Mendeleev Commun., 2019, 29, 294–295 – 294 – Mendeleev Communications © 2019 Mendeleev Communications. Published by ELSEVIER B.V. on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences. Benzimidazole derivatives play a significant role in organic and medicinal chemistry. 1–7 In continuation of our effort to synthesize triazepine derivatives, 8–10 we report here the preparation of a novel ring system containing two important cores, namely, benzimidazole and triazepinone ones. Initially, 2-aroylbenzimidazoles 1a–e were prepared from benzimidazole and benzoyl chlorides under basic conditions according to the reported procedure 11 (Scheme 1). Compounds 1a–e were alkylated with ethyl bromoacetate in the presence of Cs 2 CO 3 12 to give intermediates 2a–e. Mild hydrolysis of ethyl esters 2a–e with 5% aqueous solution of NaOH and subsequent reaction of the carboxylic acids 3a–e with tert-butyl carbazate (BocNHNH 2 ) in the presence of 1-[bis(dimethylamino)methylene]- 1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) coupling reagent afforded hydrazides 4a–e in good overall yields. Protected hydrazide 4b (Ar = Ph) was treated with a catalytic amount of 10% aqueous solution of HCl in boiling ethanol according to our earlier procedure, 9 however, complete decomposition was observed and product 5b was not detected by HPLC-MS. Unfortunately, similar results were obtained when sulfuric, p-toluenesulfonic and trifluoroacetic acids were tested as catalysts. Finally, when solutions of protected hydrazides 4 and pyridinium p-toluenesulfonate (PPTS) in ethanol were refluxed for 48 h, one-pot deprotection and ring closure reaction took place. The target compounds, 1-aryl-3H-[1,2,5]triazepino- [5,4-a]benzimidazol-4(5H)-ones 5 were obtained in low to moderate yields after chromatographic purifications. The synthesis of the desired 1-aryl-3H-[1,2,5]triazepino[5,4-a]- benzimidazol-4(5H)-ones 5 was also attempted in a different pathway (Scheme 2). This synthetic approach commenced with a p-toluenesulfonic acid catalyzed protection of the carbonyl group of 2-(4-fluorobenzoyl)-1H-benzimidazole 1a with ethylene glycol 13 to give dioxolane 6. The N-alkylation of intermediate 6 with ethyl 2-bromoacetate in the presence of Cs 2 CO 3 12 led to the corresponding ethyl benzimidazole-1-acetate derivative whose hydrazinolysis afforded hydrazide 7. Unfortunately, the anticipated cleavage of the dioxolane ring and the subsequent cyclization did not occur upon applying the usual acid-catalyzed methods 14 the starting compound 7 remained unchanged. The structures of the new compounds were confirmed by IR, 1 H and 13 C NMR measurements as well as by HRMS. In the 1 H NMR spectrum (DMSO-d 6 ) of Boc-hydrazides 4, the Boc methyl groups resonated as an interesting non-symmetric multiplet that was a result of a non-equivalence of protons due to retarded rotation. For all five hydrazides 4a–e three rotamers could be detected in a ratio of 67:18:15 based on the 1 H NMR measure- ments. The structure of the possible conformational isomers was Synthesis of 1-aryl-3H-[1,2,5]triazepino[5,4-a]benzimidazol-4(5H )-ones and quantum chemical investigation of the rotamers of the Boc-protected hydrazide key intermediate Mátyás Milen,* a Tímea Szabó, a András Dancsó, a Péter Ábrányi-Balogh* b and Balázs Volk a a Directorate of Drug Substance Development, Egis Pharmaceuticals Plc., 1475 Budapest, POB 100, Hungary. E-mail: milen.matyas@egis.hu b Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1519 Budapest, POB 286, Hungary. E-mail: abranyi-balogh.peter@ttk.mta.hu DOI: 10.1016/j.mencom.2019.05.017 N H N N N NH O HN N N NH N O Ar O Ar Boc 4 steps ring closure 5 examples 3H-[1,2,5]Triazepino[5,4-a]benzimidazol-4(5H)-ones were obtained in five steps involving C-acylation of benzimidazole, its N-alkylation with ethyl bromoacetate, the ester hydrolysis, condensation with BocNHNH 2 , and the acid-catalyzed hetero- cyclization of thus obtained 2-(2-aroyl-1H-benzimidazol-1-yl)- N'-(tert-butoxycarbonyl)acetohydrazides. The geometry of tert-butyl carbazate rotamers was estimated with quantum chemical calculations. N H N N H N O Ar N N NH O HN Ar O Boc N N NH N O Ar N N OR O Ar O 1a–e 2a–e R = Et 3a–e R = H 4a–e 5a–e 67–90% 72–98% 60–95% 70–91% 9–32% i ii iii iv v a Ar = 4-FC 6 H 4 b Ar = Ph c Ar = 3-ClC 6 H 4 d Ar = 4-ClC 6 H 4 e Ar = 4-MeOC 6 H 4 Scheme 1 Reagents and conditions: i, ArCOCl, Py, Et 3 N, room temperature, 3 h, then 40% NaOH, reflux, 1 h; ii, BrCH 2 CO 2 Et, Cs 2 CO 3 , MeCN/CH 2 Cl 2 , room temperature, ~18 h; iii, 5% NaOH, THF/EtOH, room temperature, 20 min, then 1 M HCl; iv, BocNHNH 2 , HATU, DIPEA, THF, room tem- perature, 2 h; v, PPTS, EtOH, reflux, 48 h.