Bu3SnH-mediated cyclopropyl radical cyclizations onto indole-3-carbaldehyde

Abstract

Bromocyclopropyl)alkyl)-1H-indole-3-carbaldehydes and benzimidazole analogues were obtained in ~80% yield via the decomposition of Barton ester intermediates. The bromo- indolecarbaldehydes were precursors for Bu 3SnH-mediated five- and seven-membered cyclopropyl radical intramolecular aromatic substitutions giving cyclopropane-fused adducts in ~55% yields. The cyclization yields are greater than via the direct decomposition of the Barton esters. X-ray crystal structures of 1-((2-bromocyclopropyl)-trans -methyl)-1H-benzimidazole , and cyclopropyl radicals onto the 2-position of indole-3-carbaldehyde, indole-3-carbonitrile, and benzimidazoles were accomplished. The radicals were generated via the combined thermal and photochemical decomposition of Barton ester {pyridine-2-thione-N-oxycarbonyl (PTOC) or O- acyl thiohydroxamate} 2 intermediates formed from carboxylic acids using the Garner coupling reagent, HOTT ( S-(1-oxido-2-pyridinyl)-1,1,3,3-tetramethylthiouronium hexafluorophosphate). 3 All six-membered radical cyclizations were high yielding (~80%), but the more challenging five and seven-membered cyclizations were found to give lower yields (<50%), with the exception of (i) the five-membered alkyl and cyclopropyl radical cyclizations onto indole-3-carbonitrile, which occurred in 75 and 78% yields respectively, and (ii) the seven-membered alkyl radical cyclization onto indole-3-carbonitrile gave a 61% yield. The structures of the indole five- membered cyclization adducts correspond to the skeleton of Moody's cyclopropamitosene, a hypoxic tumor cell selective cytotoxin, 4 which was previously prepared using intramolecular 1,3-