Modification of the Gewald reaction for the synthesis of 3-amino-2-(1H-1,2,3-benzotriazol-1-yl) substituted benzofurans, benzothiophenes and 1H-indoles

Abstract

Treatment of 1-chloromethylbenzotriazole (4) with salicylonitrile (5a), thiosalicylonitrile (5b), ethyl N-(2-cyanophenyl)carbamate (5c), and N-(2-cyanophenyl)methane-sulfonamide (5d) provided the corresponding intermediates 3. Cyclization of compounds 3a-3c with LDA gave 2- (2c), respectively. Attempts to accomplish elimination of the benzotriazole nitrogen under both thermal and photolytic conditions failed.

Synthesis of Heterocycles Mediated by Benzotriazole. 2. Bicyclic Systems

“…Treatment of 132 with lithium diisopropylamide (LDA) generates anion 133 that then attacks the CN group to close the heterocyclic ring. During workup, anion 134 is neutralized, and the resulting imine tautomerizes to 3-aminoindole 135 , isolated in 70% yield (Scheme ) …”

“…Treatment of 234 with LDA generates anion 235 that attacks the cyano group to give cyclic imine anion 236 . Hydrolysis and tautomerization of 236 during aqueous workup results in 237 (59% yield) …”

“…Analogously to the synthesis of 3-amino-2-(benzotriazol-1-yl)furan ( 237 ), thiosalicylonitrile ( 278 ) is alkylated with 1-(chloromethyl)benzotriazole ( 76 ), and the obtained thioether 279 is treated with LDA to give 3-amino-2-(benzotriazol-1-yl)thiophene ( 280 ) in 78% yield (Scheme ) …”

“…During workup, anion 134 is neutralized, and the resulting imine tautomerizes to 3-aminoindole 135, isolated in 70% yield (Scheme 30). 36 In a Fischer type synthesis, phenylhydrazone 136, derived from 1-(benzotriazol-1-yl)acetone, is smoothly converted to 3-(benzotriazol-1-yl)-2-methylindole (137) in 88% yield upon treatment with zinc chloride and acetic acid in a microwave oven (Scheme 31). 37 Opening the benzotriazole heterocyclic ring with elimination of a molecule of nitrogen followed by cyclization through bond formation between the C-β (of the N-1 substituent) and C-3a atoms allows conversion of 1-substituted benzotriazoles into the corresponding indoles.…”

A facile four-component Gewald reaction under organocatalyzed aqueous conditions

“…[20][21][22][23] Another interesting feature of the Gewald reaction is the use of the 2-aminothiophene products in other organic transformations. 24,25 The growing use of MCRs in synthesis led us to examine the possibility of employing more than three components in the reaction so that we can access derivatized Gewald products in a one-pot operation. In the framework of our investigations on the development of one-pot synthetic procedures, [26][27][28] we herein report a simple method for conducting a four-component Gewald reaction under inexpensive and benign aqueous triethylamine conditions.…”