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NOVEL ASPECTS OF THE CHEMISTRY OF THIOAMIDES
A thesis submitted by
ELIZABETH MARY NAYLOR
in partial fulfilment of the
requirements for the award of
DOCTOR OF PHILOSOPHY
OF THE
UNIVERSITY OF LONDON
WHIFFEN LABORATORY
DEPARTMENT OF CHEMISTRY
IMPERIAL COLLEGE
LONDON SW7 2AY DECEMBER 1987
2
Abstract
This thesis comprises three major sections.
Firstly, a review of recent developments in hetero Diels-Alder
chemistry involving mono-heteroatomic dienophiles is presented.
Particular emphasis has been placed upon the synthetic potential of
these cycloadditions and examples, specifically chosen to illustrate
this point, are included.
The second section outlines plans to conduct asymmetric
Diels-Alder reactions with a chiral diene and a chiral dienophile,
both of which were derived from thioamide precursors. The synthesis
of (2S)-2-methoxymethyl-1-(11-methylthio-1',3'-pentadienyl)pyrrolidine
and (2S)-2-methoxymethyl-l-(l'-methylthiopropenyl)pyrrolidine were
achieved; however their instability precluded investigation of the
proposed asymmetric cycloadditions.
The final part of this thesis deals with inter- and intra
molecular hetero Diels-Alder reactions of thioformamide derived
iminium salts and imino thioethers. 2-aza-9-thiabicyclo[4.3.0]-
non-4-ene systems prepared by cycloaddition of iminium iodides could
not be isolated directly. Thus, a variety of trapping reactions were
carried out in an effort to isolate a stable derivative. The thermal
reaction of N-(4,6-heptadienyl)-N-methylthiomethyliminium iodide did
not afford the [4+2]-cycloadduct, l-aza-2-alkylthiobicyclo[4.3.0]-
non-4-ene, instead formyl- and thioformylpyrrol idine derivatives were
isolated. Diels-Alder reactions between S-ethyl tetrafluoroborate
salts of thioformamides and siloxy dienes were prevented by
deprotection of the diene. The use of the tertiary thioamide,
N-benzyl-N-methylthioformamide and rigorous exclusion of proton
sources resulted in the isolation of (E)-1-(3'-(N-benzyl-N-
methylamino)-1'-oxo-2'-propenyl)cyclohexene.
3
4
CONTENTS
Page No
ACKNOWLEDGEMENTS 6
ABBREVIATIONS 8
REVIEW: 10
Diels-Alder Reactions with Mono-heteroatomic Dienophiles in Organic Synthesis
Contents 11
Review 12
References 112
RESULTS AND DISCUSSION: 121
1. Introduction to Asymmetric Diels-AlderReactions 122
1.1. Research strategy
2. Preparation of Diene (39) 137
2.1 Via alkylation of thioforniamide2.1.1 Model studies2.1.2 Preparation of thioamide (45)
2.2 Via oxygen-sulphur exchange2.2.1 Preparation of a/3-unsaturated thioamide (58)2.2.2 Preparation of^7 -unsaturated thioamide (45)2.2.3 Transformation of thioamide (45) to diene (39)
3. Preparation of Dienophile (40) 156
4. Introduction to Hetero Diels-Alder Reactions 150
4.1 Research strategy
5. Diels-Alder Reactions of Thioformamides and Iodides 171
5
5.15.1.15.1.25.1.35.1.4
Iminium salt trapping reactions Via the ketal function Via hydride reduction Via cyanide addition Via indole cyclisation
5.2 Alternative trapping reactions
6. Intramolecular Reaction of Iminium Salt (115) 185
7. Acyl Thioamides as Dienophiles 190
8. Reaction of Imino Thioethers with Siloxy Dienes 194
9. Reaction of Iminium Salts with Siloxy Dienes 200
10. Conclusions and Perspectives 205
APPENDIX 207
EXPERIMENTAL 211
REFERENCES 271
6
ACKNOWLEDGEMENTS
Firstly I wish to thank my supervisor Dr. William Motherwell for
his guidance and enthusiasm during this Ph.D. I would also like to
thank Professor Steven Ley for his assistance over the past three
years.
I am grateful to Mr J.N. Bilton and Dr. J.A. Challis for the mass
spectra and accurate mass measurements, to Mr R. Sheppard for help
with running n.m.r. spectra and to Mr K. Jones and his staff for the
microanalyses included in this thesis.
I would like to thank many members, past and present, of the
Whiffen, Perkin and Barton laboratories for making the top floor of
the Old Chemistry building such an enjoyable and stimulating place to
work. I am particularly grateful to Tony, Peter and Dave for help
with drawing diagrams; to Francine, Peter and Andrew for proof
reading and to Howard for assistance with the molecular mechanics
calculations.
I wish to thank Ian and Liz, and Sean for their very valued
friendship and Joan and Eifion for their great kindness over the
past three years.
I am very grateful to my sister, Maggie for all the time and
effort she has put into typing this thesis.
Finally I would like to thank Brian for his continual support and
understanding.
LIZ.
TO MY PARENTS AND SISTERS
ABBREVIATIONS
Bn - Benzyl
Bz - Benzoate
Cbz - Benzyloxycarbonyl
d.e. - Diastereomeric Excess
DBU - Diazobicyclo[5.4.0]undec-7-ene
DMAP - Dimethyl ami nopyridine
DMPU - Dimethyl Tetrahydropyrimidinone
DMSO - Dimethylsulphoxi de
d-TFA - Deuterated Trifluoroacetic Acid
E. I. - Electron Impact
e.e. - Enantiomeric Excess
Ether - Diethyl Ether
Eu(fod)^ - tris(6,6,7,7,8,8,8-Heptafluoro-2,2-dimethyl-3,5-
octanedionato)europium(III)
Eu(hfc)^ — tris[3-((Heptafluoropropyl)hydroxymethylene)-(+)-
camphorato]europium(III)
FAB - Fast Atom Bombardment
HMPA - Hexamethylphosphorami de
HOMO - Highest Occupied Molecular Orbital
LDA - Lithium Di-isopropylamide
LUMO - Lowest Unoccupied Molecular Orbital
MOM - Methoxymethyl
NCS - N-Chlorosuccinimide
Py - Pyridine
Red-Al - bis(2-Methoxyethoxy)aluminium Hydride
RT - Room Temperature
SM - Starting Material
9
TBDPS tert-Butyldiphenylsilyl
TBS tert-Butyldimethyl silyl
TBSOTF tert-Butyldimethylsilyl Trifluoromethanesulphonate
TES Triethyl silyl
TFA Trifluoroacetic Acid
THF Tetrahydrofuran
TMS Trimethyl silyl
Ts p-Toluenesulphonyl
Ybtfod)^ - tris(6,6,7,7,8,8,8)-Heptafluoro-2,2-dimethyl-3,5-
octanedionato)ytterbium(III)
REVIEW
DIELS-ALDER REACTIONS WITH MONO-HETEROATOMIC DIENOPHILES
IN ORGANIC SYNTHESIS.
11
CONTENTS
1. Introduction
2. C-N Dienophiles
2.1 Activated imines
2.2 Unactivated imines
2.3 Iminium salts
2.4 Imines with heterodienes
2.5 Nitriles
3. C-0 Dienophiles
3.1 Carbonyl compounds under thermal conditions
3.2 Carbonyl compounds under high pressure conditions
3.3 Carbonyl compounds under catalytic conditions
3.4 Formaldehyde
3.5 Carbonyl compounds with heterodienes
4. C-S Dienophiles
4.1 Thioketones
4.2 Thioaldehydes
4.3 Other thiocarbonyl compounds
5. Conclusions
6 . References
12
1. Introduction.-
A comprehensive review of Diels-Alder cycloadditions with
heterodienophiles appeared in the literature in 1982.* Over the past
five years a great deal more research in this area has been undertaken
resulting in a large number of additional publications. Over this
period a greater awareness of the hetero Diels-Alder reaction has led
to a broadening of the range of such cycloadditions with synthetic
potential and consequently to a variety of interesting applications.
However, mechanistic work associated with these Reactions is in many
cases severely limited. The conclusion to be drawn from the available
information is that the mechanisms of these [4+2]-cycloadditions span
the range from a concerted/non-synchronous pathway to a stepwise
dipolar process.
This literature survey is concerned with those heterodienophiles
in which the reacting multiple bond contains one carbon atom and one
heteroatom. Those Diels-Alder reactions in which the dienophiles
have two heteroatoms in the reacting multiple bond e.g. N=0, S=0, N=N
have not been included although in some cases they have provided a
useful tool for organic synthesis.*
Reviews of particular aspects of the Diels-Alder reaction with
2 3heterodienophiles * appeared around the same time as that of Weinreb
and Staib.* More recently resumes of the v/ork of particular groups in
4 5this area have appeared. ’ The aim of this review is to bring
together recent developments in hetero Diels-Alder cycloadditions with
mono-heteroatomic dienophiles with particular emphasis on their
application to organic synthesis.
13
2. C-N Dienophiles.-
2.1 Activated imines.
Diels-Alder reactions with electron deficient imines as2
dienophiles have been known for over twenty years. These imines
e.g. N-sulphonylimines, N-acylimines generally show good regio- and
stereoselectivity.*
R
R
Data from this type of cycloaddition suggests that the imine reacts
via its (E)-isomer and that in general, 7r-substituents on nitrogen are
better endo directors than the equivalent substituent on carbon. This
is exemplified by the synthesis of a bicyclic proline analogue (Scheme
14
O OH
X XPhCH20 ^ NH ^ C 0 2CH3 SOCI2, Et3N
0
PhCH20 ^ S’ C 02CH3
I f )56% W
12 h, RT
^ / V ^ c ° 2H
1. Pd/C, H22. 6N HCI
J r "v C 02CH2Ph
Scheme 1
The cycloaddition of electron deficient imines has been employed
in more complex syntheses. (±)-Isoprosopinine B (2) and
(±)-desoxoprosopinine (3) have been prepared via the common
bicycloadduct (1),7whilst the synthesis of the N(5)-ergoline (6)^
incorporated the hetero Diels-Alder reaction between imine (4),
prepared in situ, and diene (5).
COOCH3
IITsN
OTMS
C6H6,3 h 5 °C - RT
O O
( 2 )
(CHECKS
( 3 )
15
PhCH
The preparation of the 8-aza-9,ll-etheno analogue of
prostaglandin PGHj, has been achieved by two different groups of
researchers both using a similar imino cycloaddition strategy (Scheme
2 ) .9
It has been shown that cyclic electron deficient imines also
undergo Diels-Alder reactions. Reaction of 3-methyl-l,2-
benzisothiazole-1 ,1-dioxide (7) with Danishefsky's diene resulted
in the isolation of the 4-pyridone (8 ) . 10 Replacement of the 3-methyl
16
group by chlorine also gave the desired adduct whilst no reaction
occurred with a methoxy or phenylthio substituent. The lack of
reactivity in the latter cases was attributed to the +M effect of the
substituents deactivating the imine function towards cycloaddition.
