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Experimental and Theoretical Studies of a One‐Flask Synthesis of 3 H ‐1‐Benzazepines from 2‐Haloanilines and α,β‐Unsaturated Ketones
Author(s) -
Ramig Keith,
Greer Edyta M.,
Szalda David J.,
Razi Rabail,
Mahir Fahima,
Pokeza Nataliya,
Wong Wei,
Kaplan Benjamin,
Lam Joanne,
Mannan Ayesha,
Missak Christopher,
Mai Dat,
Subramaniam Gopal,
Berkowitz William F.,
Prasad Prakash,
Karimi Sasan,
Lo Ngai Hin,
Kudzma Linas V.
Publication year - 2010
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.200901468
Subject(s) - benzazepines , chemistry , imine , benzazepine , isomerization , aryl , medicinal chemistry , stereochemistry , enone , alkyl , organic chemistry , catalysis
3 H ‐1‐Benzazepines are prepared in one step from the reaction of 2‐fluoro‐ or 2‐chloroaniline and several aryl vinyl ketones. Enones 9a – c gave benzazepines 11a – c as expected, showing that alkyl substitution at C4 and C5 in the benzazepines is possible. However, enone 9d underwent decomposition due to conjugate addition of the 2‐fluoroaniline, while enone 10 gave unsaturated imine 12 as the only product able to be isolated. The failure of unsaturated imine 12 to undergo cyclization may indicate that placement of an alkyl group at C3 of the benzazepines may not be possible. Isolation of by‐products buttressed by a computational study verifies a postulated multi‐step process for benzazepine formation: a [1,5] sigmatropic shift in fluoroimine 3 , addition elimination to give carbocation 15 , formation of the unstable 5 H ‐1‐benzazepine 7 , and acid‐catalyzed isomerization to give the stable 3 H ‐1‐benzazepine 2 . The calculations also indicate why unsaturated imine 12 fails to cyclize. NMR spectroscopic experiments show that the 3 H ‐benzazepines undergo fast conformational exchange on the NMR time scale at room temperature except when there is an alkyl substituent at C5.