SOME NEW REACTIONS

OF RHOSRHONATES

BY

DASHAN LIU

A Thesis presented for the Degree of Doctor of Philosophy, in the Faculty

of Science of the University of Leicester

1983

ProQuest Number: U341650

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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 April 1980 and March 1983.

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

A summary of chapter 2 of this thesis has been published in Tetrahedron Letters, pp 2039 - 204-0, 1983.

ACKNOWLEDGEMENT

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 my fellow research workers, the staff and technicians of the Department of Chemistry for their advice and assistance, and Mrs. J. Lee for typing this thesis.

I would like to thank Dr. P. Cairns for his help in the preparation of this thesis.

I would like to thank the Chinese Government for the provision of a maintenance grant.

I would like to thank Professor Bingfâng Hu and my parents for their encouragement. Finally, I would like to thank my dear fiancee Kerlia for her great understanding and support.

The following abbreviations have been used in the text that follows :

0® (EtOjgPTHF TetrahydrofuranDMF N,N-DimethylformaraideLDA Lithium diisopropylamineMCPBA m-Chloroperoxybenzoic acid

CONTENTS

Page No1. The Chemistry of a-ketophosphonates and

Derivatives. 11.1 Review 11.2 The Chemistry of 1,3-diketoalkylphosphonates 101.3 The imines of a-aminophosphonates I. The

synthesis of pyridyl-2-phosphonates 171.4. The imines of a-aminophosphonates II.

1,3-Dipolar and anionic cycloadditionreactions * 28

1.5 Acylphosphonates. ’Ene’ reaction. Carbene intermediate? 4-3

1.6 The Chemistry of 1-(diethoxyphosphinyl)-vinyl phosphate 4-8

2. The ortho-.Lithiation of N,N,N ’ ,N ’-tetramethyl- phenyl phosphonic diamide 55

3. Trapping the Pummerer reaction intermediate 67

4.. Experimental details ' . 73

References 95

CHAPTEIR1

THE CHEMISTRY OF a-KETOPHOSPHONATES AND DERIVATIVES

1.1, ReviewThe Michaelis - Arbusov reaction is probably one of the

best understood and most widely applied reactions in organo­phosphorous chemistry;^ Scheme 1.1.

1 2 3RoPOR + RX n\f-R X®V ■

lu 3 2RjPR + RX

1 2 3R= alkyl,aryl.alkoxy etc; R = alkyl; R = alkyl,acyl;

X= I,B r,C l.

Scheme 1.1

Among the different types of product obtained from theMichaelis - Arbusov reaction, dialkyl a-ketophosphonates are

2the most readily prepared; Scheme 1.2.

° <50°C ^ 9 , .(RO).P + R'CX ► © -C R RX

R = alkyl; R = alkyl,aryl; X = Cl, Br.

Scheme1.2

Since they possess a carbonyl group and allow many variations of R ' to be present, a-ketophosphonates are ideal substrates to be used for the synthesis of a wide range of organophosphorus compounds. Not suprisingly, a great amount of work has already been done on the chemistry of the

-1-

a-ketophosphonates and their derivatives.Spectroscopic methods have been used extensively to

study various a-ketophosphonates. Although both dipole moment and n.m.r. data do not confirm the existence of the prefered conformation,^ certain a-ketophosphonates have been stated to prefer the conformation in which the C=0 and P=0 dipoles point in opposite directions with negative oxygen atoms as far apart as possible, as is also the case in a-dicarbonyl compounds;^ Scheme 1.3.

0II-OR

Scheme 1.3

On the other hand, in order to explain the infra-redabsorption of the carbonyl group in the a-ketophosphonates,which is 10-15cm"^ less than that for the carbonyl functionin the corresponding aldehydes and means that the carbon-oxygen bonds have a greater degree of single bond character,K.D.Berlin and co-workers suggested a conformation in whichmaximum overlap of the filled nonbonding orbital on oxygenof the phosphoryl group with the tc- orbital of the carbon

5atom of the carbonyl group could be achieved; Scheme 1.4-.

OR

Scheme 1.4

-2-

A study of the ultra-violet absorption of a-keto­phosphonates led to a similar conclusion.^

The chemical properties of a-ketophosphonates have been widely investigated. M.I.Kabachnik and co-workers demonstrated that the carbonyl function of a-ketophosphonates exibited a considerable reactivity analogous to that shown by a-keto- carboxylates, trichloromethyl ketones and other substanceswith an electron withdrawing group adjacent to the carbonyl

7function. Some carbonyl derivatives were prepared; Scheme 1.5. .

-H^O _ ^NHPh © -C M e + NH,NHPh ® -C M e

0II

OH

© -C M e + NaHSOg ► © -C M e

SO^Na

O 0 OH_ W CN H2O ^ I© -C M e + HON ------ ► © -C M e

CN

Schemel .5

Although there are many similarities in chemical behaviour between a-ketophosphonates and their carbon analogues as far as the carbonyl function is concerned, a noticeable difference is that the a-ketophosphonates can be hydrolyzed to carboxylic acids and dialkyl phosphite; in this sense, the dialkoxyphosphinyl group plays the same role as halide and alkoxy group in acyl halide and alkyl carboxylate

-3-

respectively. K.D.Berlin and co-workers investigated thecarbon - phosphorus bond cleavage of the a-ketophosphonatesupon acid and base catalyzed hydrolysis and found that thebase catalyzed reaction was considerably more rapid than theacid catalyzed one. The reason for this difference was givento be that the protonation of the phosphoryl group was ahighly unfavourable process since the development of apositively charged phosphorus attached to a carbonyl function

8would require considerable energy; Scheme 1.6.

€) H O n , ©o n ^ (RO)oP— C-R (ROIoPH + RCO^H + H

(ROl^P-C-R-^ G O ® 0 0M l II HoU II

^ (R O ) ,P -C -R ' -------► (ROljPO—^ (ROljPH6 h

R'COjH OH

Schemel .6

Many synthetically valuable reactions have been carried out on the a-ketophosphonates. As with aldehydes and ketones, a-ketophosphonates react readily with ammonia derivatives. Considerable attention has been paid to the preparation of a-aminophosphonates from the a-ketophosphonates, as the former can be hydrolyzed to a-aminophosphonic acids, which being analogues of a-aminocarboxylic acids are biologically active

9in some cases. The a-aminoarylmethylphosphonate was obtained by reduction of the corresponding oxime with aluminium - amalgam, whereas the more effective way to prepare a-aminoethyl phosphorate was reduction of the 0-methyloxime with diborane;^^

-4--

Scheme 1.7.

0 NOM NH;© -C A r + NHoOH ► © -C A r ► ©-CHAr

A l-H g

0 NOMe NH;©-CM e + NH,O M e ►©-CMe ►©-CHMe

Scheme 1.7

Hydrogen bonding of the oxime -OH to the phosphoryl oxygen was observed in the aroylphosphonate oximes; it causes the infra-red absorption of the phosphoryl group to move to longer wavelengths (1214 - 1252cm“ ) than the corresponding dialkyl aroylphosphonates (1250 - 1300cm’" ) Scheme 1.8.

/ O HN b II II

^ — C---P(0Et)2

Scheme 1.8

The decomposition of some phosphinyl substituted diazo-methanes has been studied. Base-induced decomposition ofp-toluenesulphonylhydrazone derivatives of the a-ketophospho-,nates led to dialkyl a-diazoalkylphosphonates which underwent

12various reactions via carbene intermediates; Scheme 1.9.

-5-

0II

X C H g C © + p-MeCgH^SOzNHNH-

XCH=CH® X C H ,C ©Cu

Scheme 1.9

NNHSOgCgH^Me-p -►XCHjC® + H^O

NQ2CO2 HjO

©X C H ,C ©©

When aroylphosphonates were treated with hydrazoic acid, Schmidt rearrangement occured to give predominantly aryl migration products. However, when R=MeO-, the diethoxy­phosphinyl migration product increased considerably;Scheme 1.10.

13

0 © NNo 11 ^

p-RCgH^C© + HN3 ►Ip-RCgH^C©) ► [p-RCgH^CEN©)]

. 1© 0lp-RCgH^N=C] [p-RCgH^NEC©! p-RCgH;CONH©)

p-RCgH^NHCHO

R =Cl,MeO.

p-RCgH^NHCO ©

Schemel.10

Some other rearrangements involving migration of the diethoxyphosphinyl group have been investigated, such as the Baeyer - Villiger oxidation of dialkyl aroylphosphonates;^^ Scheme 1.11.

-6-

0 r Oy-H ..A rC © ♦ PhCOjH ► A r C © ► A rC O ^ + PhCOjH

O^^pCOPh

Scheme 1.11

It was suggested that the high migratory aptitude of the diethoxyphosphinyl group was due to overlap of the occupied "non-bonding" p-orbital of the oxygen with the d orbitals of the phosphorus. Another example of the migration of the diethoxyphosphinyl group was the reaction of aroylphosphonates with diazomethane resulting in aroylmethylphosphonates;^^ Scheme 1.12.

0ArCCHg

00 CH2N2 r

A rC © ------- ► A rC ©

% Scheme 1.12

In both cases, the results did not alter even with Ar=p-MeOC^H^ which is known to migrate very rapidly in

16various ’carbonium ion’ type rearrangements.Vinylphosphonates can be obtained readily from

17a-ketophosphonates via the Wittig reaction; Scheme 1.13

0 CHt'l ‘2© C -R + Ph3P=CH2 ► © -C -R

Scheme 1.13

- 7 -

p-Nitrovinylphosphonates were prepared by nucleophilicaddition of nitro group stabilized carbanions to a-keto-

18phosphorates followed by dehydration; Scheme 1.14»

® Æ . R . RtH^NO, ^ ® - ? ”c HRO;-ÏÎ22.R R' «

Scheme 1.14

a-Ketophosphonates have been used in some syntheses ofdialkoxyphosphinyl substituted heterocycles, e.g. o-methoxy-benzoylphosphonate gave a dihydrobenzofuran upon treating

19with triethyl phosphite Scheme 1.15 shows the suggestedmechanism,

0 ©

V ^ O M e V ^ O M e X ©

(Et0)3P=0

./V - C H ^ - P ( O E t ) -

Scheme 1.15

Another example is the reaction between diethyl20phosphorisocyanatidite and a-ketophosphonates; Scheme l.l6

0 (EtO),PNCO + R C ®

lEtOl^PNCO -©R -C -0

I©0 EtII I

EtOP-

+

EtOP-N

^ P - N = C = 0EtcT|

0 -C -R

©

Scheme 1.16

a-Ketophosphonates have been employed in many organicsyntheses other than the preparation of phosphorus compoundsAldehydes were obtained by reducing the a-ketophosphonates

21with sodium borohydride and subsequent hydrolysis;Scheme 1.17.

_ 9, NqBH _ 9 *^ OH®© -C -R S- © -C H R RCHO

0(EtO)PH

Scheme 1.17

Dialkyl a-ketophosphonates can be used as acylating agents.

The Takanrizawa reaction involves acylation by 22a-ketophosphonates; Scheme 1.18.

-9-

0I® ©CPh

CH-CPh

DBU

Scheme 1.18

Apart from those described above, there are still many chemical aspects of the a-ketophosphonates not mentioned in this brief review. Considering the great variety of reactions which the a-ketophosphonates and derivatives could undergo, further investigations would be worthwhile.

1.2. The chemistry of 1,3-diketoalkylphosphonates Introduction

It is mentioned in the review that a-ketophosphonates react readily with ammonia derivatives and the resulting adducts can be subjected to various transformations. One such transformation is to use the nitrogen-containing phosphonates as a synthetic block to prepare phosphinyl substituted heterocyclic compounds.

1,3-Dicarbonyl compounds have long been used to prepare various heterocycles especially five membered cyclic compounds containing two hetero-atoms. Some examples are outlined in Scheme 1.19.

-10-

- 2 H ,0 „CHglCHO); + NHgNH; ---- ^

H

- H 2OEtOnCCHgCOR + NH2NH2 ---------^ // \V

-EtOH H O ^ n^H H

- 2 H 2ORCOCHjCOR + NHjOH ----- ^ f\,

R ^ c r

B O ,0:H,COR . NH,OH ^ — H O ^

Scheme 1.19

The treatment of some carbonyl compounds particularly1,3-dicarbonyl species with formamidine disulphide in the presence of a weak base resulted in highly functionalized thiazoles; Scheme 1.20.

