5 Ylides and Related Compounds

BY B. J. WALKER

1 Introduction As explained in the introduction to this volume, this year the chemistry of phosphine

oxides will no longer be covered in a separate chapter. Chemistry involving phosphine oxide- stabilised carbanions will be reviewed in this chapter and other aspects of phosphine oxides will be covered in chapter 1.

The acylation of ylides as a route to 0-carbonylalkylidenephosphoranes is restricted by transylidation. A variety of new approaches to the acylation of ylides, which largely overcome these problems, have been reported. Enantioselective reactions involving ylides have been little studied and, although there have been a number of reports of such chemistry this year, the area

has substantial application in synthesis and is worthy of further investigation. Phosphorus-based olefination has become the method of choice for the synthesis of many tetrathiafulvalene derivatives.

2 Methylenephosphoranes 2.1 Preparation and Structure.- Although n-butyllithium has been used extensively to generate methoxymethylenetriphenylphosphorane (1) from its phosphonium salts, it is now reported that large amounts of the butylidene ylide (2) are formed together with (1) in this reaction. The use of tert-butyllithium leads to the formation of (1) exclusively. The four-membered cyclic ylide (3) has been generated from the corresponding salt and undergoes Wittig reactions to give the expected alk-3-enyldiphenylphosphine oxides (4).2

The synthesis of j3-ketoylides by acylation of unstabilised ylides is complicated by transylidation which leads to reduced yields. Bestmann has now reported that silylated alkylidenephosphoranes (5 ) react with a variety of acylating agents to give P-ketoylides (6 ) in good to excellent yield (Scheme l ) .3 Bis(trimethylsily1)methylenetriphenylphosphorane (7) will even react with carboxylic acids to give acylmethylenetriphenylphosphoranes This last method has several advantages over alternatives for the preparation of simple P-ketoylides and provides the first synthesis of a-aminoacylylides (8, R=CHR"H2). The sulhr analogues (9) of (8) have been synthesised by the reaction of the corresponding acylalkylidenetriphenylphosphoranes with trifluoromethanesulfonic anhydride followed by treatment with sodium sulfide (Scheme 2).5 Compounds (9) undergo alkylation regiospecifically at sulhr to give (10) in quantitative yield. The adduct (11), obtained from tri-n-butylphosphine and carbon disulfide, reacts with two equivalents of acetylene dicarboxylate esters, dibenzoylacetylene, or methyl benzoylpropriolate to give novel dithiole-containing phosphorus ylides (e.g. 12).6 The structure of (12) was confirmed by X-ray analysis.

Stabilised a-chloroalkylphosphonium ylides (13) have been prepared in good to excellent yield by the reaction of the corresponding non-chlorinated phosphonium salt with bleaching powder in

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5: Ylides and Related Compounds 219

+ Ph3PCH20CH3

X-

SiR23 ,SiR23 Ph3P=CHR’ +XSiR23 2 [ Phf-C(Rl ] 1 Ph3P-C

‘R’

( 5 )

iii

R’ /

‘C R2

Ph3P-C

Reagents: i, PhH, Et20, RT; ii, KN(SiMe3)2, Et20, RT; iii, RCOX, THF

Scheme 1

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220 Organophosphorus Chemistry

0 II ,SiMe3

SiMe3 Ph3P=C, + RCOH - Ph3P=CH.COR + (Me3Si)20

R’ i R: ,R2 R’

COR2 Ph3P OS02CF3 $4 Ph3P=C: - + p=c\ 2 Ph3P=C:

iii 1 R: ,R2

Ph3P SMe +p=c\ r

Reagents: i, (CF3SO2),0; ii, Na2S; iii, CH3 I

Scheme 2

,C02Me S Bu~P=C, / ,S..fO2Me

+ 4.. BU~P-C :.- + 2 MeO2CC=CC02Me - ,c=c, b Me02C C02Me

+ 3Ph3PCH2R + 3Ca(OCI)CI.Ca(OH)2e5H20 + 2HCI

cr

.C‘ 3Ph3P=C, + 4CaCI, + 1 OH20

R

R = CH3C0, CN, CO2Et

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5: Ylides and Related Compounds 22 1

protic solvent^.^ Ylides (14) and (15), which contain three-co-ordinate phosphorus (v), have been synthesised and in one case (14, R'=Ph) the structure has been confirmed by X-ray analysis.8

The structures of 12 phosphonium ylides have been optimised at the HF/6-31G* leveL9 The results predict that all examples of non-stabilised ylides studied have non-planar ylidic carbon geometries, while stabilised ylidic carbons are planar. 7O N.m.r. spectra of carbonyl-stabilised phosphonium ylides (16) suggest carbonyl electrophilicities similar to those of amide groups, indicating a substantial resonance-donation effect. lo Halide extraction from the P-chlorinated ylides (17) yields unsymmetrical methylenephosphonium salts (18)! N.m.r. studies of compounds (18)

indicate rotational barriers of > 83kJm01-~ about the P=C bond. The calorific heats of deprotonation in DMSO have been determined for a number of phosphonium salts and phosphonates. 12

The structure and dynamics of thiophosphonamide carbanions (19) have been studied by n.m.r. (13C, lH, 7Li, and 31P) and X-ray crystallography and compared with the results previously obtained for phosphonamide carbanions (20).13 The major difference appears to be that (19) exist as monomeric solvent-separated ion pairs in solution while (20) are disolvated dimers.

The 1,2-(22)- and 1,3-(23)- monoaza bisylides have been prepared from the iminophosphorane-substituted benzotriazole (21) (Scheme 3) and used in the synthesis of acyclic imines and nitrogen heterocycles. l4 Phosphirene imines (24) and iminophosphaspiro[2.2]pentanes (25) are formed by the reaction of iminophosphoranes with acetylenes and methylenecyclopropanes, respectively. l5 Another example of an iminophosphorane with high basicity has been reported. The bicyclic cage (26) has a pKb of approximately 17.l6 Previously reported iminophosphorane-substituted proton sponges (e. g. 27) have been compared with classical proton sponges through their X-ray structures, lH and 13C n.m.r. spectra, and PKa values in water and water-ethanol. l7 Although the phosphorus-containing compounds are stronger bases they are of no practical value since they decompose when the acid proton is removed. The structure of 1,2h463,3-benzodithiazole phosphine imine (29), prepared by the reaction of (28) with triphenylphosphine, has been determined by X-ray crystallography. l8

