonetheless

supportive of the molecular formula determined on the basis of the mass

spectral evidence. The infrared spectrum of the tetrabromide L97 exhibited a

strong absorption at 77'l,4cm-1 indicating retention of the lactam carbonyl

moiety, whereas the absence of absorptions in the region of 1620 - 1680 cm-1

indicated the absence of an alkenyl moiåty in the molecule. The 13C Dnpt

n.m.r. spectrum of L97 indicated that the compound possessed five methylene

carbons, one methine carbon and one quaternary carbon in addition to that of

the amide, which gave rise to a characteristic resonance at õ 1,67.86. In the 1H

n.m.r. spectrum of 197 a doublet of doublets resonance observed at õ 3.06

(l = 6.0,5.8 Hz) was attributable to the two methylene protons of C3, with two

doublet of doublet of doublets resonances at õ 3.39 (l = 9.9,6.0, 5.8 IJz) and 3.44

(l = 9.9,6.0, 5.8 Hz) being consistent with the two non-equivalent methylene

Br

198

RESULTS AND DISCUSSION - IV

.r{-:,...i '.'

!':ii' "ì'::,''

1''\ ror*' l'--

"'' -':r -:: . , -

protons of C4. The methylene protons of C4' gave rise to two doublet of

doublets resonances at õ 3.62 (l = 10.5, 9.6H2) and 3.87 (l = 70.5,4.2Í12), and the

methine proton of C3' gave rise to a resonance at ô 4.10 (dddd, I = 9.6,9.6, 4.2,

3.1,}J2). Homonuclear decoupling of each of the resonances of the 1H n.m.r.

spectrum of 'I',97 confirmed the presence of two spin systems within the

molecule, thus confirming the arrangement of the one methine and

five methylene carbons within the partial structures -CH2CH2- and

-CHzCHzCHCHz- (Fígure 7). The non-equivalence of the methylene

protons of both CL' and C2' manifested by the observation of distinct

I{',ßBr

BrH I{* H I{',É

N1 2 4 Br

H I{* H Br

197

Figure 7. Numbering of 1-(3,4dibromobutyl)-5,5-dibromo-2-oxopyrrolidine (197).

resonances attributable to each of these protons, and in addition that similarly

exhibited by the methylene protons of C4', points to a particular

conformational'preference of the dibromobutyl moiety of 797. 1FI - 13ç

Heteronuclear shift correlation n.m.r. spectroscopic analysis of 197 was

performed and enabled the unambiguous assignment of the resonances of the

13C n.m.r. spectrum.

Compound 198 was identifiable on the basis of a comparison of its

spectral characteristics with those exhibited by the tetrabromide 197. Both the

EI and FAB mass spectra of 198 exhibited four moleculer ions at mlz 397,393,

45


1.02

395, and 397 in the ratio of 1:3:3:1, indicating the presence of three bromine

atoms in the molecule and being consistent with a molecular formula of

CgHl2NOzBrg. The presence of a hydroxyl substituent in 198 was indicated by

the observation of four ions at mlz 373,375,377 and 379, corresponding to the

fragmentation M+ -HzO. As for L97, elemental analyses obtained for 198

were supportive of the molecular formula deduced from the mass spectral

evidence. The retention of the lactam amide in 198 was indicated by the

observation of a characteristic infrared absorption at 1706 cm-l and a broad

absorption observed at 3440 cm-l was further evidence of the presence of a

hydroxyl substituent in the molecule. The 13C DEPT n.m.r. spectrum of 198

revealed the same pattern of carbon substitution as that of L97, namely

containing five methylene, one methine and two quaternary carbons. The

chemical shifts of each of the carbons of 198 varied little to those exhibited by

197, with the exception of the single methine carbon of 198 giving rise to a

resonance at õ 67.77, consistent with the presence of the hydroxyl substituent at

this carbon. The structure of L98 was therefore deduced as that depicted

above. Homonuclear decoupling of resonances in the 1H n.m.r. spectrum of

198 confirmed the presence of two spin systems within the molecule,

attributable to the -CHzCH2- and -CHzCHzCHCHz- substructures. The 1H

n.m.r. spectrum of the alcohol 198 bore close similarity to that of the

tetrabromide L97, with the methine proton of C3' giving rise to a resonance at

õ3.77 (dddd, I = 9.8,5.8, 4.g,3.2ff¡,) and a broad resonance of equal peak area at

õ 3.42 being attributable to the hydroxyl proton. As for L97, the methylene

protons of CL', C2' and C4' of the alcohol L98 were each non-equivalent, giving

rise to distinct 1H n.m.r. resonances, presumably indicating the adoption of a

particular conformation by the 4-bromo-3-hydroxybutyl substituent on

nitrogen.


103

The dibromide 199 was identified on the basis of characteristic

resonances in its 1H n.m.r. spectrum. The presence of the unsubstituted

pyrrolidinone ring in 199 was indicated by the observation of resonances at

õ2.05 (tt,¡ =8.3,7.0ÍIz),2.40(t,l =83Hz,) and 3.43 (t,l =7.0F{z.), attributable to

the methylene protons of C4, C3 and C5 respectively. In addition, resonances

were observed that were attributable to the dibromobutyl moiety of L99,by

comparison with the corresponding resonances of the 1H n.m.r. spectrum of

the tetrabromide 197. Similarly, the 13C n.m.r. spectrum of L99 exhibited

resonances consistent with its structure. Further confirmation of the structure

of 199 was given by the observation of three ions at mlz 298,300 and 302 in the

EI mass spectrum in the ratio of 1.:2:L, each corresponding to M+ + H.

Formation of the tetrabromide '1,97 in the above reaction of the

pyrrolidinone L7L is consistent with ionic bromination of the butenyl

sidechain by molecular bromine concomitant with free radical bromination at

the endocyclic carbon adjacent to nitrogen, as outlined in Scheme 5L.

Whereas the reactions of the pyrrolidinones T4L,L42,169 and L70 with

N-bromosuccinimide, described above, in each case gave products resulting

from molecular bromine addition to the corresponding 4,5-didehydro-

pyrrolidinones, it is peculiar in this instance that products of the analogous

reaction of 17L are not observed. It is presumable that the didehydro-

pyrrolidinone 203 formed, for example, by hydrogen bromide elimination

from the bromide 200 reacts by hydrogen bromide addition to give 203,

rather than by molecular bromine addition to give the dibromide 204

(Scheme 52).

Formation of the alcohol L98 may be explained by the same rationale as

for that of '1.97 with the exception that adventitious water presumably

intervenes in the ionic bromination of the butenyl moiety of L7L.


704

Brz

Brz

Brz

Scheme 57

203

fr Br

Br\71

Br

NBS

Br

NBS

L99

NBS

Br

N

Br201

NBS

BrBr

N

L97

204

Br

200

Br

NBr

Br202

BrBr Br

- HBr200

o

Scheme 52

RESULTS i4ND DTSCUSSION - IV

105

Production of the dibromide 199 then simply results from ionic bromination

of the butenyl moiety of 77T as described in Scheme 51 above, and points to

the facility with which this process occurs.

The N-(p-methoxyphenyl)pyrrolidinone L72 was next chosen for study

as it was envisaged that endoryclic functionalization of a pyrrolidinone bearing

a removable protecting group on nitrogen would alternatively afford the

possibility of synthesis of bicyclic pyrrolidinones, through the subsequent

incorporation of a substituent on nitrogen suitable for further elaboration.

Removal of a para-methoxyphenyl substituent from nitrogen is achieved by

oxidative dearylation with ceric ammonium nitratel2O and this has been

reported as a general method for the preparation of N-unsubstituted

azetidinones.l2l Alternatively, a p-methoxyphenyl substituent may be cleaved

from nitrogen of azetidinones electrochemically, oia anodic oxidatio¡.l22 11i5

expected that these methods may similarly apply to the N-deprotection of

N-(p-methoxyphenyl)-substituted pyrrolidinones.

1-(p-Methoxyphenyl)-2-oxopyrrolidine (L72) was treated with two mole

equivalents of N-bromosuccinimide in the presence of a catalytic amount of

AIBN in an 8:L mixture of carbon tetrachloride and dichloromethane, heated

at reflux under nitrogen for 10 minutes, whilst irradiating with a 300 W

mercury lamp. The cooled crude reaction mixture thus obtained was treated

with two mole equivalents each of ethanol and 2,6-lutidine and afforded a

complex mixture of products containing a substantial amount of the unreacted

starting material 1^42, as judged by thin layer chromatographic analysis. No

attempt was made to isolate individual components of this product mixture.

The complex mixture obtained above was rationalized as due to

decomposition of the products of bromination of 172 during treatment with

N-bromosuccinimide. Accordingly, optimal yields of the products of reaction


706

of 172 were obtained when the pyrrolidinone L72 was treated with a limited

amount of N-bromosuccinimide over a shorter reaction time than above.

1-(p-Methoxyphenyl)-2-oxopyrrolidine (L72) was treated with a slight molar

excess of N-bromosuccinimide in the presence of a catalytic amount of AIBN

in an 8:L mixture of carbon tetrachloride and dichloromethane at reflux under

nitrogen whilst irradiating as above, but for only 5 minutes. Subsequent

treatment of the cooled crude reaction mixture with two mole equivalents

each of ethanol and 2,6-lutidine afforded, after chromatography, the desired 4-

bromo-S-ethoxypyrrolidinone 205 in 38Vo yield, based on 772. In addition, the

alcohol 206 and the S-succinimidopyrrolidinone 207 were obtained in yields of

L4 and 7Vo respectively, and 33Vo of the starting material 172 was recovered

unreacted.

o

Et N

N N N

o3

206

The 4-bromo-5-ethoxypyrrolidinone 205 was identifiable on the basis of

lH n.m.r. spectral characteristics that bore close similarity to those of the ether

186. A doublet resonance at õ 5.27 (l = 0.9 FIz) was consistent with the methine

proton of C5, with a doublet of doublet of doublets resonance at õ 4.35 (l = 6.4,

7.0,09H2) being attributable to the methine proton oÍ C4. The ethoxy

substituent of 205 gave rise to characteristic triplet and two doublet of quartets

resonances, at ô 1.19, 3.54 and 3.59, respectively. The EI mass spectrum

exhibited two molecular ions of equal abundance at mlz 313 and 315,

Br'-

Br

o

ocH3

207205

RESULTS AND DTSCUSSION - IY

707

confirming the presence of bromine in 205, and other spectroscopic properties

were in accord with this structure. The substituents at C4 and C5 of 205 were

assigned a trans geometry on the basis of the vicinal coupling constant being

0.9 Hz for the methine protons of C4 and C5.


were similar to those of the 4-bromo-5-ethoxypyrrolidinone 205. A doublet

resonance at ô 5.5L with / = 7.2FIz was attributable to the methine proton of C5

and a broad resonance at õ 1,.77 with equal peak area was then consistent with

the hydroxyl proton of 206. Further evidence of the hydroxyl group of 206 was

given by the observation of a broad infrared absorption at 3400 cm-1. Two

molecular ions of equal abundance at mfz 285 and 287 were observed in the EI

mass spectrum of 206 and other spectral characteristics were consistent with

the structure. As for 205, the C4 and C5 substituents of 206 were assigned a

trans geometry on the basis of the magnitude of the vicinal coupling constant

of the C4 and C5 methine protons.

The S-succinimidopyrrolidinone 207 was identified on the basis of

characteristic resonances in its 1H n.m.r. spectrum. A doublet of doublets

resonance at ô 6.20 (l = 8.9,2.2}lz-) and a singlet resonance at õ 2.55 in the ratio

of 1.:4, were consistent with the methine proton of C5 and the methylene

protons of the succinimide ring, respectively. Further evidence of the

succinimido substituent of 207 was given by the obiervation of an infrared

absorption at 1780 cm-1, characteristic of the imide carbonyl system, in addition

to that at 1712 cm-1 due to the lactam carbonyl. A molecular ion was observed

at mlz 288 in the EI mass spectrum and other spectroscopic properties were in

accord with the structure of.207.

Formation of the ether 205 in the above reaction of t72 is attributed to

initial bromination to give the S-bromopyrrolidinone 208 (Scheme 53>,


108

which undergoes subsequent reaction to give the dibromide 2L0 as postulated

for the analogous production of L49 from L41 in Chapter III, above. Reaction of

ethanol with the dibromide 270 then affords the ether 205. Similar reaction

R_ ocH3

NBS / hv

oBr Br o N

N- HBr

208 209 207

N..R

172

NH

RN

R+N..

R

Brz

- HBr

BrBrBr

NN

Et r

3

HHzo

RR

205 206

of adventitious water with the dibromide 2L0 accounts for production of the

alcohol 206. Formation of the minor product then presumably results from

reaction of the iminium species 219, in equilibrium with the S-bromo-


709

pyrrolidinone 208, with succinimide, present in the reaction mixture as the by-

product of bromination with N-bromosuccinimide.

The yield of the 4-bromo-5-ethoxypyrrolidinone 205 obtained in the

above reaction of the pyrrolidinone "172 with N-bromosuccinimide and

ethanol represents a 687o yield of product based on the mole quantity of

N-bromosuccinimide employed in the bromination step. As such, production

of the 4bromo-S-ethoxypyrrolidinone 205 from the pyrrolidinone 172 provides

good illustration of the free radical bromination procedure, described in this

chapter, as efficient methodology for the regioselective endocyclic

difunctionalization of pyrrolidinones. It was subsequently considered to

exploit this procedure in the synthesis of bicyclic pyrrolidinones aiø the

annelation of appropriate substituents thus introduced at C4 and C5 of a

pyrrolidinone. To this end, it was envisaged that substitution of an alkenyl

moiety for bromine at C5 of the dibromide 210 derived from L72 would

provide for subsequent cyclization onto C4 of the pyrrolidinone ring.

Accordingly, reaction of the pyrrolidinone L72 with N-bromosuccinimide

followed by altyl alcohol was investigated.

1-(p-Methoxyphenyl)-2-oxopyrrolidine (L72) was treated with a slight

molar excess of N-bromosuccinimide as described previously and the cooled

crude reaction mixture was treated with excess allyl alcohol and two mole

equivalents of 2,6-lutidine. Chromatogrupiy of the crude product mixture

then afforded the desired 4-bromo-5-altyloxypyrrolidinone 21L in 29Vo yield

based on L72, representing a 52% yíeld based on the amount of N-bromo-

succinimide employed in the reaction. In addition, the alcohol 206 was

obtained in ïVo yield and 487o of the pyrrolidinone 172 was recovered

unreacted. The yield of the allyl ether 21.L from the pyrrolidinone 172, aiø

this procedure, was improved to 47To when bromination of T72 was conducted

as above, but with five mole equivalents of N-bromosuccinimide. In this

RESULTS AND D/SCUSSION - IY

110

instance the alcohol 206 was obtained in addition, in 9Vo yietd and 31'Vo of the

starting material 172 was recovered. In each case above, production of a minor

amount of the S-succinimidopyrrolidinone 207 was also detected.

N

The ether 211 was characterized on the basis of its lH n.m.r. spectral

characteristics, being similar to those of its ethyl ether analogue 205. A doublet

resonance observed at õ 5.33 (/ = 0.8 FIz) and a doublet of doublet of doublets

resonance at õ 4.37 (l = 6.3,0.9, 0.8 FIz) were attributable to the methine protons

of C5 and C4, respectively. The presence of the allyl moiety in 211 was

confirmed by the observation of resonances at õ 5.20, 5.22 and 5.81 in the lH

n.m.r. spectrum, characteristic of the three olefinic protons, with resonances at

ô 132.90 and 118.27 in the 13C n.m.r. spectrum being attributable to the two

alkenyl carbons. Although the ether 211 was not sufficiently stable for

elemental analyses, two molecular ions of equal abundance were observed at

mlz 325 and 327 in the EI mass spectrum and other spectroscopic properties

were consistent with the structure. The substituents at C4 and C5 of 2LL were

assigned a trans geometry on the basis of the observed vicinal coupling

constant for the methine protons of C4 and C5.

Intramolecular free radical cyclization of the 4-bromo-5-allyl-

oxypyrrolidinone 21,1 was investigated by treatment with tri-n-butyltin

hydride according to the methodology reported by Hart and co-we¡¡"¡537,38 ¡o.

the intramolecular cyclization of related systems. Thus a dilute solution of tri-

Br

2T1


111

rx-butyltin hydride and a catalytic amount of AIBN in benzene was added

dropwise to a solution of the bromide 21L in benzene, whilst heating at reflux

under nitrogen. Chromatography of the crude product mixture thus obtained

afforded the tetrahydrofuropyrrolidinone 212 only, in 38Vo yield from the

bromide 211.

272

The product 21.2 was identified on the basis of a diagnostic doublet

resonance observed in the 1H n.m.r. spectrum at õ1.06 (l = 6.9 Hz), consistent

with the methyl substituent of the tetrahydrofuran ring. A doublet resonance

at õ 5.78 (l = 6.2H2) was attributable to the bridgehead methine proton at C5 of

the pyrrolidinone ring of 2L2, with a doublet of doublet of doublet of doublets

resonance at õ 3.02 (/ = 10.0, 8.0, 6.4, 6.2flz) being consistent with the second

bridgehead proton, at C4 of the pyrrolidinone ring. A molecular ion at mlz

247, was observed in the EI mass spectrum and other spectroscopic properties

were in accord with the structure of 212.

Formation of the tetrahydrofuropyrrolidinone 212 in the above

reaction of the bromide 211 with tri-z-butyttin hydride is attributable to exo

cyclization of the 3-oxa-5-hexenyl radical 213, formed upon initial bromine

atom abstraction by tri-n-butyltin radical (Scheme 54). Reduction of the

resulting exocyclic rad.ical 2L5 then affords the product2l2. The reduction of

S-hexenyl radicals by bimolecular hydrogen atom transfer from tributyltin

RESULTS AND DTSCUSSION - IV

Bra \

N

772

R

n-Bu3Sn'

exo

z-Bu3SnH

endo

N

2tL

RRN

273 214

aa

Hzc

216

n-Bu3SnH n-Bu3SnH

R

2L7

f{= ocH3

Scheme 54

hydride competes with their unimolecular ring closurelz3 and low stannane

concentrations are therefore required to minimize the amount of reduction

product obtained. To an extent, the lack of reduction product 21.4 from the

RNNtR

275

NR

212


113

above reaction of 21L then reflects the facility with which the 3-oxo-5-hexenyl

radical 2L3 cyclizes to 215. This is consistent with the high rate of cyclization

exhibited by analogous 3-oxo-5-hexenyl radicals.124,125 That tlrre exo cyclization

product 212 was obtained in the above reaction of 2Ll, with none of the endo

cyclization product 277 being obtained, is consistent with the usual course of

S-hexenyl radical cyclizations wherein products resulting from exo cyclization

form preferentially to those of endo cyclization.723,726

Free radical 1.,5-cyclizations of '1.,2-disubstituted S-hexenyl systems

analogous to 211 occur with a high degree of stereoselectivity,3S,l2T-129

whereby the major diastereomer obtained is invariably the thermodynamically

less favourable product, of which the three substituents of the newly formed

S-membered ring are in an all-cis geometry. For example, free radical

cyclization of the bromide 219127 afforded 2L9 as the major diastereomer in

54Vo yield and 220 as the minor diastereomer in 6.5Vo yield (Scheme 55). The

BrH

n-Bu3SnH +AIBN

218H

21.9

Scheme 55

stereochemical preference of such cyclizations may be rationalized as due to.Ji.o'- elt-.1 e-¡clv-rç,.l {i..rr-o*¡i1

^ the requirement of reaction aia a transition state geometry that affords the

rnaximal overlap between the semi-occupied p-orbital of the radical centre and

the æ*-orbital of the alkenyl moiety.123,128,129

Both 1H and 13C n.m.r. analysis of the tetrahydrofuropyrrolidinone 212

obtained from the free radicai cyclization of the bromide 211 indicated it to be a

single diastereomer. On the basis of the stereoselectivity exhibited in the free

ÇHa.ìH

H

220


774

radical cyclization of related systems, the single diastereomer of 2L2 obtained

was assigned as that with the all-cis geometry, namely the (3S,3aR,6aS)-, (3R,

3aS, 6aR)-diastereomer (Figzre B).