RCOCH,CO,E, . Ç J > s ) ^

base

EtO 2(1.1 )

Schemel. 20

Some phosphinyl substituted heterocycles have been prepared using 1,3-dicarbonylphosphonates. M.H.Maguire and co-workers used diethyl ethoxycarbonylacetylphosphonate

-11-

(1.2) to prepare 3-phosphinylpyrazolone and uracll-6-2 /phosphonic acid; Scheme 1.21.

0 0 ( g l

©CCH^COEt + NH^NHPh ------------ HnC X (7.6%)(1 .2 ) N u

(1.2) + NHgCONHg— — ► . I. . (23%)

(1.3)0(H0)2F ,jÿÿ \j./

* H N . ^ HII 0

(1.i)Scheme 1.21

In both cases, poor yields were obtained.The use of 1,3-diketoalkylphosphonates in heterocyclic

syntheses has now been further explored.

ResultsAs with ethyl acetoacetate, diethyl ethoxycarbonyl-

acetylphosphonate (1.2) is a highly functionalized species which could, in principle, undergo various reactions at the carbonyl, methylene and carboxylic ester groups. However, the poor yield of (1.3) prevents the preparation from being considered as a successful one. As mentioned in the review, a-ketophosphonates can be easily hydrolyzed to dialkyl phosphite and carboxylic acid in basic conditions. It was

acknowledged that the ester (1.2) was particularly unstable25in hydroxylic solvents in the presence of base. Re­

examining the reaction was of interest.

-12-

When (i.2) and methylhydrazine were mixed in absoluteethanol or THF at room temperature, decomposition of (1.2)

31occurred rapidly; P n.m.r showed only the signal of diethyl31phosphite, +7.4ppm. However, a P n.m.r signal, +11.5ppm,

appeared when the reaction was carried out in the presence ofacetic acid. The amount of diethyl phosphite decreased asthe percentage of acetic acid increased in the reactionmixture. The best result was obtained when glacial acetic

31acid was used solely as solvent; the only P n.m.r signal observed was +11.5ppm. In contrast to (1.3), the isolated product gave neither carbonyl nor N-H absorptions in the IR spectrum. ^H n.m.r showed the integrations of the ester protons to be much more than they should be in the structure (1.5); Scheme 1.22,

, MeNHNHj (1.2) -

Schemel. 22

DH

%The combination of IR, H n.m.r and mass spectra, which gave a molecular ion at 262, indicated the structure of the product to be l-methyl-3-diethoxyphosphinyl-5- ethoxylpyrazole (1.6).

■ N ^ E t

Me(1.6)

-13-

(75 %)

A long time ago, F. Stolz reported a similar result in which elimination of water rather than elimination of ethanol

26is preferred under acidic conditions; Scheme 1.23.

MeCOCMgCOgEt + PhNHNHj -

Me

dil. H2SO4

neat

M e ,

Ph

Scheme 1.23

The rapid decomposition of (1.2) in the reaction mixture without acid might be via a ketene intermediate as outlined in Scheme 1.2J+,

0(0^vCH-CO,Et -----h *. o^C^H-COgEt— "-MeNHNHCCHzCOzEt

^ N H M e -NH^NHMe

Scheme 1.2^although the methylhydrazide was not isolated.

In literature, thiazoles (l.l) were prepared where27methyl, phenyl and m-nitrophenyl. However, replacement

by an electron withdrawing group such as diethoxyphosphinyl might give similar results.

The diethyl ethoxycarbonylacetylphosphonate (1.2) was mixed with equimolar amounts of formamidine disulphide and

—14- —

sodium acetate in absolute ethanol at room temperature;31after overnight stirring, P n.m.r showed one signal at

+7.1ppm. The product was isolated as nice crystal; its 1H n.m.r was as expected - a simple spectrum. Two exchange­able protons at Ô6.5 ppm are for the amino group attached to an aromatic ring. Mass spectrum gave a molecular ion at 308 along with m/e 235, 171 representing loss of ethoxy- carbonyl and diethoxyphosphinyl groups respectively. IR showed a broad band at 3300cm"^ for the amino group and l690cm~^ for the conjugated ester carbonyl group. Considering all these spectroscopic data, the structure of the product can be determined to be 2-amino-/-diethoxyphosphinyl-5- ethoxycarbonylthiazole (1.7); Scheme 1.25.

©COCH^COzEt ^ ---- " i t . (82%)/ 2B? E tO g C -^ s ^ H z

(1.7)

Scheme 1.25

The mechanism of this reaction, although not proposed2 8by the earlier reporters, is probably as outlined in

Scheme 1.26.

-15-

©CO CH,CO jEt --------- ► ©COCHCO,Et

,1.71 - = -

" % , O A g

Scheme1.26

Another 1,3-dlketoalkylphosphonate investigated was diethyl bromoacetoacetylphosphonate (1,8), which was prepared by bromination of diketene and subsequent Michaelis - Arbusov reaction; Scheme 1.27.

(EtOlsP „0 p

+ Brg------► BrC O C H jC XH jB r— ^^©CCHgCCH^Br

(1.8)

Scheme 1.27

When (1.8) was treated with methylhydrazine in aceticacid, two signals, +9.7, +/.7ppm, with equal intensity were

31observed in the P n.m.r spectrum. Separation by TLC led to two phosphorus containing products with almost identical

n.m.r spectra. However, mass spectra revealed that the31 1product, P n.m.r +9.7ppm, contained bromine, M 311/313,

31whereas the other one, P n.m.r +/..7ppm, did not contain +bromine, M 232. The former is clearly a five membered hetero

cycle : l-methyl-3-diethoxyphosphinyl-5-bromomethylpyrazole(1.9), but the structure of the latter (l.lO) is not clear; Scheme 1.28.

-16-

0 0 (g^

©CCHgCCHgBr + NH^NHMe ► + (1.10)

(1.8) % K : H 2 B rWe

(19)

Scheme 1.28

1.3 The imines of g-aminophosphonates I, The synthesis of pyridyl-2-phosphonates

IntroductionApart from the synthesis of five membered heterocycles,

the synthetic value of the nitrogen derivatives of &-keto- phosphonates in the preparation of pyridylphosphonates has been investigated.

Pyridylphosphonic acids and esters were prepared previously through several methods; Scheme 1.29.

-17-

0? . . P C I j W t O A c

BF/, 2.H2O S i ^ '1/°'

MezSO/,R

00

©,.© BF4 CPhi

0II

NaP(0R')2

*j© MeOSOa OMe

0NaP(OPr).

(OR').Ref,30

PlOPr);

(28-53%) Ref.31

M e T ^ ® M eOMe

0LiP(OEt).

H 3PO3

Ref.32

(25-28%) Ref.33

9 (30%) Ref.31N ^ ( 0 H ) 2

Scheme 1.29

A new method developed recently involves the reaction ofO c

phosphonate carbanion (l.ll) and vinamidinium salt (1.12). Pyridylphosphonate (1.13) was obtained in good yield;Scheme 1.30

-18-

dioxane No (1.11)

©(1.12)

(71%)(1.13)

Scheme 1.3036The chemistry of vinamidinium salts has been reviewed.

The mechanism of the reaction above is generalized as outlined in Scheme 1.31.

-MeoNH

-M e 2 N H

R y Y y f ^

Y Z = C,N; XzCI.CtO^: R z CO^R.CN.Betc;

R = alkyl,aryl etc.

Scheme 1.31

Since both Y and Z can be nitrogen, there are two ways of preparing pyridines. As an alternative to the preparation of pyridyl-3-phosphonate outlined in Scheme 1.30, pyridyl- 2-phosphonate (1.14-) might be synthesized using Schiff base (1.15) and vinamidinium salt (l.l6); Scheme 1.32,

-19-

+ Me2Ni^V^^^Me2 R e

<1.15) (1.16) (1.14)

Sdieme1.32

The Schiff base (1.15) was obtained by the condensation37of aldehyde and aminomethylphosphonate (1,17). As it is

mentioned in the review, the aminomethylphosphonate might be prepared by reduction of the oxime of formylphosphonate (1.18); Scheme 1.33.

0 NOH© -C H + NHgOH -------► © -C H 7 i5 ^ © -C H 2 N H 2

(118) (1.17)

Scheme 1.3 3

In practice however, (1.17) was obtained by the route3 Qoutlined in Scheme 1.34.

PhCH2l } T ^ C H 2Ph © Hkfg3 ------" |PhCH2N=CH2l ►PhCH2NHCH2©

I H2/Pd jHO Ac

(117)Scheme 1.3 4

ResultsDiethyl N-benzylideneaminomethylphosphonate (I.15a) was

prepared by condensing (1.17) with benzaldehyde; Scheme 1.35

— 20 —

© C H 2NH2 +

(1.17)

PhCHO“H2O

(1.15a)

Scheme 1.35

Equimolar amounts of (l,15a), vinamidinium salt (I.I6)and sodium hydride in dioxane were heated under reflux while 31P n.m.r spectroscopy was used to monitor the reaction progress. Results are outlined in Scheme 1.36.

dioxane

1.14 R %0 H 70b Ph 65c Cl -d Br -

CIO,0

31

Scheme 1.36

In the preparations of (I.14a) and (I.14b), a single P n.m.r signal, +9.2ppm, was observed after 24 - 36hr.

refluxing. Distillation or column chromatography led to viscous oils which gave the expected n.m.r spectra.

The mass spectrum of (l.l4a) showed the fragmentationpattern resembling that reported by D. Redmore; 39 Scheme 1.37

-21-

155

218 291(M 1247

262

m /e

Lpif%l^(OEt)JcCHoCHO

OHOEt->247

Ph' PhOH'-OEt.

PhLPK -HPO155

Scheme 1.37

Hydrolysis of (l,14.a) and (1,14-b) in 18% hydrochloric acid gave crystalline compounds which had high melting points and poor solubility in various solvents due to intramolecular salt formation.

R

0H

-22-

(l.l^c) and (1.14-d) were formed in less than 10% yields31 31which were seen from P n.m.r spectra. The P n.m.r signal

of (I.15a), +19ppm, kept nearly constant intensity evenafter adding excess sodium hydride and long time refluxing.The reason for the poor yields may be due to the formationof pyrrole (1.19);^^ Scheme 1.38.

Ç Me ^ R

fl'VeNa H ^ Me

R>

R = Cl.Br. \Me

Scheme 1.38

VHe

(1.19)

-MejNH

However, most of vinamidinium salts (l.l6c) and (l.l6d) were recovered after working up, whereas no (1.19) was isolated.

To extend the synthesis of pyridyl-2-phosphonates, the preparations of the Schiff base (I.15b) and (I.15c) were attempted.

Scheme 1.39 shows the reaction employed in the attempted preparation of (I.15b).

© C H 2 N H 2 + 0 H C C 0 2 E t ^ (E K ^ N ^ ^ ^ O g E t

(1.17) "'^2° (1.15b)Scheme 1.39

-23-

Distillation of the reaction mixture gave a pale yellowoil which did not give the expected n.m.r spectrum;there was no signal appearing at low field due to the olefinic

31proton. P n.m.r showed a complicated spectrum.The route envisaged to prepare (I.15c) was to oxidise

the secondary amine (1.20); Scheme 1.4-0.

oxida.(1.20) (1.15c)

Scheme 1.^0

It was reported that (1.20) could be prepared in 15% yield in a simple procedure Scheme 1.4-1.

0 2 (EtOjgPH + NH3 aq. + 2 CH2O ► HN[CH2© l2+N[CH2© l3

(1-20)

Scheme 1A1

However, no (l.20) was found in the products when the reaction was carried out; instead, a large amount of tertiary amine (l.2l) was isolated. The possible mechanism for its formation is outlined in Scheme 1.4-2.

-24“

((E)CH2l2NH + CH 2O ^ l©CH2]2^CH^0H

-OH®

l®CH2l2NCH3 ------ [®CH2l2^CH2 H^ ^GH11.211'22' '' *3 i\!y^n2i2^y^^2

Scheme 1.42

(1.20) was eventually obtained by de-N-tert-butylation of ( 1 . 2 2 ) Scheme 1.43.

t 9 t F3CCO2HBuN=CH2 + CH2 O + 2(EtO)2PH------ ►BuN[CH2®)2— ^^[©CHjJzNH

(1.22) (1.20)Scheme 1.43

There have been many investigations on the conversion of secondary amines into imines; most of them involveintroducing a leaving group onto the nitrogen followed by

43P-elimination. Several such reactions for the préparât;of (l.l$c) were investigated; Scheme 1.44.

