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2,3‐Dihydrospiro[1 H ‐4‐ and 5‐azabenzimidazole‐2,1′ ‐cyclohexane] ( = Spiro[cyclohexane‐1,2′(3′ H )‐1′ H ‐imidazo[4,5‐ b ]pyridine] and Spiro[cyclohexane‐1,2′(3′ H )‐1′ H ‐imidazo[4, 5‐ c ]pyridine]): Reactions with Nucleophiles
Author(s) -
Schwoch Stefan,
Kramer Walter,
Neidlein Richard,
Suschitzky Hans
Publication year - 1994
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19940770811
Subject(s) - chemistry , piperidine , morpholine , ring (chemistry) , cyclohexane , pyridine , nucleophile , medicinal chemistry , stereochemistry , isoxazole , derivative (finance) , organic chemistry , financial economics , economics , catalysis
The readily available title compounds 4a and 24 react with N‐, O‐, S‐, and C‐nucleophiles in presence of MnO 2 to give the corresponding mono‐ or disubstituted 2 H ‐azabenzimidazoles ( = azaisobenzimidazoles), e.g. , 11–18 and 26a–h , respectively, or 2,3‐dihydro‐1 H ‐azabenzimidazoles ( = dihydro‐azabenzimidazoles) such as 9 and 10 and 27 and 28 , respectively, by a 1, 4‐ or 1,6‐ Michael addition ( Schemes 2 and 4 ). The bromo‐dihydro‐1 H ‐azabenzimidazole 4b lost the Br‐atom when treated with piperidine or morpholine yielding the corresponding disubstituted 2 H ‐azabenzimidazole 21 ( Scheme 3 ). Reductive ring opening of the substituted spiro compounds leads to mono‐ and disubstituted diaminopyridines which are intermediates for fused pyridine ring systems with substituents often not available by conventional routes and of potential pharmaceutical interest (see 32 – 37 ). E.g. , starting from 4a , a three‐step synthesis of the analgesic flupirtine maleate (= ethyl {2‐amino‐6‐[(4‐fluorobenzyl)amino]pyridin‐3‐yl}carbamate maleate = Katadolon® ; 39 ) and of its non‐fluorinated derivative D‐7195 is described. Its analogue 40 was similarly made from the spiro compound 24 .