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Article

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

by
Chun-Wei Kuo
,
Chun-Chao Wang
,
Veerababurao Kavala
and
Ching-Fa Yao
*
Department of Chemistry, National Taiwan Normal University, 88, Section 4, Tingchow Road, Taipei 116, Taiwan, ROC
*
Author to whom correspondence should be addressed.
Molecules 2008, 13(9), 2313-2325; https://doi.org/10.3390/molecules13092313
Submission received: 22 August 2008 / Revised: 10 September 2008 / Accepted: 10 September 2008 / Published: 25 September 2008
Browse Figures
Versions Notes

Abstract

:
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.

Introduction

Benzodiazepines and its derivatives constitute an important class of heterocyclic compounds which possess a wide range of therapeutic and pharmacological properties. Derivatives of benzodiazepines are widely used as anticonvulsant, antianxiety, analgesic, sedative, antidepressive, and hypnotic agents [1,2]. In the last decade, the area of biological interest of 1,5-benzodiazepines has been extended to several diseases such as cancer, viral infection and cardiovascular disorders [3,4]. In addition, 1,5-benzodiazepines are key intermediates for the synthesis of various fused ring systems such as triazolo-, oxadiazolo-, oxazino- or furanobenzodiazepines [5,6,7,8]. Besides, benzodiazepine derivatives are also of commercial importance as dyes for acrylic fibers in photography [9]. Owing to their versatile applications various methods for the synthesis of benzodiazepines have been reported in the literature. These include condensation reactions of o-phenylenediamines with α,β-unsaturated carbonyl compounds [10], with ketones in the presence of BF3·Et2O, NaBH4 , polyphosphoric acid or SiO2 , MgO/POCl3 , Yb(OTf)3, Al2O3/P2O5 or AcOH under microwave conditions, Amberlyst-15 in the ionic liquid 1-butyl-3-methylimidazolium bromide ([bmim]Br), CeCl3·7H2O/NaI supported on silica gel, InBr3 , Sc(OTf)3 , sulfated zirconia, InCl3 , CAN, ZnCl2 under thermal conditions, AgNO3. [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]. These reactions also occur with various catalysts under solvent free conditions [27,28,29,30]. Nevertheless, many of these methods suffer from shortcomings such as long reaction times, harsh reaction conditions, low product yields, occurrence of several side products and difficulties in recovery of the products. Moreover, some of the reagents employed are very expensive. Consequently, the search continues for better catalysts in terms of operational simplicity and economic viability to synthesize 1,5-benzodiazepines.
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 – CH3CN 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).
Molecules 13 02313 g001 550
Scheme 1. Synthesis of 1,5-benzodiazepines.
Scheme 1. Synthesis of 1,5-benzodiazepines.
Molecules 13 02313 g001
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.
Table
Table 1. Solvent effects in the reaction.
Table 1. Solvent effects in the reaction.
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a The reaction was performed with acetone (2.5 mmol) and diamine (1 mmol) in 1 mL of solvent catalyzed by TCT.
b Isolated yield.
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-methoxy- acetophenone (Table 2, entry 8) resulted in a poorer yield after a longer period of time, whereas an acetophenone possessing a NO2 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.
Molecules 13 02313 g002 550
Scheme 2. Reaction of o-phenylenediamines with various ketones in the presence of 4 mol % of TCT.
Scheme 2. Reaction of o-phenylenediamines with various ketones in the presence of 4 mol % of TCT.
Molecules 13 02313 g002
Table
Table 2. The results of the reaction of o-phenylenediamines with various ketones.
Table 2. The results of the reaction of o-phenylenediamines with various ketones.
Molecules 13 02313 i002
a Isolated yields.
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.
Molecules 13 02313 g003 550
Scheme 3. Reaction of various o-phenylenediamines with ketones in the presence of 4 mol % of TCT.
Scheme 3. Reaction of various o-phenylenediamines with ketones in the presence of 4 mol % of TCT.
Molecules 13 02313 g003
Table
Table 3. The results of the reaction of various o-phenylenediamines with ketones.
Table 3. The results of the reaction of various o-phenylenediamines with ketones.
Molecules 13 02313 i003
a Isolated yields.
b 1:1 mixture of two regioisomers.
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.
Molecules 13 02313 g004 550
Scheme 4. Reaction of bisdiamine with acetone in the presence of TCT.
Scheme 4. Reaction of bisdiamine with acetone in the presence of TCT.
Molecules 13 02313 g004

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 (NO2) 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.

Experimental

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). 1H-NMR and 13C-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.