-25-

1. (1.20) CINICH;©);

2. (1.20)

3.(1.20)

BuOCI

0PhSCl »EtgNether

NaOEt

g\ BuOK

TCIO/®

0II

P hSN tC H ;© ]; KP03.xylene

A

(F3CS0,);0 4(1.20) --------" FgCSOzNlCH;©];

EtiN EtiN

Scheme1.44

In both entry 1 and 2, N-chloride was obtained readily;O']

it was shown by P n.m.r spectrum that the signal of (1.20) at +25ppm was replaced by +19ppm for the N-chloride.Difficulty was encountered in the second step. When the N-chloride was treated with base, (1.20) was recovered as the31P n.m.r signal, +25ppm, reappeared.

Similarly, the first step of entry 3 and 4 went smoothly whereas the second step resulted in complicated mixtures.

Another possible way to prepare (I.15c) was the condensât ion of (1.18) and (1.17); Scheme 1.45.

© O HO(1.18)

© C H 2NH2(1.17)

Scheme 1.45

“H 2O (1.15c)

-26-

It was claimed that (1.18) could be prepared by treating formic acetic anhydride with the sodium salt of diethyl phosphite;^^ Scheme 1.4-6.

0 0 0 M e-C-O-CH + (EtO)2PNa ► © C H O + MeC02Na

Scheme 1.46

However, when the reaction was carried out, only diethyl phosphite was obtained after working up. Although there is a report on the repetition of the same reaction, the spectro­scopic data provided gave no positive evidence of (1.18).^^

When formic acetic anhydride was treated with triethylphosphite at room temperature, two doublets, +17.8, -0.8ppm,

31Jpp= 30Hz, were observed in the P n.m.r spectrum. The same reaction using trimethyl phosphite led to a similar observation Distillation of the latter gave oil; its ^H n.m.r showed doublets at 53.7 and 63.9, and a triplet at 54-3; with the support of its mass spectrum, the structure of the product was determined to be dimethyl dimethoxyphosphinylmethyl phosphate (1.23). The product from triethyl phosphite is diethyl diethoxyphosphinylraethyl phosphate (1.24).

u 0

(1.23) (1.24)

-27-

Although the mechanism of these reactions is not clear, formylphosphonates are probable reactive intermediates.(1.24) might form via the elimination of ethene; the form­ation of (1.23), however, could not be explained in the same way; Scheme 1.47.

9 ^ 9 ® MeCOoEtM e-C -œ CH -------► (EtO)jP-CHO ► +

\ n çT^:PI0Et)3® S ! - h

" ----------- ® -C H -0 -P (0 E t )2w -CH,=CH2 V x

(1.24) , O -CHj-CHj-H

whereas^ © © 0 0

(Me0),P-CH-0- m i ^ 2 --- ►(Me0)2PCH20P(0Me)2 + CHf ?

Scheme 1.47

1.4 The imines of g-aminophosphonates II. 1,3-Dipolar and anionic cycloaddition reactions

Introduction1,3-Dipolar and anionic cycloaddition reactions have

been extensively investigated in both aspects of mechanistic interest and synthetic value.

A 1,3-dipole is a system of three atoms bearing four Ti

-28-

electrons. The symmetry of the HOMO of a 1,3-dipole is the same as that of the k 4-s component in the Diels - Alder reaction. Concerted + Tl2s addition is therefore anallowed process; Scheme 1.4-8.

•— ? L U M O û - i L U M O

hom o 0 ^ » HOMO

Diës-Alder reaction 1,3-dipolar cycloaddition

Scheme 1.48

The same MO considerations can be applied to 1,3-anioniccycloadditions which differ from 1,3-dipolar cycloadditionsin that the positive charge is separately accommodated at a

4.7cation; Scheme 1.4-9.

M®

* ~ ~ V J

1,3-dipolar cycloaddition 1,3-anionic cycloaddition

Scheme 1.49

The reactivity, regio - and stereoselectivity of1,3-dipolar and anionic cycloadditions are generally determined by the HOMO and LUMO energy levels, orbital coefficients and secondary orbital interactions respectively.

In some cases, two-step Michael addition happens instead

-29-

of concerted 1,3-anionic cycloaddition. The difference is that the former often leads to a mixture of diastereoisomers

I Q

whereas the latter leads to single diastereoisomers.Among numerous synthetic applications of 1,3-dipolar and

anionic reactions, there have been reports on the 1,3-dipolar cycloaddition reactions of imines of a -amino acid esters ; Scheme 1.50.

E = COgMe; X = 0,NPh; Y = C02Me, CN.

Y H

Scheme 1.50

In most cases, the adducts were obtained as single diastereoisomers. The anionic reaction which gave a mixture of diastereoisomers was found to be a two-step Michaeladdition ;

RCH

50

R

Scheme 1.51.

0,M e KOBÎi 2 toluene

EtOgC-^^

02Me

OoMe

-2B^ 0

CO,Et

02Me

Scheme 1.51

-30-

a-Aminophosphonates, as mentioned in the review, can be readily prepared; the imines have been used in the synthesis of pyridines as described in 1.3. It was of interest to explore 1,3-dipolar and anionic cycloaddition reactions of the imines of a-aminophosphonates.

ResultsDiethyl N-benzylideneamino(phenyl)methylphosphonate

(1.25) was obtained by the condensation of benzaldehyde anddiethyl a-aminobenzylphosphonate which was prepared according

51to the literature; Scheme 1.52.

0(EtO);PH H,0,HCI

(PhCH=N%CHPh ------- ► (PhÇHNH-ljCHPh------------ ►PhCI-KB)© ■ PhCHO

IOH®

P h \ . ^ ^ © ^ _________ FhCH©)I PhCHO NHj

(1.25)

Scheme 1.52

Equimolar amounts of (1.25) and N-phenylmaleimide intoluene were heated under reflux for 36hr. After working up,two crystalline compounds were isolated. No signals were

31observed in the P n.m.r spectra of the two compounds. The absence of phosphorus was also confirmed by n.m.r spectra which, however, revealed the structure of the two compounds to be diastereoisomers of 2,l,7-triphenyl-6,8-dioxo-3,7- diazabicyclo[3.3.O]oct-2-ene, (l.26a) and (1.26b); Scheme 1.53

-31-

Au tolueneA

P I X / nV ®

Ph

X -

0-(BO),PH

Ph(42%) (1.26a)

+

(1.26b)

Scheme 1.53

The stereochemistry of (l.26a) was deduced from its n.m.r spectrum; Diagram 1.1.

The coupling constants, 9Hz, indicated that the three protons with signals at 54-» 4-.8 and 5.9 ppm were cis to one another. This was further supported by the upfield shift of the signals of two aromatic protons, which was caused by the shielding effect of the carbonyl group upon the ortho protons of the phenyl group geminal to ; Scheme 1.54-.

Scheme 1.54

(1.26a)

1 3No coupling between H and H was observed.1 3A long distance coupling between H and H , however, was

observed in the n.m.r spectrum of (1.26b); Diagram 1.2.

-32-

— o

— C O

-T

Elo o D)gQ

— ts.

CD

— C D

sI

-33-

o

C N

CN

enro Q

nO

OO

“34-”

1 2The small coupling constant, 3Hz, of H and H as well as the absence of the upfield shift of aromatic protons, indicated the configuration of (l.26b) to be trans ;Scheme 1.55.

(1.26b)

Scheme 1.55

1 3The coupling between H and H , J=2Hz, could be a fivebonds coupling through C = N double bond as the four bondsW configuration was absent in the molecule.

The phosphorus containing compound (1.27), although not 31detected by P n.m.r, was presumably formed as an intermediate

which eliminated diethyl phosphite rapidly under the reaction condition through probably a concerted p-elimination;Scheme 1.56.

(OEt)

(1.27)

02 -(EtOjPH

(1.26)

Scheme 1.56

-35-

The formation of the two diastereoisomers could mean that the reaction proceeded via a two-step addition mechanism; however, it is more likely to be the result of the different conformations of (1.25) in its dipole form in the concerted transition state; Scheme 1.57.

E,EorE,Z

OPl1(1.26a)

0

(1.26b)

Z,EorZ,Z

Scheme 1.57

Despite forced conditions (prolonged refluxing in xylene), (1.25) failed to react with maleic anhydride and dimethyl acetylenedicarboxylate, although these two dipolaro-philes have been considered to be almost equally as reactive

• 2 . as N-phenylmaleimide.The reaction of (1.25) with acrylonitrile in the presence

of potassium tert-butoxide led to a crystalline product.The n.m.r of the product showed it to be the 2-phenyl-- cyano-5-phenyl-1-pyrroline (1.28); Scheme 1.58.

(78% )KOB(j

benzene A i.5hr. H

(1.28)

Scheme 1.58

-36-

An ABCX splitting pattern was observed in the n.m.rI P 1spectrum of (1.28). The signals of H , H and H appeared

in the region of 62.8 - 3.8ppm as a complicated multiplet.The signal of appeared at Ô5.5ppm with the major coupling

3 Lconstant of 7.5Hz, which indicated that H and H were on the same side of the pyrroline ring.

The elimination of diethyl phosphite was probably facilitated by the negative charge on the adjacent nitrogen; Scheme 1.59.

0 -(EtO),P0

(1.28)

Scheme 1.59

In order to prevent losing the phosphorus group, it was considered that the reaction would be better carried out at low temperature. By treating (1.25) with butyl lithium in THF at -78°C, aza-allyl lithium (1.29) was prepared; subsequent reaction with acrylonitrile led to nearly equal amounts o-f phosphorus-containing pyrrolidine (1.30) and

qi(1.28). This was seen from P n.m.r spectrum that there were two signals at +26ppra and +7.4ppm representing (1.30) and diethyl phosphite respectively. ( P n.m.r of (1.25) is +19.5ppm). However, column chromatography resulted in the elimination of diethyl phosphite; only pyrroline (1.28) was obtained; Scheme 1.60.

-37-

n-BuLi ©TH F,-78° ^

(1.29)

h + (1.28)h -g- ^ 194%)

Scheme 1.60

©

0II

-EtO),PH

It is arguable whether the reactions outlined in Scheme 1.58 and 1.60 are concerted 1,3-anionic cycloadditions or two-step Michael additions. The high stereoselectivity could mean that both reactions were proceeding by a concerted, aza-allylanion LUMO controlled mechanism. The aza-allylanion is probably most stable in the E,E conformation as shown in Scheme 1.60. A secondary orbital interaction between the central lobe of the LUMO of the aza-allylanion and the orbital of the cyano group in the transition state ensured the cis configuration of the product; Scheme 1.6l.

0

*

Scheme 1.61

-38-

Treatment of (1,29) with methyl acrylate at -78°C led to the 2-phenyl-3-methoxycarbonyl-5-phenyl-5-diethoxyphosphinyl pyrrolidine (l.3l); Scheme 1.62,

H

(129)1. C02Me

2. H 2O

MeOoC

(8W 0)(1.31)

Scheme 1.62

The H n.m.r signal of the ester methyl group appearedat 63-2ppm, which was presumably caused by the shielding

5 /effect of the vicinal phenyl group. The proton attached to was observed as a triplet. This was due to coupling with the amine proton which was strongly hydrogen bonded to the phosphoryl oxygen; the triplet collapsed to a doublet, J=9Hz, upon deuteration. These n.m.r data indicated that the ester and phenyl groups were in the cis configuration.The stereochemistry on is not yet clear.

Recently, J. Hamelin reported the preparation of 1- azabicyclo[2.1.0 Jpentanes,^^ which is outlined in Scheme 1.63

PhCH^X:H(R|CO;Me P h C H < ^ t ^ ° 2 M e +^ e

COgMe

R = Me. Ph.

R COjMe

Scheme 1.63

""^OoMe

MeO

-39-

The stereochemistry on was not determined. Using (1.25), a similar reaction was carried out;

Scheme I.64..

^ Ph^Ph

(1.25)THF,-7ff

-Br

Scheme 1.64

tOoMe(1.29)

1 rCO,Me

(82% )N— i"Ph ©(1.32)

As with (1,31), the configuration of and in (1.32)was determined by the upfield shift of the signal of theester methyl group, 03.4-Ppm, in the n.m.r spectrum. The

13stereochemistry on was deduced from the C n.m.r spectrum; Diagram 1.3.

Diagram 1.3

— 4- 0 —

The doublet represented by lines 15 and l6, J = 11.7Hz, is probably caused by the coupling of with phosphorus.It has been demonstrated that the dihedral angle affects3 3JpQ in phosphonates in the same way as it does JjjH’example is shown in Table 1.1.^^

I ^P(0)(0M e)2

0 deg.

40 5.486 0122 3.9150 19.5167 18.3

Table 1.1

Model study revealed that the dihedral angle was nearly 180° when P and were trans to each other whereas the dihedral angle was nearly 90° when P and were in the cisconfiguration. Since substituents markedly affect the

3 " 5 7magnitude of JpQ for a given dihedral angle, the observedcoupling constant, 11.7Hz, could be regarded as the result of a trans configuration of P and C^.

