Science of Synthesis

Schobert, R.; Gordon, G. J., Science of Synthesis, (2004) 27, 1018.

The Wittig reaction between alkylidenephosphoranes ‌90‌ and carbonyl compounds ‌91‌ affords a phosphine oxide and alkenes ‌92‌ with a predictably positioned double bond (‌Scheme 32‌).[‌275‌] The method dates back to 1953[‌13‌] and is one of the most widely used C=C bond-forming processes in organic synthesis.[‌2‌–‌4‌,‌6‌–‌9‌,‌441‌,‌442‌] It can be performed under neutral conditions using either isolated and purified ylides or solutions of the compounds prepared in situ from various sources, most typically from triphenylphosphonium salts and strong bases. The reaction often tolerates further functional groups, which need not be protected; for example, alkenyl, alkynyl, or alkoxide, and even carbonyl groups of lower reacitivity. The rate as well as the E/Z selectivity of the Wittig reaction depend upon a number of factors such as solvent polarity,[‌443‌,‌444‌] the presence or absence of lithium salts,[‌311‌,‌443‌,‌445‌] and on the particular combination of ylide and carbonyl components. Wittig alkenylation reactions of stabilized ylides of low reactivity can also be accelerated by the application of pressure,[‌446‌] sonication,[‌447‌] microwave irradiation,[‌448‌] or by the addition of silica gel.[‌449‌] All classes of ylides alkenate at least one type of carbonyl compound, the activity of which decreases in the order ketenes >> aldehydes > ketones > esters ≈ amides. Nonclassical alkenations of anhydrides,[‌450‌] imides,[‌451‌] enol esters,[‌452‌,‌453‌] and isocyanates[‌293‌] are also known. Unstabilized, reactive (alkylidene)triphenylphosphoranes featuring electron-donating or electroneutral substituents (e.g., R2 = H, alkyl) bonded to the ylidic carbon atom are moisture- and air-sensitive, and react rapidly with aldehydes and ketones. If carried out in media devoid of lithium salts, the reactions of such ylides with aldehydes yield predominantly Z-configured alkenes with ratios ranging from 94:6[‌7‌,‌9‌,‌445‌,‌454‌,‌455‌] to 99:1.[‌443‌] The highly trans selective (Z/E < 1:99) alkenation of aldehydes by reactive (alkylidene)triphenylphosphoranes is also possible via the corresponding betaine ylides as readily epimerizing intermediates. These can be obtained from in situ lithiation of the usual cis-oxaphosphetane intermediates.[‌9‌,‌445‌,‌456‌] The SCOOPY variant (SCOOPY = α-substitution plus carbonyl olefination via β-oxidophosphorus ylides) of this procedure allows the concomitant substitution of the ylidic carbon atom with residues other than hydrogen (e.g., deuterium, halogen, alkyl, hydroxymethyl).[‌457‌] Stabilized ylides bearing an electron-withdrawing residue, such as acyl, alkoxycarbonyl, nitrile, sulfonyl etc. in the α-position can be handled under ambient conditions. These ylides readily E-alkenate aldehydes, whereas reactions with ketones or esters require forced and/or intramolecular conditions.[‌458‌,‌459‌] Z/E Ratios <1:99 can be achieved in the reactions of aldehydes with α-alkyl branched, α-acyl substituted,[‌460‌] and α-formylated ylides,[‌461‌] or by employing trialkyl- in lieu of triarylphosphoranes.[‌330‌] Protic solvents also favour the formation of E-isomers as does the addition of lithium salts.[‌8‌] The heterogenous class of moderated ylides ‌90‌ (R1 = Ph; R2 = halo, OR3, SR3, Ar1, CH=CHR3, C≡CR3) are notorious for their low selectivity in Wittig reactions. However, the replacement of one or more of their P-phenyl ligands by (2-methoxy)methoxyphenyl[‌462‌] or by pyridyl[‌463‌] groups can dramatically increase it. Optically active allenes and cycloalkylidene derivatives[‌464‌] have been obtained employing chiral ylides with asymmetric, configurationally stable phosphorus centres. Among other reactions, the chiral ylides have also been used for the kinetic resolution of racemic ketones.[‌465‌,‌466‌] The mechanism of the Wittig reaction is still under debate and no single mechanism accounts for all types of ylides.[‌2‌] The irreversible, direct formation of oxaphosphetanes as key intermediates has been established beyond doubt for reactions of unstabilized ylides in lithium salt free media,[‌467‌] while little evidence exists for the intermediacy of often-proposed uncomplexed betaines. Oxaphosphetanes are thought to be formed initially with an O-apical geometry about the pentavalent phosphorus atom and with aldehyde and ylide substituents cis to one another, in order to minimize repulsion between R13P and R3 in the early puckered, reactant-like transition state.[‌468‌] A pseudorotation to give the O-equatorial rotamer is then mandatory, prior to syn-eliminative bond breaking and alkene formation.[‌8‌,‌469‌,‌470‌] Whether trans-oxaphosphetanes and +P—O—C—C− betaines play a role in the formation of E-alkenes from stabilized ylides remains uncertain.[‌469‌,‌471‌,‌472‌]

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References

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