Synthesis of 1-Azaazulenes Using Ring-Opening Cyclization of Spirocyclopropane with Amine

Abstract

Synthesis of 1-azaazulenes using ring-opening cyclization of spirocyclopropane with a primary amine was accomplished. The reaction of cycloheptane-1,3-dione-2-spirocyclopropane with 2,4-dimethoxybenzylamine in refluxing acetonitrile resulted in a 94% yield of 1,2,3,6,7,8hexahydrocyclohepta[b]pyrrol-4(5H)-one. The obtained product was successfully converted into 1-azaazulenes by deprotecting the amino-protecting group followed by oxidation.Azaazulenes, aza-analogues of azulene, have intriguing physical and chemical properties and potential biological activities. 1 Of the many azaazulenes, 1-azaazulenes have attracted considerable attention from chemists because of their stabilities and pharmacological activities. [2][3][4] While many examples of 1-azaazulene syntheses have been reported, [5][6][7][8][9][10][11] in most cases, troponoid compounds were used as starting materials. For example, Nitta and co-workers successfully synthesized various 1-azaazulene derivatives 3 from tropones 1 using the aza-Wittig reaction followed by the oxidation of the bicyclic intermediates 2 (Scheme 1, A). 8 Narasaka and co-workers reported the synthesis of 1-azaazulenes 3 from cycloheptatrienylmethyl ketone O-pentafluorobenzoyloximes 4 by palladium(0)-catalyzed cyclization and sequential oxidation (Scheme 1, A). 9 Although these synthetic methods are direct and efficient, tropone derivatives are expensive and difficult to prepare.Meanwhile, we have developed a synthetic method of indole employing the ring-opening cyclization of cyclohexane-1,3-dione-2-spirocyclopropanes 5 with primary amines 6 to provide 2,3,6,7-tetrahydro-1Hindol-4(5H)-ones 7 followed by its oxidation into indole 8 (Scheme 1, B). 12 Based on this approach, we envision that the use of cycloheptane-1,3-dione-derived spirocyclopronane instead of a cyclohexane-1,3-dione derivative can construct a 1-azaazulene skeleton. Herein, we report the synthesis