F{sC¡,,

FI¿,

4'rlIJr

5 N

3

35,3aR, 6aS- 3R,3aS,6aR-

212

Figure I Numbering of (3S, 3aR, 6aS)-, (3R, 3aS, 6aR)-6-(p-methoxyphenyl)-3-methyl-S-oxotetrahydro f:ur oí2,3-blpyrrolidine (212).

Synthesis of the tetrahydrofuropyrrolidinone 212 Írom 172 exemplifies

the viability of the free radical bromination procedure described in this chapter

for the synthesis of bicyclic pyrrolidinones. Moreover, this example highlights

the provision of this methodology for selective elaboration of functionality

thus introduced at both C4 and C5 of a pyrrolidinone system.

HH

RESULTS ,AND DISCUSSION - IV

115

CoNcLUSToN

Free radical bromination of N-substituted p-lactams bearing activating

substituents at exocyclic carbon adjacent to lactam nitrogen results in

regioselective reaction at the exocyclic carbon adjacent to nitrogen. Although

the major mode of free radical bromination of the analogous y-lactams is

reaction at the exocyclic carbon adjacent to nitrogen, reaction at the endocyclic

carbon adjacent to nitrogen competes in this case. That the endocyclic

methylenes adjacent to nitrogen in y-lactams are more reactive towards free

radical bromination than those in the corresponding p-lactams is presumably

as a result of the relative degrees of ring strain in the endocyclic product

radicals resulting from hydrogen atom abstraction.

In the absence of activating substituents at the exocydic carbon adjacent

to nitrogen, the predominant mode of reaction of y-lactams in free radical

bromination is at the endocyclic carbon adjacent to lactam nitrogen. With

comparison to the regioselectivity displayed in radical bromination of

y-Iactams bearing activating substituents at the exocyclic carbon adjacent to

lactam nitrogen, the regioselectivity of reaction displayed in this case serves to

illustrate the influence of activating substituents at the exocyclic carbon

adjacent to lactam nitrogen of y-lactams upon the regioselectivity of radical

bromination.

Free radical bromination of N-substituted p-lactams bearing activating

substituents at exocyclic carbon adjacent to lactam nitrogen provides viable

methodology for direct regioselective exocyclic functionalization of

N-substituted p-lactams in synthesis. The product bromides thus obtained are

116

amenable to further elaboration at the exocyclic carbon adjacent to nitrogen oîa

both ionic and free radical carbon-carbon bond forming reactions.

Free radical bromination of y-lactams with N-bromosuccinimide at the

endocyclic carbon adjacent to nitrogen affords production of 4þ-dibromo-

pyrrolidinones, thus providing novel synthetic methodology for the

regioselective difunctionalization of 1-lactams at C4 and C5. The synthetic

utility of the difunctionalized y-lactams lies in their ability to be regio-

selectively modified at C5 aia ionic methodology and at C4 aia fuee radical

methodology.

Free radical bromination followed by elaboration of introduced bromide

functionality provides significant methodology for the regioselective

functionalization of N-substituted p- and 1-lactams.

777

ExpEnTMENTAL

General

Melting points were recorded on a Kofler hot-stage aPparatus and are

uncorrected.

Electron Impact (EI) mass spectra were recorded at 70 eV on an AEI MS-

30 spectrometer. Chemical Ionization (CI) and Fast Atom Bombardment (FAB)

mass spectra were recorded on a ZAB 2HF spectrometer. Major fragments are

given with their relative abundances in parentheses.

Elemental analyses were performed by Canadian Microanalytical

Service Ltd., New Westminster, British Columbia, Canada.

Infrared spectra were recorded on a Hitachi2T0-30 spectrometer as nujol

mulls between sodium chloride plates, or as liquid films or solutions where

indicated.

1¡1 n.m.r. spectra were recorded at 60 l:|ldHlz on a Varian T-60

spectrometer, or where indicated, at 300 ll'lÍIz on either a Bruker AC-P 300 or

CXP 300 spectrometer. 13C n.m.r. spectra were recorded either at 75.5 MHz on

either a Bruker AC-P 300 or CXP 300 spectrometer, or at 20Ji|rdÍIz on a Bruker

WP-80 spectrometer. N.m.r. spectra were recorded as dilute solutions in

deuterochloroform, using tetramethylsilane as an internal standard.

Flash column chromatography was carried out using MatrexrM silica gel

(pore size 60 Å, particle size 50 pm, No. 84072). Squat colrl*rfund preparative

thin layer chromatographies were carried out using Merck silica gel 60pp-25a

# ¡làric-L,n- ic¿a A.lo , níí, ,9 ,rf EXPERIMENTAL

118

(Art. 7749). Unless otherwise indicated, preparative thin layer

chromatographies were carried out on a Chromatotron 7924T (Harrison

Research; Palo Alto, California, USA).

A WOTAN Ultra-Vitalux@ 300 W sunlamp was used as the light source

in reactions of N-bromosuccinimide. N-bromosuccinimide was recrystallized

from water and dried under reduced pressure before use. Solvents were

purified and dried using standard methods. All organic extracts were dried

over anhydrous magnesium sulphate. Light petroleum refers to the fraction

with b.p. 66 - 69"C.

EXPERIMENTAL

719

Exocyclic Functionalizatíon of N-Substitutedp-Lactams

Preparation of the 2-azetidinones 72 - 76

N-(3-Bromopropionyl)glycine ethyl ester (77)

Thionyl chloride (30.5 g, 256 mmol) was added dropwise to ethanol

(200m1). Glycine (82) (19.2g,255 mmol) was added and the solution was

stirred in dry apparatus at room temperature, overnight. The solution'was

then concentrated under reduced pressure to give glycine ethyl ester

hydrochloride (83).

3-Bromopropionyl chloride (84) (39.0 g, 228 mmol) was dissolved in

dichloromethane (300 ml) and a solution of the crude glycine ethyl ester (83)

in dichloromethane (150 ml) and water (150 ml) was added. Sodium

bicarbonate was added as required to keep the solution basic and the mixtu¡e

was stirred at room temperature for 4 hr. The reaction mixture was filtered

and the dichloromethane layer was separated, washed with water (3 x 50 ml),

dried, and concentrated under reduced pressure to give a crude white solid

which was recrystallized from ethyl'acetate / Iight petroleum to give N-(3-

bromopropionyl)glycine ethyl ester (77) as fine white crystals. (30.5 g, 56%)-

m.p. 82'C (lit.az æ"C); v*o, 3245, 7746,7646 crn-l (lit.82 3240,7740,1640 cm-l);

1H n.m.r. (CDCle) õ 1.31 (3H, t, I 7.0H2, CHa), 2.87 (2}J, t,l 6.5H2, CH2CHzBT),

3.68 (zJJ, t,l 6.5Í12, CH2Br), 4.07 (2H, d, | 5.0H2, NCHz), 4.28 (2rI, q, | 7.0H2,

OCH2), 6.10 (1H, broad, NH).

EXPERIMENTAL

720

Ethyl 2-oxo-7-azetidineacetate (ZÐez

A solution of N-(3-bromopropionyl)glycine ethyl ester (77) (2.40 g,

10 mmol) in dichloromethane and acetonitrile (19:1., 200 ml) was added

dropwise over 6 hr., to a stirred suspension of powdered potassium hydroxide

(672 mg, 12 mmol) and tetra-n -butylammonium bromide (645 mg, 2 mmol) in

dichloromethane and acetonitrile (791-., 200 ml). After the addition was

complete, stirring was continued for 30 min. The precipitate was filtered off

and washed with dichloromethane (2 x 50 ml). The combined filtrates were

dried, and concentrated under reduced pressure to give an oil that was

chromatographed on a squat column of silica gel, gradient eluting with light

petroleum and ethyl acetate. The resulting oil was distilled to give ethyl 2-

oxo-'1.-azetidineacetate (72). (958 mg, 6'1.7o)- b.p. 110'C/0.05mm (block); Ymax

(liquid film) 2980, 7736 cm-7 (tit.82 1733 cm-1), (CHzCLù 7758, 1744 cm-7;

lHn.m.r. (300MH2, CDCI¡) õ 1,.29 (3Ft t, I7.7TIz, CHa), 3.03 (2F],,t,l 4.'L}lz,

C3-Hz), 3.M (211, t, I 4.7 llz, C4-Hz) , 3 .99 (2H., s, Co.-}{2) , 4.27 (2Il', q, | 7 .7 fIz,

OCHz); 13C n.m.r. ô 168.15,'1,67.82, 6'!..31., 42.98, 39.85, 37.50, 14.00.

N-(3-Bromopropionyl)aminoacetonitrile (78)

3-Bromopropionyl chloride (84) (42.9 g, 250 mmol) was dissolved in

dichloromethane (200 ml) and a solution of aminoacetonitrile

bisulphate (86) (40 g, 260 mmol) in water (100 ml) and dichloromethane

(100 ml) was added. Sodium bicarbonate was addecl as reqttired to keep the

solution basic and the mixture was stirred at room temperature for 4 hr. The

reaction mixture was filtered and the dichloromethane layer was separated,

washed with water (3 x 50 ml), dried, and concentrated under reduced pressure

to give a crude white solid which was recrystallized from ethyl acetate / light

EXPERIMENTAL

727

petroleum to give N-(3-bromopropionyl)aminoacetonitrile (78) as fine white

crystals. (9.2g,79Vo)- m.p. 64C; (Calcd for C5H7N2OBr lM+lmlz 1,89-9742.

Found: mlz 1.89.9730); (Anal. calcd for C5H7N2OBr: C, 31'.44; H, 3.69; N, 14.66.

Found: C, 37.67; H, 3.66; N, 14.76) ) \max 3300, 2250, 1655 cm-1; 1H n.m.r.

(CDC13) ô 2.90 (2I1, t, I 6.5}12, CH2CH2BT), 3.67 (2F{, t, I 65H2, CHzBr), 4.23

(2ÍI, d, ] 6.0 Hz, CH2CN), 6.80 (1H, broad, NH).

2-Oxo-1-azetidineacetonitrile (73)

A solution of N-(3-bromopropionyl)aminoacetonitrile (78) (1.91' g,

L0 mmol) in dichloromethane and acetonitrile (1.9:7, 200 ml) was added


(672mg, 12 mmol) and tetra-z-butylammonium bromide (645 mg, 2 mmol) in

dichloromethane and acetonitrile (19:1, 200 ml). After the addition was





petroleum and ethyl acetate. The resulting oil was distilled to give 2-oxo-L-

azetidineacetonitrile (73). (611 mg, 62%)- b.p. 110'C/0.02mm (block); (Calcd

for CiH5,NzO Íl/r+l mlz 110.0480. Found mf z 110.0486); (AnaI. calcd for

CsHaNzO: C,54.54; H,5.49; N, 25.43. Found: C, 54.78; H, 5.77; N, 25.32); \max

(liquid film) 2972,2256,7754 cm-l; 1H n.m.r. (CDCls) õ 3.10 (2H, t,l 4.5ÍIz,

C3-Hz), 3.47 (2H', t,l 4.5Í12,C4-H2), 4.23 (2}{, s, CHzCN).

EXPERIMENTAL

122

N-Benzyl-3-bromopropionamide (79)

3-Bromopropionyl chloride (84) (t0 g, 58 mmol) was dissolved in

dichloromethane (80 ml) and a solution of benzylamine (88) (12.5 g,

117 mmol) in dichloromethane (20 ml) was added dropwise with stirring.

After the addition was complete the solution was stirred at room temperature

for a further 3 hr., then dichloromethane (50 ml) and water (100 ml) were

added. The organic layer was separated, washed successively with water (100

ml), dilute hydrochloric acid (2 x 50 ml), brine, saturated aqueous sodium

bicarbonate and brine again, then dried and evaporated under reduced

pressure. The residual solid was recrystallized from ethyl acetate / Light

petroleum to give N-benzyl-3-bromopropionamide (79) as fine white crystals.

(9.+ g, 677o)- m.p. 103"C (lit.sz 702 -1.,04'C); vrnaa 3288, 3092, '1.638, 1558, 726,

696 cm-l (1it.82 3280,1635 cm-l); rH n.m.r. (CDCls) õ 2.80 (zIJ., t, | 6.5H2,

CHzCHzBT), 3.68 (zIJ,t, ] 6.5Í1z,, CHzBr), 4.50 (zFl, d, ] 6.0 FIz, NCHz), 6.00 (1H,

broad, NH), 7.37 (5H, s, ArH).

1, -Benzyl -2-oxoazetidine Q Ðsz

A solution of N-benzyl-3-bromopropionamide (79) (4.84 g, 20 mmol) in

dichloromethane (200 ml) was added dropwise over 6 hr., to a stirred

suspension of powdered potassium hydroxide (1.34 g, 24 mmol) and tetra-ru-

butylammonium bromide (7.29 g, 4 mmol) in dichloromethane (200 ml).

After the addition was complete, stirring was continued for 30 min. The

precipitate was filtered off and washed with dichloromethane (2 x 50 ml). The

combined filtrates were dried, and concentrated under reduced pressure to give

an oil that was chromatographed on a squat column of silica gel, gradient

eluting with light petroleum and ethyl acetate. The resulting oil was distilled

EXPERIMENTAL

123

to give 1-benzyl-2-oxoazetidine (74). (2.26 g, Z0%)- b.p. 115C/0.08mm (block);

ymax (liquid film) 3024, 2956, 2904, 1734, "1.600, 7584, 7498, 71,4 cm-l (lit.sz

7740 cm-7); 1H n.m.r. (300MH2, CDCIs) õ 2.94 (2}l, t,l 4.1. ÍIz, C3-Hù, 3.73 (2ÍI,

t, I 4."1. Hz, C -Hz), 4.37 (2F{, s,Cg-Hz), 7.22 - 7.38 (5H, m, ArH).

N-Altyl-3-bromopropionamide (80)

3-Bromopropionyl chloride (84) (9.3 g, 54.2 mmol) was dissolved in

dichloromethane (60 ml) and allylamine (89) (6 g, '1.05 mmol) was added

dropwise with stirring. After the addition was complete the solution was

stirred at room temperature for a further 3 hr., then dichloromethane (50 ml)

was added. The solution was washed successively with water (3 x 50 ml),

dilute hydrochloric acid (2 x 50 ml), brine, saturated aqueous sodium

bicarbonate and brine again, then dried and evaporated under reduced

pressure to give an oil which solidified on standing. The residual solid was

recrystallized from ethyl acetate / light petroleum and subsequently distilled to

give N-allyl-3-bromopropionamide (80) as white crystals. (7.2 g, 69To)- b.p.

150'C/0.06mm (block); (Calcd for C6HlsNOBr Í]|l{+l mh 790.9943. Found; mlz

190.9950); (Anal. calcd for C5HlsNOBr: C,37.52;H,5.25;N,7.29. Found: C,37.73;

H,5.11; N,6.88); vTor (liquid film) 3288,3080, \640,930 cm-1; 1H n.m.r. (CDC13)

E 2.82 (2H, t, | 6.5 Hz, CHzCHzBT), 3.65 (2IF^, t, I 6.5 Hz, CHzBr), 3.90 (2H, dd, I6.0, 5.0 Hz, CH2CH=CHz), 5.00 - 5.35 (2H, m, CH=CH2), 5.57 - 6.18 (1H, m,

CH=CHz) , 6.60 (1H, broad, NH).

EXPERIMENTAL

1.24

7 - Allyl-2-oxo az etidine ( 7 5 )

A solution of N-allyl-3-bromopropionamide (80) (1.92 g, 70 mmol) in

dichloromethane and acetonitrile (79:-1,,200 ml) was added dropwise over 6 hr.,

to a stirred suspension of powdered potassium hydroxide (672m9, 12 mmol)

and tetra-n -butylammonium bromide (645 rr.g, 2 mmol) in dichloromethane

and acetonitrile (19:'1,,200 ml). After the addition was complete, stirring was

continued for 30 min. The precipitate was filtered off and washed with

dichloromethane (2 x 50 ml). The combined filtrates were dried, and

concentrated under reduced pressure to give an oil that was chromatographed

on a squat column of silica gel, gradient eluting with light petroleum and ethyl

acetate. The resulting oil was distilled to give L-allyl-2-oxoazetidine (75).

(335 mg, 30%)- b.p. 50C/0.2mm (block); (Calcd for C6HeNO [M+] mlz 1.11..0687.

Found: mlz 1.1,1..0686); \max (liquid film) 3080, 2960, 'J.744, '1,676,930 cm-l;

1H n.m.r. (300MFIZ, CDCIg) E 295 (2]F', t, I 4.1, flz, C3-Hz), 3.24 (2Í1, t,l 4.'j., Hz,

C4-Hù, 3.83 (2H, d,l6.7TIz,CHzCH=CHz), 5.19 -5.25 (2}l., m, CH=CHù,5.76

(1H, ddt, ] 77.3, 9.9, 6.'1, Hz, CH=CÍþ).

N-(3-Bromopropionyl)glycine benzyl ester (81)

Thionyl chloride (34.9 g, 293 mmol) was added dropwise to benzyl

alcohol (200 mt). Glycine (82) (20 g, 266 mmol) was added and the solution

was stirred in dry apparatus at room temperature, overnight. The white solid

that had precipitated during this time was extracted with watcr (3 x 100 ml) and

the combined aqueous layers were washed with dichloromethane (100 ml).

The aqueous solution was then concentrated under reduced pressure to give

glycine benzyl ester hydrochloride (91) as a white crystalline solid.

EXPERIMENTAL

725

3-Bromopropionyl chloride (84) (35 g, 204 mmol) was dissolved in

dichloromethane (200 ml) and a solution of the crude glycine benzyl ester

(91) in dichloromethane (100 mt) and water (100 ml) was added. Sodium

bicarbonate was added as required to keep the solution basic and the mixture

was stirred at room temperature for 4 hr" The reaction mixture was filtered


dried, and concentrated under reduced pressure to give a crude white solid

which was recrystallized from ethyl acetate / light petroleum to give N-(3-

bromopropionyl)glycine benzyl ester (81) as fine white crystals. (4 g, 7Vo)-

m.p. 73C; (Calcd for C12H1¿NOgBr llú+l mlz 299.01.57. Found: mlz 299.0t73);

(Anal. calcd for C12H1aNO3Br: C,48.02;H,4.70; N,4.66. Found: C,47.99;H,4.53;

N, 4.66); v*o* 3308,3092, 1740,1,652, 7554,754,702 cm-1; 1H n.m.r. (CDCtg) õ

2.80 (zJJ, t, I 6.5tlz, CH2CHzBT), 3.60 (zFj, t, ] 6.5H2, CHzBr), 4.12 (2F{, d,l5.0Í12, NCHÐ, 5.18 (2H, s, CH2Ph), 6.57 (1H, broad, NH), 7.33 (5H, s, ArH).

