6 Ylides and Related Compounds

BY 6. J. WALKER

1 Introduction

An edition of Chem. Rev. (1994, 94) entirely dedicated to phosphorus chemistry has been published and contains two articles relating to ylide chemistry (see refs. 1 and 45).

Fewer new studies of the Wittig mechanism have appeared this year than previously. However, stereochemical control in phosphorus- based olefina tions continues to be a topic of substantial interest. In addition to further studies of the control of olefin stereochemistry there have been a number of reports of enantioselective olefinations and the use of ylides and phosphonate carbanions to achieve high levels of asymmetric induction.

The use of complex phosphonates, phosphine oxides and phosphonium salts, in one case with a molecular mass of approximately 800, in the synthesis of a wide range of large molecules continues and increases.

2 Methylenephosphoranes

2.1 Preparation and Structure. - The nature of bonding in phosphonium ylides, phosphines and phosphine oxides has been critically reviewed in an article that perhaps finally ends speculation that d-orbitals are involved in such bonding by showing that involvement is both highly unlikely and unnecessary.’

a-Oxy ylides, e.g. (l), are suggested to be formed in the electrolysis of keto acids with triphenylphosphine (Scheme 1). Compounds (1) appear to act as novel acyl anion equivalents since cyclic a-hydroxy ketones are the products isolated.2 Dichloro- (2)3 and difluor0-(3)~ methylene ylides have been generated electro- chemically from the corresponding phosphonium salts and undergo Wittig reactions with aldehydes to give gem-dihalogenoalkenes in good yields. Ylide intermediates, e.g. (9, have been proposed for the phosphine-catalysed, unusual y-addition of alcohols to ester-activated a l k y n e ~ . ~ The reaction is illustrated here by an intramolecular example (4) but also occurs intermolecularly.

Tellurophosphoranes (6) have been prepared and shown to react with alde- hydes in siru to give vinylic tellurides with (Z)-stereoselectively.6 The first example of an a-selenoarsonium ylide (7) has been reported and shown to undergo (2)- stereoselective Wittig reactions.’ a-Mercurio-substituted phosphonium ylides (8) have been synthesised by the reaction of alkylidenephosphonium ylides with bis[di(trismethylsilyl)amino] mercury.* Compounds (8) undergo normal Wittig reactions to give vinyl mercury compounds.

264

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6: YIides and Related Cotnpounh 265

Reagents: i , BusP, MeS03H, CH2C12, PhCH2NEt3CI-; ii, 28; iii, H 2 0

Scheme 1

(M@J)3P = CX2 (2) X=CI (3) X = F

R

TePh PhSP

Ph3P=C: Ph&= CHSeR Ph

(6) (7) (5)

A number of mixed phosphine-phosphonium ylides have been prepared. The ylide (10) is the ultimate product from the iodine-induced coupling reaction of the bisphosphine carbanion (9)9 and a range of ylidic-dihalogenophosphines (1 1) have been prepared by the reaction of phosphonium ylides with phosphorus trihalides.'* The structures of (1 1) have been studied by NMR spectroscopy and X-ray crystallography. A number of, in some cases novel, heterocyclic phos- phorus ylides, e.g. (12) and (13), have been synthesised and their structures determined. * Phosphine carbanions, including tetralithiated dibenzyl(methy1)-

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266 Organophosphorus Chemistry

phosphine (14), have been generated and their structures determined.'* The 1 ,215-azaphosphete (1 6) has been synthesised in excellent yield from the azirine (15) and fully characterised by 13C, 31P, and 29Si NMR spectroscopy.13

4 Li+.2 tmeda (14)

The thermally stable acylbismuthonium ylides (1 7) have been prepared by base-treatment of the corresponding salt. l4 The formation of a,P-epoxyketones in moderate to good yields on reaction with aldehydes is typical of the reactivity of (1 7). The presumed intermediate (1 8) in boron-Wittig reactions has been synthe- sised and its structure and decomposition investigated.Is

Ph3Bi =CHCOR' + R2CH0 - Ph3Bi+ R2hH H C02R'

(17)

MeS.. - Me X K+OI 8-cs Ar -Pg Ar =

M 9 4 & C F 3 NAr

CF3 (19) X = NH (20) x=o (18)

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6: Ylides and Related Compoundy 267

New chemistry of a number of low co-ordinate P' ylide like structures has been reported. Imido-( 19) and oxo(imido)-(20) phosphoranes have been prepared and their structures confirmed by X-ray crystallography.16 Monomeric tri(imino)- metaphosphates, e.g. (21), have been generated and their X-ray structures reported. l 7 The 2,4-di-rert-butyl-6-( 1 -piperidino)phenyl group has been used to stabilise the diselenoxophosphorane structure and X-ray analysis shows that this is achieved with nitrogen co-ordination to phosphorus to form a four-membered ring (22) with a highly distorted P-C-C bond angle.'* Yet another theoretical study of the simplest phosphonium ylide (23) and its Wittig reaction with formaldehyde has appeared.I9 However, this latest report also includes a study of ylide formation from the corresponding phosphonium salt and a comparative study of the formation, structure and reactivity of ylides derived from the other elements in group 15. Explanations of the differing stabilities,. structures and modes of reaction of the different ylides are provided by the results. The energy and structure of bis(methy1ene)phosphorane (24) have been calculated for both singlet and triplet states using an ab initio MP4/6-3 lG**//MP2/6-3 1G** met hod. 2o

Reports concerning the structure of stabilised ylides include a detailed 'H, I3C, and 31P NMR study of the conformation, and the factors influencing the conformation, of phosphonium ylides (25), (26), (27), and (28) derived from succinic acid2* and a chemical, spectroscopic and X-ray structural study of the

NAr

NAr A ~ N H P ~

'I'

nBuLi

THF

LT.4 THF

+ (22)

CH~CO~R' ,CHMeC02Et P h,P = C: Ph,P=C,

C02R2 CO2Et

(26) R' = H, R2 = Et (27) R' = R2 = Et

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268 Organophosphorus Chemistry

mesomeric phosphonium ylides (29).22 The relative contributions from ylide and betaine structures in (29) depend on the nature of X.