General procedure for the preparation of 1,5-benzodiazepines

To a stirred solution of o-phenylenediamine (1 mmol) in MeOH (1 mL), a ketone (2.5 mmol) and 4 mol% TCT were added. The reaction mixture was stirred at room temperature until the reaction was complete, as judged by TLC analysis. The reaction mixture was then concentrated and washed with water to give the crude product, which was further purified by flash chromatography on silica gel (eluent: hexane-EtOAc= 5:1).
2,2,4-Trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3a): 1H-NMR δ 7.14–7.12 (m, 1H), 7.00–6.96 (m, 2H), 6.74–6.72 (m, 1H), 2.97 (br s, 1H, NH), 2.37 (s, 3H), 2.23 (s, 2H), 1.35 (s, 6H); 13C-NMR δ 172.4, 140.8, 137.9, 126.9, 125.5, 122.1, 121.7, 68.3, 45.2, 30.5, 29.9; MS (EI) m/z (relative intensity) 188 (M+, 38), 173 (100), 133 (39), 132 (50); HRMS (EI) m/z calcd. for C12H16N2 (M+) 188.1314, found 188.1314.
2,2-Dimethyl-2-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3b): 1H-NMR δ 7.16–7.14 (m, 1H), 6.99–6.95 (m, 2H), 6.73–6.71 (m, 1H) 3.10 (br s, 1H, NH), 2.61–2.57 (m, 2H), 2.22 (d, J = 12.9 Hz, 1H), 2.14 (d, J = 12.9 Hz, 1H), 1.63 (m, 2H), 1.24 (m, 5H), 0.95 (t, J = 7.5 Hz, 1H); 13C-NMR δ 175.9, 140.7, 137.9, 127.1, 125.4, 121.8, 121.7, 70.7, 42.1, 35.7, 26.9, 10.6, 10.6, 8.5; MS (EI) m/z (relative intensity) 216 (M+, 19), 201 (20), 187 (100), 145 (18); HRMS (EI) m/z calcd. for C14H20N2 (M+) 216.1627, found 216.1623.
2,2,4-Triethyl-3-methyl-2,3-dihydro-1H-1,5-benzodiazepine (3c): 1H-NMR δ 7.35 (dd, 1H, J = 7.9, 1.1 Hz), 6.97 (t, J = 8.1 Hz, 1H), 6.74 (t, J = 7.1 Hz, 1H), 6.62 (dd, J = 8.0, 0.5 Hz, 1H), 3.86 (br s, 1H, NH), 2.85 (q, J = 7.0 Hz, 1H), 2.60–2.49 (m, 2H), 1.61–1.51 (m, 2H), 1.37 (q, J = 7.4 Hz, 2H), 1.24 (t, J = 7.4 Hz, 3H), 0.96–0.88 (m, 6H), 0.79 (t, J = 7.3 Hz, 3H); 13C-NMR δ 173.6, 139.0, 132.8, 132.2, 126.7, 117.9, 117.5, 60.3, 46.1, 35.7, 28.4, 28.0, 12.3, 11.5, 7.8, 7.3; MS (EI) m/z (relative intensity) 244 (M+, 14), 216 (12), 215 (100), 147 (23); HRMS (EI) m/z calcd. for C16H24N2 (M+) 244.1940, found 244.1940.
2,3,9,10a-Tetrahydro-1H-spiro[benzo[b]cyclopenta[e][1,4]diazepine-10,1’-cyclopentane] (3d): 1H- NMR δ 7.32 (dd, J = 1.2, 1.1 Hz, 1H), 6.99–6.76 (m, 2H), 6.57 (dd, J = 1.0, 1.0 Hz, 1H), 3.98 (s, 1H), 2.77 (t, J = 9.0 Hz, 1H), 2.63–2.59 (m, 2H), 2.15–2.06 (m, 1H), 2.00–1.92 (m, 1H), 1.87–1.56 (m, 9 H), 1.48–1.42 (m, 1H); 13C-NMR δ 178.2, 139.3, 134.1, 132.4, 127.1, 119.5, 118.9, 67.5, 54.4, 39.5, 38.7, 33.6, 29.1, 24.4, 24.2, 23.6; MS (EI) m/z (relative intensity) 240 (M+ , 39), 211 (87), 183 (42), 145 (41), 132 (100); HRMS (EI) m/z calcd. for C16H20N2 (M+) 240.1626, found 240.1629.
2',3',4',10'-Tetrahydro-1'H-spiro[cyclohexane-1,11'-dibenzo[b,e][1,4]diazepine] (3e): 1H-NMR δ 7.29–7.26 (m, 1H), 6.99–6.92 (m, 2H), 6.70 (d, J = 1.4 Hz, 1H), 3.78 (br s, 1H, NH), 2.59 (t, J = 6.6 Hz, 2H), 2.4–2.36 (m, 1H), 1.86–1.18 (m, 16H); 13C-NMR δ 176.2, 138.6, 138.3, 129.4, 126.0, 121.2, 121.1, 51.9, 41.9, 40.9, 40.6, 34.2, 33.0, 27.2, 26.9, 26.7, 25.3, 24.2, 21.9; MS (EI) m/z (relative intensity) 268 (M+, 39), 225 (100), 145 (53), 132 (39); HRMS (EI) m/z calcd. for C18H24N2 (M+) 268.1940, found 268.1945.
