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

The protonation of the 1,2(4H)-diazepines 2 a, 2 b, and the 1,2(1H)-diazepine 3 a in various acidic media has been studied by u.v. and n.m.r. spectroscopy. Compounds 2 a and 3 a undergo protonation to give 4 a and 7 a, respectively, whereas 2 b provides the monoprotonated species 4 b in dilute acid and the diprotonated form 4 c in strongly acidic solution. Spectral characteristics of crystalline 1,2(4H)-diazepinium perchlorates 4 a, 4 d, 7 a, and 7 c correlate well with those observed for the corresponding free bases in acidic solutions; 7 a-ClO 4 and 7 c-ClO 4 were obtained either from 2 a and 2 c or from 3 a and 3 c, respectively. In trifluoroacetic acid-d-D 2 O, deuterium exchange at C 4 and C 6 of 2 a, 2 b, and 3 a was observed indicating the presence of small equilibrium concentrations of species 1 a, 1 c and/or 1 d, and 1 b under these conditions. Temperature variable n.m.r. spectroscopy provides evidence for ring inversion phenomena for the protonated forms 4 a and 7 a. In the case of 4 a, the activation energy, ΔG c ≠ = 10.2 ± 0.2 kcal/mol (T c = 8 ± 3°) has been estimated. The difference in the activation energy between the free base and the protonated form, ΔG ≠ ( 2 a)ΔG ≠ ( 4 a) = 6-7 kcal/mol is attributed to strong repulsive N 1 N 2 lone pair interaction in 2 a in the transition state for the ring inversion process.Under vigorous acidic conditions, the 1, 2(4H)-diazepines 2 a-c give pyrazoles ( 10 a-c), pyridines ( 12 a-c), and acetophenone. Using identical conditions, the 1,2(4H)-diazepinium salt, 7 a-ClO 4 provides pyrazole 11 a and pyridine 12 a and, in addition, the 1-methylaminopyridinium salt 13 a. However, rearrangement also proceeds under very mild conditions (ethanol-water) as shown for 7 a-ClO 4 and 7 c-ClO 4 which yield compounds 11 a and 12 a, and 11 c, 12 c, and 13 c, respectively. The 1, 2(1H)-diazepine 3 a gives 11 a, 12 a, and 13 a in ethanol-water solution and exclusively 13 a 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 2 b, 2 c, and 7 c-ClO 4 if these pathways were operative.