Q^echanism CEl> Stereochemistry o f Some

Reactions o flV -C ^ V- Co-Ordinated

Phosphorus Compounds.

e x

Co/in C. White-

A Thesis presented for the Degree of

DOCTOR OF PHILOSOPHY in the

FACULTY OF SCIENCE of the

UNIVERSITY OF LEICESTER

S ^ t e m p e i T i g 8 ^

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STATEMENT

The accompanying thesis, submitted for the Degree of Doctor of Philosophy, is based upon work carried out by the author in the Department of Chemistry of the University of Leicester, during the period between October 1981 and September 198^.

The work recorded in this thesis is original, unless otherwise acknowledged in the text or by reference. No part of this work has been submitted for another degree in this or any other University.

Results from chapter 2 of this thesis have been published in Journal of Chemical Research, 1983, 234- - 233.

Results from chapter 3 of this thesis have been published in Journal of the Chemical Society, Chemical Communications, 1984-, 251 - 252.

ACKNOWLEDGEMENTS

First and foremost, I would like to thank my super­visor, Professor S . Trippett, for his constant advice, guidance and encouragement throughout the course of this work,

I would like to thank the staff and technicians of the Department of Chemistry for their advice and assistance.

I thank Mrs J. Lee for typing this thesis, Mrs A. Crane for drawing the diagrams and Mr. M. Lee for his help in the preparation of this thesis.

I thank the Chemical Defence Establishment and S.E.R.C. for a CASE studentship.

Finally, I thank my family for all the support I have received during my research work.

AbstractMechanism and Stereochemistry of Some Reactions of IV- and V- Co-Ordinated Phosphorus Compounds by C.L.White

A series of cyclic phosphoranes and spirophosphoranes have been prepared and reacted with diethyl phosphorochlor- idite, the phosphorane acting as a nucleophile, and the sub­sequent products reacted further with methyl iodide and chloral. Reactions have also been carried out in which a nucleophilic attack on the phosphorane occurs, the nucleo­phile employed being the anion of thio-phenol. It was hoped these reactions might provide a new pathway to the type of phosphorus compound which have been involved for a number of years in the control of pestsortiioSecfcs and that an insight into the stereoelectronic requirements of reactions at phosphorus might be obtained.

The mechanism of the Michaelis-Arbusov rearrangement is generally accepted as having a two stage pathway, the second stage usually considered as being an SN2 attack of a nucleophile on the a-carbon of an alkyl group. Arbusov and related reactions with unsymmetrical phosphites contain­ing different alkyl groups have been carried out. The effect of varying the electrophile, nucleophile, temperature and solvent of the reactions has been studied. As a result of the above, the second stage of the generalised Arbusov reaction is found to have SNl character.

The stereochemistry of nucleophilic substitution at phosphoryl centres has been studied extensively by a number of groups. However, it has not hitherto been possible to investigate the stereochemistry of hydrolyses since these lead to achiral acids. A general method, involving isotopic labelling, has been developed that allows the stereochemistry of such hydrolyses to be established. The stereochemistry of the alkaline hydrolyses of Sp-methyl methylphenylphosphinate on!

methylphenylthiophosphinate have been established using the method referred to above.

CONTENTSPage No

Chapter 1 - Substitution Reactions InvolvingPhosphoranes and Spirophosphoranes

Introduction 1

Results and Discussion U

Experimental Details, including general Experimental details 39

References 55

Chapter 2 - The Michaelis-ArbusovfÎHirrangement

Introduction 58

Results and Discussion 71

Experimental 92

References 118

Chapter 3 - Nucleophilic Displacement Reactionsat Four Co-Ordinate Phosphoryl Centres

Introduction 121

Results and Discussion 126

Experimental I4.8

References 167

CHAPTER 1

Substitution Reactions involving Phosphoranes

and Spirophosphoranes

Substitution Reactions involving Phosphoranes and Spiro­phosphoranesIntroduction

Phosphoranes are a class of phosphorus compound withfive ligands covalently bonded to the central phosphorusatom. The first reported phosphorane was an intermediate,

1proposed by Ingold, in the reaction of tetramethylphosphon- ium iodide (l) with moist silver oxide. Ingold observed the liberation of methane during this alkaline hydrolysis which did not occur in the ammonium analogue, and concluded that the intermediate was not a phosphonium hydroxide but a pentaco-ordinate compound.

( M e \P ® r ♦ AQjO/H^O

(1)

Me — P -^ Me IOH

(M e L P = 0 * CH

Pentaco-ordinate phosphoranes have since been implicated as short-lived intermediates in a large number of reactions, two examples being the Wittig and Staudinger reactions, below.

-1-

Wittig: 6 '® BaseH

® àPhgP + R'CHjBr — ► P h jP -C H R ' Br

* « I h r -PhjP =CHR' -•— P h j P -

0 = CHR

Ph i 0 ♦

^ P —CHR PhgP-CHR' betaineP h ^ l I @ 1

0 - C H R 0 -C H R

JPhjPsO + RCHsCHR'

Staudinger:

-Nj

(ROlaP.PhNg

I(RO)gP=N—N=N—Ph —♦(R 0)3P =N P h

IRCHOOR ▼

RO,, I 0

J P - N P h (R O ),P -N P hRO I I -4— © I

0 — CHR 0 - CHR betaine

i(R 0),P =0 ♦ PhN= CHR

A number of thermally stable phosphoranes have now been prepared. The majority of these phosphoranes are prepared from trivalent species via an addition reaction, an example being the reaction between a phosphite and 1,2' dicarbonyl compound.^

-2 -

(RO^P ♦ V ^O ^ R O R

Other 1,3 di-unsaturated compounds also form stable 1:12 aadducts, the general equation being;

R,P + % -

X and Y = 0, S NR and CR^

The reaction of a trivalent phosphorus compound with a dialkyl peroxide yields a dialkoxy phosphorane.^

Above are the methods by which the cyclic phosphoranes and spirophosphoranes mentioned in this chapter were prepared Other methods of preparation are available, however, and some are listed below.

i) A 1-3-dipolar addition to ylides.**

® ©R “ C = N “ 0

H :C = P (C A )36" ’5'3

ii) A reaction of chloramines with diols and a phos­phorus (III) reagent.^

j ® ©

R,P + HOIClnOH * ClNPr^ R a P \ ♦ PrjNH^Cl0 ^

-3-

iii) A reaction of trivalent phosphorus compounds with 2 molecules of a monofunctional carbonyl compound.

iv) A reaction of trivalent phosphorus compounds6with certain azides.

aOMe

OH Ph, IMeOPPh, ♦ I II — ^ ^ P — NH

" " A

v) A reaction of a trivalent phosphorus compound with hydroxy acid, diol, or amino alcohol in the presence

7of diphenyl disulfide.Molecular orbital calculations and electron pair

9repulsion theory predict that the most stable configuration for simple penta co-ordinate molecules e.g. PF^is the trigonal bipyramid (t.b.p.). Other geometries, e.g. the square based pyramid, are less stable.

Ba t.b.p. Bg s.pB

Unsymmetrical substituted phosphoranes show distortions away from the t.b.p. geometry. X-ray analyses have revealed that in certain cases, especially in the cyclospirophosphor- ane series, the geometry can be much closer to the square p y r a m i d . I n neither arrangement are the 5 ligands equiva­lent; however, most of this type of compound undergo ligand

-4-

re-organisation. The classical example is PF^ where one expects two types of fluorine atom by ^^F n.m.r. In practice at room temperature all the fluorine atoms appear to be identical. As the temperature is lowered the single phos­phorus-decoupled fluorine signal broadens and eventually separates into two signals in a ratio of 3:2.

In i960 Berry^^ proposed a mechanism to explain this equilibration of the fluorine atoms. Berry Pseudorotation (B.P.R.). The mechanism of the B.P.R. is outlined in scheme A.

1 ^ 0 ^ I ^ AB V ^ D D

t.b.p. s. p.

SCHEME A

An alternative mechanism for this isomérisation was proposed by Ugi and R a m i r e z a n d is called Turnstile Rotation (T.R.). The mechanism of T.R. is outlined in scheme B.

-5-

Bc / , ^ 0

B

\ D

if

A —

E

C

B

1 3

SCHEME B

The overall result of a T.R. or a B.P.R. is the same and asa result all isomérisation processes in this thesis will bereferred to as B.P.R.

Bonding in phosphoranes can be easily visualised usingthe simple molecular orbital approach described by Rundle.The equatorial bonds of the trigonal bipyramid are formed

2from ^ hybridised orbitals on phosphorus and the apical bonds are formed from a _p orbital only. The molecular orbit als are then obtained by a linear combination of the atomic orbitals of phosphorus with the _s orbitals of the ligands. Hoffman^ has also presented a simple model of the bonding in phosphoranes by examining a set of completely delocalised molecular orbitals.

The involvement of 3d orbitals in the bonding scheme has been argued as well. There are theories of orbital hydridisation that require the inclusion of a complete d ^

-6-

orbital into the s p ^ bonding s c h e m e . H e r e the apical bond is formed by hybridisation of the 3d^^ and 3p^ orbitals. Presumably, the extent of d orbital interaction lies some­where between this extreme and the one proposed by Rundle^^ of a three-centre four-electron bond for the apical ligands. The apical bond is normally longer and hence weaker than the equatorial bond.

It has largely been found that the stability of phos­phoranes increases with the number of ligands of relatively high electronegativity and with decrease of steric bulk in the immediate vicinity of the phosphorus atom. Molecularorbital calculations on PF Cl molecules show that then 5-nstability decreases with increasing substitution by chlorineJ® Cyclic and spirocyclic phosphoranes exhibit particular stab­ility because the planar or nearly planar ring systems reduce steric crowding around the central atom significantly. In general larger groups prefer equatorial positions.

The preferred position of a ligand in a phosphorane depends on many factors. The preference of a ligand to occupy an apical position depends on the relative apicophil- icity of the l i g a n d . T h e relative apicophilicity of two groups is the change in energy when these groups exchange apical and equatorial positions in a t.b.p. Calculations by several groups® suggest that apicophilicity should be a function of:

a) electronegativity, increase favouring occupation of an apical position;

b) the presence on the atom bonded to phosphorus of a lone-pair of electrons, this favouring occupation of an equatorial position;

-7 -

and c) the presence on the atom or group of a vacant low- lying orbital, this favouring occupation of an apical position.

From the accumulated data emerges a tentative scale of relative apicophilicity such as the one shown. It must be treated with caution but agrees with much experimental data in the literature.

OPh (Me<Pr'<BuhW ►

H ^Hal^ RM Me<Pr'<C:C<Ph

20 I I I 0

C O R ™ " " 'kcal mol-1

If a ring system is present it will prefer, depending on the size of the ring, to be apical-equatorial (a,e) or equatorial-equatorial (e,e). It is generally excepted^? that small (4- or 5-membered) rings prefer to span the apical- equatorial positions of trigonal bipyramids, this being con­firmed by X-ray studies of many cyclic and spirophosphoranesi®^° Larger (6-membered) rings have very little, if any, ring strain in either the apical-equatorial position or the di- equatorial position but if they contain hetero atoms with lone pairs of electrons they prefer to be apical-equatorial because this allows the lone pair to lie in the equatorial plane when the ring adopts a boat formation.

e.g,

oC7 \CF

Lone pair orientation in the equatorial plane also contributes to the apical-equatorial positioning of five- membered rings with hetero atoms next to phosphorus.^^

Cyclic phosphoranes, saturated and unsaturated are very susceptible to hydrolysis and this can and has caused problems when working with these compounds.

Me Me

M 0 Me MeHgO 0 0 II I I— ► \ p / ♦ (MeOlgP— 0 —CH —C= 0

0 ^ ^OMe

Alcoholysis of phosphoranes occurs by a mechanism similar to that of hydrolysis, the reaction, usually base-catalysed, proceeding via a phosphorus (VI) transition state or inter­mediate .

Fragmentation reactions can occur with phosphoranes if heated to high temperatures.^^ ^®

ie RgP ^ R3P ♦ R2

-9-

Cyclic oxy-phosphoranes can if heated undergo a dis­placement reaction to give a trialkyl phosphate and an oxy^ heterocyclic compound, Denney has shown this to be useful in heterocyclic synthesis.^

c 0 = P(0 Et),+

c:p(OEt). A * 0 = PIOEt);

Phosphoranes containing a 1,3,2-dioxaphospholene ring have also found wide application in synthesis. Apart from the fact that the 1:1 adducts are capable of adding a second molecule of the diketone to form a new carbon-carbon bond, the 1:1 adducts have been employed to prepare sugar-like phosphates.

0(MeO),R^ H -C l

®IMeOLPOCH^CHO

Cl,©

Me Cl ♦

( MeOljPOCHjCHO II 0

Analogous phosphoranes will also attack acid chlorides to produce phosphate esters by a C-acylation. °

— 10 —

\/c =o

(MeO),P J l .©

(M eO L P -O -C — C I

Cl®

Me Cl + COR

(MeOLP— 0 —C — Me

COMe

R’ and R*= Me

In contrast, the use of an unsubstituted 1,3,2-dioxaphos­pholene ring leads to 0-acylation and the formation of a 2-acyloxyvinyl phosphate.

1

/(MeOlgP^

n J ~ R ‘

Cl

©(MeO),POCH=CHO. COR

Cl

r ’ and R*=H

e0 II

(MeOI,POCH = CHO.COR

MeCl

Whether ’O' or ’C ’ acylation occurs can depend on the react­ion medium^^ and the electrophile used as well as and R^. This type of phosphorane will also react with anhydrides in the manner above and with bromine.

Diethyl phosphorochloridite has been shown to react with the cyclic phosphorane (l) to give (2), indicating ’0’ acylation.

Me

3 4

Me

O -P (O E t ) 3

0n Me MeI IlEtOljPCl

* I E t 0 ) , P - 0 - C = C - 0 - P ( 0 E t ) , ♦ EtCl 100 L Tl hr. ( 2 )

-11-

In this chapter can be seen the results of reactions involving a series of cyclic phosphoranes and spirophosphoranes that was prepared and reacted with diethyl phosphorochloridite, the phosphorane acting as a nucleophile, and the subsequent products were reacted further with methyl iodide and chloral.

0II

r’ r '

b _ P ( O R » ) ♦ (EtO)jPCl — ► ( R " 0 ) , P - 0 - C = C - 0 - P ( 0 E t ) j ♦ EtCl

Mel CCUCHO

0II

r' R*I I

0II

( R - 0 l , P - 0 - C = C - 0 - P - 0 E t

• iEt Cl CH

IIecu

An attempt was then made to carry out reactions in which a nucleophilic attack on the phosphorane occurs, the nucleo­phile employed being the anion of thio-phenol. It was hoped these reactions might provide a new pathway to the type of phosphorus compound which have been involved for a numberof years in the control of pestsorvii’iniedfcs,two examples being DicWonios onà .

-12-

and that an insight into the stereoelectronic requirements of reactions at phosphorus might be obtained. Diethyl phos phorochloridite was used to provide a functional P(IIl) centre in the product on which further reactions could be carried out.

Dichlorvos(D.DV.P.)

Vapona

2 , 2 -dichlorovinyl

dimethyl phosphate(MeOLP

\ OCH = CCl,

T.E.P.R(Tetron)

0 0II II

Tetraethylpyrophosphate (E tO LP— 0 — P(OEt),

-13-

Results and DiscussionsThe cyclic and spirophosphoranes used in this chapter

are listed below with their structures.i) 2 ,2 ,2-triethoxy-4-» 5-methyl-l, 3 ,2-dioxaphospholene [a]

ii) 2,2,2-triethoxy-5-methyl-1,2-oxaphospholene [b ]. iii) 2,2,2-triethoxy-1,3,2-dioxaphospholan [c]. iv) 2-ethoxy-4,5-dimethyl-l,3,2-dioxaphospholene-2-

spiro-2'(1',3',2') dioxaphospholan [ d].V ) 2-ethoxy-3-methyl-1,2-oxaphospholene-2-spiro-2-

(13,3',2’) dioxaphospholan [e ].Cyclic phosphoranes [a ] and [b ] were prepared by react­

ion of triethyl phosphite with biacetyl (2,3-butanedione) and methyl vinyl ketone respectively, in the same manner as analogous reactions involving trimethyl phosphite.^^^^ The cyclic phosphorane [ c] was prepared by stirring 2-ethoxy- 1,3,2-phospholan with diethyl peroxide at room temperature.^

Spirophosphoranes [d ] and [e ] were prepared by reaction of 2-ethoxy-l,3,2-phospholan with biacetyl and methyl vinyl ketone respectively following the general method proposed by M .¥.White. ?

-14-

(AI IB)

OEt

(C l

As has been stated, a study was made of a series ofreactions involving diethyl phosphorochloridite with thecyclic and spirophosphoranes [a ] to [e J, the products beingreacted further with methyl iodide and chloral.

The cyclic phosphorane [a J was heated with diethylo 1phosphorochloridite for 12 hours at 100 C. H n.m.r. evid­

ence, in particular the singlet at 61.86 due.to the equivalent methyl groups on the 4- and 5 positions of the ring in A being transformed into two multiplets at 61.9 and 62.0,

3 1along with P n.m.r. signals at +135.9 and -5.9 p.p.m., shows the ring to have opened in the reaction to give 1-methyl' 2-diethoxy phosphinoxy prop-l-enyl diethyl phosphate (l).

When (l) was reacted exothermically with chloral two signals, -6.5 and—11.1 p.p.m., were observed in the n.m.r.

-15-

spectrum. Distillation gave a colourless oil whose H n.m.r., in particular a doublet at ô6.97(J=5Hz) attributed to the proton of the dichlorovinyloxy group coupled to phosphorus, along with the support of its mass spectrum, m^^27, and3 1 P n.m.r. showed the product to be l-methyl-2-2,2-dichloro-vinyloxy ethoxy phosphinyloxy prop-l-enyl diethyl phosphate(2). (1 ) heated with methyl iodide for 1 hour at 60 C gave

3 1a product with two phosphorus-containing species with P n.m.r chemical shifts of 26.8 and -5.7 p.p.m., this along with the H n.m.r. spectrum, in particular a doublet at 61.4-7 ( Jpj.=18Hz ) and the mass spectrum, m"^330, showing the product to bel-methyl-2-ethoxy(methyl)phosphinyloxy prop-l-enyl diethyl phosphate (3).

[A ]

(EfO)jPCl 1 2 hours

0II

Me Me( I I

100® C► ( EtO),P —0 ~ C =C —0 —P(OEt),. EtCl

MelIhour60®C

00 Me Me1 I I II

I EtOlj P — 0 — C = C —0 —P —OEt

Me+ EtI (3 )

CCI CHOExothermic

Me Me

( E t 0 L P - 0 - C = C - 0 - P - 0 E t I 0

EtClCH II CClj

(2 )

The cyclic phosphorane [b ] reacted exothermically with diethyl phosphorochloridite to give a product with two phosphorus-containing species with ^^P n.m.r. chemical shifts of +133.1 and +26.6 p.p.m. The attempted isolation of a pure product was unsuccessful, however the ^^P n.m.r.

-I6-

spectrum suggests the main product to be diethyl 3-diethoxy phosphinoxy but-2-enyl-phosphonate (4-).

The above product mixture reacted exothermically with chloral to give two phosphorus-containing environments with n.m.r. chemical shifts of +25.4- and -11.5 p.p.m. Distillation gave an oil whose n.m.r., in particular a doublet of doublets at Ô2.6(2H, Jpj^=20Hz, J = 8Hz); multiplets at 2.03(3H) and 4-*86(1H) and a doublet at 7.0(1H, J = 6Hz ), along with the support of the mass spectrum, m^^lO, showed the structure of the product to be diethyl 3-2,2-dichloro- vinyloxy ethoxy phosphinyloxy but-2-enylphosphonate (5).The product mixture when heated for 1 hour at 60°C with methyl iodide and then distilled gave two phosphorus-containing environments with P n.m.r. chemical shifts of +27.0 and + 26.4- p.p.m., this along with the n.m.r. spectrum, in particular a doublet at 6l.56(3H, Jpy=l6Hz), and the mass spectrum, m^31A, showed the product to be diethyl 3-ethoxy- (methyl)phosphinyloxy but-2-enylphosphonate (6).

( 4 )

IB ](EtOLPCl

MeI

Exothermic► ( E t O ) ,P - C H - C H = C - 0 - P ( 0 E t L ♦ EtCl

0II

MeI

0II

CCLCHOExothermic

0 MeII EtO ljP " CHj~CH = C — 0 —P~O Et

0I

(E tO ),P -C H ,-C H = C— 0 - P — OEt

(6) ♦ EtI

IMe (5)

E t a

I0ICHIICCI

-17-

A pure sample of the cyclic phosphorane [C ] could not be obtained for the reaction with diethyl phosphorochloridite This was due to decomposition of the phosphorane to give triethyl phosphate and epoxide.

o - p(OEt),

(E f0 l ,P = 0 + ACyclic phosphorane [c] (80% pure) reacted with diethyl phos- phorochloridite exothermically to give a reaction product with two major phosphorus-containing environments with ^ n . m . r . chemical shifts of 137.7 and -1.2 p.p.m., thought to be due to 2-diethyoxyphosphinoxyethyl diethyl phosphate (7). However, n.m.r. suggested a mixture of products, in particular a triplet at 63.65 pointing toward a 2-chloro- ethoxy group being present. Scheme C below was proposed to explain these results.

O - P(Eto),pg

(OEM, Exothermic

l E t O L P - O O-P(OEt),

EtCl

(EtOl P T f O < S ^ O “ PCOEtlj

0Et

©Cl

\ 6O V 0

(E t0 L P = 0 ♦ C l -" -^ ^ ® PlOEtlj

(8 )

-18-

Comparison of the integrations of the 3-protons of the 2- chloro-ethoxy group in 2-chloro-ethyl diethyl phosphite (8) with the a-protons in all remaining ethyl groups, taking into account the original purity of starting material, gave a ratio of the formation of 7:8 of 4-0:60, This method was used in the analogous reaction with spirophosphorane [_d ] .

These products could not he isolated by distillation and were reacted with methyl iodide and chloral without further attempted separation after the removal of ethyl chloride produced in the reaction above.

(7) and (8) reacted with excess chloral exothermically to give a reaction product with two major phosphorus - containing species with n.m.r. chemical shifts of -1.2and -5.6 p.p.m. Column chromatography isolated 2 ,2-dichloro- vinyl diethyl phosphate (9) and 2-chloro-ethyl diethyl phosphate (10), formed by pathway (i). n.m.r of reactionproduct prior to chromatography showed the presence of ethyl chloride. Comparison of the integration of the ethyl chloride protons with the proton of the 2 ,2-dichlorovinyl group indicated pathway (ii) to have taken place in the percentage shown, the product 2-2,2-dichlorovinyloxy ethoxy phosphinyl­oxy ethyl diethyl phosphate (11) was not isolated, however.

-19-

17) IhOV^)

CCI3 CHOExothermic

( 8 )

Pathway .Exothermic

OEt

(Eto) p — 0 - C H = c a .' 0 S)r

V. Pathway (I)V.

Q x ^ o - p - o - c H = c a a

OEt 112)EtCl

Pathway /(ii)

7 5 3 % ; 0II

" . /4 7 % ;

( Et 0 ) 3 P - 0 0 - P - OEt

s i( 1 1 ) CH

IICCI:

EtCl

( E t 0 ) , P - 0 - C H = CCl.

( 9 )( E t 0 ) , P - 0 " ~ ^

(10)

Cl

The product expected from the reaction of (8) with chloral, 2-chloroethyl 2,2-dichlorovinyl ethyl phosphate (12) was also not isolated.

The method of estimating the ratio of pathways (i) and (ii) in this reaction was also used in later reactions involving the spirophosphoranes [d ] and [e ] with chloral and is therefore explained below.

-20-

H n.m.r. of reaction product of (7) and (8) with chloral prior to distillation

53.45 (quartet, J=7Hz) integration 13 56.90 (d., Jpjr = 5Hz) integration 8

proton of 2,2-dichloro- vinyl A.

Total integral 860% of A as a result of pathway(iii) -4-.8 ---------

Result of pathway (ii)

3.2

-1.7

3-protons of EtCl B

13

-9.6

3.4- This remaining B must be a result of pathway (ii)

Remaining A must be a result of pathway (i).

1.5

Ratio of pathways (i) : (ii) = 1.5 / 1.7 (4-7:53).

(7) and (8) were reacted with methyl iodide by heating for 1 hour at 60°C to give a product with 4- phosphorus - containing species with n.m.r chemical shifts of 29.4-(Ufa), 28.2 (35%), 5.6 (6%) and -1.2 p.p.m. (45%). Distillation gave 2-hydroxy-ethyl diethyl phosphate.3 1P n.m.r. -1.4 p.p.m., which might have resulted from

-21-

hydrolysis of 2-iodo-ethyl diethyl phosphate (13). formed in the reaction scheme below.

60® C (7 ) ♦ Mel

1 hour(EtO):P

II00

©

IMe I

( E t O L P " ° ^ ^ I ♦ 0 = P|0Et). I ° (13,

Flash column chromatography isolated diethyl methylphosphonate (11). No evidence could be found for reaction along the lines of pathway (ii) in the chloral analogue, although this undoubtably occurs.

It can clearly be seen that given a choice the nucleo- philic attack in the second stage of the above reactions is not specific. The estimation of the product ratios, as a result of this non-specific attack was made difficult in this case by the lack of purity of the starting material.

The spirophosphorane [d ] was heated with diethyl phos- phorochoridite for 18 hours at lOO^C to give a reaction product with 2 phosphorus-containing environments with

n.m.r. chemical shifts of +138.0 and +10.9 p.p.m.Expansion of this n.m.r. spectrum showed both environmentsto be in fact 2 peaks in a ratio of 70/30, this along with ^H n.m.r. analysis, carried out in the same way as with [c] and diethyl phosphorochloridite, pointing to the following.

-22-

(D1(Eto);pg

100® c18 hours

^ ^ O - P ( O E t )

(15)

0 — P — OEt

O -P(O Et),

30 Vo

Q y ^ ^ O — PIOEDg

(17)

(16)

Evidence that the dioxaphospholene ring is left intact can be found by comparison of the n.m.r. value of +10.9p.p.m. with the examples below.

Me Me

Q0 ^ '^OMe

R =Me * 18 2 p.p.m ♦ 11 4 p.p.m.

R = Et ♦ 17 0 p pm.

stirring the above reaction mixture, which2-diethoxyphosphinoxyethyl-l, 5-dimethyl-1,3 ,2-dioxaphosphol-

-23-

enyl phosphate (15), ethyl 1,5-methyl-l,3,2-dioxaphospholenyl phosphate (l6) and 2-chloro-ethyl diethyl phosphite (17), with sulphur at room temperature for 20 minutes gave a product with two phosphorus-containing species with ^ n . m . r

chemical shifts of +67.7 and 11.7 p.p.m., the signal at +67.7 being due to the formation of thio-phosphates.

ie SS II

P(OR), —► P(OR),

The products of the reaction of spirophosphorane [d ] with diethyl phosphorochloridite were now reacted with chloral and methyl iodide, ethyl chloride produced in the initial reaction having been removed.