Polyhalo-2-acyliminopropanes (9) have proved to be very good
dienophiles reacting with cyclopentadiene to give Diels-Alder adducts
(10) in 90-93% yield.** Enhanced reactivity was observed when the
2-acyl group of imine (9a) was replaced by a polyfluoroacyl
substituent (9b, 9c) but successive replacement of fluorine atoms by
chlorine in the isopropylidene group (9c, 9d, 9e) did not lead to a
significant change in the optimum reaction conditions. The formation
of [2+4]-cycloadducts between imine (9a) and acyclic dienes
(butadiene, isoprene, and piperylene) has also been observed, though
in lower yields (30-70%).**
(9 ) (1 0 )
a. R = CH3, X = Y = Fb. R = CF3, X = Y = Fc. R = CH(CF3)2, X =Y = Fd. R = CH(CF3)2, X -Cl. Y - Fe. R = CH(CF3)2> X = Y = Cl
17
A variety of methods have been utilized for the vn situ
generation of N-acylimines prior to their intramolecular Diels-Alder
reaction. Thermolysis of acetate derivatives, such as (12), has
proven to be a useful technique which has been applied to the
4 IPpreparation of several indolizidine alkaloids e.g. slaframine (15).
Synthesis of (15) required conversion of amine (11) to the
acetate (12). In previous syntheses this transformation had been
achieved using formalin and sodium hydroxide but in this case it
gave unreproducible results. A procedure employing cesium carbonate
and paraformaldehyde was found to be more successful. Heating a
solution of acetate (12) in o-dichlorobenzene for four hours afforded
two cycloadducts (13) and (14) in the ratio 1:1.8. Both compounds
were converted to the natural product (15), although the latter
required epimerisation at the silyloxy bearing carbon.
18
59%
1. CS2CO0(HCHO)n, THF
2. AcgO
o-Dichlorobenzene Reflux, 4 h
In the synthesis (vide supra) and other similar ones poor stereo
chemical control in the bridging chain during cycloaddition to the 6/54
fused ring systems was observed.
The question of steroselectivity in the related preparation
of the 6/6 fused ring compounds was addressed through application to
the synthesis of lupinine (20) and/or epi-lupinine (19). The
cycloaddition precursor (16) was readily prepared and upon heating
afforded a single bicyclic lactam (17). None of the epimeric product
(18) was found. Catalytic hydrogenation and borane reduction of (17)
provided epi-lupinine (19).
19
(16)
This stereochemical outcome has been explained on the basis of
cycloaddition occurring via the acylimine arranged in an s-cis
conformation (21). Houk and Paddon-Row have calculated that the
s-cis conformer (21) of N-formylimine is 3 kcal/mol more stable than
the s-trans form (22) and 4 kcal/mol lower in energy than the/ \ 4nonplanar conformer (23).
H
N ' ^ O X
H
N ^ ,
„ A „ „ A „
( 2 1 ) ( 2 2 ) ( 2 3 )
It was assumed that in the preferred transition state the N-carbonyl
group would adopt an endo orientation. Significant experimental
20
evidence in support of this assumption, in both inter- and intra
molecular imino Diels-Alder reactions exists. 1 Two possible
transition states (24) and (25) were proposed. (24) leads to
cycloadduct (17) from which epi-lupinine is obtained. Originally
Weinreb and co-workers considered that the preference for transition
state (24) over (25) arose from an unfavourable interaction between
and Hg (25). However, subsequently molecular mechanics
calculations indicated that an eclipsing interaction between Hc and4
Hp was responsible for the energy difference.
OMe
( 2 6 )
H O
( 2 7 )
Similar methodology has been applied to the synthesis of the
alkaloids cryptopleurine (26)*^ and anhydrocannabisativene (27).^
The latter was readily prepared from the acetate (28) derived from
pentadienylsilane and n-hexanal. Pyrolysis of (28) produced a single
adduct (29) whose structure was confirmed by X-ray crystallography of
the acid (30). The same criteria as previously outlined (vide supra)
can be invoked to explain the observed stereochemical outcome by way
of transition state (31). Product (30) was transformed into alkaloid
(27) in several steps.
21
( 2 8 ) ( 3 1 ) ( 2 9 ) R = Me( 3 0 ) R=H
An intramolecular imino Diels-Alder reaction was utilized for a
synthesis of the drug praziquantel (34), in which both the butadiene
15and imine fragments were generated iji situ. The choice of leaving
group used to generate the imine (33) was found to be crucial. An
acetoxy group (32, I^C^OAC) proved too labile resulting in the
formation of amide (32, R=H). However, when a methoxy group was used
and the reaction conducted in the gas phase cyclobutene (32,
f^^OCHg) cyclised to praziquantel (34) in 49% yield.
Gy49%
NHR
( 3 2 )
An alternative procedure for preparation of imines (for example,
(36)) for intramolecular cycloaddition involves a retro Diels-Alder
reaction.^ Flash vacuum pyrolysis of adduct (35a) gave lactam (37a)
a precursor of 6-coniceine (37b) in an unspecified yield. The latter
has been synthesised by Weinreb et a_l^ via an imino Diels-Alder
reaction in which the acyl imine (36), generated from (35b) was
postulated to take part. Thus, this sequence (Scheme 3) provides good
evidence for the intermediacy of acyl imines in such cycloadditions.
(35a) (37a)
Cb(37b)
S chem e 3
A retro-ene reaction has also been employed as a means of
18generating imines (Scheme 4). Unfortunately the presence of the
carbonyl group which facilitates the Diels-Alder reaction is
detrimental to the retro-ene process and low yields (
23
electron rich dienes e.g. Danishefsky's diene under zinc chloride
catalysis in tetrahydrofuran at room temperature afforded cyclic
adducts in reasonable yield (Table 1). Interestingly the
c^-unsaturated imine (38c) gave the product from the reaction of the
19bimine functionality rather than the classical Diels-Alder adduct.
Better yields were obtained by increasing the molar ratio of
diene:imine. More recently, the cyclocondensation of 1-trimethyl-
20siloxyvinylcyclohexene and N-phenylbenzylimine has been reported.
Table 1
This methodology is nicely illustrated by the synthesis of (±)-
21ipalbidine (Scheme 5).
24
0 40 -45%---------
ch2ci2BFg.EtgO -78°C to RT
Scheme 5
This Lewis-acid catalysed reaction has been applied to tricyclic
22imines. Dihydro-/5-carboline (39a) reacted with siloxydiene (40) to
give a 55% yield of the tetracycloadduct (41a) which has previously
23been converted to the natural product yohimbine. The benzofuran and
benzothiophene analogues of imine (39a) reacted in a similar
22fashion. The choice of solvent for these processes was found to be
critical. Although good yields of these cyclic adducts were obtained
in acetonitrile the reaction was inhibited in tetrahydrofuran.
( 3 9 ) a X = NHb. X = Oc. X = S
OTMS ZnCI2
CHgCN 50 °C
(40) (41) O
25
The optically active dihydro-/?-carboline (42) has been subjected
24to cycloaddition with various siloxydienes (Scheme 6). These
reactions showed complete facial specificity, the diene approaching
anti to the carbomethoxy group. However the ratio of exo to endo
products, (43) and (44) respectively, was only 4:1. Further
investigation and rationalization of the stereoselectivity of this
type of imino Diels-Alder reaction is required if it is to be usefully
applied to complex alkaloid synthesis.
OTES
( 4 3 ) R = CH3, R' = H( 4 4 ) F U H ,R ’ = CH3
The thermal imino Diels-Alder reaction of dihydro-/?-carboline
(45) formed the basis of a synthesis of the aspidosperma alkaloid
vindoline (51) and the related 11-desmethoxy compound vindorosine
26
nc(50). The cycloaddition produced three products (46), (47), and
(48). However, this was not found to be a problem since under the
alkylation conditions employed a single diastereomer (49) was
isolated.
o
FU H, 71% R»O CH3, 88%
Chlorobenzene 120 °C, 4 h
( 4 8 )
(46) + ( 4 7 ) + ( 4 8 )
98% R = H 80% R » OCH3
LDA, Etl
( 5 0 ) R=H( 5 1 ) R-OCHg
27
2.3 Iminium salts.
A few accounts of the use of iminium salts as dienophilic
1 2components in Diels-Alder reactions appear in the literature. *
26A recent advancement has been reported by Grieco and Larson.
Aqueous Diels-Alder reactions between iminium ions (52) (generated
in situ from an amine and aqueous formaldehyde) and various dienes
produced cyclic products (53) in reasonable yield (Table 2). The
cycloaddition occurred with excellent regiochemical control (Table
2, entry 3) which was consistent with previous related
27observations. Chiral induction in this process using
(-)-a-methylbenzylamine hydrochloride was moderately successful giving
a separable mixture of diasterecmers in a ratio of 4:1, (Table 2,
entry 6).
?8
rnh2.hci ------► [ RNH == ch2 c rHCHO,h2o
(52)
R
Iabie 2
Entry Diene Amine Conditions Product % yield
1. O PhCH2NH2.HCI 3h, 25°C ' i - ^ ^ N C H 2Ph 100
2.
< PhCH2NH2.HCI 96h, 55°C AlL ^ N C H 2Ph62
3. X PhCH2NH2.HCI 70h, 35°C X "1H ^ N C H 2Ph 594. o MeNH2.HCI 3h, 25°C 82
5. X nh4ci 96h, 35°C k ^ ^ N H .C I 40
6. o P h ^ s‘ NH2.HC! 20h, 0°C/b v ph
4:1 86
29
The intramolecular version of this reaction has also been
studied. 6-Coniciene hydrochloride (55) has been synthesised from the
diene hydrochloride (54) in 95% yield.
Substitution of formaldehyde by other aldehydes has been
accomplished. Replacement of formaldehyde by acetaldehyde in the
reaction of benzylamine hydrochloride with cyclopentadiene afforded
a 47% yield of exo and endo adducts, (56) and (57) respectively, in a
ratio of 1 .6:1 . ^
CH,
The intramolecular cycloaddition of the iminium salt derived from
dienyl aldehyde (58) and benzylamine hydrochloride afforded a 63%
yield of adducts (59) and (60) ir. a ratio of 2.5:1.^
63%
BnNH2.CI H20, 70 °C, 20 h
( 5 9 ) ( 6 0 )
This methodology has been applied to the synthesis of racemic28
dihydrocannivonine (Scheme 7). J
30
Scheme 7
a-ketoaldehydes e.g. phenylglyoxal and glyoxylic acid have beer,
29employed as substrates in the aza Diels-Alder reaction (Table 3).