Silylmethylene aminophosphonium ylides (30) have been prepared by silylation of the corresponding methylene aminophosphonium ylide and their structures investigated by 'H, 13C, I5N, "0, 29Si, and "P NMR.23 The neutral ylide complex (31) has been isolated and its structure determined by X-ray crystal- 10graphy.~~ Methylenetriphenylphosphorane reacts with 2,4,6-trimethylphenol to give the expected phosphonium aryloxide which X-ray crystallography shows to exist as a dimer, aggregated solely through CH-O hydrogen bonding by alkyl and aryl hydrogens of the phosphonium cation, in the solid state.2s

+ 2(R2N)3P=CH2 + C12Si(OR')2 - 2(R2N)$=CHS(OR1)2 + (R2N13PCH3 CI-

I CI

(30)

2.2 Reactions of Methylenephosphoranes 2.2.2 Aldehydes. - The stereochemistry and mechanism of the Wittig reaction has been the subject of a major review26 although few significant new mechanistic studies have been reported this year. It has been reported that Wittig reactions of unstabilised ylides give equilibrium mixtures of ( E ) and (2) disubstituted alkenes when carried out under daylight lamp irradiati~n.~' According to a recent report "remarkable rate enhancements and dramatic reductions of reaction times" are achieved by using microwave irradiation in Wittig reactions of stable ylides with aldehydes2* Kinetic resolutions of racemic aldehydes, e.g. (33), by reaction with chiral phosphonates (32) have been in~es t iga ted .~~ Good levels of diastereoselec- tivity and (2)-selectivity were achieved but generally not in the same reactions. An enantioselective synthesis of 4(R)-4-hydroxycyclopntanones (35) in one-pot by the Wittig reaction of chiral glyoxals (34) followed by Pd-induced de- carboxylation (Scheme 2) has been reported.30

OCHO (32) R = Me, Et, P4, CFaCHz (33)

f.3-Enehydrazino phosphonium salts (36), and B-hydrazono phosphine oxides (37) and phosphonates (38), have been prepared and the derived ylides and carbanions used in olefination reactions for the synthesis of a,B-unsaturated

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6: YIides and Related Compoundr

0

269

Reagents: i, Ph3P=CHCOCH2C02Allyl; ii, Pd(Ph3P)*, morpholine, THF

Scheme 2

(37) R’ = Ph (38) R’ =OEt

hydrazones, pyrazolines and pyrazole derivative^.^' Enolates of acyl phosphor- anylidene carboxylate esters (39) react with aldehydes to form adducts (40) which, on oxidation with ozone, followed by acid-catalysed dehydration, give 3- hydroxyfuran-2-carboxylates (41) (Scheme 3).32 (E,Z)-Dienes have been synthe- sised with stereoselectivities of between 20:l and 2:l over the (E,E)-isomers by treatment of butadienyltriphenylphosphonium bromide with an ionic nucleophile to generate the appropriate ylide, followed by addition of an aldehyde (Scheme 4).33 The effect of the nature of the nucleophile and the aldehyde on the stereochemistry of the diene formed was also investigated. Further evidence34 that epi-phosphonium salts (43) are intermediates in the stereoselective synthesis of alkenes by treatment of 2-hydroxyalkylphosphines with PC13 and triethy- lamine35 is provided by the independent generation of (43) from the a- bromobenzylphosphonium salt (42).

Arsonium ylides continue to be studied and in some cases provide useful

1- 0

i i i , iv I

Reagents: i , LDA; ii, R3CHO; iii, 03; iv, H30+

Scheme 3

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270 Organophosphorus Chemistry

+ I - -/

Ph,P

Br-

0 - 0-

I ii m R R' 0

Reagents: i, 2Li+, - 78 "C - 0 "C, 1 h; ii, RCHO, THF, 10 rnin / / R

Scheme 4

Ph x Ph Br- PhCH= CHPh - 50-80% (2 )

alternatives to the phosphonium analogues. The previously unknown 1 -alkyl analogues (45) of l-(alkoxycarbony1)-methylenetriphenylarsonium salts have been prepared by quarternisation of triphenylarsine with the appropriate triflate ester (44). Wittig reactions of (45) with aldehydes using alumina-supported potassium fluoride as base provide good yields of the corresponding Wittig product, exclusively as the ( E ) - i ~ o m e r . ~ ~ Attempts to carry out similar reactions

F? +

8 Ph3As + CF3S-O-CHR2C02R1 - Ph3AsCHR2C02R1 X -

(44) R3COR4 (45' R3CH0

R'0& R&T C02R' H C02R'

(46)

with ketones gave, as major products, alkenes (46) derived from coupling of the arsorane ligand. The yield of (46) is optimised in reactions carried out in the absence of the carbonyl component. Many ar-selenophosphonium ylides and a- selenophosphonate carbanions are not sufficiently reactive to undergo the Wittig reaction. However, acyl- (47)37 and alko~ycarbonyl-(48)~~ (phenylseleny1)methy- lenetriphenylarsonium ylides have now been prepared by phenyiselenation of the corresponding stabilised arsonium ylide and, as expected in view of the greater reactivity of arsonium ylides, shown to react with aldehydes to give moderate

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6: Yiides and Related Compounds 27 1

yields of predominantly (2)-a-phenylselenyl a,p-unsaturated ketones and esters (49) (Scheme 5).

+ 2 Ph3As=CHCOR + PhSel - Ph3AsCH2CORI - + Ph,As=C-COR

(47) R=Alkyl SePh (48) R = 0 Alkyl 1 ii

H COR

RHSePh

(49) R = alkyl. 0 alkyl

Reagents: i, Et20, MeOH, R.T.; i i , R'CHO, CHCl3, 55-65 "C

Scheme 5

2.2.2 Ketones. - The stereochemistry of the Wittig reaction of substituted-phenyl 3-pyridyl ketones (50) with unstabilised a-carboxyalkylphosphonium ylides derived from salts ( 5 1) has been inve~t iga ted .~~ Both 3- and 4-sulfonamidophenyl 3-pyridyl ketones provide high levels of (@-selectivity, whereas other substituents generally lead to poor levels of (2)-selectivity. An explanation, involving H- bonding or salt bridging in the oxaphosphetane intermediates, is presented and supported by both experimental and theoretical results.

x-$iJ Br- NaHMDS.

