Regiospecific synthesis and structural studies of 3,5-dihydro-4h-pyrido[2,3-b][1,4]diazepin-4-ones and comparison with 1,3-dihydro-2H-benzo[b][1,4]diazepin-2-ones.
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2020
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ACS Publications
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ACS Omega 2020, 5, 25408−25422
Abstract
Nine 3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-ones, some of which contain fluoro-substituents, have been regiospecifically prepared by reaction of 2,3-diaminopyridines with ethyl aroylacetates. In two cases, open intermediates have been isolated and these are related to the reaction pathway. The X-ray crystal structure of 1-methyl-4-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]-diazepin-4-one (23) has been solved (formula, C15H13N3O; crystal system, monoclinic; space group, C2/c). This is an asymmetric unit constituted by a single nonplanar molecule and its conformational enantiomer due to the presence of the seven-membered diazepin-2-one moiety, which introduces a certain degree of torsion in the adjacent pyridine ring. The 1H, 13C, 15N, and 19F NMR spectra were obtained and the chemical shifts, together with those of the previously published 1,3-dihydro-2H-benzo[b][1,4]diazepin-2-ones (1−16), i.e., a total of 544 values, were successfully compared with the chemical shifts calculated at the gauge invariant atomic orbital (GIAO)/Becke, three-parameter, Lee−Yang−Parr (B3LYP)/6-311++G(d,p) level. The seven-membered ring inversion barrier in 5-benzyl-2-phenyl-3,5-dihydro-4H-pyrido[2,3-b][1,4]diazepin-4-one (25) was determined and, in conjunction with the data from the literature, compared with the B3LYP/6-311++G(d,p) computed values. This allowed the determination of several structural effects. The rotation about the exocyclic N1−CR bond was also calculated and its dynamic properties were discussed.
Description
Benzo[b][1,4]diazepin-2-ones are much less important in medicinal chemistry than benzo[e][1,4]-diazepin-2-ones such as diazepam and, for this reason, they have been less studied. However, there are some important drugs that contain the benzo[b][1,4] structure, for instance, the anxiolytic clobazam and the atypical antipsychotic olanzapine. The biological properties of benzo[b][1,4]diazepinones closely related to our work have been reported and described as potent noncompetitive metabotropic glutamate receptor antagonists. Moreover, the ESIPT (excited-state intramolecular proton transfer) mechanism has been observed in the photochemistry of benzo[b][1,4]diazepinones. However, their structural properties are scarcely studied. For that reasons, we present the regiospecific synthesis, X-ray crystallography data and NMR(static and dynamic) properties of nine new compounds along with the NMR data from our previous work concerning a series of sixteen benzo[b]1,4]diazepin-2-ones. Additionally, theoretical calculations of absolute shieldings and their transformation into chemical shifts (δ, ppm) have been carried out at the GIAO/B3LYP/6-311++G(d,p) and theoretical calculations have been carried out to determine the inversion barriers of the diazepinone sevenmembered ring in the gas phase.