Based on the stereochemistry of (1.32), the stereo­chemistry of the intermediate (1.33) could be deduced;Scheme 1.65.

Br

■'■S " (1.32)

(1.33)

Scheme 1.65

—4-1 -

MeOnC

By comparison, (1.33), might give some indications of the stereochemistry on of (l.3l).

To some extent, the stereochemistry of (l.3l) and (1,33) supports the mechanism used to explain the formation of(1.28) .

On treatment with a-chloroacrylonitrile, (1.29) gave pyrrolidine (1.34); Scheme 1.66.

1.CN C

2. H 2O Ph"^-^fâEt)2^ "'-0

(1.34)

Scheme 1.66

The low yield was partially caused by repeated re­crystallisation since the crude product contained a large quantity of tar - like substance.

In the n.m.r spectrum of (1.34), the signal of the proton attached to appeared at ô4-3ppm as a doublet,J=8Hz, which collapsed to a singlet upon deuteration. The reason for this is probably the same as that described for(1.31).

In contrast to the formation of (1.32), further cyclis­ation of (1.34) with elimination of HCl did not happen under the reaction conditions. This is presumably due either to the fact that chlorine is a poorer leaving group than bromine or to a stereochemical difficulty. However, the stereo­chemistry of (1.34) is not clear.

- 42 -

The inline (1.15a) was used in the same way as (1.25) in both 1,3-dipolar cycloadditicn and anionic reactions. Whereas no identifiable products were obtained when (I.15a) was treated with N-phenylmaleimide and dimethyl acetylene- dicarboxylate, treatment with maleic anhydride led to a crystalline compound (1.35) with a molecular weight of 402.The n.m.r spectrum is shown in Diagram 1.4.

Both the high resolution mass spectrum and elemental analysis indicated that (1.35) had the formula ;however, no proper structure for (1.35) could be proposed based on these data.

The anion of (1.15a), upon treatment with methyl a-bromo- acrylate, led to a viscous oil which could not be purified by column chromatography. Although the mass spectrum of the oil showed the expected molecular ion, M^339, and a fragment­ation pattern resembling that of (1.32), the structure of the product was not further identified.

1.5 Acylphosphonate. *Ene* reaction. Carbene intermediate?'Ene* reactions have found more and more applications in

organic synthesis during the past few years. Recently, the *ene’ reactions of butyl glyoxylate and dimethyl mesoxalate with alkenes have been r e p o r t e d S c h e m e 1.67.

-43-

I— o

— CJ

— CO

“ IQ

— CO

O)

_o

“44--

BUO2C-CHO +_ BUO2C

(Et02C)2C0 +

BuOjC

( Et02 C ) 2C

CH2CI2 ,UO°C, 16hr, sealed tube.

Scheme 1.67

It was considered that acylphosphonate (1.36) mightundergo similar reactions. Equimolar amounts of (1.36) and

o1-octene in a sealed tube were heated at 150 C overnight; Scheme 1.68.

0©■C~Me +

41.36)■5 11 - [ j i T '"11

OH

(1.37)

Scheme 1.68

-45-

31The P n.m.r spectrum showed a small signal at +19.4-ppni n.m.r of (1.36) is -3.2ppm). Only after 64.hr. heating

at 170°C, was the ^^P n.m.r signal of (1.36) entirely replaced by a complicated spectrum of six signals with the major one appearing at +19.4-ppni. Distillation did not separate the mixture. Mass spectrum, however, showed a major peak at m/e 274-» whereas (1.37) would have M^292. This one could expect from tertiary alcohols which normally give a strong peak at m/e M-18 due to losing water.

The reaction of diethyl benzoylphosphonate and 1-octene gave a product after 48hr. heating at 220°C with a ^^P n.m.r signal at +17ppm. Although the distilled product showed the signals of olefinic protons, the integrations of them were far less than they should be.. Mass spectrum gave a molecular ion at 355 whereas the 1:1 adduct of diethyl benzoylphosphon­ate and 1-octene should have the molecular weight of 354-.The structure of the product is not clear.

In the review of the reactions of a-ketophosphonates, a synthesis of dihydrobenzofuran was described; the suggested mechanism is shown in Scheme 1,15. A similar reaction which appeared in the same paper is outlined in Scheme 1.69.

(EtOlgP ►

■ C - ©0

Scheme 1.69

-46 -

It is well known that trialkyl phosphite can be used indeoxygenation reactions especially in the deoxygenation of

59nitro and nitroso compounds; Scheme 1.70.

2(EtO.)3P

Scheme 1.70

Although deoxygenations of carbonyl compounds with trialkyl phosphite are rare, the reactions outlined in Schemes 1.15 and 1.69 show indications that they might be proceeding via carbene intermediates created by deoxygenation with triethyl phosphite.

To test this postulation, equimolar amounts of (1.36) and triethyl phosphite were heated under reflux for 36hr.The reaction expected to happen is outlined in Scheme 1.71.

0CH3-C - © + (B0 )3P [CH3“C-©1 + (EtOl3P=Q

C H ,=C H -© (E tO )J -C -©'3' .CH.

Scheme 1.71

However, the product isolated in high yield showed two 31doublets in the P n.m.r spectrum, 20ppm,-0.5ppm, Jpp=34-Hz

The n.m.r spectrum of the product showed a multiplet at

~ 4-7 -

64--7ppra, two doublets at 61.4- and 1.6ppm as well as the signals of phosphonic ester ethyl groups. Mass spectrum showed M 318. Based on these data, the structure of the product was determined to be diethyl a-diethoxyphosphinylethyl phosphate(1.38); Scheme 1.72.

0CH3- C - © + (B 0 )3P ► CH3Ç )H -©

0- (~(1.38)

Scheme 1.72

Bearing some resemblance to that outlined in Scheme 1.4-7, the possible mechanism of this reaction is shown in Scheme1.73.

/-:PI0B)3 O ^ C H ^ C H ^ H0 O^PiOBlz

M e (C -© -------► M e -C -© ► (1.38)® -CHgzCHz

Scheme 1.73

1.6 The chemistry of 1-(diethoxyphosphinyl)vinyl phosphates Closely related to the Michaelis - Arbusov reaction,

the Perkow reaction is a general method for the preparation of vinyl phosphates; Scheme 1.74-.

— 4-S “■

0(ROlgP + XCHCR"

R'

R = alkyl; X = Cl,Br.

0(RO),P-OC=CHR' +

^ IR"

RX

Scheme 1.7

The mechanism of the Perkow reaction is still not clear, although a widely accepted mechanism is the one outlined in Scheme 1.75.^°

(EtO),P:.ÇHjCiC=0 - R-

%®> I ,

(E tO kP rC -R L i -CH^Cl

EtCl + © - 0 - C = C H ,^d '

, © ? © lEt0)3P-0-C=CH2 Cl

Scheme 1.75

Some applications have been found for vinyl phosphates in organic synthesis. Recently, there was a report on the preparation of carbon - carbon triple bonds from vinyl phosphates ; Scheme 1.76.

OPOlOEt);1.LDA ,2.CIPOIOEt),yl

l.LDA(2equiv.)2.aq.HCl ^

Scheme 1.75

“4-9 “

On the ' other hand, the 1-(diethoxyphosphinyl)vinyl phosphates (1.39) were prepared a long time ago, although few synthetic applications of them have been attempted.

It was of interest to explore the preparation of acetyl- enic phosphonates from (1.39); Scheme 1.77.

-Q\ _ r J ^

(139)

^ ©-CEC-R + (EtO),POH

Scheme 1.77

Acetylenic phosphonates have been obtained by several methods, but the yields were generally low. An example is outlined in Scheme 1.78.^^

0 (EtO)2PNa + B r-C E C 'M e ► © -C E C -M e (37% )

Scheme 1.78

Since CC-haloacid halides are readily available, various/ Q

(1.39) were prepared; Scheme 1.79.

BrCH^COBr 2(EtO)-,P©-0\

©'(1.39a)

CiCH(Me)COCl 2(EtO),P© - 0 ^ ^

(1.39b)

CICH(Ph)COCt 2(EtO)iP© - 0 \ ^ ^ h

(1.39c)

Scheme 1.79

-50-

The configuration of (l.39b) is not clear as the olefinic proton appeared as a complicated multiplet in the n.m.r. spectrum. The olefinic proton of (l.39c), however, appeared

3at Ô7ppm as a doublet with llHz, which indicated thecis configuration of the diethoxyphosphinyl and the olefinic proton.

On treatment with two equimolar amounts of LDA in THF at -78° 0, (1.39a) gave the acetylenic phosphonate (1.4-0); Scheme 1.80.

© -Q

0 Zoq.HCI

(139a)

1. LDAfzequiv.l ► ©-CHC-H (66% )

(1.40)

Scheme 1.80

However, treatment of (l.39b) with equimolar LDA did31not give any identifiable product; P n.m.r. of the reaction

mixture showed a major signal at -Ippm, which normally comes from trialkyl phosphates. No signals appeared in the region

31between -5 and -lO'ppm whereas (I.40) showed the P-n.m.r. signal at -8.7ppm. The IR of the reaction mixture did not give any absorption at 2260 - 2150cm” .

Similar reaction with (l.39c) resulted in the addition of diisopropylamine to the initially formed acetylenic phosphonate; only 2-phenyl-2-diisopropylaminovinylphosphonate (1.41), with unknown configuration, was obtained; Scheme 1.81

L i

Scheme 1.81

-51-

With NaH in THF under reflux, (l.39c) gave a mixture ofphenylacetylenic phosphonate and triethyl phosphate. The

31former gave P n.m.r signal at -6.8ppm and an IR band at 2200cm*’ . The latter was presumably formed by estérification of the diethyl phosphate anion eliminated from (l.39c) with other ethyl phosphoryl esters. The two compounds, however, could not be well separated by distillation or column chromato­graphy.

When (l.39c) was heated at 200°C overnight, a white31crystalline compound was obtained. P n.m.r signal of the

product appeared at O.Oppm. The ^H n.m.r showed a spectrumresembling that of (l.39c) with, however, different integrationratios; the doublet at 56.8ppm had a coupling constant of13Hz. The integrations indicated the ratio of phenyl groups,olefinic protons and phosphoryl ester ethyl groups to be1:1:1. Both the high resolution mass spectrum and elementalanalysis indicated the compound to have a formula ^20^22^6^2*All the data implied the molecule to have a highly symmetricalstructure. However, it was difficult to propose a structure

31which fitted the P n.m.r value aS few phosphonates have a 31P n.m.r value of about O.Oppm. X-ray crystallography

' .finally revealed the compound to be a symmetrical six-memberedring (1.42); Diagram 1.5.

The possible mechanism for the formation of (1.42) is outlined in Scheme 1.82.

-52-

o< Ml KZ&gcq OCD-Ç=:

CO X I—oZLUQzm

(jD C D O G D c D (DCO LT> ocn m 33- cD ^ in tor—J 00 -j-

z:£î!n£2S3SO O 0 0 O o OI I I I I I iÊiii§8§

"OCOLU_Joz<QZoCO

00 oooo.^<rooc^coS S S s d Q j Q Ocnvj-r^.<rC7^^oo^

O O O O O O C L O I I I I I I i ICL CL 0 _ CL O . C L O OI I I I I I I I£lfM2£2£2£2£3^:i^o o o o o o o o

LT>.

EBs ’Q

-53-

© -Q\_yPh

(1.39c)

0II 0

(EtO)2P-=-Ph + (EtO)2POH

Q OEtu 0

P h s _ ^ \ A dimerization

Q h

(1.42)

Scheme 1.82

^ ^ - = - P h + (EtO)3PO

- 54“

CHAPTER2

2. THE ORTHO-LITHIATION OF N,N,N »,N »-TETRAMETHYLPHENYL- PHOSPHONIC DIAMIDE

IntroductionThe ortho-lithiation and subsequent reaction with

electrophiles of various aromatic compounds having a substituent capable of co-ordinating to lithium have been long attracting attention due to their synthetic value and mechanistic interest; Scheme 2.1.

RLi

Z = SO^R, CONHR.CH2NR2.OROAr.2 -Oxazolyl.etc.

E = Electrophiles.

Scheme 21

A review covering a wide spectrum of this subject waspublished a few years ago.^ Many new investigations,

2however, have been carried out since then.The general mechanism of the ortho-lithiation involves

the co-ordination of the lithiating agent by the directing group as an initial step followed^ by a rate-limiting step of protophilic attack. This is illustrated by the lithiation of N,N-dimethylbenzylamine; Scheme 2.2.