THF

(51)

An intensive study of the use of the Wittig reaction of methylenetriphenyl- phosphorane to introduce a methylene group in the synthesis of a number of conjugated caradienes, e.g. (52), has been reported. All the known problems with this type of reaction, low yields, enolate formation, isomerisation, side reactions of phosphonium salt to give benzene etc., are encountered. Phosphoranes (53) derived from a,P-unsaturated esters react with 1,2-diacy- lethenes at room temperature to give poor to excellent yields of double bond isomers, e.g. (54), of cyclopentadienes and none of the alternative cyclohexadiene product^.^' The reaction of 2-allyl-1,2-dihydroindol-3-ones (55) with stabilised phosphonium ylides under vigorous conditions provides a synthesis of 3-substi- tuted indole acetates (56) in moderate to good yields via a tandem Wittig

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272 Organophosphorus Chemistry

(52)

+RR’ R’

Ph,P=CHACHC02Et + $COCH=CHCOR2 - R2COCH2 C02Et

(53) (54)

X

Ac Ac

(55) (56)

reaction/Cope rea~~angernent.~~ Enantiopure a-aminoketones (57) are converted enantiospecifically, presumably ultimately by an intramolecular Wittig reaction, into 3-pyrrolines (58) by treatment with sodium hydride followed by vinylphos- phonium salts (Scheme 6).43 The aziridyl ketones (59) have been converted, in one-pot and diastereospecifically, into the unsaturated cis-piperidines (60) by reaction with methylenetriphenylphosphorane via a combination of Wittig olefination and aza-Wittig rearrangement.44

(57) X = SOZPh, COPh (58)

SPh Reagents: i, NaH; ii, ++

PPh3

Bu‘O~C 0 +

R

2 Ph3PCH3 Er-

BULL OM€. R.T.

H

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6: Ylides and Related Compoun& 273

2.2.3 Miscellaneous Reactions. - The synthetic applications of metallated phosphonium ylides and metallated phosphine imines have been reviewed.45 Cyanomethylenetributylphosphorane (6 1) has been investigated as an alterna-

tive to DEAD/triphenylphosphine in the Mitsunobu reaction.46 A similar inter- mediate (62) is probably generated in each case but the ylide route is often superior, especially for the alkylation of weaker acids, e.g. (63) and (64).

R’OH + Bu~P=CHCN + HA - CHBCN + R’OPBU~A-

a: y, NHMe

(62)

I R‘A + Bu3P=0

PhCHzNHCOCF3

Individual enantiomers of the oxaphospholane (65) have been obtained by resolution of their tartrate salts.47 Reaction of each enantiomer with paraformal- dehyde in sulfolane provides optically pure methylidenecyclopropylmethanols (66). The reaction of 1,2-dioxetanes (67) with unstabilised and semi-stabilised phosphonium ylides leads to the formation of the dipolar phosphonium alkoxides (68) which are in equilibrium with the cyclic isomers (69).48

The reaction of the cumulated ylide (70) with alkyl halides or bromine gives the cyclic ylide/phosphonium salts (71).49 Ring-opening reactions of (71) give a

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274 Organophosphorus Chemistry

2 Ph3P=C=C=O + RX - (70) (71)

?- 0- I

RCHO + Ph3P=CHMe - Ph,G-CHMeCHR - Ph3P=?-CHR

Me

1 - ph,~*--cMecHR H Me I I

I -0 (73)

Reagents: i, BuLi, THF; ii, ICH,CH,I

Scheme 7

variety of ylide and phosphonium salt products depending on the conditions. A new, highly stereoselective route to (Z)-2-iodoalk-2-enes (73), involving the reaction of P-oxidoalkylphosphonium ylides (72) with 1,2-diiodoethane (Scheme 7), has been reported.50 A detailed kinetic study of the reaction of excess cyclopentadienylidenetriphenylphosphonium ylide (74) with bromanil and chlor- anil to give 2,5-(76) and 2,6-(75) disubstituted quinone derivatives shows that the products are formed by two parallel, second order reaction^.^' A similar reaction

0

0

X = CI or Br (74)

with fluoranil yields the corresponding Jisubstituted q ~ i n o n e . ~ * Reaction of

0

(75) Y = D P P h 3 , Z = X \

monosubstituted quinone and the 2,6- the a-pyrone-derived ylide (77) with

isocyanates followed by reductive removal of phosphorus has been used to synthesise a-pyrone acetamide derivatives (78) (Scheme 8).53 On treatment with alkali metal thiolates (1 -ethoxycarbonylcyclopropyl)phosphonium salts (79) are converted, via the ylides (80) and an intramolecular Wittig reaction, to the 4,5- dihydrothiophenes (8 1).54 Unstabilised and semi-stabilised phosphonium ylides

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6: Ylides and Related Compoundr 275

react with fullerene with elimination of triphenylphosphine to give 6,6-closed methan~fullerenes.~~

no ArNHCOCH, P h 3 P y J 0 - i . ii

Et02C NHCOPh EtO2C NHCOPh

(77) (78)

Reagents: i, ArNCO, CH2C12; ii, Zn, AcOH, CHCl3

Scheme 8

(79)

In an extension of studies of the synthesis of fluoroalkylphosphonates Shen has used the reaction of trifluoromethylated P-oxophosphonium salts (82) with dialkyl methylphosphonate carbanions to prepare trifluoromethylated allylphos- phonates (83) in moderate yields.56 Stabilised and semi-stabilised phosphonium ylides (85) react with N-fluoropyridinium salts (84) to give alkenes (86) in moderate yield.57 The reaction is thought to involve initial SET from (85) to (84) followed by dimerisation of the intermediate radical cations (87).

R R

+2Ph3P=CHY - +Ph3?0 R y+ R Y R N, R

H + Ph3P x - X -

(84) (85) (86)

The oxidation of ylides continues to be used to synthesise carbonyl compounds. Examples include the conversion of the amino acid-derived keto phosphoranes (88) to a variety of 1,2-dicarbonyl derivatives (89) by reaction with ozone in the presence of nuc le~ph i l e s~~ and the synthesis of bis(trimethylsily1) ketone (90) by treatment of bis( trime thylsi 1yl)methylene- trip hen y lphosphorane with the ozone- phosphite a d d ~ c t . ~ ~ Full details have appeared of the synthesis, via treatment of

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276 Organophosphorus Chemistry

the appropriate phosphonium ylide with elemental selenium, reactions, and X- ray structure of diary1 selenoketones (91).Ml