Benzyl 2-oxo-'1,-azetidineacetate (76)

A solution of N=(3-bromopropionyl)glycine benzyl ester (81) (2.2 g,

10 mmol) in dichloromethane and acetonitrile (79:7, 200 ml) was added


(672mg, 12mmol) and tetra-n-butylammonium bromide (645mg,2mmol) in

dichloromethane and acetonitrile (79:7, 200 ml). After the addition was




chromatographed on a squat column of silica gel, gradient eluting with tight

petroleum and ethyl acetate. The resulting oil was distilled to give benzyl2-

oxo-l-azetidineacetate(76). (490 mg, 227o)- b.p. 160"C/0.001mm (block); (Calcd

EXPERIMENTAL

126

for Cl2HreNOs [M+] mlz 21,9.A895. Found: mlz 279.0885); (Anal. calcd for

C12H13NO3: C, 65.74; H, 5.98; N, 6.39. Found: C, 65.59; H, 6.01,; N, 6.40); Ymax

(liquidfilm)3030,2964,1760,1742,1502,744,700 cm-1; 1Ff n.m.r. (CDClt õ 2.99

(2Êl,t,l AJl,lfz, C3-H/, 3.38 (2H, t,] A|l.Hz,C4-Í12), 4.01, (2Ê1,s, Ccr-Hz), 5.12(2Í1,

s, CH2Ph), 7.33 (5H, s, ArH).

EXPERIMENTAL

127

Reactions of the 2-azetidinones 72 - 76

Ethyl cr-bromo -Z-oxo-7-aze tidinea ce tate (9 2)

A mixture of ethyl 2-oxo-1.-azetidineacetate (72) (156 mg, 0.99 mmol) and

N-bromosuccinimide (1,77 mg, 0.99 mmol) in carbon tetrachloride and

dichloromethane (5:1, 9 ml) was heated at reflux under nitrogen, whilst

irradiating with a 300 W mercury lamp, for 15 min. The cooled reaction

mixture was filtered through glass wool and concentrated under reduced

pressure to give ethyl cr-bromo-2-oxo-1-azetidineacetate (92) as a pale yellow

o7l:- vrna, (liquid film) 2960, 1783, 1752 crn-7; 1H n.m.r. (300MH2, CDCI3) ô

1.33 (3H, t, I 7.t IJz, CHs), 3.01 (1H, ddd, /33' 15.6, þ4ç¡s 6.2, ]34' tro* 3.5 ÍIz, C3-H),

3.11 (1H, ddd, /33, 15.6, 13'4'çis 5.9, ]3'Atronr 3.9 Hz, C3-H'), 3.56 (1H, ddd, I++' 6.5,

IUr¡" 6.2, Ig,Atrort 3.9 Í12, C+H), 3.70 (1H, ddd, I++, 6.5, Ig,A'rir 5.9, ]34,trøns 3.5H2,

C4-H'), 4.27 (2F{, q,, I 7.1 ÍIz, OCH2), 6.33 (1H, s, Ccr-H).

Ethyl a-ethoxy-2-oxo-1-azetidineacetate (93)

Ethyl cr-bromo-2-oxo-1-azetidineacetate (92) was prepared, as described

above, from ethyl 2-oxo-1-azetidineacetate (72) (168 mg, 1.07 mmol) and

N-bromosuccinimide (190 mg, 1.07 mmol) in carbon tetrachloride and

dichloromethane (5:1, 9 ml). To the cooled crude reaction mixture was added

dry ethanol (130 ¡tl, 2.22 mmol) and 2,6-lutidine (250 pl, 2.15 mmol) and the

resulting mixture was stirred at room temperature under nitrogen for L hr.

The reaction mixture was filtered and evaporated under reduced pressure.

The residue was taken up in ethyl acetate and washed successively with very

dilute hydrochloric acid, brine, saturated aqueous sodium bicarbonate, and

EXPERIMENTAL

728

brine again. The organic layer was separated, dried and evaporated under

reduced pressure and the residue was purified by flash column

chromatography on silica, eluting with a mixture of chloroform and methanol

(100:1) to give ethyl cr-ethoxy-2-oxo-L-azetidineacetate (93) as an oil. (1.23 mg,

57%):- b.p.60"C/0.001.mm (block); (Calcd for CeHl5NO¿ [M* +H]m12202.7079.

Found: mlz 202.7089); (Anal. calcd for C9H15NO4: C,53.72; H,7.57; N, 6.96.

Found: C, 53.69; H,7.33; N, 6.85); v*o¡ (liquid film) 2984, 1750, 121'8, t094 cm-l;

lH n.m.r. (300MI{2, CDCts) õ 1.27 (3H, t, I 7.0ÍIz, CHOCHzCHù, 1.32 (3H, t, I7.2H2, COzCHzCHg), 3.01 (1H, ddd, /33' 13.4, lg4ç¡r 4.9,148tuon, 3.3ÍIz, C3-H),

3.07 (1H, ddd, /33' 13.4, lg'4'çis 4.9,143'trorr 3.9 Hz, C3-H'), 3.41' (1H, ddd, 144' 5.4,

Igari" 4.9,l4g,tror,3.9H2, C4-H), 3.46 (LH, ddd, I+t 5.4,19,4'rit 4.9,l4ltrone 3.3flz,

C4-H'), 3.59 (1H, dq,, 19.5,7.0II2, CHOCHHCH3), 3.68 (1H, dq, if9.5,7.0H2,

CHOCHHCHI), 4.26 (?,F{, q, I 7.2ÍIz, COzCHzCH¡), 5.35 (1H, s, Ccr-H).

cr-Bromo -2- oxo -I-azetidineacetonitrile (9 7)

A mixture of 2-oxo-L-azetidineacetonitrile (73) (1'62rng, L.47mmol) and





pressure to give cr-bromo-2-oxo-1-azetidineacetonitrile (97) as a yellow oil :-

vmax (CCIQ 2986,2308,7794,7725 crn-l; 1H n.m.r. (300MFIz, CDCI3) ô 3.11 (1H,

ddd, /ag' 75.7,134¿¡5 6.0, J43tuors 4.1.flz, C3-H), 3.21 (1H, ddd, /33' 1.5.7, l3'4'çis 5.9,

]4Z,tron, 4.0 Hz, C3-H'), 3.52 (7H, ddd, 144' 6.7, Iz+ci, 6.0, I+3'tron, 4.0 ÍIz, C4-H),

3.56 (1H, ddd,l++' 6.7,I3'+,rir5.9,|+Btrons 4.7Ífz, C4-H'), 6.M (1H, s, Ccr-H).

EXPERIMENTAL

729

cr-Ethoxy -2-oxo-L-azetidineacetonitrile (98)

cr-Bromo-2-oxo-L-azetidineacetonitril e (97) was prePared, as described

above, from 2-oxo-1-azetidineacetonitrile (73) (184 mg, l'.67 mmol) and


dichloromethane (2:1, 9 ml). The cooled crude reaction mixture was treated

with dry ethanol (200 ¡rl, 3.40 mmol) and 2,6-lutidine (390 ¡tl, 3.34 mmol) as

described above for the preparation of the cr-ethoxy-azetidineacetate 93. The

residue obtained upon workup was purified by flash column chromatography

on silica, eluting with a mixture of chloroform and methanol (100:1), to give

c-ethoxy-2-oxo-1.-azetidineacetonitrile (98) as an oil. (1.06m9,47Vo)¡ 115 -120C /0.08mm (block); (Calcd for CzHroNzOz [M+l mlz 1,54.0742. Found: mlz

1.54.0740); (Anal. calcd for C7H16N2O2: C, 54.54; H, 6.53; N, L8.16. Found: C,

54.97;H, 6.39; N, 18.60); v*a¡ (liquid film) 2975,2250,1755,7245,1075 cm-1; 1H

n.m.r. (300MH2, CDCIg). ô 1.27 (3H, t, I 7.0ÍIz, CI{ù, 3.07 (LH, ddd, lss'1.5.2,

]gqri"5.5,I4S¡.ans3.8H2, C3-H), 3.13 (1H, ddd,/33'75.2,13'4'¿¡55.4,I+g't ons3.9Hz,

C3-H'), 3.50 (1H, ddd,ld+,7.9,[g+rir5.5,il43'trans3.9TIz,CA-H), 3.52 (1H, ddd,l+q'

7.9,1g'+,rir5.4,l4ltrar, 3.8 TIz, C4-H'),3.63 (fFI, dq, I 9.3,7.0H2, CHHCHg), 3.62

(1H, dç 19.3,7.0H2, CHHCH3), 5.68 (1I{, s, Ccr-H).

Treatment of 1-benzyl-2-oxoazetidine (74) with

N-bromosuccinimide

A mixture of 1-benzyl-2-oxoazetidine (74) (100 rng, 0.62 mmol) and





EXPERIMENTAL

130

pressure to give a yellow residual oil. Thin layer chromatography and 1H

n.m.r. spectroscopic analysis of the residue revealed a complex mixture of

products containing benzaldehyde (10L) and a minor amount of unreacted 1-

benzyl-2-oxoazetidine (74):- 1H n.m.r. (CDCts) õ 10.03 (sharp singlet, PhCHO).

No discrete products were isolated from this mixture.

Competitive reaction between ethyl 2-oxo-L-azetidineacetate (72)

and L -be nzyl-Z-oxoazetidine (74) with N-bromosuccinimide

A mixture of ethyl 2-oxo-1-azetidineacetate (72) (57 mg, 0.36 mmol), 1-

benzyl-2-oxoazetidine (7 4) (70 mg, 0.43 mmol) and N-bromosuccinimide

(65 mg, 0.37 mmol) in carbon tetrachloride and dichloromethane (5:1, 12 ml)

was heated at reflux under nitrogen, whilst irradiating with a 300 W mercury

lamp, for L5 min. The cooled reaction mixture was filtered through glass wool

and concentrated under reduced pressure. 1H n.m.r. spectroscopic analysis

of the residue revealed a complex mixture of products containing

benzaldehyde (10L) a minor amount of unreacted 1-benzyl-2-oxoazetidine (74)

and a major amount of unreacted ethyt 2-oxo-1.-azetidineacetate (72). 1H n.m.r.

spectroscopic analysis gave no evidence for the presence of ethyl cr-bromo-2-

oxo-l-azetidineacetate (92) in the crude product mixture.

Treatment of 1-allyl-2-oxoazetidine (75) wi th N-bromosuccinimide

A mixture of 1,-allyl-2-oxoazetidine (75) (64.2 rng, 0.58 mmol) and

N-bromosuccinimide (103 mg, 0.58 mmol) in carbon tetrachloride (8 ml) was

heated at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp,

for L5 min. The cooled reaction mixture was filtered through glass wool and

EXPERIMENTAL

131

concentrated under reduced pressure to give a brown residual oil. 1H n.m.r.

spectroscopic analysis of the residue revealed a complex mixture of products

containing unreacted l-allyl-2-oxoazetidine (75). No discrete products were

isolated from this mixture.

Competitive reaction between ethyl 2-oxo-'1.-azetidineacetate (72)

and L -allyl-2-oxoazetidine (75) with N-bromosuccinimide

A mixture of ethyl 2-oxo-1-azetidineacetate (72) (97 rng, 0.62 mmol), L-

allyl-2-oxoazetidine (75) (68 mg, 0.6L mmol) and N-bromosuccinimide (109 mg,

0.6L mmol) in carbon tetrachloride and dichloromethane (5:7, '1,2 ml) was

heated at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp,

for L5 min. The cooled reaction mixture was filtered through glass wool and

concentrated under reduced pressure. 1H n.m.r. spectroscopic analysis of the

residue revealed a complex mixture of products containing a minor amount of

unreacted 1-altyl-2-oxoazetidine (75) and a major amount of unreacted ethyl 2-

oxo-l-azetidineacetate (72). 1H n.m.r. spectroscopic analysis gave no evidence

for the presence of ethyl cx,-bromo-2-oxo-1.-azetidineacetate (gZ) in the crude

product mixture.

Treatment of benzyl 2-oxo-1.-azetidineacetate (76) with

N-bromosuccinimide

A mixture of benzyl 2-oxo-7-azetidineacetate (76) (57.7 rr.g, 0.26mmol)

and N-bromosuccinimide (47 mg, 0.26 mmol) in carbon tetrachloride and



EXPERIMENTAL

1,32


pressure to give an oil comprising of an approximately 3:1 mixture of benzyl a-

bromo-2-oxo-1-azetidineacetate (109) and cr-bromobenzyl 2-oxo-7-

azetidineacetate (110) as judged by 1H n.m.r. spectroscopic analysis. No discrete

products were isolated from this crude reaction mixture.

Benzyl cr-bromo-2-oxo-7-azetidineacetate (109):- 1H n.m.r. (300MH2,

CDCIs) ô 2.93 (l!l, m, C3-H), 3.05 (1H, m, C3-H'), 3.52 (7H, ddd, ] 6.6, 6.6,

4.0 ÍIz, C4-H), 3.62 (1H', ddd, / 6.7, 6.6, 3.4H2, C4-H'), 5.18 (2H, s, CHzPh) , 6.36

(1.H, s, Ccr-H), 7.33 (5H, m, ArH).

a-Bromob enzyl 2-oxo-L-azetidineacetate (110):- lH n.m.r. (300MH2,

CDCIg) õ 2.99 (2}l,m, C3-Hz), 3.38 (2H, m,C4-H2), 4.77 (2H,,s, Ccr-Hz), 7.32-

7.56 (sIJ, m, ArH), 7.49 (1H, s, CHBr).

EXPERIMENTAL

133

Elaboration of Functional ized N-Substituted

B-Lactams

Ethyl a-phenylthio -2 -o xo -1. -azetidinea cetate (1L3 )

Ethyl o-bromo-2-oxo-1-azetidineacetate (92) was prepared, as described

above, from ethyl 2-oxo-1.-azetidineacetate (72) (779 mg, 1.14 mmol) and

N-bromosuccinimide (224 rng, 1.26 mmol) in carbon tetrachloride and

dichloromethane (5:1, 12 ml). The reaction mixture was cooled in an ice-bath

to 0 - 5"C, thiophenol (240 ¡tL,2.34 mmol) and 2,6-lutidine (270 ¡tI, 2.32 mmol)

were added and the resulting mixture was stirred under nitrogen for 2.5 hr.

The reaction mixture was filtered and evaporated under reduced pressure.

The residue was taken up in ethyl acetate and washed successively with very

dilute hydrochloric acid, brine, saturated aqueous sodium bicarbonate, and

brine again. The organic layer was separated, dried and evaporated under

reduced pressure and the residue was purified by preparative thin layer

chromatography on silica, gradient eluting with a mixture of light petroleum

and ethyl acetate to give ethyl cr-phenylthio-2-oxo-1-azetidineacetate (113) as an

oil. (192mg,647o)- b.p. 120"C/0.03mm (block); (Anal. calcd for C13H15NO3S:

C, 58.85; H, 5.70; N, 5.28. Found: C, 58.32; H,5.57; N, 5.24); vlnaa (Iiquid film)

2980, 7736,7582,1482 cm-1; 1H n.m.r. (300MH2, CDCIs) õ 7.27 (3H, t, I 7.']..Ífz,

CHa), 2.73 (7F{, ddd, /33' 74.9,124,c¡s5.9, ht'trrns3.7F{z, C3-H), 290 (1H, ddd, /33'

74.9, J3'4'cis 5.7, J3' tront 3.7 Hz, C3-H'), 3.46 (7F{, ddd, lgaçis 5.9, Iq+' 5.8, J3, trort

3.7 Hz, C4-H), 3.53 (1H, ddd, laa, 5.8, IZ'q'rir 5.7, I3+'tra* 3.7 Hz, C4-H'), 4.20 (2F{,

q, I 7.7 Hz, OCHù, 5.82 (1H, s, Ccr-H) 7.30 - 7.35 (3H, m, ArH), 7.46 - 7.57 (2}I,

m, ArH); 13C n.m.r. õ 767.24,766.46,733.23,1,30.99,729.28,728.79,62.27,58.48,

37.72,36.60,13,95.

EXPERIMENTAL

734

Di ethyl 2- (2- oxo -'I., - azetidin e ) mal e a te ( 1 1 5)

Ethyl cr-bromo-2-oxo-L-azetidineacetate (92) was prepared as described

above from ethyl 2-oxo-7-azetidineacetate(72) (202mg, 1.29 mmol) and

N-bromosuccinimide (252mg, 1.42mmol) in carbon tetrachloride and

dichloromethane (5:1, 12 ml). The crude bromide 92 was dissolved in dry

L,4-dioxane (20 ml), triphenylphosphine (675 mg, 2.57 mmol) and 2,6-lutidine

(300 pl, 2.58 mmol) were added and the resulting mixture was stirred at room

temperature under nitrogen, overnight. The reaction mixture was filtered,

evaporated under reduced pressure and the residue was worked up as

described above for the preparation of the thioether L1-3. The resulting crude

oil was purified by preparative thin layer chromatography on silica, eluting

with a mixture of light petroleum and ethyl acetate (50:50) and afforded diethyl

2-(2-oxo-'1.-azetidine)maleate (115) as an oil. (47 mg, 1.5Vo)- b.p.70"C/ 0.02mm

(block); (Calcd for C11H1sNOs lM+) mþ 247.0950. Found: mk 247.0958); (Anal.

calcd for C11H1SNOs : C,54.77;H,6.27; N, 5.80. Found: C,55.22;H,6.28; N, 5.86);

v¿a¡ (liquid film) 3080, 2988, 7774, 1722, 7628,1028 cm-1; 1H n.m.r. (300MH2,

CDCIg) ô 1.31 (3H, t,l 7.1.H2, CHs), 7.34 (3H, t, I 7.'l.Hz, CHg), 3.70 (2H.,t,l

4.9 TIz, C3'-H2), 3.92 (2F{, t, I 4.9 tlz, C4'-H2), 4.23 (2}I, q, I 7.'1. ffz, OCHz), 4.30

(zJJ, q,l 7.'l.Hz, OCHz), 6.31 (1H, s, C=CH); 13C n.m.r. ô 165.33 (C=O), 1.64.26

(COzEt),762.77 (COzEt),733.79 (C2),115.50 (C3),62.33 (OCHÐ, 60.94 (OCHÐ,42.66

(C4' ¡, 37 .55 (C3'), 1,4.06 (CFt3¡, 73.92 (CU3¡.

tzíEthyl u-altyl-2-oxo - L -aze tidine a ce tate (Æ) a i ø fr ee radical allylation

of 92

Ethyl cr-bromo-2-oxo-1-azetidineacetate (92), prepared from ethyl 2-oxo-

1-azetidineacetate (72) (754 mg, 0.98 mmol) by treatment with N-bromo-

EXPERIMENTAL

135

succinimide (774 mg, 0.98 mmol) as described above, 'was dissolved in dry

benzene (10 ml). Allyltributyltin (840 mg, 2.54 mmol) and a catalytic amount

of AIBN were added and the mixture was stirred under nitrogen at room

temperature overnight. The reaction mixture was concentrated under reduced

pressure and preparative thin layer chromatography of the residue on silica,

gradient eluting with light petroleum and ethyl acetate afforded ethyl u-ally[-2-

oxe"l.-azetidineacetate (125) as an oil. (48 mg,25Vo):- (Calcd for C1¡HlsNOg [M*]

mlz 197.1,052. Found: mlz 197.7067); vvloa (liquid film) 3075,2970, 1750, 1730,

1640 cm-1; 1H n.m.r. (300MH2, CDCIg) ô 1.29 (3H,t,17.2H2, CHs), 2.M-2.56

(1.H, m, CHHCH=CHz), 2.67 -2.70 (1H, m, CHHCH=CHz), 2.92(1H, ddd, /33'

74.7, Igq,cis 5.4,134'trønr 3.0 flz, C3-H), 2.99 (1H, ddd, /ga' 1.4.7, l3'4,¿is 5.3, Ig' trort

3.1,ÍIz, C3-H'), 3.34(1H,ddd,ldt,5.4,lgnrir5.4,l3'4trarr3.1t7z,C4-F{), 3.50 (1H,

ddd,144, 5.4,[g'4,cis5.3,l34,trans3.0Hz, C4-H'), 4.20 (2I{, q.,l 7.7 FIz, OCH2), 4.49

(1H, dd, ] 5.2,9.7H2, Ca-H), 5.72-5.27 (2H, m, CH=CHù, 5.76 (1H, dddd,l17.0,'1.0.2, 7.0, 6.4H2, CH=CHz); 13C n.m.r. ô 170.06, 767.83, 1.32.97, 71.8.49, 67.40,

53.30, 37.94, 36.48, 34.21., 74.1.6.

