Key words palladium - catalysis - amination - cyclization - benzodiazepine
There is a growing interest over the past few years in the synthesis of nitrogen containing heterocycle-fused benzazepines and benzodiazepines due to their crucial role as main structural motif in many pharmacologically active molecules. The clinical importance and commercial success associated with the benzodiazepine class of central nervous system (CNS)-active agents and the utility of 1,4-diazepines as peptidomimetic scaffolds have led the medicinal chemists to recognize them as privileged structures. Particularly, imidazobenzodiazepines[
1
] and related ligands interact selectively for a neuro-inhibitory, postsynaptic GABAA receptor[1f ]
[g ] with high affinity. Accordingly, they may act as agonists, partial agonists,[
1b
] and antagonists. The therapeutic applications of benzodiazepines include anxiolytics,[
2
] antiarrhythmics,[
3
] vasopressin antagonists,[
4
] and cholecystokinin antagonists.[
5
] Some of the benzodiazepines such as arfendazam, lofendazam,[
6
] triflubazam,[
7
] and clobazam exhibit a wide range of biological activities while others like telenzepine act as antisecretory agents.[
8
] Recently, several compounds have been formally licensed for clinical use (e.g., Nevirapine) and others are at the preclinical and/or clinical development stage (e.g., Tivirapine and UK-129 485[
9
]). Tetrahydroimidazo[4,5,1-jk ][l,4]benzodiazepin-2(1H )-thione, assigned the acronym TIBO,[1d ]
[e ] is the first member of a series of potent selective and noncompetitive inhibitors of HIV-l reverse transcriptase.
Despite the immense importance of imidazobenzodiazepines, only a few groups[
1
] have reported their synthesis. These methods either require lengthy sequence of reactions or harsh reaction conditions. For quite some time, we have been engaged in the synthesis of several benzannulated and dibenzannulated medium ring heterocycles employing palladium-catalyzed intramolecular C–N bond forming cyclization reaction.[10 ]
[11 ]
[12 ] The copper- or palladium-catalyzed intramolecular Buchwald–Hartwig aryl amination reaction[
13
] appeared particularly suitable for this purpose. In continuation of these efforts, we became interested in applying this method in the synthesis of imidazole-fused benzodiazepines. To the best of our knowledge no other group has reported the synthesis of this important synthetic target using this method.
The requisite starting materials 3a –c were prepared in good to excellent yields by reaction between imidazole-2-carbaldehyde (1 ) and either 2-bromobenzyl bromide (2a ) or substituted 2-bromobenzyl bromides 2b ,c in the presence of anhydrous potassium carbonate in anhydrous DMF at room temperature (Table 1).
Table 1 Synthesis of N-Benzylated Imidazo-2-carbaldehydesa
Entry
R1
R2
Benzyl
bromide
Product
Time
(h)
Yield
(%)b
1
H
H
2a
3a
16
95
2
OCH2 O
2b
3b
17
92
3
OMe
H
2c
3c
16
94
a Reaction conditions: imidazole-2-carbaldehyde (1 equiv), 2-bromobenzyl bromide (1.2 equiv), K2 CO3 (2 equiv), anhyd DMF (5 mL/mmol), r.t., 16–17 h.
b Isolated yield.
Imine formation with aliphatic and aromatic amines and subsequent NaBH4 reduction in ethanol afforded the desired amine precursors 4a –l in good yields (Table 2).
Table 2 Synthesis of Imidazo N-Alkylated Amines 4a –l
a
Entry
R1
R2
R3
Product
Yield (%)b
1
H
H
Ph
4a
72
2
H
H
i -Pr
4b
70
3
H
H
4c
73
4
OMe
H
i -Pr
4d
77
5
OMe
H
Ph
4e
75
6
OMe
H
Bn
4f
74
7
OMe
H
4g
71
8
OCH2 O
i -Pr
4h
69
9
OCH2 O
Bn
4i
68
10
OCH2 O
Ph
4j
71
11
OCH2 O
4-MeOC6 H4
4k
75
12
OCH2 O
4l
73
a Reaction conditions: 1) N-benzylated imidazole-2-carbaldehyde (1 equiv), amines (1.5 equiv), EtOH (10 mL/mmol), r.t., 12 h. 2) NaBH4 (2.5 equiv), EtOH (20 mL/mmol), 0 °C, 2–3 h.
b Isolated yield.