2.2 Reactions of Methy1enephosphoranes.-

2.2.1 Aldehydes- The first 1 ,2h5-oxaphosphetane (31) to be formally derived from a stabilised ylide has been prepared by methoxycarbonylation of the known 4,4-bis(trifluoromethyl)-1,2h5- oxaphosphetane (30) (Scheme 4). l9 Compound (31) has been characterised by both n.m.r. spectroscopy (13C, 19F, lH, and 31P) and by an X-ray structure. Thermolysis of (31) gave the expected alkene and cyclic phosphinate (32) and a kinetic study showed that (31) decomposed approximately 22,000 times faster than (30). The bicyclic ylide (33) reacts with aldehydes to give (E)- alkenes with selectivities generally >94%, although selectivity decreases in reactions with a-branched aIdehydes.2O Unlike similar reactions with (34), which require high temperatures, Wittig reactions with (33) occur readily at room temperature. The replacement of phenyl by 2- (methoxymethoxy)phenyl in triarylphosphonium ylides is known to substantially increase the (2)- selectivity when such ylides are used in the Wittig reaction. This approach has now been applied to the synthesis of l-alkenyl halides and vinyl ethers from the ylides (35).21 In many cases (2)-selectivity was >97% for 1-alkenyl chlorides, bromides, and iodides, and >90% for vinyl ethers, although it was

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222 Organophosphorus Chemistry

R' t

NazSe

Ph3P Se

+ + PPh3 ph-_gPh3 x

Phz;p:

ph<p x- Se

Ph4PPh3

P h3P= CHCOX

(16) X = Ar, CH3, OEt

(19) x = s (20) x = o

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5: Ylides and Related Compounds 223

iiij 1

0

0

(.*

Reagents: i, (Et0)2P,+.- : ii, BuLi; iii, Ph3P=CH2

Scheme 3

R3

Me

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224 Organophosphorus Chemistry

i-iii

Reagents: i, 4 x BuLi, THF,-40 "C; ii, CIC02Me,-40 "C; iii, NH4CI, H20,-30 "C; iv, A, 70 "C

Scheme 4

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5: Ylides and Related Compounds 225

(33) (34)

(35) X = F, CI, Br, I, OMe

R’R~NNH + R’ R*N, i,ii

R3 )=CHPPh3 X-

Me Me

i,iii R3 R’ R~N,

N O R5&FPh2

Reagents: i, Base; ii, R3CHO; iii, R3R4C0

Scheme 5

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226 Organophosphorus Chemistry

generally much lower for the corresponding fluorides. The effect of cyclodextrins on the (Z/Q- selectivity of Wittig reactions of semi-stabilised ylides with aromatic aldehydes has been investigated.22 (2)-Selectivities as high as 92% and (Q-selectivities up to 80% have been achieved by variation of the solvent used, although, as might be expected, bulky substituents on either reagent which prevent complexation reduce selectivity.

A convenient, high yield route to a,P-unsaturated ketone hydrazones is provided by olefination reactions of P-enhydratino phosphonium salts (36) or the corresponding phosphines oxides (37)

(Scheme 5).23 Compounds (36) and (37) are prepared by the reaction of the corresponding hydrazine with propargyltriphenylphosphonium bromide and allenylphosphine oxides, respectively. The reactions of 2,3-epoxyaldehydes with two mole equivalents of methoxymethylenetriphenyl- phosphorane provide a direct, one-step conversion to (Q-4-hydroxy-2-enals (38) in good yields (Scheme 6).24 Reactions with optically active epoxides indicate that the conversion takes place with >95% retention of configuration. All trans-( 1,4-phenylenehexa-1,3,5-trienylene) oligomers (39) have been prepared from terephthalaldehyde by a series of Wittig reactions (Scheme 7).25 Although spectral data indicated some cis-olefination, the product could be isomerised to the all trans form by iodine catalysis. Reactions of 1-silylalkylidenephosphoranes (40) have been used to synthesise a variety of P-carbonyl ylides (see 2.1 and 2.2.4). Siloxycarbonylalkylidenetriphenylphosphoranes (41),

prepared from the reaction of (40) with carbon dioxide, undergo Wittig reactions with aldehydes to give a$-unsaturated silyl esters in good yields with high (E)-stereoselectivity.26

The phosphine-borane adducts (42) can be deprotonated to give carbanions (43) which can be alkylated and undergo Wittig-type reactions.27 p-Hydroxyalkylphosphine adducts (44) can be isolated from the latter reaction under appropriate conditions and decomposition of these adducts to alkenes in the presence of base suggests a normal Wittig olefination mechanism. Phosphine-borane adducts (45) carrying aldehyde functions react with stabilised phosphonium ylides at room temperature to give excellent yields of the corresponding alkenes (46).z8

Oxaphosphoranes (48), derived from 3-hydroxyalkylphosphonium salts (47), react on heating with paraformaldehyde to form cyclic acetals (49) in virtually quantitative ~ i e l d . 2 ~ A novel olefin synthesis is provided by the reaction of phosphonium salts or phosphonates with organolithium reagents in DMF (Scheme 8).30 The reactions give excellent yields in most cases and presumably occur via initial formation of an aldehyde by the reaction of the organolithium reagent with DMF.

2.2.2 Ketones.- The reaction of the cyclic ylide (50) with a$-unsaturated ketones gives the cyclic phosphine oxides (51) via initial Michael addition followed by intramolecular Wittig reaction (Scheme 9).3 Similar reactions with acrolein or mesityl oxide give moderate yields of acyclic dienes derived from initial Wittig reactions of (50). The use of enolisable ketones often leads to problems in phosphonate olefination reactions. It is now reported that ultrasonic radiation leads to significant improvements in yield and to a reduction in the extent of isomerisation to (54) from the olefination reaction of sulphonylmethylphosphonate anion (52) and 4-ni t roa~etophenone.~~ It is worth noting that irradiation apparently induces some (Q to (2) isomerization of (53) even in the absence of other reagents.

A novel, one-pot synthesis of 1 -iodo- 1 -trimethylsilyl- 1,3-dienes (56) from allylidene- triphenylphosphorane (55) has been reported (Scheme 10).33The method can be applied to aldehydes

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5: Ylides and Related Compounds 227

OH + i ii,iii

2 Ph3PCH20Me Br- - 2 Ph3P=CHOMe - R-CHO

(38)

0

Reagents: i, 2 x ButOK; ii, , -78 "C-RT; R CHO

iii, H20

Scheme 6

Reagents: i, OHC a C H 0 , EtOH; ii, Ph3P=CHCHO, PhH;

iii,

PPh3

Scheme 7

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228 Organophosphorus Chemistry

R COZ R - R'CHO RIG C02SiMe,

SiMe3 Ph,P=C: - Ph3P=C:

C02SiMe3 H

(40) (41)

0 -BH3 - BH3

+ + Ph2P(CH2), I CHO + Ph3P=CHCOMe CHC'3 RT c Ph26(CH2)&CH3 + PhSP=O

(46) (45) n = 1,2

OH I

Ph3&H2CH2CHR r 5 THF

(47)

H

R (49)

