A concise and versatile route to tetrahydro-1-benzazepines carrying [a]-fused heterocyclic units: synthetic sequence and spectroscopic characterization, and the molecular and supramolecular structures of one intermediate and two products

Abstract

A concise, efficient and versatile route from simple starting materials to tricyclic tetrahydro‐1‐benzazepines carrying [a]‐fused heterocyclic units is reported. Thus, the easily accessible methyl 2‐[(2‐allyl‐4‐chlorophenyl)amino]acetate, (I), was converted, via (2RS,4SR)‐7‐chloro‐2,3,4,5‐tetrahydro‐1,4‐epoxy‐1‐benzo[b]azepine‐2‐carboxylate, (II), to the key intermediate methyl (2RS,4SR)‐7‐chloro‐4‐hydroxy‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, (III). Chloroacetylation of (III) provided the two regioisomers methyl (2RS,4SR)‐7‐chloro‐1‐(2‐chloroacetyl)‐4‐hydroxy‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, (IVa), and methyl (2RS,4SR)‐7‐chloro‐4‐(2‐chloroacetoxy)‐2,3,4,5‐tetrahydro‐1H‐benzo[b]azepine‐2‐carboxylate, C14H15Cl2NO4, (IVb), as the major and minor products, respectively, and further reaction of (IVa) with aminoethanol gave the tricyclic target compound (4aRS,6SR)‐9‐chloro‐6‐hydroxy‐3‐(2‐hydroxyethyl)‐2,3,4a,5,6,7‐hexahydrobenzo[f]pyrazino[1,2‐a]azepine‐1,4‐dione, C15H17ClN2O4, (V). Reaction of ester (III) with hydrazine hydrate gave the corresponding carbohydrazide (VI), which, with trimethoxymethane, gave a second tricyclic target product, (4aRS,6SR)‐9‐chloro‐6‐hydroxy‐4a,5,6,7‐tetrahydrobenzo[f][1,2,4]triazino[4,5‐a]azepin‐4(3H)‐one, C12H12ClN3O2, (VII). Full spectroscopic characterization (IR, 1H and 13C NMR, and mass spectrometry) is reported for each of compounds (I)–(III), (IVa), (IVb) and (V)–(VII), along with the molecular and supramolecular structures of (IVb), (V) and (VII). In each of (IVb), (V) and (VII), the azepine ring adopts a chair conformation and the six‐membered heterocyclic rings in (V) and (VII) adopt approximate boat forms. The molecules in (IVb), (V) and (VII) are linked, in each case, into complex hydrogen‐bonded sheets, but these sheets all contain a different range of hydrogen‐bond types: N—H…O, C—H…O, C—H…N and C—H…π(arene) in (IVb), multiple C—H…O hydrogen bonds in (V), and N—H…N, O—H…O, C—H…N, C—H…O and C—H…π(arene) in (VII).

Easy Access to Novel Tetrahydro-1-benzazepine-2-carboxylic Acids and Tetrahydro-1-benzazepines Carrying [a]-Fused Heterocyclic Units from 2-(Allylaryl)glycinates

“…Most of the synthesized compounds are new and their physicochemical and spectroscopic properties are reported for the first time; compounds 3a, 4a, 5a, 8e and 9e are known and their molecular and supramolecular properties were recently reported. 14…”

“…Calcd for C 16 H 20 N 2 O 4 : C, 63. 14;H,6.62;N,9.20;O,21.03. Found: C,63.11;H,6.65;N,9.17;O,21.07.…”

“…Found: C,63.11;H,6.65;N,9.17;O,21.07. 15, 186 (5), 172 (61), 158 7, 144 (14), 131 (25). ,63.66;H,6.16;N,17.13;O,13.05.…”

“…The solvent was removed under reduced pressure and toluene (20 mL) was added to the organic black residue. The resulting solution was heated at reflux for [5][6][7][8][9][10][11][12][13][14][15]. After cooling the solution to ambient temperature, the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel using heptane-EtOAc (compositions ranged from 10:1 to 3:1 v/v) as eluent to give 1,4-epoxycycloadducts 3a-k.…”

“…Found: C,63.73;H,6.35;N,6.73;O,23.19. Hydroxy-7-methyl-2,3,4,5-tetrahydro-1H-benzo[b] 14;H,6.83;N,6.33;O,21.69. Found: C,65.17;H,6.86;N,6.32;O,21.65.…”