7,8,9,10,10a,12-Hexahydro-6H-spiro[benzo[b]cyclohepta[e][1,4]diazepine-11,1'-cycloheptane] (3f): 1H-NMR δ 7.21–7.19 (m, 1H), 7.01–6.96 (m, 2H), 6.73–6.71 (m, 1H), 3.59 (br s, 1H, NH), 2.80–2.64 (m, 2H), 2.36–2.32 (m, 1H), 2.05–0.99 (m, 20H); 13C-NMR δ 179.9, 137.1, 127.1, 125.5, 121.8, 121.6, 54.0, 40.6, 38.3, 37.9, 30.2, 29.8, 29.7, 29.0, 28.3, 26.2, 23.2, 22.4; MS (EI) m/z (relative intensity) 296 (M+, 39), 239 (100), 145 (29), 132 (35); HRMS (EI) m/z calcd. for C20H28N2 (M+) 296.2253, found 296.2250.
2-Methyl-2,4-diphenyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3g): 1H-NMR δ 7.59–7.57 (m, 4H,), 7.31–7.16 (m, 7H), 7.05–7.03 (m, 2H), 6.83 (d, J = 1.7 Hz, 1H), 3.50 (br s, 1H, NH), 3.12 (d, J = 13.2 Hz, 1H), 2.95 (d, J = 13.2 Hz, 1H), 1.74 (s, 3H); 13C-NMR δ 167.6, 147.6, 140.1, 139.6, 138.0, 129.7, 128.6, 128.3, 128.0, 127.0, 127.0, 126.3, 125.4, 121.6, 121.4, 73.6, 43.0, 29.8; MS (EI) m/z (relative intensity) 312 (M+, 24), 297 (25), 235 (23), 194 (100); HRMS (EI) m/z calcd. for C22H20N2 (M+) 312.1627, found 312.1632.
2,3-Dihydro-2-methyl-2,4-di(4'-methoxyphenyl)-1H-1,5-benzodiazepine (3h): 1H-NMR δ 7.59 (d, J = 8.7 Hz, 2H), 7.51 (d, J = 8.7 Hz, 2H), 7.29 (t, J = 5.2 Hz, 1H), 7.03 (t, J = 4.4 Hz, 2H), 6.81–6.75 (m, 5H), 3.78 (s, 3H), 3.74 (s, 3H), 3.41 (br s, 1H, NH), 3.03 (d, J = 13.2 Hz, 1H), 2.90 (d, J = 13.2 Hz, 1H), 171 (s, 3H); 13C-NMR δ 167.1, 161.0, 158.5, 140.6, 140.1, 138.0, 132.3, 128.8, 128.2, 126.5, 125.8, 121.7, 121.5, 113.5, 113.3, 73.3, 55.3, 55.2, 42.8, 29.7; MS (EI) m/z (relative intensity) 372 (M+, 9), 357 (8), 225 (23), 224 (100), 133 (14); HRMS (EI) m/z calcd. for C24H24N2O2 (M+) 372.1838, found 372.1832.
2,3-Dihydro-2-methyl-2,4-di(4'-methoxyphenyl)-1H-1,5-benzodiazepine (3i): 1H-NMR δ 7.53 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.31–7.28 (m, 1H), 7.05–6.99 (m, 6H), 6.76–6.74 (m, 1H), 3.44 (br s, 1H, NH), 3.03 (d, J = 13.2 Hz, 1H), 2.92 (d, J = 13.2 Hz, 1H), 2.30 (s, 3H), 2.27 (s, 3H), 1.67 (s, 3H); 13C-NMR δ 167.3, 144.9, 140.2, 139.8, 138.1, 136.9, 136.5, 129.1, 128.9, 128.7, 128.4, 127.1, 126.0, 125.1, 121.5, 121.3, 73.2, 42.7, 29.7, 21.2, 20.8; MS (EI) m/z (relative intensity) 340 (M+, 9), 325 (7), 209 (40), 208 (100), 207 (14), 133 (15), 117 (55), 92 (26), 91 (18), 65 (10); HRMS (EI) m/z calcd. for C24H24N2 (M+) 340.1940, found 340.1944.
2-Methyl-2,4-di(4-chlorophenyl)-2,3-dihydro-1H-1,5-benzodiazepine (3j): 1H-NMR δ 7.52–7.46 (m, 4H), 7.28 (d, J = 2.0 Hz, 1H), 7.21–7.18 (m, 4H), 7.08–7.04 (m, 2H), 6.82 (d, J = 8.8 Hz, 1H), 3.42 (br s, 1H, NH), 3.08–3.04 (d, J = 13.2 Hz, 1H), 2.87 (d, J = 13.2 Hz, 1H), 1.72 (s, 3H); 13C-NMR δ 166.0, 145.8, 139.9, 137.7, 137.6, 136.0, 133.0, 128.6, 128.3, 128.2, 127.0, 126.6, 122.0, 121.5, 73.4, 42.9, 29.7; MS (EI) m/z (relative intensity) 380 (M+, 4), 365 (5), 231 (18), 230 (40), 229 (60), 228 (100), 193 (12), 137 (12), 133 (11); HRMS (EI) m/z calcd. for C22H18N2Cl2 (M+) 380.0847, found 380.0849.
2,4-bis(4-Nitrophenyl)-2,3-dihydro-1H-benzo[b][1,4]diazepine (3k): yellow solid; m.p. 152—154°C; 1H-NMR δ 8.05 (d, J = 8.5 Hz, 4H), 7.75 (d, J = 8.7 Hz, 2H), 7.69 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.16 (t, J = 7.5, 7.4 Hz, 1H), 7.09 (t, J = 7.6, 7.3 Hz, 1H), 6.90 (d, J = 7.7 Hz, 1H), 3.67 (br s, 1H), 3.31 (d, J = 13.6 Hz, 1H), 3.00 (d, J = 13.6 Hz, 1H), δ 1.84 (s, 3H); 13C-NMR δ 164.0, 154.2, 148.6, 147.1, 144.9, 139.0, 137.4, 129.8, 127.9, 127.8, 127.0, 123.7, 123.6, 122.3, 121.5, 73.5, 43.1, 30.4; MS (EI) m/z (relative intensity) 402 (M+, 18), 387 (17), 280 (18), 239 (100), 193 (20); HRMS (EI) m/z calcd for C22H18N4O4 (M+) 402.1328, found 402.1323.