The reaction of cyclopentadiene with benzylamine hydrochloride in the
presence of phenylglyoxal afforded a 3:2 mixture of exo and endo
adducts (Table 3, entry 1). Replacement of benzylamine hydrochloride
by ammonium chloride provided an 89% yield of exo and endo products
(61a, 61b) (Table 3, entry 2). Treatment of this mixture with zinc in
acetic acid gave the cyclopentene (62), a potentially useful precursor
to carbocyclic analogues of purine ribo- and desoxyribonucleosides.
Similarly cycloaddition of cyclopentadiene and the iminium salt
generated j_n situ from glyoxylic acid and methyl amine (in this case it
is not necessary to use the hydrochloride) produced a good yield of
the bicyclic products (Table 3, entry 3).
Table. 3
Entry Substrate Amine ProductsExo : Endo ratio
% yield
1. P h ^ v HO
PhCH2NH2.HCI
Bn
3 : 2 82
2.o
NH4Q ^ NHCI ■ a61 a-exo/61b-endo
1 :2 89
3.h o ^ y h
0
MeNH2
Me
1.9 : 1 86
31
(61a) + (61b)
PhCO
76%NH2.HCI
Zn, HAc
(62)
2.4 Imines with heterodienes.
The addition of electron rich imines to electron deficient dienes in
an inverse electron demand Diels-Alder fashion has been
accomplished. The reaction of hydrazones and aryl imines with
tetrazine (63) occurred in excellent yield (Table 4). The
analogous cycloaddition with imino ether (64) gave a mixture of
products (65) and (66) in poor yield.
Benzene,Reflux
E = C 02CH3
32
IablS-4
Imine Product % yield
N(Mg)2Ei .A r
t r V 78(M efeN ^
N N(Me)2E
CD2O% EJL ^Ar
90
M e 0 ^ s^V N'A r
E
II
a "
E
N ^ )
TO99
E EN(Me)2 N 'V*' N ̂ V Af (65) 11
N y N H N ^ N(66) 7
MeCrE E
(64) (65) (66)
More successful Diels-Alder reactions of imino ethers and imino
31thioethers were achieved by Boger and Panek. Addition of imidate
(67) or thioimidate (68) to tetrazine (63) afforded the expected
product (71) although the latter proceeded in better yield. The
amidines (69) and (70) failed to produce the desired product. It
is apparent from these results that the cycloaddition is sensitive to
both the nucleophilic character of the dienophile and the leaving
group ability of X (Scheme 8 ) . 31
33
(67) X = OEt 37%(68) X = sch3 68%(69) x = nh2 0%(70) X = NEt2 0%
(71) E = C02CH3
Scheme 8
A formal synthesis of streptonigrin (76) utilizes this
32methodology (Scheme 9). Reaction of thioimidate (72) with
tetrazir.e (63) afforded triazine (73) which underwent an all-carbon
inverse electron demand Diels-Alder reaction to give tetracycle (74)
comprising the complete carbon framework of streptonigrin (76). (74)
was converted in three steps to compound (75), a key intermediate in
33Kende's synthesis of the natural product (76).
o
(7 6 )
34
Scheme 9
Cyclic imines, imidates, thioimidates and amidines have also
34been reacted with tetrazines. Cycloaddition of dihydroisoquinoline
(77) with tetrazines (78) and (63) produced cyclic adducts (79) and
(80) in 25 and 54% yield respectively.
35
R
IN
NIIN
R
+
(63) R = C02CH3 (78 ) R = Ph
The cycloaddition of imines with acyl and thioacyl isocyanates
35 36has been reviewed relatively recently. ’ Trifluoroacetyl
isocyanate reacts with aryl Schiff bases to give oxadiazines (Scheme
10). Thioacyl isocyanates, generated from heterocycles (81), add
37to imine (82) to afford cycloadducts (83) in excellent yields.
Scheme 10
O
X % YieldH 80o c h 3 78N(CH3 )2 77Cl 89n o 2 81
o
R Bu3P
(81)
R = Aryl,Alkyl
88-98%
Ph (82)
ch2ci2
( 8 3 )
36
2.5 Nitriles.
Pyridines and other nitrogen containing heterocycles have been
synthesised by the Diels-Alder reaction of nitriles with different
dienes.* An intramolecular version of this reaction led to the first
38synthesis of pyrazino[2,3-c]quinoline (Scheme 11). The
cycloaddition precursor (84) was heated at reflux in diphenyl ether to
afford the tricyclic adduct (85) and the deacylated, fully aromatic
system (86). In a similar fashion compound (87) was converted to the
benzopyranopyrazine (88) in 45% yield. Sammes et a K previously
39reported a related intramolecular process.
Scheme 11
The fused bicycle (91) has been prepared by a synthetic sequence
involving a Diels-Alder reaction of a nitrile (90) (Scheme 12).^
The initially formed ketene imine (89) undergoes a 1,5-hydrogen
migration to afford diazatriene (90) which then cyclises to triazine
(91).
37
SCH,
^ CN C 0 2 CH3 Ph2 C— N = C
c h 2 c i2,Reflux
CNI
P h2 CO2 CH3
Ic CHPh2 >1 I
Ny N
s c h 3
(89)
1,5-Shift
CH3 0 2C
(91)
Seitz and Mohr have reacted aryl nitriles and cyanamides with
tetrazine (92) to give the inverse electron demand Diels-Alder adduct
(93) which spontaneously loses nitrogen to produce triazines (94)
41(Scheme 13). The reaction conditions employed indicate that the
cyanamides react more readily than the aryl nitriles due to the former
being more nucleophilic.
38
CF3
1N ^ N I IIN^ x N
c f 3
R— C = N
(92) (93)
R %Yield Conditions
-N(CH3)2 41 Toluene, reflux/----V
-N Ov _ y
49 Toluene, reflux
- Q och3 44 Neat, 100 °C, 1 Torr
—̂ N(CH3)2 22 Chlorobenzene, reflux
CF3
N^ N
CF3
R
(94 )
Scheme 13
2-acyliminopropanes (9) which have been shown to be good carbon-
nitrogen dienophiles (vide supra) behave as dienes in the presence of
nitriles affording Diels-Alder adducts (95) in moderate to good
11 42yield. * The mechanism of this reaction is unlikely to be a fully
concerted process;- some degree of charge separation in the transition
state would be expected. A plausible mechanism is outlined in Scheme
14 but it should be noted that the positive and negative charges on
the different intermediates might well be only partially developed.
N = C -F TCF3
c f 3
(9)
F*C
11N ^ RI H ------- N s C - F T
^ C F a
(95)
R* FT % yield
Ph Me 89Ph Ph 73OEt Me 64
R O -
Hn .
X +f3 c ' c f 3R w
N N
F3 Cf CF3
(95)
Scheme 14
3. C-0 Dienophiles.-
3.1 Carbonyl compounds under thermal conditions.
Activated carbonyl compounds are known to behave as dienophilic
components in [4+2]-cyc1oadditions. A typical example of this type of
dienophile is diethyl ketomalonate (96) which reacts with a wide
range of dienes under thermal conditions to afford cyclic adducts in
modest yield (Table 5).^
40
Zable,5.
e = c o 2Et
An interesting ring fused pyran (97) has been synthesised utilizing
the Diels-Alder reaction of this diester (96) prior to a 1,3-dipolar
/ % 44cycloaddition (Scheme 15).
o
E E+
(96)E = C 02Et
Scheme 15
n o 260%
Toluene, 110°C. 15 h
41
Glyoxylate esters are another commonly used carbonyl dienophile.
Reaction of keto-ester (98) with diene (99) provided a mixture of
adducts (100), (101), and (102). Lewis acid catalysed epimerisation
of pyran (101) gave the more stable c*-anomer (102). Transformation of
(102) into the thromboxane intermediate (103) was achieved in a
45further seven steps. A similar cyclocondensation was employed as
the initial step in the synthesis of the phorbol analogue (111)
(Scheme 16).^ Treatment of ethyl glyoxylate with 2-methoxybutadiene
afforded a single pyran product (104). This was converted into the
trienone (105) which underwent an all-carbon Diels-Alder reaction to
give cycloadduct (106). The heterodiene (107), readily prepared from
(106) reacted with ketene acetal (108) to produce the unstable lactone
acetal (109). Ring opening of (109) gave keto ester (110) which upon
further elaboration provided the phorbol analogue (111). This
synthetic sequence encompasses three different types of Diels-Alder
reaction and is, as such, an excellent example of their versatility
and strength.
42
CH3 0 '
OAc
O
, X^ ^ o c h3 h ^ ^ c o o r
(99) (9 8 ) R = (-)-menthyl
^6^6’120 °C, 72 h
rOAc
XX' exCOOR CHaO Nr
OAc
( 1 0 0 )
1 COOR CH3(
(Exo), 30%
( 1 0 1 )
I__________BF3 .Et20
COOR
(Exo), 6 %
( 1 0 2 )
OTBS
(103)
43
c h 3o+
o
COOEt
60%
Toluene,110°C
COOEt
OCH3
52%
Xylene, 145 °C
(104)
(107)
_ v 0Et ( 10 8 )^ ^ O T B SZnCI2, CH2 CI2
( 111 )
72% HF, CH3 CN
Et02C
Scheme 16
44
The hetero Diels-Alder reaction of glyoxylate esters and diethyl
ketomalonate has been utilized in the preparation of a variety of
saccharides.47,48 The antigenic determinants of blood groups A and B,
(115) and (116) respectively, have been synthesised from a common
intermediate (114) derived from pyrans (113a-d) (Scheme 17). The
cyclocondensation of (-)-menthyl glycxylate with the trans diene
(112) produced the four dehydropyranyl ethers (113a-d). Epimerisation
of the /?-D isomer (113a) to the a-D pyran (113c) was accomplished with
boron trifluoride etherate. The required pyran (113c) was thus
obtained in a combined yield of 38%. The product distribution shows
high facial selectivity but poor exo/endo preference. These results
48are consistent with previous findings for related systems. The
regioselectivity has been attributed to the influence of the asymmetry
of the sugar moiety acting through either steric or electronic
effects.4 ̂ The cr-D epimer (113c) was converted to enone (114) and
ultimately to the antigenic determinants.
