Quantum Mechanical Investigation of the Horner-Wadsworth-Emmons Reaction of Benzyl Pyridyl Ketone

Abstract

The Horner-Wadsworth-Emmons (HWE) reaction is one of much versatile tools in syntheses of α ,β-unsaturated esters, α ,β-unsaturated ketones, and other conjugated systems. Mechanistically, it is generally accepted that the HWE reaction occurs with the addition of enolate derived from phosphonoacetate to aldehyde or ketone, followed by oxaphonphetane formation, pseudorotation, P-C bond cleavage, and then O-C bond cleavage. Stereochemically, the general phosphonoacetates with alkyl phosphonate substituents give E-olefins, which can be explained as a result of the predominant formation of thermodynamically more stable threo adducts. According to an ab initio calculation performed by Ando, in the transition states of the nucleophilic addition to the carbonyl group of acetaldehyde with the trimethyl phosphonoaceate enolate, a transition state leading to Z-olefin (erythro-TS-1) is more stable than threoTS-1 due to a repulsive interaction between the phosphonate moiety and the methyl substituent of aldehyde in threo-TS-1 (Fig. 1). On the other hand, the transition state for the oxaphosphetane formation favors a transition state leading to E-olefin (threo-TS-2) over erythro-TS-2 due to the steric hindrance between the ester moiety and the alkyl substituent of the carbonyl compound (Fig. 1). Based on the energy difference calculated, Ando concluded that the rate-determining transition state for the HWE reaction is TS-2 and, therefore, the threo-olefin is the product of choice. In our recent attempt to convert benzyl phenyl ketone (1, Table 1) to its corresponding olefinic compound (3 and 4, Table 1), the strong preference for E-olefin (3) was also observed (E:Z > 99:1, Table 1) regardless of the base used. However, to our surprise, benzyl 2-pyridyl ketone (2, Table 1), by the reaction with triethyl phosphonoacetate in the presence of t-BuOK, provided a 1:1 mixture of the corresponding E(5) and Z(6) olefins (Entry 4, Table 1) in fairto-good yields. Interestingly, the increased Z-selectivity was not reproduced by use of NaH or LiHMDS as a base (Entires 5 and 6, Table 1), which indicates that the counter cation of the base plays the key role in determining the stereochemi-