2-Methyl-2,4-di-thiophen-2-yl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3l): 1H-NMR δ 7.39 (d, J = 4.8 Hz, 1H), 7.30–7.28 (m, 1H), 7.12–7.11 (m, 1H), 7.08–7.03 (m, 4H), 6.94–6.91 (m, 2H), 6.83–6.80 (m, 1H), 3.60 (br s, 1H, NH), 3.06 (d, J = 13.2 Hz, 1H), 3.00 (d, J = 13.2 Hz, 1H), 1.84 (s, 3H); 13C-NMR δ 162.4, 153.2, 137.2, 130.4, 128.6, 127.9, 127.6, 126.8, 126.3, 124.2, 122.8, 122.6, 122.0, 72.6, 44.4, 30.6; MS (EI) m/z (relative intensity) 324 (M+, 11), 201 (32), 200 (100), 109 (18); HRMS (EI) m/z calcd. for C18H16N2S2 (M+) 324.0755, found 324.0761.
2,2,4-Trimethyl-2,3-dihydro-8-chloro-1H-1,5-benzodiazepine (3m): 1H-NMR δ 7.07 (s, 1H), 7.00 (d, J = 8.4 Hz, 1H), 6.89–6.85 (m, 2H), 6.67 (s, 1H), 6.60 (d, J = 8.3 Hz, 1H), 3.02 (br s, 2H, NH), 2.30–2.29 (m, 6H), 2.19–2.16 (d, J = 12.3 Hz, 4H), 1.27 (s, 12H); 13C-NMR δ 173.8, 172.6, 141.4, 139.1, 138.4, 136.5, 130.0, 128.1, 126.4, 126.3, 125.1, 122.5, 121.3, 120.7, 68.2, 67.6, 45.1, 45.0, 30.4, 30.2, 29.64, 29.62; MS (EI) m/z (relative intensity) 222 (M+, 35), 209 (28), 207 (100), 167 (39), 166 (56); HRMS (EI) m/z calcd. for C12H15ClN2 (M+) 222.0924, found 222.0924.
2-Methyl-2,4-diphenyl-8-chloro-2,3-dihydro-1H-1,5-benzodiazepine (3n): 1H-NMR δ 7.60–7.56 (m, 8H), 7.35–7.18 (m, 14H), 7.05 (dd, J = 8.4, 2.4 Hz, 0.7H), 7.01–6.98 (dd, J = 8.4, 2.4 Hz, 1.3H), 6.85 (d, J = 2.4 Hz, 1.3H), 6.78 (d, J = 8.4 Hz, 0.7H), 3.62 (br s, 1.3H, NH), 3.52 (br s, 0.7H, NH), 3.17 (t, J = 13.4 Hz, 2H), 3.00–2.96 (m, 2H), 1.78 (s, 3H), 1.77 (s, 3H); 13C-NMR δ 168.7, 167.6, 147.1, 139.4, 139.1, 138.1, 131.0, 130.1, 130.1, 129.9, 128.4, 128.4, 128.1, 128.0, 127.2, 127.1, 127.0, 126.0, 125.3, 122.4, 121.3, 120.5, 73.7, 72.9, 43.2, 43.0, 30.0, 29.8; MS (EI) m/z (relative intensity) 346 (M+, 12), 230 (35), 229 (32), 228 (100), 167 (19), 103 (53); HRMS (EI) m/z calcd. for C22H19ClN2 (M+) 346.1237, found 346.1229.
2,2,4,8-Tetramethyl-2,3-dihydro-1H-1,5-benzodiazepine (3o): 1H-NMR δ 7.00 (d, J = 7.8 Hz, 1H), 6.93 (s, 1H), 6.77–6.75 (m, 2H), 6.62 (d, J = 7.8 Hz, 1H), 6.50 (s, 1H), 2.87 (br s, 1H, NH), 2.33 (s, 3H), 2.32 (s, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 2.19 (s, 2H), 2.16 (s, 2H), 1.30 (s, 6H), 1.29 (s, 6H); 13C- NMR δ 172.4, 171.3, 140.9, 137.8, 137.7, 135.2, 135.1, 131.6, 126.9, 126.8, 126.0, 122.6, 121.9, 121.7, 68.3, 67.5, 45.1, 45.0, 30.4, 30.1, 29.7, 20.8, 20.5; MS (EI) m/z (relative intensity) 202 (M+, 30), 187 (100), 147 (23), 146 (38); HRMS (EI) m/z calcd. for C13H18N2 (M+) 202.1470, found 202.1469.
2-Methyl-2,4-diphenyl-2,3-dihydro-8-methyl-1H-1,5-benzodiazepine (3p): 1H-NMR δ 7.65–7.59 (m, 8H), 7.32–7.18 (m, 14H), 6.93 (d, J = 7.8 Hz , 0.8H), 6.88 (d, J = 7.8 Hz, 1.2H), 6.78 (d, J = 7.8 Hz, 0.8 H), 6.67 (s, 1.2H), 3.51 (br s, 2H, NH), 3.15 (t, J = 13.2 Hz, 2H), 2.98 (q, J = 7.2 Hz, 2H), 2.37 (d, J = 3.6 Hz, 6H), 1.77 (d, J = 4.2 Hz, 6H); 13C-NMR δ 167.8, 166.6, 147.7, 140.4, 139.8, 139.5, 137.9, 137.2, 136.2, 135.4, 131.2, 129.7, 129.5, 128.9, 128.6, 128.2, 128.0, 127.9, 127.0, 126.9, 125.4, 125.4, 125.3, 122.3, 121.4, 121.5, 73.8, 72.8, 43.3, 42.9, 29.9, 29.6, 21.0, 20.5; MS (EI) m/z (relative intensity) 326 (M+, 16), 311 (19), 209 (40), 208 (100), 207 (27), 200 (21), 103 (17), 77 (23); HRMS (EI) m/z calcd. for C23H22N2 (M+) 326.1783, found 326.1780.
