Unequivocal Experimental Evidence for a Unified Lithium Salt-Free Wittig Reaction Mechanism for All Phosphonium Ylide Types: Reactions with β-Heteroatom-Substituted Aldehydes Are Consistently Selective for cis-Oxaphosphetane-Derived Products

Abstract

ABSTRACT:The true course of the lithium salt-free Wittig reaction has long been a contentious issue in organic chemistry. Herein we report an experimental effect that is common to the Wittig reactions of all of the three major phosphonium ylide classes (non-stabilized, semi-stabilized and stabilized): there is consistently raised selectivity for cis-oxaphosphetane and its derived products (Z-alkene and erythro-β-hydroxyphosphonium salt) in reactions involving ald ehydes bearing heteroatom substituents in the β-position. The effect operates with both benzaldehydes and aliphatic aldehydes and is shown not to operate in the absence of the heteroatom su bstituent on the aldehyde. The discovery of an effect that is common to reactions of all ylide types strongly argues for the operation of a common mechanism in all lithium salt-free Wittig reactions. In addition, the results are shown to be most easily explained by the [2+2] cycloaddition mechanism proposed by Vedejs and co-workers as supplemented by Aggarwal, Harvey and co-workers, thus providing strong confirmatory evidence in support of that mechanism. Notably, a co-operative effect of ortho-substituents in the case of semi-stabilized ylides is confirmed and is accommodated by the cycloaddition mechanism. The effect is also shown to operate in reactions of triphenylphosphine-derived ylides, and has previously been observed for reactions under aqueous conditions, thus for the first time providing evidence that kinetic control is in operation in both of these cases.

The modern interpretation of the Wittig reaction mechanism

“…Some triphenylphosphine-derived stabilised ylides do not undergo Wittig reactions or require heating to effect the reaction, 3 but we have observed methyldiphenylphosphinedrived stabilised ylides to react rapidly with aldehydes even at -78 °C. 38,39 This is consistent with the observation of Frøyen that 80 the reaction rates of fluorenylides with p-nitrobenzaldehyde increases with successive replacement of the P-phenyl groups of the ylide phosphonium moiety with P-ethyl groups. 53 A very significant aspect of the Wittig reaction is that, broadly speaking, the nature of the ylide used in a Wittig reaction dictates 85 the stereoselectivity of the reaction.…”

“…65 OPAs have been shown to be the only observable intermediates many times in reactions of non-stabilised ylides. 38,65,68,69,88 It has also been demonstrated in such reactions that the final step of the Wittig reaction is decomposition of OPA to alkene and phosphine oxide, since the rate of OPA decomposition equals the rate of 70 alkene formation (i.e. this is a first order process), 69,70 and since the diastereomeric ratio of the OPA generally matches that of the derived alkene.…”

“…35 Irreversibility of OPA formation has been demonstrated for selected examples of these reactions (ones 70 showing low selectivity). 38 Thus, the betaine mechanism is unable to account for moderate to low Z-selectivity under kinetic control in Wittig reactions of non-stabilised ylides. Furthermore, the reactions of certain non-stabilised ylides (primarily ethylides -see later) are the only ones that are know not to be irreverisble 75 under Li salt-free conditions.…”

“…See section 4 for full details. The positive crossover results in the epoxide-cleavage experiments of Scheme 4 were obtained under conditions in which betaine was necessarily generated (and at a temperature much higher than is 25 typically used for Wittig reactions), and do not mean that betaine is an essential intermediate in Wittig reactions of stabilised ylides, especially since it has been demonstrated that both high E 60 and high Z-selectivity 38 are possible under kinetic control in reactions of these ylides. 30 (v) Explanation of stereoselectivity of reactions of semistabilised ylides within context of the betaine mechanism: Reactions of triphenylphosphine-derived semi-stabilised ylides show little or no selectivity (i.e.…”

“…Li + -free stereochemical drift and has been observed only for the OPAs produced in the reactions of trialkylphosphonium 30 alkylides with tertiary or aromatic aldehydes, 68,69,92 and in reactions of aromatic aldehydes with the ethylides of triphenylphosphine, 38,65 ethyldiphenylphosphine 38 and P-phenyl-5H-dibenzophosphole. 38 In the first two cases, the augmentation of trans-OPA at the expense of the cis-isomer occurred at 35 temperatures below which OPA cycloreversion to alkene and phosphine oxide could not occur, and thus it could be monitored by NM R. These experiments represent the only examples in which stereochemical drift has been observed in action. In the latter three cases, the OPA cis/trans ratio was invariant with time 40 below the temperature at or above which alkene formation could occur, and so stereochemical drift could only be detected to have occurred by comparison of the kinetic OPA cis/trans and alkene Z/E ratios.…”