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5: Ylides and Related Compounds

D i +

Ph3PCH2R’ Br-

229

Reagents: i, R2U, DMF

Scheme 8

Q c104- i , [”I- Ph2P fyy2 P i ‘Ph Ph Ph

(50) (51)

Reagents: i, ButOK, THF, RT; ii, R’

Scheme 9

(Et0)2P-S02Me ! + 6 - 02Nq o:xso2Me - -

S02Me COCH3

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230 Organophosphorus Chemistry

ii 2Ph3Pe * 2 P h 3 P v S i M e 3 - 2 P h3P- si Me3

(55)

iii 1 1- +

SiMe3 + P h 3 P v S i M e 3

' 1 4 S i M e 3 R2

(56)

Reagents: i, CISiMe3; ii, BuLi, -78 "C; iii, I,; iv, R1R2 CO

Scheme 10

R' COAr

OMe

Ar= 0 i YAr H CO2Et + Et02C

20 1 (R' = CF3CHZ) 1 2 (R1=CH3CH2)

& Reagent: i, Ph3P=CHC02Et

Scheme 11

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5: Ylides and Related Compounds 23 1

or ketones and gives good to moderate (E)-selectivity with the former. a-Fluorinated alkyl ketones react much faster and show reversal of olefin stereochemistry compared to non-fluorinated ketones in both ylide- and phosphonate-based olefinations (Scheme 1 1).34

Compared to the current intense interest generally in enantioselective methods of synthesis reactions of chiral phosphorus-stabilised carbanions have been relatively little studied and those reactions which have been reported have tended to involve similar systems. The olefination reactions of substituted cyclohexanones previously reported for the C2 symmetrical phosphonamides (57) and (58), derived from (R,R)- and (S,S)-N,N-dimethyl 1,2-trans-cyclohexane diamine, respectively, have been extended to other derivatives, e.g. (59) and (60), and other cyc lohe~anones .~~ Again high yields and high enantioselectivity are obtained. Similar olefination reactions of 2-benzylcyclohexanone with the chiral phosphonate (61) derived from mannitol, provide chiral alkenes (62) with 40 to 90% e.e and recovered ketone with up to 30% e.e. depending on the conditions used.36 The chiral phosphonoacetate (63) differentiates between the enantiotopic carbonyl groups in the ketone (64) to give the (2)-alkene (65) in high yield and high enantiomeric excess (Scheme 12).37

2.2.3 Ylides Co-ordinated to Metals.- Titanium (IV) complexes (66) with bridging phosphonium ylide ligands have been reported.38 These compounds, which are potentially both Wittig and Tebbe reagents, act as synthetic equivalents of carbon atoms as illustrated by their reaction with aromatic aldehydes to give allenes (67). The first stable 2-chromaoxetane (69) has been prepared by the reaction of diphenylketene with the ylide complex (68), which is itself the first example of a chromium (VI) complex containing a formal Cr-C double bond.39 In chromium complexes where it is the counter ion the PPN cation (70) is reported to act as an electron acceptor in charge- transfer interacti~ns.~o Previously (70) had been assumed to be a non-interacting cation. Further reported examples of ylide complexes of metals in the same group as chromium are those (71) of molybdenum and tungsten.41 Rhenium also forms related complexes (72).

Both reactive and stabilised alkylidenetriphenylphosphonium ylides undergo oxidative addition to Ru3(C0)12 to yield a wide range of Ru3 clusters (e.g. 73) containing triply bridging organic ligands derived from the y l i d e ~ . ~ ~ Similar reactions with the stabilised trimethylphosphonium ylide (74) lead to the formation of the binuclear complex (75) and its trimethylphosphine derivative (76) .43

2.2.4 Miscellaneous Reactions.- Acylation of ylides is frequently an inefficient process (see 2.1 and 2.2.1). The reactions of carbonyl-(77), imino-(78), and thiocarbonyl-(79) stabilised ylides have been investigated in some A variety of products are formed depending on the acid chloride used. Two new methods specifically for the acylation of stabilised phosphonium ylides have been rep0rted.~5 The first involves reaction with acyl anhydrides or acyl chlorides in the presence of bis(trimethylsilyl)acetamide, while the second couples the ylides with carboxylic acids in the presence of N-ethyl-N’-(3-dimethylaminopropyl)carbodiimide (Scheme 13). Both methods are substantially superior to earlier approaches. The alkaline hydrolysis or oxidation of bis(1- acylalkylidenetriphenylphosphoranes) (81), prepared from the corresponding acid anhydride (80), provide useful methods for the synthesis of a,P-unsaturated cyc lohe~anones .~~ The reactions of a wide range of phosphonium ylides with perfluoroalkyl-substituted arnides, anhydrides and esters, to

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232 Organophosphorus Chemistry

a y C H 2 R

Me

(57) R=Me (59) R=Ph

(58) R = Me (60) R = Ph

OSiR3

PCH2C02Me i,ii

OSiR3 H

OSi R3 Reagents: i, NaH, THF, -78 "C; ii,

OSi R3 0

Scheme 12

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5: Ylides and Related Compounds 233

c19.. ,x /Ti\

( Me2N)3P= C, ,C=P( NMe2)3 ,Ti.

CI 'x

Cr(NR)2C12 + 2Ph3P=CH2

(71) M = Mo, W

Me3P=CHCOPh

(74)

ArCHO H.. ;c=c=c /Ar

'H THF Ar

NR

Ph Ph

(72) (73)

H I n

(75) x = co (76) X =Me3P

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234 Organophosphorus Chemistry

X

Ar 4 Ph3P=CH-C,

(77) X=O; (78) X=NPh; (79) X = S

,c0r2 C02R’

P h3 P = C,

7 P h3P=CH*C02R’

PPh3

Reagents: i, R2COX, CH3CON(SiMe3)2; ii, R2C02H, Me2N(CH2)3 N=C=NEt

Scheme 13

0

0 R

SiMe3

K xKo 0 +Ph3P=C: PPh3 PPh3

Ph3P0,

0

-g 0

x+R

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5: Ylides and Related Compounds 235

give olefination of the carbonyl group in each case, have been investigated in A new one-pot synthesis of 4H-1-benzothiopyran-4-ones (84) in excellent yield is available from the reaction of S- acyl thiosalicylic acids (82) with N-phenyl(triphenylphosphorany1idene)ethenimine (83).4*

Halolactonization of 2-ketophosphonium ylides (85) containing carboxylic acid finctions at the 4- or 5-position has been achieved using bromine or thionyl chloride in the presence of triethylamine.49 The reaction proceeds via an a-halophosphonium salt intermediate (86). Analogous lactonization of the p-ketophosphorane-substituted phenylalanine (87), followed by incorporation of an amino acid into the product, provides a synthesis of the acylated cyclic enamino ester dipeptide analogues (88) (Scheme 14).50 Both the thermal and the electron-impact induced fragmentation of heteroaroylmethylenetriphenylphosphoranes (e.g. 89) have been investigated.51 Thermolysis reactions under conditions previously used to generate ethynes from other acylphosphoranes gave only low yields of alkynes from (89). However, almost quantitative yields were obtained from thermolysis at low pressure (<lO-4mm Hg).