H2N(CH3);RLi

^ j C H 3 ) 2 11,

^ (CH3)2

Scheme 2.2

-55-

The ortho-directing potentials of different directing groups have been compared. The most powerful directing groups are those being electron withdrawing and having the ligand atom with strong Lewis base character, such as CONR^» CONHR, 2-oxazolyl etc.^

Among organophosphorus compounds only triarylphosphine oxides and imides have been ortho-lithiated; Scheme 2.3.

0 0 B u L i/T H F /2 5 ° / ,t- t,------

NCgHs P

Ref.4

II

Ref. 5CO; (HgC?) k j l

Scheme 2.3

Undoubtedly, the ortho-lithiation of various organophosphorus compounds deserves more investigation.

The N,N,N * ,N’ -tetramethylphenylphospho.nic diamide (2 .1) was expected to be able to undergo ortho-lithiation, since the bis(dimethylamino)phosphinyl group should meet the criteria of the strong directing groups. The synthetic value of the ortho-lithiation of (2.1) might be further justified by the ready conversion of the phosphonic diamide into phosphonic acid or phosphonate,^ so that many ortho­substituted phenylphosphoryl compounds might be prepared by an effective route.

-56-

0 î?(NMe2l2

(2.1)

ResultsThe treatment of the phosphonic diamide (2.1) in dry

THF at -5°C with n-butyl lithium gave a deep red solution containing the aryl-lithium (2.2); electrophile was added subsequently; Scheme 2.^.

‘(NMe2)2 n_BuLi

THF - 5 $

(2.1) (2.2)

Scheme 2Â

The results are shown in Table 2.1.

-57-

TABLEZ.1

electrophile product

PhCHO

HPh

(2.3)OH

(2.5)

<2.6)

Me

26 25PhoCO

(27)(2.8)

-58-

productelectrophile

•P(NMeo)

(2.9)SiMe

CO, (-78°C)(2.10)

PiNMe,), (2.12)

2PhCN

(2.13)

-59-

The low yield of (2.4) is presumably caused by the enolization of the acetaldehyde. Twelve percent yield was obtained when the reaction was carried out at -5^C. At low temperature (-4-0°C), which reduced the end form, the yield was increased to thirty two percent.

The cyclised and uncyclised products (2.3 - 2.8) reflect the competition of the increasing nucleophicility of the alkoxide and steric interactions.

The stereochemistry of the benzoxaphosphole (2.4-) was deduced by the comparison of it’s n.m.r. spectrum with

7that reported by R.C. Grabiak and co-workers; the ring3hydrogen trans to the phosphoryl oxygen would have Jpg=10Hz,

3whereas the cis would have Jpp=3Hz.O AThe treatment of (2.2) with benzoyl chloride at -100 G

did not give any identifiable product, whereas (2.2) reacting with diethyl benzoylphosphonate led to the benzoxaphosphole (2.12). The diphenyl ketone (2.14-) was probably formed as an intermediate; Scheme 2.5.

0 q l P0 0 [ H e M o j o

% . - L i t e .

yNMe;N^Me, (2.2)

o'^gHs ' (216)

(NMejla

(NMe2)2

(2.12)

Scheme 2.5

-60-

The somewhat unexpected product (2,13) was obtained as pale yellow crystal. Both mass spectra and elemental analysis suggested it to be a 1:2 adduct of (2.1) and benzonitrile.

n.m.r. showed that there were four protons in the olefinic region, an exchangeable proton, and a chiral centre which was responsible for two doublets due to the inequivalent dimethyl- amino groups; Diagram 2.1,

To accommodate the spectroscopic data, at least four structures might be drawn for (2.13); Scheme 2.6.

0

a

0

■6H5

c

0II

b

0

6^5

Scheme 2.6

Among them, structure (a) was considered to be the best prospective candidate, as it had the longest conjugation and a chiral centre close to the phosphorus group. However, X-ray crystallography revealed the structure of (2.13) to be (b); Diagram 2.2.

-61-

a>

o

WEoL _engQ

gQ.O .

-62-

LO X I—ozÜJQzoCO

L n ir)L r)c o o O L r> ^ :p rc x )o o L n •^ tO L O X— OOOCNIcj)C^COCT> ^ roro ro LO LO ro CN

w -iLO toKt:?o o o o o o o z z z zI I I I I I I 1 I I I

£2::: L£Z iôX:::5Q OQ o o o o o o o o o o o

g> %? i7513lBtn s^î LoCî:3t?5C?în ■o o Q s s â o s s ^ a s â a- « j - ^ e n ‘«J-o vj-(N ro'-3'CN CD co ^ T-; LOGO tD'0(0 <X)LO’a D K ^ 'J - ’ LU CNcN cNCNICNCNOo O C N N O ’'—

s<QzoCÛ f e ë s s â g g e g e g g

ééèéièèÉÉéèèèJLJL * ' I I I I I I L J Lo o o o o o o z z O z z z

CNCNIQ

2

-63-

The possible mechanism for the formation of (2,13) involves nucleophilic attack of nitrogen on the aromatic ring in the initial 1:2 adduct (2.15) to give the spiro-compound (2.16) followed by formation of the cyclopropane (2.17), electrocyclic ring opening, and protonation; Scheme 2.7.

0 I i

(MeîNljP (Me2N)2^ (Me2N)2

(2.15)

©

(2.16)

(2.13)

©H

0II

(2.17)

Scheme 2.7

Although there are many investigations in the reactions of metalated aryl compounds with benzonitrile/^ there have not been previous reports on the preparation of similar compounds.

The treatment of (2.2) with methyl iodide gave a complex mixture of arylphosphonic diamides which, from its n.m.r. and mass spectra contained ortho ethyl and isopropyl groups as well as the expected methyl. The reaction of (2.2) with methyl disulphide or methanesulphonothioic acid S-methylester did not give the expected phenyl methylsulphide; only

-64.-

starting material (2.1) was recovered after working up.The treatment of (2.2) with DMF gave a pale yellow oil with

n.m.r. +27ppm ( n.m.r. of (2.1) ; +29ppm). The31P n.m.r. value changed rapidly to +31, 28, 24 etc, with corresponding colour change to deep brown on standing. This might be due to the hydration of the carbonyl group and subsequent reactions; Scheme 2.8.

0HgO

:HII0 hr

-HNM62

H/NMe;

Scheme 2.8

31The crude product of (2.2) with ethyl chloroformate,

P n.m.r. +27/ was a deep brown coloured viscous oil.H n.m.r. of the crude product showed that the integrations of the ester protons were less than they should be. The product could not be purified by column chromatography since its Rf on TLC in various solvents was virtually zero.

Despite the ready ortho-lithiation of (2.1), the actual atom responsible for co-ordinating the lithiation agent is arguable. Since the P=0 bond in (2.1) is better represented

-6$ -

by the zwitterion form, P^- O", both the phosphoryl oxygen and the dimethylamino nitrogen could co-ordinate with lithium However, it is likely that the dimethylamino nitrogen plays the major role of the co-ordinating function. This is in some way supported by the experimental result that the ortho- lithiation of diethyl phenylphosphonate did not give any identifiable ortho-substituted product.

Although there are more than one atoms on the phosphorus group of (2.1) capable of co-ordinating lithiation agent, the treatment of (2.1) with two equivalent of butyl lithium and benzaldehyde gave only mono-substituted product (2.3). This could mean that a co-planar geometry is required for the co­ordinating atom, butyl lithium and the phenyl group in the protophilic attack step. Once the aryl-lithium (2.2) is formed, the co-ordination of the lithium and the ligand prevents rotation of the C-P bond which in turn prevents further lithiation happening.

Li'-'

-66 -

CHAPTER 3

3. TRAPPING THE PUMMERER REACTION INTERMEDIATE

IntroductionThe Pummerer reaction may be generalised as a reaction

involving the reduction of a ‘sulphonium sulphur with concomitant oxidation of the a-carbon;^ Scheme 3.1.

Rf(X)CHR'R" R X Y R 'R ''+Y®

X = acyloxy, alkoxy. Y = nucleophile. .

Scheme 3.1

The mechanism of the Pummerer reaction is believed to involve intermediate ylide and alkylidenesulphonium ion as outlined in Scheme 3.2.

^ % ©RS-CHR R" ------- ► R -S -rC R 'R "--------►RS=CR’R"© © '■© ,he

RS-CR'R"I©

X.Y : same as in Scheme 3.1

Scheme 3.2

Experimental evidence shows that the ylide is formed in the rate-limiting step followed by the rapid formation and trapping of the alkylidenesulphonium ion, as the rate of the

I » Treaction is increased when R or R is an electron withdrawing 2group.

67-

The alkylidenesulphonium ion, an a-thiocarbocation, can3be trapped in many ways. There have been wide investigations

of electrophilic aromatic substitution by the Ct-thiocarbo- cations; Scheme 3.3.

MeO"MeO

MeOMeO

©SMe

Scheme 3.3

Only recently, however, was the trapping of the a-thiocarbocations with olefins via *ene* reactions reported. Y. Tamuk and co-workers prepared (E,E)-2 ,4--alkadienoic esters by trapping the Pummerer reaction intermediate with 1-alkenes and subsequent oxidative desulphurization;^ Scheme 3.4-.

0MeSCHgCOzEt

(32)

(FjCCClO ©[Me-S=CH-C02Etl

F3CCO2H

\ '-CHCOnEt - HI ^ --

©

(32)SMe

1.NalO^2. A

Me

p "COoEt

Scheme 3.4

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It was- conceivable that the phosphorus analogous of (3.2) and (3.3) might be prepared in a similar manner; Scheme 3.5.

n l-lFgCCOkO 1 [o]M e S C H z © ----

- % % “

Scheme 3.5

ResultsThe experimental procedure was as follows: trifluoro-

acetic anhydride and 1-alkene were added successively to atrifluoroacetic acid solution of the sulphoxide (3.4) at 0° C.

31The reaction was completed after 3-4hr. stirring, as P n.m.r31indicated that nearly all the sulphoxide, P n.m.r +l6ppm,

31was converted into a product having P n.m.r +27ppm.31Although the P n.m.r spectra of the distilled product showed

only small signals of impurities, the n.m.r spectra of the adduct of; ( 3.4) with' hex-l-ene'or ’ oct-1-ène Were not consistent with the general structure of (3.5); the integration of the signals in the olefinic region, 65.5ppni, was only 1/4 of that due to the phosphoryl ester methylene and I/6 of the ester methyl group. This implies that, instead of two, there isonly one olefinic proton present in the molecule. A migration of the doub Scheme 3.6.of the double bond could give the observed n.m.r spectra;

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CH3(CH2)n-'’ î5-''3^H© ____^ C H 3 ( C H 2 ) n \ _ ^ M eSMe

a. n = 2 a. n = 4b. n = 4 b. n = 6

(3.5) (3.7)

Scheme 36

Howeverp ozonolysis of the product derived from (3.4)and hex-l-ene resulted in butanal only, as the melting pointand mass spectrum of the 2,4-dinitrophenylhydrazone indicated.

13C n.m.r. spectroscopy can be used in determining the13structure of the products. In the C n.m.r. off resonance

spectrum, structure (3.5) would give a doublet of doublets dueto the a-carbon whereas (3.7) would give a doublet. In orderto simplify the C n.m.r. spectrum, an adduct (3.8) of thesulphoxide (3.4) with but-l-ene was prepared. The n.m.r.of (3.8) resembled those of the previous products. In the 13C n.m.r. spectra, a doublet of doublets in the off resonance spectrum with corresponding doublet having a large coupling constant (l51Hz) in the broad band decoupled spectrum was observed. This indicates clearly that a methine group,attached directly to the phosphorus atom is present in the molecule. Therefore, the formation of (3.7) can be ruled out.

In order to explain the observations encountered, a much more pure sample would be desirable. However, getting(3.8) pure was difficult as both redistillation and column chromatography only resulted in more complicated products.One way to solve the problem is to prepare crystalline compounds which can be purified readily by recrystallization. Diphenyl alkylphosphine oxides are suitable candidates for this aim. Following the known method, the diphenylphosphinylraethyl methyl

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nsulphoxide ' (3.Il) was prepared. The adduct of (3.11) with but-l-ene was obtained as a crystalline compound in high yield; Scheme 3.7.

(3.9) (3.10)

PhoKo,^

0 0 PhjPCHjSMe

(3.11) .(FjCCOjO

2.but-i-ene F3CCO2H

SMe (3.12)

Scheme 3.7

The H n.m.r spectrum of (3.12) matches well with its structure. The signals in the olefinic region showed the similar pattern as that of (3.8), but had the expectedintegration ratio.

