A Comparison of the Effects of Steric Crowding at Phosphorus on the Steric Course of Wittig Reactions of Stabilised and Semistabilised Ylides

David W. Allen*

Department of Chemistry, Sheffield City Polytechnic, Pond St., Sheffield S 1 1WB, U.K.

Z. Naturforsch. 35b, 1455-1458 (1980); received May 28, 1980

Alkene cis-trans Ratio, Reaction Mechanism The cis-trans ratio of the alkenes formed in Wittig reactions of semistabilised ylides (derived from benzyltriarylphosphonium salts in ethanolic sodium ethoxide) with benz- aldehyde, acetaldehyde or trimethylacetaldehyde increases as steric crowding at phos- phorus increases. In contrast, the cis-trans ratio of the unsaturated esters formed in the related reactions of the stabilised ethoxycarbonylmethylene ylides decreases as steric crowding at phosphorus increases. The relevance of these results to recent proposals for the mechanism of the Wittig reaction is considered.

Recently, we have shown that increasing steric The reactions were carried out at room tem- crowding at phosphorus in Wittig reactions of the perature by treatment of the appropriate benzyl or semistabilised ylides (1) with benzaldehyde in ethoxycarbonylmethylphosphonium salt with so- ethanol leads to an increase in the cis-trans ratio of dium ethoxide (1 mol) in dry ethanol, followed by the resulting stilbenes [1]. It was suggested that addition of the appropriate aldehyde. The relative these findings could be accounted for in terms of the proportions of the eis- and frans-alkenes were cycloaddition mechanism proposed by Vedejs and determined by GLC analysis and the results are Snoble [2] for the reactions of reactive ylides in presented in Tables I and II. salt-free media, involving orthogonal approach of It is apparent that in the reactions with benz- P=C and C=0 to form the pentacovalent phos- aldehyde, whereas increasing steric crowding at phorane intermediate directly, without the involve- phosphorus in the semistabilised ylides (1) results ment of betaine intermediates. in an increase in the proportion of the cis-alkene, EtOH the opposite is true for the stabilised ylides (2) such Ar21Ar2P=CHPh + PhCHO that when two or three o-tolyl groups are present 1 at phosphorus, the proportion of cis-isomer in the Ar21Ar2P=0 + PhCH=CHPh We have now extended our preliminary studies to Table I. cis-trans Ratios of Isomeric alkenes formed in Wittig reactions of the semistabilised ylides include the reactions of the semistabilised ylides (1) Ar21Ar2P = CHPh with aldehydes in ethanol. with other aldehydes, and also an investigation of the steric and electronic effects of substituents at cis-trans Total phosphorus on the stereochemical course of Wittig Ylide RCHO Ratio(%) yield(%) reactions of the fully-stabilised ylides (2) in ethanol. Ar1 = Ar2 = Ph R = Ph 52: : 48 87 Our results show, in general, that the effects of 1 2 Ar = Ph; Ar = o-tolyl 99 62: : 38 70 1 2 increasing steric crowding at phosphorus in stabilised At = o-tolyl; AR = Ph 99 67: 33 >95 1 2 ylides are the reverse of those observed for semi- Ar = Ar = o-tolyl 9 9 70: : 30 76 Ar1 = Ar2 = p-tolyl 42: : 58 >95 stabilised ylides, indicating significant differences in » mechanism for the two types of ylide. Ar1 = Ar2 = Ph R —Me 50: : 50 50 1 2 Ar = Ph; Ar = o-tolyl 99 51: : 49 74 1 2 Ar = o-tolyl; Ar = Ph 9 9 63: : 37 58 1 2 Et H 1 2 Ar2 Ar P=CHC02Et + PhCHO ° • Ar = Ar = o-tolyl 99 78: : 22 44 1 2 2 Ar = Ar = p-tolyl 99 48: : 52 53 Ar21Ar2P=0 + PhCH=CHC02Et Ar1 = Ar2 = Ph R = Bu< 73: : 27 <10 Ar1 = Ph; Ar2 == o-tolyl >5 77: : 23 <10 1 2 Ar = o-tolyl; Ar = Ph 99 85: : 15 <10 1 2 Ar = Ar = o-tolyl 99 — 0 * Reprint requests to Dr. D. W. Allen. 1 2 Ar = Ar = p-tolyl 99 65: : 35 <10 0340-5087/80/1100-1455/$ 01.00/0 1456 D. W. Allen • Wittig Reactions of Stabilised and Semistabilised Ylides