The amine precursor 4a was then used as model substrate for the optimization of intramolecular cycloamination reaction. Initially with the conditions used by Buchwald[
13a
] (Table 3, entry 1) no desired product was obtained and the starting material 4a was recovered. Changing the catalyst to Pd2 (dba)3 or Pd(OAc)2 also failed to afford the desired product in the absence of a ligand (entries 2, 3). The reaction did take place in the presence of a ligand, with Pd2 (dba)3 proving superior to Pd(OAc)2 at equivalent (10 mol% Pd) catalyst loading (entries 4–7), but the yield was still low (58%). Then, the Pd loading was varied from 6 to 40 mol% using Pd2 (dba)3 as Pd source, which improved the yield to 73% at 20% Pd loading (entry 9). Changing the base to Cs2 CO3 , using other monodentate (tri-o -tolylphosphine) or bidentate (DPPF) ligands and employing different solvents (DME or 1,4-dioxane) proved less satisfactory (entries 12–16).
Table 3 Optimization of the Cycloamination Reaction of 4a
Entry
Reaction conditions
Pd (mol%)a
Yield (%)b
1
Pd(PPh3 )4 , K2 CO3 , toluene, reflux, 16 h
10
–c
2
Pd2 (dba)3 , K2 CO3 , DMF, 120 °C, 17 h
10
–c
3
Pd(OAc)2 , K2 CO3 , DMF, 120 °C, 16 h
10
–c
4
Pd(OAc)2 , (o -tol)3 P, t -BuOK, toluene, reflux, 18 h
10
20
5
Pd(OAc)2 , DPPF, K2 CO3 , toluene, reflux, 17 h
10
22
6
Pd(OAc)2 , DPPF, t -BuOK, toluene, reflux, 18 h
10
30
7
Pd2 (dba)3 , (±)-BINAP, t -BuOK, toluene, reflux, 16 h
10
58
8
Pd2 (dba)3 , (±)-BINAP, t -BuOK, toluene, reflux, 17 h
6
43
9
Pd2 (dba)3 , (±)-BINAP, t -BuOK, toluene, reflux, 16 h
20
73d
10
Pd2 (dba)3 , (±)-BINAP, t -BuOK, toluene, reflux, 17 h
30
70
11
Pd2 (dba)3 , (±)-BINAP, t -BuOK, toluene, reflux, 17 h
40
67
12
Pd2 (dba)3 , (±)-BINAP, t -BuOK, DME, reflux, 17 h
20
35
13
Pd2 (dba)3 , (±)-BINAP, t -BuOK, 1,4-dioxane, reflux, 17 h
20
43
14
Pd2 (dba)3 , (±)-BINAP, Cs2 CO3 , toluene, reflux, 17 h
20
35
15
Pd2 (dba)3 , (o -tol)3 P, t -BuOK, toluene, reflux, 18 h
20
30
16
Pd2 (dba)3 , DPPF, t -BuOK, toluene, reflux, 18 h
20
56
a Pd (10 mol%) refers to Pd2 (dba)3 (5 mol%), Pd(OAc)2 (10 mol%), and Pd(PPh3 )4 (10 mol%).
b Isolated yield.
c No desired product was isolated.
d Optimized reaction conditions: 4a (1 equiv), Pd2 (dba)3 (10 mol%; 20 mol% in Pd), (±)-BINAP (10 mol%), t -BuOK (2 equiv), toluene (10 mL/mmol), reflux.
Use of copper catalyst (CuI, 5 mol%) and t -BuOK (2 equiv) with different ligands [1,10-phenanthroline or (±)-trans -1,2-cyclohexanediamine or N ,N ′-dimethylethylenediamine, 10 mol%] and solvents like DMF (at 120 °C) or toluene (reflux) also did not lead to the desired cyclic product.