13In the C n.m.r broad band decoupled spectrum, a doublet31 13due to the a-carbon with a P- C coupling constant of 68Hz

was observed. Considering all the experimental evidence, it can be said that the adducts of (3.4) with hex-l-ene, oct-l-ene and but-l-ene have the expected general structure of (3.5); the ambiguity in the ^H n.m.r spectra of them are caused merely by the impurities which consisted mainly of ethyl phosphoryl esters.

13Apart from determining the structures, the C n.m.r spectra of (3.8) and (3.12) reveal some interesting phenomena of the coupling.

The n.m.r spectrum of (3.8) showed a large couplingconstant of the phosphorus and the a-carbon, ^j=151Hz, whereas

that of (3.12) is 68Hz. Such a difference is normally

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explained by the S-character of the P-C bond.Although no coupling between the phosphorus and p-carbon

was observed in (3.12), a large coupling constant, 86Hz,2was observed in that of (3.8). Such a large value is

9rather unusual and rarely reported in literature.(3.8) was oxidised with sodium periodate to give the

sulphoxide (3.13) which decomposed upon distillation to give 1 ,3-dienephosphonate (3.14);^^ Scheme 3.8.

MeN alQ

0=5Me (3.13)le (3.8)

(3.14)

Scheme 3.8

(3.14-) is remarkably unreactive towards dienophiles.When (3.14) and dimethyl acetylenedicarboxylate or 1-diethyl- aminopropyne in toluene were heated under reflux for 72hr., no n.m.r signal other than that of (3.14-) was observed.This poor reactivity of (3.14-) might be due to a cis configuration of the vinyl and phosphorus groups, although no band was observed in the region of 730-675cm” of the infra­red spectrum of ( 3.14-) . The actual geometry of (3.14-) is not clear.

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CHAPTER A

A. EXPERIMENTAL DETAILS

GeneralExperiments involving air or moisture sensitive compounds

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

Dioxane was distilled from sodium hydride and THE was distilled from lithium aluminium hydride immediately prior to use. Ethanol and dichloromethane were distilled from calcium hydride. Ether was distilled from lithium aluminium hydride.

Small scale distillations were- carri'ed out using aIIKugelrohr 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.

Instrumentationn.m.r spectra were recorded using a Varian T-60,

60MHz spectrometer or a Varian EM 390, 90MHz spectrometer, with TMS as the internal standard. Deuteriochloroform was the solvent.

31Fourier transform P n.m.r spectra were recorded on a Jeol JWM-FX60 spectrometer. The external standard was aqueous tetrahydroxyphosphonium perchlorate and the solvent was dichloromethane. Chemical shifts are quoted as being positive to lowfield of the standard.

"'G n.m.r spectra were recorded on the same instrument with TMS as a standard.

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Infra-red spectra were recorded on Perkin' Elmer 237,257 or 298 spectrometers. Liquid samples were run as thin films or in solution in dichloromethane. Solid samples were run as solutions in dichloromethane or as Nujol mulls.

Mass spectra were recorded using a V.G. Micromass 16B instrument.. Only the molecular ion is quoted.

Melting points were determined using a Kofler heating stage and are uncorrected.

Diethyl Ethoxycarbonylacetylphosphonate (1.2)This compound was prepared from triethyl phosphite and

ethoxycarbonylacetyl chloride according to literature.^B.p. 10X-106°/ 0.05mm (Lit. b.p, 115°/ 0.9mm).l-Methyl-3-diethoxyphosphinyl-5-ethoxypyrazole (1.6)

To a solution of (1.2) (5g, 20 mmol) in 20cm^ glacial acetic acid was added methylhydrazine (ig, 20 mmol) at room temperature. The mixture was well shaken and left standing overnight. The reaction mixture was evaporated and the residuetaken up in dichloromethane (20cm ). This solution waswashed with water and dried over MgSO^. Removal of thedichloromethane led to a yellow oil which was purified by column chromatography (neutral alumina, ether). (1.6) was obtained as a pale yellow oil in 75^ yield (2g, 7.5 mmol).

^^P n.m.r. + 11.5.n.m.r 51.4-, 9H, t, J = 7Hz

63.7, 3H, s54-.2, 6H, quintet, J = 7Hz65.8, IH, d, J=2Kz.

IR: 1560, 1230 cm"^M" 262

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2-Amino-4--diethox.yphosphinyl-5-ethoxycarbonylthiazole (1.7)Formamldine disulphide dihydrobromide was prepared from

u 2thiourea and bromine.(1.2) (l.5g, 6 mmol), formamldine disulphide dihydro­

bromide (l.87g, 6 mmol) and sodium acetate (0.52g, 6 mmol)3were mixed in 20cm abs. ethanol at room temperature. The

mixture was stirred at room temperature overnight. Thesolvent was evaporated and the residue was dissolved indichloromethane. The solution was washed with dilute NaHGO^solution and dried over MgSO^. Removal of the dichloromethaneled to white crystals which were recrystallized from carbontetrachloride and dichloromethane (l:l). (1.7) was obtainedin 82^ yield (l.51g, 4.9 mmol). M.p. 130-132°.

n.m.r. + 7.1.n.m.r. 51.4, 9H, t, J-7Hz

54.2, 6H, quintet, J=7Hz56.5, 2H, br. s., exchangeable with 0^0.

IR: 3300, 1690, 1250 cm'l.M'*' 308.

[Found: 0,38.9; H, 5.47; N, 8.95%. ^10^17^2^5 ^ requiresc, 39.0; H, 5.5; H, 9.1% -].Diethyl bromoacetoacetylphosphonate (1.8)

3To a solution of diketene (2.5g, 30 mmol) in 30cm carbon

tetrachloride at -20°C was added dropwise bromine (4.8g,30 mmol) and triethyl phosphite (5g, 30 mmol) successively.The pale green solution was stirred overnight under N^.Evaporation of the carbon tetrachloride led to (1.8) in quantitative yield.

^^P n.m.r. +3.n.m.r. 51.4, 6H, t, J=7Hz

63.9, 2H, 854.2, 4H, quintet, J=7Hz66.4, 2H, d, J=8Hz.

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l-Methyl-3-'diethoxyphosphinyl-5-bromoffiethylpvr'azole (1.9)To a solution of (1.8) (l.5g, 5 mmol) in 20cm^ glacial

acetic acid was added methylhydrazine (0.25g, 5 mmol) at room temperature. The resulting solution was well shaken and left standing overnight under N^. Evaporation of the solvent by vacuum pump at room temperature led to a deep red oil which was washed with water in dichloromethane, dried over MgSO^ and separated by TLC (neutral alumina, ether). (1.9) was obtained as the more polar fraction.

n.m.r. +9.7.n.m.r. 51.4, 6H, t, J=7Hz

63.9, 3H, s64.2, 4H, quintet, J=7Hz64.4, 2H, s56.7, IH, d, J=2Hz.

311/313.(1.10) was obtained as the less polar fraction.

^^P n.m.r +4.8.n.m.r. 61.4, 6H, t, J=7Hz

63.9, 3H, 864.2, 4H, quintet, J=7Hz64.4, 2H, s66.7, IH, d, J=2Hz.

IR: 3450. 2990, 1450, 1300 cm'l.m'*' 232.

Diethyl aminomethylphosphonate (1.17)This compound was prepared by hydrogenolysis of the re­

distilled diethyl N-benzylaminomethylphosphorate in glacial acetic acid with palladium-on-charcoal. B.p. 80-85°/ 0.1mm. Diethyl N-benzylideneaminomethylphosphonate (l.l5a)

This compound was prepared by condensation of (1.17) and benzaldehyde in benzene at 0°C and subsequent distillation.^

B.p. 160 / 0.1mm.

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Vinaraidinium salts (I.I6)(1.16a), R=H. This compound was prepared from 1,5-

diaza-1,5-dimethyl-1,5-diphenyl-lH-pentadienium perchlorate and dimethylamine. M.p. 119-120° (Lit. m.p. 119-120 ). (1.16b), R=Ph. This compound was prepared by the Vilsmeier formylation of phenylacetic acid, as described in the literature.^ M.p. 195-196° (Lit. m.p. 195-196 ).

(1.16c), R=G1. This compound was prepared by the7 oVilsmeier formylation of chloroacetic acid. M.p. 122-123

(Lit. m.p. 123-124°).(I.l6d), R=Br. This compound was prepared by bromination

of (1.16a).® M.p. 144-146° (Lit. m.p. 144-146°).2-Diethoxyphosphinyl-6-phenylpyridine (l.14a)

To a solution of (1.15a) (4g, 15 mmol) in 30cm drydioxane was added sodium hydride (60%, 0.63g, 15.7 mmol).The mixture was stirred for 15 min. at room temperature;vinamidimium salt (l.l6a) (3.54g, 15 mmol) was added. Thereaction mixture was refluxed for 36hr. then evaporated.The residue was taken up in dichloromethane. This solutionwas washed with water and dried over MgSO, Evaporation ofthe dichloromethane gave an oil which was distilled to give(I.I4&) in 70% yield (3.1g, 10 mmol). B.p. 170 / 0.06mm.

^^P n.m.r. +9.2.n.m.r. 61.4, 6H, t, J=7Hz

64.2, 4H, quintet, J=7Hz67.1-8.1, 8H, m.

IR: 3040, 1570, 1300 cm'l.m'*' 291.(I.14a) (3.1g, 10 mmol) was hydrolyzed in 18% hydro­

chloric acid solution for 6hr. under reflux. After evaporation

-77-

of the hydrochloric acid, the phosphoric acid was obtained as crystalline compound in ethanol on trituration and re­crystallized from IMS, Yield 90% (2,lg, 9 mmol). M.p. 215-217°.

M'*' 235.[Found: C, 55.90; K, 4-33; N, 5.8%. G^^H^qNO^P requires

C, 56.1; H, 4.25; N, 5.95%].2-Diethoxyphosphinyl-4>6-diphenylpyridine (l.l4b)

This compound was prepared in a similar manner described for (1.14a) with (I.15a) (2.55g, 10 mmol) and vinamidimium salt (l.l6b) (3g, 10 mmol). The crude product was purified by flash column chromatography (ether). Yield: 65% (2.4g,6. 5 mmol) .

^^P n.m.r. +9.3.M'*' 367.(1.14b) (2.4g, 6.5 mmol) was heated under reflux in 18%

hydrochloric acid solution for 6hr. The phosphonic acid was obtained as pale yellow crystalline compound in ethanol on trituration in 90% yield (l.85g, 5.9 mmol). M.p. 265-267 .

IR (Nujol): 3300, 1610, 1375 om'^. '311.

[Found: C, 63.21; H, 4.55; N, 4.41%. requires0, 65.6; H, 4.5; N, 4.5% ].Bis(diethoxyphosphinylmethyl)-amine (1.20)

(1.22), prepared according to literature,^ was dissolved in excess trifluoroacetic acid, the solution was heated at 60-70°G overnight. After removal of the trifluoroacetic acid by evaporation, the residue was dissolved in chloroform; ammonia gas was passed into the solution; ammonium salt was

-78-

separated by filtration; the filtrate was washed with waterand dried over MgSO^, (1.20) was obtained by distillation.B.p. 140°/ 0.1mm.

n.m.r. +24.4.n.m.r. 51.4, 12H, t, J=7Hz

51.6, IH, br.s53.1, 4H, d, J=10Hz64.1, 8H, quintet, J-7Hz.

IR: 3300, 124.0 cm'l.M'*' 317. .

Dimethyl dimethoxyphosphinylmethyl phosphate (1.23)Formic acetic anhydride was prepared according to liter-

. 1 0 ature.Trimethyl phosphite (l.24g, 10 mmol) and formic acetic

anhydride (2.64g, 30 mmol) were mixed and stirred overnightat room temperature. The excess formic acetic anhydride wasevaporated and the residue distilled to give (1.23) in 82%yield (2g, 8 mmol). B.p. 120°/ 0,2mm.

^^P n.m.r. +19.7, d; +1.4, d; Jpp=29Hz.^H n.m.r. 53.7, 6H, d, J=4Hz

63.9, 6H, d, J=4Hz64.3, 2H, t, J=8Hz.

IR: 3500, 1270 cm'l.m'*' 24.8.

Diethyl diethoxyphosphinylmethyl phosphate (1.24)Triethyl phosphite (4.15g, 25 mmol) and formic acetic

anhydride (6.6g, 75 mmol) were mixed and stirred overnight at room temperature. (1.24) was obtained in 87% yield (3.3g,10 mmol). B.p. 110°/ 0.2mm.