The synthesis of acetylenes by the pyrolysis of P-carbonyl ylides has been known for more than thirty years. However, recently Aitken and co-workers have considerably extended the reaction through a number of detailed studies using flash vacuum pyrolysis (FVP). Enynes (93) have been prepared in poor to moderate yield from cinnamoyl ylides (92).61 At 500 OC the (2)-alkene is obtained almost exclusively, while at 7OOOC equal mixtures of isomers are formed. u- Ethoxycarbonyl ylides retain the carboxyl group on FVP at 500°C but de- carboxylate at 750OC. For example, (94) gives (95) or (96),62 and (97) gives (98) or (99)63 depending on the pyrolysis temperature. A variety of, in many cases novel, trioxophosphonium ylides (1 00) have been prepared and subjected to FVP

R-C,C-CSC-C02Et

(98)

R-CEC-CGCH

d (99) (97)

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6: Ylides and Related Compounds 277

to give diacylalkynes.@ At 700°C FVP of 2-methoxy- and 2-methanethio- benzoylalkylphosphonium ylides (101) gives the expected alkynes (102) while at 850 OC further reaction occurs to give benzofurans or benzothiophene~.~~ Moderate yields of naphthalene derivatives (104) are obtained by FVP of substituted cinnamoylphosphoranes (103) at 900 O C and the mechanism of the reaction has been investigated using deuterium labelling studies.&

EtSN Ph3P=CHCOR' + R2COCOCI

R' 0

500 "C, FVP 1 8 f?

R'C-CZC-CR~

(101) x =o, s c\lP

R' ' c' ac= (102)

XMe

850 "C. N P 1

- FVP R2pR3 900 "C

A variety of metal complexes, e.g. (105), based on the isophosphindolylium structure have been synthesised and ~ha rac t e r i s ed .~~ P-H-Functionalised ylide- carbene complexes (106) and (107) have been prepared and the structure has been confirmed in the case of (106) by X-ray crystallography.68

OEt

(106) M=Cr (107) M = W

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278 Organophosphorus Chemistry

3 The Structure and Reactions of Phosphine Oxide Anions

De-racemisation of (1 -methyl)benzyldiphenylphosphine oxide ( 108) has been achieved by treatment of the corresponding racemic carbanion with a number of chiral acids.69 The highest e.e. value (88%, which could be increased to > 99% by one crystallisation) was obtained using the chiral acid (109). The comprehensive study carried out on the reaction suggests that the asymmetric induction derives from protonation directly by ( 1 09) rather than protonation of a complex of (1 09) and the carbanion during the work-up. Continuing his investigation of acyl transfer in phosphine oxide carbanions, Warren has investigated such reactions of single diastereoisomers, e.g. (1 lo), of benzoates of 3-hydroxyalkyldiphenyl- phosphine oxides in the presence of trimethylsilyl chloride to trap the stabilised tetrahedral intermediates, e.g. (1 1 l ) , and shown'O that there is a high degree of stereochemical control at the two newly created chiral centres (Scheme 9).

? xr" 'NHPh

Reagents: i, 4 Me,SiCI; ii, 1.2 LDA; iii, H20

Scheme 9

P-Hydroxyphosphine oxides ( 1 12) containing a tertiary alcohol function, and hence 1,l-disubstituted alkenes, have been conveniently prepared by the reaction of P-ketophosphine oxides with organolithium reagents in the presence of anhydrous cerium trichloride." This type of approach was first used by Johnson72 to reduce the basicity of alkyllithium reagents. Homochiral diphenyl- phosphinoyl hydroxy aldehydes (1 14) have been synthesised with moderate diastereoselectivity by addition of methyldiphenylphosphine oxide carbanion to the chiral keto aminal ( I 13).73 Reduction of a single isomer of ( 1 14) by lithal leads to the corresponding diol(ll5) with > 97% e.e. An alternative enantioselec- tive approach, with e.e. values in the range 10-88%, to diols (1 15) and related compounds using Sharpless dihydroxylation of the corresponding allylic- phosphine oxide has also been rep~r ted . '~

A range of benzyldiphenylphosphine oxides (1 16), conveniently prepared in one-pot from aromatic aldehydes by sequential reaction with chlorodiphenyl- phosphine and reduction, give excellent yields of (0-stilbenes with greater than

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6: Ylides and Related Compoundr 279

0 0 0 OH

P h 2 b 1 d R' + R2Li '''I3 THF P h 2 $ 4 R I

R2

2% HCI. CH2CIz I (113) R = Ph, Me

LiAIH, 0

P h 2 k / X C H 0 HO R

(114)

95% selectivity on treatment with butyllithium and an aldehyde (Scheme The authors note that similar reactions using lithium bases generally give intermediate P-hydroxidophosphine oxides rather than alkenes. However, i t seems likely that the conjugated alkene product is an important factor in determining the course of such reactions.76

(1 16)

Reagents: i, Ph2PCI; ii, NaBH,, DMSO; iii, BuLi; iv, RCHO

Scheme 10

CI * ? ! ? LDA: R'CHO

Ph2pYSR CI

l-Chlorovinyl sulfoxides (1 17) have been prepared, with excellent (2)-selec- tivity in most cases, by the reaction of (1 -chloro)sulfinylmethyldiphenylphosphine oxide anions with aldehyde^.'^ Thio- and seleno-amides have been prepared in good to excellent yields by the reaction of a-aminoalkyldiphenylphosphine oxide anions with sulfur and selenium, re~pectively.~~

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280 Organophosphorus Chemistry

4 The Structure and Reactions of Phospbonate Anions

Continuing their investigations of chiral phosphorus-stabilised carbanions, Denmark's group have synthesised the camphor-based phosphonates (1 18), ( I 19), and (120) and investigated their olefination reactions with 4-substituted cyclohe~anones.~~ The best yields and highest levels of enantioselectivity (up to 86% e.e.) were obtained using phosphonates (118) and (120). The normal

difficulties associated with the sensitivity of a-aminoaldehydes to base-induced racemisation has been turned to advantage to achieve a dynamic kinetic resolution. Treatment of the racemic aldehydes (1 21) with chiral phosphonates (122) in the presence of excess base gives the alkene product (123) with d.e. values of up to 94%.80 Poor to moderate diastereomeric excesses and moderate to good olefin stereoselectivity have been obtained in the Wadsworth-Emmons reaction of the dimethyl phosphonate (1 24) with (+)-2-phenylpropanol under various conditions.8' Similar d.e. values but much higher olefin stereoselectivity is obtained from similar reactions of the corresponding diisopropyl phosphonates (1 25) and diphenylphosphine oxides (1 26).