The optimized protocol for the palladium-catalyzed intramolecular aryl amination of 4a thus employs Pd2 (dba)3 (10 mol%) as catalyst, (±)-BINAP (10 mol%) as ligand, t -BuOK (2 equiv) as base, and toluene as solvent at reflux to furnish 5a . Employing these conditions, other substrates 4b –l were treated to afford 5b –l in 63–76% yield (Table 4). A probable mechanism[13b ]
[c ]
[14 ] of intramolecular aryl amination for the synthesis of benzodiazepines is outlined in Scheme [1 ].
Scheme 1 Proposed mechanism for the synthesis of imidazobenzodiazepine
Table 4 Synthesis of Imidazobenzodiazepines 5b –l
a
Entry
Substrate
Product
Time (h)
Yield (%)a
1
4b
5b
18
68
2
4c
5c
17
65
3
4d
5d
16
71
4
4e
5e
18
68
5
4f
5f
15
76
6
4g
5g
14
72
7
4h
5h
16
70
8
4i
5i
18
75
9
4j
5j
15
74
10
4k
5k
17
67
11
4l
5l
16
63
a Isolated yield.
The assigned structures of 5b –l were determined on the basis of their IR, 1 H NMR, 13 C NMR, mass spectra, and elemental analysis. The 1 H NMR spectrum of 5a consisted of two singlets at δ = 4.95 and 4.86 for the benzylic methylene protons and methylene protons attached to nitrogen of the aniline moiety, along with signals for eleven aromatic protons (δ = 6.77–7.42). The 13 C NMR spectrum showed signals assignable to 17 carbons in agreement with the structure. The mass spectrum displayed a peak at m /z 262 for the [M + H]+ ion. The features of the 1 H and 13 C NMR spectra of compounds 5b –l were broadly similar to those of 5a , except for the signals for the aromatic moieties and the alkyl/aryl groups, which exhibited the expected changes in signal patterns.
The present strategy thus establishes transition-metal-catalyzed cycloamination as a suitable synthetic tool for the preparation of imidazole-fused benzodiazepine. But it could not be extended to the synthesis of pyrrole-fused benzodiazepines.
In summary, we have established a straightforward efficient three-step synthetic route to imidazole-fused seven-membered diazacycles from imidazole-2-carbaldehyde using palladium-catalyzed intramolecular cycloamination reaction as the key step. Development of new analogues of benzodiazepines is highly desirable as this may lead to a promising antidepressant drug. This finding opens up the possibility of obtaining synthetically challenging imidazole-fused seven-membered benzoheterocycles.
Reactions at r.t. imply a temperature of 25 °C. Required reagents were obtained from commercial sources and used without purification. The solvents used were of technical grade, and freshly distilled prior to use. All melting points were obtained on a laboratory melting point bath and are uncorrected. 1 H (300 MHz, 600 MHz) and 13 C (75 MHz, 150 MHz) NMR spectra were recorded using CDCl3 as solvent and TMS as internal standard on Bruker DPX 300 MHz and Bruker DRX 600 MHz NMR instruments. Chemical shifts are stated in parts per million in δ scales. IR spectra were recorded on a Jasco-FTIR Model-410 using KBr pellets or in neat condition. Mass spectra were measured in ESIMS (+) or EIMS mode. DI-EIMS were recorded on a Shimadzu GCMS (model no QP5050A) and ESIMS were done on a Waters Micromass Q-TOF microTM mass spectrometer. TLC was performed on precoated plates (0.25 nm, silica gel 60 F254 ). Petroleum ether (PE) used refers to the fraction boiling in the 60–80 °C range.