^^P n.m.r. +17.8, d; -0.8, d; Jpp=30Hz.^H n.m.r. 51.3, 12H, t, J=7Hz

54.2, 8H, m.

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IR: 3500, 1250 cm'l304.

Diethyl N-benzylideneamino(phenyl)methylphosphonate (1.25)Diethyl &-aminobenzylphosphonate hydrochloride^^ (2.8g,

10 mmol) was treated with dilute sodium hydroxide solution indichloromethane, the organic layer was dried with MgSO^ andevaporated. The resulting a-aminobenzyl phosphonate (2.43g,10 mmol) was treated with benzaldehyde (ig, 10 mmol) inbenzene at 0°C. After removal of the benzene, more benzenewas added and evaporated. The residue was dried with MgSO^in dichloromethane then distilled to give (1.25) as a paleyellow viscous oil in 75% yield (2.5g, 7.5 mmol). B.p.140°/ 0.5mm.

n.m.r. +19.9.n.m.r. 61.3, 6H, t, J=7Hz

6 4, 4H, quintet, J = 7Hz54.8, IH, d, J=20Hz67.2-7.9, lOH, m68.3, IH, d, J=5Hz.

IR: 1635, 1600, 1250 cm"^.331.

2 , 4 ,7 - ' T r i p h e n Y l - 6 ,8 - d l o x o - 3 ,7 - d i a z a b i c v c l o f 3 . 3 . o ] o c t - 2 - e n e (1.26)

(1.25) (I.14g, 3.4 mmol) and N-phenylmaleimide (0.62g, 3.6 mmol) in toluene were heated under reflux for 36hr. Evaporation of the toluene led to a white solid, to which was added chloroform; the insoluble solid (1.26a) was separated by filtration and recrystallized from toluene. The filtrate was evaporated to give (1.26b) which was recrystallized from ethanol. Yield: (1.26a), 42% (0.52g, 1.4 mmol); (1.26b),40% (0.49g, 1.36 mmol).

-80-

(1.26a): M.p. 250-251°.n.m.r. 54, IH, t, J=9Hz

54.8, IH, d, J=9Hz65.9, IH, d, J=9Hz56.7, 2H, m 57-7.7, IIH, ffi68.3, 2H, m .

IR(Nujol): 1710, 1615 cm"^.M'*' 366.

[Found: C, 78.36; H, 5.04; N, 7.51%. ^24%8^2®2C, 78.7; H, 4.9; N, 7.65% ].

(1.26b): M.p. 182-184°.n.m.r. 53.7, IH, dd, J=9Hz, 4Hz

6 4.8, IH, dd, J=9Hz, 2Hz 6 5.8, IH, m67.1-7.6, 13H, m68.3, 2H, m .

IR(Nujol): 1710, I6l0 cm"^.M'*' 366.[Found: C, 78.22; H, 5.06; N, 7.48%. ^24^18^2^2 requires

0, 78.7; H, 4.91; N, 7.65%].

2-Phenyl-cis-4-cyano-5-pheny1-1-pyrroline (1.28)

Method 1. (1.25) (l.6g, 4.8 mmol), acrylonitrile(0.24g, 4.5 mmol) and potassium tert-butoxide (0.5g, 4.8 mmol) in benzene were refluxed for 1.5hr. The benzene was removed by evaporation and the residue was taken up in dichloromethane The solution was washed with water and dried with MgSO,.4-Crystalline compound (1.28) was obtained after column chromatography (neutral alumina, ether) in 78% yield (0.86g,3.5 mmol).

Method 2. To a solution of (1.25) (2.65g, 8 mmol) in THF at “78°C with stirring was added n-butyl lithium (l.Ol M, 8ml) through a syringe; the resulting red solution

-81-

was stirred for 0.5hr., acrylonitrile (0.5g, 0,8 mmol) was added dropwise at -78°C. After overnight stirring at room temperature under N^, the THF was evaporated and the residue was worked up in the same way described in method 1. (1.28)was obtained in 94% yield (l.84g, 7.5 mmol).

M.p. 121-122°.n.m.r. 52.8-3.9, 3H, m

65.5, IH, dt, J=7.5Hz, 2Hz67.3, 8H, m67.8, 2H, m.

IR(Nujol): 2220, 1600 cm'^.M'*' 246.[Found: G, 82.33; H, 5.78; N, 11.26%. H^^N requires

C, 83.0; H, 5.7; N, 11.4% ].

cis-2-Phenyl-3-inethoxy carbonyl-5-phenyl-5-diethoxyphosphinyl- pyrrolidine (1.31)

This compound was prepared from (1.25) (2g, 6 mmol) and methyl acrylate (0,52g, 6 mmol) in a similar manner to thatdescribed in method 2 for the preparation of (1.28). Flashchromatography (ether) led to a yiscous oil which crystallized upon trituration in ethyl acetate to give (l.3l) (2.1g, 5 mmol) in 84% yield. M.p. 98-100°.

^^P n.m.r. +24.2.^H n.m.r. 61.2, 3H, t, J=7Hz

61.3, 3H, t, J=7Hz62.6-3.2, 4H, m63.2, 3H, s63.7-4.3, 4H, m64.4, IH, t, J=8Hz57.3, 8H, m67.6, 2H, m.

IR(lIujol): 3290, 1740, 1240 cm"^.M" 417.[Found: C, 63.19: H, 6.76; N, 3.37%. requires

C, 63.3; H, 6.76; H, 3.

- 82 -

r-2-Phenyl-t-2-die thoxypho sphinyl-jb-m ethoxy carbonyl-jt-5-phenyl-l-azabicyclo[2.1.0]pentane (1.32)

Methyl a-bromoacrylate was prepared according to literature.

(1.32) was prepared from (1.25) (3.31g, 10 mmol) and methyl a-bromoacrylate (l.68g, 10 mmol) in a similar manner described in method 2 for the preparation of (1.28), Crystalline (1.32) was obtained in ether on standing after working up. Yield: 82% (3.4-g, 8 mmol). M.p, 133-135 .

^^P n.m.r. +20.6.n.m.r. 61.2, 3H, t, J=7Hz

61.3, 3H, t, J=7Hz •62.8-3.8, ni'i/u63.5, 864.2, 4H, m67.3, lOH, s.

IR(lIujol): 1740, 1250 cm'l.m'*' 415.[Found: C, 64.15: H, 6.40; N, 3.23%. requires

C. 63.61; H, 6.31; N, 3.37%].n.m.r. 616.1, 16.5

53.5, 47.6, 51.7554.2, d, J=11.7Hz663.7, d, J=170Hz562.8, 63.4, 63.9, 64.45127.6, 128.1, 133.2, 136.35168.3,

Diethyl acetylphosphonate (1.36)This compound was prepared from triethyl phosphite and

acetyl chlori de. B.p . 101-105°/ 5.5mm (Lit. b.p. 81-86 /4mm ).

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Diethyl q-diethoxyphosphinylethyl phosphate (1.38)(1.36) (l8g, 100 mmol) and triethyl phosphite (l6.6g,

100 mmol) were heated under reflux for 48hr. Distillation gave (1.38) (25g, 78 mmol) in 78% yield. B.p. 160-170 /0.3mm

n.m.r. +20, d; -0.5, d; Jpp=34-Hz.n.m.r. 61.3, 12H, t, J=7Hz

61.6, 3H, dd, J=16Hz , 7Hz64.1, 8H, m64.7, IH, m.

IR: 1270, 1040 cm'l.M'*' 318.

Diethyl 1-(diethoxyphosphinyl)vinyl phosphates (1.39)These compounds were prepared from triethyl phosphite

and the corresponding a-haloacid halides according to literature.

(1.39a): b.p. 120°/ 0.5mm (Lit. b.p. 125-126°/ 0.5mm ). (l,39b): b.p. 130°/ 0.08mm ( Lit. b.p. 128-129°/ 1.5ciml. (l.39c): b.p. 160 -180°/ 0.18mm.

Diethyl ethynylphosphonate (I.40)(1.39a) (l.59g, 7.9 mmol) was added to a solution of

LDA (16 mmol) in THF at -78°C with stirring; the reaction mixture was allowed to warm up to room temperature. The THF was eyaporated and the residue was taken up in dichloro­methane. This solution was washed with dilute hydrochloric acid and dried with MgSO^. Distillation gave (I.40) (0.84g, 5.2 mmol) in 66% yield. B.p. 110°/ 0.1mm (Lit.^^ b.p.75-77 /0.1mm).

^^P n.m.r. -8.7.^H n.m.r. 61.3, 6H, t, J=7Hz

63.3, IH, d, J=13Hz64.1, 4H, quintet, J=7Hz.

- 8 4 -

IR: 3400, 2050, 1250m'*' 162.

The crystalline compound from (l.39c) on heating at 200 C(1.42)(1.39c) (3g, 7.6 mmol) was heated at 200°C (oil bath

temp.) overnight; the resulting deep red viscous oil gave white crystals upon cooling. The crystals were separatedby filtration and recrystallized from ethyl acetate. Yield:

: (:31.(l.02g, 2.4 mmol). M.p. 213-214°.T n.m.r. 0.0.

n.m.r 61.2, 6H, t, J=7Hz6 4.1, 4H, m66.8, 2H, d, J=13Hz67.1-7.9, lOH, m.

IR(Nujol): 1730, 1650, 1270M'*' 420.[Found: C, 56.60; H, 5.29; P, 14.56%. *^20^22^2^6 acquires

C, 57.15; H, 5.28; P, 14.74%!

N,N,N’,N*-Tetramethylphenylphosphonic diamide (2.1)This compound was prepared from phenylphcsphonic dichloride

and dimethylamine, recrystallized from ethyl acetate.^^P n.m.r. +29.5.

n.m.r. 62.6, 12H, d, J=10Hz 67.3-7.9, 5H, m.

N,N,N’,N ’-Tetramethyl £-hydroxy(phenyl)methylphenyl phosphonic diamidë (2.3)

To a solution of (2.1) (2.12g, 10 mmol) in dry THF at -5° with stirring under was added n-butyl lithium (l.lM,10ml) through a syringe; the resulting deep red solution was stirred for 0.5hr. at room temperature then cooled to -5°C; benzaldehyde (l.2g, 11 mmol) was .then added. After 3hr.

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stirring at'room temperature, the solvent was evaporated and the residue was taken up in dichloromethane. The solution was washed with water and dried with MgSO^. The red oil obtained after removing dichloromethane crystallized from ether on standing to give (2.3), which was recrystallized from ethyl acetate. Yield: 72% (2.3g, 7.2 mmol). M.p. 125-127

n.m.r. +32.0n.m.r. 62.5, 6H, d, J=10Hz

52.7, 6H, d, J=10Hz56.2, IH, d, J=7Hz56.8, IH, d, J=7Hz, exchangeable with D„057.3, 9H, br.s.

IR(Nujol): 3230, 1300 cm‘ .M'*' 318.[Found: C, 63.90; H, 7.27; N, 8.60%. ^17^23^2^2^ requires

G, 64.0; H, 7.2; N, 8.8%].

2-Dimethylamino-jt-5-methyl-5H-l, 2-benzoxaphosphole r-2 (P) - oxide (2.4)

This compound was prepared from (2.1) (2.12g, 10 mmol) and acetaldehyde (0.44g, 10 mmol) in a similar manner to (2.3) at -40°G. Crystalline (2.4) was obtained after flash column chromatography (ether). Yield: 32% (0.67g, 3.2 mmol).M.p. 169-171°.

^^P n.m.r. +37.7.n.m.r. 61.6, 3H, d, J=6Hz

62.6, 6H, d, J=10Hz65.4, IH, quartet, d, J=6Hz , 3Hz67.2-7.7, 4H, m.

IR(lIujol): 1600, 1230 cm"^M'*' 211.[Found: C, 56.87; H, 6.71; N, 6.56%. ^10^14^^2^ requires

C, 56.9; H, 6.6; N, 6.6% ].

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2-Dimethylamino-5 ♦ 5-dimethyl-l, 2-ben.zoxaphosphole 2-oxide (2.5)This compound was prepared from (2.1) (2.12g, 10 mmol)

and acetone (0,58g, 10 mmol) in a similar manner to (2.3).Crystalline (2.5) was obtained after flash column chromatography(ether). Yield: 53% (l.2g, 5.3 mmol). M.p. 115-117°.

n.m.r. +35.7.n.m.r. 61.6, 3H, s

61.7, 3H, s52.6, 6H, d, J=10Hz57.1-7.7, 4H, m.

