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-
Highlights
We reported the first radical cyclizations to give cyclopropane-fused heterocycles, as shown in Scheme 1.1 Initiator-free intramolecular aromatic substitutions of nucleophilic alkyl and cyclopropyl radicals onto the 2-position of indole-3-carbaldehyde, indole-3-carbonitrile, and benzimidazoles were accomplished
As the starting carboxylic acid can be recovered upon inefficient decarboxylation and subsequent hydrolysis of the intermediate Barton ester, it was decided to test the efficiency of the Barton ester formation and radical decarboxylation by carrying out reactions in the presence of a large excess of bromotrichloromethane (~50 equiv.)
The resulting cyclopropyl bromides were utilized as precursors for investigating the Bu3SnH-mediated five- and seven-membered radical cyclization reactions onto indole-3carbaldehyde and benzimidazole
Summary
We reported the first radical cyclizations to give cyclopropane-fused heterocycles, as shown in Scheme 1.1 Initiator-free intramolecular aromatic substitutions of nucleophilic alkyl and cyclopropyl radicals onto the 2-position of indole-3-carbaldehyde, indole-3-carbonitrile, and benzimidazoles were accomplished. The resulting cyclopropyl bromides were utilized as precursors for investigating the Bu3SnH-mediated five- and seven-membered radical cyclization reactions onto indole-3carbaldehyde and benzimidazole.
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