1-(2-Bromobenzyl)-1H -imidazole-2-carbaldehydes 3a–c; General Procedure
1-(2-Bromobenzyl)-1H -imidazole-2-carbaldehydes 3a–c; General Procedure
To a stirred solution of imidazole-2-carbaldehyde (1 ; 0.5 g, 5.2 mmol) in anhyd DMF (20 mL) was added K2 CO3 (1.4 g, 10.41 mmol) and the mixture was stirred at r.t. for 30 min. Thereafter, the appropriate 2-bromobenzyl bromide 2 (6.25 mmol, 1.2 equiv) was added and the stirring was continued for about 16–17 h at r.t. On completion of the reaction as monitored by TLC (eluent: PE–EtOAc, 1:1), the solution was poured into H2 O (70 mL), and extracted with EtOAc (4 × 30 mL). The combined organic layers were washed with H2 O (40 mL), followed by brine (30 mL), dried (Na2 SO4 ), filtered, and the solvent was evaporated in vacuo. The crude product was purified via column chromatography over neutral alumina (EtOAc–PE, 1:9) to give 3a –c .
1-(2-Bromobenzyl)-1H -imidazole-2-carbaldehyde (3a)
1-(2-Bromobenzyl)-1H -imidazole-2-carbaldehyde (3a)
Yield: 1.30 g (95%); yellow solid; mp 80–82 °C; Rf
= 0.55 (PE–EtOAc, 3:2).
IR (KBr): 2846, 1678, 1465, 1411, 1337, 1294, 1244, 1155, 1024, 774, 664 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 5.73 (s, 2 H), 6.91 (d, J = 6.9 Hz, 1 H), 7.15 (s, 1 H), 7.18–7.30 (m, 2 H), 7.32 (s, 1 H), 7.61 (d, J = 7.5 Hz, 1 H), 9.87 (s, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 50.8 (CH2 ), 123.2 (C), 126.2 (CH), 128.0 (CH), 129.1 (CH), 129.9 (CH), 131.9 (CH), 133.1 (CH), 135.2 (C), 143.4 (C), 182.1 (CHO).
MS (ESI): m /z = 265, 267 ([M + H+ ] for 79 Br and 81 Br), 287, 289 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C11 H9 BrN2 O: C, 49.84; H, 3.42; N, 10.57. Found: C, 49.64; H, 3.47; N, 10.67.
1-(2-Bromo-4,5-methylenedioxybenzyl)-1H -imidazole-2-carbaldehyde (3b)
1-(2-Bromo-4,5-methylenedioxybenzyl)-1H -imidazole-2-carbaldehyde (3b)
Yield: 1.47 g (92%); white solid; mp 84–86 °C; Rf
= 0.65 (PE–EtOAc, 3:7).
IR (KBr): 2908, 2842, 1681, 1626, 1478, 1412, 1249, 1110, 1036, 929, 858, 763, 681, 521 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 5.64 (s, 2 H), 5.99 (s, 2 H), 6.54 (s, 1 H), 7.05 (s, 1 H), 7.20 (s, 1 H), 7.31 (s, 1 H), 9.87 (s, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 50.4 (CH2 ), 102.0 (CH2 ), 109.3 (CH), 112.9 (CH), 114.1 (C), 125.9 (CH), 128.1 (C), 131.9 (CH), 143.1 (C), 147.9 (C), 148.5 (C), 182.2 (CH).
MS (ESI): m /z = 309, 311 ([M + H+ ] for 79 Br and 81 Br), 331, 333 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C12 H9 BrN2 O3 : C, 46.63; H, 2.93; N, 9.06. Found: C, 46.85; H, 2.88; N, 9.18.
1-(2-Bromo-5-methoxybenzyl)-1H -imidazole-2-carbaldehyde (3c)
1-(2-Bromo-5-methoxybenzyl)-1H -imidazole-2-carbaldehyde (3c)
Yield: 1.48 g (94%); white solid; mp 78–80 °C; Rf
= 0.65 (PE–EtOAc, 2:3).
IR (KBr): 2863, 1683, 1569, 1476, 1412, 1339, 1259, 1159, 1044, 1018, 919, 879, 805, 745, 598 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.70 (s, 3 H), 5.67 (s, 2 H), 6.48 (d, J = 3.0 Hz, 1 H), 6.73 (dd, J = 3.0 Hz, 8.7 Hz, 1 H), 7.17 (s, 1 H), 7.30 (s, 1 H), 7.47 (d, J = 8.7 Hz, 1 H), 9.85 (s, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 50.7 (CH2 ), 55.4 (OCH3 ), 113.4 (C), 115.2 (2 CH), 126.2 (CH), 131.9 (CH), 133.7 (CH), 136.1 (C), 143.3 (C), 159.4 (C), 182.1 (CHO).