The first example of C-F bond cleavage in fluoroarenes by phosphonium ylides has been reported.52 When allowed to react with stabilised ylides, pentafluorobenzenes (90) carrying an electron-withdrawing substituent (NO2 or CN) undergo C-F bond cleavage at the 4-position under mild conditions to give ylides (91) and phosphonium salts (92). An X-ray structure of one example of (91) is also reported.

It has been reported that a$-unsaturated carbonyl compounds (93) undergo cyclopropanation in poor to moderate yield on reaction with isopropylidenetriphenylpho~phorane.5~ Similar reactions with a,P-unsaturated derivatives (94) derived from D-glyceraldehyde provide enantioselective syntheses of the corresponding ~yclopropanes.5~ The use of carbenoids to synthesise cyclopropanes from electron-deficient alkenes is generally precluded by preferential reaction of the carbenoid with the alkene activating substituents. It has now been reported that such reactions can be readily achieved in moderate to excellent yield for alkenes (95) carrying P-ketophosphonium ylide substituents since in such cases the carbonyl group does not react preferentially. 55

Reactions between N-methylnitrilium trifluoromethanesulfonate salts (96) and benzylidene- triphenylphosphorane give the enaminophosphonium salts (97) as the major product except in the case of (96, R=tBu) where the a-iminophosphonium salt (98) is formed.56 Extending these reactions to trimethylsilylmethylenetriphenylphosphorane provides a synthesis of a-unsubstituted enamino- phosphonium salts (99).57 The reaction of P-ketophosphonium ylides (100) with methyl propynoate gives a mixture of adducts (101) and (102) depending on the conditions used.58 In methylene chloride at 9OoC compounds (102) are formed in greater than 90% yield and reaction of (102) with methyl petfluoroalkynoates provides the adducts (103), which in turn undergo intramolecular Wittig reaction to provide a synthesis of substituted phenyl-1,3-dicarboxylates (104).

The reactions of stabilised ylides (105) with the phthalimidobenzoic acid a ides (106) have been investigated and shown to give a number of methylenephosphorane- and iminophosphorane- containing products.59 Phosphonium ylides are known to react with (2,4,6-tri-tertbutyl)- phenylmonochlorophosphine (107) to form h3-phosphaalkenes (108). This reaction has now been extended to the synthesis of h3-phosphaallenes (109) and h3-phosphabutatrienes (110) by use of the corresponding reactions of phosphacumulenes.60

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236 Organophosphorus Chemistry

+ PhN=C=O Reflw

R + PhSP=C=C=NPh aco2H SCOR

PPh3 /

Br

H02C(CH2),CO-C, Br- 0 "C I C02Et

(86)

n =2,3

0 . CbzNH

q p p h 3 A PhCHi*Q, PhCH;

CbzNH

C02Et

0

(87)

CbzNH

'7-H

(88) Co2Et R'

Reagents: i, THF, reflux; ii, H2NXC02R2 ; iii, M e 0 \ / S03H

Scheme 14

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5: Ylides and Related Compounds 237

QCiC-COR + QCO - C E C -R 300 “C

PPh3 CO-C-COR ,Gg

(89) X = 0, S, MeN

F F R F F

PhsP=CHR + .#-. =!:::@:= + ‘ox F

P h 3 P 5 H R F

F F F (90)

R = C02Et, CONMe2 (91) (92)

(93) Md Me

X = OMe, OPr‘, Pr‘, NMe2, CI

PPh3

R2 I I

+ R’-C-Li - R

X

R/\ccolfco2Et PPh3

(95)

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238 Organophosphorus Chemistry

+ + Yh Ph,P=CHPh + RCENMe -0Tf - Ph,P-C=CRNHMe -0Tf

(96) (97)

?2 Ph3P=CHSiMe3 + [R2CZNR3]+-OTf - Ph3&CH=CNHR3

-0Tf

(99)

COR

CH=CHC02Me Ph3P=CHCOR + H C 3 C 0 2 M e - Ph3P=C \

Ph,P=CHX

(105) X = CN, COCH3, COPh E N a C o N 3

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5: Ylides and Related Compounds 239

0 II

Ph2PCH2R' 'Iii *

Reagents: i, BuLi; ii,

ArP=CR2

ArP= (C)," CR2

(109) n = 1 (110) n = 2

f iii Ph2pYR'

DMSO, Et3N

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240 Organophosphorus Chemistry

3 The Structure and Reactions of Phosphine Oxide Anions A variety of 1-(diphenylphosphinoy1)enones (111) have been prepared by the reaction of

phosphine oxide carbanions with enones followed by Swern oxidation (Scheme 15).61 A combination of X-ray, l H n.m.r., and infrared methods and complexation with Lewis acids has been used to define the conformation (111) in solution as either s-rruns (112) or s-cis (113).

o-Hydroxyalkylphosphine oxides (114) undergo olefination reactions with non-enolisable aldehydes to give unsaturated alcohols and the reaction can be extended to enolisable aldehydes through the use of the corresponding phosphine oxide silyl ethers (115).62 Although only moderate (Z)-stereoselectivity is observed in these reactions individual alkene isomers can be prepared by separation of the diastereomeric hydroxyphosphine oxide intermediates. Rearrangement, by acyl transfer, of esters derived from (114) gives (116) which, on reduction and based-induced decomposition, give (a-hydroxyalkenes stereoselectively (Scheme 16). Individual isomers of phosphine oxide epoxyalcohols (e.g. 117), obtained by stereoselective epoxidation, have been used to synthesise R or S, E or 2-unsaturated a-amino acids via amine-induced ring opening followed by base-treatment (Scheme 17).63 Alternatively the epoxyalcohols (e.g. 118) can be converted into the urethane derivatives (e.g. 119) to provide a stereoselective synthesis of alkenyloxazolidinones (e.g. 120) by a tandem intramolecular ring-closure-Homer-Wittig elimination sequence (Scheme The phosphine oxide-stabilised carbanion (121) reacts with cyclohexene oxide to give (122) in a highly stereoselective manner.65 Oxidation of (122) to the corresponding ketone followed by Baeyer- Villiger rearrangement gave the lactone (123) (Scheme 19). Lactones analogous to (123) have previously been shown to give (Z)-alkenes highly stereoselectively. Ring-expansion of cyclic ketones to give cyclic hydroxyketones containing two or three more carbon atoms in the ring has been achieved by reaction of the ketoenamines, or their anions, with phosphine oxide-hnctionalised alkylating agents, followed by Baeyer-Villiger oxidation, to give (124).66 Finally intramolecular attack at the carbonyl group of the carbanion derived from (124) provides (125) (Scheme 20).

