Base-Promoted Isomerization of cis-4-Formyl-2-azetidinones: Chemoselective C4-Epimerization vs Rearrangement to Cyclic Enaminones

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Abstract
Two simple, efficient, and complementary methods for the regiospecific C4-epimerization of cis-4-formyl-2-azetidinones 1-3 are described. The first method uses 40% aqueous dimethylamine as reagent in heterogeneous medium with benzene at room temperature, in the presence of benzyltributylammonium bromide (3-4 mol%) as the phase-transfer catalyst. This transformation tolerates alkyl, alkenyl, alkynyl, aryl, and alkoxy substituents at the C3 of the 2-azetidinone ring. However, limitations of this isomerization are as follows: (i) only N-(p-methoxyphenyl)-beta-lactams can be used, and (ii) transformation is less compatible with heteroatomic substituents bonded to the C3 position of the 2-azetidinone ring. A highly general solution to these problems relies on the use of sodium carbonate as the isomerization reagent in different solvents. We also describe a novel base-promoted rearrangement of the beta-lactam ring to cyclic enaminones 6 and 21, involving an E1cB-elimination reaction in cis-4-formyl-2-azetidinones.

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