45
(114)
Scheme 17
(115 ) R = NHCOCH3(116) R = OH
3.2 Carbonyl compounds under high pressure conditions.
The application of high pressure to carbonyl Diels-Alder
50reactions has been extensively studied by Jurczak and coworkers.
The reaction of Danishefsky's diene or its tert-butyldimethyl si 1yl
analogue with butyl glyoxylate under thermal conditions was
inefficient but when subjected to high pressure a twofold increase in
yield was observed together with improved diastereoselectivity (Table
46
6 ) . ^ a Use of the Lanthanide catalyst, tris(6,6,7,7,8,8,8-hepta-
fluoro-2,2-dimethyl-3,5-octanedionato)europium (Eu(fod)3) at normal
pressure allowed preparation of the desired products in comparable
yield (to the high pressure technique) but with reduced selectivity.
R(CH3)2S O v ^ s .CCfeBu R C H a ^ S iO ^ ^ ^ ^ C C fe B u* TT * X XOCH3 0 °^
(118) (119)
Diene Reaction Conditions Adduct % Yield DiastereomericRatio
(117a) C6 H6, Reflux, 1 atm., 2 0 h (118a):(119a) 40 1 : 1
(117a) Ether, RT, 10 kbar, 24 h (118a):(119a) 80 5 : 1
(117b) C6 H6, Reflux, 1 atm., 15 h (118b):(119b) 30 4 : 1
(117b) Ether, RT, 10 kbar, 24 h (118b):(119b) 85 1 0 : 1
(117b) Ether, RT, 1 Atm.,1% Eu(Fod)3, 48 h (118b):(119b) 75 7 : 3
RfCHgkSiO^^ V o ^
^ + O
0 CH3
(1 1 7 ) a. R ® CH3 b. R ■ t-Bu
Table 6
The utilization of high pressure (15-25 kbar) has allowed simple
aldehydes to be used as carbonyl dienophiles in cyclocondensa-
t i on s. ^ More recently it has been demonstrated that similar
reactions may be carried out at lower pressures (10 kbar) in the
presence of Eu(fod)3< Aldehydes bearing /3heteroatoms gave
significantly better yields than those without hetero substituents
(Table 7). This is probably due to coordination of the europium
catalyst to both the carbonyl oxygon and the /3-heteroatom.
H
47
R'
CH2 CI2, Eu(Fod)3,10 KBar, 50 °C, 20 h
OCH3
Table 7
Entry R’ % Yield Product cisitrans ratio
1 . — CH2 NHC02 CH2Ph 50 1 : 1
2 . — CH(CH3 )OSi(CH3 )2 t-Bu 35 6 :4
3. ------( 53 1 : 1°1
4. — c h 3 15 3 :7
5. — Ph 1 2 1 :1
6 . 17 4:6
OCH3
Under high pressure conditions (22 kbar, 50 °C, ether) the reaction of
chiral aldehyde (120) with 1-methoxybutadiene afforded a mixture of
four diastereomers (121a-d).^ The formation of the major isomer is
rationalized by assuming Cram selectivity and endo alignment. The
diastereomeric excesses (d.e.) of the endo and exo addition routes
were 67 and 52% respectively, although they were found to be dependent
on temperature and pressure. An increase in temperature had a
detrimental effect on the d.e., whilst increasing the pressure
improved the selectivity. An interesting extension of this work
would be the study of the reaction in the presence of Eu(fod)g (vide
supra). Danishefsky and coworkers have investigated the reaction of
aldehyde (120) with the more highly oxygenated diene (117b) under the
influence of Lewis acids at room temperature and normal pressure and
obtained only one isomer whose stereochemistry was consistent with
51Cram selectivity (vide infra).
48
(121a) 66% (121b) 16%
(121c) 13% (121d) 5%
Jurczak et aj_. have applied high pressure techniques to the
cyclocondensation of the sugar derived aldehyde (122) and 1-methoxy
butadiene and obtained a single stereoisomer of the cycloadduct 50e
(123). The improved diastereoselectivity observed in this case
compared to that with aldehyde (120) is attributed to the more
sterically demanding environment of aldehyde (122).
$ \ — o c h 3
( 12 2 ) (123)
49
3.3 Carbonyl compounds under catalytic conditions.
Gramenitskaya and coworkers have reported that the reaction of
a^-unsaturated aldehydes with dienes under the influence of boron
trifluoride etherate gave two products:- the expected, all-carbon
Diels-Alder product (124) and the dihydropyran (125). The ratio
of the two compounds was dependent upon the substituents on the diene
and aldehyde (Table 8).
Table 8
Entry R1 R2 R3 R4 Ratio(124):(125)
% Yield
1 Me Me Me H 9 2 :8 59
2 Me Me Me Me 77:23 63
3 Me Me Me Ph 0 : 1 0 0 70
4 Me H H Ph 1 0 0 : 0 39
5 H H Me Ph 85:15 51
The relative amounts of the dihydropyran (125) formed decreased as
the electrophilicity of the carbon-carbon double bond increased
(R=H>CH2>Ph, Table 8, entries 1,2,3 respectively). The dependence of
the product ratio on the diene substitution pattern (Table 8, entries
3,4,5) can be explained if a two stage mechanism is invoked for the
formation of the dihydropyran (Scheme 18). The greater preference for
formation of the pyran with 1,1,3-dimethylbutadiene reflects the
increased stability of intermediates (126) and (127).
50
More recently highly oxygenated dienes have been shown to react
53 54with aldehydes in the presence of Lewis acid catalysts. ’ A
variety of aldehydes including those with a^-unsaturation react with
l-ethoxy-3-trimethylsilyloxybutadiene and other related dienes in the
presence of bornyloxyaluminium dichloride (ROAIC^) in ether to affordroL
dihydropyrones in moderate yield (Table 9, entries 1-6).
It has also been found that similar reactions take place under
the influence of zinc chloride or boron trifluoride etherate (Table . 54
9, entries 7-15). Although the reaction occurs reasonably well
with alkyl and aryl aldehydes better yields were obtained with
aldehydes bearing a hetero substitution.
1OR
sO R 1
rN2
. R - l A ?
TM SO A , " T M S O ^ k A R<
b Ft*
51
Table 9
Entry R1 R2 R3 R4 Reaction Conditions % Yield Ref.
1 Et H H i-Pr ROAICI2, Ether, 15 min, 75 °C 65 53b
2 Et H H c h c h 2 ROAICI2, Ether, 3 h, 25 °C 60 53b
3 Er H H Ph ROAICI2, Ether, 2 0 min, 50 °C 70 53b
4 Et H Et i-Pr ROAICLj, Ether, 36 h, 50 °C 35 1 53b
5 Et Et H Ph ROAICI2, Ether, 36 h, 50 °C 60 53b
6 Et OEt H Ph ROAICI2, Ether, 24 h, 50 °C 45 53b
7 Me H H CH2 OCH2Ph ZnCI2, C6H6,36h, RT 87 54a,b
8 Me H H CH2SPh ZnCI2, C6H6,36h, RT 70 54a
9 Me H H CH2NHCbz ZnCI2, C6H6,36h, RT 80 54a
1 0 Me H H Ph ZnCI2, C6H6,36h, RT 65 54a
1 1 Me H H o-C6 H4 OCH3 ZnCI2, C6H6,36h, RT 58 54a
1 2 Me H H i-Pr ZnCI2, C6H6,36h, RT 43 54a
13 Me H OTMS CH2 OCH2Ph BF3 .Et2 0 , CH2 CI2, -78 °C 42 54a
14 Me H H c h c h 2 BF3 .Et2 0 , Ether, -78 °C 50 54a
15 Me H H CHCHCHg BF3 .Et2 Of Ether, -78 °C 70 54c
Note 1. Cis and trans mixture (3:1) separated by H.P.L.C.
An extensive study of the stereochemical outcome of these
cyclocondensation processes with different catalyst systems and the
inferences which can be drawn with regard to their mechanisms has5
been conducted by Danishefsky and co-researchers at Yale University.
Diene (128), with its in-built stereochemical markers reacted with a
selection of aldehydes under either zinc chloride or boron trifluoride
etherate catalysis to give dramatically different ratios of pyrones
(129) and (130) (Table 1 0 ) . The catalyst system of zinc chloride in
tetrahydrofuran showed a marked preference towards £^s adducts (129)
whilst boron trifluoride etherate in dichloromethane promoted trans
selectivity.
A « i) BF3 .Et2 0 , CH2 CI2, -78°C ii)7FA
B = i) ZnCI2, THFii) NaHCO,iii) TFA
Evidence for the intermediacy of (131), previously presumed, was
obtained by rapid quenching of the reaction between diene (128) and
benzaldehyde in the presence of zinc chloride which afforded enol
ether (131) in 41% yield together with pyrone (129) (26%). (131)
was converted to (129) on treatment with trifluoroacetic acid (TFA).
Table 1 0
Entry R Method % Yield (1291
% Yield (1301
1 nC5Hn A 2 1 69
2 nC5Hn B 91 2
3 Ph A 23 6 8
4 Ph B 78 < 2
5 Ph(CH2 )3 A 17 64
6 - Ph(CH2 )3 B 83 < 2
(128 ) PhCHO TFA (129 )
Ph
Reaction of a 4:1 mixture of dienes (132) with benzaldehyde for
36 hours under the influence of zinc chloride yielded enol ether
(133) and pyrone (134) in 53 and 31% respectively, together with
unreacted (E,E)-diene (132b). The (E,E)-diene was recovered and
resubjected to the reaction conditions. After 86 hours the cis and
trans adducts (134) and (135) were isolated but only in 3% and 11%
yield respectively.
OTBS OTBS
OCH3 OCH3
(132a) (132b)
TBSO
(133) (134) (135)
The significant difference in the rate of reaction of dienes
(132a) and (132b), the lack of detectable acyclic intermediates and
the strict stereochemical suprafaciality in the mode of diene addition
are all consistent with established findings in the greatly studied
all-carbon pericyclic Diels-Alder reaction. By analogy with the
latter reaction the preference for £i^ isomers can be considered to be
due to endo alignment of the 'R ' group of the aldehyde. Secondary
orbital overlap does not explain this selectivity since such an effect
is observed even when the 'R ' group is aliphatic (Table 10, entry 2).
A reasonable alternative interpretation has been proposed based on the
anti orientation of the 'R ' group relative to the Lewis acid/solvent
array co-ordinated to the carbonyl oxygen. If the catalyst/solvent
array has greater steric requirements than the 'R 1 group then the
apparent endo selectivity for the 1R ’ group actually reflects a
preferential exo orientation of the catalyst/solvent array.