It is interesting to note that, unlike analogous alkyl esters, the diphenyl phosphonate (127) reacts with aldehydes in the presence of Triton B or sodium hydride as base to give alkenes with high (Z)-selectivity.82 Olefination reactions

(124) R = OM? (125) R = Opt' (126) R=Ph

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6: Ylides and Related Compounds 28 1

of ester-stabilised phosphonates with a-hydroxy ketones in the presence of molecular sieves give butenolides (1 28) in moderate to good yields.83 Reactions in the absence of molecular sieves give very poor yields. Copolymers of styrene and methyl methacrylate with diethyl vinylbenzylphosphonate have been prepared and used in Wittig reactions to synthesise polymers carrying stilbene substitu- e n t ~ . ~ ~ Treatment of diethyl trichloro-methylphosphonate with base followed by aldehyde at - 100 OC has been reported to give 1,l -dichl~roalkenes.~~ However, it

C02Me

R2?' + (Me0)2PCHC02Me E - LtOH. R2 vo + R3fOH THF 4 A

I R

mol. sieves R' R2 R1 R' OH

C02Me

R2?' + (Me0)2PCHC02Me E - LtOH. R2 vo + R3fOH THF 4 A

I R

mol. sieves R' R2 R1 R' OH

is now reported that by increasing the reaction temperature to - 7 O O C and using half an equivalent of base, vinylphosphonates become the major products.86 I t is suggested that the reaction occurs via initial formation of the bisphosphonate (129) followed by olefination. A new approach to p,y-unsaturated amines, using the reaction of amines with p-diethoxyphosphonyl-y-butyrolactones (1 30) to generate the appropriate Wadsworth-Emmons intermediate (1 3 l) , has been

! 0 II

(Et0)2PCC12Li +CI,C-P(OEt)2

rep~rted.~' A tandem Wadsworth-Emmons-Michael addition reaction of hemi- aminals (1 32) with phosphonate anions gives 5-substituted proline derivatives (1 33) with high diastereo- and enantio-selectivity.88

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282 Organophosphorus Chemistry

A study of the optimum conditions required for the synthesis of phos- phonoacetates (1 34) by reaction of phosphonate carbanions with methyl chlor- oformate has been reported.89 The reaction of dimethyl methylphosphonate carbanion with cyclic anhydrides, lactones and other electrophiles has been used to prepare a variety of functionalised phosphonates, e.g. (135) and (136).90 As might be expected the reaction of dicarboxylate esters with excess lithiomethyl- phosphonates leads to the formation of bis-0-ketophosphonates ( I 37).9' Com- pounds (1 37) provide access to phosphorylmethyl cycloalkenones (1 38) viu

intramolecular olefination reactions. The acylated fluoroalkylphosphonates ( 1 39) have been prepared by the reaction of diethyl fluoro(carboethoxy)methyl- phosphonate carbanion with alkyl oxalyl chlorides.92 The reaction of (1 39) with Grignard reagents provides a route to a-fluoro-a,p-unsaturated diesters (1 41), presumably via the Wadsworth-Emmons intermediates (1 40). Highly selective y- functionalisation of 2-butenylphosphonates to give (142) and (143) has been

Li+

(EtO).&FC02Et + CICOC02R -

F

EtO&C=CR'CO2R c-

(? (EtO)zP-~FCOC02R

(139)

CO2Et

R'MgX

1 1

. o

(140) -I

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6: Ylides and Related Compounh 283

achieved by specific a-silylation of the carbanion followed by reaction with the appropriate electrophile (Scheme 1 l).93 A highly (a-selective, one-pot synthesis of primary allylic amines in good yield, by reaction of methylphosphonate carbanion with nitriles followed by olefination and reduction, has been reported (Scheme 1 2).94 A new, one-pot synthesis of a,p-unsaturated trifluoromethyl ketones involves the reaction of phosphonate carbanions with N-phenyl-trifluoro- acetimidoyl chloride followed by olefination and hydrolysis (Scheme 1 3).95

Me$i Li'

I iv, v

Me

(142)

4 (EtO),P-CO,Et ?

Me

(143)

Reagents: i, 3 LDA, T H F , - 70 "C; ii, Me3SiC1, - 70 "C; iii, HC02Et; iv, HsO'; v, ClCOzEt

Scheme 11

Stabilised phosphonate carbanions derived from 2-phosphoryl-substituted cyclic ketones (144) react with activated alkenes or mono activated alkynes to give 1,4-addition and enantio-selective Robinson annulation depending on the e l e~ t roph i l e .~~ Similar reactions with dimethyl acetylenedicarboxylate lead to [n + 21 ring-expansion reactions (Scheme 14).96,97 A mechanism analogous to that previously suggested for the reactions of certain stabilised phosphonium ylides with activated alkynes, and involving tandem Michael-aldol-fragmentation, is suggested.

iv- vi I R2

Reagents: i, BuLi, THF, -78 "C, 1 h; ii, R'CN, - 78 "G- - 5 "C, 1 h; iii. R2CH0, - 5 "C - r.t., 30 min; iv, NaBH,, MeOH, - 78 "C; v, H,O+; vi, -OH

Scheme 12

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284 Organophosphorus Chemistry

H R% CF3

CF3

iv, HCI, rat. CI Reagents: i, 2 LDA, THF, -70 "C; ii, P N P h , -70 "C; iii, R2CH0. -70 "C;

Scheme 13

(144) n = 1,2,3,4

Reagents: i, Base; ii, Me02CC=CC02Me

Scheme 14

a-Phosphorylvinyl selenides (146) have been prepared in excellent yield from a- phosphoryl sulfoxides ( 145).98 Oxidation of (146) followed by heating in benzene provides alkynylphosphonates (147), also in good yield (Scheme 15). Autoxida- tion of the carbanions generated from the phosphonates (148) in the presence of oxygen gave pale blue light emission in the dark.w This chemiluminescence is suggested to provide strong evidence for the involvement of phospha- 1,2- dioxetanes (149) in these reactions.

