Large-Scale Synthesis of 2-Chlorotetrahydroquinoline and 2-Chlorotetrahydroquinolin-8-one

Abstract

An efficient large-scale preparation of 2-chlorotetrahydroquinoline with cyclohexanone and benzylamine as starting materials was developed and well optimized, in which benzyl-protected enamide was successfully cyclized and benzyl group was directly removed under Vilsmeier conditions. Azeotropic distillation provided 264 g of 2-chlorotetrahydroquinoline (79%) on a 2 mol scale of reaction without intermediate isolation. The downstream product 2-chlorotetrahydroquinolin-8-one was acquired through Boekelheide rearrangement, hydrolysis of acetate via NaBH₄ reduction, and Anelli oxidation. With the developed procedure, the intermediates were not necessary to be isolated and 2-chlorotetrahydroquinolin-8-one was conveniently obtained with solvent slurry in 65% overall isolated yield in a four-step sequence.

Key words

2-chlorotetrahydroquinoline - 2-chlorotetrahydroquinolin-8-one - large-scale synthesis - enamide - cyclization - Boekelheide rearrangement

• References

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