To obtain further insight into the mechanism of the boron
trifluoride mediated cyclocondensation process the reaction between
diene (128) and benzaldehyde was quenched 5 minutes after the addition
of the catalyst. The products consisted of an 8:1 mixture of trans
54
and cis pyrones (136) and (137) respectively in 48% yield and a 2:1
mixture of threo and erythro a 1 do1-like products (138) and (139) in
46% yield. (138) and (139) were converted to the pyrones (136) and
(137) respectively by treatment with trifluoroacetic acid. When a
1.5:1 mixture of the threo and erythro products (138) and (139) was
resubjected to the reaction conditions for 30 minutes, adducts (136)
and (137) were isolated in 28% yield in a ratio of 4:1 together with a
1:1.2 mixture of hydroxy enone starting materials (138) and (139)
respectively. These findings indicate that although alcohols (138)
and (139) do undergo cyclisation the rate is too slow to account for
the formation of the bulk of the pyrones.
1. CH2 CI2, -78 °C, BF3 .Et2 0,5 min2. Quench
(140) (141)
55
These observations (vide supra) together with similar results
obtained from an investigation of the reaction between Danishefsky's
56diene and cinnamaldehyde led to the proposal of siloxonium species
(140) and (141) as intermediates in the process. By analogy with the
ring closure reaction of (138) and (139) it is reasonable to expect
that (140) would cyclise more rapidly than (141), whilst the latter
would prefer to form the alcohol (139). It is apparent from the
ratios of both the pyrones and the aldo!-like products that the
preferred siloxonium species is the threo isomer (140). This threo
selectivity has been observed in the aldol reaction of enol silanes
57with aldehydes in the presence of boron trifluoride etherate.
This methodology has been applied to the synthesis of the lactonecc
(142) (Scheme 19) a key intermediate in Masamune's synthesis ofCO
6o-deoxyerythronolide B aglycone (143). Lactone (143) represents
the Cj-Cg portion of the macrocycle (143). Reaction of chiral
aldehyde (144) with diene (128) under the influence of boron
trifluoride etherate afforded a mixture of cis and trans pyrones (145)
in the ratio 4.3:1 with complete Cram facial control.
56
(128)
♦ V ' -Ph
(144)2. TFA
(145a) 4.3
(145a)
O
(146) R-COOH(147) R = CHO
( 1 2 8 )
(148a)
43%
(148b)
27%
Scheme 19
(149) R = CHO (142) FUH
(1 4 3 )
57
The major isomer (145a) was converted into the Prelog-Djerassi
lactone (146) in four steps.Cyclocondensation of aldehyde (147),
derived from (146), with diene (128) in the presence of zinc chloride
provided a mixture of cis products (148). X-Ray crystallography of
the major stereoisomer confirmed that it was the desired Cram product
(148a) and thus, the minor isomer was concluded to be the opposite
facial isomer (148b). Ozonolysis of (148a) provided the formyl
protected intermediate (149).
This synthesis served a dual purpose; not only did it provide an
attractive illustration of the cyclocondensation methodology but, it
also addressed the question of facial selectivity. The first
cyclocondensation was achieved with complete Cram control whilst the
second occurred with moderate facial specificity. Furthermore, the
utility of the cyclocondensation methodology for the construction of
both cyclic and acyclic stereochemical arrays is highlighted. In the
synthesis (vide-supra) two cyclocondensations replaced the two
58stereo-controlled aldol reactions used by Masamune.
It should be noted that small changes in either the diene
substitution pattern or the solvent system when using the same
aldehyde and catalyst can result in reversal of selectivity. The
reaction of diene (128) with benzaldehyde in the presence of boron
trifluoride etherate in dichloromethane gave a 1:4.6 ratio of the
pyrones (129) and (130). When dichloromethane was replaced by toluene
a 2.2:1 ratio was obtained. It is suggested that the cis preference
of the latter may reflect a greater tendency for the involvement of a
pericyclic mechanism in toluene.
58
When the 4:1 mixture of dienes (132a,b) was reacted with
benzaldehyde under the influence of boron trifluoride etherate a
2.8:1 ratio of ci_s (134) to trans adduct (135) was obtained in 73%
55cyield . This result stands in sharp contrast to the previously
observed trans preference with diene (128). Again greater
contribution from a pericyclic mechanism has been proposed to explain
55cthis selectivity reversal.
Cis-selectivity with either zinc chloride or boron trifluoride
etherate was observed when a mixture of the trioxygenated dienes
(150, R = ^Bu) reacted with acetaldehyde (Scheme 20).^*
o c h 3
R(CH3)2SiO
OCOPh
(150a)
o c h 3
f ^ O C H 3
R(CH3)2SiOx' ' ^ RfCHskSiO
OCOPh
(150b) (1 50c)
r ^ O
OCOPh
CH3CHO Lewis Acid
OCOPh
(151a) (151b)
Scheme 20
CatalystDiene Ratio R = t*Bu(150a):(150b):(150c)
Product Ratio (151a):(151b)
%Yield
ZnCI2 4 : 2 : 1 3.3 : 1 90
BF3 .Et20 3.1 : 3.4 : 1 4 : 1 73
(152 ) (153)
59
This cis preference with boron trifluoride catalyst and the diene
mixture (150, R = ^Bu) is not fully understood. The inductive effect
and potential chelating ability of the benzoyloxy group have been
suggested as candidates to explain these results. The major pyrone
(151a) has been further transformed to the a and /3-methyT fucosideC 1
triacetates (152) and to (±)-methyl 3,4-diacetyldaunosamide (153).
The synthesis of /5-methyl 1incosaminide (157) constituted the
first fully synthetic route to a higher mono-saccharide (Scheme
21). The synthetic sequence contained two key steps. The first
was a cyclocondensation between diene mixture (150, R = Me) and
crotonaldehyde. In the presence of boron trifluoride etherate the
cis pyrone (154) was produced in 67% yield. The trans pyrone could
be detected in the crude reaction mixture. The second critical step
was electrophilic addition of bromohydrin to methyl glycoside (155)
which occurred with high diastereofacial selectivity to afford the
bromohydrin (156). The latter was transformed into the mono
saccharide (157).
60
(150) +
r =ch3
Scheme 21
A similar strategy (vide supra) has been applied to the synthesis
of (±)-3-deoxy-D-manno-2-octulopyranosate (KDO).^ In this case, a
modification to the cyclocondensation step was made in the light of
the poor results obtained with acrolein and suitable dienes. The
synthesis was successfully completed by employing
a-(phenylse1eno)propionaldehyde as an acrolein equivalent.
Danishefsky and Bednarski explored the possibility of using
complexes of oxaphilic rare-earth metals as catalysts for cyclo-
64condensation reactions. Success was achieved with the complex
Euffod)^. The reaction of various aldehydes with the substituted
diene (128) afforded cyclic enol ethers (158). Virtually complete
endo specificity was observed in this reaction with both aromatic and
aliphatic aldehydes. This was contrary to results with Danishefsky's
diene in which aromatic but not aliphatic aldehydes gave good endo
selectivity.
61
(128) + RCHO
R % Yield
Ph 66CH3 66n̂ 6R13 9̂
The Euffod)^ catalysed cyclocondensation of the aldehyde (159),
formed by two all-carbon Diels-Alder reactions, and diene (160) was a
crucial reaction in the synthesis of vineomycinone methyl ester _
(161) (Scheme 22). The mildness of the catalyst system, which allows
the isolation of the enol ether (162), is note worthy. In this
synthesis (vide supra), hydroboration of the enol ether double bond
sets up the chiral centres of the C-glycoside ring (Scheme 22).
TESOH
TESO
TESO,,,.
1.CH2CI2i BH3. Me2S
62
An alternative rare-earth metal complex:- tris(6,6,7,7,8,8-
hep tafluoro-2,3-dimethy1-3,5-octanedionato)ytterbium (Yb(fod)g) was
employed in the synthesis of the monensin lactone (163) (Scheme
23).^ Reaction of aldehyde (164) with diene (165) under the
influence of Ybffod)^ afforded the required Cram product_(166) in 56%
yield. The long reaction time required for complete consumption of
the reagents necessitated the use of the more stable triethylsilyloxy
diene rather than the trimethyl silyloxy derivative to avoid conversion
of the cyclic product into the dihydropyrone (167). The enol ether
(166) was transformed into the desired lactone (163) in six steps.
The latter is a degradation product of monensin and an intermediate ^n
Still's total synthesis of this ionophore.^
Scheme 23
o
The cyclocondensation of aldehydes with 1,1,3-trioxygenated
dienes (168) in the presence of Eu(fod)g has been reported by threero
different sources (Table 11). A particularly significant discovery,
made by Midland and Graham, was that unactivated ketones also react
with diene (168b) under the influence of various Lewis acids (ZnClg*
63
BFg.I^O, Euffod)^) to afford cyclocondensation products (169). The
intermediacy of the readily hydrolyzed, orthoester (170) was proven by
its isolation from the reaction of acetophenone with diene (168b).
Table 11
uon3
(169 )
Diene R4 R5 % Yield (169) Ref.
(168a) Ph H 85 68a,b
(168a) CH3(CH2)5 H 73 68a
(168a) (CH3)2CH H 69 68b
(168a) CHgCH:CH H 70 68b
(168b) Ph H 70 68c
(168b) Ph c h3 40 68c
(168b) CHg c h 3 67 68c
(168b) CHg H3CCi C 63 68c
(168b) -(C2̂ )5 " 52 68c
The availability of both antipodes of the chiral europium
complex, tris[3-(heptafluoropropylhydroxymethylene)-camphorato]-
europium(III) (Eu(hfc)g), provided the opportunity to investigate
the possibility of chiral induction in the cyclocondensation of
aldehydes with siloxy dienes. Reaction of a variety of dienes with
benzaldehyde in the presence of (+)-Eu(hfc)g in deuteriochloroform
afforded cis-pyrans (171) but with only modest enantiomeric enrichment
(Table 1 2 ) . Slight improvements in the enantiomeric excess
64
(e.e.)» ascertained by optical and n.m.r. measurements on
hydroxyesters (172), were found when the methoxy group at in the
diene was replaced by t-butoxy. In each case, reactions performed
with (+)-Eu(hfc)g resulted in an enantiomeric excess in favour of the
L-dihydropyrone (171).
o
o c h 3 o h
V Ph(172 )
Table 12
R1 R2 R3 % ee
c h 3 H H 18
t-Bu H H 38
c h 3 c h 3 c h 3 36
t-Bu c h 3 CHg 42
t-Bu c h 3 H 39
t-Bu OTMS H 42
A second 'approach towards chiral induction in cyclocondensations
utilized chiral auxiliaries installed in the 1-alkoxy group of the
diene. Thus, a selection of dienes were prepared containing either 1-
or d-menthyloxy groups. Their reactions with benzaldehyde in the
presence of the Euffod)^ catalyst afforded approximately equal
quantities of the L- and D-pyranoses (174) and (175) respectively
(Table 13). ^* ^ The ratios obtained with the d-menthyloxy diene
65
(173b) were as expected equal and opposite to those obtained with the
enantiomeric auxiliary (173a).