Table II. cis-trans Ratios of isomeric alkenes formed in conditions used, presumably a reflection of the Wittig reactions of the stabilised ylides, reduced nucleophilicity of the stabilised ylide and Ar21Ar2P = CHC02Et with aldehydes in ethanol. the increased steric crowding at the carbonyl carbon. Aide- cis-trans Total It is of considerable interest that in the Wittig Ylide hyde Ratio(%) yield(%) reactions of both semistabilised and stabilised ylides, while the steric effects of the phosphorus Ar1 = Ar2 = Ph R = Ph 21: : 79 90 Ar1 = Ph; Ar2 = o-tolyl 8: : 92 72 substituents are significantly different, their elec- Ar1 = o-tolyl; Ar2 = Ph 99 2: : 98 71 tronic effects are similar, in that electron-with- Ar1 = Ar2 = o-tolyl 0: : 100 76 99 drawing substituents favour the cis-alkene and Ar1 = Ar2 = p-tolyl 12:: 88 >95 » electron-donating substituents the Jrans-isomer [3]. Ar1 = Ar2 = Ph R =Me 28: : 72 71 We have suggested previously [1] that the in- Ar1 = Ph; Ar2 = o-tolyl 25: : 75 83 Ar1 = o-tolyl; Ar2 = Ph 17:: 83 >95 creasing proportion of cis-alkene in the reactions of Ar1 — Ar2 = o-tolyl 24: : 76 65 the semistabilised ylides as steric crowding at Ar1 - Ar2 = ja-tolyl 29: : 71 >95 phosphorus increases can be accounted for in terms

of the n2a +.i2s cycloaddition mechanism of Vedejs product becomes very low. Clearly there must be, and Snoble [2], involving orthogonal approach of the at some stage, a significant difference in the mecha- ylide P=C and carbonyl groups, which leads prefer- nism of the reactions of the two types of ylide. entially to the CTs-oxaphosphetan (3). The increase The situation in the related reactions with acet- in the proportion of the cis-alkene in the reactions aldehyde is similar, but not as well defined. Whereas of the above triarylphosphonium ylides as steric in the reactions of the semistabilised ylides, a crowding increases at the carbonyl carbon parallels similar increase in the proportion of cis-isomer is Vedejs and Snobles' observations in the reactions of seen, in the case of the stabilised ylides increasing reactive ylides under salt-free conditions, which steric crowding at phosphorus again results in a supported their proposal of the cycloaddition mech- decrease in the proportion of the cis-isomer for the anism. introduction of up to two o-tolyl substituents.

However, on introduction of a third o-tolyl group, Ar , Ar J\r the proportion of the cis-isomer increases. Never- 0 >—Ar •v theless, there is still a decrease in the proportion of f' H H the as-isomer compared to that observed for the 3 tris-p-tolylphosphonium ylide. It has also been suggested that the predominant The results of the reactions with trimethylacet- formation of £rans-alkenes in Wittig reactions of aldehyde are also of interest. The reactions of the fully stabilised ylides can be accounted for in terms semistabilised ylides, although proceeding in poor of a cycloaddition mechanism involving the coplanar yield in comparison to the related reactions in- combination of P=C and C=0 in a jiZ- -j-nZg cyclo- volving acetaldehyde or benzaldehyde also show an addition mode [4]. In this mechanism, the effects of increase in the proportion of cw-isomer as steric increasing steric crowding at phosphorus would crowding at phosphorus increases. It is also note- result in formation of the C-C bond in advance of worthy that the proportion of the cis-alkene in the the P-0 bond (as in the transition state (4)) and reactions of the triarylphosphonium ylides is signifi- thus steric interactions between the substituents on cantly greater in the reaction with trimethylacet- the ylide carbon and carbonyl carbon will favour the aldehyde than with either acetaldehyde or benz- fra?w-oxaphosphetan which, assuming a «^-elimina- aldehyde. Under the conditions used, the corre- tion of the phosphine oxide [5] would give rise to sponding reaction of the tris-o-tolylphosphonium the Jraws-alkene. ylide gave only traces of the alkenes, the main product being benzyl ethyl ether, the result of attack of ethoxide ion on the benzylphosphonium jf salt in equilibrium with the ylide. I 9>h Unfortunately, the stabilised ylides (2) also did not react with trimethylacetaldehyde under the 1457 D. W. Allen • Wittig Reactions of Stabilised and Semistabilised Ylides