The reaction mixture reacted exothermically with chloral to give a product with two main phosphorus-containing species with ^^P n.m.r. chemical shifts of +11.9 and -5.8 p.p.m.^H n.m.r. analysis showed (15) to be reacting in the way shown to give 2-2,2-dichlorovinyloxy ethoxy phosphinyloxy ethyl 1,5-dimethyl-l,3,2-dioxaphospholenyl phosphate (18) (65%), 2 ,2-dichlorovinyl diethyl phosphate (19) (35%) and 2-chloro-ethyl 1,5-methyl-1,3,2-dioxaphospholenyl phosphate (20) {35%) • Distillation gave a product which was found by ^^P n.m.r., n.m.r. and mass spec, to consist of a 55/4-5 mixture of (19) and 2-chloro-ethyl 2,2-dichlorovinyl ethyl phosphate (21) which is formed as a result of chloral react­ing with (17).

-24- -

(17) + CCl,CH0

(15) ♦ CCI3 CHO

Exothermic

+EtCl

0° ' ' ~ ^ 0 - P - 0 E t

I(18) 0

CH»CCI,

Exothermic

% 0— P - 0 -CH = CC(;

(21)

(E t0 ) ,P -0 -C H = C C lII0 (19)

I0Et

* EtCl

The reaction mixture reacted with methyl iodide to give a product with two phosphorus-containing environments with ^ n . m . r . chemical shifts of 29.6 and +11.1 p.p.m.Comparison with the n.m.r. chemical shift of an authenticsample of diethyl methyl phosphonate, +31.1 p.p.m., showed this not to be present. This along with the comparison of the integral of the methyl group attached to phosphorus with the integral of the 3-protons of ethyl iodide on n.m.r., both produced in this reaction, pointed towards only 2-ethoxy- (methyl) phosphinyloxy ethyl ^ ,5-dimethyl-1,3,2-dioxaphos- pholenyl phosphate (22) and 2-chloro-ethyl ethyl methylphos­phonate (23) being formed.

-25-

Me

(22)

(15) ♦ Mel

60®C

Me

1 hour

V 0I n II

0 — P -O E t

0♦ EtI

Me

(17) + Mel

60® C 1 hour

0

He+EtI

(23)

The spirophosphorane [e] reacted in a slightly exo­thermic manner with diethyl phosphorochloridite to give a reaction product with L, phosphorus-containing environments with n.m.r. chemical shifts of +139.2 (38%), +4-9.0(37%), +48.0 (8%) and +32.1 p.p.m. (17%).

From the n.m.r and by comparison of the integralsof the olefinic proton with the 3-protons of ethyl chloride, formed in the reaction, in the n.m.r. spectrum, it can be seen that the following has taken place;

- 2 6 -

IE ] + (EtO)jPCl

_;7%83Vo slightly

exothermic

Me ( E t O ) j P ^ ° ^ ^ C l

y ? . ‘25)\_ p-'O'v/ o-PIOEt),

IIMe

0 • y ° ,

(241 n “ ° “0 (26)

The chemical shift at +32.1 p.p.m. is probably due to slight hydrolysis of the phospholene ring.

Evidence that the oxaphospholene ring is still present can be gained from the phosphorus, environments having ^ n . m . r . chemical shifts of +49.0 and +48.0 p.p.m. and the trans coupling constant (Jpjj) of the olefinic proton coupling to phosphorus changing from 45Hz to 33Hz. In the case of [ b J reacting with diethyl phosphorochloridite, where the ring is opened, the coupling is destroyed.

The above reaction mixture, which contains 2-diethoxy- phosphinoxy ethyl 5-methyl-l,2-oxa-phospholenyl phosphate (24), 2-chloro-ethyl diethyl phosphite (25) and ethyl 5- methyl-1,2-oxaphospholenyl phosphate (26), was now reacted with sulphur, chloral and methyl iodide, ethyl chloride produced in the initial reaction having been removed.

The reaction mixture when stirred with sulphur at roomtemperature gave a reaction product with 4 phosphorus- containing species with n.m.r. chemical shifts +67.9,+49.4 , +48.2 and +32.0 p.p.m., the signal at +67.9 p.p.m.

-27-

being due to thiophosphates, and when reacted exothermically with chloral gave a reaction product with U phosphorus - containing environments with P n.m.r. chemical shifts of 4-47.6 (35%), +46.0 (9%), +31.2 (19%) and -5.7 p.p.m. (37%).H n.m.r. analysis showed (24) to be reacting in the way shown to give 2-2,2-dichlorovinyloxy ethoxy phosphinyloxy ethyl 5-methyl-l,2-oxaphospholenyl phosphate,(27) (38%),2-chloro-ethyl 5-methyl-l,2-oxaphospholenyl phosphate (28) (62%) and 2 ,2-dichlorovinyl diethyl phosphate (29) (62%).

( 2 4 ) (25)

CCijCHO

Exot)iermic

Me(27)(28)

^•'”' ^ 0 — P—OEt

(29) (EtOjP-G-CHsCCl

II 0

II0+

EtCl CHIICCI.

CCI3 CHO Exothermic

0E tO -P ''® '" -^ 0

I 0 I CH II CCI 2

(30)

2-chloro-ethyl 2,2-dichlorovinyl ethyl phosphate is presumed to be formed as a result of (25) reacting with chloral.

The reaction mixture with methyl iodide gave a reaction product with 4- phosphorus-containing environments with n.m.r. chemical shifts of +4-7.6, +4-6.2, +31.6 and +29.9 p.p.m. n.m.r. and n.m.r. analysis, carriedout as in the analogous reaction involving spirophosphorane [d ] ,

-28-

showed only 2-ethoxy(methyl)phosphinyloxy ethyl 5-methyl-1,2-oxaphospholenyl phosphate (31) and 2-chloro-ethyl ethyl methylphosphonate (32) to have been formed.

(24)

60*C 1 hour

Me

IpII 0

(31)

Mel

(2 5 )

60°C Mel1 hour

1r

Me Me1P -O E t EfO—P —0II II0 C)

♦ EH (32) ♦ EtI

In the reactions of the cyclic and spirophosphoranes [a ], [b J, [c ], [ d J and [e ] with diethyl phosphorochloridite and in subsequent reactions with chloral and methyl iodide, the final or second stage is always attack of a nucleophile on a quaternary phosphonium cation to give a phosphoryl species.

IX

(ROljP - 0 — R:©

(R0)2P=0 4 R -Y I X

It has been found that the nucleophilic attack is non­specific when more than one centre for such attack is available, except in the reactions of (15) and (24-) with methyl iodide. This choice of attack appears to be finely

-29-

balanced and specific reasons for preferential attack at a certain centre are difficult to comprehend and will not be discussed here.

A further study of nucleophilic attack at a phophonium intermediate was carried out using the "Arbusov" and related reactions, the results of which can be found in chapter 2.

Although in some cases above it was not possible to isolate products it can be seen that ring opening is occur- ing when reacting [a ] , [B], [c], [d ] and [e ] with diethyl phosphorochloridite with ’0 ’-acylation taking place.

The order of reactivity of the different oxygen environ­ments attached to phosphorus can be obtained from the experi­mental results. From the reactions of D and E with diethyl phosphorochloridite it can be seen that the most reactive ring is that of the 1,3,2-dioxaphospholan. Due to the fact that ring opening always occurs in cyclic phosphor- anes, an oxygen environment of a phosphorane P(OR)^ would appear to have the lowest reactivity. Finally the reactions of [a ] and [b ] with diethyl phosphorochloridite, one requir­ing heat and the other being exothermic, respectively, point to the oxygen environment in the ring structure, of [b ] being the most reactive of the two.

Hence we have a reactivity order for the reaction involving ’0 ’-acylation with diethyl phosphorochloridite, with no solvent, as follows:

Me

Eto—l >

v‘ ’0 — P

Me

O - P :

INCREASING REACTIVITY

-30-

Evidence for attack by oxygen from an apical, as expected, or an equatorial position can be obtained from the relative rate of reactivity of [ a J and [b] , It has been found that oxygen will be preferentially apical over carbon in a case such as [b ]. The difference in their relative apicophilicities has been found to be in the order of ^6-7 Kcal mol ^ ^ This in fact means that the equilibrium of the pseudorotation needed to get the oxygen equatorial, below, would be well over to the left hand side.

Me

O ^ O E t

In the case of [A ] there is already an equatorial oxygen without any need for pseudorotation. Hence, if attack was by the equatorial oxygen one would expect [ a ] to react faster than [b] . The reverse was found, thus pointing to­wards apical attack.

The reason why [a] and [b] are slower to react than [c] could be due to the rings in [a ] and [b ] possessing a double bond. The double bond in both cases can take part in resonance stabilisation with a lone pair of electrons on oxygen in a £ orbital. This increased stabilisation may well be the reason for the difference in reactivity. The reason [b ] is less reactive than [a J is probably due to the carbon at the 3-position in B being replaced with oxygen in [a ]. The lone pairs on both oxygens in [ a] are capable of taking part in w-bonding involving certain d-orbitals on

-31-

phosphorus and £ orbitals on oxygen. This may lead to greater stabilisation in [ a J than in the ring system [ b J with only one oxygen thus giving the relative reactivity observed.

'O'-acylation occuring in the cyclic phosphoranes involves ring breaking with release of any ring strain and this is probably the reason why a P(OR)s phosphorus environ­ment is the slowest to react.

As has been stated, an attempt was made to carry out reactions in which a nucleophilic attack on a cyclic phos­phorane or spirophosphorane occurs. The nucleophile employed was the anion of thiophenol as this is a relatively soft base and would therefore facilitate attack at carbon rather than phosphorus which is a hard centre.

The cyclic phosphorane [A ] was stirred with thiophenol, with cooling (ice-bath). An exothermic reaction took place giving a product with one phosphorus-containing species with a ^^P n.m.r. chemical shift of -1.0 p.p.m. Preparative t.l.c. isolated two products. I.R. spectroscopy of one of the products indicated the presence of a carbonyl group and this along with the mass spectrum, m^l80, and the n.m.r, showed the product to be 3-phenylthiobutan-2-one (33), the other product being triethyl phosphate.

0Exothermic \ __ //

PhSH -------------------► ) — \ + 0=P(0Et).PhS

(33)

-32-

The cyclic phosphorane [b ] with thiophenol, at -50°C, gave after 5 minutes a product with one phosphorus-containing species with a n.m.r. chemical shift of + 31.2p.p.m.Preparative t.l.c. gave ethyl phenyl sulphide (34-). Distil­lation isolated a product whose I.R. spectrum, in particular a stretch at 1720 cm~^ attributed to a carbonyl group, along with the support of its mass spectrum, m^208, and n.m.r. showed it to be diethyl 3-ketobutylphosphonate (35).

^ 1 -5 0 “C PhSEt (34)\ - P ♦ PhSH — — ► ♦

(OEt), 0 QII

(B ) (EtO),P

(35)

The spirophosphorane [e ] reacted exothermically with thiophenol to give a product with two phosphorus-containing species with ^^P n.m.r. chemical shifts of -3.2 (75%) and -4-.8 p.p.m. (25%). From the ^^P n.m.r. shifts the products were thought to be of a five co-ordinate nature. Further­more the n.m.r. (400 MHz) showed no trace of the olefinic proton of the original spirophosphorane [ e ] , and contained two signals, 61.56 and 61.51, due to the methyl group at the five position of the original spirophosphorane. The proposed structures (36) could explain these data with the two P n.m.r. chemical shifts being due to the two dia- stereoisomers shown.

-33-

Me SPhP h S ^ M e « J^ 0 ( ^ 0

O , 3 6 , O

0This product was found to be stable at -4-0 C. However, on leaving to stand at room temperature for 24- hours under N 2 t h e ^ n . m . r . spectrum showed a change had occurred to give two phosphorus-containing species with chemical shifts of +32.3 (29%) and +31.3 p.p.m. (71%).

The attempted isolation of a pure product was unsuccess­ful. The ^ n . m . r . chemical shifts point towards the prod­ucts being four co-ordinate species, phosphonates, which along with n.m.r. decoupling experiments, the I.R. spectrum, in particular a stretch at 1715 cm” attributed to a carbonyl group, and the reaction of the product with concentrated hydrochloric acid followed by flash chromatography giving 2-(phenylthio)ethyl chloride provides evidence towards the structure of the major product being (37).

(37)

The n.m.r of the 2-(phenylthio)ethyl chloride was compared with that of the product of the reaction of 2-(phenylthio)- ethanol with concentrated hydrochloric acid and was found to be the same. The ^^P n.m.r. chemical shift at +31.3 p.p.m.

-34-“

can be attributed to (37) with that at +32.3 p.p.m. being possibly due to a product formed by hydrolysis of (37).

When the spirophosphorane [ d J was stirred with thio­phenol for 4-8 hours at room temperature and then heated for 1 hour at 60°C it gave a product with two phosphorus - containing species with n.m.r. chemical shifts of -34-.1(60%) and -35.1 p.p.m. (4-0^), which was thought to be of a similar structure to (36) . On further heating for 24- hours at .80* 0 the ^^P n.m.r. spectrum showed a change had occurred with one phosphorus-containing species now with a chemical shift of -1.4-1 p.p.m. and the I.R. spectrum showing the presence of a carbonyl stretch at 1710 cm~^. Distillation gave a product whose n.m.r. showed it to be 3-phenylthio- butan-2-one (38). A further fraction from the distillation gave a ^^P n.m.r. spectrum with two phosphorus-containing species with chemical shifts of +17.15 {^U%) and +0.2 p.p.m. (36%).

The following reaction scheme was proposed to account for the above. The ^^P n.m.r. signal at +17.15 p.p.m. is probably due to (39) with the signal at +0.2 p.p.m. being possibly due to hydrolysis of (39).

-35-

" I I / O HID ] ♦ PhSH — ► 0 —

1 ^ 0

i(381 (39)

The n.m.r. chemical shift at -1.41 p.p.m. may be due to dimérisation or polymerisation of (39)» distillation reform­ing (39). This polymerisation process has been observed by a number of workers, one example being Roberts and Weichmann^* when carrying out work on structures such as (40).

cV H X = (one pair, SI ® ®CH"3 (40)

The mechanism being proposed as a result of the react­ions of spirophosphoranes [ d ] and [e ] with thiophenol is as follows: The anion of thiophenol initially attacks theolefinic bond of the five membered ring at the carbon next to oxygen to give a five co-ordinate intermediate. This intermediate then breaks down losing the thiophenol anion which re-attacks in the ways shown to give the observed products.

-3 6 -

Y

X - POEf

OR

HX —

OR

♦ PhSH

IPIOR

OEt

OR

1) Y=H, X =CH;

2 Y = CH^, X = 0

iP h S ^ ^

X -OEt

Stable intermediate with [D] and [EJ

I ^ O R OR

P h S ® ^

Products

Although no intermediates were observed in reactions involving phosphoranes [ Aj and [ B ] the above mechanism can account for the products of their reactions with thiophenol.

The initial attack is shown as an acid catalysed step due to comparisons with the reactions of ethyl vinyl ether

4 0with ethane thiol and thiophenol, the observations of which are below.

When thiophenol was reacted with ethyl vinyl ether at room temperature it gave 1 -phenylthio-2-ethoxy ethane (4.1) as the product. However, when the reaction was repeated with a catalytic amount of acid the product was 1,1-bisphenyl-

-37-

thio-ethane (A3) which presumably has come from 1-phenyl- thiol-ethoxy ethane (A2).

PhSH

PhS ' ^ Y ^ O E t (411

PhSH /H ®SPh PhSH/H®

A

SPh

SPhOEt

(42 )

The initial attack of PhS” on the spirophosphorane [e ] can be compared with attack at C-2 above, which is a result of acid catalysis.

Conclusion : -Reactions have been carried out where nucleophilic

attack on a phosphorane occurred and where the phosphorane acted as a nucleophile. Both types of reactions gave rise to products with phosphoryl centres and in the cases where the phosphorane was the nucleophile a good deal emerged about the stereoelectronic requirements of these reactions.

—38 —

GENERAL EXPERIMENTAL DETAILSExperiments involving air or mositure sensitive com­

pounds were carried out under an atmosphere of dry, oxygen- free nitrogen.

All solvents were dried prior to use. Ether and T.H.F. were distilled from lithium aluminium hydride. Ethanol and dichloromethane were distilled from calcium hydride.Benzene, carbon tetrachloride and chloroform were distilled after drying over calcium chloride.

Small scale distillations were carried out using a Kugel rohr apparatus; boiling points are quoted at the oven temperature at which distillation occurred.

Flash column chromatography separations were carried out using MN-Kieselgel 60 silica, gel.

InstrumentationMelting points were determined using a Kofler heating

stage.Mass spectra were recorded using a V.G. Micromass 16 B

instrument.Infra-red spectra were recorded on a Perkin Elmer 298

spectrometer. Liquid samples were run as thin films, solid samples as Nujol mulls.

n.m.r. spectra were recorded using a Varian T-60,60 MHz spectrometer or a Varian EM 390, 90 MHz spectrometer, with TMS as the internal standard. Deuteriochloroform was the solvent unless stated otherwise.

Fourier transform ^^P n.m.r. spectra were recorded on a Jeol JNM-FX60 spectrometer. The external standard was aqueous tetrahydroxyphosphonium perchlorate and the solvent

-39-

was diethyl ether unless stated, otherwise. Chemical shifts are quoted as being positive to lowfield of the standard.

n.m.r. spectra were also recorded on a BruWcr 4-00 MHz spectrometer.

-39a-

EXPERIMENTALPreparation of 2,2 ,2-Triethoxy-X,5-methyl-l,3,2-dioxapho8-pholene LA

To triethyl phosphite (l6.02g, 0,096 mol) was added dropwise, freshly distilled biacetyl ( 2 ,3-butanedione ) (4-.4-g» 0.05 mol), an exothermic reaction taking place. Distillation gave 2 ,2 ,2-tr iethoxy-4- » 5-methyl-l, 3,2-dioxaphospholene , (8.88g, 68%) b.p. 68 - 72*^0 at 0.15 mmHg.

^^P n.m.r. -51.8 p.p.m.n.m.r. (CClJ 61.1 (t, 9H, J=7Hz); 1.86 (s, 6H) and

3.85 (d quartets, 6H, J = 7Hz , Jpj^=7Hz)

Preparation of 2 ,2 ,2-Triethoxy-5-niethvl-l,3 ,2-dioxaphos­pholene B

To triethyl phosphite (21.6g, 0.13 mol) was added freshly distilled methyl vinyl ketone (10.Og, 0.1X3 mol).The reaction mixture on stirring for 36 hours at room temperature gave a reaction product with a major phosphorus- containing species with a ^^P n.m.r. chemical shift of -23.8 p.p.m. Distillation gave 2,2,2-triethoxy-5-methyl-1,3,2-dioxaphospholene, (13.Og, X3%) b.p. 56 - 60^0 at 0.1 mmHg.

^^P n.m.r. -23.8 p.p.m.'n n.m.r. (CC1„) 61.1 (t, 9H, J=7Hz) ; 1.72 (bs, 3H);

2.A (dt, 2H, Jpjj = 18Hz, J=2Hz): 3.75 (d quartets, 6H, J=7Hz , J-g = 7Hz) and A.36 (d m, IH. Jpjj = A5Hz).

Preparation of 2-Chloro-l,3,2-dioxaphospholanThis was carried out according to literature preparation.

-39b-

3 8

Preparation of 2-Ethoxy-l,3>2-dioxaphospholanA solution of ethanol (l6.77g, 0.364- mol) in diethyl

ether (20 cm^) was added dropwise to a stirred solution of 2-chlorO“l , 3 > 2-dioxaphospholan (4-6g, 0.364- mol) and pyridine (32g, 0.4-0 mol) at 0^0. The reaction mixture was refluxed for 2 hours on completion of addition. Filtration andremoval of the ether, followed by reduced pressure distil­lation gave 2-chlor0-1 ,3,2-dioxaphospholan, (27.8g, 56^) b.p. 4-6 - 50°G at 11 mmHg.

^ n . m . r . (CDCI3) +133.9 p.p.m.'H n.m.r. 61.22 (t, 3H, J=7Hz) and 3.95 (m, 6H).

Preparation of Diethyl PeroxideThis was prepared by the method of Denney.

(20%), b.p. 61 - 66°C, (Lit. b.p. 60 - 6l°C).^’

3 7Preparation of 2,2,2-Triethoxy-l,3,2-dioxaphospholan C2-Ethoxy-l,3,2-dioxaphospholan (5.l6g, 0*038 mol) and

diethyl peroxide (3.69g, 0.04- mol) on stirring for 28 days at room temperature gave a major phosphorus-containing species with a ^^P n.m.r. chemical shift of -52.0 p.p.m. Distil­lation gave 2,2,2-triethoxy-l,3,2-dioxaphospholan, (2.0g,

%) b.p. 52 - 58°C at 0.1 mmHg, in a purity of ^80#.

P n.m.r. -52.0 (80#) and -0.80 p.p.m. (20#).3 1

Preparation of 2-Ethoxy-l,5-methyl-l,3,2-dioxaphospholene- 2-spiro-2'(l',3',2') dioxaphospholan [dJ

To 2-ethoxy-l,3,2-dioxaphospholan (6.12g, 0.04-5 mol)was added, with stirring and cooling (ice-bath), biacetyl

—4- 0 -

(2,3-butanedione) (4.3g, 0.05 mol). An exothermic reaction occurred giving a product containing two phosphorus-contain ing species with ^ n . m . r . chemical shifts of +5.44 (6#)and “28.8 p.p.m. (94#). Distillation gave 2-ethoxy-4,5-methyl-l,3,2-dioxaphospholene 2-spiro-2’(1',3',2’) dioxa­phospholan, (5.90g, 59#) b.p. 92 - 96°C at 0.1 mmHg.

^^P n.m.r. (CHgClg) -28.8 p.p.m.^H n.m.r. 61.25 (d t, 3H, Jp^=2Hz, J=7Hz); 1.8

(s, 6H) and 3.95 (m, 6H).

Preparation of 2-Ethoxy-5-methyl-l,3,2-oxaphospholene-2-spiro-2'-(l*,3',2*) dioxaphospholan E

To methyl vinyl ketone (3.97g, 0.057 mol), which had been dried over KjCOg and then CaClg and then distilled, was added 2-ethoxy-l,3,2-dioxaphospholan. Heating at 60°C for 24 hours gave a product having three phosphorus- containing species with ^^P n.m.r. chemical shifts of +133.1 (23#),+31.9 (32#) and -2.42 p.p.m. (45#). Distillation gave 2-ethoxy-5-methyl-l,2-oxaphospholene-2-spiro-2 *-(l*,3',2')- dioxaphospholan, (2.01g, 33#) b.p. 86 - 90°C at 0.3 mmHg.

^^P n.m.r. (001%) -2.4 p.p.m.“h n.m.r. (CClJ 61.22 (t, 3H, J=7Hz); 1.72 (m, 3H);

2.k (d m, 2H, Jpjj=18Hz): 3.8 (m, 6H) and 4-4 (d m, IH, Jpjj=15Hz).

Reaction of 2,2,2-Triethoxy-4,5-methyl-l,3,2-dioxaphospholene A with Diethyl Phosphorochloridite

To 2,2,2-triethoxy-4,5-methyl-1,3,2-dioxaphospholene(3.66g, 0.0145 mol) was added diethyl phosphorochloridite

— 41 —

(2,27g, 0.0145 mol) and the resulting mixture heated for 12 hours at lOO^C. P n.m.r. showed the reaction product to consist of two major phosphorus environments with chemical shifts of +134.3 and -6.3 p.p.m. Distillation gave 1-methyl- 2-diethoxy phosphinoxy prop-l-enyl diethyl phosphate,(2.5g, 50#) b.p. 155 - 170°C at 0.15 mmHg. (Lit. value b.p.106- 107°C at 0.025 mmHg)

P n.m.r. (CDGI3) +135.9 and -5.9 p.p.m.^H n.m.r. 61.25 (t, 6H, J = 7Hz); 1.34 (t, 6H, J = 7Hz);

1.9 (m, 3H); 2.0 (m, 3H); 3.93(d quartets, 4H, J = 7Hz, Jpjj=7Hz) and 4.16 (d quartets, 4H, J=7Hz, Jpp=7Hz).

Reaction of l-Methyl-2-diethoxy phosphinoxy prop-l-enyl diethyl phosphate with Methyl Iodide

To the phosphate (l.Og, 0.0029 mol) was added methyliodide (0.68g, O.OO48 mol) and the resulting mixture wasrefluxed at 60°0 for 1 hour. A P n.m.r. spectrum showedthe product to consist of two phosphorus-containing specieswith chemical shifts of +26.6 and -5.9 p.p.m. Distillation(kugel-rohr apparatus) gave l-methyl-2-ethoxy(methyl)phos-phinyloxy prop-l-enyl diethyl phosphate, (0.195g, 20#) b.p.175 - 190°C at 0.15 mmHg.

^'P n.m.r. (GCl^) +26.8 and -5.7 p.p.m.n.m.r. (CCI ) 61.32 (t, 9H, J=7Hz); 1.47 (d, 3H,4

Jpg=18Hz); 1.95 (m , 6H) and 4.05 (d quartets, 6H, J=7Hz , Jp„=7Hz).PH2990, 1260, 1200, 1030 and 810 cm-1

mass spec. m/e 330, 206, 176, 149, 147, 99, 97, 79.

-42-

Reaction of l-Methyl-2-diethoxy phosphinoxy prop-l-enyl diethyl phosphate with Chloral

To the phosphate (l.Og, 0.0029 mol) was added, drop- wise with cooling (ice-bath), chloral (0.43g, 0.0029 mol).An exothermic reaction took place giving a product contain­ing two phosphorus environments with n.m.r. chemicalshifts of -6.45 and -11.09 p.p.m. Distillation gave 1-methyl- 2-2,2-dichlorovinyloxy ethoxy phosphinyloxy prop-l-enyl diethyl phosphate, (1.24g, 28#) b.p. 180 - 200*^0 at 0.125mmHg.

^^P n.m.r. (001^) -6.3 and -10.7 p.p.m.n.m.r. (CClJ 61.32 (t, 6H, J=7Hz ); 1.35 (t, 3H,

J=7Hz); 1.96 (m, 6H); 4 .10 (m, 6H) and6.97 (d, IH, J=5Hz).2990, 1285, 1205, 1150, 1125, 1030 and 820 cm ^.

mass spec. m/e 427, 314, 178, 155, 150, 99.

Reaction of 2,2,2-Triethoxy-5-methyl-l,2-oxaphospholene [pj with Diethyl Phosphorochloridite

To the cyclic phosphorane (4»78g, 0.02 mol) was added with stirring and cooling (ice-bath), diethyl phosphoro­chloridite (3.13g, 0.02 mol). An exothermic reaction occurred giving a reaction product with two major phosphorus-contain­ing environments with ^^P n.m.r. chemical shifts of +133.1 and +26.6 p.p.m. Distillation gave a colourless oil, diethyl 3-diethoxy phosphinoxy but-2-enylphosphonate in a purity of ~85# (12.99g).

b.p. 56 - 65^0 at 0.1 mmHg.This mixture was subsequently used for reaction without further purification.