PhCHOEu(Fod) 3
( 1 7 3 ) a. R ■ l-Menthyl b. R =d-Menthyl
Table 13 Results with diene (173a)
R' R- Ratio(174a):(175a)
H H 33 : 67
c h 3 H 45 : 55
OAc H 45 : 55
c h 3 c h 3 49 : 51
Chiral induction in cyclocondensations was brought to fruition
by the combined use of menthyloxy dienes and Eu(hfc)g. The results
of (+)-Eu(hfc)g mediated reactions between benzaldehyde and the chiral
dienes (173) are outlined in Table 14.70’̂ Combination of the
modestly L-pyranose selective d-menthyloxy diene with (+)-Eu(hfc)g,
which also has a small intrinsic enantiotopic preference" for the
L-pyranoses, showed little change in overall selectivity from those
obtained with Eu(fod)g. In sharp contrast the reaction of
benzaldehyde with the D-selective L-menthyloxy dienes catalysed by
L-selective (+)-Eu(hfc)g displayed a strong preference for the
L-pyranoses (Table 14).7^ ’71
Ph66
~ y - cWSO/ R'OR
PhCHO,(+)-Eu(hfc) 3
( 1 7 3 ) l*Menthylb. R =d-Menthyl
Ph
Table 14
R* R" Ratio(174a):(175a)
Ratio(174b):(175b)
H H 25 (63): 75 (37) 37 (37): 63 (63)
c h 3 H 8 (55): 92 (45) 41 (45): 59 (55)
OAc H 7 (55): 93 (45) 41 (45): 59 (55)
CHg c h 3 18(51): 87 (49) 49 (49): 51 (51)
Figures in parentheses indicate the facial selectivityobtained for Eu(fod) 3 reactions of the same dienewith benzaldehyde.
The select!vities indicated in Table 14 are not caused by double
diastereoselection in which two isolated complementary steric biases
mutually reinforce one another, since it is the mismatched pair of
chiral moieties which afford good selectivities in these cases. The
cyclocondensations are controlled by a specific interactivity between
the two chiral elements which results in the inherent facial
selectivity of the auxiliary being inverted upon interaction with the
chiral catalyst.
This type of methodology has been applied to the synthesis of
L-glucose (175) (Scheme 24).^ The Eu(hfc)g mediated reaction of
diene (173a, R'=R"=H) with benzaldehyde yielded a 3:1 ratio of L- and
D-pyranose derivatives (174a, R'=R"=H) and (175a, R'=R"=H)
respectively. When the modified diene (176), (incorporating an
1-8-phenmenthyl auxiliary and t-butyldimethylsilyl protection), was
utilized in the cyclocondensation reaction a 25:1 ratio of L- and
D-pyranoses, (177)
67
and (178), was obtained. Treatment of enantiomerically pure (177)
with trifluoracetic acid afforded pyrone (179) in 75% overall yield.
The latter was converted in a series of steps to L-glucose (175).^
Ph Ph
R = l-8 -phenmenthyl
TFA
(175) (179)
It should be noted that this methodology is limited to those
glycosides with a cis relationship between the anomeric substituent
and the side chain at the 5-position (i.e. ^-glycosides) because of
the endo selectivity of Eu(hfc)^. Furthermore no enantioselection70
was obtained (181) with trioxgenated dienes of the type (180).
Thus, in order to prepare chiral galactosides by this type of protocol,
separation of the mixture of pyranoses (181) would be necessary.
TESO
ArCHO(+)-Eu(hfc) 3
( 1 8 0 ) R = Menthyl
The reaction of triethylsilyl 1-menthyloxydiene (183) with
furfural in the presence of Eufhfc)^ afforded a 5:1 mixture of
72products. The major component (184), isolated in 66% yield, was
converted by a sequence of reactions including a novel carbon Ferrier
displacement to the dihydropyran (185). Burke and coworkers have
68
indanomycin and Nicolaou has utilized (186) as an intermediate in
74the total synthesis.
transformed (185) into (186), the dihydropyranoid segment of
73
o
( 1 8 6 )
Burke
When a nr /? hetero substituted aldehydes are used as dienophilic
components in cyclocondensations the stereochemical outcome of the
process is dependent upon whether or not chelation control is
operative. The reaction of aldehyde (187) with diene (188) in the
presence of zinc chloride, boron trifluoride etherate or Ybtfod)^
yielded a mixture of pyrones (189) and (190) in approximately equal
quantities. However, with magnesium bromide in tetrahydrofuran
cycloadduct (189) was isolated as the sole product in 76-80% yield.^
Similarly, high stereoselectivity was obtained in the reaction of
75other a-oxygenated aldehydes with a selection of dienes.
6S
o
Et
(187)
Approach of the diene
(191)
(189)
(190)
The stereochemical assignment of (189) and related systems was
proven by n.m.r. analysis and conversion to rigid bridged ketals.
The latter chemical sequences also served to illustrate some uses of
these cyclocondensation products. For example, pyrone (189) upon
debenzylation, cyclisation, reduction and deoxygenation afforded
75cexo-brevicomin (192). Similarly the debenzylated product (193) was
75rconverted in three steps to the mouse androgen (194).
( 1 8 9 )86%
BF3 .Et2 o,DMS
H
( 1 9 4 )
70
The stereoselectivity of the cyclocondensation reaction (vide
supra) can be explained by invoking the Crain chelation model.
Coordination of the two oxygens by magnesium affords the syn conformer
(191). Approach of the diene from the least hindered a face of (191)
corresponds to the observed stereospecificity. Support for this
hypothesis came from the reactions of diene (128) with benzaldehyde and
the aldehyde (195) in the presence of magnesium bromide. The
former, a control experiment, afforded a mixture of pyrones (196a) and
(197a) in a ratio of 38:1 and in 50% yield. The preferential
formation of the cis. adduct (196a) was consistent with a pericyclic
mechanism and endo topology, analogous to cyclocondensations mediated
55cby zinc chloride. In the case of aldehyde (195) if chelation
control was effective then an exo disposition of the 2-benzyloxy-
propanyl group in the product would be expected. This was borne out
in practice. Reaction of aldehyde (195) with diene (128) and
magnesium bromide catalyst afforded the trans pyrone (197b) as the
sole product in 50% yield.
OCH,
o
T * xTM S O -^^s
( 1 2 8 ) a. R = Phb. R = CH(OCH2 Ph)CH2 CH3 (1 9 5 )
o
When the same two reactions (vide supra) were conducted with
titanium tetrachloride as catalyst completely contrary results were
obtained. The titanium tetrachloride catalysed reaction of aldehyde
(195) with diene (128) afforded a mixture of cyclic and a1dol-like
products. Complete cyclisation was achieved by treatment with
trifluoroacetic acid which provided only the £is pyrone (196b) in 93%
yield. When the reaction was repeated with benzaldehyde a mixture of
71
cis and trans products, (196a) and (197a) respectively was produced
in a 1:8 ratio. The isolation of a 1 do!-like products and the
threo-specificity obtained with benzaldehyde suggested that titanium
75tetrachloride behaves in a similar fashion to boron trifluoride. It
should be noted however that this may well be an over simplification
in view of the ability of titanium to form six-coordinate species; a
facility not available to boron. Again the difference in selectivity
between benzaldehyde and aldehyde (195) suggests that the latter
reacts via the syn conformer (191).
This type of methodology has been applied to the synthesis of
methyl peracetyl-a-hikosaminide (198) (Scheme 25).^ The cyclo
condensation product (200) derived from furfural and diene (199) in
the presence of Eu(fod)^ was converted to the heptodialdose (201).
Magnesium bromide mediated cyclocondensation of aldehyde (201) and
diene (199) afforded the undecose (202) as the sole product in 75%
yield. The latter was then readily transformed into the target
compound (198).
AcO-AcO-
AcO-
CH2 OAc
OAcOAc
OAc
( 1 9 8 )
72
OBz
(199)
( 2 0 2 )
Exo, chelation Control
O
75%
(199)MgBr2, 0 °C, CH2 CI2 : PhCH3
( 2 0 1 )
AcO-AcO-
AcO-
CH2 OAc
OAcOAc
Scheme 25
(198)
The reaction of (R)-glyceraldehyde acetonide (203) with
Danishefsky's diene in benzene in the presence of zinc chloride
produced the (5S,6R)-heptulose (204) in 722 yield. 51 Similar
cyclocondensation of aldehyde (203) with magnesium bromide as catalyst
afforded predominantly heptulose (204) (37%) together with the C^-
epimer (3%). The stereochemistry of (204) is consistent with Cram
formulation. The absence of chelation control with this aldehyde is
73
not properly understood but the same phenomenon has been observed
78with organometal1ic nucleophiles.
o
(203)
+
OTMS
OCH3
OCH(CH3 ) 2
(205)
(204) has been converted into chiral 2,4-dideoxy-D-glucose (205)
which corresponds in both relative and absolute configuration to the
51pyranose portion of the antihypocholestemic agent compactin.
Cyclocondensations of sugar derived aldehydes provides a
75c 79convenient route to carbon linked disaccharides. ’ The boron
trifluoride mediated reaction of aldehyde (206), derived from
D-galactose, with trioxygenated diene (150, R=Me) afforded a crude
product mixture which upon treatment with trifluoroacetic acid
/ % 79provided a single cyclocondensation product (207) in 62% yield. The
stereochemistry of the product indicates reaction occurred with endo
topology and Cram controlled diastereofacial selectivity. This has
been rationalised on the basis of an anti orientation of the
carbon-oxygen bond of the pyran ring and the formyl group (206) which
79minimises the dipole-dipole repulsions. Attack of the diene then
occurs from the least hindered face; opposite to the hexose ring.