Both phosphine oxide- (126) and phosphonate- (127) substituted carboxamides undergo normal olefination reactions and so provide convenient syntheses of enamides and dienamides (Scheme 21).67 Attempts at similar reactions with analogues of (127) containing an NH group led to intractable 2-DiphenylphosphinoyI-3-hydroxy-(131), -3-amino-(132), and -3-alkyl-(133) indole derivatives have been prepared by base-induced intramolecular cyclisation of the phosphine oxide derivatives (128), (129), and (130), re~pectively.6~

4 The Structure and Reactions of Phosphonate Anions Activated barium hydroxide C-200 has been used as the base in the P-ketophosphonate-

olefination of firfural and piperonal to give the corresponding alkenes in excellent yield.7o Phosphonate-based olefination using (4-substitutedbenzyl)phosphonates has been used to prepare a range of (E,E)-1,4-diarylbuta- 1,3-dienes (134) suitable as components for liquid crystal display devices.71 Olefination reactions involving carbanions derived from P-ketophosphonate derivatives (135) of amino acids provide a new synthesis of a$-unsaturated amino acids (136) (Scheme 22).72

The reactions of a-lithio-a-phosphoryl dithioacetals (137) with a$-unsaturated aldehydes and ketones have been i n ~ e s t i g a t e d . ~ ~ Studies using l P n.m.r. show that aldehydes undergo normal olefination reactions by initial 1,2-addition to the carbonyl group to give conjugated ketene

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5: Ylides and Related Compounds 24 1

II Ph2PCH2(CH2), OSiMe2Bu‘

(114) n = 2

J vi

0 I I

iii

R h2pT H0’- OH

Reagents: i, 2 x BuLi; ii, PhCHO; iii, NaH, DMF; iv, RCOCI; v, LDA; vi, NaBH4, CeCI3

Scheme 16

oy- ..-? LOy-4- ..-? i-w OH OH OH

Ph2P=0 Ph2P=o Ph2P\\ NHBz 0

Reagents: i, Ru04, NaI04, MeCN; ii, BzNH2, H20; iii, KOH, DMSO; iv, CH2N2

eoMe Scheme 17

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242 Organophosphorus Chemistry

- Ph,P=O Ph2P=0 ,60

BzNH

(1 18) (1 19)

Reagents: i, BzNCO, Et3N; ii, KOH, DMSO

Scheme 18

II

0

Ph2P

CH3

Reagents: i, 0 0 ; ii, NaCI,AcOH; iii, CF3C03H

Scheme 19

0 N

111 ~ 4) '.'

0 0 f o r A Ph,;(CH,),

0 x> L = 3

0 0 Q- II II Reagents: i, Ph2PCH=CH2; ii, Ph2P(CH2),I; iii, CF3C03H;

iv, LDA; v, H20 Scheme 20

iv,v 0 1

P h2b' 0 H

0

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5: Ylides and Related Compoiinds 243

0 0

i,ii R' N y R5

R2 R2 R4

(126) R3=Ph (1 27) R3 = OEt

Reagents: i, LDA, THF, -78 "C; ii, R4COR5, THF

Scheme 21

LDA, THF -78 "C, - d F P h 2

R' R'

(1 28) X = CONEt2 (129) X = C N (1 30) X = COR2

(131) Y = OH (132) Y=NH2 (133) Y = R 2

(1 34) X = CN, F, CI, Br, or OR; R = CH3 (CH2)n

R' R2 1

i,ii - R4CH=(!XONHCHC02R3 O II w2

(EtO), PCH R' CNHCHC02R3

(1 35) (136)

Reagents: i, 2 x LDA; ii, R4CH0

Scheme 22

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244 Organophosphorus Chemistry

dithioacetals (138). However, the corresponding ketones undergo initial Michael addition followed by rearrangement to the 1 ,2-adducts and ultimately olefin formation. The carbanions of phosphorylated dithioacetal disulfides (139) undergo olefination reactions with aldehydes to give ketene dithioacetal disulfides (140) and react with alkylating agents to give [tris(alkylthio)methyl]phosphonates (141) via a [ 1,2]-Stevens'-type r e a ~ ~ a n g e m e n t . ~ ~ Virtually quantitative yields of ketene selenoacetals (142) are obtained fiom reactions of 1, 1-bis(pheny1seleno)methylphosphonate anions with non-enolisable aldehydes (Scheme 23).75 Similar reactions with enolisable ketones give 2-phenylselenoketones, for example, acetophenone gives (143).

The recent interest in highly stereoselective syntheses of dissymmetric olefins continues. Reaction of the cis-N-isopropyl-(2S,6S)-1,3,2-oxaphosphorinane (144) with base and 4- terrbutylcyclohexanone gave a single adduct (145) in excellent yield? Unfortunately attempts to decompose this adduct to alkene with potassium bases gave poor results. However, treatment of (145) with ttityl triflate and 2,6-lutidine gave the (5')-alkene (146) virtually stereospecifically (Scheme 24).

The reactions of 2-oxoalk-3-enylphosphonates (147) with carbonyl-stabilised carbanions give cyclohexen- 1-ones via initial Michael addition followed by intramolecular ~ l e f i n a t i o n . ~ ~ a-Fluoro- a$-unsaturated diesters (148) have been prepared in moderate yields and with high (@- stereoselectivity by the reaction of diethyl carboethoxyfluoromethylphosphonate carbanion with alkyloxalyl chlorides followed by reaction of the product with Grignard reagents (Scheme 25).78

Both deuterium- and tritium-labelled methylenebisphosphonic acids (149) have been prepared by quenching the sodium salt of tetraethyl methylenebisphosphonate with deuterated and tritiated trifluoroacetic acid, respectively, followed by de-esterification with brom~trimethylsilane.~~ Analysis of the deuterated product by proton-coupled 31P n.m.r. showed it to contain un-, mono-, and di- deuterated species. Phase-transfer catalysed reactions between a,o-dibromoalkanes and appropriate phosphonates provide alicyclic phosphonate derivatives (150) in moderate yield.80 A new synthesis of diethyl 2-(3,4-disubstitutedpyrrole)phosphonates (152) by the reaction of nitroalkenes with the carbanion of diethyl isocyanomethylphosphonate (151), has been reported.8 The reaction of nitroethene with diethyl methylphosphonate carbanion provides a method of generating the 1,3-dipole (153) which can be trapped by activated alkenes to give hnctionalised 4,5-dihydroisoxazole derivatives (154) (Scheme 26).*2 Enantiomerically pure phosphonic acid derivatives (156) of pyroglutamic acid have been prepared by Michael addition of the lithiated (+)-camphor phosphonate ester (155) to a$-unsaturated esters (Scheme 27).83