2,2,4,7,8-Pentamethyl-2,3-dihydro-1H-banzo[b][1,4]diazepine (3q): 1H-NMR δ 6.92 (s, 1H), 6.52 (s, 1H), 2.34 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 2.18 (s, 3H), 1.32 (s, 6H); 13C-NMR δ 171.6, 138.5, 135.5, 133.7, 130.1, 127.9, 122.8, 67.9, 45.3, 30.4, 29.8, 19.2, 18.9; MS (EI) m/z (relative intensity) 216 (M+, 26), 201 (100), 161 (29), 160 (39), 145 (20); HRMS (EI) m/z calcd. for C14H20N2 (M+) 216.1626, found 216.1621.
2,7,8-Trimethyl-2,4-diphenyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3r): 1H-NMR δ 7.57 (t, J = 8.6 Hz, 4H), 7.23–7.12 (m, 7H), 6.62 (s, 1H), 3.40 (br s, 1H, NH), 3.09 (d, J = 8.7 Hz, 1H), 2.96 (d, J = 8.7 Hz, 1H), 2.24 (s, 6H), 1.73 (s, 3H); 13C-NMR δ 166.8, 147.8, 139.8, 137.7, 135.8, 134.8, 129.7, 129.6, 129.4, 128.2, 127.9, 126.9, 125.4, 122.3, 73.1, 43.3, 29.8, 18.4, 18.8; MS (EI) m/z (relative intensity) 340 (M+, 19), 325 (27), 223 (47), 222 (100); HRMS (EI) m/z calcd. for C24H24N2 (M+) 340.1939, found 340.1934.
2,4-bis(4-Chlorophenyl)-2,7,8-trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3s): 1H-NMR δ 7.52–7.19 (m, 8H), 7.9 (s, 1H), 6.62 (s, 1H), 3.32 (br s, 1H, NH), 3.05 (d, J = 13.2 Hz, 1H), 2.87 (d, J = 13.2 Hz, 1H), 2.24 (s, 6H), 1.71 (s, 3H); 13C-NMR δ 165.2, 146.1, 138.1, 137.1, 135.8, 135.4, 135.3, 132.9, 130.0, 129.7, 128.4, 128.3, 128.2, 127.1, 122.4, 73.0, 43.1, 29.8, 19.4, 18.8; MS (EI) m/z (relative intensity) 408 (M+, 3), 305 (12), 304 (70), 289 (100), 131 (18); HRMS (EI) m/z calcd. for C24H22N2Cl2 (M+) 408.1160, found 408.1155.
7,8-Dichloro-2,2,4-trimethyl-2,3-dihydro-1H-benzo[b][1,4]diazepine (3t): 1H-NMR δ 7.20 (s, 1H), 6.81 (s, 1H), 3.07 (br s, 1H, NH), 2.34 (s, 3H), 2.25 (s, 2H), 1.33 (s, 6H); 13C-NMR δ 173.9, 139.7, 137.7, 128.3, 128.1, 124.4, 122.2, 67.7, 45.3, 30.5, 29.9; MS (EI) m/z (relative intensity) 256 (M+, 28), 258 (18), 243 (58), 241 (100), 203 (25), 202 (37), 201 (46), 200 (58); HRMS (EI) m/z calcd. for C12H14N2Cl2 (M+) 256.0534, found 256.0529.
(E)-7,8-Dichloro-2-methyl-2,4-diphenyl-2,3-dihydro-1H-benzo[b][1.4]diazepine (3u): 1H-NMR δ 7.54 (t, J = 6.8, 6.6 Hz, 4H), 7.40 (s, 1H), 7.33-7.17 (m, 6H), 6.92 (s, 1H), 3.59 (br s, 1H, NH), 3.17 (d, J = 13.4 Hz, 1H), 2.97 (d, J = 13.4 Hz, 1H), 1.75 (s, 3H), 1.57 (s, 1H); 13C-NMR δ 168.8, 146.8, 139.2, 138.9, 137.7, 130.2, 129.9, 128.8, 128.1, 127.1, 125.3, 124.1, 121.8, 72.9, 43.2, 29.9; MS (EI) m/z (relative intensity) 380 (M+, 8), 260 (10), 265 (19), 264 (61), 262 (100), 103 (23), 77 (12); HRMS (EI) m/z calcd. for C22H18N2Cl2 (M+) 380.0874, found 380.0842.
2,2,4-Trimethyl-2,3-dihydro-1H-naphtho[2,3-b][1,4]diazepine (3v): 1H-NMR δ 7.72 (d, J = 7.8 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.55 (s, 1H), 7.33-7.29 (m, 2H), 7.08 (s, 1H), 2.38 (s, 3H), 2.17 (s, 2H), 1.33 (br s, 1H, NH); 13C-NMR δ 173.1, 141.9, 137.6, 131.9, 130.3, 127.4, 125.8, 125.2, 124.0, 123.6, 117.6, 65.9, 44.6, 29.9, 29.6; MS (EI) m/z (relative intensity) 238 (M+, 25), 224 (18), 223 (100), 183 (42), 182 (37), 115 (17); HRMS (EI) m/z calcd. for C16H18N2 (M+) 238.1470, found 238.1465.
2,2',4,4,4',4'-Hexamethyl-4,4',5,5'-tetrahydro-3H,3'H-7,7'-dibenzo[b][1,4]diazepine (3w): mixture of two isomers; 1H-NMR δ 7.39 (s, 1H), 7.20 (m, 3H), 6.92 (d, 1H, J = 9.7 Hz), 6.74 (d, 1H, J = 5.0 Hz) 1H), 3.01 (br s, 2H), 2.36 (s, 6H), 2.56 (s, 4H), 1.32 (s, 12H); 13C-NMR δ 172.8, 172.7, 172.5, 172.4, 138.4, 138.3, 138.1, 138.0, 137.5, 136.9, 134.4, 127.5, 127.4, 125.3, 124.8, 123.9, 123.7, 122.1, 122.0, 120.5, 120.2, 119.8, 119.6, 68.1, 67.9, 45.4, 45.3, 30.7, 30.6, 29.9, 29.8. MS (EI) m/z (relative intensity) 374 (M+, 40), 359 (100), 319 (23), 263 (7).