-43-

Reaction of Diethyl 3-diethoxy phosphinoxy but-2-enylphos- phonate with Methyl Iodide

To the phosphonate (l.2g, 0.0035 mol) was added methyl iodide (l.Og, 0.007 mol) and the resulting mixture was re­fluxed for 1 hour at 60°C. n.m.r. showed the productto have two major phosphorus-containing environments of chemical shifts +26.0 and +25.2 p.p.m. Distillation (kugel- rohr apparatus) gave diethyl 3-ethoxy(methyl)phosphinyloxy but-2-enylphosphonate.(0.185s, 17#) b.p. l66 - 176^0 at 0.07 mmHg.^^P n.m.r. +27.03 (d, J =5.3Hz) and +26.42 (d,P -P

Jp_p=5-3Hz).n.m.r. 61.32 (t, 9H. J=7Hz): 61.56 (d, 3H,

Jpjj=l6Hz); 2.05 (m, 3H) ; 2.62 (d.d, 2H, Jpjjl9Hz, J=8Hz)î 4.1 (d quartets, 6H, J=7Hz, Jpjj=7Hz) and 4.85 (m, IH) .2985. 1255, 1030, 970 and 800 cm"'

mass spec. m/e 314, 190, 177, 134, 125, 111, 97.

Reaction of Diethyl 3-diethoxy phosphinoxy but-2-enylphos- phonate with Chloral

To the propene (1.88g, 0.0055 mol) was added, dropwisewith cooling (ice-bath), chloral (0.81g, 0.0055 mol). Anexothermic reaction occurred giving a product containing twomajor phosphorus environments with ^^P n.m.r. chemicalshifts of +25.6 and -11.5 p.p.m. Distillation (kugel-rohr)gave diethyl 3-2,2-dichlorovinyloxy ethoxy phosphinyloxybut-2-enylphosphonate, (0.233g, 10#) b.p. 190 - 200°C at O.lmmHg.

^^P n.m.r. +25.4 and -11.5 p.p.m.*H n.m.r. (CClJ SI.3 (t, 6H, J=7H z ); 1.4 (t, 3H, J=7Hz):

-44-

2.03 (m, 3H); 2.6 (d d, 2H, Jp^=20Hz, J=8Hz); 4.0$ (d quartets, 2H, J=7Hz, JpH=7Hz); 4.15 (d quartets, 4H, J=7Hz, JpH=7Hz); 4.86 (m, IH) and 7.0 (d, IH, JpP=6Hz).2980, 1280, 1155, 1120, 1030, 980 and840 cm"^,

mass spec. m/e 410, 375, 299, 284, 243, 21$, l6l,124, 109, 81.

Reaction of 2,2,2-Triethoxy-l,3,2-dioxaphospholan [c] with Diethyl Phosphorochloridite

To the cyclic phosphorane (0.928g, 0.004 mol) was added with stirring and cooling (ice-bath), diethyl phosphoro­chloridite (0.64g, 0.0040 mol). An exothermic reaction occurred giving a product with two major phosphorus-contain­ing environments with ^^P n.m.r. chemical shifts of +137.7 and -1.2 p.p.m.

n.m.r. (CCl^) 63.63 ( t , J=6Hz ) integration *7 .64.06 (m) integration ”7^.

Distillation, 150 - 170°C at 0.2 mmHg, failed to separate products.

Reaction of the products (7) and (8), of the reaction of2,2,2-Triethoxy-l,3,2-dioxaphospholan [cj with Diethyl Phosphorochloridite, with Chloral

To the products (7) and (8) was added with stirring and cooling (ice-bath), excess chloral (0.60g, O.OO4I mol). An exothermic reaction took place giving a reaction product with two major phosphorus-containing environments with

-45 “

^ n . m . r . chemical shifts of -1.2 and -5.6 p.p.m. Flash column chromatography using diethyl ether / pet. ether (2/l) and then diethyl ether gave 2,2-dichlorovinyl diethyl phos­phate and 2-chloro-ethyl diethyl phosphate.

2,2-dichlorovinyl diethyl phosphate:

^^P n.m.r. (CCl^) -5.2 p.p.m.n.m.r. (CCl^) 61.35 (t, 6H, J=7H z ); 4.06 (d quartets,

4H, J = 7Hz, Jpj^=7Hz) and 6.9 (d, IH,JpH=5Hz).

2-chloro-ethyl diethyl phosphate:^^P n.m.r. -1.2 p.p.m.^H n.m.r. (CClJ 61.32 (t, 6H, J=7Hz); 3.62 (t, 2H,

J=6Hz ) and 4*02 (m, 6H).

^H n.m.r. of reaction products prior to chromatography: 63.45 (quartets, J=7Hz) integration 13.66.90 (d, Jpp=5Hz) integration 8.

Reaction of the products (7) and (8), of the reaction of2,2,2-Triethoxy-l,3,2-dioxaphospholan [0- with DiethylPhosphorochloridite, with Methyl Iodide

To the products (7) and (8) was added methyl iodide (0.57g, 0.004 mol) and the resulting mixture heated to 60 G for 1 hour giving a product with 4 phosphorus-contain' ing species with ^^P n.m.r. chemical shifts of 29.4 (14#), 28.2 (35#), 5.6 (6#) and -1.2 p.p.m. (45#). Distillation gave 2-hydroxy-ethyl diethyl phosphate, b.p. 65 - 70°C at 0.3 mmHg.

^^P n.m.r. -1.4 p.p.m.

— 4 6 -

n.m.r. (CClJ 61.32 (t, 6H, J=7H z ); 62.82 (broad s,IH, DgO exchangable); 3.6$ (t, 2H, J = $Hz) and 4.1 (m , 6H).

mass spec. m/e 181.Flash column chromatography using diethyl ether and then methanol gave diethyl methylphos^onate.^ n . m . r . +28.2 p.p.m.^H n.m.r. 61.3 (t, 6H, J=7H z ); 1.5 (d, 3H, Jp^ =

17Hz) and 4.02 (d quartets, 4H, J=7Hz, JpH=7Hz).

Reaction of 2-Ethoxv-4,5-dimethyl-l,3,2-dioxaphospholene-2spiro-2* ( 1 3 2 Mdioxaphospholan D with Diethyl Phos­phorochloridite

To the spirophosphorane [*d] (2.06g, 0.0093 mol) was added diethyl phosphorochloridite (1.46g, 0.0093 mol) and the resulting mixture heated for 18 hours at 100°C.

3 1P n.m.r. +138.0 (45#) and +10.9 p.p.m. (55#).Expansion of^^P n.m.r. +138.2 (14#), +138.0 (34#), +10.9

(37#) and +10.7 p.p.m. (15#).^H n.m.r. (001^) 63.62 (m) integration 9.

64.10 (m) integration 124.

Reaction of the products (15), (I6) and (17), of the react­ion of spirophosphorane _ D with Diethyl Phosphorochloridite,with Sulphur

The products (15), (16) and (17) were stirred with sulphur at room temperature for 20 minutes.3 1P n.m.r. (CH^Cl^) +67.8 and +11.7 p.p.m.

-47-

Reaction of the products (15), (l6) and (17), of the reactionof spirophosphorane D with Diethyl Phosphorochloridite,with Chloral

To (15), (16) and (17) (0.91g, 0.0029 mol) was added with stirring and cooling (ice-bath), excess chloral (0.52g, 0.0035 mol). An exothermic reaction took place giving a product with two main phosphorus-containing species.

^^P n.m.r. (CHgClg) +11.9 and -5.8 p.p.m.n.m.r. 63.5 (quartet, J=7Hz) integration 12.

66.93 (d, J=5Hz) integration 8. Distillation (kugel-rohr apparatus) gave a product with twophosphorus-containing species, b.p. 100 - 110°C at 0.3 mmHg.

^^P n.m.r. -5.4 (55#) and -5.8 p.p.m. (45#).mass spec. m/e 286, 284, 282, 250, 248.

Reaction of the products (15), (l6) and (17), of the reaction of spirophosphorane [dJ with Diethyl Phosphorochloridite, with Methyl Iodide

To the products (15), (l6) and (17) (1.5g, 0.005 mol)was added methyl iodide (0.85g, 0.006 mol) and the resultingmixture heated to 60°C for 1 hour.

^^P n.m.r. +29.6 and +11.1 p.p.m.Authentic sample of diethyl phosphonate: +31.1 p.p.m.^H n.m.r. 61.5 (d , Jpj^=17Hz) integration 28.

63.17 (quartet, J=7Hz) integration 19.

— 48 —

Reaction of 2-Ethoxy-5-niethyl-l ,2-oxaphospholene-2-spiro-2 (l',3',2') dioxaphospholan E with Diethyl Phosphoro­chloridite

To the spirophosphorane E (0.49g, 0.0024 mol) was added diethyl chlorophosphoridite (0.37g, 0.0024 mol), a slightly exothermic reaction taking place.

n.m.r. +139.2 (38%), +49.0 (37%), +48.0 (8%)and +32.1 p.p.m. (17#).

n.m.r. 63.52 (quartet, J=7Hz) integration 10.64.95 (d m, Jpp=35Hz) integration 6.

Reaction of the products (24), (25) and (26), of the reactionof spirophosphorane E with Diethyl Phosphorochloridite,with Sulphur

The products (24), (25) and (26) were stirred with sulphur at room temperature for 20 minutes.

n.m.r. (CH2CI2) +67.9 (37%), +49.4 (35%), +48.2 (10%)and +32.0 p.p.m. (18#).

Reaction of the products (24), (25) and (26), of the reactionof spirophosphorane E with Diethyl Phosphorochloridite,with Chloral

To (24), (25) and (26) was added excess chloral, an exothermic reaction taking place.

®'P n.m.r. +47.6 (35%), +46.0 (9%), +31.2 (19%)and -5.7 p.p.m. (37#).

n.m.r. (CCl^) 63.5 (quartet, J=7Hz) integration 56.06.95 (d, Jpp=5Hz) integration 57.

-49 ~

Reaction of the products (24), (2$) and (26) of the reactionof spirophosphorane E with Diethyl Phosphorochloridite,with Methyl Iodide

To (24), (25) and (26) was added excess methyl iodide and the resulting reaction mixture heated to 60°C for 1 hour.

^'P n.m.r. +47.6 (35%), +46.2 (7%), +31.6 (21%)and +29.8 p.p.m. (37#).

n.m.r. (CCI4) 61.4 (d , Jpp=15Hz) integration 24.Ô3 .I3 (quartet, J=7Hz) integration I6 .

Reaction of 2,2,2-Triethoxy-4,5-dimethyl-l,3,2-dioxaphos-pholene A with Thiophenol

To the cyclic phosphorane [aJ (0.5g, 0.002 mol) was added dropwise with stirring and cooling (ice-bath), thio­phenol (0.3g, 0.0027 mol). A slightly exothermic reaction took place giving a product with one phosphorus-containing species with a chemical shift of -1.0 p.p.m. Preparative t.l.c. using petroleum ether (60 - 80°C) / ether, 2/1, as solvent gave triethyl phosphate (58#) and 3-phenylthio- butan-2-one.

triethyl phosphate;^^P n.m.r. -1.0 p.p.m.'H n.m.r. (CC1„) 61.32 (t, 9H, J=7Hz) and 3.97 (d

quartets, 6H, J=7Hz, Jpp=7Hz).

3-phenylthiobutan-2-one;'H n.m.r. 61.37 (d, 3H, J=7Hz); 2.22 (s, 3H);

3.71 (quartet, IH, J=7Hz) and 7.25 (m, 5H).

-50-

mass spec. m/e 180.2925, 1710, 1205, 1060, 745 and 690 cm - 1

Reaction of 2,2,2-Triethoxy-5-methyl-1,2-oxaphospholene [ B 1 with Thiophenol

To the phosphorane B (0.45g, 0.0019 mol) at -50°C was added thiophenol (0.22g, 0.0019 mol). ^ n . m . r . after 5 minutes showed the product to have one major phosphorus- containing species with a chemical shift of +31.2 p.p.m.The product mixture on being allowed to warm to room temp­erature showed no change by ^^P n.m.r. Preparative t.l.c. using petroleum ether (60 - 80^0) as solvent gave ethyl phenyl sulphide.

n.m.r. 61.27 (t, 3H, J=7Hz); 2.9 (quartet,2H, J=7Hz) and 7.20 (m, 5H).

Distillation (kugel-rohr apparatus) gave diethyl 3-keto- butylphosphonate, (56#) b.p. 100 - 120°C at 0.5 mmHg.

3 1P n.m.r. (CH^Gl^) +31.4 p.p.m.^H n.m.r. 61.26 (t, 6H, J=7H z ); 1.89 (m, 2H);

2.13 (s, 3H); 2.70 (m, 2H) and 4.03(d quartets, 4H, J = 7Hz, Jpj^=7Hz) .

mass spec. m/e 208.2990, 1720, 1235, 1025 and 965 cm -1

Reaction of 2-Ethoxy-5-methyl-l,3,2-oxaohosnholene-2-spiro- 2'-(l*,3',2') dioxaphospholan [e ] with Thiophenol

To the spirophosphorane [e ] (0.59g, 0.0028 mol) wasadded, at room temperature, thiophenol (0.32g, 0.0029 mol).An exothermic reaction took place giving a product with two

-51-

phosphorus-containing species with n.m.r. chemicalshifts of -3.2 (75#) and -4.8 p.p.m. (25#). This product

0was found to be stable at -40 0.400 MHz H n.m.r. (001%)

61.5587 (s) integration 49.6.61.5052 (s) integration 26.3

On standing at room temperature under for 24 hours the 31

P n.m.r. spectrum showed a change had occurred in the product with two phosphorus-containing species now with chemical shifts of +32.3 (29#) and 31.3 p.p.m. (71#).V 2980, 1715, 1240, 1020, 965 and 740 cmDistillation failed to isolate a product. Decoupling experiments were carried out on the H n.m.r. spectrum prior to distillation.

'h n.m.r. (CCI ) 61.27 (t, J=8Hz); 1.82 (m); 2.054

(singlet); 2.55 (m); 3.1 (t , J=8Hz);3.5 (m); 3.95 (m) and 7.2 (m) .

Decoupling :

-1

Signal being irradiated

Change in coupling of 1.27 1.82 2.05 2.55

signal3.10 3.50 3.95 7.20

1.27 1 V1.82 V2.052.55 V /3.10 V3.503.95 ^ collapsed to ^ collapsed to

7.20 singlet singlet

-52-

The product’mixture was heated to 80°C for 2 hours with concentrated hydrochloric acid. The mixture was taken up in dichloromethane (30ml), washed with water and sodium bicarbonate solution and the organic layer dried over mag­nesium sulphate. The solvent was removed, followed by column chromatography, using pet ether/ether (50/50), which isolated 2-(phenylthio)ethyl chloride.

'k n.m.r. 63.15 (t, 2H, J=7Hz)î 3.6 (t, 2H,J=7Hz) and 7.28 (m, 5H).

A similar reaction was carried out to the above with 2-(phenylthio)ethanol and concentrated hydrochloric acid, the resulting product being the same by n.m.r. analysis.

Reaction of 2-Ethoxy-4,5-methyl-l,3,2-dioxaphospholene-2-spiro-2*(1 *,3 *,2 *) dioxaphospholan D with Thiophenol

To the spirophosphorane [ D ] (2.2g, 0.01 mol) was added thiophenol (l.l6g, 0.0106 mol). The reaction mixture was stirred for 48 hours at room temperature and then heated for 1 hour at 60°C to give a product with two phosphorus- containing species with n.m.r. chemical shifts of-34.1 (60#) and -35.1 p.p.m. (40#). On heating for 24 hours at 80 0 a ^^P n.m.r. spectrum showed a change had taken place in the product, with one phosphorus-containing species with a chemical shift of -1.41 p.p.m.

2980, 1710, 1475, 1440, 1260, 1025 and 745 cm” .

Distillation (kugel-rohr) gave 3-phenylthiobutan-2-one,(54%) b.p. 120 - 135°C at 0.3 mmHg.'h n.m.r. 61.32 (d, 3H, J=6Hz)î 2.18 (s, 3H);

3.66 (d, IH, J=6Hz ) and 7.22 (m, 5H).

-53-

A further fraction of the distillation, b.p. 135 - 160°C at 0.3 mmHg, contained two phosphorus-containing species with n.m.r. chemical shifts of +17.15 (64#) and +0.20 p.p.m. (36#).

Reaction of Ethyl Vinyl Ether with ThiophenolEthyl vinyl ether was stirred at room temperature with

an equivalent amount of thiophenol for a period of 100 hours. A clean reaction took place giving 1-phenylthio-2-ethoxy ethane .

'H n.m.r. 61.15 (t, 3H, J=6Hz): 3.05 (t, 2H,J=6Hz )î 3.47 (m, 4H) and 7.2 (m, 5H).

The above reaction was repeated with a catalytic amount of _p-toluene sulphonic acid being added to the reactants. A clean reaction had occurred after 100 hours, the product being 1,1-bisphenylthio-ethane.

H n.m.r. 61.55 (d, 3H, J = 7Hz); 4.47 (quartet,IH, J=7Hz); 7.21 (m, 6H) and 7.4 (m ,4H) .

-54“

REFERENCES1. a) G.W.Fenton and C.K.Ingold, J. Ghem, Soc., 1929,

2342.b) L.Hey and C.K.Ingold, J. Ghem. Soc., 1933, 531.

2. F.Ramirez, Pure Appl. Ghem., 19&4 9., 337.2a. L.D.Quin, "Tervalent Phosphorus Compounds as Dieneo-

philes" in 1-4-Cycloaddition Reactions, Academic Press, New York, 1967.

3. D.B.Denney and D.H.Jones, J. Am. Ghem. Soc., 1969, 91, 5821.

4. R.Huisgen and J.Wulff, Tetrahedron Lett., 1967, 917.5. S.Antezak, S.A Bone, J.Brierley and S.Trippett, J. Chem.

Soc., Perkin Trans.1, 1977, 278.6. J .I .G.Cadogen, N.J.Stewart and N.J.Tweddle, J. Chem.

Soc., Chem. Commun., 1978, 182.7. Y.Kimuro and M,Miyamoto, J. Org. Chem. 1982, 6, 916.8. R.Hoffman, J.M.Howell and E.L.Muetterties, J . Am. Chem.

Soc., 1972, 94, 3047.9. R.J. Gillespie, J. Chem. Educ., 1970, 18.

10. J.A.Howard, D.R.Russell and S.Trippett, J. Chem. Soc., Chem. Commun., 1973, 856.

11. R.S.Berry, J. Chem. Phys., I960, _32, 933.12. a) F.Ramirez, S.Pfohl, E.A.Tsolis, J.F.Pilot, O.P.Smith,

I.Ugi, D.Marquarding, P.Gillespie and P.Hoffmann., Phosphorus, 1971, 1, 1.b) I.Ugi, D.Marquarding,H.Klusacek, P.Gillespie and F.Ramirez, Acc. Chem. Res., 1971, 4, 288.

13. R.E.Rundle, J. Am. Chem. Soc., 1963, 112.14. E.L.Muetterties, ¥.Mahler and R .Schmutzler, Inorg.

Chem. 1963, 2, 613.

-55-

15. P.C.Van Der Voorn and R.S.Drago, J. Am. Chem. Soc.,1966, 88^ 3255.

16. S.Trippett, Phosphorus Sulfur, 1976, 1, 89.17. F .H.Westheimer, Acc. Chem. Res., 1969, 1, 70.18. W.C.Hamilton, S.J.La Plaça, F.Ramirez and C.P.Smith,

J. Am. Chem. Soc., 1967, _89., 2268.19. M.Ul-Haque, C.N.Caughlan, F.Ramirez, J.F.Pilot, and

C.P.Smith, J. Am. Chem. Soc., 1971, 9^, 5229.20. J.H.Barlow, S.A.Bone, D.R.Russell, S.Trippett and

P.J.Whittle, J. Chem. Soc., Chem. Commun., 1976, 1031.21. S.A.Bone, S.Trippett and P.J.Whittle, J. Chem. Soc.,

Perkin Trans.1, 1977, 80.22. S.A.Bone, Ph.D. Thesis, Univ. of Leicester, 1975.23. F.Ramirez, O.P.Madan and O.P.Smith, J. Am. Chem. Soc.,

1965, 670.24. F.Ramirez, K.Tasaka, N.B.Desai and O.P.Smith, J. Am.

Chem. Soc., 1968, 90.» 751.25. A.Bond, M.Green and S.C.Pearson, J. Chem. Soc. 1968,

929.26. D.B.Denney and Li Shang Shih, J. Am. Chem. Soc., 1974,

96, 317.27. B.C.Chang, W.Conrad, D.B.Denney, D.Z.Denney, R.Edelman,

R.L.Powell and D.W.White, J. Am. Chem. Soc., 1971, 93,4004.

28. D.B.Denney, R.L.Powell, A.Taft and D.Twitchell, Phosphorus, 1971, 1, 151.

29. F.Ramirez, S.L.Glaser, A.J.Bigler and J.F.Pilot, J. Am. Chem. Soc., 1969, 91, 496.

30. F.Ramirez, S.B.Bhatia, A.J.Bigler and C.P.Smith, J. Org. Chem., 1968, 33, 1192.

- 56-

31. F.Ramirez, S.L,Glaser, A.J.Bigler and J.F.Pilot, J. Am Chem. Soc., 1969, 91.» 5696.

32. F.Ramirez, J.F.Maracek, S.L.Glaser and P.Stein, Phosphorus, 1974, 4, 65.

33. F.Ramirez and N.B.Desai, J. Am. Chem. Soc., I960, 82, 2652.

34. I.P.Gozman, J. Gen. Chem. U.S.S.R. (Engl. Transi.),1969, 39, 1916.

35. F.Ramirez, N.Ramanathan and N.B.Desai, J. Am. Chem. Soc., 1962, 8^, 317.

36. D.Gorenstein and F.H.Westheimer, J. Am. Chem. Soc.,1970, 92 634.

37. M.W.White, Ph.D Thesis, Univ. of Leicester, 1975 177.38. H.J.Lucas, F.W.Mitchell and C.N.Scully, J. Am. Chem.

Soc., 1950, 72, 5491.39. J.B.Robert and H.Weichmann, J. Org, Chem., 1978, 43

3031.40. M.F.Shostakovskii, E.N.Prilezhaeva and E.S.Shapiro,

Izvest. Akad. Nauk. S.S.S.R, Otdel. Khim. Nauk 1953, 357-67; Chem. Abstr., 1954, 48, 93111.

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CHAPTER 2

The Michaelis- ArbusovRe-arrangament

The Michaelis-Arbusov Rearrangement Introduction

The Michaelis-Arbusov rearrangement, also known as the Arbusov rearrangement, Arbusov reaction or Arbusov trans­formation, was first discovered by Michaelis^ in 1898 and was explored in greater detail by Arbusov.^

The Arbusov reaction is a cornerstone of organo-phos- phorus chemistry, being one of the most versatile pathways for the formation of carbon-phosphorus bonds, and is one of the most thoroughly investigated among organo-phosphorus reactions .

A recent review can be found in the literature^ by Bhattacharya and Thyagarajan.

In its simplest form the Arbusov rearrangement is the reaction of an alkyl halide with a trialkyl phosphite, yielding a dialkyl alkylphosphonate (l).

5 / O R(ROjjP + R' — hat R '— P * R — hat

^ O R t1)

Thus, during the transformation a tervalent phosphorus P(lll) is converted into a pentavalent phosphorus P(V).

The production of a wide range of phosphonates in the Arbusov reaction has become of increasing importance as the phosphonates can be employed in the Horner-Emmons reaction to synthesise olefins.

-58-

0 II

( R O ) , P - C H j - R *♦

Base

0U CHR'

(ROI^P ♦ Il^ 0 CR"

© *

0II

( R O ) j P - C H - R '

0 = C - R "I

I0II

iR O L P - r C H - R '

® 0 - C - R "

The corresponding phosphinites [ROPR^] and phosphonites pROj^PRj undergo identical reactions to the Arbusov react- ion with alkyl halides to give phosphine oxides and phosphin ates respectively.

RO.^ P - R ' ♦ R " -h a l

R O ^( phosphonite)

\•/ P - O R

( phosphinate )

R'

R'

^ P - O R ♦ R " ' - h a l

( phosphinite)

R'*^R

P = 0

( phosphine oxide )

A number of reactions analogous to the Arbusov reaction are now known,^ and may be thought of in general terms as a reaction between a phosphorus ester ABP-OR, where A and B may be primary alkoxy, secondary alkoxy, aryloxy, alkyl, aryl or dialkyl amino group, with species XY, e.g. alkyl halide or halogen.

-59-

A 0 l ^ P - O R + X - Y — ► RY ♦

e x '

The driving force for the Arbusov rearrangement is thought to be the formation of the very strong P=0 bond.The fact that the Michaelis-Arbusov reaction is less common with phosphorotrithioites (RS)3P and does not take place at all with alkylphosphorus triamides, where the expected product would be phosphine imide (2 ), may be due to the difference in bond energies

(R jN l jP - R ' — ► I R . N I j P - R '/ ' I II ( 2 )( n r n r

X ® ' ^ R

between P=0 (150 Kcal mol ^) and P=N (110 Kcal mol ^) which are formed in the corresponding reactions. It has also been reported^ that the conversion of >P-0-C linkage into >P(=0)-C involves a net gain of 32, and possibly 6$, Kcal/mol energy in the total bond stability.

The mechanism of the Arbusov reaction has been invest­igated on numerous occasions^ and it is generally accepted that the reaction has a two stage pathway, of which the first is the rate determining step. The first stage is thought to be quaternisation of the phosphite, by nucleo- philic attack of the phosphorus lone pair on the halide, to give the phosphonium salt (3 ) as the intermediate.

In the second stage the intermediate is broken down by a dealkylation process to give a phosphoryl compound (4 ).

-60-

13)@

(ROjPR*

X®

Stage 1

(RO),P (RO),P

W

V ♦ R ~ X Stage 2 ^ R '

Evidence for the formation of the quasiphosphonium intermediate is obtained by the i s o l a t i o n o f crystalline (5)f m.p. 56 - 58°C, when ethyl diethylphosphinite was reacted with methyl iodide and (6), m.p. 79 - 81°C, when reacted with ethyl iodide.

Eh ® , M e p

OEt

I ® ( 5 )

Et. ® / E f

E r OEt

I©

(6)

In the case of tri-alkyl phosphites the phosphonium intermediate cannot normally be isolated. However, by employing a methylating agent with a very weakly nucleo- philic leaving group, e.g. methyl trifluoromethanesulfonate [CHgOgSCFg], the phosphonium salt intermediate with tri­alkyl phosphites also have been i s o l a t e d . S i m i l a r work has been carried out by Dimroth,^^ trialkyloxyphosphonium perchlorates and tetrafluoroborates (7) being prepared, as heavy oils.

