Organic & biomolecular chemistry

Furan ring opening-pyrrole ring closure: a new synthetic route to aryl(heteroaryl)-annulated pyrrolo[1,2-a][1,4]diazepines.

PMID 20523958


A method of synthesis of pyrrolo[1,2-a][1,4]benzodiazepines is described. This method is based on the recyclization of N-(furfuryl)anthranilamides under treatment with an aq. HCl/AcOH system and allows one to form both diazepine and pyrrole rings in one step. The reaction proceeds via furan ring opening into a diketone moiety followed by consecutive interaction of the NH(2)-group with both carbonyl functions. The process is not efficient in the presence of alkyl or aryl groups on amide nitrogen due to competitive furfuryl cation elimination. But alkylation of pyrrolo[1,2-a][1,4]benzodiazepines yields efficiently the corresponding N-alkyl derivatives. Steric effects also prevent cyclization due to reversibility of diazepine ring formation under these reaction conditions. However, the corresponding pyrrolo[1,2-a][1,4]benzodiazepines can be obtained by a stepwise process, i.e., 1) furan ring opening with aq. HCl/AcOH and 2) cyclization of isolated aminodiketones under treatment with glacial acetic acid. Another efficient procedure for the synthesis of pyrrolo[1,2-a][1,4]benzodiazepines consists of acid-catalyzed furan ring opening of N-(furfuryl)-2-nitrobenzamides followed by treatment of the formed nitrodiketone with Fe/AcOH. It leads to a one pot reduction of nitro group to amine, cyclization into diazepine and pyrrole ring formation. This procedure is efficient both for substrates with steric demands and for N-alkyl- or N-aryl-N-(furfuryl)amides. The proposed approach can be also applied to the synthesis of parent pyrrolo[1,2-a][1,4]diazepines or their analogues annulated to heterocycles.

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Anthranilamide, ≥98%