Conformational Complexity in Seven-Membered Cyclic Triazepinone/Open Hydrazones. 1. 1D and 2D Variable Temperature NMR Study Kalevi Pihlaja,* Mario F. Simeonov, † and Ferenc Fu ¨ lo ¨p ‡ Department of Chemistry, University of Turku, FIN-20014 Turku, Finland Received December 11, 1996 X The stereochemistry and conformational behavior of a series of 22 2-methyl-2-alkyl(phenyl, aryl)- 4-N-methyl-1,2,3,4-tetrahydro-5H-1,3,4-benzotriazepin-5-ones and their open-chain hydrazone tautomers in various solvents were studied by 1D and 2D NMR techniques in the temperature range from 193 K to 410 K. Molecular rearrangements involving interconversions of the ring and open-chain forms (the latter via amide bond and Z/E CdN double bond isomerization), pseudoro- tation of the ring forms, and N-inversion processes with different rates on the NMR time scale took place, leading to the observation of average and deceptively simple 1 H and 13 C NMR spectra for most of them at room temperature. Introduction The therapeutic and commercial success of 1,4-benzo- diazepines has stimulated considerable interest in related systems. 1 Since the biological activity is dependent on the stereochemistry of the seven-membered ring, 2 we were interested in studying a series of variably substi- tuted 1,3,4-benzotriazepinones. Considerable confusion has surrounded the preparation 3 of these 1,4-benzodiaz- epine analogues due to the tautomeric process. 4 Many of the early benzotriazepinone structures were reassigned later as quinazolinones, imidazolines, oxadiazoles, and other structures, 3 i.e. the reactions of -aminocarbohy- drazides with oxo reagents can result in hydrazone, pyrimidinone, or triazepinone derivatives, depending on the substituents and the conditions employed. 5 The first example of the formation of a seven-mem- bered ring from an o-amino-substituted aromatic hy- drazide was the reaction of anthranilic acid N,N′- dimethylhydrazide with carbonyl compounds. 5a Later, the rearrangements of o-aminobenzoyl N-methylhydra- zones of -dicarbonyl 5b and simple monocarbonyl 5c com- pounds were shown by NMR spectroscopy to involve a ring/open-chain equilibrium in solution. N-Methyl car- bohydrazides were observed to react with acetaldehyde, acetone, and cyclohexanone to yield cyclic products (condensed triazepinones), with benzaldehyde 5c to yield open forms (hydrazones), and with acetophenone to yield a hydrazone benzotriazepinone ring/open-chain equilib- rium, with tautomerism, in a 1:1 ratio (Scheme 1). † Institute of Organic Chemistry with Center of Phytochemistry, Bulgarian Academy of Sciences, BG-1113 Sofia, Bulgaria. ‡ Institute of Pharmaceutical Chemistry, Albert Szent-Gyo ¨rgyi Medical University, H-6720 Szeged, POB 121, Hungary. X Abstract published in Advance ACS Abstracts, July 1, 1997. (1) Bachman, G. B.; Levine, H. A. J. Am. Chem. Soc. 1947, 69, 2341. (2) Fryer, R. I.; Cook, C.; Gilman, N. W.; Walser, A. Life Sci. 1986, 39, 1947 (3) (a) Sunder, S.; Peet, N. P.; Trepanier, D. L. J. Org. Chem. 1976, 41, 2732. (b) Peet, N. P.; Sunders, S. J. Heterocycl. Chem. 1984, 21, 1807. (c) Scheiner, P.; Frank, L.; Giusti, I.; Arwin, S.; Pearson, S. A.; Excellent, F.; Harper, A. P. J. Heterocycl. Chem. 1984, 21, 1817. (d) Leiby, R. W. J. Heterocycl. Chem. 1984, 21, 1825. (e) Peet, N. P. Synthesis 1984, 1065. (f) Fu ¨ lo ¨p, F.; Simeonov, M.; Pihlaja, K. Tetra- hedron 1992, 48, 531. (4) Valters, R.; Fulo ¨p, F.; Korbonits, D. Adv. Heterocycl. Chem. 1996, 68, 1. (5) (a) Hromatka, O.; Knollmu ¨ ller, M.; Krenmu ¨ ller, F. Monatsh. Chem. 1969, 100, 941. (b) Ga ´l, M.; Fehe ´r, O.; Tihanyi, E.; Horva ´ th, Gy.; Jerkovich, Gy. Tetrahedron 1982, 38, 2933. (c) Ga ´ l, M.; Tihanyi, E.; Dvortsak, P. Acta Chim. Hung. 1986, 123, 55. (d) Reddy, P. P.; Reddy, C. K.; Reddy, P. S. N. Bull. Chem. Soc. Jpn. 1986, 59, 1575. Scheme 1. Compounds Studied 5080 J. Org. Chem. 1997, 62, 5080-5088 S0022-3263(96)02322-5 CCC: $14.00 © 1997 American Chemical Society