- 6l -

(î) © @ ©(EfOIsP + Et,0 BF — (EtO)^PEt BF, + Et^O

(7)

Hudson and co-workers^^ have reported the isolation of raethyltrineopentyloxyphosphonium iodide as the first stable crystalline Michaelis-Arbusov intermediate to be obtained from a trialkyl phosphite. A stable 1:1 inter­mediate can, however, be obtained in several instances from triaryl p h o s p h i t e s . T h e intermediates are stable up to ^200^0 at which point decomposition takes place giving the expected phosphonate (8).

0 T P —R

0>200“C / ^

► { P / - 1 + ( PhOjjPR

(8)

The need for high temperature is explained in terms of the second stage in the reaction, which involves the attack of a nucleophile on an aromatic nucleus, being a very slow process unless the ring is especially activated.

There is evidence that five co-ordinate phosphoranesmay also play a part in the r e a c t i o n . 8 i g thoughtthat the five co-ordinate species (9) is in equilibrium with the phosphonium salt, de-alkylation from either giving the expected phosphoryl product.

-62-

^ P - O R —

\ / / P - O R

(9)

1 1

Y

R - X

As has been stated, the mechanism of the first stage appears to be a bimolecular displacement of halide ion by- phosphorus, since the expected variation of reactivity with the structure of the halide is observed, Me>primary>secondary, and inductive electron withdrawal lowers the reactivity of the phosphorus compounds.

e.gEqP (O E t)^ EtP(OEt);)> P(OEtK

Relative rates of reactivity in the Arbusov reaction.

Second order kinetics have been observed with primary1 9

1 9

halides.Aksnes and Aksnes*" have convincing quantitative

evidence showing this first stage to be the rate-determining step. Using the reaction of triethyl phosphite with ethyl iodide they showed, using infra-red analysis, that:

a) ethyl iodide is not consumed to a measureable extent at any stage,

b) the rate is proportional to the concentration of ethyl iodide.

-63“

c) the rate is not affected by added iodide ion, andd) the reaction is much faster in acetonitrile (di­

electric constant 36) than in benzene (dielectric constant 2.3), or in the absence of solvent.

These results are uniquely consistent with a rate determin­ing first stage, the formation of the phosphonium inter­mediate .

The second stage, the dealkylation of the phosphonium salt, is generally thought to occur by a nucleophilic attack on the intermediate by the anion produced in the first stage of the reaction. However, it has been shown^° that in certain cases the dealkylation can be brought about by the nucleophilic attack of a molecule of phosphite on the phos­phonium salt, thus creating an ionic chain reaction.

e £R'

^ P - O C H , + R"X

r / \R ^ O C H , 1i

R' . 0 R ' ^ e / O C H . « V

r X c, * " - ^ ^ r / V • R - ^ o

,0X

The second stage, being a nucleophilic substitution type reaction, could proceed by an SNl or SN2 process.

SNl and SN2 mechanisms were proposed by Hughes and

- 64- “

Ingold in the 1930’s.

R - X R ® . X ® R - N u + X ®FAST

Sn. 2 g_ g.Nu® ♦ R — X Lnu R— -X R - Nu + X®

Because a carbonium ion is formed in an SNl reaction one would expect a reaction rate of tertiary>secondary>prim- ary for attack at the alkyl group. However, with the SN2 mechanism, one would expect the primary alkyl group would be attacked more rapidly by the nucleophile, with inversion of configuration. One would expect racémisation in an SNl mechanism where a free carbonium ion is produced as this can be attacked by the nucleophile from either side.

The general mode of attack of the nucleophile in the dealkylation of the phosphonium intermediate has been thought to follow an SN2 mechanism, Nu” attacking from the "back side" with simultaneous 0-R bond breaking and R-Nu bond formation.

This has been supported by the observation that in the decomposition of the alkoxy phosphonium salt (10), formed in the reactions between 2 -actylphosphite with both alkyl halides^^ and with h a l o g e n s , i n v e r s i o n of configur­ation of the asymétrie carbon in (11) occurred.

-63-

HI . PCL

M e - C - O H ------- ^I

(♦)

Me — C —0

6"13 3

H \ 0 HI.*

Me — C—0 ♦ M e ^ C — X (11)

CeH,3 4 (-) C,H,3

In conformity -with the SN2 mechanism, the reactivities of mixed trialkyl phosphites have been shown by Rydon, without the benefit of n.m.r., to decrease with the alkyl group in the order Me>Et>i-Pr.

EtO-P(OMe); + Mel — ► + MelM e O ^ '^Me

Neopentyl phosphites with alkyl halides give neopentyl halides (12) without rearrangement.^^ This again points to an SN2 mechanism as any carbonium ion formed in an SNl mechanism would rearrange as shown.

-66-

l ” * \ Sn2 / l " 'P + O - C H 2 - C - C H 3 J ♦ R - X — ► ICH 3 — C — CHj—0

CH3 I CH3

CH, ,CCH,X

Sni ©CH3 carbonium ion CH3

X

C M .-C -C H . C«.œ,Ç(CH,l,

CH. CH. X0X '-"3

There have, however, been reports that t-butyl is attacked in the phosphonium salt intermediate (3) in prefer­ence to methyl or ethyl, indicative of an SNl type mechanism.

Burn and Cadogon^^ showed that triethyl phosphite with t-butyl alcohol and CCl^ or BrCCl^, reactions in which the probable intermediates are (13), gave entirely triethyl phosphate, and Mark^^ showed that

P(0 Et ) 3 + Bu^OH » ( E tO )^ OBu^— ► (Et 0 )3 P = 0

X - (13)

( X r C l . B r )

reactions of hexachlorocyclopentadiene with t-butyl diethyl or dimethyl phosphites gave the t-butyl pentachlorocyclo- pentadiene (14-). In this reaction, pentachloro-cyclopenta- diene anion is the nucleophile.

Cl

+ Bu^OP(OR), — ► [ X * * (RO),PC l ^ w ^ Bu^

(R=MeorEt) QÜ4-)

-67-

Cl

ClCl

0'^Cl

D.C o o p e r h a s shown that reactions between mixed phosphites and elemental bromine and iodine produce in most cases a mixture of products.

£:2' / H II( M e 0 ) , P - 0 - < I ♦ I , — ► (M e O L P I - 3 0 %

aM e O ^ 0

; p ^ - 7 0 %0 ^ I

These reactions are not proceeding totally by an SNl or SN2 mechanism. The mechanism could be a con-current operation of both. More recently the generally accepted concept of ion-pairs has been put forward by Winstein,^^^® as being involved in a mechanism for nucleophilic substitution Ion-pairs have also been invoked by Sneen^^*^^ in a merged mechanism to accomodate both SNl and SN2 reactions.

A discussion on how this can be applied to the reactions carried out in this study will follow later.

As can be seen, although the generally accepted mode of attack of the nucleophile in the dealkylation step (stage 2) is of an SN2 nature there is evidence to suggest that an SNl mechanism may be occurring in certain cases.

In view of the above observations and the observed products obtained from reactions between phosphoranes and spirophosphoranes with diethyl chlorophosphoridite and sub­sequent reactions with chloral and methyl iodide (see chapter l) , a mechanistic study of the second stage of the Arbusov reaction was undertaken.

-68-

A number of Arbusov reactions were carried out with unsymmetrical phosphites containing different alkyl groups Reactions have been carried out varying both X and Y in intermediate (14-) below and the effect on the products of the reactions observed.

o r"

® ©R ' O - P — Y X (14)

OR"

A solvent study and temperature study have also been carried out on the reaction of diethyl cyclopentylphosphite with methyl iodide.

Related reactions to the Arbusov reaction have also been carried out using unsymmetrical phosphites, one of the most widely used in this study being the Perkow reaction.

An example of the Perkow reaction is given below, tri­ethyl phosphite with chloral giving a vinyl phosphate.

0 P( 0 Et ) 3 ♦ CClaCHO — ► (E t0 ) ,P -0 -C H = C C l3 ♦ EtCl

The mechanism of the Perkow reaction^^^^ follows a two stage pathway, the second stage being the same as the second stage in the Michaelis-Arbusov reaction, dealkylation of a phosphonium intermediate.

Several mechanisms have been proposed for the first stage, the formation of the phosphonium intermediate, but

-69-

it is generally thought to involve attack by the phosphorus lone pair at the carbonyl carbon followed by a rearrangement to give the intermediate.

C o r ® oII Staae 1 ® I

(E tO ) ,P :^C H - (EtOjjP-^CHI ^1CCI3 CCI 2

Irearrangement

0

II ®(EtOjjP-O-CHsCCIj (DOj^P-O-CHzCCI;

Stage 2♦Et Cl c

-70-

Results and DiscussionThe unsymmetrical phosphites containing different

alkyl groups used in the study of the mechanism of the second stage of the Michaelis-Arbusov reaction are listed below;

i) t-butyl diethyl phosphite, ii) methyl dicyclopentyl phosphite,

iii) dimethyl cyclopentyl phosphite,iv) t-butyl methyl cyclopentyl phosphite.v) ethyl dimethyl phosphite,

vi) diethyl cyclopentyl phosphite.Phosphites (iii), (v) and (vi) were prepared by react­

ion of trimethyl or triethyl phosphites with the required alcohol in the presence of sodium alkoxide.^^ Phosphites (i), (ii) and (iv) were prepared from diethyl phosphoro- chloridite or methyl phosphorodichloridite by treatment with the required alcohol(s), in ether, in the presence of pyridine.

As has been stated, an attempt was made to study the effect, of varying X and Y in the intermediate (14-)» on themechanism of its breakdown by studying the products producedin an Arbusov and related reactions.

or"

R ' O - P ^ Y ®X (14)

It has proved very difficult to vary just one parameter in a series of reactions, but every effort has been made to vary as little as possible. The product(s), of a reaction, and their ratio if there was more than one product produced.

-71-

were calculated using ^ n . m . r . and n.m.r. The ratios are accurate to ±3^.

Each of the mixed phosphites were reacted in turn with methyl iodide, chloral and bromine.

Ethyl dimethyl phosphite on refluxing for 3 hours with methyl iodide with diethyl ether as solvent, gave one phos­phorus-containing species with a ^^P n.m.r. chemical shift of +29.5 p.p.m, ethyl methyl methylphosphonate. It reacted exothermically with chloral to give one phosphorus-containing species with a ^^P n.m.r. chemical shift of -4-.4- p.p.m.,2.2-dichlorovinyl ethylmethyl phosphate, in a Perkow reaction and with bromine at -78°C, with carbon tetrachloride as sol­vent, gave one phosphorus-containing species with a ^^P n.m.r. (CCl^) chemical shift of -6,65 p.p.m, ethyl methyl phosphoro- bromidate.

t-Butyl diethyl phosphite reacted exothermically with chloral to give three phosphorus-containing species with P n.m.r. chemical shifts of +14-.3 , +5.6 and -5.6 p.p.m. Distillation gave 2,2-dichlorovinyl diethyl phosphate,^^P n.m.r. -5.6 p.p.m.; the signal at +5.6 p.p.m. was due to diethyl phosphite formed by breakdown of the original phosphite. Comparison of the product from the reaction between chloral and diethyl phosphite with the reaction prod­uct above showed the signal at +14-.3 p.p.m. to be diethyl -2.2.2-trichloro 1-hydroxyethylphosphonate.

Reaction of t-butyl diethyl phosphite with bromine inCDgClg at -78^0, carried out by D . C o o p e r , g a v e diethylphosphorobromidate as the only Arbusov reaction product.

On reacting t-butyl diethyl phosphite with methyl iodide,the main product had a ^^P n.m.r. chemical shift of +5.4-5p.p.m

-72-

(CCl^) which is probably due to decomposition of the phosphite yielding diethyl phosphite as experienced by Mark^® in react­ions of tri-t-butyl phosphite with alkyl halides, this problem being encountered with all the unsymmetrical alkyl phosphites containing a t-butyl group. t-Butyl diethyl phosphite heated at 65°C for one hour gave predominantly the decomposition product at +5.4- p.p.m. on P n.m.r.

It was thought that the decomposition in the reaction of t-butyl diethyl phosphite with methyl iodide might be acid catalysed and as a result proton sponge [1,8-bis(dimethyl- amino)-napthalene] was added to try and increase the Arbusov product. t-Butyl diethyl phosphite on refluxing for four hours with methyl iodide and proton sponge, with diethyl ether as solvent, gave two phosphorus-containing species with P n.m.r. chemical shifts of +28.2 (62%) and +5.65 p.p.m (38^). Flash column chromatography gave diethyl methyl­phosphonate, ^^P n.m.r. +28.2 p.p.m., as the only product as a result of an Arbusov reaction.

t-Butyl methyl cyclopentyl phosphite reacted exothermic­ally with chloral to give a reaction product with three phosphorus-containing species with ^^P n.m.r. chemical shifts of +14-.7, +6.25 and -5.4-2 p.p.m. Distillation gave 2,2- dichiorovinyl methyl cyclopentyl phosphate, ^^P n.m.r. -5.2 p.p.m. (CCl^). The same phosphite with bromine in CD2CI2 at -78^0, a reaction carried out by D.Cooper,^® gave methyl cyclopentyl phosphorobromidate and on refluxing for three hours with methyl iodide and proton sponge gave two phosphorus containing species with ^^P n.m.r. chemical shifts of +28.4- and +6.05 p.p.m. Flash column chromatography gave methyl cyclopentyl methylphosphonate.

-73-

Control experiments were carried out to substantiate that this phosphonate was in fact formed from an Arbusov reaction, that it is the only product of the Arbusov react­ion and that the t-butyl group leaves as t-butyl halides.

The phosphonate may have come from reaction of methyl- iodide on methyl cyclopentyl phosphite, formed by breakdown of the original phosphite, in the presence of proton sponge. No reaction, however, occurred between this

MeO' MeO^ MeO^ ^Me

phosphite and methyl iodide in the presence of proton sponge, under identical conditions to the reaction involving t-butyl methyl cyclopentyl phosphite and methyl iodide.

The reaction of t-butyl methyl cyclopentyl phosphite with methyl iodide was carried out using GDCI3 as solvent.A H n.m.r. spectrum taken immediately on completion of the reaction gave a signal at 61.9 (singlet) which was attributed to t-butyl iodide.

To determine whether methyl cyclopentyl methylphosphon­ate is the only product of the Arbusov reaction the other possible phosphorates that could be produced, t-butyl cyclo­pentyl methylphosphonate and t-butyl methyl methylphosphonate were prepared and their retention times on gas liquid chromat­ography, under the same conditions, were compared with those of methyl cyclopentyl methylphosphonate and the components of the reaction product. The n.m.r. chemical shifts ofthe phosphorates were also compared with the reaction product.

- 74- “

All the results pointed to methyl cyclopentyl methylphosphonate being the only phosphonate produced in this Arbusov reaction.

In the above reactions t-butyl was always eliminated as t-butyl halide in preference to cyclopentyl, ethyl or methyl groups, thus showing the breakdown of the phosphonium salt (14.) to have considerable SNl character. In the case, how­ever, of ethyl dimethyl phosphite the methyl group was always removed, as found by R y d o n , i n d i c a t i v e of the breakdown being entirely of SN2 character. In these reactions there has not been formed a mixture of products as a result of the dealkylation step.

The reactions of methyl dicyclopentyl phosphite and diethyl cyclopentyl phosphite with methyl iodide, chloral and bromine have, however, given in most cases mixtures of products.

Methyl dicyclopentyl phosphite on refluxing for 12 hours with methyl iodide with diethyl ether as solvent, gave one ^ n . m . r . peak in the phosphonate region with a chemical shift of +26.4- p.p.m. Distillation gave dicyclopentyl methyl­phosphonate. The same phosphite reacted exothermically with chloral to give two major phosphorus-containing species with ^ n . m . r . chemical shifts of -5.2 and -7.1 p.p.m. Distil­lation gave a product mixture of 2 ,2-dichlorovinyl methyl cyclo­pentyl phosphate and 2,2-dichlorovinyl dicyclopentyl phos­phate in a ratio of 70/30. Flash column chromatography, using diethyl ether/pet. ether, 4-0/60, as solvent, isolated the two phosphates.

Dimethyl cyclopentyl phosphite with bromine in GD^Cl^ at -78^0, a reaction carried out by D . C o o p e r , g a v e a mix­ture of products, dimethyl phosphorobromidate and methyl

-75-

cyclopentyl phosphorobromidate, in a ratio of 4-0/60.The ratio of products was obtained in this and subse­

quent reactions directly from n.m.r. and by comparingthe integrations of the alkyl groups in the n.m.r. spectrum In reactions involving diethyl cyclopentyl phosphite a com­parison was made between the signal due to the proton on the a-carbon of the cyclopentyl and the signals due to the ethyl group.

Diethyl cyclopentyl phosphite on refluxing with methyl iodide with diethyl ether as solvent, gave two major products on ^^P n.m.r. at chemical shifts +28.2 and +27.4- p.p.m. corresponding to diethyl methylphosphonate and ethyl cyclo­pentyl methylphosphonate respectively and formed in a ratio of 1:3 (25/75). The same phosphite reacted exothermically with chloral to give a reaction product with phosphorus- containing species with ^^P n.m.r. chemical shifts of +15.7 (minor), +14-.7 (minor), -5.2 (major) and -6.05 p.p.m. (major). The minor products are phosphorates formed as a result of an Arbusov reaction between the phosphite and chloral. The major products, due to a Perkow reaction, are due to 2,2- dichlorovinyl diethyl phosphate and 2,2-dichlorovinyl ethyl cyclopentyl phosphate formed in the ratio of 3:1 (75/25).

Diethyl cyclopentyl phosphite reacted exothermically with a solution of bromine in carbon tetrachloride to give two phosphorus-containing species with ^^P n.m.r. chemical shifts of -8.07 and -9.28 p.p.m, these being diethyl phos­phorobromidate and ethyl cyclopentyl phosphorobromidate respectively formed in a ratio of 4- : I (80/20).

With the exception of the reaction of methyl dicyclo­pentyl phosphite with methyl iodide, which loses the methyl

-76-

group in the dealkylation of the intermediate (14.) indicative of SN2, a mixture of products has been observed for the other reactions which indicates the dealkylation step is not pro­ceeding entirely by SNl or SN2 type mechanisms. The ratio of products is seen to vary with changes in Y in (14). As Y is changed from Me to 0CH=CC1^ to Br the ratio of products changes in favour of the product expected from an SNl mechan­ism .

PhosphiteMethyl dicyclopentyl phosphite

Diethyl cyclopentyl phosphite

Me0CH=CC1Br

Me0CK=CC1Br

Ratio corrected for the stat­istical factor

SNl product : SN2 product

100%7 : 64 : 3

In these reactions it is not simply Y which is being varied;X has also changed from I to 01 to Br" but as will be seen in reactions involving acetyl chloride and acetyl bromide with diethyl cyclopentyl phosphite this does not seem to have a great influence on ratio of products. The reaction conditions have been varied also, methyl iodide being refluxed in diethyl ether, the chloral reaction being carried out at 0* 0 in the absence of solvent and the bromine reactions normally carried out at low temperatures in carbon tetrachloride. The reaction of diethyl cyclopentyl phosphite

-77-

with methyl iodide varying first temperature and then solvent, as will be seen later, shows temperature to have little effect on the ratio of products while an increase in solvent polarity does increase the SNl character product. Taking these factors into account however, the increase of SNl character about the substitutions to such an extent is prob­ably due to the order of increasing positive charge on phosphorus in (14) as Y changes from Me to 0CH=CCl2 to Br.

A summary of the reactions between unsymmetrical phos­phites containing different alkyl groups and methyl iodide, chloral and bromine can be found in table (A).

Besides varying with the nature of Y, one might also expect the relative rates of attack of nucleophiles on the alkyl groups R^-R^ in (14) to vary with the nucleophile X". Attack of nucleophile on ethyl and cyclopentyl in (14) has been seen to be well balanced and it was therefore decided to use diethyl cyclopentyl phosphite with other Y-X reagents in order to study the effect of varying X ” in (14).

Diethyl cyclopentyl phosphite reacted exothermically with acetyl chloride to give a reaction product with two phosphorus-containing species with n.m.r. chemical shiftsof -3.02 and -3.63 p.p.m. corresponding to diethyl acetyl- phosphonate and ethyl cyclopentyl acetylphosphonate formed in a ratio of ^1:1 (49/51). A similar reaction with acetyl bromide gave diethyl acetylphosphonate and ethyl cyclopentyl acetylphosphonate in a ratio of 1:1 (50/50).

The same phosphite with iodine gave two phosphorus- containing species with n.m.r. chemical shifts of -42.6and -44.2 p.p.m., diethyl phosphoroiodidate and ethyl cyclo­pentyl phosphoroiodidate in a ratio of 4:1 (81/19). It

-78-

reacted with methane sulpKenyl chloride‘s ° at -30 C in etherto give a mixture of 0,0-diethyl S-methyl thiophosphate (77%)and 0-ethyl 0-cyclopentyl S-methyl thiophosphate (23%),chemical shifts on n.m.r. of +26.4 and +25.4 p.p.m.

0respectively, and with methyl iodide at 125 C in a Pitschmuka reaction gave 0,0-diethyl S-methyl phosphate (53%) and 0- ethyl 0-cyclopentyl S-methyl thiophosphate (47%).

(EfO)

0 0II II

(E tO l jP -S M e + E t 0 - P - 0 - ( J I ^ S Me

\ "

® /— I( E f O l z P - O - Q

S I® Me

Varying X from Cl to Br in (14) in the reactions of acetyl chloride and acetyl bromide with diethyl cyclopentyl phosphite under the same conditions has not affected the product ratio. Comparison of the results of the reactions of bromine and iodine with diethyl cyclopentyl phosphite also shows no change in the product ratio, X" changing from Br to I , although Y also changes from Br to I in this case However the ratio of attack on ethyl and cyclopentyl, corrected for the statistical factor, changed from 1:7 with methane sulfenyl chloride to 1:2.2 in a Pitschmuka reaction. These two reactions involve the same intermediate (l4;Y=SMe) with Cl and I as the respective nucleophiles, but the different results may be largely a temperature effect.

Diethyl cyclopentyl phosphite with S-methyl methane-

- 79 -

thiosulphonate reacted exothermically giving a mixture of 0,0-diethyl S-methylthiophosphate (82%) and 0-ethyl 0-cyclO' pentyl S-methyl thiophosphate (18%). In this reaction the sulphinate anion attacks with the hard oxygen to give sulphinate esters.

LÊ: @P(0R)3 ♦ MeSSOjMe — ► (R 0)3 p -S M e

0Q+ ^ 0 - S - M e

(ROIgP-SMe ♦ RO-SMe

The ratio of products in this reaction was determined by comparing the ot-proton of the cyclopentyl groups in the thio­phosphate and the sulphinate ester.

Methyl d i s u l p h i d e o n refluxing for 90 hours with diethyl cyclopentyl phosphite in benzene again gave a mixture of 0,0-diethyl S-methyl thiophosphate (39%) and 0-ethyl 0- cyclopentyl S-methyl thiophosphate (6l%).

Diethyl cyclopentyl phosphite with ethyl thiocyanate^^ after 4-0 hours reflux in benzene gave a product mixture of 0,0-diethyl S-ethyl phosphate (84%) and 0-ethyl 0-cyclopentyl S-ethyl phosphate (l6%) with chemical shifts on n.m.r.(benzene) of +26.4 and +25.4 p.p.m. respectively.

In the three reactions above and the reaction involving methane sulfenyl chloride the intermediates are very similar (14; X=MeS or EtS). The varying ratio of attack on ethyl and cyclopentyl, taking into account the statistical factor, can be seen below.

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Increase in softness of nucleophile

Nucleophile

CN“MeSOjCl"MeS"

Attack at ethyl

1111

Attack at cyclopentyl10.5971.3

Indeed, the increase of attack at ethyl follows the trend of increasing softness of nucleophile, but in terms of this concept the position of ON , usually considered to be soft, is anomalous. Recent theoretical calculations by Parr and Pearson have shown however, that ON may be a harder nucleophile than first thought.

Other reactions carried out in this series involved cyanogen bromide and phenyl disulfide. Diethyl cyclopentyl phosphite on refluxing for 4è - 5 hours with phenyl disulfide in benzene gave a reaction product with two phosphorus - containing species with chemical shifts on ^^P n.m.r. of +20.4 and +21.2 p.p.m,, 0,0-diethyl S-phenyl thiophosphate (30%) and 0-ethyl 0-cyclopentyl S-phenyl thiophosphate (70%) respectively.

Diethyl cyclopentyl phosphite reacted exothermically4 5with cyanogen bromide to give two phosphorus-containing

species with chemical shifts on ^^P n.m.r. (benzene) of -21.2 and 22.2 p.p.m. corresponding to diethyl cyanophos- phonate (74%) and ethyl cyclopentyl cyanophosphonate (26%).A summary of the reactions of Y-X reagents with diethyl cyclopentyl phosphite can be found in table B. All the reactions in this series have given a mixture of products due to attack of Nu on ethyl and cyclopentyl groups. They

- 81 -

are not proceeding entirely by an SNl mechanism, where one would expect attack exclusively at cyclopentyl, or entirely by an SN2 mechanism, where one would expect attack exclusively at ethyl.

The effect of varying solvent and temperature on the relative rates of nucleophilic attack on the alkyl groups R^-R^ in (14) was also studied.

The effect of varying solvent on the reaction of methyl0iodide with diethyl cyclopentyl phosphite at 35 C to give

the two phosphonates (15) and (I6 ) is shown in table C. As expected, SNl character in the elimination step increases with increased solvent polarity.

( E t o j j P - o - Q (EfO)^p:^° ♦^ ^ M e 0 “ O

(15) (16)

When methyl iodide was reacted with diethyl cyclopentyl0 0phosphite at 40 C and then at 100 G there was no change in

the product ratio of diethyl methylphosphonate (25%) andethyl cyclopentyl methylphosphonate (75%), but the rate ofreaction did of course increase.

As mixtures of products have been produced in these Arbusov reactions, indicating SNl as well as SN2 character in the dealkylation step, trineopentyl phosphite was prepared and reacted with methyl iodide, chloral, bromine and S- methyl methanethiosulphonate which are in the order of increasing SNl character product in reactions with diethyl cyclopentyl phosphite. As has been stated earlier, Hudson^s reacted neopentyl phosphites with alkyl halide to give

-82-

neopentyl halide without rearrangement, indicative of entirely an SN2 mechanism in the dealkylation step. Re­arrangement of a carbonium ion formed in an SNl type mechan­ism would give 2-halo, 2-methyl butane. Evidence for the presence of neopentyl halide and 2-halo 2-methyl butane was taken from n.m.r., the integration being compared with the a-proton of the neopentyl groups of the phosphoryl product. Trineopentyl phosphite reacted with methyl iodide, chloral and bromine to give the expected phosphoryl product and neopentyl halide, the reactions proceeding with consider­able SN2 character. In the case of S-methyl methanethio­sulphonate two phosphorus-containing species were seen on

n.m.r. with chemical shifts of +68.7 and -0.8 p.p.m. which are probably due to trineopentyl thiophosphate and trineopentyl phosphate respectively.

