A facile and efficient synthesis of α-hydrazine-α, β-unsaturated nitroalkenes via Morita-Baylis-Hillman reaction
Morita-Baylis-Hillman (MBH) reaction is the coupling of the α-position of activated alkenes (vinyl anion equivalents) with various carbon electrophiles mediated by a tertiary amine or tertiary phosphine. MBH reaction has emerged as a simple, convenient and one-pot methodology for C-C bond forming reaction in organic synthesis. However, C-N bond formation via similar strategy has been barely investigated despite the fact that C-N bond forming strategies offer convenient access into natural/unnatural amino acids and other synthetically and biologically useful building blocks.
Prof. Irishi N.N. Namboothiri and his students at Department of Chemistry have developed a method of preparation of a-Hydrazino-a, β-Unsaturated Nitro Compounds. Although, ß-unsaturated nitro compounds (conjugated nitroalkenes) are powerful Michael acceptors and the first step in the MBH reaction is the Michael type addition of the nucleophilic amine catalyst, conjugated nitroalkenes are evident by their absence from the activated alkenes used in coupling with various electrophiles. This is presumably because the Michael type addition of amine catalyst to nitroalkenes, though takes place rapidly, suffers from the competitive retro-Michael addition. Furthermore, due to the poor nucleophilicity of the nitronate (arising from initial Michael type addition of the nucleophilic amine catalyst) and the propensity of the nitroalkenes to undergo polymerization, all previous attempts to carry out the MBH type reaction of nitroalkenes were fraught with difficulties.
The compounds have been found to inhibit human cervical cancer cell proliferation by binding to microtubules/tubulins (Figure). It has been a long standing need in the industry and in the scientific community to provide simplistic methods for C-N bond formation which have wide applications especially in the synthesis of amino acids and other biologically useful building blocks. The main objective of the present invention is to provide commercially viable single pot process for the preparation of a-hydrazinoa, β-unsaturated nitro compounds from, β-unsaturated nitro compounds in high yields. To obtain this, a conjugated nitroalkene was reacted with an azo compound in the presence of a cyclic or acyclic amine as catalyst and a-hydrazinoa, β-unsaturated nitro compound produced (Scheme). During a standard reaction procedure a solution of nitroalkene and azo compound is stirred at room temperature until the reaction goes to completion. The reaction mixture is then diluted with aqueous acid and the aqueous layer is extracted with a suitable organic solvent. Finally, the combined organic layers are concentrated to yield a substantially pure a-hydrazino-a, β-unsaturated nitro compound. This reaction is carried out in the presence or absence of a range of solvents (e.g. methanol, chloroform, benzene, acetone etc.) which do not react with either of the coupling partners. Several a-hydrazino- a, β-unsaturated nitro compounds were prepared to establish the process.
- Irishi N N Namboothiri, Mamata Dadwal