(Et0)2!+ - i-iii

iv, v * (EtO),PCGCR f R

(1 45) (146) (147)

Reagents: i, BuLi, - 78 "C, THF; ii, PhSeBr; iii, 80 "C; iv, H202; v, heat, benzene

Scheme 15

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6: Ylides and Related Compoundr 285

M e N g BU'OK

0 2

Me N$ 0 ::: M e N g O * +OPR2 - R

Tricarbonyl(vinylketenimine)iron(O) complexes (1 5 1) have been prepared in moderate to excellent yield by the reaction of the corresponding vinylketene complex (1 50) with N-alkyl(ary1)phosphoramidate anions.Im

5 Selected Applications in Synthesis

5.1 j3-Lactams. - Intramolecular Wittig reactions continue to be used to construct five- and six-membered rings in bicyclic B-lactam structures. For example, the phosphonium ylides (1 52), derived from the corresponding alcohol, have used to synthesise 3-benzoylpenams (1 53). lo' The ylides (1 54), which cyclise

on heating in toluene to give penams (155), have been efficiently synthesised under mild conditions from the a-keto ester derivative (Scheme 16).lo2 The ylide (1 56), obtained from 3,4-di-O-trimethylsilyl-~-arabinal in six steps, is a key intermediate in the synthesis of 6(R)-4-ter~-butoxycarbonyl-7-hydroxymethyl-l- oxa-3-cepha m (1 57). lo3

The sidechains for a range of potent j3-lactam antibiotics, e.g. (160), have been constructed using the Wittig reaction with a-keto oximes (158) to form vinyl- oximes (1 59).Iw Cephalosporin C-3-phosphoranes, generated in siru from the salt (1 6 I), react with 1,2-dicarbonyl compounds to give 3-alkenylcephams (1 62) and the novel tricyclic derivatives (163) depending on the nature of the dicarbonyl

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286 Organophosphorus Chemistry

R02C' R02C'

OR

Reagents: i, (Et0)2PMe, Ph3P; ii, Toluene, heat

Scheme 16

B"'O*C

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6: Ylides and Related Compounds 287

compound.'05 Primary amine groups have been protected as s-triazine derivatives during Wittig reactions and the method applied to p-lactam chemistry.106

5.2 Carbohydrates. - Carbohydrate-derived P-ketophosphonates, e.g. ( 164), have been prepared by acylation of dimethyl lithiomethylphosphonate and converted into a variety of enone derivatives, e.g. (165), by reaction with

0 II

COCH2P(OMe)2

BnO O O M e OMe

aldehydes.'" The Wittig reaction of the ylide (166), derived from (R)-( +)- limonene, with P-D-ribo- 1,4-dialdofuranoside ( I 67) provides ( I 68) which, fol- lowing hydrogenation, acts as a model intermediate for the synthesis of terpenyl tetraols.Io8 Hydroxy alkenes, e.g. (169), generated by Wittig reactions of saccharides, continue to be useful intermediates in carbohydrate synthesis. lo9

0 0

X CH20Bn C H 2 0 B n

+ Ph,P=CH2 - BnO- BnO BnO

B n o T L J d H OBn OBn

5.3 Carotenoids, Retenoids, Pheromones and Polyenes. - Synthetic approaches to carotenoids"O."' and retenoids"' have been the subject of recent reviews. The many examples of the use of Wittig-type olefinations in this area include the synthesis of 2,3- and 3,4-[3H2]-9-cis-retinoic acids1I2 and a number of 4- hydroxyretinals, e.g. (1 70).'13 The latter work allows the absolute stereochemistry of one of the visual pigment chromaphores in the firefly squid, Watasenia scintiffans, to be determined.

All trans-(6E)-5-thia-2,3-oxidosqualene (1 72) and the 9-thia-, 16-thia, and

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288 Organophosphorus Chemistry

20-thia analogues have been prepared as potential OSC inhibitors by introducing the vinylic thio function via Wittig-Horner reactions of the appropriate 01-

thioalkyldiphenylphosphine oxide.' I4 Separation and decomposition of the syn- isomer, e.g. (171), of the fl-hydroxyphosphine oxide intermediates formed provides (1 72), etc. (Scheme 17).

sYn4 1 71 )

R'=H& \ \ \ \ ltv Py R'

(1 72)

Reagents: i, LDA, - 100 "C; ii, R'CHO; iii, AcOH, H,O; iv, NaH, THF

Scheme 17

The various forms of phosphorus-based olefination have been widely used in the synthesis of polyenes. Linear, conjugated pentaenoic acids ( I 73) and (1 74),

(173) n = 0,3,6 (1 74)

potential linear fluorescent, membrane probes, have been conveniently synthe- sised by Wittig and phosphonate olefinations.' Wittig reactions of dipho- sphonium salts (175) have been used to synthesise, as materials with non-linear optical properties, dithienyl polyenes (176) with up to ten double bonds.'16 Poly(phenyleneviny1ene) oligomer phosphonates, e.g. (1 78), have been synthe- sised, for use in new molecularly engineered multilayered structures, by olefinations involving the bisphosphonates (1 77). I

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6: Ylides and Related Compounds

2x-

(175) n = 1,2

289

NaOE1, EtOH m = 1,2,3

5.4 Leukotrienes, Prostaglandins and Related Compounds. - The Wittig reaction continues to be commonly used in the synthesis of leukotrienes. Examples include the preparation of the proinflammatory dihydro-l2-ketoeicosatetraenoic acid metabolite (1 79)' '* and the total synthesis of 1 1-(R), 12-(R)-dihydroxyeicosa- trienoic acid (180), a metabolite of the cytochrome P-450 epoxygenase path-

The use of the tris(3-methoxyphenyl)phosphonium salt (1 8 l), rather

omco2H HO OH

than the triphenyl analogue, in Wittig reactions provides much greater cis- selectivity and this has been applied to the synthesis of 12-0xo-LTB.+~~~ A new synthetic approach to enantiopure hydroperoxyeicosatetraenoic acids (HPETE's), e.g. (1 83), involves Wittig reactions with protected hydroperoxyaldehydes, e.g. (182), to construct the functionalised skeleton.l2l Skipped conjugated polyene structures exist in a variety of physiologically active natural products. A useful

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290 Organophosphorus Chemistry

synthon (184) for the construction of such structures has now been prepared and used in a Wittig reaction as a key step in the synthesis of docosahexaenoic acid (1 85, R = H), the dominant fatty acid in the brain.122

-PPh3 G G 3 -OTs

5.5 Macrolides and Related Compounds. - Intramolecular phosphorus-based olefination continues to be widely used as a method of macrocyclisation. Examples include the use of complex phosphonates, e.g. ( 1 86), in the synthesis of macrocyclic analogues of the lank acid in^'^^ and an analogous phosphine oxide reaction in the total synthesis of the antitumour macrolide rhizoxin. 124 D

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7 on

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7818

4755

4475

-002

64

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6: Ylides and Related Compound 29 1

Phosphonate olefinations with good (E)-selectivity using (1 87) and (1 88) are key steps in the construction of the carbon skeleton in an enantioselective total synthesis of the macrocycle chlorothricolide, the aglycon of the antibiotic c h l ~ r o t h r i c i n . ~ ~ ~ A convergent synthesis of the polyene antibiotic roxaticin uses a Wadsworth-Emmons reaction of the phosphonate (1 89) to couple the polyol and polyene fragments in excellent yield. 126+127 The report also includes a new and more convenient synthesis of (189)?