From the reactions carried out in this study one can see that the second stage of the Arbusov reaction is clearly not limited to an SN2 mechanism. There are cases where the mechanism of the second stage is totally of SN2 character and others in which it is totally of SNl character. However, there are many cases where a mixture of SNl and SN2 type products are obtained. A number of theories have been proposed to explain this mixture or "borderline” behaviour, as has been stated previously. One theory is that border­line behaviour is caused by simultaneous operation of both SNl and SN2 mechanisms, that is, some molecules react by SNl, while others react by the SN2 mechanism. The otherXI • X j -1_ TT- X • 2 7 , 2 8 -, 2 9 . 3 0 , 4 6 , 4 7theories, put forward by Winstein and Sneen, * 'involve ion-pairs. Winstein's theory can be applied to the above Arbusov and related . reactions as follows;

-83-

Ql

1 1I <2 g_®c.-ë I ->f O I- M a:A

“3 CD0 “

6 — 0 4 " — o

coZA

w AÊZAI -

g

Of

I % 1 +

’*1dCD

O — 0ÛL — o

3CD.2 4U) Olg ɣ A

ë

- 8 4 -

Reaction pathway with a rate KSj is true SN2 and as a result has relative rates for attack of nucleophile on "R" groups as shown. The intimate ion-pair and the solvent separated ion-pair both involve a carbonium ion and as a result the relative reactivity rates for the ”R" groups are now reversed. In both cases one gets inversion of configur­ation as with true SN2. Finally we have the separated ions which react with the nucleophile in true SNl fashion with racémisation occurring.

Sneen^^'^°*^^'^^ has taken the ion-pair theory of Winstein and used it to propose a merged or unifying mechan­ism. The central feature of this unifying mechanism requires the intermediacy of a configurationally stable ion-pair whose formation is rate determining at the SNl end of the mechan­istic spectrum and whose destruction by nucleophilic attack is rate determining at the SN2 end. "Borderline” behaviour is presumed to result when the rates of formation and dest­ruction of the intermediates are competitive. For this to occur one would have ion-pairs in the reactions of primary and methyl systems, a condition one would not expect from knowledge of the literature of dissociated carbonium ions.It then follows either (l) that primary and methyl compounds choose on alternative mechanism (SN2) of substitution, as with Winstein’s theory, bypassing the unstable ion-pair, or (2) that the ion-pairs derived from primary and methyl substrates do not parallel, at least quantitatively, in stability the corresponding dissociated carbonium ions. Sneen believes the latter to be the case and thus proposes the merged or unified mechanism.

— 8 5 ~

ConclusionFrom the work carried out one can see that the second

stage of the Arbusov reaction would appear to not be of a simple SN2 nature but that considerable SNl character also plays a part. The amount of SNl or SN2 character product formed in these reactions has been shown to vary with both X and Y in (14) and with polarity of solvent.

- 86 -

One of the reasons why the problem of mixed trialkyl phosphites in Arbusov-type reactions was investigated, besides results obtained in chapter 1,•is the use of inter­mediate phosphites in polynucleotide synthesis. Here, after each coupling, the dinucleoside phosphite is oxidised to phosphate by treatment with iodine in aqueous tetra- hydrofuran (THF) without dealkylation even in the case of methyl dinucleoside phosphites. Certainly this is not the case with simple methyl phosphites. Dimethyl 1-methoxy 2- propyl phosphite when reacted with iodine in aqueous tetra- hydrofuran gave a complex n.m.r. spectrum after 5 minuteswith chemical shifts +12.9» +10.5, +10.1, +0.6 and— 0.4 p.p.m. After 2 hours n.m.r. showed only two phosphorus-containingspecies at +0.6 (43%) and -0.4 p.p.m. (57%). The signal at +0.6 p.p.m. was shown to be the expected phosphate by comparison with an authentic sample of the phosphate prepared from the phosphite with meta-chloro-perbenzoic acid. The signals at +12.9, +10.5 and +10.1 p.p.m. are thought to be hydrolysis products which are subsequently oxidised to the acid which is the signal at -0.4 p.p.m. The initial methyl 1-methoxy 2-propyl phosphoric acid formation may have come, however from hydrolysis of the dialkyl phosphoroiodidate which would be formed as a result of the Arbusov reaction. Analytical g.l.c. experiments were carried out to substan­tiate the formation of a dialkyl phosphoroiodidate by looking for the formation of methyl iodide which would also be formed. From g.l.c. experiments it was found that methyl iodide was produced amounting to 13% of an Arbusov reaction. No trace of 1-methoxy 1-iodopropane was found by g.l.c.

— 8 7 —

The following reaction pathways would appear to be taking place as a result of ^ n . m . r . and g.l.c. studies; hydrolysis (44%), dealkylation (13%), oxidation (43%).

h y d ro ly s is (44% )

Hj 9xi dation

R'0 - p / ° ” * o x i d a t i o n ( M e O ) , P - Q R '

^OMe(R'=CH,CH-CH,-OCHJ

dealkylation ( 13%)

(Arbuso\//^\^^ 0MeO — P —I

1OR'

OR'^ 0 I

(MeOjjP'^ ♦ M e 0 - P = 0\ OH I OH

hydrolysis

- 88 -

H-

H

25H-

ID*

-89-

TABLE BARBUSOV REACTIONS OF DIETHYL CYCLOPENTYL PHOSPHITE

YX Solvent Tarperature ( °C)

Product ratio (Et0)2P(0)Y:EtO^^^O

CsHgO^ ^YCH3COCI 0 49:51CHaCCBr 0 50:50PhSSPh CeHe Reflux 30:70BrCN CsHe 0 74:26I2 CCI4 0 81:19MeSSOaMe CeHe Roan Temperature 82:18MeSSMe CeHe Reflux 39:61EtSCN CeHe Reflux 84:16MeSCl EtzO -30 77:23

TABTiE CREACTION OF DIETHYL CYCLOPENTYL PHOSPHITE WITH METHYL ICDIDE

Solvent Ratio of (15):(16)Time for canpletion

(hours)CeHii* (petroleum ether) 1:5 200CeHe (benzene) 1:3 50EtaO (diethyl ether) 1:3 20THE (tetrahydrofuran) 2:5 20MeNDz (nitro-methane) 2:3 4MeCN (acetonitrile) 3:4 4.5HCONHMe (N-methyl formamide) 4:3 20

-90-

General Experimental DetailsThese were described in chapter 1

” 91 -

EXPERIMENTAL Preparation of Diethyl Cyclopentyl Phosphite

To triethyl phosphite (66.5g, 0.4- mol) was added cyclo- pentanol (34»5g, 0.4 mol) and a catalytic amount of sodium metal. The reaction was heated to a temperature sufficient to distil off ethanol, produced in the reaction, using a 21 cm vigreux column. Distillation gave a colourless oil, diethyl cyclopentyl phosphite, (24.7g, 30/S) b.p. 70 - 72 C at 0.1mm Hg.

^^P n.m.r. (CCI ) +137.3 p.p.m.n.m.r. 61.2 (t, 6H, J=7H z ); 1.65 (m, 8H);

3.8 (d quartets, 4H, J=7Hz, 0"p^=7Hz) and 4.6 (m, IH).

Preparation of Ethyl Dimethyl PhosphitePreparation was carried out in the same manner, on a

0.6 mol scale, as for diethyl cyclopentyl phosphite. Distil­lation gave a colourless oil, ethyl dimethyl phosphite,(18.Og, 22%) b.p. 86 C at 205mm Hg.

P n.m.r. +139.6 p.p.m.n.m.r. 61.25 (t, 3H, J=7Hz) : 3.4-5 (d, 6H,

J=10Hz) and 3.8 (d quartets, 2H, J=7Hz, JpH=7Hz).

Preparation of Dimethyl Cyclopentyl PhosphitePreparation was carried out in the same manner, on a

0.2 mol scale, as for diethyl cyclopentyl phosphite. Distil­lation gave a colourless oil, dimethyl cyclopentyl phosphite, (2.14g, 6%) b.p. 68 - 72 C at 0,2 mmHg.

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p n.m.r, +139.5 p.p.m, H n.m,r, 61.7 (m, 8H) ; 3.4 (d, 6H, Jpj^=10Hz)

and 4.55 (m, IH)

Preparation of Methyl Dicyclopentyl PhosphiteTo a solution of methyl phosphorodichloridite (5.27g,

0.039 mol) in ether (200 cm^) at 0* 0 was added, with stirring and cooling (ice-bath) a solution of cyclopentanol (6.70g, 0.078 mol) and pyridine (9.48g, 0.12 mol) in the same solvent (70 cm^). Following the addition the reaction mixture was stirred at room temperature for a period of 45 minutes. Pyridium hydrochloride salt was separated by filtration (celite aided) and solvent removed from the filtrate to give a colourless oil consisting of one major phosphorus- containing component. [^^P n.m.r. +138.0 p.p.m.] Distillation gave a colourless oil (3.70g) which was found to be a mix­ture of methyl dicyclopentyl phosphite and methyl cyclo­pentyl phosphite in a ratio of 3:1.

b.p. 100 - 116^0 at 2.0 mmHg. methyl dicyclopentyl phosphite;^^P n.m.r. +138.0 p.p.m.'h n.m.r. (CCIJ 61.65 (m, 16H); 3.3 (d, 3H, Jpg=10Hz)

and 4.5 (m , 2H).

methyl cyclopentyl phosphite;^^P n.m.r. +6.05 p.p.m.'h n.m.r. (CCIJ 61.65 (m, 8H) ; 3.6 (d, 3H, Jpjj=12Hz):

4.85 (m, IH) and 6.45 (d, IH, J=680Hz).

This mixture was subsequently used for reaction without

-93-

further purification.

Preparation of t-Butyl Methyl Cyclopentyl PhosphiteTo a solution of methyl phosphorodichloridite (9.65g,

0.073 mol) in ether (250 cm^) at 0 C was added dropwise, with stirring and cooling (ice-bath), a solution of t-butanol (5.4g, 0.073 mol) and pyridine (6.36g, 0.08 mol) in the same solvent (50 cm^). Following the addition the reaction mix­ture was stirred at room temperature for a period of 45 min.

^^P n.m.r. +165.2 (major product); +130.5 and+2.6 p.p.m.

The reaction mixture was cooled (ice-bath) and a solution of cyclopentanol (6.29g» 0.073 mol) and pyridine (6.36g,0.08 mol) in ether (50 cm^) was added, with stirring. Follow­ing the addition the reaction mixture was stirred at room temperature for a period of 45 minutes.

^^P n.m.r. +133.7 (major product).

Pyridium hydrochloride salt was separated by filtration (celite aided) and solvent removed from the filtrate to give a colourless oil.

Distillation gave a colourless oil (4.6g), t-butyl methyl cyclopentyl phosphite in a purity of -90%, the im­purity being methyl cyclopentyl phosphite.

b.p. 68 - 74°C at 3.2 mmHg. t-butyl methyl cyclopentyl phosphite;^^P n.m.r. +133.9 p.p.m.'h n.m.r. 61.4 (s, 9H); 1.7 (m, 8H); 3.35 (d. 3H.

Jpjj=10Hz) and 4.6 (m, IH) .

-94-

This mixture was subsequently used for reaction without further purification.

Preparation of t-Butyl Diethyl PhosphitePreparation was carried out in the same manner, on a

0.04 mol scale, as for methyl dicyclopentyl phosphite. Distillation gave a colourless oil, t-butyl diethyl phos­phite (5.49g, 71%), b.p. 40 C at 0.2 mmHg.

^^P n.m.r +133.3 p.p.m.^H n.m.r. 61,25 (t, 6H, J=7H z ); 1.35 (s, 9H) and

3.75 (d quartets, 4H, J=7Hz, Jpp=7Hz).

Preparation of Diethyl Phosphorochloridite This wa

preparation.This was carried out according to the literature

3 6

Preparation of Methyl PhosphorodichloriditeThis was carried out according to the literature

X • 3 7preparation.

Reaction of Ethyl Dimethyl Phosphite with Methyl Iodide To a solution of ethyl dimethyl phosphite (2.31g,

0.0167 mol) in diethyl ether (5 cm^), was added methyl iodide (2.84g, 0.02 mol). The reaction mixture was re­fluxed for 3 hours to give reaction product having one phosphorus-containing component of ^^P n.m.r. chemical shift +29.5 p.p.m. Distillation (kugel-rohr apparatus) gave ethyl methyl methylphsphonate, (1.74g, 75%) b.p.60 - 65 0 at 1.3 mmHg.

-95-

n.m.r. +29.5 p.p.m.n.m.r. (CCIJ 61.22 (t. 3H, J=7Hz); 1.25 (d, 3H,

Jpjj=18Hz); 3.55 (d, 3H, Jpg=10Hz) and 3.9(d,quartets, 2H, J=7Hz, Jpjj=7Hz).

Reaction of Ethyl Dimethyl Phosphite with ChloralTo ethyl dimethyl phosphite (l.97g, 0.0143 mol) was

added, with ice-cooling and stirring, chloral (2.11g,0.0143 mol). An exothermic reaction took place to give reaction product having one phosphorus-containing component of P n.m.r. chemical shift -4.4 p.p.m. Distillation (kugel-rohr apparatus) gave 2,2-dichlorovinyl ethyl methyl phosphate, (3.07g, 90%) b.p. 100 - 110 °C at 0.3 mmHg.

P n.m.r. -4.4 p.p.m.n.m.r. 61.35 (t, 3H, J=7Hz): 3.75 (d, 3H,

JpH=10Hz); 4 .10 (d quartets, 2H,J=7Hz, Jpp=7Hz) and 6.9 (d , IH, Jpp=6Hz)

Reaction of Ethyl Dimethyl Phosphite with BromineTo ethyl dimethyl phosphite (0.44g » 0.0032 mol) was

4added a solution of bromine (0.576g, 0.0032 mol) in 001 (5 cm^), at -78°0. A reaction product formed having one phosphorus-containing component of P n.m.r. chemical shift -6.65 p.p.m. (001^^). Distillation (kugel-rohr apparatus) gave ethyl methyl phosphorobromidate, (0.45g,

%) b.p. 65 - 70° 0 at 0.25 mmHg.

P n.m.r. -6.65 p.p.m. (001 ).'H n.m.r. 61.42 (t, 3H, J=7Hz); 3.8 (d, 3H,

Jpp=15Hz) and 4.2 (d quartets, 2H,

J=7Hz, Jpp=10Hz).-96-

Reaction of t-Butyl Diethyl Phosphite with ChloralTo a solution of t-butyl diethyl phosphite (0.918g,

0,0047 mol) in diethyl ether (15 cm^) was added a solution of chloral (0.695g, 0.472 mol) in the same solvent (15 cm^) at 0 °G (ice-bath). An exothermic reaction took place giving a reaction product having three phosphorus-containing com­ponents of ^^P n.m.r. chemical shifts +14.3 p.p.m. (19%); +5.6 p.p.m (43%); -5.6 p.p.m. (38%). Distillation (kugel- rohr apparatus) gave 2 ,2-dichlorovinyl diethyl phosphate, (0.35g, 30%) b.p. 75 - 95 °0 at 0.1 mmHg.

^^P n.m.r. -5.6 p.p.m.^H n.m.r. 51.35 (t , 6H, J=7Hz); 4.2 (d quartets,

4H, J=7 J=5Hz).4H, J=7Hz, Jpp=7Hz) and 6.95 (d, IH,

Reaction of Diethyl Phosphite with ChloralTo a solution of diethyl phosphite (0.7g, 0.005 mol)

in diethyl ether (25 cm ) was added, with cooling (ice- bath), an equimolar amount of chloral. Reflux for four hours gave a reaction product having one phosphorus-contain­ing component of ^^P n.m.r. chemical shift +14.5 p.p.m.(CCI^). Distillation (kugel-rohr apparatus) gave diethyl2 ,2 ,2-trichloro, 1-hydroxyethyl phosphorate, (0 .55g, 40%) b.p. 155 - 170°C at 0.2 mmHg.

^^P n.m.r. +14.5 p.p.m. ( CCI )'h n.m.r. 61.35 (t, 6H, J=7Hz); 4.25 (m, 5H) and

5.5 (broad s, IH, D^O exchangeable).

-97-

Reaction of t-Butyl Diethyl Phosphite with Methyl Iodide To a solution of t-butyl diethyl phosphite (0.519g,

0.0027 mol) and proton sponge [1.8-bis(dimethyl amino)- napthalene ] (0.575g, 0.0027 mol) in diethyl ether (10 cm^) was added methyl iodide (0.426g, 0.003 mol). The reaction mixture on refluxing for four hours gave a reaction product having two phosphorus-containing components of ^^P n.m.r. chemical shift +28.2 (62%) and +$.65 p.p.m. (38%).

The reaction product was taken up in dichioromethane and washed with dilute sulphuric acid (2M) and then water to remove proton sponge, the solvent layer being dried over magnesium sulphate before solvent removal on a rotary evaporator. Flash column chromatography using first diethyl ether and then methanol / ether (20/80) gave diethyl methyl- phosphate,

^^P n.m.r. +28.8 p.p.m. (CCl^)'h n.m.r. 61.3 (t, 6H, J=7Hz ) j 1.3 (d, 3H,

J=18Hz) and 3.95 (d quartets, 4H, J=7Hz, JpH='7Hz) .

Effect of heating t-Butyl Diethyl PhosphiteA sample of t-butyl diethyl phosphite was heated under

nitrogen at 65°C for one hour, the effect of heating being3 1.monitored by P n.m.r.

^^P n.m.r. before heating, +133-3 p.p.m. (77%), +5.4 p.p.m.(23%).

^^P n.m.r. after heating, +133.3 p.p.m. (8%), +5.4 p.p.m.(92%).

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Reaction of t-Butyl Methyl Cyclopentyl Phosphite with ChloralTo t-butyl methyl cyclopentyl phosphite (0.65g, 0.0029mol)

was added chloral (0.4?g, 0.0032 mol) with cooling (ice - bath) and stirring. An exothermic reaction took place giving a reaction product containing three phosphorus-containing species with chemical shifts of +14.7 (28%), +6.25 (33%), and -5.45 (39%) p.p.m. on ^^P n.m.r. Distillation (kugel- rohr apparatus) gave 2,2-dichiorovinyl methyl cyclopentyl phosphate, (0.192g, 24%) b.p. 140 - 170 C at 2.75 mmHg.

^^P n.m.r. -5.24 p.p.m. (CCl^)*H n.m.r. 51.8 (m, 8H) ! 3.8 (d, 3H, Jpjj=12Hz);

4.95 (m, IH) and 6.92 (d, IH, Jpg=5Hz).

Reaction of t-Butyl Methyl Cyclopentyl Phosphite with Methyl Iodide

To t-butyl methyl cyclopentyl phosphite (0.65g,0.0029 mol) was added methyl iodide (0.426g, 0.003 mol) and proton sponge (0.64g, 0.003 mol). Heating at 50°C for three hours gave a reaction product containing two phosphorus species with chemical shifts on ^^P n.m.r. of +28.4 (81%) and +6.05 p.p.m. (19%). Proton sponge was removed as in reaction of t-butyl diethyl phosphite with methyl iodide.Flash column chromatography using first diethyl ether and then methanol / ether (10/90) gave methyl cyclopentyl methyl phosphonate (53%).

^^P n.m.r. +28.4 p.p.m.n.m.r. 61.33 (d, 3H, Jpjj=18Hz); 1.7 (m, 8H) ;

3.56 (d, 3H, Jpj^=10Hz) and 4.8 (m, IH) .

-99-

Reaction of Methyl Cyclopentyl Phosphite with Methyl Iodide To methyl cyclopentyl phosphite (0.98g, 0,006 mol) was

added methyl iodide (0.852g, 0,006 mol) and proton sponge (l.286g, 0,006 mol), the reaction mixture being heated to 50-60°C and being monitored by P n.m.r. After 3 hours P n.m.r. showed no reaction to have taken place.

Preparation of Methylphosphonic Dichloride^To phosphorus pentachloride (113g, 0.54 mol) was added

dimethyl methyl phosphonate (30g, 0,24 mol) and the result­ing reaction mixture heated at 95°C for 4 hours.

^^P n.m.r. +40.14 p.p.m. (40%), +0.40 p.p.m. (60%)Distillation gave methylphosphonic dichloride, (23.6g, 73%)b.p. 50 - 60°C at l6 mmHg.

^^P n.m.r. +39.3 p.p.m.^H n.m.r. 62.42 (d, Jpj^=17Hz)

Preparation of Methyl MethylphosphorochloridateTo a solution of methylphosphonic dichloride (19.Og,

0.143 mol) in diethyl ether (100 cm^) was added a solution of pyridine (11.06g, 0.143 mol) and methanol (4.5g, 0 .143mol) in the same solvent (200 cm^). The reaction mixture was heated to reflux for 10 hours at which point pyridium hydrochloride salt and diethyl ether were removed leaving a colourless oil, predominantly methyl methylphosphoro­chloridate .

^^P n.m.r. +38.0 p.p.m.This compound was subsequently used for reaction without

-100-

further purification.

Preparation of t-Butyl Cyclopentyl MethylphosphonateTo a solution of methylphosphonic dichloride (lOg,

0.073 mol) in diethyl ether (60 cm^) was added with stirring and cooling (ice-bath) cyclopentanol (6.3g, 0.073 mol) and pyridine (3.98g, 0.0737 mol) in the same solvent (130 cm^).

3 1After stirring overnight at room temperature P n.m.r. showed a major product with a chemical shift of +33.5 p.p.m.

To the reaction mixture was added a solution of t-butanol (5.6g, 0.0757 mol) and pyridine (6.0g, 0.0757 mol) in diethyl ether (50 cm ), the resulting mixture being stirred at room temperature for 72 hours.

^^P n.m.r. +26.0 p.p.m. (major)Pyridium hydrochloride salt was separated by filtration(celite aided) and solvent removed on a rotary evaporatorto give a pale yellow oil which on distillation gave t-butyl

0cyclopentyl methylphosphonate, b.p. 110 C at 4 mmHg.

^^P n.m.r. +25.0 p.p.m. (CH2CI2)n.m.r. (CCIJ 61.25 (d, 3H, Jpg=17Hz); 1.42 (s, 9H);

1.7 (m, 8H) and 4.76 (m, IH).

Preparation of t-Butyl Methyl MethylphosphonateTo a solution of methyl methylphosphorochloridate

(3.4g, 0.027 mol) in diethyl ether (30 cm^) was added a solution of t-butanol (2.Og, 0.027 mol) and pyridine (2.133g, 0.027 mol) in the same solvent (20 cm^). The reaction mix­ture was refluxed for 4 hours and then stirred at room temperature overnight. Pyridium hydrochloride salt and

-101-

solvent were removed and the resulting reaction product taken up in dichloromethane, washed with dilute sulphuric acid (IM) and water and the organic layer dried over mag­nesium sulphate. Removal of solvent gave t-butyl methyl methylphosphonate

P n.m.r. (CCl^) +26.4 p.p.m.' H n.m.r. (CC1„) 61.2 (d, 3H, Jpjj=17Hz)j 1.4 (s, 9H)

and 3.5 (d, 3H, Jp^^llHz).

Reaction of t-Butyl Methyl Cyclopentyl Phosphite with Methyl Iodide. Analysis of reaction products by P n.m.r.spectros­copy and analytical g.l.c.i) P n.m.r. spectroscopySample Chemical shift (p.p.m.)

(diethyl ether)reaction products +28.64 (70%), +5.85

(30%)t-butyl cyclopentyl methylphosphonate +23.60t-butyl methyl methylphosphonate +25.82methyl cyclopentyl methylphosphonate +28.64

ii) analytical g.l.c. (Column 3% Q.V. 17)Sample g.l.c. retention times (mins)

operating temp operating temp 0 o142 C 136 Creaction products 5.2 (major) 6.7 (major)

4.5 5.6t-butyl cyclopentyl methylphosphonate 7.4t-butyl methylmethylphosphonate 1.4methyl cyclopentylmethylphosphonate 5.2$ 6.6

-102-

Reaction of Methyl Dicyclopentyl Phosphite with Methyl Iodide

To a solution of methyl dicyclopentyl phosphite (I.18g, 0.0051 mol) in diethyl ether (10 cm^) was added methyl iodide (0.7Bg, 0.0055 mol). The reaction mixture was heated to reflux for 12 hours after which time n.m.r. showed amajor product with a chemical shift of +26.4 p.p.m. Distil­lation (kugel-rohr apparatus) gave dicyclopentyl methyl­phosphonate, (0.54g, 46%) b.p. 120° - 130°C at 0.2 mmHg.

31P n.m.r. (CCI^) +26.6 p.p.m,^H n.m.r. (CCIJ 61.3 (d, 3H, Jp^=17Hz); 1.77 (m, 16H)

and 4.82 (m, 2H).

Reaction of Methyl Dicyclopentyl Phosphite with ChloralTo methyl dicyclopentyl phosphite (0.66g, 0.0028 mol)

was added chloral (0.443g, 0.003 mol) with cooling (ice - bath) and stirring. An exothermic reaction occurred giving a reaction product containing four phosphorus-containing species with chemical shifts of +14.9 p.p.m. (18%), +3.8 p.p.m (16%), -5.2 p.p.m. (44%) and -7.1 p.p.m. (22%). Distil­lation (kugel-rohr apparatus) gave a product mixture of2,2-dichlorovinyl methyl cyclopentyl phosphate and 2,2- dichlorovinyl dicyclopentyl phosphate in a ratio of 70/30, b.p. 140 - 160°C at 0.25 mmHg. N.B., The ratio of products was determined as follows ;

-103-

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Flash column chromatography using diethyl ether / petroleum ether ( 4 - 0 ) , 40/60 gave (A) and (B) above in a ratio of 69:31.2.2-dichlorovinyl methyl cyclopentyl phosphate;

n.m.r. ( CCI -5 . 04 p.p.m.n.m.r. 61.82 (m, 8H) ; 3.75 (d, 3H, Jpjj=llHz);

4.8$ (m, IH) and 6.9 (d , IH, Jpg=5Hz).

2.2-dichlorovinyl dicyclopentyl phosphate ; n.m.r. ( CCI i) -7.26 p.p.m.^H n.m.r. 61.80 (m, 16H); 4.82 (m, 2H) and 6.9

(d, IH, Jpp=$Hz),.

Reaction of Diethyl Cyclopentyl Phosphite with Methyl Iodide Diethyl cyclopentyl phosphite (0.94g, O.OO46 mol) was

refluxed for 20 hours in diethyl ether (10 cm ) with methyl iodide (0.8$g, O.OO6 mol). The resulting reaction product was pumped down at 0.1 mmHg to remove excess methyl iodide, solvent, ethyl iodide and cyclopentyl iodide. ^^P n.m.r. and ^H n.m.r. showed the reaction product was a mixture of diethyl methyl phosphonate and ethyl cyclopentyl methyl­phosphonate in the ratio 1:3 (2$/7$).

n.m.r. +28.2 (25?) and +27.4 p.p.m. (75?).^H n.m.r. 64.8 (m) integration 6.

