Two-Carbon Homologation of Aldehydes and Ketones to α,β-Unsaturated Aldehydes

Richard J Petroski,Karl Vermillion,Allard A Cossé

doi:10.3390/molecules16065062

Abstract

Phosphonate reagents were developed for the two-carbon homologation of aldehydes or ketones to unbranched- or methyl-branched α,β-unsaturated aldehydes. The phosphonate reagents, diethyl methylformyl-2-phosphonate dimethylhydrazone and diethyl ethylformyl-2-phosphonate dimethylhydrazone, contained a protected aldehyde group instead of the usual ester group. A homologation cycle entailed condensation of the reagent with the starting aldehyde, followed by removal of the dimethylhydrazone protective group with a biphasic mixture of 1 M HCl and petroleum ether. This robust two-step process worked with a variety of aldehydes and ketones. Overall isolated yields of unsaturated aldehyde products ranged from 71% to 86% after the condensation and deprotection steps.

Highlights

A recurring theme in the synthesis of various polyketide natural products and other compounds is two-carbon homologation of aldehydes or ketones to unbranched or branched (e.g., α-methyl or β-methyl) α,β-unsaturated aldehydes
This paper describes work detailing the preparation (Scheme 1) and use (Scheme 2) of diethyl methylformylphosphonate dimethylhydrazone (1) and diethyl 1-ethylformyl-2-phosphonate dimethylhydrazone (2) for the two-carbon homologation of a variety of aldehydes or ketones to α,β-unsaturated aldehydes after deprotection
Reagent 1 could be prepared (Scheme 1) from commercially available diethyl-2,2-(diethoxy) ethylphosphonate by deprotection to give ethylformyl-2-phosphonate, the aldehyde functional group could be protected as the dimethylhydrazone derivative [13]

Summary

Introduction

A recurring theme in the synthesis of various polyketide natural products and other compounds is two-carbon homologation of aldehydes or ketones to unbranched or branched (e.g., α-methyl or β-methyl) α,β-unsaturated aldehydes. Aldehyde phosphonates (where the ester group is replaced by an aldehyde) can be readily prepared [6], but using them directly in Wittig-Horner reactions is not practicable because of self-condensation. Acidic ionic liquid-catalyzed homologation of α,β-enals was reported, but the scope of the reaction did not include aliphatic aldehydes [11].We chose to further explore phosphonate chemistry with a better carbonyl protective group because the scope of the reaction would include a variety of aldehydes and ketones. This paper describes work detailing the preparation (Scheme 1) and use (Scheme 2) of diethyl methylformylphosphonate dimethylhydrazone (1) and diethyl 1-ethylformyl-2-phosphonate dimethylhydrazone (2) for the two-carbon homologation of a variety of aldehydes or ketones to α,β-unsaturated aldehydes after deprotection. Preparation of phosphonate 2: (c) diethyl ethylphosphonate, THF, BuLi; (d) Me2NCHO; (e) 3 M HCl, 1a–1c in one pot; (b) H2N-NMe2, MgSO4, CH2Cl2, 25 °C, 48 h. Reagents and conditions: (a) Phosphonate 1 or 2, LiN(iPr), THF, 25 °C, 3 to 20 h, time varies with compound; (b) 1 M HCl and Pet ether, 25 °C, 5 to 48 h, time varies with compound

Preparation of Phosphonate Dimethylhydrazone Reagents

Use of the Phosphonate 1 and 2 Reagents in Synthesis

Assignment of Double-Bond Configuration

Experimental

Conclusions