In a subsequent preparation of 125, as described above, chromatography

of the reaction mixture gave, in addition, ethyl ø-hydroxy-2-oxo-L-

azetidineacetate (726) as an oil:- \max (CnCtg) 3350 (broad), 1755, 1735,

7720 qn-L; 1H n.m.r. (300MFIz, CDCI¡) ô 1.34 (3H, t, 17.7Í12, CHr), 3.01, (2}l,t,l

4.6flz, C3-Hz), 3.29 (7H, dt,l 4.6,4.6H2, C4-H), 3.48 (1H, dt,l 4.6, 4.6H2, C4-H'),

4.32(2ÞI, q,,l7.1Hz,OCHz), 4.86 (1H, broad (exchanges), OH), 5.49 (1H, s, Ccr-H).

This compound was not stable for complete characterization.

EXPERIMENTAT

736

Ethyl u- altyl-Z-oxo - 1 -azetidine acetate ( 1 2 5) a i a ionic allylation

of 92

Ethyl cr-bromo-2-oxo-1-azetidineacetate (92) was prepared from ethyl 2-

oxo-1.-azetidineacetate (72) (174mg, 1..11. mmol) by treatment with N-bromo-

succinimíde (217 mg, 'I-..22 mmol) in a mixture of carbon tetrachloride and

dichloromethane (5:'1,, 72ml) as described above, and the crude reaction

mixture was cooled in an ice bath to 0 - 5"C and stirred over powdered

molecular sieves @ Ã, 100 mg). Allyltrimethylsilane (700 ¡tl, 4.40 mmol) was

added with stirring followed by boron trifluoride etherate (550 pl, 4.47 mmol)

and the mixture was allowed to warm to room temperature whilst stirring

under nitrogen overnight. The reaction mixture was vacuum filtered into

brine (20 ml). The organic layer was separated, washed with brine (2 x 20 ml),

dried and evaporated under reduced pressure. Preparative thin layer

chromatography of the residue on silica, eluting with a mixture of light

petroleum and ethyl acetate (50:50) afforded ethyl o-allyl-2-oxo-L-

azetidineacetate (125) as an oll (74mg,347o).

E thyl u- (2-fur yI) -2 - ox o - 1 - azetidin e a c e ta t e (127 )

Ethyl c-bromo-2-oxo-1-azetidineacetate (92), prepared as described

above, from ethyl 2-oxo-L-azetidineacetate (72) (304 mg, 1.93 mmol) by

treatment with N-bromosuccinimide (378 rr.g, 2.12 mmol) in carbon

tetrachloride and dichloromethane (5:1, 18 ml), was dissolved in anhydrous

tetrahydrofuran (20 ml) and stirred over powdered molecular sieves (4 L,

250 mg). Furan (2.8 ml, 38.6 mmol) and zinc chloride (527 mg, 3.87 mmol)

were added and the resulting solution was stirred at room temperature for

3.5 hr. The reaction mixture was filtered into water (20 ml) and the resulting

EXPERIMENTAL

737

mixture was extracted with dichloromethane (3 x 50 ml). The combined

organic extracts were dried and evaporated under reduced pressure.

Preparative thin layer chromatography of the residue on silica, eluting with a

mixture of ethyl acetate and methanol (100:2) gave ethyl a-(2-furyl)-2-oxo-1-

azetidineacetate (127) as an oil. (268 mg,62Vo):- (Calcd for C11H1aNIO¿ lM+l mlz

223.0845. Found: mlz 223.0853); \møx (CHzClz) 2968, 1752, '1.608, 1504 cm-1;

lHn.m.r. (300MLIZ,CDCIg) õ 1.23(3H,t, I7.\tIz,CHs), 2.88(1H, ddd,lss,'1.4.7,

Igqrit 5.6, ]z+t ons 2.9 Hz, C3-H), 2.99 (1H, ddd, /33' 1,4.7, J3,4'ç¡s 5.5, I3'4trort 2.8 ÍIz,

C3-H'), 3.17 (lF{, ddd, laa' 5.5, |g+cis 5.6, l4g,t ons 2.8 ÍIz, C4-H), 3.61 (1H, ddd, l+t'

5.5, ]3,4'"is 5.5,lg4,trorr 2.9Hz, CA-H'), 4.18 (1H, dq,, I 1,"1,.2,7.0H4 OCIIHCHS),

4.22 (1H, dq J 1,7.2,7.0H2, OCHHCHù, 5.62 (1H, s, Ccr-H), 6.31 (1H, d, ] 3.2ÍIz,

C3'-H), 6.34(1H,dd,l'3.2,1-..9ÍIZ,C4'-H), 7.37 (1H,d,17.9H2,Cs'-}j); 13Cn.m.r.

õ 1.68.M,1,67.32,'].,46.96,1,43.76,110.60, 1,09.39,62.72,57.46,38.75,36.83,74.02.

N-Carboethoxyphthalimide (1gr) t os

Phthalimide (13 0 ) (72.5 g, 493 mmol) was dissolved in

dimethylformamide (325 ml) with the aid of triethylamine (90 ml) and the

solution was cooled to 3 - 5'C. Ethyl chloroformate (100 ml, 1046 mmol) was

added dropwise with vigorous stirring whilst the temperature of the mixture

wus Àaintained at 3 - 5C. After the addition was complete the mixture was

stirred for a further 1. hr., during which time the mixture was allowed to warm

to room temperature. The reaction mixture was then poured into water

(3000 ml) with vigorous stirring. The crystalline white precipitate was

collected by vacuum filtration, washed thoroughly with water, air dried and

recrystallized from ethanol to give N-carboethoxyphthalimide (L31) as fine

white crystals. (98.95 g,92To)- m.p. 78"C (lit.tos 80"C); v*o, 1808, 7768,7724,

EXPERIMENTAL

138

l604cm-1; 1Hn.m.r. (CDCI3) õ 1.48 (3H,t,l7.5flz, CHs), 4.53(2F{,q,17.5ÍIz,

OCHz), 7.77 - 8.1.3 (4H, m, ArH).

N-Phthaloylserine (1gg) t os

Serine (132) (2.1,0 g,20 mmol) and sodium carbonate (2.15 g, 20 mmol)

were dissolved in water (15 ml), then finely powdered N-carbo-

ethoxyphthalimide (131,) (4.5 g, 21 mmol) was added and the mixture was

stirred at room temperature for 30 min. The mixture was filtered and the

filtrate was extracted with ether (5 x 50 ml) to remove the by-product of

reaction, urethane. The aqueous layer was acidified with 6N hydrocNoric acid

to approximately pH 3, then extracted with ether (3 x 60 ml) and the resulting

organic extracts were dried and concentrated under reduced pressure. The

residue was recrystallized from ethyl acetate / Light petroleum to give

N-phthaloylserine (133) as a white crystalline solid. (4.05 g, 867o)- m.p. 152C

11i¡.10s 152C); v*o¡ 3528,3284,1752,7694,1606 cm-1; 1H n.m.r. (CDCls) E 4.24

(2IJ, d,l 6.5 Hz, CHzOH), 5.02 (1H, t, ] 6.5 Hz, Co-Il), 7.68 - 8.05 (4H, m, ArH).

N-Phthaloylserylglycine methyl ester (136)

A solution of N-phthaloylserine (133) (8.0 g, 34.0 mmol) in thionyl

chloride (70 ml) was heated at 80 - 90'C in dry apparatus for 4 hr. After

cooling, the solution was concentrated under reduced pressure, benzene

(30 ml) was added and the solution was again concentrated under reduced

pressure to give N-phthaloylseryl chloride (134) as a yellow oil.

The crude acid chloride 134 was dissolved in dichloromethane (200 ml)

and a solution of glycine methyl ester hydrochloride (135) (4.70 g, 37.4 mmol)

EXPERIMENTAL

739

(prepared as described below in the preparation of methyl 2-oxo-7-

pyrrolidineacetate (14L)) in water (100 ml) was added with stirring. Sodium



and the dichloromethane layer was separated, washed with water (2x100 ml),

dried and evapourated under reduced pressure. The residue was

chromatographed on a squat column of silica, gradient eluting with a mixture

of ethyl acetate and light petroleum to give N-phthaloylserylglycine methyl

ester (136) as a foamy toffee-like solid. (5.22 g, 57%)- v^o, (CHzClz) 3432, 3040,

2976,1776,1748,1722 c:n-7; 1H n.m.r. (300MH2, CDCIg) õ 2.93 (1H, broad, OH),

3.68 (3H, s, OCHa), 4.02 (1H, dd, I 1'1'.4, 5.4Í12, CH}{;OH), 4.03 (zfl', d, ] 5.4ÍIz,

NCHz), 4.38 (1H, dd, I 1,1,.4,7.6H2, CFT.HOH), 4.94 (7H, dd, I 7.6,5.4H2,

CHCHzOH), 7 .51. (l H, broad, NH), 7 .66 - 7 .72 (2H m, ArH), 7.76 - 7.84 (2}l, m,

ArH); (lit.to¿ 3.0 - 3.4 (1H, br), 3.73 (3H, s), 3.94 - 4.6 (3H, m), 4.9 - 5.06 (1H,

m), 7.6 - 8.0(5H, m)); 13C n.m.r. ô 170.33,168.78,1.68.07,1.34.29,]..3'1..6't',123.58,

60.72, 54.19, 52.40, 41,.29.

M e thyt 2- oxo -3 -phth aI o yI-L - azetidine ac e t v¡s (129)1' 0 a

N-Phthaloylserylglycine methyl ester (136) (7.57 g, 5.13 mmol) and

triphenylphosphine (1.36 g, 5.'J.9 mmol) were dissolved in tetrahydrofuran

(100 ml), then diethylazidodicarboxylate (DEAD) (O.Sf ml, 5.14 mmol) was

added dropwise under nitrogen. The reaction mixture was stirred at room

temperature overnight then quenched by the addition of water (100 ml) and

the resulting mixture was extracted into dichloromethane (2x100 ml). The

organic layer was washed with brine, dried and concentrated under reduced

pressure. The residue was purified by repeated preparative thin layer

chromatography on silica, eluting with a mixture of dichloromethane, light

EXPERIMENTAL

740

petroleum and íso-propanol (80:20:0.8) to give N -phthaloyl-cr, p-

didehydroalanylglycine methyl ester (137) as fine white needles (564 mg, 38Vo)

and a mixture of methyl 2-oxo-3-phthaloyl-1,-azetidineacetate (129) and

dicarboethoxyhydrazine. Repeated recrystallization of this mixture from

dichloromethane / light petroleum afforded methyl 2-oxo-3-phthaloyl-1-

azetidineacetate (729) as a white crystalline solid (48 mg,37o).

Methyl 2-oxo-3-phthaloyt-L-azetidineacetate (L29)- m.p. 178'C (lit.to¿

1,78 - f 80C); \max (CHCls) 7786, 7775, 7748, 1720 cm-7 (lit.to¿ (CHCI3) 1785,

'1,770, 1750, 1.720 cm-l); lH n.m.r. (300MFI2, CDCIg) ô 3.80 (3H, s, CHs), 3.84

(1H, dd, ]++, 5.3, 134,t orr 2.9 Í12, C4-H'), 3.91 (1H, dd, lZqrit 5.5, lq4, 5.3 Hz, C4-F{),

4.02 (1H, d,lglo, 18.0H2, Ccr-H), 4.58 (1H, d, Iao' 'l-.8.0H2, Cc-H'), 5.56 (1H, dd,

Igqri"5.5,lg4,tronr2.9ÍIz,C3-H), 7.73 -7.89 (4H,m, ArH); 13C n.m.r. ô "1.68.22,

766.86, 'l..64.99, ]34.M, 737.78, "123.69, 54.49, 52.42, 47.04, 43.76.

N-Phthaloyl-ø,8-didehydroalanylglycine methyl ester (137)- m.p. 121 -1,22"C; \max 3264, 7752,'].,722,']-,662,1628 cm-l; 1H n.m.r. (300MFIZ, CDCIg) ô

3.75 (3H, s, OCHe), 4.1,3 (2F{, d, / 5.1 FIz, NHCHz), 5.83 (1H, d, I 1..2H2, C=CHH),

6.24 (1H, d, I ],.2LIz, C=CFIH), 6.73 (1H, broad, NH), 7.73 - 7.77 (zFl,, m, ArH),

7.87 - 7.89 (2H, m, ArH); 13C n.m.r. õ 170.08, 1.66.40, 763.08, 1.34.55, 7432.29,

73]'66, 123.94, 120.9'1., 52.53, 41..57 .

N-Phthaloyl-B-chloroalanylglycine methyl ester (138)

N-Phthaloylserylglycine methyl ester (L36) (7,79 g, 5.84 mmol) was

dissolved in freshly distilled dry tetrahydrofuran (60 ml) under nitrogen.

Calcium carbonate (58 mg, 5.84 mmol) was added and the stirred mixture was

cooled in an ice bath to 0 - 5"C. Phosphorous pentachloride (7.46 g,

7.01 mmol) was added and the mixture was stirred at 0 - 5C for 10 min. The

EXPERIMENTAL

74't

ice bath was then removed from the reaction mixture and stirring was

continued at room temperature for a further t hr. The reaction mixture was

filtered, dried and evaporated under reduced pressure to give an oily residue

that was chromatographed on a squat column of silica, gradient eluting with

light petroleum and ethyl acetate. Recrystallization from ethyl acetate / light

petroleum afforded N-phthaloyl-B-chloroalanylglycine methyl ester (138) as a

white crystalline solid (1..31, g, 697o)- m.p. L3L'C; EI mass spectrum: mlz

326([M+], 1), 324 ([M+], 3),289 ([M+ - Ct],2), 288 ([M+ -HCl], 4), 257 (3), 238 (4),

236 (72), 21,0 (33), 208 (100); (Calcd for C1aH13N2O5CI [U+1 mlz 324.051,3.

Found: mlz 324.0502); (Anal. calcd for C14H1¡NzOsCl: C,57.78;H,4.04; N, 8.62.

Found: C, 52.07 ; H, 4.12; N, 8.42); v max 3272, 7782, 17 M, 7720, 7650, 722 cm-7 ; 7H

n.m.r. (300MIIZ, CDCIg) õ 3.77 (3H, s, CHr), 4.05 (2H., dd,15.7,2.7ÍIZ,NHCH2),

4.27 (7H, dd, ] 7'1,.3,5.7 flz, CIIHCI), 4.35 (lH, dd, I 1.'].,.3,70.5Ífz, CHHCI), 5.13

(lH dd, ] '1,0.5,5.7 Í1z., CHCHzCI), 6.77 (1H, broad, NFf), 7.76 -7.92 (4H, m, ArH);

13C n.m.r. õ 1,69.71.,'1.67.56,'1.66.45,734.65,"13'1,.35,1,23.95,55.13, 52.52, 47.36, 40.99.

Attempted cyclization of N-phthaloyl-B-chloroalanylglycine

methyl ester (138)

A solution of N-phthaloyl-B-chloroalanylglycine methyl ester (138)

(854 mg, 2.63 mmol) in dichloromethane and acetonitrile (19:1, 100 ml) was

added dropwise over 4 hr., to a stirred suspension of powdered potassium

hydroxide (177 mg, 3.15 mmol) and tetra-n -butylammonium bromide (1.46 mg,

0.53 mmol) in dichloromethane and acetonitrile (79:7, 100 ml). After the

addition was complete, stirring was continued for 30 min. The precipitate was

filtered off and washed with dichloromethane and the combined filtrates were

dried, and concentrated under reduced pressure. The residue was separated by

preparative thin layer chromatography on silica, eluting with a mixture of

EXPERIMENTAL

742

light petroleum and ethyl acetate to give N-phthaloyl-cr,p-didehydro-

alanylglycine methyl ester (137) (435 mg, 577o) and unreacted starting material

138 (165 mg,19Vo).

M ethyl cr-bromo -2- oxo-3-phthalo yl-7 - azetidine ace tate (13 9 )

A mixture of methyl 2-oxo-3-phthaloyL-'1.-azetidineacetate (129) (5.0 mg,

17.3 pmol) and N-bromosuccinimide (3.1 mg, 17.4 pmol) in carbon

tetrachloride and dichloromethane (5:1, 3 ml) was heated at reflux under

nitrogen, whilst irradiating with a 300 W mercury lamp, for 15 min. The

cooled reaction mixture was filtered through glass wool and concentrated

under reduced pressure to give a 3:2 mixture of diastereomers of methyl a-

bromo-2-oxo-3 -phth aüoyl-1. - azeti dine acetate ( L 3 9 ) : -

Major diastereomer: 1H n.m.r. (300MlIz, CDCte) ô 3.83 (3H, s, CHs), 3.96 (1H,

dd, I+q' 6.3, Ig¡'trors 3.8FJ2, C4-H'), 4.12 (7F{, dd, I+t' 6.3,lgatit 6.0H4 C4-H), 5.56

(1H, ddd, Ig¿rir 6.0, I34,t onr 3.8, /eo 0.8 Llz, C3-H), 6.M (1H, d, /go 0.8 Hz, Co-}{),

7.74 - 7.91 (4H, m, ArH).

Minor diastereomer: 1H n.m.r. (300MH2, CDCIs) ô 3.84 (3H, s, CHg), 4.02 (7H,

dd, ]+4, 6.8,lgqrit 6.5H2, C4-H), 4.08 (1H, dd, ]++' 6.8,I3t'trons3.5ÍIz, C4-H'), 5.M

(1H, ddd, Iz+tit 6.5, Isq't onr 3.5, /ao 0.8 ÍIz, C3-H), 6.46 (1H, d, /ac, 0.8 Hz, Co.-FI),

7.74 -7.97 (4I{, m, ArH).

EXPERIMENTAL

1.43

Functionalization of N-Substituted y-Lactams

Preparation of the 2-pyrrolidinones 14L and \42

N-(4-Chlorobutyryt) glycine methyl ester (143)

Thionyl chloride (30.5 g, 256 mmol) was added dropwise to methanol

(150 mt). Glycine (82) (19 g,253 mmol) was added and the solution was stirred

in dry apparatus at room temperature, for 3 hr. The solution was then

concentrated under reduced pressure to give glycine methyl ester

hydrochloride (135).

4-Chlorobutyryl chloride (L45) (32 g, 227 mmol) was dissolved in

dichloromethane (200 ml) and a solution of the crude glycine methyl ester

(135) in dichloromethane (100 ml) and water (100 ml) was added. Sodium




dried, and concentrated under reduced pressure. The residue was distilled to

give N-(4-chlorobutyryl)glycine methyl ester (143) as an oil. (20.6 g,47Vo)i b.p.

136"C / O.0S mm; (Calcd for C7H12NO3C1 [M+] mlz 193.0506. Found: mf z

193.0699); (Anal. calcd for CTHzNO3CI: C, 43.41,; H, 6.25; N, 7.23. Found: C,

43.23; H,6.55; N,7.15); v*a¡ (liquid fitm) 3304,2952,7752,1656 cm-l; 1H n.m.r.

(300MH2, CDC13) õ 2.13 (2F{, tt,l 7.2,6.2H2, CHzCHzCI), 2.46 (2F{, t,l 7.2H2,

CHzCONH), 3.63 (2F{, t, | 6.2H2, CHzCI), 3.76 (3H, s, CH3), 4.04 (2I{, d, | 5.4H2,

NCHz), 6.67 (7H, broad, NH); 13C n.m.r. E 172j17, 770.30, 52.1.5, M.20, 41'.03,

32.62,27.98.

