Experimental and Theoretical Studies of a One‐Flask Synthesis of 3H‐1‐Benzazepines from 2‐Haloanilines and α,β‐Unsaturated Ketones

Abstract

Abstract3H‐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 5H‐1‐benzazepine 7, and acid‐catalyzed isomerization to give the stable 3H‐1‐benzazepine 2. The calculations also indicate why unsaturated imine 12 fails to cyclize. NMR spectroscopic experiments show that the 3H‐benzazepines undergo fast conformational exchange on the NMR time scale at room temperature except when there is an alkyl substituent at C5.

Interplay of Nitrogen-Atom Inversion and Conformational Inversion in Enantiomerization of 1H-1-Benzazepines

“…The diphenylbenzazepine unsubstituted at nitrogen, namely, 2,4-diphenyl-1 H -1-benzazepine ( 2d ), would have been ideal to complete the series of benzazepines, including 2a – c . However, this compound is not known and not obtainable by either of our methods for benzazepine synthesis. , We have found that this N-unsubstituted benzazepine is much less thermodynamically stable than its 3 H -isomer 1 and is therefore not detected in the reaction mixture containing 1 . So the N-unsubstituted 2d remained a compound for computations only, and for experimental work, we used diester 4 to complete the series of 1 H -benzazepines, bearing in mind that the carboalkoxy groups of 4 could cause unexpected changes in properties.…”

“…However, this compound is not known and not obtainable by either of our methods for benzazepine synthesis. 3,30 We have found that this N-unsubstituted benzazepine is much less thermodynamically stable than its 3H-isomer 1 and is therefore not detected in the reaction mixture containing 1. 3 So the N-unsubstituted 2d remained a compound for computations only, and for experimental work, we used diester 4 to complete the series of 1H-benzazepines, bearing in mind that the carboalkoxy groups of 4 could cause unexpected changes in properties.…”

“…2 We have shown that the enantiomers of 3H-benzazepine 1 and its derivatives interconvert rapidly at room temperature by a ring-flipping process. 3,4 The case of N-alkylated 1H-benzazepines such as 2 might be complicated by the nitrogen atom, which, if it is nonplanar, becomes a chiral center that could undergo stereochemical inversion. Thus, benzazepines 2 could exist as a mixture of four stereoisomersthat is, two pairs of enantiomersinterconverting at rates which may depend strongly on the surrounding structural features.…”

NMR Spectroscopic and Computational Study of Conformational Isomerism in Substituted 2-Aryl-3H-1-benzazepines: Toward Isolable Atropisomeric Benzazepine Enantiomers

“…Seven benzazepines were chosen for the NMR study (Table ). Benzazepines 2a , 2b , 2c , and 2d are known compounds, and were obtained by literature procedures. The (5-methyl-2-furyl)-substituted benzazepine 2e was prepared by condensation of 2-fluoroaniline with 2-acetyl-5-methylfuran (Scheme ) .…”

“…The (5-methyl-2-furyl)-substituted benzazepine 2e was prepared by condensation of 2-fluoroaniline with 2-acetyl-5-methylfuran (Scheme ) . The 4-( o -toluyl)-substituted benzazepine 2f was synthesized in three steps from the trimethylsilyl enol ether of 4′-methylacetophenone ( 4 ), 2′-methylacetophenone, and 2-fluoroaniline (Scheme ). ,, The 3-methyl-substituted benzazepine 2g was prepared by deprotonation of benzazepine 2a with LDA, followed by alkylation of the presumed anion with methyl iodide (Scheme ). This procedure was suggested by the work of Streef and van der Plas, who alkylated 3 H -azepines at C3 in a similar fashion .…”