MS (ESI): m /z = 295, 297 ([M + H+ ] for 79 Br and 81 Br).
Anal. Calcd for C12 H11 BrN2 O2 : C, 48.84; H, 3.76; N, 9.49. Found: C, 48.64; H, 3.80; N, 9.59.
1-(2-Bromobenzyl)-2-(phenylaminomethyl)-1H -imidazoles 4a–l; General Procedure
1-(2-Bromobenzyl)-2-(phenylaminomethyl)-1H -imidazoles 4a–l; General Procedure
To an ethanolic solution (20 mL) of 3a –c (0.85–1.89 mmol, 1 equiv) was added the respective alkyl/aryl amine (1.27–2.83 mmol, 1.5 equiv) and the reaction mixture was stirred at r.t. for 12 h. After cooling to 0 °C, NaBH4 (2.12–4.72 mmol, 2.5 equiv) was added portionwise and the mixture was stirred for 2–3 h. On completion of the reaction as monitored by TLC (eluent: EtOAc), the solvent was removed under vacuum. The mixture was extracted with EtOAc (2 × 20 mL), and the combined organic extracts were washed with sat. aq NaHCO3 (25 mL) and H2 O (2 × 20 mL), dried (Na2 SO4 ), filtered, and concentrated. The crude residue was purified by column chromatography over neutral alumina (EtOAc–PE, 3:1) to afford the compounds 4a –l .
1-(2-Bromobenzyl)-2-(phenylaminomethyl)-1H -imidazole (4a)
1-(2-Bromobenzyl)-2-(phenylaminomethyl)-1H -imidazole (4a)
Yield: 0.22 g (72%); brownish sticky mass; Rf
= 0.38 (PE–EtOAc, 1:1).
IR (neat): 2923, 1685, 1601, 1501, 1436, 1315, 1262, 1216, 1105, 1026, 752 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 4.30 (s, 2 H), 5.24 (s, 2 H), 6.64–6.76 (m, 4 H), 6.89 (s, 1 H), 7.08 (s, 1 H), 7.14–7.26 (m, 4 H), 7.60 (d, J = 6.0 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 41.1 (CH2 ), 49.7 (CH2 ), 113.2 (2 CH), 118.2 (CH), 121.0 (CH), 122.5 (C), 127.7 (CH), 128.0 (CH), 128.1 (CH), 129.2 (2 CH), 129.7 (CH) 133.1 (CH), 135.3 (C), 145.4 (C), 147.4 (C).
MS (ESI): m /z = 342, 344 ([M + H+ ] for 79 Br and 81 Br).
Anal. Calcd for C17 H16 BrN3 : C, 59.66; H, 4.71; N, 12.28. Found: C, 59.86; H, 4.75; N, 12.18.
1-(2-Bromobenzyl)-2-(isopropylaminomethyl)-1H -imidazole (4b)
1-(2-Bromobenzyl)-2-(isopropylaminomethyl)-1H -imidazole (4b)
Yield: 0.35 g (70%); yellowish sticky mass; Rf
= 0.27 (PE–EtOAc, 3:7).
IR (neat): 2964, 2866, 1685, 1643, 1469, 1441, 1346, 1279, 1165, 1117, 1027, 747, 665 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 1.02 (d, J = 6.3 Hz, 6 H), 2.76–2.84 (m, 1 H), 3.78 (s, 2 H), 5.30 (s, 2 H), 6.68 (d, J = 6.9 Hz, 1 H), 6.86 (s, 1 H), 7.02 (s, 1 H), 7.09–7.33 (m, 2 H), 7.59 (d, J = 7.8 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 22.6 (2 CH3 ), 43.3 (CH2 ), 48.4 (CH), 49.6 (CH2 ), 120.6 (CH), 122.3 (C), 127.5 (CH), 127.9 (2 CH), 129.4 (CH) 132.8 (CH), 136.0 (C), 146.8 (C).
MS (ESI): m /z = 308, 310 ([M + H+ ] for 79 Br and 81 Br).