Acknowledgements

Financial support provided by the National Science Council of Republic of China and National Taiwan Normal University (96TOP001) is gratefully acknowledged.

References

  1. Schutz, H. Benzodiazepines; Springer: Heidelberg, Germany, 1982. [Google Scholar]
  2. Randall, L. O.; Kamel, B. Benzodiazepines; Garattini, S., Mussini, E., Randall L., O., Eds.; Raven Press: New York, 1973; p. 27. [Google Scholar]
  3. Merluzzi, V.; Hargrave, K. D.; Labadia, M.; Grozinger, K.; Skoog, M.; Wu, J. C.; Shih, C.-K.; Eckner, K.; Hattox, S.; Adams, J.; Rosenthal, A. S.; Faanes, R.; Eckner, R. J.; Koup, R. A.; Sullivan, J. L. Inhibition of HIV-1 replication by a nonnucleoside reverse transcriptase inhibitor. Science 1990, 250, 1411–1413. [Google Scholar]
  4. Di Braccio, M.; Grossi, G.; Romoa, G.; Vargiu, L.; Mura, M.; Marongiu, M. E. 1,5-Benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepine derivatives as nevirapine analogues. Eur. J. Med. Chem. 2001, 36, 935–949. [Google Scholar] [CrossRef]
  5. El-Sayed, A. M.; Khodairy, A.; Salah, H.; Abdel-Ghany, H. Part 7: Synthesis of some new 1,5-benzodiazepines fused with different heterocyclic moieties. Phosphorus Sulfur Silicon Relat. Elem. 2007, 182, 711–722. [Google Scholar] [CrossRef]
  6. Nagaraja, G. K.; Vaidya, V. P.; Rai, K. S.; Mahadevan, K. M. An efficient synthesis of 1,5-thiadiazepines and 1,5-benzodiazepines by microwave-assisted heterocyclization. Phosphorus Sulfur Silicon Relat. Elem. 2006, 181, 2797–2806. [Google Scholar]
  7. Nabih, K.; Baouid, A.; Hasnaoui, A.; Kenz, A. Highly regio- and diastereoselective 1,3-dipolar cycloaddition of nitrile oxides to 2,4-dimethyl-3H-1,5-benzodiazepines: Synthesis of bis[1,2,4-oxadiazolo]-[1,5]benzodiazepine derivatives. Synth. Commun. 2004, 34, 3565–3572. [Google Scholar] [CrossRef]
  8. Reddy, K. V. V.; Rao, P. S.; Ashok, D. Facile synthesis of 2-benzoyl- 6-hydroxy-3-methyl-5- (2-substituted-2,3-dihydro-1H-1,5- benzodiazepin -4-yl) benzo[b]furans. Synth. Commun. 2000, 30, 1825–1836. [Google Scholar] [CrossRef]
  9. Haris, R. C.; Straley, J. M. Cationic polymethine dyes for acrylic fibers. U.S. Patent 1,537,757, 1968. [Chem. Abstr. 1970, 73, 100054w]. [Google Scholar]
  10. Claramunt, R. M.; Sanz, D.; Aggarwal, S.; Kumar, A.; Prakash, O.; Singh, S. P.; Elgueroc, J. The reaction of o-phenylenediamine with α,β-unsaturated carbonyl compounds. Arkivoc 2006, 35–45. [Google Scholar]
  11. Herbert, J. A. L.; Suschitzky, H. Syntheses of heterocyclic compounds. Part XXIX. Substituted 2,3-dihydro-1H-1,5-benzodiazepines. J. Chem. Soc. Perkin Trans. 1 1974, 2657–2661. [Google Scholar] [CrossRef]
  12. Morales, H. R.; Ulbarela, B. A.; Contreras, R. New synthesis of dihydro- and tetrahydro-1,5-benzodiazepines by reductive condensation of o-phenylenediamine and ketones in the presence of sodium borohydride. Heterocycles 1986, 24, 135–139. [Google Scholar] [CrossRef]
  13. Jung, D. I.; Choi, T. W.; Kim, Y. Y.; Kim, I. S.; Park, Y. M.; Lee, Y. G.; Jung, D. H. Synthesis of 1,5-benzodiazepine derivatives. Synth. Commun. 1999, 29, 1941–1951. [Google Scholar] [CrossRef]
  14. Balakrishna, M. S.; Kaboudin, B. A simple and new method for the synthesis of 1,5-benzodiazepine derivatives on a solid surface. Tetrahedron Lett. 2001, 42, 1127–1129. [Google Scholar] [CrossRef]
  15. Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O. Ytterbium triflate promoted synthesis of 1,5-benzodiazepine derivatives. Tetrahedron Lett. 2001, 42, 3193–3195. [Google Scholar] [CrossRef]
  16. Kaboudin, B.; Navaee, K. Alumina/phosphorus pentoxide (APP) as an efficient reagent for the synthesis of 1,5-benzodiazepines under microwave irradiation. Heterocycles 2001, 55, 1443–1446. [Google Scholar] [CrossRef]
