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One‐Pot Regioselective Double‐Mannich Annulations Affording Azabicyclononanones as a Key Step in the Synthesis of Natural Products
Author(s) -
Neochoritis Constantinos G.,
StephanidouStephanatou Julia,
Tsoleridis Constantinos A.
Publication year - 2011
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.201100700
Subject(s) - chemistry , regioselectivity , methylhydrazine , hydroxylamine , ring (chemistry) , hydrazine (antidepressant) , pyrazole , formaldehyde , indazole , organic chemistry , stereochemistry , medicinal chemistry , chromatography , propellant , catalysis
The first regioselective one‐pot syntheses of a number of azabicyclic ring systems (compounds 3 ) in very good yields, under green‐chemistry conditions in the presence of water without use of organic solvents, through acid‐catalysed double‐Mannich reactions from 2‐acetylcyclohexanone, ring‐substituted anilines and formaldehyde have been developed. In addition, treatment of the acetylazabicyclononanones 3 with hydrazine, methylhydrazine and hydroxylamine was thoroughly investigated, leading in the case of hydrazine to the formation of the pyrazole‐fused azatricyclic derivatives 6 as the main reaction products. In the cases of methylhydrazine and hydroxylamine, though, the tetrahydroindazoles 8 and 9 and the tetrahydrobenzisoxazoles 10 , respectively, were obtained, through subsequent ring opening of the initially formed pyrazole‐ and oxazole‐fused azatricyclic ring systems. Plausible mechanistic schemes for the formation of compounds 8 , 9 and 10 are proposed. Structure elucidation of the products and full assignment of all 1 H and 13 C NMR chemical shifts was accomplished by 1D and 2D NMR experiments. COSY H–H and COLOC C–H correlations as well as H–H coupling constants were analysed in detail in combination with conformational analysis to determine the final stereochemistries of products 3 .