A variety of 2-phosphorus-substituted 3-hydroxy-1H-indoles (158) have been synthesised by base-induced cyclisation reactions of the a-aminoalkylphosphorus analogues (157).84 Dimethyl 2- oxoalkenylphosphonates (160) have been prepared in one step fiom pulegone hydrochloride adduct (159) by reaction with dimethyl lithioalkylpho~phonates.~~

5 Selected Applications in Synthesis 5.1 Carbohydrates.- The reaction of ethoxycarbonylmethylenetriphenylphosphorane with the furanose lactol (161) is the key step in a new synthesis of the anti-tumour compound goneofufurone (162).86 The fucose ketophosphonate (163) has been used in olefination reactions with sialic acid-aldehyde to provide a synthesis of novel disa~charides.8~ The aldehyde is

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5: Ylides and Related Compounds 245

R (1 40)

5) /sR2 s /SR4 (R10)2PCH

(R'0)2P-C-SR3 'S-SR3

'5r2 (1 39)

0 II i,ii

RCH = C( SePh), ( Et0)2PCH (SePh)2

(1 42)

Reagents: i, LDA, THF, -78 "C; ii, RCHO, -78 OC, RT

Scheme 23

Reagents: i, Bu'Li, THF, -78 "C; ii, 0- ;

iii, Ph3COTf, 2,6 - lutidine, CH3CN, 60 "C

Scheme 24

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246 Organophosphorus Chemistry

0 0 II i,ii ~ II R:

(Et0)2PCHFC02Et (EtO)2PyFCOC02R A C=C FC02Et I

CO2Et R02C (1 48)

Reagents: i, BuLi, THF, -78 "C; ii, CICOC02R; iii, R1MgX,-78OC - RT

Scheme 25

0 0 II II

(H0)2PCXY P(OH)2

(149) X = H, Y = D; X = Y = D; X = Y = T

! 0 II

50% NaOH/

R4N+Br- Br(CH2), Br + (R0)2PCH2R1

n = 1,2,3 R' = C02But,

l? P ( W 2

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5: Ylides and Related Compounds

R2

0 II i,ii df N P(0Et)2 (Et0)2PCH2NC + 02N

H

(151 1 (1 52)

247

Reagents: i, LDA, THF, -78 "C; ii, NH4CI, H20; iii, P N O 2 ;

iv, CISiMe,; v, P R 2 , Et,N; vi, H30+

Scheme 26

Reagents: i,

Scheme 27

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248 Organophosphorus Chemistry

0 II

(157) R2 = Ph, OMe

HO ,H

0 H

(Me0)2PCH2COCH2 0 II M&Ize HO OB2

(1 63)

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5: Ylides and Related Compounds 249

extremely base-sensitive and caesium carbonate in tenbutanol was the base system ultimately chosen.

5.2 Carotenoids, Retenoids, Pheromones and Polyenes.- Novel, modified carotenoids with nine-(164) and eleven-(165) double bonds have been prepared by double phosphonate-based olefination of the appropriate polyene dialdehydes (Scheme 28). 88 The acceptor-substituted P-apo- 8'-carotenoid (166), a compound with potential non-linear optical properties, has been prepared by olefination of the corresponding carotenal with diethyl 4-nitrobenzylpho~phonate.~~ The Wittig reaction has been used to prepare a number of sulfones (e.g. 167) for use in the synthesis of carotenoidal alkylideneb~tenolides.9~

The allylphosphonate (169) has been prepared for the first time by base-catalysed isomerization of the corresponding vinylphosphonate (168) (Scheme 29).91 This result is surprising since equilibrium for the corresponding phosphonium salts favours the vinyl derivative. Olefination with the phosphonate (169) has been used in a new synthesis of all trans ethyl retinoate (170). Both ylide-based and phosphonate-based olefinations have been used in a convergent synthesis of various retenoid aldehydes.92 Standard phosphonate-olefination methods have been used in the synthesis of all (E)-8,18-ethanoretinal(171).93

Alkyl-branched (e.g. 172) and cyclic (e.g. 173) analogues of (2)-5-decenyl acetate, the sex pheromone of the turnip moth, Agrutis segetum, have been synthesised using (2)-selective Wittig reactions of the corresponding y l i d e ~ . ~ ~

A reported synthesis of the polyenone antibiotic neocarzilin A (174) in the natural (5') configuration involves repeated use of a Wittig-reduction-oxidation sequence to construct the polyene system.95 Both phosphonate- and phosphonium ylide-olefination methods have been used to construct the tetraene fragments (175) of calyculins which are marine sponge component^.^^ Attempts to synthesise the parallel preorganised polyenes (179) using Wittig reactions of 1,8- bis(tripheny1phosphoniomethyl)naphthalene dibromide (176) with unsaturated aldehydes (177, n=2 or 3) gave instead the rearranged product (178) (Scheme 30).97 A similar reaction with the aldehyde (177, n = 1) gave the expected bis(diene) (179, n = 1). Conjugated polyene systems (e.g. 181) containing bicyclo[2.2.2]octane as a spacer have been synthesised from the dialdehyde (180) by Wittig methods.98

The ylide (182) has been used to introduce the enyne entity in a synthesis of the first example of a fulvalene-type system containing two large (13- and Smembered) rings.99 A Whig reaction of the polyene dialdehyde (183) with [(3-terrbutyl)pent-2-en-4-ynyl]triphenyl- phosphorane is a key step in a synthesis of the methano-bridged tetradehydro[36]annulene (184) (Scheme 31).100

5.3 Leukotrienes, Prostaglandins and Related Compounds.- A key step in a reported synthesis of novel photoactivatable 7(2),9(E)- and 7(@,9(E)-dienic peptidoleukotriene derivatives is a Wittig reaction between the (a-phosphonium ylide (185) and the c h i d epoxy aldehyde (186) to give a 3: 1 mixture of the 7(Z),9(E)- and 7(Q,9(E)-dienes. lol

The Wittig reaction continues to be the method of choice in the synthesis of eicosatetraenoic acids and their derivatives. These include the preparation of 17-(R)-(187)- and 18-

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250

[ OHC- ] i*ii

Organophosphorus Chemistry

OMe 0

Reagents: LMeo+I (OMe)2, NaH, THF; ii, Me2C0, H+

0

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5: Ylides and Related Compounds 2s 1

OH 0

(174) , I

(175) R' or R2 = CN or H

Reagents: i, 2.2 x BuLi, THF, w y o - (1 77)

Scheme 30

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252 Organophosphorus Chemistry

OHC DCHO

Me

CHO

(181)

R = 9-anthryl TPP = 2-tetraphenylporphyrinyl

p p But But

But

CECH Reagents: i, 2 x Ph3P=CHCH=C: ; ii, Cu(II), py, MeOH

Scheme 31

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5: Ylides and Related Compounds 253

0

OMe PPh3 + OHC

c9H19-/

c ~ H ~ ~ ~ c H = c H . . . .