  17. Pozarentzi, M.; Stephanatou, J. S.; Tsoleridis, C. A. An efficient method for the synthesis of 1,5-benzodiazepine derivatives under microwave irradiation wihout solvent. Tetrahedron Lett. 2002, 43, 1755–1758. [Google Scholar] [CrossRef]
  18. Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.; Anuradha, K. Amberlyst-15®: a novel and recyclable reagent for the synthesis of 1,5-benzodiazepines in ionic liquids. Green Chem. 2002, 4, 592–594. [Google Scholar] [CrossRef]
  19. Jarikote, D. V.; Siddiqui, S. A.; Rajagopal, R.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Room temperature ionic liquid promoted synthesis of 1,5-benzodiazepine derivatives under ambient conditions. Tetrahedron Lett. 2003, 44, 1835–1838. [Google Scholar] [CrossRef]
  20. Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Reddy, N. M.; Yadav, J. S. A new, efficient and environmentally benign protocol for the synthesis of 1,5-benzodiazepines using cerium (III) chloride/sodium iodide supported on silica gel. Adv. Synth. Catal. 2004, 346, 921–923. [Google Scholar] [CrossRef]
  21. Yadav, J. S.; Reddy, B. V. S.; Kumar, S. P.; Nagaiah, K. Indium(III) bromide: A novel and efficient reagent for the rapid synthesis of 1,5-benzodiazepines under solvent-free conditions. Synthesis 2005, 480–484. [Google Scholar]
  22. De, S. K.; Gibbs, R. A. Scandium(III) triflate as an efficient and reusable catalyst for synthesis of 1,5-benzodiazepine derivatives. Tetrahedron Lett. 2005, 46, 1811–1813. [Google Scholar] [CrossRef]
  23. Reddy, B. M.; Sreekanth, P. M.; Lakshmanan, P. Sulfated zirconia as an efficient catalyst for organic synthesis and transformation reactions. J. Mol. Catal. A: Chem. 2005, 237, 93–100. [Google Scholar] [CrossRef]
  24. Yadav, J. S.; Reddy, B.V.S.; Satheesh, G.; Srinivasulu, G.; Kunwar, A. C. InCI3-catalyzed stereoselective synthesis of optically pure 1,5-benzodiazepines. Arkivoc 2005, (iii), 221–227. [Google Scholar]
  25. Varala, R.; Ramu, E.; Sreelatha, N.; Adapa, S. R. Ceric ammonium nitrate (CAN) promoted efficient synthesis of 1,5-benzodiazepine derivatives. Synlett 2006, 1009–1014. [Google Scholar]
  26. Pasha, M. A.; Jayashankara, V. P. Synthesis of 1,5-benzodiazepine derivatives catalyzed by zinc chloride. Heterocycles 2006, 68, 1017–1023. [Google Scholar] [CrossRef]
  27. Chen, W.-Y.; Lu, J. Molecular iodine catalyzed one-pot synthesis of 1,5-benzodiazepine derivatives under solvent-free conditions. Synlett 2005, 1337–1339. [Google Scholar] [CrossRef]
  28. Kumar, R.; Chaudhary, P.; Nimesh, S.; Verma, A. K.; Chandra, R. An efficient synthesis of 1,5-benzadiazepine derivatives catalyzed by silver nitrate. Green Chem. 2006, 8, 519–521. [Google Scholar] [CrossRef]
  29. Li, Z.; Sun, Y.; Ren, X.; Li, W.; Shi, Y.; Ouyang, P. Efficient synthesis of 1,5-benzodiazepines mediated by sulfamic acid under neat condition or in solution. Synth. Commun. 2007, 37, 1609–1615. [Google Scholar] [CrossRef]
  30. An, L.-T.; Ding, F.-Q.; Zou, J.-P.; Lu, X.-H. Montmorillonite K10: An efficient catalyst for solvent-free synthesis of 1,5-benzodiazepine derivatives. Synth. Commun. 2008, 38, 1259–1267. [Google Scholar] [CrossRef]
  31. De Luca, L.; Giacomelli, G.; Porcheddu, A. An efficient route to alkyl chlorides from alcohols using the complex TCT/DMF. Org. Lett. 2002, 4, 553–555. [Google Scholar] [CrossRef]
  32. De Luca, L.; Giacomelli, G.; Porcheddu, A. Beckmann rearrangement of oximes under very mild conditions. J. Org. Chem. 2002, 67, 6272–6274. [Google Scholar] [CrossRef]
  33. Kangani, C. O.; Day, B. W. Mild, efficient Friedel−Crafts acylations from carboxylic acids using cyanuric chloride and AlCl3. Org. Lett. 2008, 10, 2645–2648. [Google Scholar] [CrossRef]
