Protonation and Acid-catalyzed Rearrangement of 1,2-Diazepines

Abstract

The protonation of the 1,2(4H)-diazepines 2a, 2b, and the 1,2(1H)-diazepine 3a in various acidic media has been studied by u.v. and n.m.r. spectroscopy. Compounds 2a and 3a undergo protonation to give 4a and 7a, respectively, whereas 2b provides the monoprotonated species 4b in dilute acid and the diprotonated form 4c in strongly acidic solution. Spectral characteristics of crystalline 1,2(4H)-diazepinium perchlorates 4a, 4d, 7a, and 7c correlate well with those observed for the corresponding free bases in acidic solutions; 7a-ClO4 and 7c-ClO4 were obtained either from 2a and 2c or from 3a and 3c, respectively. In trifluoroacetic acid-d-D2O, deuterium exchange at C4 and C6 of 2a, 2b, and 3a was observed indicating the presence of small equilibrium concentrations of species 1a, 1c and/or 1d, and 1b under these conditions. Temperature variable n.m.r. spectroscopy provides evidence for ring inversion phenomena for the protonated forms 4a and 7a. In the case of 4a, the activation energy, ΔGc≠ = 10.2 ± 0.2 kcal/mol (Tc = 8 ± 3°) has been estimated. The difference in the activation energy between the free base and the protonated form, ΔG≠ (2a)—ΔG≠ (4a) = 6–7 kcal/mol is attributed to strong repulsive N1—N2 lone pair interaction in 2a in the transition state for the ring inversion process.Under vigorous acidic conditions, the 1, 2(4H)-diazepines 2a–c give pyrazoles (10a–c), pyridines (12a–c), and acetophenone. Using identical conditions, the 1,2(4H)-diazepinium salt, 7a-ClO4 provides pyrazole 11a and pyridine 12a and, in addition, the 1-methylaminopyridinium salt 13a. However, rearrangement also proceeds under very mild conditions (ethanol–water) as shown for 7a-ClO4 and 7c-ClO4 which yield compounds 11a and 12a, and 11c, 12c, and 13c, respectively. The 1, 2(1H)-diazepine 3a gives 11a, 12a, and 13a in ethanol–water solution and exclusively 13a in trifluoroacetic acid. The mechanism of these reactions is discussed in terms of formation of open-chain (15) and diaziridine-type (19) intermediates. Electrocylic mechanisms are eliminated from consideration on the basis of the absence of products 23, 24, and 25 which should have been observed from the reactions of 2b, 2c, and 7c-ClO4 if these pathways were operative.