74
Similar cis selectivity with diene (150 R=t-Bu) and acetaldehyde in
the presence of boron trifluoride etherate has been observed (Scheme
20).61
( 1 5 0 )R-CHg
62%
1. BF3 .Et2 0 , Ether, -78 °C2. TFA, CCI4, RT
O
O
( 1 5 0 )
R-CHg
54%
1. BF3 .Et2 0 ,2 . TFA
( 2 0 8 )
When aldehyde (208), derived from D-ribose, was treated with
diene (150 R=Me) under the influence of boron trifluoride etherate,
79the cyclocondensation product (209) was isolated. X-Ray
crystallographic analysis of (209) indicated that the facial
selectivity had again occurred in a Cram controlled manner. However,
a trans substitution pattern in the pyranose ring indicated exo
selectivity. Thus, changing the sugar moiety can have a dramatic
effect on the topology of the reaction. This may be duer to a
reduction of steric encumbrance to exo approach of the diene in the
case of aldehyde (208). Aldehyde (208) has been employed as the
dienophilic component of a cyclocondensation in the synthesis of
80(heptaacetyltunicaminyl)uracil.
75
The lability of /?-alkoxy aldehydes compared to their
a-oxygenated counterparts necessitated an acceleration of the rate of
cyclocondensations with these substrates. This was achieved by
75altering the solvent system. Thus, reaction of/3-alkoxy aldehyde
(210) with diene (128) in the presence of magnesium bromide in 4:1
benzene/ether (c.f. tetrahydrofuran witha-alkoxy aldehydes) produced
a mixture of cyclic and acyclic products which were treated with acid
in the usual way. Two pyrones (211) and (212) were isolated in a
ca .1:1 ratio.^
(128)BnO
( 2 1 0 )
80%
1 . MgBr24:1 C6 H6;Ether2 . TFA
(128) + (210) 94%BnO
1. BF3 .Et20 CH2 CI22 . TFA
(213) 60%
Three other isomers
The enforced solvent change resulted in a shift of reaction
55cmechanism towards the Mukaiyama aldol type. Though good chelation
control was observed there was virtually no endo/exo selectivity.
When the reaction (vide supra) was repeated with boron trifluoride
etherate as catalyst the major product (213) isolated from the four
component isomeric mixture (ratio 22:4:4:1) was that predicted by
Cram controlled diastereofacial selectivity with overall exo
75topology. The search for a catalyst with which chelation control
together with high endo specificity would be achieved led to titanium
tetrachloride. When this was employed as catalyst in the reaction of
76
diene (128) and aldehyde (210) and the resultant product treated with
trifluoracetic acid the only dihydropyrone isolated was (211) in 55%7c
yield. (211) possessed the stereochemistry expected from cis-
chelation control. Cyclocondensation product (211) has been utilized
in the synthesis of the polypropionate sector of the ansa antibiotic
. c 81 rifamycm S.
The first total synthesis of the ionophore zincophorin (214) has
recently been achieved (Scheme 26). The synthetic strategy required
cyclocondensation of aldehyde (215) with diene (128). This was
accomplished in 80% yield using magnesium bromide catalysis in
dichloromethane. The stereochemistry of the resulting product (216)
is that which would be predicted from a chelation controlled process
with exo topology. The high exo selectivity is somewhat surprising in
view of previous observations with aldehyde (210).^ One possible
explanation is the use of dichloromethane as solvent. Modification of
(216) afforded (217) which upon successive ring opening, protection
and oxidation afforded aldehyde (218). The aldehyde (218) formed
from the anomeric site was then subjected to a second cyclo
condensation reaction with the 4E diene (132b) under the influence of
boron trifluoride etherate. The desired product (219), formed in
46% yield, was converted to the aldehyde (220) required for the Julia
coupling reaction. Coupling with the previously synthesised sulphone
(221) followed by reduction, deprotection and esterification afforded
zincophorin methyl ester (222).
77
( 1 2 8 ) +
46%1. BF3 .Et202. PPTS
O
Scheme 26
It is clear (vide supra) that the stereochemical outcome of
cyclocondensation reactions with aldehydes susceptible to chelation is
governed by the catalyst system employed. Table 14 contains a brief
78
summary of cyclocondensations with diene (128) The fourth selectivity
permutation of cis selectivity with Cram control has not yet been
achieved. It should be noted that as examples have shown (vide supra)
small changes in aldehyde, diene or solvent can have a striking effect
upon both the topology and facial selectivity of the cyclocondensation
reaction.
Table 14
Lewis Acid MechanismType
Endo/ExoTopology
Cram/ChelationControl
MgBr2 Pericyclic exo * Chelation
BF3 .Et20 Mukaiyama exo Cram
T iCI4 Mukaiyama endo Chelation
* Poor selectivity observed with beta-alkoxyaldehydes
3.4 Formaldehyde.
B.B. Snider's formal synthesis of pseudomonic acids A and C
incorporates a novel quasi-intramolecular Diels-Alder reaction which
83employs paraformaldehyde as the dienophilic component. The diene
precursor (224) for this cycloaddition was prepared by a dimethyl-
aluminium chloride mediated ene reaction of 1,5-hexadiene (223) with
paraformaldehyde followed by acetylation. Reaction of (224) with
paraformaldehyde in the presence of 4.5 equivalents of ethyl aluminium
dichloride afforded a 37% yield of a 16:1 mixture of (225) and (226).
An outline of the reaction course is included in Scheme 27.
79
EtAICI2
+ ° CH ^OH
37%
HCHO,EtAICIo
0 . o1:1 C H ^C R jN O ., £25 °C, 12 h
(225)
IJ oA
o c oS
TBDPSO
(230)
OH
(2 2 6 )
(2 2 4 )
EtAlCI2I
0+
(227)
HCHO
AcO' .o*°+ -
Al̂Cl' xci
h2o
(225)
OAc
Scheme 27
80
It has been suggested that initially the ethylaluminium dichloride
coordinates to the acetate group which is more basic than
bond so that this second ene reaction occurs at the terminal double
bond affording the complex (227). Formal loss of ethane from (227)
provided (228) which then coordinated further with formaldehyde.
This complex (229) was set up for the quasi-intramolecular Diels-Alder
reaction which occurred in a stereospecific manner to yield (225)
after hydrolysis. The formal synthesis was completed by conversion of
(225) into (230), an intermediate in Kozikowski's synthesis of
84pseudomonic acids A and C.
The quasi-intramolecular reaction of diene (231) with
paraformaldehyde in the presence of dimethylaluminium chlorideoo
afforded the alcohol (232) in 68% yield. When the reaction was
repeated with acetaldehyde a 1 :1.2 mixture of the endo and exo
products, ((233) and (234) respectively), was isolated in 57% yield.
Replacement of acetaldehyde by a more bulky aldehyde could well
improve the selectivity.
83formaldehyde. This apparently deactivates the internal double
(HCHO)nMe2AICICH2CI2, 24 h
(2 3 1 ) ( 2 3 2 )
(CH3 CHO)n Me^lCI CH2CI2, 24 h ( 2 3 3 ) 1 : 12 (2 3 4 )
81
The cyclocondensation of monomeric formaldehyde with the
dioxygenated diene (235, R=Et) has been accomplished by catalysis
with bornyloxyaluminium dichloride. The product (236) was isolated
in 50% yield. 535
OR
HCHOO
TMSO
(2 3 5 )
82
The zinc chloride mediated cyclocondensation of paraformaldehyde with
the diene mixture (150, R=Me) afforded the desired pyrone (237).
Reduction of (237) provided an 8.5:1 mixture of alcohols (238a) and
(238b) respectively. The major isomer (238a) was converted in a three
step sequence to a separable anomeric mixture of arabinopyranosides
(239a/b, 1:1). Deesterification and reprotection of either anomeroc
afforded (±)-diacetone arabinose (240) (Scheme 28). Clearly cyclo
condensations with paraformaldehyde provide a convenient route to
natural products based on pyrans with an unsubstituted 2-position.
3.5 Carbonyl compounds with heterodienes.
The boron trifluoride mediated reaction of 2-aza-l,3-butadienes
with aldehydes provided good yields of dihydrooxazines (241) (TableO C
16). In some cases (Table 16, entries 1,2) the reaction took place
in the absence of the catalyst. Spectral data on (241) established
the c_i_s relationship between the C-5 and C-6 substituents of the
oxazine ring. Such stereochemistry was rationalized in terms of a
concerted [4+2]-cycloaddition with endo selectivity. However, the
reaction of diene (242) with benzaldehyde afforded a 2.5:1 mixture of
trans-oxazines (243) and (244) respectively. This stereochemical
outcome was attributed to a change in the reaction mechanism to a two
step process via the zwitterionic species (245). No explanation was
provided for this mechanistic change, but it would be reasonable to
assume that the presence of the bulky cyclohexyl group disfavours the
more sterically demanding pericyclic mechanism.
+
c h 2 r 2
1N ^ R '
R2
BF3 .OEt2 C6Mb, 608C 1 - 2 days
Table 16
Entry R1 R2 R3 % Ylield
1 Ph Me Ph 95
2 Ph Me 4-N02 *C6 H4 90
3 Ph Me 4-CH3 -C6 H4 75
4 Ph Me c 4 h4o 76
5 Ph Me n-C4 H9 70
6 Ph Me i-C3 H7 75
7 Ph Et Ph 85
8 4-CH3 -C6 H4 Me Ph 80
9 4-CH3 -C6 H4 Me 4*CH3 -C6 H4 75
BF3
84
A variety of carbonyl compounds undergo [4+2]-cycloaddition
reactions with polyfluoro-2-acyliminopropanes (Scheme 29). The
iminopropanes (246) and (9) reacted with aromatic and a#-unsaturated
aldehydes to provide excellent yields of the adducts (247) and (248)
respectively. The process is analogous to the reaction of nitriles
with acyl imines (Section 2.5).
nY ° F 3 + H"
cf2x
A s / V 70 - 90 %
v X — -Ph' Y ° ^ caH
N Oc Xf3c/ cf2x
(2 4 6 ) X»N02 .F Y=H, N02, NMg2, OMg (247 )
y °N^ x CF3
1cf3
0
. J L 60-80%
11 -----------------------y T n
- N °
F3c r c F 3
(9) (248)
R = Me, CF3i CH (CF3) 2 R1 = H, Me
Scheme-29
Thioacyl isocyanates (249), generated from the thermal
decomposition of heterocycles, behave as diene components in
88 89Diels-Alder reactions with carbonyl compounds. * Thus (249)
reacted with aldehydes, ketones and a/3-unsaturated aldehydes to afford
oxathiazinones (250)(Table 17). In the case of the
c^-unsaturated compounds addition occurred across the carbon-oxygen
rather than the carbon-carbon double bond.
