Synthesis of Substrates for Aldolase-Catalysed Reactions: A Comparison of Methods for the Synthesis of Substituted Phenylacetaldehydes

Abstract

Methods for the synthesis of phenylacetaldehydes (oxidation, one-carbon chain extension) were compared by using the synthesis of 4-methoxyphenylacetaldehyde as a model example. Oxidations of 4-methoxyphenylethanol with activated DMSO (Swern oxidation) or manganese dioxide gave unsatisfactory results; whereas oxidation with 2-iodoxybenzoic acid (IBX) produced 4-methoxyphenylacetaldehyde in reasonable (75%) yield. However, Wittig-type one-carbon chain extension with methoxymethylene-triphenylphosphine followed by hydro­lysis gave an excellent (81% overall) yield of 4-methoxyphenylacetaldehyde from 4-methoxybenzaldehyde (a cheap starting material). This approach was subsequently used to synthesise a set of 10 substituted phenylacetaldehydes in good to excellent yields.

Key words

benzaldehyde - phenylacetaldehyde derivatives - homologation reaction

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• 25 General Procedure for Benzaldehyde Homologation (Scheme [2]) To a stirred suspension of [(Ph)₃PCH₂OCH₃]Cl (6.70 g, 19.5 mmol, 1.2 equiv) in dry THF (12 mL) was added t-BuOK (2.40 g, 21.4 mmol, 1.3 equiv) at 0 °C. The reaction mixture was stirred for 20 min. Then, the benzaldehyde derivative (16.2 mmol, 1 equiv) was added, and the mixture was stirred for 16–24 h at r.t. (see Table 1). The reaction mixtures were monitored by TLC, and when the reactions were deemed complete they were quenched by the addition of water (30 mL) and extracted with diethyl ether (3 × 100 mL). The combined organic layers were dried (MgSO₄), filtered, and the solvent was evaporated. The crude enol ether products were purified by column chromato­graphy (8:1 n-pentane/ethyl acetate); for yields and E/Z ratios, see Table 1. The purified enol ether product (E/Z mixture) was dissolved in dichloromethane (30 mL, entries 1–5) or dichloro­ethane (30 mL, entries 6–10). Then, formic acid (98%, 3 mL) was added, and the mixture was heated to reflux for 3–36 h (see Table 1). The reaction mixtures were monitored by TLC and when the reactions were deemed complete, the mixtures were cooled to r.t., diluted with dichloromethane, and washed with aq NaHCO₃. The organic layer was dried (MgSO₄), filtered, and the solvent was evaporated. In some cases (see Table 1) purification of the crude products on a short silica gel column (100:0 to 95:5 toluene/ethyl acetate gradient) was performed. For NMR spectroscopic data of the individual compounds, see Supporting Information.