5.6 Nitrogen Heterocycles. - There continue to be a large number of reports of the use of the reactions of iminophosphoranes, primarily the aza-Wittig reaction, to synthesise a wide range of heterocyclic systems and the area has been the subject of a recent review.'28

Examples of five-membered heterocyclic rings prepared by aza-Wittig and related methods include the P-carboline ring in new syntheses of the alkaloids fascaplysin ( 190)'29 and eudistomin U ( 1 91),130 the 6,7-dihydro-SH-dicycIohepta- [b,d]pyrrole ( 192),13' and the azacarboline framework, e.g. ( 193).132

cJ--$=J H

Six-membered ring examples include a convenient entry into the isoquinoline alkaloid skeleton, e.g. ( 194),133 the synthesis of 2-aryl-tetrahydroquinolines (196) from vinyliminophosphoranes, e.g. ( 1 95),134 and dihydroquinoline derivatives (1 98) by the reaction of the N-vinylphosphazene (1 97) with diethyl ketomalo- nate.'35 Alternatively, the reaction of (197) with aldehydes provides imidazo [ 1,5-a]pyridines (199). Polycyclic guanidine derivatives, e.g. (200) and (201),136 (202),' 37 and benzimidazo[ 172-a]benzimidazoles (203) and 173,6-benzothiadiaze- pino[3,2-a]benzimidazoles (204)'38 have also been prepared.

The synthesis of larger rings includes that of pyrrolo[2,1 -c][ 1,4]benzo- diazepines, e.g. (205)139 and 5-azaazulene derivatives, e.g. (206).l4O A one-pot synthesis of cyclic carbodiimides, e.g. (209), involving the reaction of bis(imino- p hosphoranes), e. g . (207), with di( tertbu toxycarbony1)an hydride in the presence of DMAP, has been reportedi4I and probably involves initial formation of the

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292 Organophosphorus Chemistry

Me0 JTH=c=O k4

R2

+ M e 0

OBu

I R2

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6: YIides and Related Compounds 293

9 N ab N FNHR

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294 Organophosphorus Chemistry

iminophosphorane isocyanate, e.g. (208), which can be trapped intramolecularly in appropriate cases.

Full details of the in situ preparation of 1 -aza-l,3-bis(triphenylphosphor- any1idene)propane (2 1 1) from the N- 1 -(benzotriazole)methyl substituted phos- phine imine (210) has been reported (Scheme 18).142 Compound (21 1) reacts with dicarbonyl compounds to give heterocycles, e.g. (21 2), and with monocarbonyl compounds to give amines, imines, and amides, e.g. (213). The related phos- phonate (214) has also been prepared in situ by a similar approach and converted into the corresponding carbanion (215).'43 A variety of reactions of (214) and (21 5 ) , including olefination, are reported. New carbonyl complexes, e.g. (21 7) and

0

(213) Reagents: i, Ph3P=CHz ; ii, BuLi; i i i , ArCOCOAr; iv, PhN=C=O

Scheme 18

1 BuLi

? (EtO)ZP-N=PPh3

- Lit (215)

(218), have been prepared by aza-Wittig reactions with the corresponding fumaraldehyde complexes, e.g. (21 6).IU The Pd(0)-catalysed allylic alkylation of the N-(tertbutoxycarbony1)phosphoramide carbanion (2 19) provides the doubly N-substituted phosphoramides (220) in moderate to excellent yield and hence, following deprotection, a new route to primary allylic a m i n e ~ . ' ~ ~ Cyclic iminophosphoranes (22 1) have been prepared and their reactions with aldehydes, to give iminophosphine oxides (222), and isocyanates, to give ureas (223), have been investigated (Scheme 1 9).146 The six-membered phosphine imines (224) and (225) have been ~ynthesised.'~' Compound (225) thermally decomposes in refluxing toluene to give 1 ,2h5-azaphosphetes (226) which undergo reactions with electrophiles to give mainly ring-opened products.

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6: Yiides and Related Compounds 29 5

0

N A N R1 + - L o Lp”N

“ W W 2 ) ” , Ph’ ‘Ph Ph2P

H H (221) n = 1,2

(223)

Reagents: i, RCHO; ii, R’N=C=O; iii, H20

Scheme 19

R2P-N=N=C-PR2 + - ! + R’CECR2 - R 2 P R ! R2

R’

(224)

112 “C, Toluene I

5.7 Tetrathiafulvalene Derivatives. - Both phosphonate and phosphonium ylide-substituted 1,3-dithioles continue to be extensively used in the synthesis of a wide range of tetrathiafulvalene (TTF) analogues.

These include the use of phosphonates (227) in the synthesis of bis(l,3- dithioles) (228),14* (229) to synthesise a variety of thiophene-derived non-linear optical c h r o m ~ p h o r e s , ’ ~ ~ and (230) in an improved synthesis of TTF vinylogues (231).lS0 Olefination with the bis(phosphonate) (232) has been used to synthesise cage-li ke molecules, e.g. (233), incorporating extended tetrathiafulvalene~.~~~

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296 Organophosphorus Chemistry

Both phosphonate carbanions (234) and phosphonium ylides (235) have been used to synthesise a variety of new TTF-containing structures, e.g. (236).15* The 4,5-bis(benzothio)- 1,3-dithiole phosphonium salt (237) has been prepared and converted into the corresponding ylide (238) by treatment with di(isopropy1)ethyl

S (229) R = H, RR = (= , ( (230)