EXPERIMENTAL

.I.M

Methyl 2-oxo-1-pyrrolidineacetate (141)

A solution of N-(4-chlorobutyryl)glycine methyl ester (143) (1.94 g,

10 mmol) in dichloromethane and acetonitrile (\9:7, 200 ml) was added


(672mg, 12 mmol) and tetra-n-butylammonium chloride (556 mg, 2 mmol) in

dichloromethane and acetonitrile (79:'1,, 200 ml). After the addition was





petroleum and ethyl acetate. The resulting oil was distilled to give methyl 2-

oxo-1-pyrrolidineacetate (14L). (877 rng, 55Vo)¡ b.p. 130'C /0.02 mm (block);

vrry¡ï (liquid film) 2940,1754,1.685,1430 cm-1 (lit.trz 2960,1752,1685, 1440 cm-l);

1H n,m.r. (300MH2, CDCIa) ô 2.01 (2I{,tt, ]'8.1,7."1.ÍIz,C4-H2), 2.43(zfl,,t,l

8.1.H2, C3-H2), 3.50 (2H, t, I 7.7H2, CS-Hz), 3.74 (3H, s, CH¡), 4.08 (2FI, s,

Ccr-Hz); 13C n.m.r. õ 775.32 (amide C=O), 168.85 (ester C=O),51.83 (CH3¡, 47.41,

(c5), 43.61(Ca), 29.96 (C3),17.66 (C4) (lit.ltz 175.36,'1.68.94,5'1..87, 47.43, 43.69,

30.02,17.68).

N- (4-Chlorobutyryl) aminoacetonitrile (1-44)

4-Chlorobutyryl chloride (145) (35.3 g, 250 mmol) was dissolved in

dichloromethane (200 ml) and a solution of aminoacetonitrile

hydrochloride (146) (24 g, 259 mmol) in water (100 ml) and dichloromethane

(100 ml) was added. Sodium bicarbonate was added as required to keep the

solution basic and the mixture was stirred at room temperature for 4 hr. The

EXPE,RIMENTAL

1.45

reaction mixture was filtered and the dichloromethane layer was separated,

washed with water (3 x 50 ml), dried, and concentrated under reduced pressure

to give a crude white solid which was recrystallized from ethyl acetate / light

petroleum to give N-(4-chlorobutyryl)aminoacetonitrile (744) as fine white

crystals. (21,.5 9,547o)- m.p. 73"C; (Calcd for C6HeNzOCl ïi|'l+l mlz 160.0403.

Found: mlz 160.0478); (Anal. calcd for C6HeN2OCI: C, M.86; H, 5.65; N, 17.43.

Found: C, 45.06; H, 5.47; N, 17.56); \,tmax 3325, 2250, 1645 cm-1; 1H n.m.r.

(300MFIZ, CDCts) õ 2.1,4 (2}l, tt, ] 7 .2, 6.2Í12, CHzCHzCI), 2.47 (2ÉI, t, ] 7.2H2,

CH2CONH), 3.62 (2F{, t, I 6.2Í12, CH2CI), 4.79 (2F{, d, / 5.8 Hz, NCHz), 6.62 (1H,

broad, NH); 13C n.m.r. õ 772.24,1.'1.6.1,5, M.20, 32.49,27.63,27 .51..

2-Oxo-L -pyrrolidineacetonitrile (1,42)

A solution of N-(4-chlorobutyryl)aminoacetonitrile (L44) (1.6t g,

10 mmol) in dichloromethane and acetonitrile ('1,9:1,, 200 ml) was added


(672m.9, 12 mmol) and tetra-n-butylammonium chloride (556 mg, 2 mmol) in

dichloromethane and acetonitrile (79:'1., 200 ml). After the addition was



dried, and concentrated under reduced pr"rr,rr" to give an oil that was


petroleum and ethyl acetate. The resulting oil was distilled to give 2-oxo-1-

pyrrolidineacetonitrile (L42), which solidified upon refrigeration as a

translucent white crystalline solid. (842mg, 677o):- m.p. 32 - 34"C; b.p.

115"C/0.02mm (block); (Calcd for C6HgNzO [M+] mlz 724.0637. Found: mlz

724.0699); (Anal. calcd for C5,H3N2O: C, 58.05; H,6.50; N, 22.56. Found: C,57.78;

H,6.29;N,22.79); ymax (liquid film) 2940,2725, 1685, 1420 cm-1; 1H n.m.r.

EXPERIMENTAL

746

(300MFIZ,CDCI¡) E 2.1.4(2I-{,tt,18.7,7.'l.flz,C4-Hz),2.42(2Í1,t,]'8.'l.TIz,C3-Hz),

3.53 (zIJ', t, I 7.1,H2, C5-H2), 4.26 (2}{, s, CHzCN); 13C n.m.r. õ 774.4'1., 'j..74.29,

46.03, 29.97, 29.'1.4, 1,6.75.

EXPERIMËNT.AL

147

Functionalization of tlrre 2-pyrrolidinones L4l and T42

Methyl a-ethoxy-2-oxo-'1.-pyrrolidineacetate (149) and methyl trans-

4-bromo -5 -e thox y -Z-oxo -L -pyrrolidine ace tate (1 5 0 )

A mixture of methyl 2-oxo-1-pyrrolidineacetate (141) (412mg'

2.62 mmol) and N-bromosuccinimide (514 mg, 2.89 mmol) in carbon

tetrachloride (15 ml) was heated at reflux under nitrogen, whilst irradiating

with a 300 W mercury lamp, for 10 min. The reaction mixture was then cooled

to room temperature, dry ethanol (310 pl, 5.28 mmol) and 2,6-lutidine (620 ¡tl,

5.32 mmol) were added and the mixture was stirred at room temperature

under nitrogen for 2.5 hr. The reaction mixture was filtered and evaporated

under reduced pressure. The residue was taken up in ethyl acetate and washed

successively with very dilute hydrochloric acid, brine, saturated aqueous

sodium bicarbonate and brine again. The organic layer was dried and

concentrated under reduced pressure and flash column chromatography of the

residue on silica, eluting with a mixture of ethyl acetate and light petroleum

(40:60), yielded two products,149 and 150.

Methyl a-ethoxy-2-oxo-L-pyrrolidineacetate (L49) as an oil. (195 mg,

37Vo)- b.p. 75'Cl0.015 mm (block); FAB mass spectrum: mfz 201 ([M+], 12),

156 ([M+ - OEt], 100), 142 ([M+ - CO2Me),36), 728 (77), t08 (79); (Calcd for

C7H12NO2 [M+ - CO2Me] mlz 142.0868. Found: mlz 142.0875); Ymax (liquid

film) 2980,7754,1702,741,8,1268,1100 cm-1; lH n.m.r. (300MH2, CDCIg) õ 1'.26

(3H, t, 17.0ÍIz, OCHzCHa), 2.70 (2I{, m, C4-H2), 2.47 (2F{,1,] 8.7H2, C3-Hz),

3.37 (1H, ddd, / 9.8,7.8, 6.5}l2, Cs-H), 3.47 (7H, ddd, / 9.8, 7.8, 6.2Ílz, Cs-H'),

3.57 (zIJ, q, I 7.0}ir2, OCHzCHg), 3.79 (3H, s, CO2CHù, 5.75 (lH, s,Ca-H); 13ç

EXPERIMENTAL

748

n.m.r. ô 'J,76.04,'I..67.45, 78.36, 64.32, 52.50, 42.39, 30,80, 77.94,'1,4.58. This

compound was not stable for elemental analyses.

Methyl trans-4-bromo-5-ethoxy-2-oxo-1-pyrrolidineacetate (150) as an oil.

(60 mg, 9Vo)¡ b.p. 85'C/0.015 mm (block); EI mass spectrum: mlz 282 ([M+ +

Hl,7), 280 ([M+ + H, M+ - H], 72), 278 ([M* - H], 5), 249 ([M+ - MeOH], 8), 247

([M+ - MeOH] , 8), 235 ([M+ - EtOH], 11), 234 ([M+ - H - EtOH],98), 233 ([M+ -EtOHl, 11), 232 ([M+ - H - EtOH], 100), 199 ([M+ - HBr], 28); (Anal. calcd for

CsHr¿NO4Br: C, 38.59; H,5.04; N, 5.00. Found: C, 38.58; H,4.95;N,4.90); vrnay

(liquid film) 2980, 1750, 1720, 1.M2, 121.2, ],072, 702 crn-7; 1H n.m.r. (300MIIz,

CDCIa) õ 1,.24 (3H, t, I 7.0 Í12, OCH2CHI), 2.76(7H, dd, Iz3' 1.8.2, ls'4¡¡ans 2.9 Í12,

C3-H'), 3.23 (7H, ddd, /33' 1.8.2, ls4ç¡e 7.4, Isg- 0.9 Hz, C3-H), 3.67 (1H, dq, J 9.4,

7.0ÍIz, OCHHCH3), 3.70 (1H, dq, 19.4,7.0Ílz,OCI{HCÍb), g.ZZ (3H, s, COzCHs),

3.81 (1H, dd, /o,o,' 77.6,lg¡^ 0.9H4 Ccr-H), 4.24 (1H, dd, Igqr¡t 7.4, Iz'+tror, 2.9,

Ils'trorr7.5Hz, C -H), 4.43 (1H, d, Ioo' 77.6H2, Cg-H'), 5.2'l' (1H, d, I4s'tront

'l'.5ÍIz, CS-H'); 13C n.m.r. õ 17"1.22,1'68.64,96.30,64.35,52.'l'8,41'.3'l',4'l'.'l'7,39.48,

75.17.

In a subsequent treatment of the pyrrolidinone 1-41 with N-bromo-

succinimide and ethanol as described above, chromatography of the crude

product mixture yielded, in addition, methyl trøns-4-bromo-5-hydroxy-2-oxo-L-

pyrrolidineacetate (151) as an oil- vrn6 (liquid film) 3400,2980,1750,1722,7256,

7057, 706 cm-l;1H n.m.r. (300MH2, CDCIg) ô 2.73 (1lH, dd, /ss' 78.7, ls'4¡ysng

2.4Ífz, C3-H'), 3.33 (1H, dd,lgg'78.7,lg4ç¡56.9flz, C3-H), 3.78 (3H, s, COzCHg),

4.09 (1H, d, /crs, 77.8}{2, Ccr-H), 4.27 (7H, ddd, J3aç¡t 6.9,lg,4tront2.4, I1s'tront

'1..5Í12, C4-H), 4.36 (7H, d, /oo' 77.8H2, Ccr-H'), 5.11 (1H, broad, OH), 5.40 (1H,

d, I4s'trons1..5Hz, CS-H'). This compound was not stable for complete

characterization.

EXPERIMENTAL

749

cr-Ethox y -2- oxo -1, -pyrrolidineace to ni trile (1 5 9 ) and tr ans -4 -bromo -

S-ethoxy -2- oxo -'1,-pyrrolidineace tonitrile (L 6 0 )

A mixture of 2-oxo-1-pyrrolidineacetonitrile (L42) (260 mg, 2.09 mmol)

and N-bromosuccinimide (410 mg, 2.30 mmol) in carbon tetrachloride and

dichloromethane (2:1,, 78 ml) was heated at reflux under nitrogen, whilst

irradiating with a 300 W mercury lamp, for L0 min. The reaction mixture was

then cooled to room temperature, dry ethanol (250 pl, 4,26 mmol) and 2,6-

lutidine (490 pl,4.2L mmol) were added and the mixture was stirred at room

temperature under nitrogen for 2.5 hr. The reaction mixture was filtered and

evaporated under reduced pressure. The residue was taken up in ethyl acetate

and washed successively with very dilute hydrochloric acid, brine, saturated

aqueous sodium bicarbonate and brine again. The organic layer was dried and

concentrated under reduced pressure and flash column chromatography of the

residue on silica, eluting with a mixture of ethyl acetate and light petroleum

(40:60) yielded two products, 159 and L60.

cr-Ethoxy-2-oxo-L-pyrrolidineacetonitrile (L59) as an oil. (92.2mg,26Vo)-

b.p.70"C/ 0.01 mm (block); EI mass spectrum: mlz 768 ([M+], 7), 167 ([M+ - H],

M), 1.42 ([M+ -CN], 46), 1,23 ([M* - OEt], 100); (Calcd for CsHl2N2OzlM+)mlz

168.0899. Found: mlz 1.68.0897; Calcd for CTFJ¿NOz [M+ - CN] mlz 1,42.0868.

Found: mlz 1,42.0875); (Anal. calcd for C3H12N2O2: C,57.'1.3;H,7.79; N, 16.65.

Found: C, 56.07; H, 6.86; N, 16.26); v^o, (CHzClz) 2900, 2250, 1772, 1.404, 1260,

1084 cm-1; lH n.m.r. (300MH2, CDC\) õ 1.25 (3H, t, I7.0flz, OCHzCHg), 2J1,5

(2IJ, m, C4-H:), 2.48 (2H., t, I 8.2H2, C3-Hù, 3.53 - 3.66 (4H, m, OCHzCH3 and

CS-HÐ, 6.02 (1}{, s, Ca-H); 13C n.m.r. õ 775.74,1.1.4.77,70.08,64.49,42.63,30.24,

17.36,14.20.

trans-4-Bromo-5-ethoxy-2-oxo-1-pyrrolidineacetonitrile (160) as an oil.

(39.5 mg, 8Vo)- b.p.75"C/ 0.01 mm (block); FAB mass spectrum: mlz 249 (ÍMr+

EXPERIMENTAL

150

+ Hl, 51), Z+7 ([M+ + H),52), 203 ([M+ - EtOH], 9B), 201. ([M* - EtOH], 700), 178

(85),776 (87), 1,67 (Í]¡l'{+ - HBrl, 52), (Anal. calcd for CgH11N2O2Br: C, 38.89; H,

4.49;N, 11.33. Found:C,38.58;H,4.47;N,L1.11); vmax (CDCLI)2984,2248,1730,

'1,4'1,0,7262,7078,708 cm-1; 1H n.m.r. (300MH2, CDCIg) õ 1.29 (3H,t,17.0ÍIz,

OCH2CH3), 2.76 (1H, dd, þy 1,8.4, 13'4t orr 2.1. Hz, C3-H'), 3.24 (1F{, ddd, lgg, ]..8.4,

Igati"7.2,]so0.8Hz,C3-H), 3.77(1H,dq,19.4,7.0Í|4OCHHCH1).3.76(7H,dql

9.4,7.0ÍIz, OCHHCHg), 4.07 (7H, dd, /ocr, 17.5,lg.-0.8Ífz, Ccr-H), 4.25 (1H, ddd,

IUc¡s7.2, Ig'¡trons2.7,l45,t øns'I.,.7H2, C -H), 4.51, (7H, d, I9.g, 77.5ÍIz, Ca-H'), 5.1.5

(1H, d, I45,tror, 1..7 Í12, CS-H'); 13C n.m.r. ô 177.73, 774.17, 95.77, 64.85,40.80,

39.'1.0,29.54,15.05.

In a subsequent treatment of the pyrrolidinone 142 with N-bromo-

succinimide and ethanol as described above, chromatography of the crude

product mixture yielded, in addition, 3,4-didehydro-5-ethoxy-2-oxo-L-

pyrrolidineacetonitrile (161) as an oil:- EI mass spectrum: mlz 166 (llll'4+1,2),

121 ([Vf+ - OEt], 100), 55(35); (Calcd for CaHrolrizOz [M+] mlz 166.0742. Found:

mlz 1.66.0730); ymax (liquid film) 3090, 2978, 7776, 1598, 7406, 1098 cm-li 7H

n.m.r. (CDCI¡) õ '1,.25 (3H, t, I 7.7H2, OCHzCHI), 3.60 (1H, dq,,]f9.3, 7.1. Hz,

OCHHCH3), 3.61(1H, dq, I 9.3,7.7H4 OCHHCHg), 4.77 (1H, d, lg;s' 17.5fI2,

Ca-H), 4.46 (1H, d,loo,77.5Hz, Ccr-H'), 5.53 (1H, d,lqs7.5ffz, C5-H), 6.30 (1H,

d,lgq6.7ÍIz, C3-H), 7.07 (7H,dd,lsq6.7,lqS7.5flz, Ca-H); 13C n.m.r. õ '1.68.46,

'1.45.5'].., 728.99, 11,4.7 g, g7 .69, 60.24, 27 .32, 74.93.

EXPERIMENTAL

151

Endocyclic Functionalization and Elaborationof y-Lactams

Preparation of the 2-pyrrolidinon es L71. and 172

1 -(3-Butenyl) -2-oxopynolidine (17 1)

Sodium hydride (80% w/w, 1.83 g,61.0mmol) was washed with light

petroleum and then stirred in xylene (125 ml) under nitrogen. To this

suspension, Z-pyrcolidinone (L73) (4.75 g, 55.8 mmol) in xylene (50 ml) was

added slowly with stirring under nitrogen. After the foaming had subsided the

mixture was heated at 110"C for L hr. Upon cooling to room temperature,4-

bromo-l-butene (77.25 ml, 111 mmol) was added to the salt, and the mixture

was then heated at reflux overnight under nitrogen. The reaction mixture was

cooled to room temperature, washed with water (150 ml), dried, and

concentrated under reduced pressure. The residue was distilled to give 1-(3-

butenyl)-2-oxopyrrolidine (771) as a colourless liquid. (1,.43 g, 747o)7 b.p.

80'C/0.Lmm (block); EI mass spectrum: mfz 139 ([M+],9), 98 ([M+ - C¡HS],

100), 70 (28); (Calcd for CsHl3NO [M+] rnlz 1.39.0997. Found mlz 139.1003);

Vmax (liquid film) 3076 ,2920, 7674, 1,61,8,918 cm-1; 1H n.m.r. (300MIlz, CDCIg) ô

2.00 (zIJ, tt, I 8.7, 7.7 Hz, C4-r{), 2.29 (2}l, ddt, / 7.2, 6.9, '1..7 flz, CH2CH=CH2),

237 (2}J, t, I 8.7 Hz, C3-Hz), 3.36 (2H, t, | 7.2H2, NCHz), 3.39 (2}j,', t, I 7.7 Hz,

C5-H2), 5.01 - 5.1,2 (2}]., m, CH=CH2), 5.77 (tI-{, ddt, / 1.7.1., 70.2, 6.9H2,

CH:CHz); 13C n.m.r. õ 774.64 (C=O), 734.87 (C3'), 116.53 (C4'), 46.88 (C5),41,.43

(Cl'¡, 37.54 (Cz',¡,30.77 (C3), 77.64 (C4).

EXPERIMENTAL

L52

N- (p-Me thoxyphenyl) -4 -chlorobutyrami de (17 5)

4-Chlorobutyryl chloride (146) (30 g, 213 mmol) was dissolved in

dichloromethane (200 ml) and a solution of freshly recrystallized p-anisidine

(L74) (28.8 g,266 mmol) in dichloromethane (100 ml) was added dropwise with

stirring. After the addition was complete the solution was stirred at room

temperature for a further 4 hr. The solution was then washed with water (3 x

100 ml), dried, and evaporated under reduced pressure to give an oil that

solidified on standing. The residual solid was recrystallized from ethyl acetate

/ light petroleum to give N-(p-methoxyphenyl)-4-chlorobutyramide (L75) as a

white crystalline solid. (23.8 g,547o):- m.p. 85"C; (Calcd for C11H1¿NOzCI [M+]

mlz 227.071.3. Found: mlz 227.0757); (Anal. calcd for C11H1¿NOzCI: C, 58.01.; H,

6.20; N, 6.15. Found: C, 58.31 ; H, 5.87; N, 6.14); v*o, 3308, '1.662, 7620, 1518, 1240,

7024, 840 cm-1; 1H n.m.r. (300 MHz, CDCIa) õ 2.73 (2}l, tt, I 7.2, 6.2H2,

CHzCHzCI), 2.48 (2F{, t, I 7.2ÍIz, CHzCI), 3.59 (2}l., t, J 6.2H2, CH2CONH), 3.76

(3H, s, OCH3), 6.80 (2H, m, ArH), 7.38 (zIF', m, ArH), 8.06 (1H, broad, NH); 13ç

n.m.r. õ']..69.U,756.40,1.30.70,721,.80,774.07,55.44,M.50,33.89,27.94.