The suggestion of the above cycloaddition mecha- Very recently [5], it has been argued that in nism is also supported by studies of the kinetics of general, steric factors will favour the formation of reactions of stabilised ylides in non-polar aprotic the fra?is-oxaphosphetan, rather than the cis-isomer solvents, and also in glycols, which are consistent as suggested by other workers [2, 10, 11], and that with the concept of a highly oriented transition this, in the presence of salts, will undergo syn- state of low polarity [6-9]. elimination of phosphine oxide to give the trans- alkene. Increasing steric crowding at phosphorus should then favour formation of the trans-oxa- * ^ D1 V-Ar X r phosphetan and, in turn, the frans-alkene, which r H'V S we observe for the stabilised ylides. However, under H-C^R1 I +,Ar H*C_0 0 fV the same conditions, increasing steric crowding at R2 At phosphorus in the semi-stabilised ylides results in a 5 6 marked decrease in the proportion of the trans- alkene, a result opposite to that expected on the Bestmann et al. [10] have proposed recently that basis of this argument. in the attack of ylide on the carbonyl group, the c?'s-oxaphosphetan is formed via a betaine-like tran- Experimental sition state (5) (equivalent to the erythro-anti- Operations involving tertiary phosphines or orientation of reactants [11]), and that following related phosphonium ylides were conducted under pseudorotation of the oxaphosphetan, cleavage of nitrogen. XH NMR spectra were recorded at 60 MHz the apical P-C bond occurs to give the new betaine using a JEOL spectrometer. (6), which si/w-eliminates the phosphine oxide to A. Preparation of phosphonium salts form the ct's-alkene. Increasing steric crowding at The benzylphosphonium salts were prepared by phosphorus would presumably favour the above quaternization of the appropriate triarylphosphine orientation of reactants, leading preferentially to with benzyl bromide in either toluene or aceto- the cis-oxaphosphetan, and also favour elimination nitrile, according to standard procedures. The tri- of phosphine oxide which would be associated with arylethoxycarbonylmethylphosphonium salts were relief of steric strain. However, it is more difficult similarly prepared by quaternization of the appro- priate triarylphosphine with ethyl bromoacetate to see how this mechanism can account for the under reflux in acetonitrile, followed by precipita- increasing proportion of frans-alkene on increasing tion with ether, and recrystallisation. The following steric crowding at phosphorus in the reactions of compounds appear to be new: the stabilised ylides. Bestmann et al. have argued that factors which slow down the elimination of Ethoxycarbonylmethyldiphenyl( o-tolyl )phosphonium bromide phosphine oxide from the betaine (6) (such as the m.p. 157 °C (decomp.) (from chloroform-ethyl ace- presence at the carbanionic carbon of an electron- tate). withdrawing group e.g. C02Et, as in the above C23H24Br02P reactions) will favour the formation of the trans- Found C 62.3 H 5.7, isomer, as is generally observed in the reactions of Calcd C 62.3 H 5.5. stabilised ylides. Similarly, the presence at phos- <5(CDC13) ppm: 8.3-7.35 (m, 14ArH); 5.4 (d, 2H, phorus of electron-donating groups will also retard VPCH 14.2 Hz); 4.05 (q, 2H); 2.3 (s, 3H) and 1.0 elimination of phosphine oxide, and favour forma- (t,3H). tion of the frans-alkene. Presumably, both o-tolyl and p-tolyl groups have similar electron-donating Ethoxy earbonylmethylf phenyl )di( o-tolyl )phos- phonium bromide ability, and yet the proportion of Ci's-alkene in the reactions of the carbonyl-stabilised tris-p-tolylphos- m.p. 106-107 °C (from chloroform-ethyl acetate). phonium ylide is greater than that derived from the C24H26Br02P tris-o-tolyl analogue, which, in the reaction with Found C 62.6 H 6.0, benzaldehyde, gives rise almost exclusively to the Calcd C 63.0 H 5.7. fraws-isomer. Clearly there is also a significant steric (5(CDC13) ppm: 8.3-7.1 (m, 13ArH); 5.2 (d, 2H, effect in this reaction. VPCH 13.3 Hz); 3.9 (q, 2H); 2.3 (s, 6H) and 0.95 (t, 3H). 1458 D. W. Allen • Wittig Reactions of Stabilised and Semistabilised Ylides

Ethoxycarbonylmethyltri( o-tolyl) phosphonium B. Wittig Reactions bromide (i) Benzylphosphonium salts: The reactions were m.p. 161 °C (decomp.) (from chloroform-ethyl ace- carried out by dissolving the appropriate phos- tate). phonium salt (1.25 X 10-4 moles) and the aldehyde 4 3 C25H28Br02P (1.25 X 10~ moles) in dry ethanol (1,5 cm )* to Found C 63.5 H 6.0, which was then added sodium ethoxide (1.25 X Calcd C 63.7 H 6.0. 10-4 moles) in ethanol (1 cm3). After 1 h at room temperature, the solutions were analysed for cis- <5(CDCL) ppm: 8.2-7.1 (m, 12ArH); 5.2 (d, 2H, and fraws-alkenes by GLC (5' column of SE 30 on 2JPCH 12.6 HZ); 3.9 (q, 2H); 2.3 (s, 9H) and 0.95 celite, using a flame ionisation detector). (t, 3H). This salt was further characterised by conversion (ii) Ethoxycarbonylmethylphosphonium salts: The to the Perchlorate, m.p. 172-173 °C (from aqueous reactions were carried out as above, except that the ethanol). reaction mixtures were allowed to stand at room C25H28C106P temperature for 24 h before analysis. Found C 61.3 H 5.8, Calcd C 61.1 H 5,7. and picrate, m.p. 130 °C (from aqueous ethanol). C31H30N3O9P Found C 60.3 H 5.0 N 6.8, I thank Miss H. Ward and Mr. K. Osbourne for Calcd C 60.1 H 4.9 N 6.8. experimental assistance.

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