A Variation of the Fischer Indolization Involving Condensation of Quinone Monoketals and Aliphatic Hydrazines

Abstract

The indole ring system is one of the most ubiquitous heterocycles in nature. Many indole-containing natural products show a wide scope of biological activities, in particular because they bind to many receptors with high affinity. Since Baeyer s first synthesis of indole from oxindole in 1866 (indigo!isatin!oxindole!indole), numerous methods for the synthesis of indoles have been reported. One of the most efficient and widely employed syntheses is the Fischer indolization discovered in 1883. Compared with other indole syntheses, the importance of Fischer indolization lies in its simplicity and convenience, that is, formation of a critical C C bond to an unactivated aromatic carbon through a [3,3] sigmatropic rearrangement of enolizable Narylhydrazones. After more than a century of development, the Fischer indole synthesis remains a reliable and versatile method for the preparation of a variety of indole natural products and medicinal compounds. Many new variations have been developed in recent years. Most recently, the first catalytic asymmetric version of Fischer indole synthesis was reported by the group of List. Although the Fischer indole synthesis is widely used, several disadvantages still remain. The classical Fischer indole synthesis starts with arylhydrazines, which are generally made either from anilines through diazonium salts, or from aryl halides through transitionmetal-mediated coupling reactions. These processes involve the use of aniline precursors and toxic reagents (nitrous acid, stannous chloride, etc.) and potentially explosive diazonium intermediates, or expensive transition metals. We report herein a novel variation of the Fischer indolization involving a one-pot condensation of quinone monoketals with aliphatic hydrazines (Scheme 1). To the best of our knowledge, this is the first Fischer-type indole synthesis using an aliphatic hydrazine as the nitrogen source and a quinone monoketal as a masked benzene ring. We envisioned that condensation of quinone monoketal 1 and aliphatic hydrazine 2 would ultimately lead to an indole via alkylaryldiazene 5 and arylhydrazone intermediate 6, as illustrated in Scheme 2. The feasibility of this method relies on the initial formation of alkylaryldiazene 5 from a 1,2addition/dehydration sequence. It should be noted that there has been no report on the synthesis of alkylaryldiazenes 5 from quinone derivatives and aliphatic hydrazines, although arylaryldiazenes (azobenzenes) have been synthesized from condensations of arylhydrazines with quinones, quinols, quinone monoketals, and quinone bisketals. There is a single report on the condensation of an aliphatic hydrazine (N,N-dimethylhydrazine) with naphthoquinone monoketal, which, however, gave a 1,4-addition product in high yield. Therefore, our first object was to test the practicality of the Scheme 1. Strategies for the synthesis of indoles.