53.9$ (d quartets, J=7Hz, Jpp=7Hz) integration 20.

-105-

Reaction of Diethyl Cyclopentyl Phosphite with Chloral Diethyl cyclopentyl phosphite (0.94g, 0.004-6 mol)

reacted exothermically on the addition of chloral (0.74-g, 0.00$ mol) with ice-cooling (ice-bath) and stirring. The resulting reaction product was treated in the same manner as in the reaction of the above phosphite with methyl iodide ^^P n.m.r. and n.m.r. showed the reaction product to be a mixture of 2,2-dichlorovinyl diethyl phosphate and 2,2- dichiorovinyl ethyl cyclopentyl phosphate in the ratio of 3:1. A small percentage of phosphonates was also present as a result of an Arbusov reaction.

3ip n.m.r. (CCIJ +1$.7 (12%), +14.7 (8%), -$.2 ($8%)and -6.0$ p.p.m. (22%).

n.m.r. 64.9 (m) integration $64.1 (d quartets, J=7Kz, Jpp=7Hz) integration 70.

Reaction of Diethyl Cyclopentyl Phosphite with BromineTo diethyl cyclopentyl phosphite (0.$64g, 0.0027 mol)

was added with stirring and cooling (ice-bath) a solution of bromine (0.44g, 0.0028 mol) in carbon tetrachloride ($ cm ), an exothermic reaction taking place. The reaction product was pumped down at 0.1 mmHg after which time ^^P and ^H n.m.r. showed the reaction product to be a mixture of diethyl phosphorobromidate and ethyl cyclopentyl phosphorobromidate in the ratio 4:1.

3ip n.m.r. (CClJ -8.07 (84%) and -9.28 p.p.m. (l6%).H n.m.r. 6$.0$ (m) integration 3.

54.2$ (d quartets, J=7Hz, Jpp=9Hz) integration $6.

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Reaction of Diethyl Cyclopentyl Phosphite and Acetyl Chloride

To diethyl cyclopentyl phosphite (0.94-g» O.OO46 mol) was added acetyl chloride (0.393g, 0.00$ mol) with cooling (ice-bath) and stirring. An exothermic reaction occurred giving a reaction product which was shown by ^^P n.m.r. and

n.m.r. to be a mixture of diethyl acetophosphonate (49%) and ethyl cyclopentyl acetylphosphonate ($1%).

31P n.m.r. -3.02 p.p.m. ($2%), -3.63 p.p.m (48%).n.m.r. 64.12 (d quartet, J=7Hz, Jpp=7Hz)

integration 112.Ô4.9 (m) integration 19.

Reaction of Diethyl Cyclopentyl Phosphite and Acetyl Bromide Reaction carried out in the same manner as with acetyl

chloride on a 0.0024 mol scale. An exothermic reaction occurred giving a reaction product which was shown by ^^P n.m.r. and n.m.r. to be a mixture of diethyl aceto­phosphonate ($0%) and ethyl cyclopentyl acetylphosphonate (50%).

^^P n.m.r. -3.02 p.p.m. (50%), -3.43 p.p.m. (50%).n.m.r. 64.18 (d quartets, J=7Hz, Jpp=7Hz)

integration 24.65.0 (m) integration 4.

Reaction of Diethyl Cyclopentyl Phosphite and IodineTo a solution of diethyl cyclopentyl phosphite (0.5g,

0.0024 mol) in carbon tetrachloride (3 cm^) was added iodine (solid) (0.75g, 0.003 mol) with cooling (ice-bath). The

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reaction mixture was allowed to warm to room temperature at which point the solid iodine went into solution giving a reaction product which was shown by n.m.r. and ^H n.m.rto be a mixture of diethyl phosphoroiodidate (81%) and ethyl cyclopentyl phosphoroiodidate (19%).

^^P n.m.r. (CCl^) -42.56 p.p.m. (80%), -44.17 p.p.m.(20%).

n.m.r. 64.15 (d quartets, J=7Hz, Jpp=8Hz)integration 117.

65.05 (m) integration 6.5.

Reaction of Diethyl Cyclopentyl Phosphite and Cyanogen Bromide ** °

To a solution of diethyl cyclopentyl phosphite (0.5g, 0.0024 mol) in benzene (5 cm^) was added with cooling (ice- bath) a solution of cyanogen bromide (0.27g, 0.0026 mol).An exothermic reaction occurred giving a reaction product which after pumping down at 0.1 mmHg to remove benzene, ethyl bromide and cyclopentyl bromide was shown by ^^P n.m.r. and ^H n.m.r. to be a mixture of diethyl cyanophosphonate (74%) and ethyl cyclopentyl cyanophosphonate (26%).

^^P n.m.r. (Benzene) -21.2 p.p.m. (75%), -22.2 p.p.m. (25%). ^H n.m.r. 64.2 (d quartets, J = 7Hz, Jpp=7Hz)

integration 68.65.02 (m) integration 5.

Reaction of Diethyl Cyclopentyl Phosphite with Phenyl Disulfide

To a solution of diethyl cyclopentyl phosphite (0.94g, 0.0046 mol) in benzene (10 cm ) was added phenyl disulfide

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(1.004g, 0.0046 mol) in the same solvent (5 cm^). Reflux for 4è “ 5 hours gave a reaction product which was shown by n.m.r. and n.m.r. to be a mixture of 0,0-diethyl-8-phenyl thiophosphate (30%) and 0,0-ethyl cyclopentyl-S- phenyl thiophosphate (70%).

^ n . m . r . (Benzene) +20.4 p.p.m. (30%), +21.2 p.p.m. (70%) n.m.r. 64.02 (d quartets, J=7Hz, Jpp=7Hz)

integration 8.64.85 (m) integration 30.

Reaction of Diethyl Cyclopentyl Phosphite with S-Methyl Methanethiosulphonate

To a solution of diethyl cyclopentyl phosphite (0.5g, 0.0024 mol) in benzene (5 cm^) was added, dropwise with stirring, methyl methylthiosulponate (0.378g, 0.003 mol).An exothermic reaction occurred which was shown by ^^P n.m.r. and n.m.r. to be a mixture of 0,0-diethyl 8-methyl thio­phosphate (82%) and 0-ethyl 0-cyclopentyl 8-methyl thio­phosphate (18%).

^^P n.m.r. (Benzene) +27.0 p.p.m. (82%), +26.0 p.p.m. (18%). n.m.r. (CCl^) 64.62 (m) integration 41.

64.85 (m) integration 9.

Reaction of Diethyl Cyclopentyl Phosphite with Methyl Disulfide

To a solution of diethyl cyclopentylphosphite (0.5g, 0.0024 mol) in benzene (5 cm^) was added methyl disulfide (0.283g, 0.003 mol) and the reaction mixture was refluxed for 90 hours. The product mixture was pumped down at O.lmmHg

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after which P n.m.r. and H n.m.r. showed a mixture of 0,0-diethyl S-methyl thiophosphate (39%) and 0-ethyl 0- cyclopentyl S-methyl thiophosphate (6l%) to be present.

^^P n.m.r. (Benzene) +26.8 p.p.m. (38%), +25.8 p.p.m. (62%). ^H n.m.r. (GCl^) 64.02 (d quartets, J = 7Hz, Jpp=7Hz)

integration 92.64.85 (m) integration 20.

Reaction of Diethyl Cyclopentyl Phosphite with Ethyl Thio- cyanate

Reaction carried out in the same manner and on the same scale as with methyl disulfide. Reflux for 40 hours gave a reaction product which was shown by ^^P n.m.r. and ^H n.m.r. to be a mixture of 0,0-diethyl S-ethyl phosphate (84%) and 0-ethyl 0-cyclopentyl S-ethyl phosphate (16%).

^^P n.m.r. (Benzene) +26.4 p.p.m. (84%), +25.4 p.p.m. (l6%) n.m.r. 64.02 (d quartets, J=7Hz, Jpp=7Hz)

integration 114.64.9 (m) integration 5.

Reaction of Diethyl Cyclopentyl Phosphite with Methane Sulfenyl Chloride

To a solution of methyl disulphide (0.226g, 0.0024 mol) in diethyl ether (5 cm^) was added dropwise at -30°C a solution of sulphuryl chloride (0.324g, 0.0024 mol) in the same solvent (3 cm^). An orange-red colour formation after 20 minutes at -30°C showed methane sulfenyl chloride to have formed. To the orange-red solution was added diethyl cyclopentyl phosphite (l.Og, O.OO48 mol) at -30°C and the

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reaction warmed to room temperature. After removal of solvent and by-products at 0.1 mmHg ^ n . m . r . and H n.m.r showed the reaction product to be a mixture of 0,0-diethyl S-methyl thiophosphate (77%) and 0-ethyl 0-cyclopentyl S- methyl thiophosphate (23%).

^^P n.m.r. +26.4 p.p.m. (77%), +25.4 p.p.m. (23%)^H n.m.r. 64.15 (d quartets, J=7Hz, Jpp=9Hz)

integration 110.65.0 (m) integration 7.

Reaction of Diethyl Cyclopentyl Phosphorothioate with Methyl Iodide

To diethyl cyclopentyl phosphite (l.Og, 0.0048 mol)was added sulphur flowers (0.32g, 0.01 mol), the reactiontemperature being kept between 15 - 25 °C using an acetone/CO 2 bath.

3 1P n.m.r. +67.0 p.p.m.

The reaction mixture with methyl iodide (0.8$g, 0.006 mol) was placed in a resealable "Carius" tube, degassed and heated for 4 - 5 hours at 120°C. The product mixture was pumped down at 0.1 mmHg and ^^P n.m.r. and ^H n.m.r, showed 0,0-diethyl S-methyl thiophosphate (53%) and 0-ethyl 0-cyclO' pentyl S-methyl thiophosphate (47%).

3 1P n.m.r. +27.0 p.p.m. (56%), +25.8 p.p.m, (44%)^H n,m,r, 64.05 (d quartets, J = 7Hz, Jpj^=7Hz)

integration 115,64.9 (m) integration 18.

-Ill-

Reaction of Diethyl Cyclopentyl Phosphite with Methyl Iodide in various solvents

To a solution of diethyl cyclopentyl phosphite (0.94g,0.0046 mol) in various solvents (15 cm^) was added methyliodide (0.85g, 0.006 mol) and the reaction mixture heated

0at 35 C until completion, reaction being monitored byP n.m.r. By-products and solvent were removed by pumping

down at 0.1 mmHg and the ratio of products, diethyl methyl phosphonate and ethyl cyclopentyl methyl phosphonate, determined by both P n.m.r. and H n.m.r.

CsHi4 Time for completion 200 hours.^^P n.m.r. (petroleum ether) +27.6 p.p.m. (22%), +26.6 p.p.m

^H n.m.r. (CCl^) 63.95 (d quartets, J=7Hz,JpH=7Hz) integration 42.64.8 (m) integration 15.

8 sH 6^^P n.m.r. (benzene) +28.6 p.p.m., +27.6 p.p.m. (81%).^H n.m.r. 64. 02 ( d quartets, J = 7Hz, Jpjj=7Hz)

integration 26.64.85 (m) integration 8.

Time for completion 50 hours.

Et?0 Time for completion 20 hours.^^P n.m.r. +28.2 p.p.m. (25%), +27.4 p.p.m. (75%).^H n.m.r. 63.95 (d quartets, J=7Hz, Jpp=7Hz)

integration 20.64.8 (m) integration 6.

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T.H.F. Time for completion 20 hours.” p n.m.r. (T.H.F.) +28.6 p.p.m. (28?), +27.8 p.p.m. (72?)

n.m.r. 64.02 (d quartets, J=7Hz, Jpjj=7Hz)integration 80.64.85 (m) integration 22.

MeNO ? Time for completion 4 hours.” p n.m.r. (MeNOz) +29.2 p.p.m. (47?), +28.4 p.p.m. (53?)

n.m.r. 64.02 (d quartets, J=7Hz, Jpjj=7Hz)integration 104.64.85 (m) integration 22.

MeCN Time for completion 4*5 hours.^ n . m . r . (MeCN) +29.4 p.p.m. (44%), +28.4 p.p.m. (56%)

n.m.r. (CClj^) 63.96 (d quartets, J = 7Hz, Jpp=7Hz)integration 98.64.78 (m) integration 19.

HCONHMe Time for completion 20 hours.” P n.m.r. (HCONHMe) +31.1 p.p.m. (57?), +30.1 p.p.m. (43?)

n.m.r. (CCl^) 64.08 (d quartets, J=7Hz, Jpp=7Hz)integration 52.64.86 (m) integration 7.

In the case where the solvent was N-methyIformamide the phosphonates were extracted with dichloromethane as N - methyIformamide could not he removed.

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Reaction of Diethyl Cyclopentyl Phosphite with Methyl Iodide at various temperatures

To a solution of diethyl cyclopentyl phosphite (0.2g,0.001 mol) in toluene (2 cm^) was added methyl iodide (0.23g»0.0017 mol). The reaction mixture was placed in a sealedvessel and heated to 4-0°C until completion. The reactionwas repeated at 100^0. The product ratio, diethyl methylphosphorate : ethyl cyclopentyl methyl phosphorate, wasestimated using n.m.r. and n.m.r.

4-0^0 Time for completion 30 hours.n.m.r. (toluene) +28.6 p.p.m. (23%), +27.6 p.p.m. (73%).n.m.r. 63.93 (d quartets, J = 7Hz, Jpj^=7Hz)

integration 83.64..82 (m) integration 26.

100°C Time for completion 18 hours.^^P n.m.r. (toluene) +28.6 p.p.m. (28%), +27.6 p.p.m. (72%).

n.m.r. 63.98 (d quartets, J=7Hz, Jpp=7Hz)integration 93.64..82 (m) integration 27.

Preparation of Tri-neopentyl PhosphiteThis was carried out according to the literature

preparation. ®

^^P n.m.r. +137.8 p.p.m.n.m.r. 60.9 (s, 9H) and 3.4-1 (d , Jpp=6Hz).

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Reaction of Trineopentyl Phosphite with Methyl IodideA mixture of tri-neopentyl phosphite (O.lg, 3.4x10 mol)

and methyl iodide (O.lg, 7.0 x 10” mol) was heated in a sealed tube at 90^0 for 20 hours. P n.m.r. and H n.m.r. showed the reaction product to consist of dineopentyl methyl phosphonate and neopentyl iodide.

^^P n.m.r. (001%) +29.0 p.p.m.^H n.m.r. (001%) 63.10 (s) integration 8.

63.55 (m ) integration 16.

Reaction of Trineopentyl Phosphite with ChloralTo trineopentyl phosphite (O.lg, 3.4 x 10 mol) was

added chloral (0.074g, 5 x 10 mol) at room temperature.An exothermic reaction occurred giving a reaction product which was shown by ^^P n.m.r. and n.m.r. to consist of 2,2-dichlorovinyl dineopentyl phosphate and neopentyl chloride.

^^P n.m.r. -8.8 p.p.m.n.m.r. 63.28 (s) integration 7.

63.70 (d, Jpj^=5Hz) integration 15.

Reaction of Trineopentyl Phosphite with BromineTo trineopentyl phosphite (0.3g, 1 x 10~^ mol) was

added bromine (0.3g, 1 x 10 mol) in carbon tetrachloride (3 cm^) at 0°C with stirring. An exothermic reaction occurred giving a reaction product which was shown by ^^P n.m.r. and n.m.r. to contain dineopentyl phosphoro- bromidate, chemical shift of -7.86 p.p.m. on ^^P n.m.r., and neopentyl bromide as the only products of an Arbusov

-115-

reaction.^ n . m . r . (001%) -7.86 (55%), -2.0 (25%) and -40.3 p.p.m.

(20%).n.m.r. (001%) 63.18 (s) integration l6.

63.76 (m) integration 35.

Reaction of Trineopentyl Phosphite with Methyl Methyl Thio- sulphonate

To trineopentyl phosphite (0.22g, 7.6 x 10 mol) was added dropwise at room temperature methyl methyl thio- sulphonate (O.lg, 8 x 10 mol). An exothermic reactionoccurred giving a reaction product containing two phosphorusspecies of chemical shifts +68.7 (34%) and -0.8 p.p.m.

Reaction of Dimethyl l-Methoxy-2-propyl Phosphite with Iodine in aqueous T.H.F.

Dimethyl l-methoxy-2-propyl phosphite (0.67g, 0.0037 mol)was added to a stirred solution of iodine (l.Og, 0.004 mol)in aqueous T.H.F. (20^cm THF, 10 cm^ H 2O ) .

^^P n.m.r. (Aq THF) after 5 mins;Chemical shift (p.p.m.) Peak height (units) % of total

phosphorus+12.9 26 10+10.5 55 23+10.1 70 30+ 0.6 54 22- 0.4 34 14

-II6-

^ n . m . r . after 2 hours;Chemical shift (p.p.m.) % total phosphorus+0.6 43-0.4 57

g.l.c. analysis for production of methyl iodide Column 3% O.V. 17, operation temperature 48°C.Calibration - methyl iodide solution; 0.008 mol in THF (lOcm^) 0.2 ul, 1.6 X 10 mol injected - retention time = 5.8 mins, peak (cut and weighed) = 0.64g.

reaction mixture - total volume = 30.5 cm^, originally con­tained 0.0037 mol of phosphite. 1.6 pi, 1.9 x 10"? mol injected - retention time 5.8 mins, peak (cut and weighed)= O.OlOg, equivalent to 2.5 x 10 ® mol of methyl iodide.

Preparation of Dimethyl 1-Methoxy 2-propyl phosphateTo a solution of meta-chloro-perbenzoic acid (0.64g,

0.0037 mol) in dichloromethane (5 cm^) was added dropwise dimethyl 1-methoxy 2-propyl phosphite (0.673g, 0.0037 mol), the resulting reaction mixture being stirred at room temperature for 1 hour. Meta-chloro-perbenzoic acid was filtered off and the resulting reaction product taken up in chloroform and washed with sodium bicarbonate solution.Drying and removal of solvent gave a pale yellow oil, dimethyl 1-methoxy 2-propyl phosphate.

3 1P n.m.r. (CH^Cl^) +0.2 p.p.m.

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REFERENCES1. A.Michaelis and R.Kaehne, Chem. Ber., 1898, 31 , 104-8.2. A.E.Arbusov, J.Russ. Phys. Chem. Soc., 1906, 38.* 687.3. A.K.Bhattacharya and G.Thyagarajan, Chem. Rev. 1981,

415 - 430.4. For general references see Houben - Weyl, "Methoden

der Organische Chemie", Verlag Chemie, Stuttgart, 1964, 4th Edn., vol. 12/2.

5. V.Mark, Mech. Mol. Migr., 1969, 2, 319.6. A.S.Abramov, Khim. Priraen. Fosfororgn. Soedin. Akad.

Nauk SSSR, Tr. Konf. 1st, 71 (1951); Chem. Abstr.,1958, 52, 240b.

7. A.S.Abramov and G.Karp, Dokl. Akad. Nauk SSSR, 1953,91, 1095; Chem. Abstr., 1954, 48, 9906g.

8. A.S.Abramov and G.Karp, Zh. Obshch. Khim., 1954, 2 4 ,1823; Chem. Abstr. 1955, 4^, 13887c.

9. A.S.Abramov and A.P.Rekhman, Zh. Obshch. Khim., 1956,26, 163; Chem. Abstr., 1956, _50, 13723h.

10. A.I.Razumov and N.N.Bankovskaya, Dotd. Akad. Nauk.SSSR., 1957, 116, 241; Chem. Abstr., 1958, 52* 6164.

11. K.S.Colle and E.S.Lewis, J. Org. Chem., 1978, 4J, 571.12. K.Dimroth and A.Nurrenbach, Chem. Ber., I960, 9^, 1649.13. H.R.Hudson, R.G.Rees and J.E.Weekes, J. Chem. Soc.,

Chem. Commun., 1971, 1297.14. S.R.Landauer and H.N.Rydon, J. Chem. Soc., 1953, 2224.15. A.E.Arbusov and P.V.Nesterov, Dokl. Akad. Nauk SSSR,

1953, 92, 57; Chem. Abstr., 1954, 48, 10538b.16. A .Skowronska, J.Mikolajczak and J.Michalski, J. Chem.

Soc., Chem. Commun., 1975, 791.17. J .Milchalski, J.Mikolajczak, M.Pakulski and A.Skowronska,

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Phosphorus Sulfur, 1978, 4, 233.18. J.Milchalski, M.Pakulski and A .Skowronska, J. Chem. Soc.,

Perkin Trans. 1, 1980, 833.19. G.Aksnes and D.Aksnes, Acta Chem. Scand., 1964, 18_, 38.20. E.S.Lewis and D.Hamp, J. Org. Chem., 1983, 4^, 202$.21. W.Gerrard and W.J.Green, J. Chem. Soc., 1951, 2$$0.22. W.Gerrard and G.J.Jeacocke, J. Chem. Soc., 1954, 3647.23. H.R.Hudson, R.G.Rees, and J.E.Weekes, J. Chem. Soc.,

Perkin Trans. 1, 1974, 982.24. A.J.Burn and J .I .G.Cadogan, J. Chem. Soc., 1963, 5788.25. V.Mark, Tetrahedron Lett., 1961, 295.26. Unpublished.27. S.Winstein, E.Clippinger, A .H .Fainberg, R.Heck and

G.C.Robinson, J. Am. Chem. Soc., 1956, 7_8, 328.28. S.Winstein, B.Appel and R.Baker, Chemical Soc. (London),

Special Publication No. 19, 196$, 109.29. H.Weiner and R.A.Sneen, J. Am. Chem. Soc., 1965, 87,

292.30. R.A.Sneen and J.W.Larsen, J. Am. Chem. Soc., 1969, 91,

362, 6031.31. W.Perkow, K.Ullerich and F.Meyer, Naturwissenschaften,

1952, 39, 353.32. I .J .Borowitz, S.F.Firstenberg, G.B.Borowitz and

D .Schuessler, J. Am. Chem. Soc., 1972, £4, 1623.33. P.A.Chopard, V.M.Clark, R.F.Hudson and A.J.Kirby,

Tetrahedron, 196$, 21, 1961.34. M.G.Imaev, J. Gen. Chem. USSR (Engl. Transi.), 1961,

31, 1654.35. V.Mark, J. Org. Chem., 1967, 32, 1187.36. H.G.Cook, J.D.Ilett, B.C.Saunders, et al., J. Chem. Soc.,

1949 2924.- 119 -

37. D.R.Martin and P .J.Pizzolato, J. Am. Chem. Soc., 1950, 72, 4584.

38. V.Mark and J.R.Van Wazer, J. Org. Chem., 1964, 2_9, 1006.39. H.Quest, M.Henschmann and M .0.Abdel-Rahman, Synthesis,

1974, 49.40. D. C.Morrison, J. Am. Chem. Soc., 1955, 7_7, 181.41. J.Michalski, J.Modro and J .Wieczorkowski, J. Chem. Soc.,

I960, 1655.42. H.I.Jacobson and V.Jensen, J. Am. Chem. Soc., 1955,

77, 6064.43. W.A.Sheppard, J . Org. Chem. 1961, 2^, I46O.44. R.G.Parr and R.G.Pearson, J. Am. Chem. Soc., 1983, 105,

7512.45. S.Yamada, Y.Kasai and T.Shioiri, Tetrahedron Lett.,

1973, 1595.46. Sneen, Fett and Dickason, J. Am. Chem. Soc. 1973, 95,

638.47. Sneen, Acc. Chem. Res. 1973, 46 - 53.48. V.Gold, J. Chem. Soc., 1956, 4633.49. R.L.Letsinger and W.B.Lulsford, J . Am. Chem. Soc.,

1976, 98, 3655.

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CHAPTER 3

Nucleophilic Displacement Reactionsat

Four Co-Ordinate Phosphoryl Centres

Nucleophile Displacement Reactions at Four Co-ordinate Phosphoryl CentresIntroduction

Nucleophilic displacement reactions at phosphorus in tetra co-ordinate pentavalent phosphorus esters and related compounds have been studied extensively.^»^ These reactions are often highly stereoselective occurring v/ith essentially complete inversion or retention of configuration.

Cl

0MeO

Et OH► Inversion

M e ^ ^ N H

0-15M HCI-MeOH

MethanolysisInversion'

EtO, .SM e

0 ^ ^ O R

MeI

NaOMe

R =

MeOOMe

OMe

E tc, .OMe

Retention®

In other instances the reactions show only marginal stereoçdejfhv'rfg the relative importance of the reactionpathways leading to products with inversion or retention of configuration being very much a function of the nucleO'

-121-

phile, leaving groupé and reaction condition.^ The mechanism put forward to explain retention and inversion involves tri­gonal bi-pyramidal intermediates (t.b.p.) which were firstused to explain the experimental results of the hydrolysis

2of phosphate esters by Westheimer.For inversion to occur the nucleophile attacks opposite

the leaving group to give a t.b.p. with the incoming nucleo­phile and the leaving group both apical. The leaving group then departs from the apical position before any ligand re­organisations has. taken place (Scheme 1 ) .

L L a ^I I

’ " N . ^ r b N N

t.bf.

Scheme 1

For retention to take place it is considered that the nucleophilic attack occurs at phosphorus in an apical position opposite a ligand that is not a leaving group. A pseudorotation process, (see chapter 1), then takes place which puts the leaving group apical; this then departing to give a product with retention of configuration (Scheme 2).

C c L* Pseudorotation f '

* / V " ' - ' N ba b N

Scheme 2 \N

-122-

The above mechanism explains how a reaction can proceed with inversion and retention of configuration. It is assumed that the nucleophile attacks at phosphorus opposite the most apicophilic group and, as can be seen, whether this group is the leaving group or not affects the stereochemistry of the reaction. The preference for the leaving group, or any ligand, to occupy an apical position depends upon the relative apicophilicities of the ligands. The reasons why certain groups are more apicophilic than others have already been dealt with in Chapter One.

Apart from the apicophilicities of ligands affecting the pathways of the reaction one also has to consider the case where phosphorus is part of a ring. Here the ring can have a large bearing on the configurational outcome of a reaction as in the trigonal bi-pyramidal intermediate a preference to be equatorial, equatorial (e,e) or axial, equatorial (a,e) can affect the reaction pathway. The preferences of different ring sizes for e,e or a ,e has again been dealt with in Chapter One. Part of this chapter is the analysis of the stereochemistry involved in the hydrolysis of a phosphetan oxide, r-l-chloro 2,2,3-trans-4->4--penta methylphosphetan-l-oxide (l).

( 1 )

The four membered ring in this case will, in a t.b.p., prefer to be in a axial, equatorial position due to ring strain. The effect this can and does have on a nucleophilic substitution will be discussed with the results of the

-123-

hydrolysis reaction carried out on (l).One group of reactions that it has not hitherto been

possible to investigate the stereochemistry of is the hydrolyses at phosphoryl centres, since these lead to achiral acids.