1 - (p-Methoxyphenyl) -2-oxopyrrolidine (L7 2)

A solution of N-(p-methoxyphenyl)-4-chlorobutyramide (175),(2.28 g,

10 mmol) in dichloromethane (200 ml) was added dropwise over 6 hr., to a

stirred suspension of powdered potassium hydroxide (672mg, 12 mmol) and

tetra-n-butylammonium chloride (556 mg, 2 mmol) in dichloromethane

(200 ml). After the addition was complete, stirring was continued for 30 min.

The precipitate was filtered off and washed with dichloromethane (2 x 50 ml).

The combined filtrates were dried, and concentrated under reduced pressure to

give an oil that was chromatographed on a squat column of silica gel, gradient

EXPERIMENT,AL

1s3

eluting with light petroleum and ethyl acetate. The resulting solid was

recrystallized from ethyl acetate / light petroleum to give 1-(p-methoxy-

phenyl)-2-oxopyrrolidine (172) as fine transparent leaves. (1.19 g,63Vo)- m.p.

108C; (Calcd for C11H1gNOz [M+) mlz 791..0946. Found: mlz 791..7005); (Anal.

calcd for C11H13NO2: C,69.09;H,6.85;N,7.32. Found: C,69.09;H,6.93; N, 7.35);

v*or 1,682,]612,151,4,1252,],032,830 cm-1; lH n.m.r. (300MH2, CDCIg) õ 2.12

(2Ê1, tt, I 8.1, 7 .0 ÊIz, C4-Hz), 2.56 (2Il, t, I 8.'1. TIz, C3-H2), 3.78 (3H, s, OCHg), 3.80

(zIJ, t,l 7.0H2, CS-Hz\, 6.89 (2f1, m, ArH), 7.48 (2t{, m, ArH); 13C n.m.r. õ

173.90,756.49,1,32.53,'1,21..79,'1.'1.3.96,55.4'1,,49.'1.5,32.42,17.98.

EXPERIMENTAL

tv

Functionalization of the 2-pyrrolidinones 769 - L72

tr ans-4-Bromo-5-ethoxy- L,3,3-trimethyl-2-oxopyrrolidine (1 76) and

4,4- dlbr omo -5 -e th oxy -1,3,3- trim e thyl-2 - ox op yrr oli d ine (17 7 )

A mixture of 1.,3,3-trimethyl-2-oxopyrrolidine (L69) (252 mg, 1.98 mmol)

and N-bromosuccinimide (705 mg, 3.96 mmol) in carbon tetrachloride (a0 ml)


lamp, for 10 min. The reaction mixture was cooled to room temperature, dry

ethanol (240¡rl,4.09mmol) and 2,6-lutidine (230¡.t1, 1.97 mmol) were added

and the mixture was stirred under nitrogen for 3 hr. The reaction mixture was

filtered and evaporated under reduced pressure, the resultant residue was

taken up in ethyl acetate and washed successively with very dilute

hydrochloric acid, brine, saturated aqueous sodium bicarbonate and brine. The

organic layer was dried and concentrated under reduced pressure and flash

column chromatography of the residue on silica, eluting with a mixture of

light petroleum and ethyl acetate (2:5), then afforded two products, L76 andL77.

trans-4-Bromo-5-ethoxy-1.,3,3-trimethyl-2-oxopyrrolidine (176) as an oil.

(46mg,9Vo)- EI mass spectrum: mlz 251 ([M+],6), 249 (íM+),6), 206 ([M+ -OEtl, 66), 204 ([M+ -OEt], 67), 792 (11), 190 (77), 770 ([M+ - Br],21), 1,49 (13.5),

1.47 (1,4), 113 (100), 85 (81); (Calcd for CqHrcl.JOzBr lM+1m12249.0364. Found:

mlz 249.0¡55); ymax (liquid film) 2972, 7708, 1,276, 7064,760 cm-l; 1H n.m.r.

(300MH2, CDCIs) E 1,.22 (3H, s, C3-CHg), 1.28 (3H, s, C3-CHg), 1..29 (3}j,, t,l7 .0 Hz, OCH2CH s), 2.87 (3H, s, NCH3), 3.74 (7H, dq, | 9.4, 7 .0 Hz, OCHHCHa),

3.80 (1H, dql9.4,7.0Hz,CHHCH3), 3.98 (1H, d, Ils'trans3.8Hz,C4-H),4.89 (1H,

d,145'trrnr 3.8F{z, C5-H'); 13C n.m.r. õ 775.55,95.57, 65.67,57.92, 44.84,27.1.3,

24.19,23.95,75.47.

EXPERIMENTAL

155

4,4-D ibr omo-S- eth oxy -1.,3,3 -trimethyl- 2-oxopyrrol idine (L7 7) as an oil.

(91 mg, l47o)- EI mass spectrum: mlz 337 ([M+], 9), 329 ([M+], 18), 327 ([M+],

9), 286 ([M* - OEt], 21), 284 ([M+ - OEt], 42), z9z ([M+ - OEt], 21), 250 ([M+ - Br],

5), 248 ([M+ - Br], 5), 206 (31.), 204 (32), 165 (98), 163 (100); (Calcd for

CeHl5NOzBrz [M+] mlz 326.9470. Found: mlz 326.9a6D; v,,a¡ (liquid film) 2976,

17'1.4, 1294,'1.064,770 cm-7; 1H n.m.r. (300MFIz, CDCIg) õ 1.30 (3H, t,l 7.0ÍIz,

OCHzCHa), 1.38 (3H, s, C3-CHs), 1..42 (3H, s, C3-CH3),2.92 (3H, s, NCHs), 3.81

(1H, dq, 19.4,7.0ÍIz, OCHHCHg), 4.77 (1H, dq, 19.4,7.0H2, OCHHCHù, 5.02

(1H, s, C5-H); 13C n.m.r. ô 173.52,98.55, 75.70, 68.39,51.81., 26.97, 24.54, 24.08,

15.15.

Treatment of 1-methyl-2-oxopyrrolidine (L70) with

N-bromosuccinimide

A mixture of l-methyl-2-oxopyrrolidine (170)177 1239 ng, 2.32mmol)

and N-bromosuccinimide (826 mg, 4.64 mmol) in carbon tetrachloride (20 ml)


lamp, for 1.0 min. The cooled reaction mixture was filtered through glass wool

and concentrated under reduced pressure to give an oil containing an

appfoximately 5:2 mixture of trans-4,5-dibromo-1-methyl-Z-oxopyrrolidine

(184) and 4,4,5-tribromo-1-methyl-2-oxopyrrolidine (L85) as judged by 1H n.m.r.

spectroscopic analysis. No discrete products were isolated from this reaction

mixture.

trans-4,5-Dibromo-L -methyl-2-oxopyrrolidine (184):- 1H n.m.r. (300MH2,

CDCIg) õ 2.90 (3H, s, NCH3), 3.08 (1H, d,133'78.5H2, C3-H'), 3.29 (1H, dd, /s¡'

1.8.5, Is+c¡s 5.9 Hz, C3-H), 4.87 (1H, d, ]sqr;r 5.9 Hz, C4-H), 6.72 (7H, s, C5-H').

EXPERIMENTAL

156

4,4,5-Tribromo-L-methyl-2-oxopyrrolidine (185):- 1H n.m.r. (300MH2,

CDCIs) õ 2.95 (3H, s, NCH3), 3.39 (1H, d,I33'77.5Í1,2, C3-H), 3.47 (7H, d, ]33'

17.5ÍIz, C3-H'), 6.34 (1H, s, CS-H).

tr ans - 4-Bro mo -5 - etho xy- L -me thyl- 2-oxopyrr olidine ( L 8 6 ) and

4,4-dibr omo-5-ethoxy- 1 -methyl-2-oxopyrrolidine (L87)

A mixture of l-methyl-2-oxopyrrolidine (170)117 (769mg, 1,.7L mmol)

and N-bromosuccinimide (607 rr.g,3.4L mmol) in carbon tetrachloride (20 ml)


Iamp, for 10 min. The reaction mixture was cooled to room temperature, dry

ethanol (200 ¡.t1, 3.41 mmol) and 2,6-lutidine (200 ¡tI, 7.72 mmol) were added

and the mixture was stirred under nitrogen for 3 hr. Upon workup, as above

for the similar treatment of the pyrrolidinone 169, the residue obtained was

purified by preparative thin layer chromatography on silica, eluting with a

mixture of light petroleum and ethyl acetate (50:50), affording two products,

186 and 187.

trans-4-Bromo-5-ethoxy-L-methyl-2-oxopyrrolidine (186) as an oil.

(34rng, 97o)- EI mass spectrum: mlz 223 (îM+1,9), 221. ([M+1,9), 178 ([M+ -OEtl, 98), 776 ([M+ - OEt], 100), 150 (28), 748 (29), 1,42 ([M* - Br], 11); (Calcd for

CTHl2NOzBr [M+] mlz 221,.0051. Found: mlz 221.0058); v¡7aa (liquid film) 2976,

7772,'1.262, 1.068,708 cm-l; 1H n.m.r. (300MFIz, CDCIa) õ 7.26 (3H, t, I 7.0f12,

OCHzCHg), 2.65 (7H, dd, /gg' 77.9, ]z'q,tror, 7.4H2, C3-H'), 2.92 (3H, s, NCHg),

3.2'1. (7H, dd, /g¡' 77.9,lzq,cis 6.8}{2, C3-H), 3.63 (1H, dq, J 9.2,7.0ÍIz, OCHHCH3),

3.68 (1H, dq., I 9.2,7.0H4 OCHHCHT), 4.24 (7H, ddd, Izqc¡s 6.8, I3,Atrons 7.4,

EXPERIMENTAL

1,57

I4s,tronr 0.9 tIz, C4-H), 4.97 (1H, d, I1s't orr 0.9 Hz, CS-H'); 13C n.m.r. ô 771,.29,

97 .90, 63.93, 4'1..64, 39.54, 27 .50, 1.4.99.

4,4-Dibromo-5-ethoxy-1-methyl-2-oxopyrrolidine (187) as an oil. (54 mg,

'1.'1,7o)- EI mass spectrum: mlz 303 ([M+], 18.5), 301 ([tt4+¡ ,37.5), 299 ([M+] , 19),

258 ([M+ - OEr], 49.5), 256 ([M+ - OEt], 't00), 254 ([M+ - OEt],50.5), 230 (9), 228

(18), 226 (9), 222 ([M+ - Brf,7), 220 ([M+ - Br],7); (Catcd for CTHIlNOzBrz [M+]

mlz 298.9157. Found: mlz 298.9153); v¡nay (Iiquid film) 2976, 17'1,0, 1,282,1..072,

752 cm-l; 1H n.m.r. (300MH2, CDC13) ô 1.32 (3}]', t, ] 7.0 ÍIz, OCH2CH), 2.93

(3H, s, NCH3), 3.36 (1H, d,lss' 17.6Ílz, C3-H), 3.51 (1H, d,l3s, 17.6Í12, C3-H'),

3.80 (1H, dq, I 9.3, 7 .0 Hz, OCHHCH3), 4.07 (1H, dq,, I 9.3, 7 .0 I{2, OCHHCHT),

5.02 (1H, s, CS-H); 13C n.m.r. õ 168.8,99.19,67.76,57.33,52.29,27.64,74.89.

Upon a subsequent treatment of 170 (691, mg, 6.97 mmol) with N-bromo-

succinimide (1.37 g,7.67 mmol) followed by treatment with dry ethanol and

2,6-lutidine as described above, chromatography of the crude product mixture

thus obtained afforded 186 (30 mg, 2Vo) and Í87 (137 mg, 6%) and in addition

189 and L90.

4-Bromo-3,4-didehydro-5-ethoxy-1-methyl-2-oxopyrrolidine (189) as an

oil. (26l¡:.g,2%)- (Calcd for CTHlsNO2Br [M+] mlz 278.9895. Found: mlz

218.9887); v*r, (liquid film) 3078, 2980, 1706, 1,633, 7282,1118, 950, 688 cm-1;

1Hn.m.r. (300MH2, CDCIg) ô 1.25 (3H, t, J 7.OHz, OCHzCHg), 2.93 (3H, s,

NCHa), 3.32 (2fI, q, I 7.OHz, OCH2CHg), 5.21, (1H, s, C5-H), 6.42 (1H, s, C3-H);

13C n.m.r. õ 1,67.58,138.08, 130.00, 90.9'1., 58.37, 26.40, 74.96.

4,4-Dtbromo-5-hydroxy-1.-methyl-2-oxopyrrolidine (190) as an oll.;- v¡nay

(CHzClz) 3380, 7708, '1256,1034 cm-1; 1H n.m.r. (300MH2, CDCII) õ 2.96 (3H, s,

NCH3), 3.40 (1H, d,]zz'17.6ÍIz, C3-H), 3.57 (7H, d,133'17.6H2, C3-H'), 4.69 (1H,

broad, OH), 5.29 (7H, s, CS-H).

EXPERIMENTAL

158

trans-4-Bromo-L-methyl-2-oxo-5-phenylthiopyrrolidine (191) and

L -phenylthiomethyl-2-oxopyrrolidine (192)

A mixture of 1-methyl-2-oxopyrrolidine (170) (195 mg, 1.97 mmol),

N-bromosuccinimide (740mg,4.1.6 mmol) and a catalytic amount of AIBN in

carbon tetrachloride (35 ml) was heated at reflux under nitrogen, whilst

irradiating with a 300 W mercury lamp, for 6 min. The reaction mixture was

immediately cooled to room temperature, thiophenol (410 ¡tt,3.99 mmol) and

2,6-lutidine (460 pl, 3.95 mmol) were added and the mixture was stirred at

room temperature under nitrogen for 2 hr. The residue obtained upon

workup was purified by preparative thin layer chromatography on silica,

eluting with a mixture of light petroleum and ethyl acetate (50:50) and afforded

two products, 191 and 192.

trans-4-Bromo-L-methyl-2-oxo-5-phenylthiopyrrolidine (191) as an oil.

(139 mg, 25Vo)- EI mass spectrum: mlz 287 ([M*], 3), 285 ([M+], 3), 205 ([Vf+ -HBrl, 45), 177 ([M* - PhSH], 98), 775 ([M* - PhSH], 1.00), 749 (50), 1,47 (51), 108

(7t¡; (Calcd for CrrHr2NOSBr lM*l mlz 284.9823. Found: mlz 2M.9871); ymax

(liquid film) 3054,2934, 1722, 1,584, 7476 crn-1; 1H n.m.r. (300MI{2, CDCIg) ô

2.38 (7H, dd, .lgg' 78.4, Jg4ç¡e 6.5 TIz, C3-H), 2.57 (1H, dd, /ga' 18.4, l3'4¡yans L.2H2,

C3-H'), 3.06 (3H, s, NCH¡), 4.53 (1H, ddd, Izq,c¡s 6.5, I3,4trons 7.2,l4s'trans 1..LÍIz,

C4-H) , 4.98 (7H, d, I 45' tron, '!. .7 tIz, Cs-H'), 7 .23 - 7 .57 (slts,', m, ArH); 13C n.m.r.

'ô 171.08, 734.55,734.75,129.60,729.36,77.27,44.63,40.20,28.20. This compound

was not stable for elemental analyses

1-Phenylthiomethyl-2-oxopyrrolidine ('1.92) as an oil. (10.4 mg, 3Vo)- EI

mass spectrum: mfz 207 ([lr4+],14), 93 ([M+ - PhS], 100), Z0 (23); (Calcd for

CrrHl3NOS Í]l.l+l mlz 207.0778. Found: mlz 207.0727); (Anal. calcd for

C11H13NOS: C, 63.74; H, 6.32; N, 6.75. Found: C, 63.66; H, 6.52; N, 7.02); ,,/max

(tiquid film) 3054,2926, 1,696,7584,1488 cm-1; 1H n.m.r. (300MH2, CDCIe) ô

EXPERIMENTAL

759

7.96(zIJ',tt,18.'1.,7.7ÍIz,C4-}l),2.30(2Il,t,lg.7Hz,C3-Hz),3.44(2}{,t,17.7H2,

CS-Hz), 4.77 (2f1, s, NCH2S), 7.27 - 7.33 (3H, m, ArH), 7.42 - 7.46 (zFI, m, ArH);

13Cn.m.r. ô 174.85,'1,33.51,130.87,1,29.07,127.16,46.65,45.86,30.80,77.54.

Treatment of 1-(3-butenyl)-2-oxopyrrolidine (l7l) withN-bromosuccinimide

A mixture of 1-(3-butenyl)-2-oxopyrrolidine (L77) (238 rr.g, 1.71 mmol),

N-bromosuccinimide (668 mg,3J5 mmol) and a catalytic amount of AIBN in

carbon tetrachloride and dichloromethane (4:"1,,25 ml) was heated at reflux

under nitrogen, whilst irradiating with a 300 W mercury lamp, for L0 min.

The cooled reaction mixture was concentrated under reduced pressure and the

residue was taken up in ethyl acetate and washed with brine. The organic layer

was separated, dried and evaporated under reduced pressure and preparative

thin layer chromatography of the residue on silica, eluting with a mixture of

ethyl acetate and light petroleum (50:50) yielded three products, L97,198 artd

199.

5,S-Dibromo-l -(3,4-dibromobutyl)-2-oxopyrrolidine ('1.97) as an oil.

(77 m9,1,07o)- EI mass spectrum: mlz 461. ([M+], 3), 459 ([M*], 12), 457 ([M+],

18), 455 ([M+], 72), 453 ([M+], 3), 379 ([ttt* - HBr], 29), 377 ([M* - HBr], 87), 375

([M+ - HBr], B8), 373 ([M+ - HBr], 29.5), 297 (lM+ - 2IJ.Br),77), 295 ([M+ - 2FIBr]

22), 293 ([M+ -2H,Br],1,1), 257 (49.5), 255 (100), 253 (50.5), 2'1.6(1,0), 274(10);

(Calcd for CsHllNOBra Í]l.l+l mlz 456.7533. Found: mlz 456.7543); (Anal. calcd

for CgHllNOBr4: C, 27.03; H, 2.43; N, 3.07. Found: C, 22.38; H, 2.48; N, 3.18);

v1a¡ (liquid film) 171,4,698 cm-l; 1H n.m.r. (300MH2, CDCIa) ô 1.98 (1H, dddd,

IZ,Z'* 14.8, ]2,3, 9.6, Jy*2' 7.3,17,2' 5.2H4 C2'-H), 2.52 (1H, dddd, I2,Z'* 14.8,1t2*

7.4,ly*2'* 7.4,l2'*g, 3.7H2, C2'-H*), 3.06 (2H., dd,l3qtrons 6.0,134^ri,5.8H2, C3-F{),

3.39 (1H, ddd, 144* 9.9,lgttrors 6.0, Jg+r¡, 5.8I{2, C -H), 3.M (7H, ddd, I++* 9.9,

EXPERIMENTAL

160

]34t ont 6.0, ]gqcis 5.8H2, C4-}{*), 3.49 (1H, ddd, /1'1,* 14.0, ly2,* 7.4,/t2, 5.2H2,

CL'-H), 3.59 (1H, ddd, /1'1'* 74.0,11,*2,* 7.4,11,.2, 7.2H2, C7'-H*), 3.62 (7H, dd,

I4'4'* 10.5,1g'+'9.6H2, C4'-H), 3.87 (1H, dd, 14,4,* 10.5, fu'4'* 4.2ÍIz, C4'-H*), 4.1.0

(1H, dddd, I2'g' 9.6, Ig'4, 9.6, þ'4'* 4.2, 12,*g, 3.'1, ÍIz, C3'-H); 13C n.m.r. ô 1,67.85

(C=O), 55.26 (C5), 48.51 (C3'), M.93 (C4), M.1,0 (C3), 42.17 (Cl'¡, 35.97 (C4'),33.37

(cz'¡.