  34. Das, B.; Kumar, R. A.; Thirupathi, P. One-pot three-component synthesis of α-amino nitriles catalyzed by 2,4,6-trichloro-1,3,5-triazine. Helv. Chim. Acta. 2007, 90, 1206–1210. [Google Scholar] [CrossRef]
  35. Blotny, G. Recent applications of 2,4,6-trichloro-1,3,5-triazine and its derivatives in organic synthesis. Tetrahedron 2006, 62, 9507–9522. [Google Scholar] [CrossRef]
  36. Sharma, G. V. M.; Reddy, J. J.; Lakshmi, P. S.; Krishna, P. R. A versatile and practical synthesis of bis(indolyl)methanes/bis(indolyl)glycoconjugates catalyzed by trichloro-1,3,5-triazine. Tetrahedron Lett. 2004, 45, 7729–7732. [Google Scholar] [CrossRef]
  37. Bigdeli, M. A.; Mahdavinia, G. H.; Jafari, S.; Hazarkhani, H. Wet 2,4,6-trichloro[1,3,5]triazine (TCT) an efficient catalyst for synthesis of α,α′-bis(substituted-benzylidene) cycloalkanones under solvent-free conditions. Catal. Commun. 2007, 8, 2229–2231. [Google Scholar] [CrossRef]
  38. Yan, M.-C.; Tu, Z.; Lin, C.; Ko, S.; Hsu, J.; Yao, C.-F. An investigation of the reaction of 2-aminobenzaldehyde derivatives with conjugated nitro-olefins: An easy and efficient synthesis of 3-nitro-1,2-dihydroquinolines and 3-nitroquinolines. J. Org. Chem. 2004, 69, 1565–1570. [Google Scholar] [CrossRef]
  39. Kuo, C. -W.; More, S.; Yao, C. -F. NBS as an efficient catalyst for the synthesis of 1,5-benzodiazepine derivatives under mild conditions. Tetrahedron Lett. 2006, 47, 8523–8588. [Google Scholar] [CrossRef]
  40. Lin, C.; Fang, H.; Tu, Z.; Liu, J.-T.; Yao, C.-F. Stereoselective three-component synthesis of trans-endo-decahydroquinolin-4-one derivatives from aldehydes, aniline, and acetylcyclohexene. J. Org. Chem. 2006, 71, 6588–6591. [Google Scholar] [CrossRef]
  41. Ko, S.; Yao, C.-F. Ceric ammonium nitrate (CAN) catalyzes the one-pot synthesis of polyhydroquinoline via the Hantzsch reaction. Tetrahedron 2006, 62, 7293–7299. [Google Scholar] [CrossRef]
  42. Ko, S.; Yao, C.-F. Heterogeneous catalyst: Amberlyst-15 catalyzes the synthesis of 14-substituted-14H-dibenzo[a,j]xanthenes under solvent-free conditions. Tetrahedron Lett. 2006, 47, 8827–8829. [Google Scholar] [CrossRef]
  43. More, S.; Sastry, M. N. V.; Yao, C.-F. Cerium (IV) ammonium nitrate (CAN) as a catalyst in tap water: A simple, proficient and green approach for the synthesis of quinoxalines. Green Chem. 2006, 8, 91–95. [Google Scholar] [CrossRef]
  44. More, S.; Sastry, M. N. V.; Yao, C.-F. TMSCl-catalyzed aza-Diels-Alder reaction: A simple and efficient synthesis of pyrano and furanoquinolines. Synlett 2006, 1399–1403. [Google Scholar]
  45. Khodaei, M. M.; Bahrami, K.; Nazarian, Z. TCT as a rapid and efficient catalyst for the synthesis of 1,5-benzodiazepines. Bull. Korean Chem. Soc. 2008, 29, 1280–1282. [Google Scholar] [CrossRef]
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Kuo, C.-W.; Wang, C.-C.; Kavala, V.; Yao, C.-F. Efficient TCT-catalyzed Synthesis of 1,5-Benzodiazepine Derivatives under Mild Conditions. Molecules 2008, 13, 2313-2325. https://doi.org/10.3390/molecules13092313

AMA Style

Kuo C-W, Wang C-C, Kavala V, Yao C-F. Efficient TCT-catalyzed Synthesis of 1,5-Benzodiazepine Derivatives under Mild Conditions. Molecules. 2008; 13(9):2313-2325. https://doi.org/10.3390/molecules13092313

Chicago/Turabian Style

Kuo, Chun-Wei, Chun-Chao Wang, Veerababurao Kavala, and Ching-Fa Yao. 2008. "Efficient TCT-catalyzed Synthesis of 1,5-Benzodiazepine Derivatives under Mild Conditions" Molecules 13, no. 9: 2313-2325. https://doi.org/10.3390/molecules13092313

APA Style

Kuo, C.-W., Wang, C.-C., Kavala, V., & Yao, C.-F. (2008). Efficient TCT-catalyzed Synthesis of 1,5-Benzodiazepine Derivatives under Mild Conditions. Molecules, 13(9), 2313-2325. https://doi.org/10.3390/molecules13092313

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