Preparation of tetrahydrobenz[cd]indoles from 1-tetralones

Abstract

Bridged indoles (5) are prepared from readily available aromatic ketones (1 ) by conversion into the epoxides (2), ring opening with azide ion to give the azido alcohols (3), dehydration, and thermolysis of the resulting vinyl atides (4).The tetrahydrobenz[cd]indole ring system is a key structural feature in a number of naturally occurring indoles, such as the well known ergot alkaloids,' a-cyclopiazonic acid,2 and the more recently isolated ha pal in dole^.^ Since many of these indoles possess important pharmacological properties, new routes to them are of interest: and therefore we now report the full details of a novel approach to this, and related, ring systems which starts from readily available aromatic ketones. Results and DiscussionThe route, which is shown in the Scheme, is based on cyclisation reactions of vinylnitrenes,6 obtained by thermolysis of vinyl azides, and stems from our use of such reactions in the synthesis of the left-hand unit of the antitumour antibiotic CC-1065.' The required vinyl azides (4) were prepared from the commercially avaiIable aromatic ketones (1) by conversion into the corresponding epoxides (2), ring opening with azide ion, and dehydration of the resulting azido alcohols (3).Preparation of Ep0xide.s.-The epoxides were readily prepared from aromatic ketones by reaction with dimethylsulphoxonium methylide in dimethyl sulphoxide (DMSO). Thus 1-tetralone (la), and its 5and 7-methoxy derivatives (lb,c) were converted into the corresponding epoxides in good yield. The epoxide derived from 6-methoxy-1 -tetralone is known to be very unstable, rapidly rearranging into the corresponding acetaldehyde deri~ative,~ and therefore was not investigated. Benzosuberone (la) was also readily converted into its epoxide (2d), and the epoxides (h), (20, and (2g) were prepared from 4,4-dimethyl-1-tetralone, l o dibenzosuberone, and benzocyclo-octanone ' respectively, although in the case of dibenzosuberone, the more reactive dimethylsulphonium methylide had to be used. No spiro-epoxides could be obtained from anthrone due to rapid enolisation, or from chroman-4-one due to competing attack of the sulphur ylide at C-2 with formation of the cyclopropyl ketone (6) in 29% yield.12 A variety of other conditions were tried to prepare these epoxides, but without success. To investigate the effect of an electronwithdrawing group, the glycidic ester (2b) of 1-tetralone was prepared using the Darzen's reaction. 'Ring Opening of Epoxides with Azide.-In general, this proved to be a troublesome step. The epoxides (2a-d) could be opened to the corresponding azido alcohols (3) using sodium a i d e and lithium chloride in dimethylforrnamide (DMF). The presence of lithium chloride is necessary for this reaction, which presumably involves the in situ formation of lithium azide. The

Synthetic routes to benzosuberone-based fused- and spiro-heterocyclic ring systems

“…Dehydration of the azido alcohol 23 to the vinyl azide 24, was carried out using thionyl chloride in pyridine. The cyclohepta[cd]indole 25 was obtained in 72% yield by thermolysis of the azide 24 35 (Scheme 11).…”