S,S-Dibromo-1-(4-bromo-3-hydroxybutyl)-2-oxopyrrolidine (198) as an

oil. (138 mg, 2'l.Vo)- EI mass spectrum; mlz 397 (lt¡+1, 5.5), 395 ([M+], 16),

393([M+],76),39'].. ([M+],5.5),379 ([M+-HzO],4),377 ([M+-HzO], 12),375(Í]ll.{+

-HzOl,72), 373 ([M+-HzO],4), 3t5 ([M*-HBr],29.5),313 ([M+-HBr], 60), 37'l-.

([M* - HBr], 30.5), 297 (lM+ - HBr - HzOl, 31.5), 295 ([M+ -HBr - HzO], 64), 293

([M+ - HBr - HzO], 32.5), 245 (50), 243 (700), zal $0); (Calcd for CaH12NO2Br3

lM+l mlz 392.8398. Found: mlz 392.8387); (Anal. calcd for CsH12NO2Br3: C,

24.39;H,3.07; N, 3.55. Found: C,25.70; H, 3.01; N, 3.67); v¡naa (Iiquid film) 3440,

1706,'j,066,698 cm-1; lH n.m.r. (300MH2, CDCIa) ô '1..69 (7H, dddd, Iz,z,* 14.1,

I2B, 9.8, Jy*2' 5.8,1.1,2, 4.9H2, C2'-}{), 1.91 (1H, dddd, ]2,2'* 14.1, It*2,* 9.3, f y2'*

6.2, f2,*g, 3.2flz, C2'-H*), 3.07 (2}l, dd,l3qtronr 6.l,lzqris 5.8TIz, C3-Hz), 3.31 (1H,

ddd, /1'1'* 1.4.7, Jy2'* 6.2, Itz' 4.9 Í12, C1'-H), 3.37 (1H, ddd, I¡ø* 10.1, I34t ons 6.1,

Ig+at 5.8F{z,, C4-H), 3.47 (1H, dd, J4,4,* 1.0.4,1g,4, 5.8}lz,, C4'-H), 3.42 (1}l, broad,

OH), 3.45 (1H, dd, l4'4'* 1.0.4, lg'4'* 4.9H4 C4'-H*), 3.46 (7H, ddd, 144* !Q.1,

]34tront 6.1,13+cis 5.8}l2, C4-H*), 3.70 (7H, ddd, /1'1'. 1.4.1,ly*2,* 9.3,11,*2, 5.8LIz,

C1'-H*), 3.77 (1H, dddd, Iz'2, 9.8, Ig'+' S.B, Iz,q'* 4.9, J2,*g, 2.2ÍIz, Cj'-}l); 13C

n.m.r. ô 1,68.72 (C=O), 67.77 (C3'), 55.04 (C5), 45.10 (C4), M.tS (C3), 40.93 (Cl'¡,

38.52 (C4'¡, 32.29 (CZ'¡.

1-(3,4-Dibromobutyl)-2-oxopyrrolidine (199) as an oil. (26 mg,57o)- EI

mass spectrum: mfz 302 ([M+ + H],5), 300 ([M+ + H], L0), 298 (M+ + Hl, 5), 220

([M+ - Br], 98), 218 ([M+ - Br], 100), 138 ([M* - HBr - Br), 44); (Calcd for

CsHlaNOBr2 [N4+ + H] mlz 2979M2. Found: mlz 297.9433); v¡nw (liquid film)

EXPERIMENTAL

767

2940,7774, 646 cm-7; 1H n.m.r. (300MH2, CDCIg) ô 7.99 (lIF., dddd, I2'2,* 73.7,

12, 3, 9.3, I y*2' 7 .2, ] n, 5.5 ffz, CZ -}{), 2.05 (2F{, tt, I 8.3, 7 .0 ÍIz, C*F{z), 2.40 (2F{, t,

/ 8.3 ÍIz, C3-H2), 2.46 (1H, dddd, IZ'2,* 13.'1,, 17,2,* 7.4, f1'*2,* 7.2, 12,*g, 3.3ÍIz,

C2'-H'+), 3.43 (zFJ, t, I 7.0H4 CS-Hz), 3.43 (7H, ddd, Iyt,* 74.0, It,z,* 7.4, It,z,

5.5H2, Cl.'-H), 3.54 (1H, ddd, /1'1'* 1.4.0,ly*2,*7.2,ly*2, 7.zÍfz, Cl.'-H'ß), 3.68 (1H,

dd, l4'4'*'1.0.5,13'4'9.3ÍIz, C4'-H), 3.90 (1H, dd, J4'4,* 10.5, /3,4,* 4.3H2, C4'-}l*),

4.74 (1H, dddd, I2B, 9.3, Ig,4'9.3, 1g,4,* 4.3, 12,3, 3.3flz, C3'-H); 13C n.m.r. ô

175.34 (C=O), 49.1,8 (C3'), 47.40 (C5),40.57 (C1'), 36.24 (C4'),33.80 (C2'),30.86 (C3),

17.e1. (C4).

tr ans-4-Bromo-5 -ethoxy- 1 - (p-methoxyphenyl) -2-oxopyrrolidine(2os)

A mixture of 1.-(p-methoxyphenyl)-2-oxopyrrolidine (172) (92.3 rng,

0.48 mmol), N-bromosuccinimide (100 mg, 0.56 mmol) and a catalytic amount

of AIBN in carbon tetrachloride and dichloromethane (8:1, 18 ml) was heated

at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp, for

5 min. The reaction mixture was cooled to room temperature, dry ethanol

(60 ¡tl, 1.02 mmol) and 2,6-lutidine (720 ¡tl, 1.03 mmol) were added and

the mixture was stirred at room temperature under nitrogen for 2 hr. The

residue obtained upon workup was purified by preparative thin layer

chromatography on silica, eluting with ethyl acetate, to give trans-4-bromo-5-

ethoxy-1-(p-methoxyphenyl)-2-oxopyrrolidine (205), the alcohol 206, the

S-succinimidopyrrolidinone 207 and unreacted starting material 172

(30 mg, 33Vo).

trans-4-Bromo-5-ethoxy-1-(p-methoxyphenyl)-2-oxopyrrolidine (205) as

an oil which solidified on standing. (58.1 mg, 387o):- m.p. 53"C; b.p.

EXPERIMENTAL

1.62

105C/0.02mm (block); EI mass spectrum: mlz 375 ([M+],84), 313 ([M+],86),

269 ([M+ - EtOH], 42), 267 ([M+ - EtOH], 43), 234 ([M* - Brf ,1.4),203 (36),799

(100); (Calcd for C13H16NO3Br ÍM+l mlz 313.0314. Found: mlz 3'1,ï0306); ymax

(liquid film) 2972, 1722,1,670, 7574, 7250, 7066,700 cm-1; 1H n.m.r. (300MH2,

CDCIg) ô 1.19 (3H, t, | 7.0H2, OCH2CH1), 2.82 (1H, dd, lss,L8.2,l3,4trorr'/.,.0H2,

C3-H'), 3.42 (1H, dd, /eg' L8.2, ls4ç¡s 6.4H2, C3-H), 3.54 (1H, dq, I 9.3,7.0ÍLz,

OCHHCH3), 3.59 (1H, dç I9.3,7.jtIz,OCÍLHCHa), 3.81 (3H, s, OCH3), 4.35 (1H,

ddd, Igqrit 6.4, Ig,4tran, 1.0, I4s,tron, 0.9 Hz, C4-H), 5.27 (1H, d, I4s'tron¡ 0.9 Hz,

Cs-H'), 6.93 (2}l, m, ArH), 7.34 (2}{, m, ArH); 13C n.m.r. ô 177.29, 158.30,

129 .35, 125.98,'I.,'l., 4.3 4, 98.37, 64.52, 55.40, 42.57, 40.78, 1 5. 20.

trans-4-Bromo-5-hydroxy-1-(p-methoxyphenyl)-2-oxopyrrolidine (206) as

an oil. (19.7 mg,1,4%)- EI mass spectrum mlz 287 ([M+], 54), 285 ([M+, 55), 269

([tvl+ - HzO], 98), 267 ([M+ - HzO], 1.00), 254 (29.5), 252 (30), 205 ([M+ -HBr],23),

760 (61); (Calcd for CllHrzNOsBr [M*] mlz 285.0001. Found: mlz 284.9992);

Ymax (CDCI3) 3400, 1704, 7670, 7574,7254, 1034 cm-1; 1H n.m.r. (300MH2,

CDCIg) ô 1,.77 (1H, broad, OH), 2.74 (1H, dd, /¡g' 78:4,13,4¡¡ans 1.4H2, C3-H'),

3.36 (1H, dd, /gg' 1,8.4,l3aç¡s 6.5 Hz, C3-H), 3.89 (3H, s, OCHg), 4.23 (1H, ddd,lgaç¡g

6.5,l3, tronr 1.4,l45,trons 1..2ÍIz, C -H), 5.51 (1H, d, I4s,tron, 1..2H2, Cs-H'), 6.90

(2IJ, m, ArH), 7.32 (2}l, m, ArH); 13C n.m.r. õ 1,71,.95, 158.39, 729.02, 125.9'1.,

11,4.40, 92.47, 55.45, M.7 0, 40.95.

1-(p-Mettroxyphenyl)-2-oxo-5-(l-succinimido)pyrrolidine (207) as a white

crystalline solid. (9.7 mg,77o)- m.p.77"C; EI mass spectrum: mlz 288 ([M+],

100), 233 (33), 190 ([M+ - CaHaNOz],38), 734 (52), 123 (53); (Calcd for

C15H16NzO¿ [M+] mlz 288.'1,110. Found: mlz 288.1113); ymax (CHzClz) 2960,

1780, 7772, 1.61.0, 1514 cm-1; 1H n.m.r. (300MH2, CDCII) E 2.20 - 2.26 (1H, m,

lactam methylen e) , 2.52 - 2.77 (2F{, m, lactam methylen e) , 2.55 (4H, s, 2 x CHz) ,

2.98-3.12(7H,m, lactammethylene),3.78(3H,s,OCHg), 6.20(7H,dd,145ç¡58.9,

EXPERIMENTAL

1,63

]A'strors 2.2H2, Cs-H), 6.87 (2t{^, m, ArH), 7.22 (2F{, m, ArH); 13C n.m.r. ô

176.09,174.62, L58.03, 128.24,725.93,1.'1,4.47,65.95,55.34,30.59,27.74,22.57.

tr ans-S- Allyloxy-4-bromo- L - (p -methoxyphenyl) -2-oxopyrrolidine

(27L)

A mixture of 1.-(p-methoxyphenyl)-2-oxopyrrolidine (172) (37'1. mg,

L.94 mmol), N-bromosuccinimide (380 mg, 2.1-.3 mmol) and a catalytic amount

of AIBN in carbon tetrachloride and dichloromethane (6:1, 55 ml) was heated

at reflux under nitrogen, whilst irradiating with a 300 W mercury lamp, for

L0 min. The reaction mixture was then cooled to room temperature, allyl

alcohol (3 ml, excess) and 2,6-lutidine (450 pl, 3.86 mmol) were added and the

mixture was stirred at room temperature under nitrogen overnight. The

reaction mixture was filtered and evaporated under reduced pressure. The

residue was taken up in ethyl acetate and washed successively with very dilute

hydrochloric acid, brine, saturated aqueous sodium bicarbonate and brine

again. The organic layer was then dried and concentrated under reduced

pressure. Preparative thin layer chromatography of the residue on silica,

eluting with a mixture of ethyl acetate and light petroleum (50:50), afforded

trans-5-allyloxy-4-bromo-1-(p-methoxyphenyl)-2-oxopyrrolidine (2Tl) (181 mg,

297o), the alcohol 206 (46 mg, 8%), unreacted starting material L72 (1,77 rng,

48%) and a minor amount of the S-succinimidopyrrolidinone 207.

A greater yield of 2'1,1, was obtained from 172 when the pyrrolidinone

172 was treated with excess N-bromosuccinimide. Thus, 1-(p-methoxyphenyl)-

2-oxopyrrolidine (172) (108 mg, 0.56 mmol), was treated with N-bromo-

succinimide (502 m9,2.82 mmol) in the presence of a catalytic amount of AIBN

in carbon tetrachloride and dichloromethane (6:1, 35 ml) as described above.

The reaction mixture was then cooled to room temperature, allyl alcohol

EXPERIMENTAL

764

(1 ml, excess) and 2,6-lutidine (130 ¡rl, 1.12 mmol) were added and the mixture

was stirred at room temperature under nitrogen for 4.5 hr. Upon workup,

preparative thin layer chromatography of the residue on silica, eluting with a

mixture of ethyl acetate and light petroleum (50:50), afforded trans-5-ally[oxy-4-

bromo-l-(p-methoxyphenyl)-2-oxo-pyrrolidine (211) (87.3mg,47Vo), the alcohol

206 (1,4m9,9Vo), unreacted starting material 172 (33.8mg,31.Vo) and a minor

amount of the S-succinimidopyrrolidinone 207.

trans-5-Allyloxy-4-bromo-L-(p-methoxyphenyl)-2-oxopyrrolidine (211) as

an oil:- EI mass spectrum: mf z 327 (l},l+1, 1.3.5), 325 ([M+], 14), 270 ([M+ -C3H5O], 17.5), 268 ([M+ - C3H5OJ ,18), 245 (M+ - HBr], 10), 189 (100); (Calcd for

C1aH15,NO3Br Ílú+l mlz 325.0374. Found: mlz 325.0299); Ymax (CDCI3) 3020,

77'1.4,'1.612,1.572,1224 cm-7; 1H n.m.r. (300MFIz, CDCIg) õ 2.82 (1H, dd, [ss,1.8.2,

Ig,Atronr 0.9Hz, C3-H'), 3.43 (1H, dd, /¡e' 1.8.2,l3aç¡s 6.3ÍIz, C3-H), 3.81 (3H, s,

OCH3), 4.00 (1H, dddd, 172.8,5.7,7.5,7.3Ílz, CHHCH=CHz), 4.04(1H, dddd,/

12.8,5.7,'l.,.5,7.3flz CÍXICH=CHz), 4.37 (7H, ddd, J3aç¡s 6.3, ]3'4t ort0.9, ]41trans

0.8ÍIz, C4-H), 5.20 (1H, ddt, / 70.5,7.4,'1..3H2, CH=CHH), 5.22 (1H, ddt, I 17.'1.,

7.5, '1..4 Hz, CH=CHH), 5.33 (1H, d,l41tronr0.8Hz, Cs-H), 5.81 (1H, ddt,l 17.1.,

1.0.5,5.7H2, CH=CHz), 6.94 (2}j', m, ArH), 7.33 (2}l, m, ArH); 13C n.m.r. ô

77'1..36,158.31,73290,129.53,726.72,779.29,1.74.28,97.67,69.64,55.32,42.45,40.02.

(3S, 3aR , 6aS)-, (3R, 3aS , 6aR)-6-(p-Methoxyphenyl)-3-methyl-S-

oxotetrahydrofu rol2,3 -blpyrrolidine (21-2)

A solution of tri-n-butyltin hydride (475 ¡tl, 1.77 mmol) and a catalytic

amount of AIBN in dry benzene (15 ml) was added dropwise with stirring,

over 2.5 hr. to a solution of. ftøns-5-allyloxy-4-bromo-1-(p-methoxyphenyl)-2-

oxopyrrolidine (2lL) (384mg, 1.18mmol) in dry benzene (20mt) heated at

EXPERIMENTAL

165

reflux. After the addition was complete the reaction mixture was further

heated at reflux under nitrogen, overnight. The reaction mixture was then

evaporated under reduced pressure and preparative thin layer

chromatography of the resultant residue on silica, gradient eluting with amixture of light petroleum and ethyl acetate gave an oil which solidified on

standing. Subsequent recrystallization from dichloromethane / light

petroleum afforded (3S, 3aR, 6aS)-, (3R, 3aS, 6aR)-6-(p-methoxyphenyl)-3-

methyl-S-oxotetrahydrofuro [ 2,3-b)pyrrolidine (212) as a white crystalline solid.

(111 mg, 38Vo)- m.p. 95C; (Calcd for C14H1zNOs [M+]mlz 247.1,208. Found

mlz 247.121,6); ymax (CHzCtz) 2960, 7700, 1.672, 1.51.4, 1036 cm-1; 1H n.m.r.

(300MH2, CDCIg) õ 1.06 (3H, d, Isz 6.9 }]rz, C7-Hù, 2.49 (1I! dddq , l2s7'L.3,lsguris

8.0,lgz 6.9, ]z'g 6.8Í1z,, C3-H), 2.53 (7}J, dd,l+q,18.2,1sv470.0Í12, C4-H), 2.62 (1H,

dd, ]qq' 1,8.2, lga4' 6.4H2, C4-H'), 3.02 (1H, dddd, lg¿4'!,0.0, I3gacis 8.0, 13v4, 6.4,

I3a6acis 6.2H2, C3a-H), 3.44 (7H, dd, Izg 11.3, 122, B.BfIz, CZ-H), 3.80 (3H, s,

OCH3), 3.98 (1H, dd, Izz' 8.8,12'z 6.8Í12, Cz-}jr'), 5.78 (1H, d, ]ga6acis 6.2H2,

C6a-H), 6.97 (2I{, m, ArH), 7.48 (2H', m, ArH); 13C n.m.r. ð "172.49,'L,SZ.SB,

130.62,124.71.,7"1.4.1.0,95.97,77.50,55.36,39.59,36.07,30.12,1,0.97.

EXPERIMENTAL

4.

5.

766

RnpEnENCES

1. Fleming, A. Brit. ]. Exp. Pøthol. L929, 10, 26.

Chain, E.; Florey, H.W.; Gardener, A.D.i |ennings, M.A.; Orr-Ewing, I.;

Sanders, A.F.; Heatly, N. G. l-ancet 11L940,226

Johnson, I. R.; Woodward, R. B.; Robinson, R. In The Chemístry tfPenicillins; Clarke, H. T.; johnson, I. R.; Robinson, R., Eds.; Princeton

University Press: Princeton, N. I., 7949, p. M0.

Hodgkin, D. C. Adoancemt. Sci.1949,6,85

Sheehan, I. C; Henry-Logan, K. R. l. Am. Chem. 9oc.1957,79, 7262; 1959,

81_,3089.

6. Ohno, M.; Otsuka, M.; Yagisawa , M; Kondo, S. In Ullman' s

Encyclopedia of Industríal Chemistry; Gerhartz, W., Ed.; Verlag Chemie:

Weinheim , 1,985, Vol. 42, p. 467.

Floover, I. R. E.; Nash, C. H. In Kírk-Othmer Encyclopedia of Chemical

Technology; 3rd ed.; Grayson, M.; Eckroth, D., Eds.; Wiley: New York,

1978, Vol. 2, p.871..

See for exmple: Sykes, R. B.; Matthew, M. /. Antimícrob. Chemother.

L976,2,1,'1,5.

Cooper, R. D. G. In Topics ln Antibiotics Chemistry; Sammes, P. G., Ed.;

Ellis Horwood Ltd.: Chichester, 1,980, Vol. 3, p. 39. fung, F. A.; Pilgrim,

W.R.; Poyser, I. P.; Siret, P. J. ibid.7980, Vol. 4, p. 13.

2.

3.

7

8

9

REFERENCES

11.

72.

13.

1,4.

19

'1.67

10. Kametani, T. Heterocycles 1982,77, 463.

Johnston, D. B. R.; Schmitt, S. M.; Bouffard, F. A.; Christensen, B. G. /.

Am. Chem. Soc. 1978, L00, 3'j,3.