R" OR" R" 0

Chiral Achiral

Included in this chapter is a description of a general method that allows the stereochemistry of such hydrolyses to be established. The two compounds this work was carried out on are Sp-methyl methylphenylphosphinate (2) and Sp-S- methyl methylphenylthiophosphinate (3).

Ph . 0 Ph oO\p-:>' \ p : - '

'^OMe M e ^ SMe

12) (3 )

An outline of this general method is given below:The phosphinate (2) was hydrolysed using (60^) togive isotopically labelled methylphenylphosphinic acid, (4-) This acid was then esterified with the diazocompound ($) to give a menthyl phosphinate as two diastereoisomers. The menthyl esters are known^ and their absolute configurations have been established.

-12 4- ~

(2) H^O

INVERSION

(4 )M e ^ 1*0

RETENTION

Ph J3 Men18

OMen

^ '^OMen Me 1*1(S p ) (R p)

Me OMen(Sp)

INVERSION RETENTION

By making use of the n.m.r. isotopic shifts® onecan deduce from the n.m.r. spectrum whether the producthas retained the starting configuration or in fact inversion has taken place. The Rp diastereoisomer is found upfield of the Sp on a ®^P n.m.r. spectrum. As the estérification process does not affect the bonding to phosphorus any con­figurational changes can be attributed to the hydrolysis process.

-125-

Results and DiscussionsThe original phosphinate that was to be studied regard­

ing the stereochemistry of hydrolysis was menthyl methyl­phenylphosphinate which was prepared by the method described by Korpuin et.al.,^ the resolution of the two diastereo- isomers also following their method.

Various attempts were made to carry out the hydrolysis of the above phosphinate, all unsuccessful due probably to the bulk of the menthyl group. As a result of this the Rp-1-: methylphenylphosphinate was converted, with 100%inversion, to Sp-methyl methylphenylphosphinate using the general method described by De Bruin (scheme 3).

R.OMIÎ, "’" - • • f / ’''* Mg Cf.OOOH,

R "^ ^OM en R " ^ ^OMen R" ^ 0

R’. R '*=aryl or alkyl, R = Me or Et, X = 0 or 5

MLn= PFg, BF or SbClg

( Scheme 3 )

The opticoL pori-F of the Sp-methyl methylphenylphosphin­ate was checked by optical rotation ,[ otj -55 . 0 (c 7.3, benzene), and by the method of Harger.^° This method involves adding to a ^H n.m.r. sample of the phosphinate an equimolar amount of optically pure (+)-(R)-phenyl-t-butylphosphinothioic acid, (6). If any Rp-mathyl methylphenylphosphinate werepresent the n.m.r. chemical shift at 63.55 due to theP-methoxy group, which is a doublet, would separate into two doublets due to diastereoisomeric complexes being formed,(7) and (8).

-126-

S

Bu^ S M eO , ..Ph But, .S M eO , .vMeV p ^ ^ p '

p 0 —H — 0 ^^Me Ph^^ 0 — H 0 ^ Ph

(7) (8)No Rp isomer could be detected and the ester is at least 98.5% Sp.

Alkaline hydrolysis was now carried out on the Sp-methyl methylphenylphosphinate using 60% and sodium hydroxide,followed by acidification, at room temperature, with conc.HCl and extraction with CH^Cl^ to give labelled methylphenyl­phosphinic acid (4-). The phosphinate was also hydrolysed with to give the unlabelled acid.

Both the labelled and unlabelled acids were esterified with a mixture of the diazo-compounds (11) which was preparedaccording to the reaction scheme 4-» via the hydrazone (10).

-127-

I -menthol

H,CrO,

l*menthone

BaO

NH2NH2.H2O

Redcolour

Ag^O. -25*C

Anhydrous Mg SO Xylene

N -N H

(101

Pr

Scheme 4

Estérification of the unlahelled acid with (11) gave products whose n.m.r. spectrum is shown, (Spectrum l)

The signals in this spectrum were attributed to menthyl, isomenthyl, neomenthyl and neoisomenthyl methylphenylphos- phinates, in each case, there being two diastereoisomers, as shown. To enable the assignment of the spectrum to be

3 1carried out the P n.m.r. sample was spiked in turn with the diastereoisomers of the neomenthyl ester, isomenthyl ester and menthyl ester, which were all prepared from methylphenylphosphinyl chloride with the relevant alcohol, and also with pure Rp-menthyl methylphenylphosphinate.

- 128 -

UJ<=>

“O“D3

fSJ

LU

«JÜ roCi Qi3 3O. O-LH oz 3S roo 3(/*o3ro33"

So_

Ol U)3 oQ. 3ro

§

LHrsjLH

roI -3

o\

±

•VÔ

-129-

At some point in the production of the diazo-compounds (ll), épimérisation of the isopropyl group must have occurred.

Spectrum 2 is the ^ n . m . r . spectrum of the products from the estérification of the labelled acid with (ll). As was explained in the introduction, the isomers expected for inversion and/or retention are (12), (13), (14) and (15), below.

Ph .OM en Ph ,..p* Ph^ .OMen Ph ,.0" ^ p ' " . \ p > "

Me' ^0 Me^ ^OMen Me^ ^0* Me^ ®OMe(R p) (Sp) (Rp) (S p )

(12) (13) (14) (15)

INVERSION RETENTION

From spectrum 2 it can clearly be seen that in these esters the isotopic upfield shift caused by a P,^®0 single bond is approximately 4.6 Hz whereas that due to a P,^®0 double bond is approximately 7.3 Hz. In diethyl ether, the over­lapping isomenthyl and neomenthyl signals (peak 4) are resolved and show isotopic shifts of 7.4 and 4.6 Hz respectively.

Analysis of resonance 6, which is due to Rp-menthyl ester, shows the presence of a major additional peak, at higher field, due to 0^® labelling. The isotopic shift is4.7 Hz which corresponds to the presence of a P,^®0 single bond; this isomer is therefore labelled as in (12).Similarly resonance 2, which is due to Sp-menthyl ester, shows the presence of a major labelled isomer with an iso­topic shift of 7.1 Hz. This shift corresponds to the pres­ence of a P,^®0 double bond and the major labelled Sp-

-130-

>T3 00

WÔ

-O-o

on

ho

00

on

O

w

Oo

N)

~o —

m

m

%; \- /

"0=0

m

-131-

isomer is therefore (13) .These major labelled products correspond to inversion

of configuration at phosphorus in the hydrolysis of (2),However, there is also an additional minor peak in

resonance 6 with an upfield isotopic shift of 7.6 Hz which1 8corresponds to the presence of a P, 0 double bond, thus

showing the formation of (14-) which is due to retention of configuration at phosphorus in the hydrolysis of (2).Minor isomers due to retention are also clearly visible in resonance 7, the upfield neomenthyl signal.

The ratio of inversion to retention of configuration3 1is calculated from P n.m.r. to be 92:8 for the alkaline

hydrolysis of Sp-methyl methylphenylphosphinate (2).The result is somewhat surprising if one considers

the energy differences in the trigonal bipyramidal inter­mediates leading to inversion and retention of configuration For inversion, the t.b.p. will be of the structure (16) and for retention, (17).

OMe MeP h , I M eO ,, I

J P — 0® ^ P — 0®M e ^ l P h ^ l

'®0H '*0H

(16) (17)

The expected energy difference between (16) and (17), mainly due to the relative apicophilicities of '0' and 'C’, is in the range of 6 - 10 Kcal mol ^ ^ although theoretical calculations by Bestmann^^ have pointed to this energy difference being less. For retention product, via (17),one would expect the energy difference to be nearer

-132-

151.5 Kcal mol

Green and Hudson'" have shown the methanolysis of methyl ethylphenylphosphinate to proceed with total in­version of configuration. In view of the above a number of control experiments were carried out in order to substan­tiate that the retention product was a direct result of hydrolysis.

Firstly, the methyl ester involved in the hydrolysis has been shown to be > ^S.5% Sp. However, there is a possibility that the labelled acid could racemise on lib­eration from the sodium salt, as shown.

H,0Ph

Me

?0H

H

H

MeOH

Ph ,0

® HMe

♦ H^O

One would also expect wash out of ^^0 label, as shown, and doubly-labelled product, from H^^^O attack, from the above process.

PhP>.

M e ^ t ^ O H

H,0:

18,WASH OUT OF '"0 LABEL

Me

Hj®0

Mass spectrometry and n.m.r. spectroscopy (isotopicshift of 5.3 Hz in methanol) of the labelled acid formed

-133-

from hydrolysis of Sp-methyl ester showed that, as with methyl diphenylphosphinate,^ hydrolysis involved complete attack at phosphorus and there was no subsequent exchange of oxygen.

To provide further evidence that no exchange had occurred the alkaline hydrolysis of Sp-methyl ester was repeated with the sodium salt being acidified at below 0°C with conc. HCl to pH ~1. The phosphinic acid was extracted and immediately esterified with (ll). The product, which was purified as before, gave an identical n.m.r. toSpectrum 2, the same percentage of retention product being formed.

In the original hydrolysis the Sp-methyl ester was acidified in the presence of a large excess of H^^^O with no attention being paid to cooling or speed of work-up.If any racémisation of the phosphinic acid were to occur one would expect a washing out of label which was notobserved by ^^P n.m.r. and mass spec.

In the repeat experiment the acid was liberated in ~50/50, Hg^^O / Hg^^O. If exchange were to occur here one would expect doubly labelled products; none were observed

The fact that the ratio of the retention product is the same in both experiments again points to no exchange.One would expect less exchange to take place under the conditions of acidification in the.repeat experiment.

Finally methylphenylphosphinic acid was converted into its sodium salt and acidified at 0°C, to pH = 1, in the presence of H^^®0. No evidence for incorporation of by mass spec, or ^^P n.m.r. could be found.

The other possibility of racémisation which must be

-134-

ruled out is one involving the formation of pyrophosphates. It may be possible for the sodium salt to react with un­changed methyl ester to give a pyrophosphate which is sub­sequently attacked by ”0H to give the sodium salt, as shown, (Scheme 5).

Ph

Me ^O M e

i0 Ph

Phv^ll I^ P — 0 — P = 0

M g / I ( Scheme 5 )

Me ® 0 HJ

Ph oO Ph . 0

X e K , ® .Me' ^0 Me' ^OH

Again with this process, as it is taking place in 60%Hg^^O and 4-0% Hg^^O one would expect to see both washing out of label and doubly-labelled material, both of which, as has been stated, are not observed. We can therefore rule this pathway out as a possible route to a retention product.

As far as the experimental work, at present, can establish the ~8% retention product is due to the hydrolysis reaction.

The analysis of the stereochemistry of hydrolysis was

-135-

now extended to Sp-S-raethyl methylphenylphosphinate (3). Firstly a pure sample of (3) had to be prepared. Methyl- phenylphosphinothioic acid was prepared according to scheme 6 .

0MeOH Mel II

PhPClg PhP(OMe). ► PhP-OMepyridine

Me

PCI5

15-/. P h P -c i

Me^ ^OH conc "1 |Scheme 6

Resolution of the acid^* was carried out using quinine.The quinine salt of the Sp-phosphinothioic acid was con­verted via the acid into the dicyclohexylamine salt at which point the optical rotation showed the enantiomer to be pure. This was backed with further evidence gained from a n.m.r. study of the acid.^° A single enantiomerof the acid gives rise to only one P-methyl resonance, as does the racemic mixture. Mixtures of the enantiomers display two P-methyl resonances having a separation that decreases as the amounts of the two enantiomers in the mixture become more nearly equal. n.m.r. of the isolatedSp-acid showed only one doublet at 61.85, showing the enantiomer to be pure.

The dicyclohexylamine salt was converted into Sp-S- methyl ester (3) using methyl iodide.

Alkaline hydrolysis of (3) in 60% followed by

- 136 -

acidification at 0* C with conc. HCl to pH ~1 and estérific­ation with (ll) were carried out as with (2). The product, which was purified as before, gave n.m.r. spectrum 3.The spectrum can be analysed exactly as before as in both cases we are starting with Sp-enantiomer and hydrolysing to the acid. Again resonance 6, which is due to Rp-menthyl ester, shows the presence of a major additional peak at high field, due to labelling. The isotopic shift is4.7 Hz corresponding to a P,^®0 single bond which is found in (12). Resonance 2 shows a major isotopic shift of 7.2 Hz corresponding to a P,^®0 double bond which is found in (13). Again the major labelled products correspond to inversion of configuration. Additional upfield isotopic shifts can clearly be seen in resonance 6, 7.5 Hz, corresponding to a P,^®0 bond which is found in (14), a retention product.Minor isomers due to retention can again clearly be seen in resonance 7, the upfield neomenthyl signal.

The ratio of inversion to retention of configuration is calculated from ^^P n.m.r. to be 81:19 for the alkaline hydrolysis of Sp-S-methyl methylphenylthiophosphinate,(3) .

The formation of the retention product is somewhat surprising as the expected energy difference in the t.b.p. intermediates, (18) and (19), would be expected to be of the same order of magnitude as those involved in the hydrolysis of (2).

-137-

wun

&ô

“D

LH

ISO

00

onO

NJ

o00

o ZD

-138-

SMe Me

M e ^ l P h ^ l’®0H ’®0H

(18) (19)

However, there is an increase in the formation of the retention product. There is a good deal of experimental evidence that suggests that an S-alkyl substituent present as the leaving group on a phosphoryl centre helps favour the formation of the retention product.^ ® ^ ^ This could perhaps be due to a lone pair of electrons of sulphur, in an equatorial position of a forming t.b.p., aiding the in­coming nucleophile in some way, the sulphur lone pair being of greater assistance than the oxygen analogue.

©_ I I . . - 0C j RS— P,

0 Nu

Although the method described in this chapter does allow an analysis of the stereochemistry of hydrolysis of phosphinate esters, the use of a mixture of diazo-compounds (11), formed due to épimérisation, produces four pairs of diastereoisomers in the final analysis. An attempt was made to find a substitute for diazo-compounds (11) which when reacted with methylphenylphosphinic acid (4-) would produce only one pair of diastereoisomers.

A similar reaction to the one below, carried out by Marmor and Seyferth,^^ was attempted using methylphenyl-

-139-

phosphinic acid (i) and diphenylphosphinyl-diazonethane (20) .

0 0 /M e

(MeO)jPCNjMe ♦ CH3 CO3 H — ► (MeO)jPCH q\ "

OCCH3

Diphenylphosphinyl-diazomethane (20) was prepared according to the reaction scheme 7.

The diazo-compound (20) was refluxed in methanol with the phosphinic acid (4-) for 5 - 6 hours. Work-up of the product mixture gave a white powder, diphenyl(phenylmethyl- phosphinyloxymethyl)phosphine oxide (21), whose n.m.r.spectrum showed two phosphorus-containing species with chemical shifts of +23.2 and +4-3.6 p.p.m. which both appeared as doublets due to phosphorus-phosphorus coupling.

-14-0-

o r .nhformaldehyde

23

HgCO O I ; nch , oh

HBr23

PhjPCI*

MeOH

HC — PPhj IIN:

(20)

'Arbusov Reaction'*

25 0II

25

H,C-PPh.

H,N

Scheme 7

- 14-1 -

0 Ph. . 0Il \ ^

HC— PPh. ♦ ^ P \II Me'^ OH

( 20 ) ( 4 )

10 0 MeII 1 1 /

P h j P - C H j — 0 - P \ (21)Ph

The next step would be to introduce a chiral group into the diazo-compound (20) and to then carry out the reaction with phosphinic acid (4-) to give, hopefully, one pair of diastereoisomers. The diastereoisomers would have to be separated and X-ray analyses carried out to determine their absolute configurations, which were already known in the case of the 1-menthol esters.

An analysis of the stereochemistry of hydrolysis of phosphinic esters could then be carried out, as previously, with one pair of diastereoisomers only present in the

P n.m.r. spectrum.This project, unfortunately, had to be prematurely

terminated due to my three years research reaching a con­clusion .

As has been stated, an analysis of the stereochemistry of hydrolysis of p-l-chloro-2 ,2 ,3-trans-4-,X-pentamethyl- phosphetan 1-oxide (l) was carried out.

(l) was prepared according to the method of Jungermann & M c B r i d e . A l k a l i n e hydrolysis of (l), followed by acidific­ation with dilute HCl, gave the phosphetan acid (22).

-142-

0This was esterified at 0 C with diazomethane, prepared from a diazald solution, to give a product with two phosphorus- containing species with n.m.r. chemical shifts of +54-»2and +55.5 p.p.m., these being attributed to the two geometric isomers of l-methoxy-2 ,2 ,3 ,4-> 4.-pentaraethylphosphetan 1-oxide,(23) and (24).

I l l / K \ l “ lO'Q^O

H

OMe

ICHgN,(23) ^ ♦ (24)

P

M e O

trans c|s

The trans-geometric isomer (23) was prepared by methanolysis of (1 ) at 0* C. This reaction has been shown to proceed specifically with retention of configuration.^^^® A sample of the trans-geometric isomer was added to the ^ n . m . r .

sample of the product containing (23) and (24-), resulting in an enhancement of the low field chemical shift at 435*5 p.p.m. in the ^ n . m . r . The trans-geometric isomer’s ^^P n.m.r. chemical shift is, therefore, at low field relative to the cis-isomer.

Alkaline hydrolysis of (l) was now carried out using % H iGQ and potassium hydroxide. The potassium salt of

-143-

the phosphetan acid(25), which is formed, was esterifiedby forming a complex with 18-crown-6-ether and reaction

2 9with methyl iodide, according to the method of Lowe.3 1Spectrum 4- is the P n.m.r. spectrum of the products of

the above estérification.Alkaline hydrolysis with H 2 O/KOH can proceed by

retention or inversion to give isotopically labelled pot­assium salts of the phosphetan acid (25). Estérification of (25), with methyl iodide, would give (26), (27), (28) and (29).

(1 )

(26)

MeOCIS

H2®0KOH

(25)

RETENTION

(27)

18-crown-6ether,

Mel(28)

transMe

CIS

18

INVERSION

(29)

OMetrans

RETENSION INVERSION

1 8Analysis of the 0 isotopic shifts in spectrum 4- allows a determination of the stereochemistry involved in the hydrolysis of (l). The resonance at low field, the trans-geometric isomer, shows the presence of an additional

-144“

CL

O

00

ro_ o_

cr

UJCL00

coin{/)

ai

O if)ih

>oobin

N

x:CLCL

- 145 “

peak, at higher field, due to ^®0 labelling. The isotopic shift is 5.5 Hz which corresponds to the presence of a P , ^ s i n g l e bond; this isomer is therefore labelled as in (27). Similarly the resonance at high field, which is due to the cis-geometric isomer, show the presence of a labelled isomer with an isotopic shift of 8.4 Hz. This shift corres­ponds to the presence of a ?,^®0 double bond and the labelled isomer is therefore (26). These labelled products, (25) and (26), correspond to retention of configuration at phos­phorus in the hydrolysis of (l). There was no evidence for the products due to inversion and hence one can conclude that hydrolysis of (l) proceeds with total retention of configuration.

This result was expected and falls into line with other work carried out on four membered ring systems. The reason why the hydrolysis proceeds with retention is that the four membered ring prefers to be placed apical-equatorial in the trigonal by-pyramidal intermediate (t.b.p.). The nucleophile (HO") attacks at an apical position to form the t.b.p. (30) with the ring in an apical-equatorial position, thereby placing the leaving group (Cl ) in an equatorial position. A pseudorotation process now occurs to give (31), the incoming nucleophile having effectively changed places with the leaving group and the ring staying apical-equatorial. The leaving group now departs from an apical position to give the acid (32) with retention of configuration.

— 14 6—

(1) — — ►

(32)

* ^ î vOH

(30)

Pseudorotation

f (31)— P,:— Cl

rk "ohG qFor inversion to occur the four membered ring would

have to be placed diequatorial in the t.b.p. (33).

(1)OH

OH

(33)

HO

Inversion

The energy required to place the ring diequatorial is 17 - 18 Kcal mol” and is too large to be overcome by apicophilicity factors, hence this pathway is energetically unfavourable and inversion does not occur.

-147-

EXPERIMENTAL Preparation of Menthyl Methylphenylphosphinate

This was carried out according to the literature preparation as was the resolution of the two diastereo-

7isomers.

Reaction of Menthyl Methylphenylphosphinate with Na0H/H20To the phosphinate (0.15g, 5 x 10” mol) in THE (0.5 cm^)

was added sodium hydroxide (0.04g, 0.001 mol) in HgO (0.5 ml) and the mixture was stirred and heated to 85°C for 3s hours. No reaction took place.

The above was repeated using Dioxan in place of THE; again no reaction occurred.

Conversion of Rp-l-Menthyl Methylphenylphosphinate into Sp-Methyl Methylphenylphosphinate

The Rp-l-menthyl ester (3.0g, 0.0102 mol) in drieddichloromethane (30 cm^) was stirred for 22 hours withtrimethyloxonium tetrafluoroborate (l.627g, 0.011 mole)at room temperature.

3 1P n.m.r. +72.8 p.p.m. (80%), +54.1 p.p.m. (20%

The phosphonium salt was now purified. Dichloromethane was removed on a rotary evaporator without heating. The residue was redissolved in a minimal amount of dichloromethane, making it less viscous, and this was rapidly added to a ten­fold volume of anhydrous ether causing an oil to form.The ether layer and the oil, the phosphonium salt, were separated.

^^P n.m.r. +72.6 p.p.m.

— 14 8 —

To the phosphonium salt was added trifluoroacetic acid (15 cm^) and the resulting solution was stirred at room temperature for 18 hours.

^ n . m . r . +68.9 p.p.m.

The reaction mixture was taken up in dichloromethane(300 cm^) and washed with water (50 cm^), saturated sodium bicarbonate solution (50 cm^) and then water. Drying and evaporation of solvent gave a brown oil.

^^P n.m.r. +42.7 p.p.m.

Flash column chromatography, using first pet. ether (60° - 80°) and then methanol/chloroform (10/90) as eluting solvents gave Sp-methyl methylphenylphosphinate (0.87g, 50%).

n.m.r. 61.56 (d, 3H, Jp%=l6Hz); 3.55 (d, 3H,JpH=12Hz) and 7.6 (m, 5H).

[a]^® -55.0 (c 7.3 benzene), (Lit. Value® [o]p-56.0 (c 4.0 benzene) ).

n.m.r. Shift Experiments involving Sp-Methyl Methylphenyl­phosphinate and an Optically Active Phosphinothioic acid ®

The following experiments were carried out in order to check the optical purity of Sp-methyl methylphenylphosphinate, prepared from Rp-l-menthyl methylphenylphosphinate.

i) To a racemic sample of methyl methylphenylphosphin­ate (0.064g, 3.76 X 10 mol) was added (+)-(R)-phenyl-t- butylphosphinothioic acid (0.08g, 3.76 x 10 * mol).

n.m.r. (60MHz) (phosphinate) 63.55 (d , Jp^=12Hz) n.m.r. (60MHz) (phosphinate + acid) 63.55 (d d , Jpp=12Hz,

A6=4Hz ) .

-149-

The doublet of doublets were of equal intensity.

ii) To Sp-methyl methylphenylphosphinate (0.045g,2.65 X 10” mol) was added (+)-(R)-phenyl-t-butylphosphino- thioic acid (0.057g, 2.65 x 10 mol).

n.m.r. (60MHz) (phosphinate) 63.55 (d, Jpp=12Hz)n.m.r. (60MHz) (phosphinate + acid) 63.55 (d, Jpp=12Hz)

iii) The above was repeated with one equivalent of the acid being added to 98.5% Sp + 1.5% Rp phosphinate.The doublet of doublets formation at 63.55 could be clearly seen.

From these experiments it can be concluded that the methyl methylphenylphosphinate is greater than 98.5% Sp.

Alkaline Hydrolysis of Sp-Methyl Methylphenylphosphinate(2) in 60% H 2

To the phosphinate (0.085g, 5.0 x 10 mol) was added sodium hydroxide (0.06g, 15 x 10 mol), Hg^^O (0 .06g,33 X 10"^ mol) and H^^^O (0.15g, 75 x 10"^ mol). The reaction mixture was sealed in a reactor vial and heated at 100°C for 18 hours. The product was first extracted with dichloromethane to remove any unchanged methyl ester and by­products. Concentrated hydrochloric acid was added to con­vert the sodium salt to the acid, this being extracted with dichloromethane. Drying and removal of solvent gave labelled methylphenylphosphinic acid.

^H n.m.r. (60MHz) 61.56 (d, 3H, Jpp=l6Hz); 7.6 (m, 5H)and 11.2 (b s , IH).

n.m.r. (400MHz) (MeOH) +40.9673 p.p.m. (39%) (6636.7Hz)

-150-

+ 40.9344- p.p.m. (61%) (6631.4Hz) mass spec. m/e 158 (56%)

156 (44%)

Conversion of 1-Menthol into 1-Menthone^A solution of 1-menthol (15.6g, 0.1 mol) in ether

(40 cm^) was placed in a 250 cm^ round bottom flask fitted with a dropping funnel, stirrer and condenser. Chromic acid solution, prepared from sodium dichromate dihydrate (lOg, 0.034 mol) and 96% sulphuric acid (7.5 cm^, 0.13 mol, diluted to 50 cm^), was stirred at room temperature for 2 hours. The ether layer was separated and the aqueous layer washed with ether (3 x 25 cm^). The ether fractions were combined, washed with saturated sodium bicarbonate solution, water and then dried over magnesium sulphate. Removal of solvent and distillation gave 1-menthone, (10.9g, 70%) b.p.75 - 77°C at 5.0 mmHg. (lit. value, 66 - 67 C at 4 mmHg^^).

2950, 2860, 1705. 1150 and 1195 om"‘'h n.m.r. 50.9 (m , lOH); 1.35 (m , 2H) and 2.0

(m, 6H)

Conversion of 1-Menthone into, the Hydrazone^Barium oxide (pulverized) (3g) was placed in a solution

of freshly distilled hydrazine hydrate (4.5g, 0.09 mol) in ethanol (15 cm^). To this was added, dropwise with stirring, 1-menthone (10.8g, 0.07 mol), the resulting mixture being heated for 4 hours at 100°C. Ether (50 cm^) was added and the barium oxide filtered off. The product mixture was stored for 24 hours at -20°C over solid sodium hydroxide

-151-

pellets. Removal of solvents and distillation gave the hydrazone, (5.17g, 44%) b.p. 92 - 95^0 at 0.1 mmHg.