IR(Nujol): 1600, 1300 cm“ .M'*' 225.[Found: C, 58.4-8; H, 7.07; N, 6.18%. ^n^i6^^2^ requires

C, 58.6; H, 7.1; N, 6.2%].

2-Dimethylamino-5,5-pentamethylene-l,2-benzoxaphosphole 2-oxide(2.6T

This compound was prepared from (2.1) (2.12g, 10 mmol) and cyclohexanone (0.98g, 10 mmol) in a similar manner to (2.3). Crystalline (2.6) was obtained after flash column chromatography (ether). Yield: 67% (l.8g, 6.7 mmol). M.p. 117-119°.

n.m.r. +35.3.n.m.r. 51.8, lOH, br.s

62.6, 6H, d, J=10Hz67.1-7.8, 4-H, m.

IR(Nujol): 1600, 1235 cm"^.265.

[Found: C, 63.4-5; H, 7.55; N, 5.17%. ^1A^20^^2^ requiresC, 63.0; H, 7.5; N, 5.3%].

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N,N,N’,N’-Tetramethyl £-hydroxy(diphenyl)methyl phenylphosphonic diamide (2.7) '

This compound along with (2.8) were prepared in a similarmanner to (2.3). Separation by flash column chromatographyled to (2.7) (ig, 2,5 mmol) in 25% yield. M.p. 165-167 .

n.m.r. +33.4.n.m.r. 52.4, 12H, d, J=10Hz

57.2, 14H, s6 9.3, IH, s, exchangeable with D^O.

IR(Nujol): 3450, 1580, 1300 cm"^.394.

[Found: C, 69.71; H, 6.89; N, 6.94%. C^^H^yN^O^P requires C, 70.0; H, 6.85; N, 7.1%].

2-Dimethylamino-5,5-diphenyl-1,2-benzoxaphosphole 2-oxide (2.8)This compound was separated from (2.7) by flash column

chromatography (ether). Yield: 26% (0.9g, 2.6 mmol).M.p. 170-172°.

^^P n.m.r. +36.9.^H n.m.r 6 2.5, 6H, d, J=10Hz

6 7.3, 14H, m.-1IR(Nujol): 1590, 1230 cm

m’*' 349.[Found; C, 71.97; H, 5.79: N , 3.91%. * 21 20 * 2 requires

C, 72.2; H, 5.77; H, 4.0% ].

N,N,N ’,N’-Tetramethyl £-trimethylsilylphenylphosphonic diamidel2.9)

This compound was prepared from (2.1) (2.12g, 10 mmol) and trimethylsilyl chloride (l.OSg, 10 mmol) in a similar manner to (2.3). (2.9) was obtained as an oil after flashcolumn chromatography (ether). Yield: 74% (2.2g, 7.4 mmol).

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n.m.r +30.H n.m.r. 50.4., 9H, s

62.6, 12H, d, J=10Hz57.2-7.8, 4H, n.

IR: 1640, 1200 cm'^.M'*' 284.

N,N,N *,N *-Tetramethyl o-lithocarboxyphenylphosphonic diamide (2.lOT

This compound was prepared from (2.1) and dry ice at-78^C in a similar manner to (2.3). The solid product wasrecrystallized from ethyl acetate. Yield; 87^ (2.3g, 8.7 mmol)M.p. >350°.

n.m.r +34-.n.m.r 6 2.6, 12H, d, J = 9Kz

6 7.3, 4-H, br.s 6 7.9, IH, br.s.

IR(Nujol): 1620, 1300, 1200 cm” .

N,N,N’,N'-Tetramethyl o-diphenylphosphinylphenyl phosphonic diamide (2.11) ^

This compound was prepared by oxidation of the triaryl- phosphine which was obtained in a similar manner to (2.3) from (2.1) and chlorodiphenylphosphine. Thus, the crude product from (2.1) (2.12g, 10 mmol) and chlorodiphenylphosphine(2.2g, 10 mmol) was dissolved in dichloromethane. To this solution was added excess dropwise at 0°C with stirring.After 4-br. stirring at room temperature, the reaction mixture was washed with water and dried with MgSO^.Crystalline (2.11) was obtained after removal of the dichloro­methane; recrystallized from ethyl acetate. Yield: 81^(3.35g, 8 mmol). M.p. 138-14-0°.

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n.m.r. +33.4, 28.2.n.m.r. 52.5, 12H, d, J=9Hz

57.1-7.8, 14H, m.IR(Nujol): 1590, 1300, 1200 on"^.M'*' 412.

[Found: C, 59.23; H, 6.29; N, 6.19%. ^22^26^2°2^2

requires C, 64-.0; H, 6,36; N, 6.8%. ^22^26^2^2^2' requires C, 58.8; H, 6.68; N, 6.2%].

2-Dimethylamino-5-phenyl“5-p -bis (dimethylamino ) phosphinyl- phenyl-1,2-benzoxaphosphole 2-oxide (2.12}

This compound was prepared from (2.1) (l.7g, 8 mmol) and diethyl benzoylphosphonate (2g, 8 mmol) in a similar manner to (2.3). Crystalline compound was obtained in ether onstanding and recrystallized from toluene. Yield(2g, 4-. 1 mmol). M.p. 202-204-^.

^^P n.m.r. +37.2, +27.2.n.m.r. 52.4, 18H, m

57-8.2, 13H, m.IR(Nujol): 1600, 1300, 1240, 1200 cm"^.

483.[Found: 0, 62.22; H, 6.49; N, 8.55%. C2-H01N3O3P2

requires C, 62.0; H, 6.47; N, 8.7% ].

8-Bis(diemthylamino)phosphinyl-2,3 a-diphenyl-1,3a-dihydro- cycloheptimidazole (2.13)

This compound was prepared from (2.1) (2.12g, 10 mmol)and benzonitrile (2.1g, 20 mmol) in a similar manner to (2.3).Pale yellow crystalline (2.13) was obtained after flash columnchromatography (1:1 ether/ethyl acetate). Yield 82%(3.4-g, 8.1 mmol). M.p. 116-118°.

-90-

n.m.r. +34-.n.m.r. 61.9, IH, br.s. exchangeable with DpO

62.4, 6H, d, J=10Hz62.6, 6H, d, J=10Hz65.8-6.5, 4H, m66.9-7.4, 8H, m6 7 . 8,. 2 H , m.

IR(Nujol): 3200, I6OO, 1290 cm"^.418.

[Found: C, 68.44; H, 6.6I; N, 12.98%. Cg.HgyN.OPrequires C, 69.0; H, 6.5; N, 13.4%].

Methyl 1-diethoxyphosphinylmethyl sulphoxide (3.4)This compound was prepared from chloromethyl methyl

sulphide and triethyl phosphite followed by oxidation with1 7 31sodium periodate according to literature. P n.m.r. +l6

(Lit. ^^P n.m.r. +17.6).

1-Methylthio-l-diethoxyphosphinyl-trans-hept-3-ene (3.5a)

To a solution of (3.4) (2.14g, 10 mmol) in 20cm^ tri-fluoroacetic acid at 0°C with stirring was added trifluoro-acetic anhydride (2.2g, 10 mmol) and hex-l-ene successively;the reaction mixture was stirred at room temperature overnight,the trifluoroacetic acid was evaporated, and the residuetaken up in dichloromethane, washed with dilute aq.NaHCO^and dried with MgSO^. (3.5a) with trace of impurities wasobtained by distillation in 75% yield (2.1g, 7.5 mmol).P.p. 90°/ 0.001mm.

^^P n.m.r. +26.n.m.r. 60.9, 3H, t, J=7Hz

61.3, 6H, t, J=7Hz61.8-2.8, m q ,6 2 . 2 , s ; 4 b6 4.2, 4H, quintet, J=7Hz 6 5.5, 2H, m.

— 91 -

IR: 1640, 1220, 970 cm"^M'*' 280.

l-Methylthio-l-diethoxyphosphinyl-trans-non-3-ene (3.5b)

This compound was prepared from (3.4) (2.2g, 10 mmol)and oct-l-ene (l.3g, 11 mmol) in a similar manner to (3.5a)in 73% yield (2.25g, 7.3 mmol). B.p. 130°/ 0.001mm.

n.m.r. +26.2.n.m.r. 61.9, 3H, m

61.3, 6H, t, J-7Hz61.8-2.8, m62.2, s6 4.2, 4H, quintet, J=7Hz 6 5.5, 2H, m.

M'*’ 308.

5-Methylthio-5-diethoxyphosphinyl-trans-pent-2-ene (3.8)

This compound was prepared from (3.4) (2.2g, 10 mmol) and but-l-ene (ig, 18 mmol) in a similar manner to (3.5a) in 73% yield (l.83g, 7.3 mmol). B.p. 60°/ 0.002mm.

^^P n.m.r. +25.8.n.m.r. 61.3, 6H, t, J=7Hz

61.7, 3H, t, J=7Hz62.2, 3H, s6 2.3-2.9, 3H, m64.2, 4H, quintet, J=7Hz 6 5.5, 2H, m.

IR: 1210, 970 om"^.m'* 252.

^^0 n.m.r. 614.8516.2, 16.6 5 185 28.8, d, J=86Hz 541, d, J=151Hz 5 63.2, 63.75126.7, 128.3.

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Methyl diphénylphosphinylmethyl sulphoxide (3.11)Methyl diphénylphosphinylmethyl sulphide (3.10) was

18prepared according to literature,(3.10) (5.24g, 20 mmol) and MCPBA (85%, 4.45g, 22 mmol)

in dichloromethane were stirred overnight at room temperature; after washing with dilute aq. NaHGO^, the dichloromethane solution was dried with MgSO^. Evaporation of the dichloro­methane gave white solid which was recrystallized from ethyl acetate. Yield: 92% (5.1g, 18 mmol).

n.m.r. +25n.m.r. 6 2.9, 3H, s

63.8, 2H, d, J=9Hz •6 7.5-8, lOH, m.

5-Methylthio-5-diphenylphosphinyl-trans-pent-2-ene (3.12)

This compound was prepared from (3.11) (2.78g, 10 mmol) and but-l-ene (excess) in a similar manner to (3.5a). White solid was obtained in ethyl acetate on standing. Re­crystallization from ethyl acetate gave (3.12) (2.7g, 8.6 mmol) in 86% yield. M.p. 124-126 .

^^P n.m.r. +32.n.m.r. 61.6, 3H,m

Ô 2, 3H, s 6 2.5, 2H, m 6 3, IH, m 6 5.5, 2H, m 6 7.4, 6H, m 6 7.8, 4H, m.

IR(Nujol): 3040, 1180, 960 om"^.m '*' 316.[Found: C, 68.19; H, 6.72; S, 10.11%. requires

C, 68.35; H, 6.7; S, 10.1%].

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n.m.r. 514.7, 18, 30643.5, d, J = 6 8 H z6128.1, 128.6, 130.7, 131.1, 131.6, 135.

1-Diethoxyphosphinyl-l,3-pentadiene (3.14)To a solution of (3.8) (2.52g, 10 mmol) in methanol at

0°C with stirring was added dropwise aq. solution of sodiumperiodate (2.14g, 10 mmol). The reaction mixture was stirredat room temperature overnight; solid was separated by-filtration; the filtrate was extracted with CHGl^ (20cm^x 3),dried with MgSO^. The resulting sulphoxide (3.13) decomposedto give (3.14) on distillation. Yield: 65% (1.3g, 6.5 mmol).B.p. 60 / 0.05mm.

n.m.r. +19.1.n.m.r. 61.3, 6H, t, J=7Hz

61.9, 3H, d, J=5Hz64.1, 4H, quintet, J=7Hz 6 5.3-7.7, 4H, m.

IR: 1650, 1600, 1250, 960 cm'l.m'*' 204.

-94“

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SOME NEW REACTIONS OF PHOSPHORATES

byDASHAN LIU

ABSTRACTS

The chemistry of a-ketophosphonates has been reviewed. New applications of a-ketophosphonates in synthesis are described. 1,3-Diketoalkylphosphonates have been used to prepare phosphinyl - substituted heterocycles and imines derived from a-aminophosphonates have been used in syntheses of pyridyl phosphonates and in 1,3-dipolar and carbanion additions to olefins.

Acetylenic phosphonates have been prepared from a-phosphinylvinyl phosphates. The reactions of a-keto­phosphonates with trialkyl phosphites are described; their use in 'ene' reactions has been investigated.

N,N,N’,N’-Tetramethylphenylphosphonic diamide has been ortho-lithiated and the resulting aryl-lithium reacted with a series of electrophiles.

The Pummerer reaction intermediate from methyl diethoxy- phosphinylmethyl sulphoxide has been trapped with 1-alkenes and the oxidative desulphurization of the products investigated