Efficient TCT-catalyzed Synthesis of 1,5-Benzodiazepine Derivatives under Mild Conditions

2,4,6-Trichloro-1,3,5-triazine (TCT) efficiently catalyzed the condensation reactions between 1,2-diamines and various enolizable ketones to afford 1,5-benzodiazepines in good to excellent yields. Simple and mild reaction conditions, the use of a cheap catalyst and easy workup and isolation are notable features of this method.

In recent years, 2,4.6-trichloro-1,3,5-triazine (TCT) has received considerable attention due to its commercial availability and efficient delivery of anhydrous HCl in reaction media. It is inexpensive, and has been found to be versatile in functional group transformations such as conversions of alcohols to alkyl chlorides, oxidations of sulfides to sulfoxides, oxidative couplings of thiols and selenols, cleavage of thioacetals, etc. [31][32][33][34][35][36]. TCT reacts with 'incipient' moisture and produces three moles of HCl and cyanuric acid as a by-product (removable by simple washing with water). The HCl generated in situ acts as a protic acid, activates the carbonyl oxygen to promote the condensation to give the products [37]. In continuation to our efforts for the development of simple and novel methods for the synthesis of different heterocyclics [38][39][40][41][42][43][44], we report herein a simple and efficient method for the synthesis of 1,5-benzodiazepines using TCT as catalyst. While this paper was under peer review, Khodaei et al. [45] reported a similar procedure, differing from ours in the preferred solvent -CH 3 CN vs. MeOH -and the amount of solvent required, 10 mol % vs. 4 mol %; the yields were similar although their reported reaction times were shorter, possibly due to the higher catalyst load used.

Results and Discussion
In the first instance, o-phenylenediamine (1 equiv.) and acetone (2.5 equiv.) were stirred at ambient temperature in dichloromethane with 4 mol% of TCT (Scheme 1). The reaction was complete within 5.5 h. After screening various solvents like methanol, ethanol, isopropanol, ethyl acetate and acetonitrile, we found that the reaction proceeds well in polar solvents, giving slight variations in reaction time and that methanol was the best choice for this reaction (Table 1).

Scheme 1. Synthesis of 1,5-benzodiazepines.
We assume that in the reaction medium TCT generates anhydrous HCl, which would be the active catalyst. When a similar reaction was performed using 10 mol% of aqueous HCl, the reaction took longer time (24 h) for completion, whereas the same conversion was achieved in 1 h with anhydrous 10% HCl in methanol. This further supports the proposed in-situ generation of anhydrous HCl in the reaction as the source of the catalytic action.  Under the optimized conditions, aliphatic ketones such as acetone reacted with 1,2-phenylenediamine in methanol (Scheme 2) to form the corresponding benzodiazepine in excellent yield ( Table 2, entry 1). However, the reaction was sluggish with the substrates 2-butanone and 3-pentanone (Table 2, entries 2 and 3), resulting in poor yields. This may be due to the steric hindrance of a methyl group in the proximity of the carbonyl carbon. Alicyclic ketones such as cyclopentanone, cyclohexanone and cycloheptanone ( Table 2, entries 4-6) gave excellent yields of products. With the present methodology, aromatic ketones such as acetophenone (Table 2, entry 7) and substituted acetophenones with both electron-donating and withdrawing groups generally produced the corresponding benzodiazepines in good to excellent yields, with the latter performing somewhat better. Thus, for example, an acetophenone bearing a OMe electron-releasing group such as 4-methoxyacetophenone ( Table 2, entry 8) resulted in a poorer yield after a longer period of time, whereas an acetophenone possessing a NO 2 electron-withdrawing group, such as 4-nitroacetophenone (Table 2, entry 11) underwent a smooth reaction to afford a good yield of the corresponding product 3k.  Having successfully performed the reactions of 1,2-phenylenediamine with a wide range of ketones, we focused our attention on examining the reactions of various ketones and structurally diverse diamines (Scheme 3). The results revealed that both mono-and disubstituted phenylenediamines reacted with ketones to produce the corresponding benzodiazepines in excellent yields. Diamines bearing substituents with various electronic effects reacted with acetone with equal ease (Table 3, entries 1, 3, 5 and 8). The reactions of aromatic ketones with monosubstituted diamines furnished the corresponding benzodiazepines in shorter times (Table 3, entries 2 and 4), whereas disubstituted diamines took relatively longer times to afford good yields of products (Table 3, entries 6, 7 and 9). All the monosubstituted diamines gave 1:1 mixtures of regioisomers. The results are summarized in Table  3.

Scheme 3
Reaction of various o-phenylenediamines with ketones in the presence of 4 mol % of TCT. Finally, the reaction of acetone with a bisdiamine in the presence of 8 mol % TCT gave the corresponding bisbenzodiazepine in moderate yield (Scheme 4). The product 3w thus obtained proved unstable in solution and readily decomposed in methanol when it was subjected to crystallization.

Conclusions
In summary, we have disclosed an efficient and economic method for the synthesis of 1,5-benzodiazepines. We also demonstrated the electronic effects on the reaction of various substitutions on the ketone and the diamine participants. Electron withdrawing groups like the (NO 2 ) group stimulate the reaction rate, whereas electron releasing groups reduce the reactivity of the ketone. Simple workup and easy isolation under mild reaction conditions are the best features of the present methodology.

General
All reagents and chemicals were purchased from Sigma-Aldrich Chemical Company, Acros organics and Merck and were used as received. Analytical thin layer chromatography was performed with E. Merck silica gel 60F glass plates and flash chromatography by the use of E. Merck silica gel 60 (230-400 mesh). 1 H-NMR and 13 C-NMR spectra were recorded at 400 and 100 MHz, respectively, on a Bruker Avance EX 400 FT-NMR instrument. Chloroform-d was used as the solvent and TMS (δ = 0.00 ppm) as an internal standard. Chemical shift values are reported in ppm relative to TMS in delta (δ) units. Multiplicities are recorded as s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublet), br (broadened), m (multiplet). Coupling constants (J) are expressed in Hz. MS and HRMS were measured on JEOL JMS-D300 and JEOL JMS-HX110 spectrometers, respectively.