Bouffard, F.A.; Johnston, D. B. R.; Christensen, B. G. ].Org.Chem.1980,

45,1.,'130. Schmitt, S. M.; )ohnston, D. B. R.; Christensen, B. G. íbid.L980,

45,1."1.35. Schmitt, S. M.; Johnston, D. B. R. ibid.1.980, 45,'1.'142.

Scartazinni, R.; Peter, Hi Bickel, H.; Heusler, K.; Woodward, R. B. HeIo

Chim. Acta 1972, 55, 408.

Nayler, I. H. C.; Osborne, N. F.; Pearson, M. I.; Southgate, R. /. Chem.

Soc., Perkin Trans. 17976, 1,675.

Bormann, D. Liebig's Ann. Chem.L974, 1.391..

Branch, C. L.; Nayler, J. H. C.; Pearson, M. I. /. Chem. Soc., Perkin Trans. IL978,1450.

17. Baxter, A. I. G.; Dickinson, K. H.; Roberts, P. M.; Srnale, T. C.; Southgate,

R. l. Chem. Soc., Chem. Commun.1979,236.

18. Cama, L. D.; Christensen, B. G. l. Am. Chem. 9oc.L978,L00,8006.

Ernest, I.; Gosteli, J.; Greengrass, C. W.; Holick, W.; Jackman, D. E.;

Pfaendler, H.R.; Woodward, R. B. l. Am. Chem. Soc.\978,L00,821,4.

Lang, M.; Prasad, K.; Holick, W.; Gosteli, ].; Ernest, I.; Woodward, R. B.

íbid.1979,10L,6296. Ernest, I.; Gosteli, J.; Woodward, R.B íbid.L979,1,01,,

6301. Pfaendler, H. R.; Gosteli, J.; Woodward, R. B. íbid.7979,L0L, 6306.

15.

1,6.

Heusler, K.; Woodward, R. B. German Offenlegungsschrift 1 935 970,75

June 1969. Woodward, R. B.; Heuslet,Ki Ernest, I.; Burri, K; Friary, R. j.;

20.

REFËRENCES

21,.

168

Flaviv, F.; Oppolzer,W.; Panioni, R.; Syhora, R.i Wenger, R.; Whitesell,

l. K. Nouaeau l. Chim.1977,'1., 85.

See also : Heusler, K. In Cephalosporins and Penícillins: Chemístry and

Biology; Fllmn, E. H., Ed.; Academic Press; New York, 1972, p.273.

Proctor, P.; Gensmantel, N. P.; Page, M. I. l. Chem. Soc., Perkin Trans. IlL982,11.85. Page, M.I. Acc. Chem. Res.1984,'17,1,M.

Bachi, M. D.; Hoornaert, C. Tetrahderon Lett.1981,22,2689; 198L,22,

2693; 7982,23,2505.

See also: Bachi, M. D.; De Mesmaeker, A.; Stevenart-De Mesmaeker, N.

ibid. 1987, 28, 2637 ; L987, 28, 2887.

Bachi, M. D.; Frolow, F.; Hoornaert, C. I. Org. Chem. t983,48,"1.84'i...

Azzouzi, A.; Dufour, M.j Gramain, I. -C.; Remuson, R. Heterocycles 1988,

27,"1.33.

Robins, D. l. Fortschr. Chem. Org. Naturst.1982, 41, '1.'1.5

Bull, L. B.; Culvenor, C. C. I.; Dick, A. T. The Pyrrolizidine Alkaloíds;

North Holland: Amsterdam,'1.968.

Atal, C. K. Lloydiø7978,41,312.

Gelbaum, L.T.; Gordon, M.M.; Miles, M.; Zalkow, L. H. l. Org. Chem

1992,47,2501..

Kametani, T.; Honda, T.; Fukumoto, K.; Ihara, M. In Ullman's

Encyclopedía of Industrial Chemistry; Gerhartz, W., Ed.; Verlag Chemie:

Weinheim,'1985, Vol. 41, p. 362.

22.

29

23.

24.

25.

26.

27.

28.

REFERENCES

30

31.

1,69

Kugelman, M.; Liu, W. C.; Axelrod, M.; McBride, T. |.; Rao, K. V. Lloydiø

7976,39,'1.25. Kovach,J. S.; Ames, M.M.; Powis, G.; Moertel, C. G.; Hahn,

R.G.; Cregan, E.T. Cancer Res.1979,39,4540.

Robins, D.l. Ada. Heterocycl. Chem.7979,24,247. Narasaka,K. l. Syn.

Org. Chem. 1985, 43,464.

Ikeda, M.; Sato, T.; Ishibashi, H. Heterocycles 1988,27, 1.465.

Speckamp, W. N.; Heimstra, H. Tetrahedron'1.985,41., 4367.

Nossin, P. M. M.; Speckaûrp, W. N. Tetrahedron Lett.7979,20,4'1.'1,.

Wijnberg, I. B. P. A.; Schoemaker, FI. E.; Speckamp, W. N. Tetrahedron

1979,34,779.

36. Ffart, D.I.; Tsai, Y. -M. /. Am. Chem. Soc.'1.982,104,1.430.

Burnett, D.A.; Choi, I.-K.; Flart, D.J.; Tsai, Y. -M. /. Am. Chem. Soc.L984,

L06,8201..

Flart, D. I.; Tsai, Y. -M. /. Am. Chem. 50c.7984,1.06, 8209.

Choi, J. -K.; Flart, D. I.; Tsai, Y. -][r/.. Tetrahedron Lett.1982,23, 4765. Choi,

I.-K.; Flart, D. l. Tetrahedron L985,41,3959. Dener, J.M.; Hart, D. f.

Tetrahedron 1988, 44, 7037.

40. Kano, S.; Yuasa, Y.; Asami, K.; Shibuya,S. Chem. Lett.7986,735.

41, Ross, S.D.; Finkelsteir, M.j Peterson, R. C. I.Am.Chem.9oc.1966,88,

4657. Finkelsteir, M.i Ross, S. D. Tetrahedron 1972,28, M97. Rudd, E. |.;

Finkelsteir, M.i Ross, S. D. /. Org. Chem. L972,37,7763.

32.

33.

34.

35.

37.

38.

39.

42. Shono, T. Tetrahedron 1.984, 40, B\7.

REFERENCES

43.

M.

45.

4.6.

47.

48.

49"

770

l'litzlaff , M.; Warning, K.; Rehling, H. Synthesis 1980, 315.

Okita, M.; Mori, M.; Wakamatsu, T.; Ban, Y. Heterocycles L985,23,247.

Mori, M.; Kagechika, K.; Tohjima, K.; Shibasaki, M. Tetrahedron Lett.

1999,29,"1.409.

Easton, C. I.; Love, S. G. Tetrahedron Lett. L986,27, 2375.

Easton, C. f.; Love, S. G.; Wang, P. l. Chem. Soc., Perkín Trans. I 1990,277.

Rawlinsoh, D. J.; Sosnovsky, G. Synthesis 1972,'I...

Russell, G. A. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York, 1973,

Vol. 1., p.275.

Henrikson, T.i MelQ, T. B.; SaxebQI, G. In Free Radicals ín Bíology; Pryor,

W. 4., Ed.; Academic Press: New York, 7976, Yol. 2, p. 213.

Miyagawa, Ii Kurita, Y.; Gordy, W. I. Chem. Phys.1960,33, 7599.

Katayama, M.; Gordy, W. /. Chem, Phys.196L,35,1.17. Livingston, R.i

Doherty, D. G.; Zeldas, H. l. Am. Chem. 50c.7975, 97 , 3198.

Augenstein, |. A.; Ray, B. R.; I. Phys. Chem.L957,6L,'I..385

Stella, L.; ]anousek, Z.; Merényi, R.; Viehe, H. G. Angew. Chem., Int. Ed.

8ng1.7978,17 , 697. Veihe, H. G.; Merényi, R.; Stella, L.; |anousek, Z. ibid.

L979,L8,977. Veihe, H.G.; ]anousek, Z;}l4erênyi, R.; Stella, L. Acc.

Chem. R¿s. 1-985, 18,748.

54. Dewar, M. I. S. J. Am.Chem. 1oc.1952,74,3353.

50.

51.

52

53

55. Balaban, A. T. Rea. Roum. Chim,7971,L6,725

REFERENCËS

56

57.

58.

59

77't

Baldock, R. W.; Fludson, P.; Katrizky, A. R.; Soti, F. l. Chem. Soc., Chem

Perkin Trans. I1974, 1422.

Louw, R.; Bunk, l.l. Recl. Traa. Chim. Pays-Bas 1983, L02,'/.."1.9.

Barbe, W.; Beckhaus, H. -D.; Rückhardt, Ch. Angew. Chem., lnt. Ed

Engl. 1987,26, 573.

Korth, H.-G.; Lommes. P.; Sustmann, R. I.Am.Chem.9oc.1984,1.06,

663.

Maclnnes, I.; Walton, J. C.; Nanhebel, D. C. I. Chem. Soc., Chem

Commun.7985, 712,

Katrizky, A.R.; Zerner, M.C.; Karelson, M. M. I.Org.Chem.L987,52,

3062.

Pasto, D.I.; Kransky, R.; Zercher, C. I. Org. Chem. 7987, 52,3062. Pasto, D.

I. ]. Am. Chem. Soc. 1988, L06, 663.

Poutsma, M. L. In Free Radicals; Kochi, J. K., Ed.; Wiley: New York, 1973,

Vol. 2, p. 159.

Adam, J.; Gosselain, P. A.; Goldfinger, P. Nøture1953,1.7L,704.

Sixma, F. L. ].; Reim, R. H. K. Ned. Akød. Wet. Proc. 1958, 61.8, '1,83.

McGrath, B. P.; Tedder, l. M. Proc. Chem. Soc.l96t,80.

Walling, C.; Rieger, A.L; Tanner, D. D. I. Am. Chem. \oc.1.963,85,3129.

Russell, G.A.; DeBoer, C.; Desmond, K. M. /. Am. Chem.50c.1963,85,

365; 1963,85,31.39.

68. Easton, C.I.;Hay, M. P. ]. Chem. Soc., Chem. Commun 1986,55.

60.

61,

62.

63.

64.

65.

66

67

REFERENCES

172

69 Easton, C. I.; Hay, M.P.; Love, S. G. I. Chem. Soc., Perkin Trans.I1988,

265.

70. Easton, C. I.; Scharfbillig, I. M.; Tan, E. W. Tetrahedron Lett.1988,29,

Burgess, V. A.; Easton, C. f.; Hay, M. P. I. Am. Chem. 50c.7989,111,1.047

Easton, C.I.; Flutton,C.A.; Rositano, G.; Tan, E. W. I.Org.Chem.l99\,

56,561.4.

73. Lidert, Z.; Gronowitz,S. Synthesis1980,322.

74. Friedrich, S. S.; Friedrich, E. C.; Andrews, L. I.; Keefer, R. M. I. Org

Chem. L969,34,900.

Okita, M.; Wakamatsu, T.; Ban, Y. l. Chem. Soc., Chem. Commun.L979,

749.

Warning, K.; Mitzlaff , M. Tetrøhedron Lett. 1979, 20, 7563

Gramain, I.-C.; Remuson, R.; Troitr, Y. l. Chem. Soc., Chem. Commun.

1976,194.

Pavlik, I. W.; Tantayon , S. I. Am. Chem. 50c.198L,103, 6755

Easton, C. J.; Peters, S. C.; Love, S. G. Heterocycles 1988, 27, 2405.

Malatesta, V.; Ingold, K. U. J. Am. Chem. Soc.\987,103,609.

l{inz, |.; Rüchardt, Ch. Líebig's Ann. Chem. L972,765,94. Beckhaus,H. -

D.; Schoch, J.; Rüchardt, Cliu Chem. Ber.'1976,109,7369. Applequist, D.

E.; Klug, I.H. I. Org. Chem. \978, 43, 7729.

1565

7't.

72.

75.

76.

77.

78.

79.

80.

81.

REFERENCES

83.

84.

85.

82.

86.

773

Takahata, H.; Ohnishi, Y.; Takehara, H; Tsuritani, K.; Yamazaki, T.

Chem. Pharm. BuIl. L981, 29, 7063.

Wasserman, FI. H.; Hlasta, D.I.; Tremper, A. W.; Wu, I. S. Tetrahedron

Lett.1979,20,549.

Barrow, K. D.; Spotswood, T. M. Tetrahedron Lett. L965,6,3325.

For reviews see: Zil'berman, E. N. Russ. Chem. Rea.7962, 31, 6'1,5

Compagnon, P. L.; Miocque, M. Ann. Chím. Qaris) 1.970,5,1.1.;1970,5,23

Greene, T. W. Protectiae Groups in Organic Synthesis; Wiley: New

York, 1987; p.171, -778.

87. Hartung, W.H.; Simonoff, R. Org. ReactíonsL953,VII,263 -326.

Koppel, G.A.; McShane, L.; |ose, F.; Cooper, R. D. G. l. Am. Chem. Soc.

1979,100,3934.

88.

89 Huffman, W. F.; Hall, R. F.; Grant, J. A; Holden, K. G. l. Med. Chem.

L978,21, 4'1.3. Lammert, S. R.; Ellis, A. I.; Chauvette, R. R.; Kukolja, S. /.

Org. Chem. 1978, 43, 7243.

See for example: Cama, L.D.; Christensen, B. G. l. Am. Chem. Soc.1978,

1.00,8006. Barton, D. H. R.; Comer,Fi Greig, D. G. T.; Sammes, P. G:,

Cooper, C.M.; Hewitt, G.; Underwood, W. G. E. l. Chem. Soc.; Ct97'1,,

3540.

Bateson, I.H.; Baxter, A. I.G.; Roberts, P.M.; Smale, T.C.; Southgate, R. /Chem. Soc., Perkin Trans. 11.981, 3242.

90.

91,.

92. Sharma, R.; Stoodley, R. l. Tetrahedron Lett.1981,22,2025

REFERENCES

93.

94.

95.

96.

174

Bestmann, H. I.; Seng, F. Tetrøhedron L965,21., 7373.

Keck, G.E.; Yates, l.B. I.Am. Chem.50c.7982,L04,5829. Keck, G.E.;

Enholm, E. ].; Yates,I.B.; Wiley, M. R. Tetrahedron1985,41,4079.

Easton, C. J.; Scharfbillig, I. M. /. Org. Chem.L990,55,3U

Baldwin, I. E.; Adlington, Il. M.; Lowe, C.; O'Neil, I. A.; Sanders, G. L.;

Schofield, C. I.; Sweeney, J.B. I. Chem. Soc., Chem. Commun L988, 1030.

97. Giese, B. In Radicals in Organic Synthesis: Formation of Cørbon-Carbon

Bonds; Baldwin, l. 8., Ed.; Pergamon: New York, 1'986; Vol. 5 in the

Organic Chemistry Series.

Kametani, T.; Honda, T. Heterocycles 1982, 1.9, 1.867.

Castelhano, A. L.; Horne, S.; Taylor, G. J.; Billedeau, R.; Krantz, A.

T etr ahedr on L988, 44, 5451..

100. Williams, R. M.; Hendrix, I. A. I. Org. Chem.'/..990, 55, 3723.

101. Aoki, H; Sakai, H.-I.; Kohasaka, M.; Konami, T.; Hosoda, J.; Kubochi, Y.;

Iguchi, E.; Imanaka, H. /. Antibiot.1976,29, 492. Hashimoto, M.;

Komori, T.; Kamiya, T. I. Am. Chem. Soc.1976, 98, 3023, ldem.,l.

Antibiot. 797 6, 29, 890.

1,02. Wolfe, S.; Hasan, S. K. Can. I. Chem.'1970,48, 3572. Kamiyã, T.)

Hashimoto, M.i Nakaguchi, O.; Oku, T. Tetrahedron 1979,35, 323.

103. Osby, I. O.; Martin, M. G.; Ganem, B. Tetrahedron Lett.L984,25,2093.

L04. Miller, M. I.; Mattingly, P. G. Tetrahedron 7983,39,2563

105. Nefkens, G. H.; Tesser, G. I.; Nivard, R. l. F. Recueil 7960, 79 , 688.

98.

99.

REFERENCES

775

1,06. Townsend, C. A; Salituro, G. M.; Nguyen, L. T.; DiNovi, M. I.Tetrøhderon Lett. L986, 27, 381..9.

'/-.07. Townsend, C.A.; Nguyen, L. T. l. Am. Chem.5oc.198L,103,4582.

Townsend, C. A.; Nguyen, L. T. Tetrahedron Lett.7982,23, 4859.

108. Mitsunobü, O. Synthesís 1981, 1.

109. Carman, R. M.; Shaw, I. M. Aust. I. Chem.L976,29, 733

110. Putina, G.; Iacobescu, S. C.; Scarlete,P.; Burghelca, T.; Ceclar, R.i Cinca,

L.; Popescu-Dimofte, L. M.; Cosofret, V.; Visan, N.; Ionescu, M.

Romanian Patent RO 77,1.80, 30 ]une 1981; Chem. Abstr. 99:1'39760k.

Daskalov, Kh.; Georgiev, A.; Konstantinova, K. Tr. Nauchnoizsled.

Khim. -Førm. Inst.1985, L5,2'1,; Chem. Abstr. L05:152866m.

111. Instituto Internacional Terapeutico S.A. Japanese Patent 74,'1.09,323, 17

October 1974.; Chem. Abstr. 85:77990k.

1.12. Bartels, G.; }Jinze, R.-P.; Wullbrandt, D. Liebig's Ann. Chem.1980, 168.

113. Silverstein, R. M.; Bassler, G. C.; Morrill, T. C. Spectrometric

Identification of Organic Compounds; St}r. ed.; Wiley: New York, 1'997;

p.796.

1,1,4. ]ackman, L. M., Sternhell, S. Applications of NMR Spectroscopy in

Organic Chemístry; 2nd ed.; Pergamon: New York, 7969.

1L5. Gassman, P.G.; Fox, B. L.l. Org. Chem.1966,31,982

11,6. Department of Organic Chemistry, The University of Adelaide.

717. Merck: Art. 806072, used without further purification

REFERENCES

118.

119.

120.

121,.

122.

123.

124.

125.

126.

127.

128.

129.

176

Mazzocchi, P. H.; Thomas, j.; Danisi, F. l. Org. Chem.1979, 44, 50.

schmid, H.; Karrer, P. HeIa. Chim. Acta L946, 29, 573. Dauben, H. I.,Ir.;

McCoy, L. L. I. Am. Chem. 9oc.7959, 81 , 4863.

Fukuyamà,Ti Frank, R.; ]ewell, C.F., lr. l. Am. Chem.50c.L980,L02,

2122.

Kronenthal, D. R.; Han, C.Y.; Taylor, M. K. ].Or8.Chem.1982,47,2765.

Corley, E. G.; Karady, S.; Abramson, N. L.; Ellison, D.; Weinstock, L' M'

Tetrahedron Lett. 1988, 29,]..497.

Beckwith, A. L. l. Tetrahedronl'987,37, 3073.

Beckwith, A. L. J.; Blair, I.; Phillipou, G. I. Am. Chem. 50c.L974,96,76'l'3'

Beckwith, A. L. ].; Gara, W. B. I. Am. Chem. 9oc.L969,91'' 5697.

Beckwith, A. L. ].; Easton, C. I.; Serelis, A. K. /. Chem. Soc., Chem.

Commun. L980, 482.

Wolff, S.; Agosta, W.C. l. Chem. Res., Synop.L981',3,78.

Beckwith, A. L. l.; Phillipou, G.; serelis, A. K. Tetrahedron Lett.L981,2'1.,

2811..

Curran, D. P.; Rakiewicz, D. M. TetrahedronL985,4L,3943.

RËFERENCES

Documents

tituted l'I-Sub Functionalization of · Reaction of B-lactams bearing activating substituents at exocyclic carbon adjacent to nitrogen with N-bromosuccinimide resulted in regioselective