S

amine.'53 The reaction of (238) with 2-(methylseleno)-substituted 1,3-dithiolium cations (239) provides entry into a variety of unsymmetrical tetrathiafulvalene structures and 1,3-dithiol-2-ylidene derivatives (Scheme 20). Other related syntheses involving Wittig reactions include that of the first allylic alcohol TTF derivative (240),'" the first vinologous 2,5-bis( 1,3-dithioI-2-ylidene)-1,3,4,6-tetra- thiapentalene (241),155 and the rigid TTF-bithiophene hybrid systems, e.g. (242).lS6

5.8 Vitamin D Analogues and Related Structures. - Phosphine oxide-based olefinations continue to be the method of choice in convergent syntheses of

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6: Ylides and Related Compounds 297

PhCOS PhCOS

PhCOS PhCOS PhCOS

(239) Scheme 20

0. ' PPh2

I

TBSO" kms Q5- HO

0 I t PPh,

vitamin D analogues. A new, efficient and highly stereoselective route to the key ring A synthon (243) for the preparation of la,25-dihydroxy vitamin D3

analogues has been reported.IS7 The hydrindanol phosphine oxide (244) has been prepared and the derived dianion used in an olefination reaction with a- methacrolein as a key step in the synthesis of racemic Grundmann's ketone, a useful synthon in vitamin D syn thes i~ . '~~ A stereocontrolled total synthesis of both isomers of the calcitriol derivative (245), an analogue of an osteoporosis

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298 Orgmophosphorus Chemistry

OzPPh2 I

HO‘

CH*

drug, involves, as a key step, resolution of the racemic A-ring phosphine oxide (246) by reaction with the enantiomerically pure C,D-ring fragment (247).’59 An intramolecular olefination of the phosphonate (248) provides a highly diaster- eoselective (98% d.e.) synthesis of the hydrindene (249), which in turn was converted into the ketone (250), a new synthetic precursor for 1 a,25-dihydroxy vitamin D3.160 The conversion represents an example of an intramolecular asymmetrization using phosphorus-based olefination (see also section 4).

Bu‘OK

THF P

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6: Ylides and Related Compounds 299

5.9 Miscellaneous Reactions. - The highly enantioselective Michael addition reactions of the carbanion of the chiral allylphosphonamide (25 1) developed by Hanessian have been used as a key, stereochemistry-controlling step in a synthesis of the sea hare defensive agent ( + )-acetoxycrenulide.

The reaction of the 3-alkoxycarbonyl-2-propenylidenephosphonium ylide (252) with 1,2-diacylethenes gives an isomeric mixture of 2-ethoxycyclopentadienes which can be converted into a single compound (253) by treatment with acid.16* The reaction sequence has been applied to the synthesis of (*)-methyl dehydro- jasmonate. Phosphonium ylides, e.g. (254), are likely intermediates in the phosphine-catalysed cycloaddition of 2,3-butadienoates or 2-butynoates with electron-deficient alkenes, a reaction which provides a new (3 + 21 annulation approach to cyclopentenes.'63

OEt Ph3P+ A'COCH= CR'COR' b

COZEt

(252)

The stereochemistry

A of an olefination reaction of phosphonylglycinate (255)

with o-formyl esters can be controlled to a large extent by varying the temperature of aldehyde addition. 164 Hydrogenation of the individual isomers (256) and (257), using the same chiral catalyst in each case, provides a synthesis of both (R)-(258)- and (S)-(259)- a-amino carboxylates (Scheme 21). Phos- phonylation of the methylphosphonate carbanion (260) to give (261) is a key step in a one-pot, multi-stage synthesis of transition state analogues (262) of enzymatic transcarbonylation reactions. 165

Wittig reactions using phosphonium salts carrying large alkyl groups have been used to construct the carbon skeleton in syntheses of a variety of compounds with long saturated, unsaturated, and functionalised aliphatic chains. The asym- metric total synthesis of the potent immunosuppressive thennozymocidin (264) has been reported and involves a highly selective (E)-alkenylation using the salt

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300 Organophosphorus Chemistry

C02Me C02Me I

HI(CH2’ff (CH2)ff H - M + AcNH CO2Et

B , C O ~ E ~ i,ii (Et012P CH,

NHAc AcNH C02Et

(255) n =2,3,4 (256) (257)

iii 1 iii (C\H2)n (C,H2)n

C02Me

1

AcN H - * kCO2Et

C02Me I I

CH2 CHZ

AcN H - * H H CO2Et

(258) (259)

Reagents: i, Bu‘OK, THF; ii, OHC(CH& C02Me; iii, (R )-BINAP-Ru(II)(AcO),, H2, MeOH

Scheme 21

B 0 ( RO)$H2Li+ + XPCI2 -

0 X R’ II I I

II 0

(262)

( R0)2PCH2PNHCHC02R2

(263) under Schlosser-modified Wittig conditions.IM A separate report of the synthesis of both thermozymocidin and its (2)-isomer has also appeared.’67 Although the details of the overall method are different the salt (263) is used in the same way to give highly selective (9-alkenylation. However, in this case the product of (2)-alkenylation is also isolated from the mixture and converted into

0

Ho2c*(CHz) H2N”’ 6A(CH2)IMe

HO

HO OH

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6: Ylides and Related Comp0und.v 30 1

(2)-thermozymocidin. Interestingly both publications come from the same institution but do not have any authors in common. The sphingosine derivative (265) has been synthesised from D-mannose using a Wittig reaction with dodecylidenetriphenylphosphorane to introduce the unsaturated side-chain.I6* Exclusive (2)-alkenylation using the phosphonium salt (266) has been used in the synthesis of the powerful antimitotic curacin A (Scheme 22).169

i , i i 1

Reagents: i, LiHMDS, THF, HMPA, - 78 “C -0 “C; ii,

/ Scheme 22

A (2)-selective Wittig reaction of the complex phosphonium salt (267) has been used to couple the two structural components in a convergent total synthesis of a truncated form of brevetoxin B [AFGHIJK].’70 A similar coupling using the complex phosphonium salt (268) has also been used in the first total synthesis of the full structure of the natural “red tide” neurotoxin brevetoxin B.171 Both phosphonium ylide and phosphonate carbanion olefinations have been used to construct semi-synthetic analogues (269) of the antibiotic pseudomonic acid. 172

Quinolines (272) are formed in moderate to excellent yield by the reaction of imides (27 1 ) with N-phenyl(triphenylphosphorany1idene)ethenimine (270). 173

+ PPh, I -

Me

Me H Me H

+ PPh3 I -

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302

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