85
(250)
Table _17
R1 R2 R3 % Yield Ref
OEt PhCH:CH H 65 89b
OEt PhCHC H 62 89b
OEt n o 2 -c 6 h4 H 48 89b
OEt CHg CHgCO 69 89b
OEt -(CH2 )5 - 63 89b
CI-C6 H4 CH2 :C(CH3 ) H 35 89a
c i-c 6 h 4 CH2 :C(Ph) H 64 89a
4. C-S Dienophiles.-
4.1 Thioketones.
Many Diels-Alder reactions using a diverse array of thioketones
are recounted in the literature.* The susceptibility of- simple
aliphatic thioketones to enethiolization and polymerisation has
generally restricted the use of these substrates. However, polycyclic
aliphatic thioketones such as adamantanethione (251) readily undergo
90cycloadditions with a variety of dienes. The reaction of thione
86
(251) with substituted butadienes afforded the desired cycloadducts in
90moderate to excellent yield (Scheme 30).
(2 5 1 )
R
(251 )
toluene 110°C , 48 hr
(2 5 2 )
a. R1 « Me, 80% ^b. R1 a H, R2 a Me 82% 4 5 55
(2 5 1 )
OMe
OTMStoluene
110 °C, 24 hr
OMe
64%
H +
( 2 5 4 )
Scheme 30
The unsymmetrical diene, piperylene provided a single cycloadduct
(252a). However, isoprene yielded a 55:45 mixture of regioisomers
(252b) and (253b). Frontier molecular orbital theory predicted
products which did not coincide with the experimental observations.
The outcome of the reaction between piperylene and (251) was explained
on the basis of the steric interaction between the adamantane skeleton
87
and the terminal methyl group of the diene disfavouring formation of
(253a). Similar reasoning was proposed to rationalize the formation
of adduct (254), the sole product of the reaction between (251) and
Danishefsky's di e n e . ^
The cycloaddition of adamantanethione (251) with isoindole and
isobenzofuran afforded the adducts (255) in good yields. Similar
reactions with furan and 1,3-diphenyl-isobenzofuran were unsuccessful.
P
p
o^-Unsaturated carbonyl compounds behave as dienes in their
91reactions with thione (251) (Scheme 31). The stability of the
4H-1,3-oxathiines (256) isolated from these cycoadditions was
dependent upon diene substitution. Crystals of (256a) were stable to
the atmosphere at room temperature whilst (256d), an oil, decomposed
at 5 °C. o-Quinone methanides (257), generated in situ from
substituted sal icy! alcohols (258a) or the amines (258b) proved to be
91beffective diene components in Diels-Alder reactions with (251).
The high regiospecificity of these cycloadditions has been explained
in terms of frontier molecular orbital theory in which the dominant
overlap is between the LUMO of the diene and the HOMO of the
91dienophile; an inverse electron demand Diels-Alder reaction. Data
88
from kinetic studies was consistent with a second order rate
expression. The activation parameters were similar to those reported
for 'conventional' Diels-Alder reactions and the rate constants were
found to be almost independent of solvent polarities. These findings91suggested a pericyclic mechanism.
a R1 = R2 = R3 = H 94%b. R1 = R3 = H, R2 = Me 71%c. R1 *= R2 *= H, R3 = Me 29%d . R1 =M ef R2 = R3 = H 82%
(258b )
a W = X = Y = Z = H 90%b. W = Y = Z = H, X = Me 55%c. W = X = Z = H ,Y = N 0 2 89%d. X = Y»=Z = H, W = OMe 51%
Scheme 31
The cycloaddition of thiobenzophenone with acrolein occurred at
140 °C but the adduct was too unstable to be isolated. However,
thiobenzophenone reacted with o-quinone methanide (257a) to afford
the diphenyl cycloadduct (259) in 79% yield.
89
Dondoni has reported an unusual hetero Diels-Alder reaction of
thiobenzophenone (258) and N-ary1 ketenimines (Scheme 32). The
reaction of C,C-diphenyl- and C,C-dimethylketenimines (259) with (258)
provided the [4+2]-cycloadducts (260) in good yields. The analogous
reaction with N-phenylmethylketenimine (261) produced the
benzothiazine (262) together with the thietane (263). Thietanes
(264) were the sole products in the reactions of (258) with C,C-
disubstituted ketenimines where in the N-aryl group possesses ortho
(259)
a R = Ph, X = 4-CHg 85% b R = Me, X = 4-CHg 80% c R - Me, X - 3-OCHg 85%
1 J
(263)47%
(2 5 8 ) +
R
°^NAr CCl4 ,45 - 60 °C
(265)
R
(264)
R = Me, Ar = 2,6-(CH3 )2 C6 H3 30%R - Ph, Ar - 2,4,6-(CH3 )3 C6 H3 30%
Scheme 32
90
From kinetic and theoretical studies on these two cycloaddition
pathways it was concluded that both processes occurred by pericyclic
mechanisms. The relative amounts of thietanes and benzothiazines
formed was rationalized by a combination of steric and electronic
effects. With C,C-disubstituted ketenimines the electronically
favoured 1,2-cycloaddition pathway is suppressed due to inhibition of
approach of the thione to the carbon carbon double bond from either
face. In the case of ortho substituted N-aryl ketenimines the
reaction across the heterodiene is restricted so thietane formation
is preferred.
When C-vinylketenimines are reacted with thione (258) a third
mode of cycloaddition is possible. This new reaction pathway was
promoted by a judicious choice of substrate (266) which contained the
elements necessary to suppress the alternative addition processes.
Thus, reaction of (258) with (266) afforded the adduct (267) in 86%
yield.93
(266)
+ (258)
4.2 Thioaldehydes.
Simple aliphatic thioaldehydes, like their thioketone
counterparts, are unstable. Over the past few years several methods
of generating both aliphatic and aromatic thioaldehydes in situ have
91
94-96been developed. Baldwin and Lopez prepared thioacetaldehyde
and thiobenzaldehyde by thermolysis of the appropriate thiosulphinate
(268) in toluene. The thiocarbonyl compounds (269) were immediately
94trapped with a selection of dienes (Scheme 33). With 2-ethoxy-
butadiene and thiobenzaldehyde a mixture of regioisomeric
dihydrothiopyrans (270) were formed which hydrolysed to the thianones
(271).
Ft ^ S '
(268)
cri;
IX]
[ X(269)
(272a)
Heat
Toluene, 1 0 0 °C
RCHjSOH * [X](269)
_ Toluene,OEt 1 0 0 “C E,°
XL, • "°XlPh(270a)
I
(270b)
I
Ph
(271a)
31%
(271b)
13%
R'
x x(272a) R = Ph, R' = H 97%(272b) R *P h , R’ *=Me 87% (273a) R - Me, R '» H 82% (273b) R - Me, R’ - Me 76%
( 2 7 4 ) R = Ph 95%R ts Me 83%
Scheme 33
The anthracene adduct of thiobenzaldehyde (272a) proved to be a
good source of the thioaldehyde. When (272a) was heated with
2,3-dimethylbutadiene, dihydrothiopyran (274) was isolated together
92
with anthracene. In the case of thioacetaldehyde, the anthracene
adduct (273a) proved resistant to thermolysis. However the
9.10- dimethyl analogue (273b) liberated thioacetaldehyde which was
trapped by 2,3-dimethylbutadiene. The lability of the
9.10- dimethyl anthracene adduct (273b) to thioaldehyde extrusion
compared to the unsubstituted case (273a) is, as the authors suggest,
most likely the result of the relief of steric congestion. This
method of generating thioaldehydes has the advantage that the
by products, anthracene and 9,10-dimethylanthracene, are relatively
inert. Thus, the possibility of incorporating more sensitive
functionality into the diene component of the reaction is available.
An intramolecular Diels-Alder reaction of an aliphatic
thioaldehyde was accomplished by the thermolysis of the sulphinate
(275) and afforded a l z l mixture of thiabicyclononenes (276).^
An alternative method of generating thioaldehydes is by the
fluoride induced /^-elimination of stabilized aryl thiolate anions
from a-silyldisulphides (277).^ The efficiency of the elimination
and the stability of (277) is dependent upon the stability of the
aryl thiolate leaving group. 2-nitro and 4-chlorophenyldisulphides
were relatively stable but on exposure to fluoride underwent
93
*elimination to the desired thioaldehydes. These were trapped by
cyclopentadiene to afford a mixture of exo and endo adducts (278)
95(Table 18). In each case the endo isomer predominated.
SiMe2 R'
R ^ S - S /^
(277)
R R* X Conditions Exo/Endo % Yield
H Me 4-CI A - 67
Et Ph 2-N0 2 A 1 : 6 92
i-Pr Ph 2-NOz B 1 :7 6 6
Ph Me 4-CI A 1 :7 90
c-Hex Ph 2-N0 2 B 1 :5 58
i " - 1
Ph 2-N0 2 A 1 :4 65
Method A CsF, THF, RT Method B Bu4 NF, 0 °C
The first stable aliphatic thioaldehyde was isolated by Vedejs
and Perry. Photolysis of phenacyl neopentyl sulphide (279)
afforded an insoluble white polymer (280). Vacuum distillation of
(280) provided 2,2-dimethylpropanethial (281). This is stable in
solution for up to 16 h at 20 °C. Reaction of thial (281) with
Danishefsky's diene provided the desired adduct (282) after acidic
workup in 25% yield.
94
PhY ^ S^ C(CH3)3O
(279)
59%
C6H6, hv
(C u S 0 4, filter)
ft-BuCHS^
(280)
40 - 50%
250 °Ct-BuCHS
(281)
t-BuCHS +
TMSO
OMe
25%
1 . CH2 CI2 ,RT 5 min
2 . THF, HCI
t-Bu
(282)
The photolysis of phenacyl sulphides has been used to generate a
variety of thioaldehydes which were subsequently trapped by various
dienes in a Diels-Alder fashion (Tables 19,20). This thioaldehyde
preparation is thought to proceed by a six centre Norrish type
/ % 97fragmentation (Scheme 34).
Scheme 34
The process has been applied to the synthesis of thioaldehydes
with aliphatic and aryl substituents and also to those possessing, 97
electron withdrawing groups (for example acyl, ester, cyano).
Diels-Alder reactions of the latter class of thiocarbonyl compounds,
acceptor substituted thioaldehydes, occurred readily with a 1-2 fold
excess of diene providing the desired adducts in reasonable yield
(Table 19).97
96
The regio- and stereospecificity of the reactions
closely resemble the outcome of 'conventional' Diels-Alder
processes. The major isomers formed are those in which the
thioaldehyde substituents are 'ortho' or 'para' to the diene donor
group. This selectivity is opposite to that obtained with activated
carbonyl dienophiles such as ethyl glyoxylate. (Section 3.1). The
major component of the thiocarbonyl Diels-Alder product mixtures
results from an endo orientatio