H

H OH

?co2Me

- - Ph,P-

CHO

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254 Organophosphorus Chemistry

(R)-(188)-hydroxyeicosatetraenoic acids from the chiral ylides (189) and (190), respectively, 102 and that of all cis-5,8,11,14,17-eicosapentaenoic acid (191) from the nona-3,6-dienyltriphenyl- phosphorane (192) and the aldehyde (193).103 Wittig olefination, that of the lactol (194) with the ylide (195), is also a key step in the synthesis of methyl esters of (10s)-hepoxilin B3 and (10s)- trioxilin B3.104

Use of the Wittig reaction of salt (196) to introduce the carboxylic acid side-chain in a synthesis of the 14-nonstereogenic carbaprostacyclin (197) leads to a 1:l mixture of (2) and (4 isomers. lo5 The carbacyclin iloprost (199) has been synthesised with 90% stereoselectivity by a Wittig reaction of the bicyclic ketone (198) with 4-carboxybutylidenetriphenylphosphorane. 106

5.4 Macrolides and Related Compounds.- Construction of the major segment of the latrunculin backbone has been achieved by means of a three component coupling of the aldehyde (200), the p- ketoester (201), and the phosphonium salt (202). lo7 A new, total synthesis of (R)-(+)-patulolide (204), using ketenylidenetriphenylphosphorane (203) in a coupling-cyclisation sequence, has been reported. lo8 Wittig reactions, involving the ylides (205) and (206), have been used extensively in the synthesis of six of the seven macrolide components (e.g. 207) of the pheromone components of grain beetles of the genera Oryzaephilis and Cryptolestes. lo9

Phosphonate-olefination has been used both in the construction of the carbon skeleton and, by intramolecular reaction under high dilution conditions, in the macrocyclization step in the first total synthesis of the anti tumour 16-membered macrolide rhizoxin.l1° A key step in the first total synthesis of (+)-jatrophone is formation of the C-ring by an intramolecular olefination of the phosphonate (208).l l1 The phosphonate (209) has been used to introduce the Ci-Cg unsaturated dienic ester fragment in a convergent asymmetric synthesis of the anti tumour, antibiotic macrocycle macbecin I. The use of (209) in 8 fold excess gave the required (3-isomer in >70% yield. l2

5.5 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 various heterocyclic systems.

Examples of the synthesis of five-membered heterocyclic ring systems include that of methanocycloundeca[b]pyrrole systems (e.g. 210), 113 A2-pyrrolin-4-ones (21 1) and hence pyrrolo[ 1,2-c]quinazolines (212), l 4 3-(oxazol-5-yl)indoles (213) (Scheme 32) and hence pimprinine-type alkaloid derivatives, l5 derivatives (e.g. 214) of aplysinopsine alkaloids, bicyclic guanidines (e.g. 215), l7 and bis(l,2,4-triazoles) (217) from the diazide (216) (Scheme 33).1 The 6-aza-(218)- and 6,7-diaza-(219)-azuleno[l,2-a]azulenes have been prepared by the reaction of [(azulen-2-yl)imino]triphenylphosphoranes with 2-brom~tropone~ l9 and a one-pot conversion of azides (220) into benz[flindoles (221) via sequential reaction with triphenyl- phosphine, diphenylketene and manganese dioxide has been reported (Scheme 34). 120

Six-membered heterocyclic systems which have been synthesised by similar methods include heteroannulated 3,l-oxazin-4-ones (e.g. 223) from (222), 121 pyrimido[4,5-b]quinolines (224) (Scheme 33, 122 6H-pyrido[4,3-b]-, 1 lH-pyrido[4,3-a]-, and llH-pyrid0[3,4-a]-carbazoles (e.g. 225), 123 pyrido[2,3,4-de]quinazolines (226) and benzo[de][ 1,6]naphthyridines (227, 124

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5: Ylides and Related Compounds 255

HOQ---mC5H 11 __t

+ Ph3P\

-C02Me

-

O X 0

+ Ph3P(CH2)4C02H Br-

(1 96)

Me +

Ph3P(CH2)4C02H Br- - OR OR OR OR

(198) (199) R = H

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256 Organophosphorus Chemistry

O H C W +Ph3P=C=C=0 - PhMe ****G 0

OH

0 (203)

(204)

OPS

C02-Na+

f : f : CCH,P(OEt)2

'OR

Me02C,p, f P (OCH2CF3)*

Me

(209)

%R2

0 R3

Dioxane

h2504 A

- %.. 0 R3

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5: Ylides and Related Compounds 257

NHR

Reagents: i, Bu3P, CH2C12; ii, RNCO, CH2CI2

Scheme 32

(214) X = NH, 0

i,ii

R

Reagents: i, Ph3P; ii, RCOCI

Scheme 33

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258 Organophosphorus Chemistry

(218) X = CH (219) X = N

Ar

Reagents: i, Ph3P; ii, Ph,C=C=O ; iii, A; iv, Mn02

Scheme 34

C02Me PhCOCl P

Et3N 02N N=PPh3 02N

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5: Ylides and Related Compounds 259

+ R2 do / R’02co R

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260 Organophosphorus Chemistry

and 4-arylpyridines (228). 125 The reaction of iminophosphoranes with isocyanates has been used as a key step in a synthesis of 7-ethoxycarbonyl-7,8-dehydrorutecarpine derivatives (229). 126

5.6 Tetrathiafulvalenes and Related Compounds.- Both phosphonate- and phosphonium ylide- based olefination methods have been widely used to synthesise a wide range of tetrathiafulvalene (TTF) derivatives for use as electron donors to prepare charge transfer adducts as potential organic-based conductors and semi-conductors.