-1cmYmax. 3360, 2950, 2860, 1450 and 1380 H n.m.r. (001^) 60.9 (m, lOH); 61.65 (m, 8H) and

4.66 (b s, 2H)

Reaction of Methylphenylphosphinic acid with the Diazo- compound (11) formed from Hydrazone (10)^^

To a solution of silver oxide (4»36g, 0.0188 mol) and anhydrous magnesium sulphate (l.969g) in dried xylene (25 cm^) was added, at -25^0, the hydrazone (10) (2.26g, 0.0135 mol), formed from 1-methone. After approximately 20 minutes of stirring, keeping the temperature at -25°C, a pale red colour was observed which is attributed to the diazocompound (11). To the reaction mixture was added methylphenylphosphinic acid, produced by alkaline hydrolysis of the racemic phosphinate, a gas evolving. The reaction mixture was stirred for a further 15 minutes at -25^0 after which excess acetic acid was added to react with any excess diazocompound produced in the reaction. The silver oxide and magnesium sulphate were filtered off and the xylene evaporated off. The product mixture was taken up in di­chloromethane and washed with sodium bicarbonate solution, water and then dried over magnesium sulphate. The dichloro­methane was removed and flash column chromatography , using firstly pet. ether/ether (50/50) and then ether/methanol (95/5) as eluting solvents, gave a product (0 .049g) whose ^ n . m . r . chemical shifts point to it being a mixture of phosphinates.

-152-

n.m.r. (400MHz) (33% d methanol, 67% ether).Spectrum 1.

The above reaction was repeated using labelled phos­phinic acid, produced by alkaline hydrolysis of Sp-methyl methylphenylphosphinate.

P n.m.r. (400MHz) (33% d methanol, 67% ether).Spectrum 2.

As a control experiment, labelled phosphinic acid was produced from the Sp-ester by alkaline hydrolysis with the acidification being carried out at 0 °C with conc. HCl at pH ~1. The acid was extracted with GH^Cl^and immediately esterified, as above, with (11). The product, after purifiC' ation gave a ^^P n.m.r. spectrum identical to Spectrum 2.

Preparation of Methylphenylphosphinyl ChlorideTo methyl methylphenylphosphinate (15.2g, 0.089 mol)

in CCl^ (90 cm^) was added phosphorus pentachloride (19.8g, 0.095 mol) at such a rate as to keep the temperature below 40°C. The reaction mixture was stirred for 4 hours at room temperature after which time ^^P n.m.r. showed a reaction had taken place.

^^P n.m.r. +47.59 p.p.m. (84%) and -0.81 p.p.m.(16%).

Distillation gaye methylphenylphosphinyl chloride, (10.9g,) b.p. 128 - 134°C at 0.5 mmHg.

3 1P n.m.r. (CCI ) +46.59 p.p.m.^H n.m.r. (CClJ 62.14 (d, 3H, Jp%=15Hz); 7.5 (m, 3H)

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and 7.78 (m, 2H).

Preparation of Isomenthyl, Neomenthyl and Menthyl Methyl- phenylphosphinates

To a solution of methylphenylphosphinyl chloride in ether was added, dropwise at 0°C, a solution of pyridine and the releyant alcohol in ether. The acid is in approx­imately 15% excess. The reaction mixture was stirred over­night at room temperature. Filtration of pyridine hydro­chloride and removal of ether gave a colourless oil which on standing gave a crystalline solid, the phosphinate.

®^P n.m.r. study of reaction products of Methylphenyl­phosphinic acid with Diazocompounds (11)®^P n.m.r. of reaction products - Spectrum 1. (400MHz, 33%d^ methanol, 67% ether).+43.3057 p.p.m. (l); +43.1277 p.p.m. (2); +42.9948 p.p.m. (3); +42.7540 p.p.m. (4 ); +42.5488 p.p.m. (5); +42.3468 p.p.m. (6) and +42.0761 p.p.m. (7).

i) Addition of 1 equivalent of Rp-menthyl methylphenyl­phosphinate :Enhancement of signal (6).

ii) Addition of 1 equivalent of menthyl methylphenyl­phosphinate diastereoisomers:Enhancement of signals (2) & (6).

iii) Addition of 1 equivalent of isomenthyl methylphenyl­phosphinate diastereoisomers:Enhancement of signals (l) & (4).

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iv) Addition of 1 equivalent of neomenthyl methylphenyl­phosphinate diastereoisomers:Enhancement of signals (4) & (7).

N.B. Spectrum 1 run in diethyl ether resolves the over­lapping isomenthyl and neomenthyl signals.

Conversion of Methylphenylphosphinic acid to its sodium salt followed by acidification in the presence of H 2^®0

To methylphenylphosphinic acid (0.05g, 3.2 x 10 mol)was added 5M sodium hydroxide (0.02g, 5 x 10 mol in 0.1 cm^of HgO), followed by H2^®0 (0.2 cm^, 0.01 mol). The sodiumsalt was now acidified, at 0 C , by adding 5.4M HCl (0.1 cm^),the addition of this producing an acid solution of O.IMstrength, pH=l. The solution was left for 2 - 3 minutes at 00 C before the phosphinic acid was extracted with dichloro­

methane .The methylphenylphosphinic acid (0.35g, 70%) showed

no incorporation of when analysed by mass spectrometryand P n.m.r. spectroscopy.

mass spec. m/e 1563 1P n.m.r. (400MHz) (MeOH) +41*3224 p.p.m.

Preparation of Methyl Methylphenylphosphinate^To a solution of phenyl dichlorophosphine (300g,

1.676 mol) and pyridine (3.54 mol) in diethyl ether (900 cm^) was added, dropwise with stirring at 0°C, a solution of methanol (110.6g, 3.46 mol) in diethyl ether (50 cm^), over a period of 2 hours. After additional stirring for 1 hour the pyridine hydrochloride was removed by filtration and solvent removal on a rotary evaporator gave an oil.

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^ n . m . r . +158.7 p.p.m.

A small amount of the oil was added to a few drops of methyl iodide and the mixture warmed until a violent exo­thermic reaction occurred. The remainder of the oil was then added at such a rate as to maintain the temperature at ~100°C. Methyl iodide was added periodically to ensure a continuous reaction, Stirring was continued overnight, resulting in a thick brown oil.

3 1P n.m.r. +42.76 p.p.m.

Distillation gave methyl methylphenylphosphinate, (I36g,48%) b.p. 100°C at 0.5 mmHg.

^H n.m.r. (CClJ 61.5 (d, 3H, Jp%=15Hz); 3.44 (d, 3H,Jp%=12Hz); 7.36 (m, 3H) and 7.6 (m, 3H)

Methylphenylphosphinyl chloride was prepared from the above phosphinate, as before.

Preparation of Methylphenylphosphinothioic Chloride and conyersion to Methylphenylphosphinothioic acid ®

Phosphorus pentasulphide (33.34g, 0.15 mol) was added to methylphenylphosphinyl chloride (78g, 0.45 mol) and stirred for 5 hours at l60°C.

Distillation gave methylphenylphosphinothioic chloride, (i5g, 5 3 P b.p. 112 - 116°C at 0.1 mmHg.

n.m.r. (CCl^) +77.6 p.p.m.*H n.m.r. (CCl^) 62.4 (d, 3H, Jpjj=15Hz): 7.42 (m, 3H)

and 7.90 (m, 2H) .

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The chloride (45g» 0.236 mol) was added to a 15% solution of sodium hydroxide and stirred at room temperature upon which an exothermic reaction occurred. The solution was then refluxed for 2 hours. On acidifying with conc. HCl an oil separated out of solution. After separating the oil, the aqueous layer was extracted with benzene (3 x 50 cm®).The combined fractions plus the oil were dried over magnesium sulphate, evaporation of the benzene giving the desired product, methylphenylphosphinothioic acid, (36.6g, 89%).

® n . m . r . (001^) +80.27 p.p.m.n.m.r. (CClJ 61.85 (d, 3H, Jpp=15Hz); 7.22 (m, 3H);

7.74 (m , 2H) and 7.9 (s, IH, exchangeable in DgO).

Resolution of Methylphenylphosphinothioic acid ®Quinine was dried by azotroping with chloroform. To

a boiling solution of anhydrous quinine (0.213 mol) in acetone (1500 cm®) was added the thio-acid (36.6g, 0.213 mol), the solution being refluxed for 1 hour. Hot filtration gave a white solid, I. On cooling to room temperature a second fraction of crystals was obtained, II. Fraction II was recrystallised from acetone-methanol (5:2) to give fraction III. I and. II were combined and recrystallised (x3) from acetone-methanol (8:1) to give a white solid (4*65g), the quinine salt.

3 1P n.m.r. (CHOI ) +61.1 p.p.m.

To the quinine salt (0.64g) was added H^O (9cm^) and 2M3sodium hydroxide (1.5 cm ). Addition of chloroform produced

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two clear layers. The chloroform layer was separated and the aqueous layer extracted with chloroform. The aqueous layer was now acidified with conc. HCl, potassium chloride added and extraction of the thio-acid (0.28g) carried out with chloroform.

The thio acid was converted to the dicyclohexylamine salt by stirring at room temperature in a solution of di­cyclohexylamine (0 .316g, 1.75 X 10 mol) in diethyl ether.

[cij “ ^-10.23° (0 1.77) (Lit.value, -10.42°)[oij 5^8-9.55 °(o 1.77) (Lit.value, -9.55°)

The rest of the quinine salt was now converted to the dicyclohexylamine salt, (2.78g).

The Sp-enantiomer of the methylphenylphosphinothioic acid has been obtained as the dicyclohexylamine salt. A ^H n.m.r. study of the Sp-methylphenylphosphinothioic acid showed the enantiomer to be pure. A sample of quinine salt was taken from which there had been some Sp-enantiomer crystallised out. This was converted to the thio-acid.

^H n.m.r. 61.85 (d d , Jpp=15Hz, A6=2Hz)^H n.m.r. (Sp-enantiomer) 61.85 (d , Jpp=15Hz)

Estérification of the Dicyclohexylamine salt of Sp-Methyl- phenylphosphinothioic acid to Sp-S-Methyl Methylphenyl- thiophosphinate (3)

A solution of the dicyclohexylamine salt (2.78g,7.9 X 10“ mol) and methyl iodide (2.25g, 1.59 x 10 ^mol) in dichloromethane was stirred overnight at room temperature Filtration of dicyclohexylamine iodide and solvent removal gave (3), (l.4g, 97%).

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3 1P n.m.r. (CH Cl ) +46.8 p.p.m.iH n.m.r. (CClJ 61.82 (d, 3H, Jpp=12Hz); 2.08 (d, 3H,

Jpp=12Hz); 7.47 (m, 3H) and 7.70 (m, 2H)

Alkaline Hydrolysis of Sp-S-Methyl Methylphenylphosphinate(3) in 60% H2^®0, followed by Estérification with Diazo- compounds (11)

The alkaline hydrolysis was carried out on Sp-S-methyl ester (0.093g, 5 x 10"^ mol) using the same method as with(2). The acidification was carried out at 0°C with conc. HCl to pH *-1; the liberated acid being esterified straight away with the diazocompounds (ll), as previously.

®^P n.m.r. (400MHz) (33% d methanol, 67% ether)4

Spectrum 3.

Preparation of N-Hydroxy-methyl-phthalimide^®Finely pulverized phthalimide (20g, 0.136 mol) was

suspended in a solution of 40% formaldehyde (18 cm^), water (45 cm^) was added and the reaction mixture refluxed at 103 - 108°C for 4 hours. Filtration of hot mixture followed by cooling gave white crystals. The crystals were filtered, washed with water and dried. ^H n.m.r. showed the product to be N-hydroxy-methyl-phthalimide, (22.62g, 94%).

m.p. 142 - 145°C (Lit. value 142 - 145°C, Aldrich n.m.r.Vol. 7).

^H n.m.r. (dg D.M.S.O) 64-94 (d, 2H, J=7Hz); 6.32 (t,IH, J=7Hz) and 7.85 (s, 4H).

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Preparation of N-Bromomethyl-ph^ol imide ®N-Hydroxy-methyl-phthalimide (20g, 0.113 mol) was

stirred with 48% hydrobromic acid (38 cm®). Concentrated sulphuric acid (11.3 cm®) was added dropwise and the mix­ture was heated to 50°C for 2 hours. The thick suspension that formed was filtered and the solid washed first with water and then 10% ammonia solution. The white solid was recrystallised from acetone to give N-bromomethyl-phthali- mide, (I3.l6g, 49%).

m.p. 147 - 149°C (Lit. value.:: 148°C).n.m.r. (CCl^/d^ D.M.S.O) 64.92 (s, 2H) and 7.76 (s,

4H) .

Preparation of Methyl Diphenylphosphinite °A solution of chlorodiphenylphosphine (20g, 0.091 mol)

in diethyl ether (30 cm^) was added slowly to methanol (2.9g, 0.091 mol) and pyridine (7.2g, 0.91 mol) in diethyl ether (150 cm^), with cooling and stirring. The reaction mixture was stirred at room temperature for 30 minutes after which time pyridine hydrochloride was filtered offand ether removed to give an oil. Distillation gave methyl diphenylphosphinate, (11.Ig, 57%) b.p. 136 - I40 C at 0.4 mmHg, (Lit. value,^ 151 - 152°C at 10 mmHg).

^^P n.m.r. +116.1 p.p.m.^H n.m.r. 63.6 (d, 3H, Jpp=15Hz) and 7.27 (m,

lOHz).

-16 0 —

Preparation of Phthalimidouiethyldiphenylphosphine Oxide To a solution of N-bromoniethylphthalimide (7.2g,

0.03 mol) in dried xylene (150 cm®) was added methyl diphenylphosphinite (6.47g, 0.03 mol) in xylene (50 cm®).The reaction mixture was taken up to reflux and heating stopped 30 minutes after no more methyl bromide, white fumes, was produced. Methyl bromide was immediately removed as it was produced by flushing through with nitrogen and trapping in a 002/acetone bath. On cooling the reaction mixture a precipitate formed which was filtered off and recrystallised in dioxan to give phthalimidomethyldiphenyl- phosphine oxide, (5.25g, 71%).

m.p. 206 - 208°C, (Lit. v a l u e , 2O6 - 207°C).®^P n.m.r. (D.M.S.O./CCl^) +23.4 p.p.m.^H n.m.r. (d^ D.M.S.O.) 64.78 (d, 2H, Jpp=6Hz);

7.68 (m, 6H); 7.85 (m, 4H) and 7.95 (s, 4H).

Preparation of Diphenylphosphinyl-diazomethane (20)^

Phtalimidomethyldiphenylphosphine oxide (5.25g,1.45 X 10 mol), hydrazine hydrate (0.727g, 1.45 x 10 mol) and glacial acetic acid (1.746g, 2.9 x 10 mol) in methanol (20 cm^) were refluxed for 1 hour. After cooling to -5°C, a solid which had come out of solution was filtered off.The filtrate was evaporated down, the temperature not exceeding 30^0, and the residue was placed in water (15 cm/) and glacial acetic acid (l.75g). The solution was extracted with dichloromethane ( 3 x 5 cm/) to remove any unreacted phosphine oxide. The aqueous phase was added to dichloro-

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methane (10 cm®) and was stirred, at -5 C, with sodium nitrite (1.003g, 1.4-5 x 10 ^mol) in water (3 cm®) to diazotise.

After 1 hour at 0°C the organic phase was separated and the water layer extracted with dichloromethane. The combined organic layers were washed in turn with sodium bicarbonate and sodium chloride solutions and dried over sodium sulphate, Dichloromethane was evaporated leaving a yellow solid, diphenylphosphinyl-diazomethane, (l.4-5g,41%).

m.p. 59 - 6l°C (Lit. value, 6l - 62°C )3 1P n.m.r. (GDGl^/CCl^) +25.2 p.p.m.

n.m.r. (GDGl /GGl ) 64.05 (d, IH, J^„=12Hz); 7.50 (m,3 4 -t n

6H) and 7.70 (m, 4H).

Reaction of Diphenylphosphinyl-diazomethane (20) with Methylphenylphosphinic Acid

To a solution of diphenylphosphinyl-diazomethane (0.105g, 4.34 X 10” mol) in dired methanol (3 cm^) was added methylphenylphosphinic acid (0.4g, 2.56 x 10 ),the resulting solution being refluxed for 5 - 6 hours.The product was taken up in dichloromethane and washed with sodium bicarbonate solution and water and dried oyer magnesium sulphate. Evaporation of solvents gave a milky oil which on scratching in diethyl ether gave a white powder, diphenyl(phenylmethylphosphinyloxymethyl)phosphine oxide, (0.08g, 50%).

m.p. = 134 - 137°G

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mass spec. m/e 370, 201, 119.n.m.r. (xylene) +23.2 (d, Jp_p=29Hz) and +13.6 (d,

Jp_p=29Hz)n.m.r. 61.55 (d, 3H, Jp_p=HHz); 1.13 (d m,

2H, Jp_p=18Hz) and 7.3 (m, 15H)

Preparation of r-l-Chloro~2,2,t-3» 1>l-pentamethylnhosphetan 1-oxide ®

In a 500 cm^ round bottom flask fitted with a stirrer, condenser and dropping funnel, was placed dichloromethane (100 cm^), phosphorus trichloride (23g, 0.167 mol) and aluminium trichloride (22.2g, 0.167 mol). This mixture was cooled to between 0 - 10°C and 2 ,l,l-trimethyl-2- pentene (I8.67g, 0.167 mol) added over a period of 20 - 30 minutes, the aluminium trichloride dissolving as addition proceeded. After addition the reaction mixture was stirred for 1 hour at 0 - 10^0. Water (100 cm^) was now added dropwise keeping the temperature below 25°C. The organic layer was separated, washed with water and dried over magnesium sulphate. Evaporation of solvent gave a white solid which was recrystallised from dried petroleum ether (60-80 0) to give r-l-chloro-2 ,2, t-3 , , /.-pentamethyl- phosphetan 1-oxide (13.54-g, 42%).

m.p. 70 - 73°C (Lit. value = 74 - 75°C=*)^^P n.m.r. +76.2 p.p.m.“h n.m.r. ^0.92 (d d, 3H, J=9Hz, J__y=2Hz);

1.39 (a, 6h , Jp_jj=23Hz): 1.45 (d, 6H, Jp_H”22Hz) and 1.73 (a, IH) 1250, 1215, 1170, 660 and 635 cm"‘

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Preparation of l-Methoxy-2,2,t-3t4 >4~pentamethylphosphetan 1-oxide

r-l-Chloro-2,2,t-3,4 »4-pentamethylphosphetan 1-oxide (l.Og, 5.14 X 10” mol) in methanol (5 cm^) was added slowly at O^C to a mixture of sodium (0.149g» 6.5 x 10 ^mol) in methanol (10 cm^). The resulting solution was heated to 50 - 60°C for 1 hour. Methanol was evaporated, the residue taken up in dichloromethane and washed with water. Drying and evaporation of solvent gave a colourless oil, l-methoxy-2,2,t-3,4,4-pentamethylphosphetan 1-oxide, (0.81g,

).

^^P n.m.r. (MeOH) +60.7 p.p.m.n.m.r. 60.97 (d d, 3H, J = 8Hz, Jp_jj=2Hz) ;

1.0 (m, IH); 1.26 (d, 6H, Jp_p=18Hz); 1.30 (d, 6H, Jp_p=20Hz) and 3.87 (d, 3H, Jp_p=10Hz)

Conversion of r-l-Chloro-2,2,t-3,4>4-pentamethylphosphetan 1-oxide into l-Methoxy-2,2,3,4,4-pentamethylphosphetan 1-oxide via the Acid

To a solution of the chloro-phosphetan oxide (O.lg,5.14 X 10” mol) in dioxan (5 cm^) was added, dropwise at 0 0, sodium hydroxide (0.076g, 1.9 x 10 mol) and water (0.108g, 6.0 X 10"^ mol) in dioxan (5 cm^). After stirring at room temperature for 30 minutes, dioxan and water were removed on a rotary evaporator to give a white powder. The white powder, the sodium salt, was taken up in water (5 cm^) and acidified with dilute hydrochloric acid. The "freed" acid was extracted with dichloromethane, (0.04g, 45%).

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n.m.r. 54.6 p.p.m.*H n.m.r. SO.9 (d, 3H, J=6Hz); 1.23 (d, 6H,

Jp_g=18Hz): 1.27 (d. 6H, Jp_jj=18Hz):1.65 (m, IH) and 10.95 (s, IH) .

Diazo-methane was now prepared from a diazald solution, (N-methyl-N-nitroso-p-toluenesulphonamide). As the diazo- methane was produced in an ether solution it was distilled into a solution of the acid in ether at 0°C. A vast excess of diazo-methane was added and this was left to evaporate overnight. Solvent was removed to give l-methoxy-2,2,3,4,4- pentamethylphosphetan 1-oxide.

n.m.r. +54.2 (56%) and +55.5 p.p.m. (44%)

To the above ^^P n.m.r. sample was added l-methoxy-2,2,-t- 3,4,4-pentamethylphosphetan 1-oxide.

3 1P n.m.r. +54.2 (24%) and +55.5 p.p.m. (76%)

Alkaline hydrolysis of r-l-Chloro-2,2,t-3,4,4-pentamethyl- phosphetan 1-oxide in 60%.H2^^0, followed by Estérification with Methyl Iodide^

To a solution of the chlorophosphetan oxide (O.lg,5.14 X 10 * mol) in dioxan (5 cm^) was added KOH (0.084g,15 X 10‘“ mol), n y ^ O (0.06g, 33 x 10"'* mol) and h / ^ O (0.15g, 75 X 10” mol), the reaction mixture being stirred at room temperature for 30 minutes. The product was taken up in water and acidified to pH ~1 using 2M hydrochloric acid. The potassium salt of the acid and potassium chloride were now isolated as a solid by evaporating off water and dioxan.

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The solid was partitioned in dioxan and 1 equivalent of 18-crown-6 ether (relative to K"*” ions, 15 x 10 mol) was added to the mixture, at which point all the solid dissolved due to complex formation. The dioxan was evap­orated off and the complex dried by addition of dry dioxan and evaporation (x3). The complex was now dissolved in D.M.S.O. (1.5 cm^) and excess methyl iodide added. The flask containing the reaction mixture was covered in silver foil and stirring was carried out at room temperature for 1 hour after which time estérification had taken place.

n.m.r. (400MHz) (D.M.S.O.)Spectrum 4.

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REFERENCES1. C.R.Hall and T.D.Inch, Tetrahedron, 1980, _36, 2059.2. F .H .Westheimer, Acc. Chein. Res., 196f, 1, 70.3. J.M.Harrison, T.D.Inch and G.J.Lewis, J. Chem. Soc.,

Perkin Trans. 1, 1974, 1053.4. M .J .P .Harger, Chem. Commun. 1976, 520.5. T.D.Inch, G.J.Lewis, R .G .Wilkinson and P.Watts, Chem.

Commun., 1975, 500.6. W.S.Wadsworth, S.Larsen and H.L.Horton, J. Org. Chem.,

1973, J8, 256.7. 0.Korpiun,R.A.Lewis, J.Chickos and K.Mislow, J. Am.

Chem. Soc., 1968, 9_0_, 4842.8. G.Lowe, B.V.L.Potter, B.S.Sproat and W.E.Hull, Chem.

Commun., 1979, 733.9. K.E.Bruin and D.E.Perrin, J. Org. Chem. 1975, 4G, 1523.

10. M.J.P.Harger, J. Chem. Soc., Perkin Trans II, 1980,1505.

11. H.C.Brown and C.P.Garg, J. Am. Chem. Soc., 1961, 83,2952.

12. V.K.Heyns and A.Heins, Annalen, 1957, 604. 133.13. S.Trippett, Phosphorus Sulfur, 1976, 1, 89.14. H.J.Bestmann, J. Chandrasekhar, W.G.Downey and

P .V.R.Schleyer, Chem. Commun., 1980, 978.15. M.Green and R.F.Hudson, Proc. Chem. Soc., 1962, 307.16. P.Haake, C.E.Diebert and R.S.Marmor., Tetrahedron Lett.,

1968, 5247.17. D.E.Applequist and H.Babad, J. Org. Chem., 1962, 22,

288.18. A.Ratajczak, Roczniki Chem., 1962, 26, 175; Chem. Abstr.,

1962, 22, 15147f.

-167-

19. H.P.Benschop and G.R.Van Den Berg., Rec. Trav. Chim., 1968, 87, 362 and 387.

20. M.J.P.Harger, J. Chem. Soc., Perkin Trans II, 1978,326.

21. T.D.Inch and G.J.Lewis, Carbohydrate Res., 1975, 45,65.

22. R.S.Marmor and D.Seyferth, J. Org. Chem., 1971, 36,128.

23. G.W.Pucher and T.B.Johnson, J. Am. Chem. Soc., 1922,44, 817.

24. I.C.Popoff, L.K.Huber, B.P.Block, P.D.Morton and R.P.Riordan, J. Org. Chem., 1963, 28.» 2898.

25. M.Regitz, M.Martin and W.Anschutz, Annalen, 1971,748. 207.

26. E.Jungermann and J.J.McBride, J. Org. Chem., 1962, 27,606.

27. J.R.Corfield and S.Trippett, Chem. Commun., 1971, 721.28. J.R.Corfield, R.K.Oram, D.J.H.Smith and S.Trippett,

J. Chem. Soc., Perkin Trans I, 1972, 713.29. G.Lowe, R.L.Jarvest and B.V.L.Potter, J. Chem. Soc.,

Perkin Trans I, 1981, 3186.30. A.E.Arbusov and K .V.Nikonorov, J. Gen. Chem. (USSR),

1948, 18, 2008; Chem. Abstr., 1949, 43, 38011.31. R.K.Oram and S.Trippett, J, Chem. Soc., Perkin Trans I,

1973, 1300.

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AbstractMechanism and Stereochemistry of Some Reactions of IV- and V- Co-Ordinated Phosphorus Compounds by C.L.White

A series of cyclic phosphoranes and spirophosphoranes have been prepared and reacted with diethyl phosphorochlor- idite, the phosphorane acting as a nucleophile, and the sub­sequent products reacted further with methyl iodide and chloral. Reactions have also been carried out in which a

. nucleophilic attack on the phosphorane occurs, the nucleo­phile employed being the anion of thio-phenol. It was hoped these reactions might provide a new pathway to the type of phosphorus compound which have been involved for a number of years in the control of p e s t s a n d that an insight into the stereoelectronic requirements of reactions at phosphorus might be obtained.

The mechanism of the Michaelis-Arbusov rearrangement is generally accepted as having a two stage pathway, the second:stage usually considered as being an SN2 attack of a nucleophile on the a-carbon of an alkyl group. Arbusov and related reactions with unsymmetrical phosphites contain­ing different alkyl groups have been carried out. The effect of varying the electrophile, nucleophile, temperature and solvent of the reactions has been studied. As a result of the above, the second stage of the generalised Arbusov reaction is found to have SNl character.

The stereochemistry of nucleophilic substitution at phosphoryl centres has been studied extensively by a number of groups. However, it has not hitherto been possible to investigate the stereochemistry of hydrolyses since these lead to achiral acids. A general method, involving isotopic labelling, has been developed that allows the stereochemistry of such hydrolyses to be established. The stereochemistry of the alkaline hydrolyses of Sp-methyl methylphenylphosphinate OfA

raethylphenylthiophosphinate have been established using the method referred to above.