The TTF 1,4-phenylene analogue (232) has been prepared by the reaction of the dithiole phosphonate anion (230) with 1,4-dithiophenoylbenzene (231)127 while related 1,3,5-analogues (233) and (234) have been synthesised by similar olefination reactions with 1,3,5-triacylbenzenes and by Wittig reactions using trisylides derived from 1,3,5-substituted benzene (Scheme 36), respectively. 128 2,2'-(Cyclopenten-3,5-diylidene)bis( 1,3-dithiole)s (235) have been prepared in poor yield by phosphonate olefination using (236)129 and both Wittig-, using (237, and phosphonate-, using (238), methods have been applied to the synthesis of a range of heterocyclic analogues (239) related to (235).130, A variety of highly functionalised derivatives (241) of the z-electron donor 9,lO-bis( 1,3-dithiol-2-ylidene)-9,1O-dihydroanthracene have been prepared using the phosphonate (240).132 Other examples of similar reactions include the preparation of bis(2- methylidene)-l,3-dithiolo[4,5-d]tetrathia~lvalenes (243),133 and the related TTF derivatives (244) and (245), from the phosphonate (242) and that of ethylenedithiotetrathiafblvalenes (e.g. 246) from the phosphonate (247).135

Phosphonium ylides have been less used than phosphonate anions in reactions to generate TTF analogues. However, in addition to the examples already given, vinylogs (249) of TTF have been synthesised by four-fold Wittig olefination of the tetraformyl derivatives (248)*36 and a number of TTF donors (e.g. 251) containing methylene spacer groups have been prepared from the bisphosphonium salts (250). 137

5.7 Vitamin D Analogues and Related Structures.- Coupling reactions of phosphine oxide anions with appropriate ketones continue to be the method of choice to introduce the A ring in syntheses of vitamin D and its analogues and metabolites. Examples include the use of (252) in a new convergent synthesis of dihydrotachysterol2,138 the use of the c h i d ylide (253) to construct stereoselectively the hydroxylated side-chain in a new synthesis of 25-hydroxydihydro- tachyster012,~39 the use of (254) in a new route to calcitriol lactone (255),l40 and olefinations involving the anion (256) in a reported synthesis of 24-oxavitamin D3 (257).

5.8 Miscellaneous Reactions.- The synthesis of the stilbene homologues (258), which contain rnetu-phenylene units as conjugation barriers, has been achieved using standard Wittig methods followed by isomerization to the all tram form. 142

Examples of the synthesis of coumarin derivatives include those of coumarins 7,8-fused onto furan, pyran, and dioxole rings (259) by the reaction of stabilised and semi-stabilised ylides with 4-methylchromene-2,7,8-trione. 143 Depending on the conditions used 3-(2-hydroxyaryl)- coumarins (262) and coumestans (263) were among the products obtained from reactions of the ylide (260) with o-hydroxybenzaldehydes (261). 144

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5: Ylides and Related Compounds 26 1

(233) R = r'IxR2 R' R2

+ CH2PPh3 I

i,ii

R A R

Scheme 36 Dow

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262 Organophosphorus Chemistry

+ (237) X = Ph3P (238) X = (Me0)2P

II

(239) X = 0, S, NMe

0

R = CH20SiPh2Bu' s K s

MeS H SMe

(241 1

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5: Hides and Related Compounds 263

+ 4

‘+PPh2 I

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264 Organophosphorus Chemistry

TBSO'" kTBS (254)

R\R \ R \ R

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

Me Go X

(259)

OCR'=CR~, etc. x = OCHR'CHR~,

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5: Ylides and Related Compounds 265

X ho PPh3

0

Ph3P=CHCO(CH2)&02Et

(264)

OR 0

Me2N OR

Me Me

(267)

H JLJPMB Me Me

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266 Organophosphorus Chemistry

0 /QrOTBDMtLi + (Et0)2PCHC02Et THF

0 / D O T B D M

But& N A c H o H

But OK H N -COzEt

Reagents: i, NaH, DMSO; ii, Bu'OCOCI, Et3N, 2-pyridylpiperazine; iii, LiAIH4

Scheme 37

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5: Ylides and Related Compounds 267

Ph3P(CH&CH=CH2 + BT + cH3FcH0 NHBoc i,ii ~ CH3 W C H 2 ) & H = C H 2

NH2

Reagents: i, KOBU‘, THF, - 78 “C; ii, 2, 6-lutidine, Bu‘Me2 SiOTf, CH2CI2

Scheme 38

R’Y-N=pph3 R2

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268 Organophosphorus Chemistry

A Wittig reaction of the ylide (264) has been used to introduce the exocyclic double bond, in moderate yield but with exclusively (a-stereochemistry, in a synthesis of the racemate of the natural algae-growth inhibitor (265). 145 The reaction of alkylidenetriphenylphosphoranes with a- oxoesters has been used as a route to the cis-isomers of very long chain fatty acid methyl esters but yields are at best moderate, 146

The first total synthesis of (+) calyculin A has been achieved using a (Q-stereoselective Wittig coupling of the C1-C25 and C26-C37 subunits, the latter in the form of the complex ylide (266), as the final step. 147 The complex phosphine oxide (267, representing the C1o-C21 portion of rapamycin, has been stereoselectively synthesised and shown to undergo olefination with the aldehyde (268) to give predominately the (E,E,Q triene. 148

A variety of novel cephalosporins having substituted-vinyl functionalities at C3 have been synthesised via Wittig reactions of the appropriate cephalosporin phosphonium ylides (269). 149 The protected N14 to C18 amino acid subunit (270) of the peptide cyclotheonamide A has been stereoselectively prepared by a Wadsworth-Emmons reaction.150 Although a mixture of (E)- and (a-isomers is initially produced in the reaction, complete isomerization to the (Q-isomer occurs if the reaction mixture is left at O°C for 30 minutes before quenching. A mechanism involving Michael addition for this isomerization is suggested and supporting evidence is provided. A Wittig reaction involving dec-2-enylidenetriphenylphosphorane has been used to prepare the acetates, (271) and (272), of structures previously suggested for pseudodistomins A and B, respectively. 151 Comparisons with the natural materials, and conversion of (271) and (272) and the natural materials into the fully saturated compound (273), indicate that although the carbon skeleton previously suggested for the pseudodistomins is correct the positions of unsaturation require re- investigation. The (S)-4-substituted 1-phenylcyclohexene (275) which, unlike its enantiomer, has dopamine agonist properties has been synthesised by intramolecular Wittig reaction of the phosphonium salt (274) as the key step (Scheme 37). 152 (2S,3E,52)-2-Amin0-3,5,13-tetra- decatriene (277, which has both cytotoxic and anti fungal properties, has been synthesised for the first time by a Wittig reaction of the (5')-y-aminoenal (276) (Scheme 38).153 Vinyl tricarbonyl structures (e.g. 279), usehl as polyelectrophiles in the synthesis of vincamine-related alkaloids, have been prepared by the oxidation of P,P'-dicarbonyl ylides (e.g. 278) with ozone or singlet 0 x y g e n . 1 ~ ~

The iminophosphorane function has been used as a highly effective base-labile amino protecting group. 55 The reaction of the allylic iminophosphoranes (280), prepared from the corresponding azide, with ketenes provides a synthesis of 4-pentenenitriles (281). 56 Reaction of (280) with acyl halides surprisingly leads to formation of the phosphonium salt (282). A mechanism is suggested for this reaction.

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81.

82.

83.

84.

85.

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