Anal. Calcd for C14 H18 BrN3 : C, 54.56; H, 5.89; N, 13.63. Found: C, 54.77; H, 5.86; N, 13.73.
1-(2-Bromobenzyl)-2-(3,4- methylenedioxybenzylaminomethyl)-1H -imidazole (4c)
1-(2-Bromobenzyl)-2-(3,4- methylenedioxybenzylaminomethyl)-1H -imidazole (4c)
Yield: 0.25 g (73%); yellowish sticky mass; Rf
= 0.30 (PE–EtOAc, 3:7).
IR (neat): 2956, 2860, 1409, 1305, 1161, 1011, 846, 510 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.69 (s, 2 H), 3.80 (s, 2 H), 5.92 (s, 2 H), 6.64–6.75 (m, 4 H), 6.86 (s, 1 H), 7.03 (s, 2 H), 7.14–7.23 (m, 3 H), 7.60 (dd, J = 1.2, 6.6 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 45.0 (CH2 ), 49.6 (CH2 ), 53.2 (CH2 ), 100.8 (CH2 ), 108.0 (CH), 108.6 (CH), 120.6 (CH), 121.2 (CH), 122.3 (C), 127.7 (CH), 127.9 (2 CH), 129.3 (CH), 132.8 (CH), 133.6 (C), 136.1 (C), 146.5 (C), 146.6 (C), 147.6 (C).
MS (ESI): m /z = 400, 402 ([M + H+ ] for 79 Br and 81 Br).
Anal. Calcd for C19 H18 BrN3 O2 : C, 57.01; H, 4.53; N, 10.50. Found: C, 57.22; H, 4.58; N, 10.50.
1-(2-Bromo-5-methoxybenzyl)-2-(isopropylaminomethyl)-1H -imidazole (4d)
1-(2-Bromo-5-methoxybenzyl)-2-(isopropylaminomethyl)-1H -imidazole (4d)
Yield: 0.24 g (77%); yellowish sticky mass; Rf
= 0.35 (EtOAc).
IR (neat): 2962, 1593, 1470, 1375, 1288, 1238, 1164, 1118, 1056, 1018, 925, 856, 809, 734 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 1.03 (d, J = 6.0 Hz, 6 H), 2.77–2.83 (m, 1 H), 3.67 (s, 3 H), 3.78 (s, 2 H), 5.25 (s, 2 H), 6.25 (s, 1 H), 6.70–6.73 (dd, J = 2.4, 8.7 Hz, 1 H), 6.87 (s, 1 H), 7.02 (s, 1 H), 7.47 (d, J = 8.7 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 22.6 (2 CH3 ), 43.5 (CH2 ), 48.5 (CH), 49.5 (CH2 ), 55.3 (OCH3 ), 112.4 (C), 113.9 (CH), 114.6 (CH), 120.5 (CH), 127.6 (CH), 133.4 (CH) 137.1 (C), 146.9 (C), 159.4 (C).
MS (ESI): m /z = 338, 340 ([M + H+ ] for 79 Br and 81 Br), 360, 362 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C15 H20 BrN3 O: C, 53.26; H, 5.96; N, 12.42. Found: C, 53.48; H, 5.92; N, 12.56.
1-(2-Bromo-5-methoxybenzyl)-2-(phenylaminomethyl)-1H -imidazole (4e)
1-(2-Bromo-5-methoxybenzyl)-2-(phenylaminomethyl)-1H -imidazole (4e)
Yield: 0.33 g (75%); white solid; Rf
= 0.58 (PE–EtOAc, 2:3).
IR (KBr): 2927, 2845, 1688, 1600, 1471, 1286, 1160, 1056, 1019, 924, 865, 810, 748 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.59 (s, 3 H), 4.23 (s, 2 H), 5.19 (s, 2 H), 6.19 (d, J = 3.0 Hz, 1 H), 6.64–6.78 (m, 4 H), 6.90 (s, 1 H), 7.08–7.18 (m, 3 H), 7.45 (d, J = 8.7 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 41.2 (CH2 ), 49.7 (CH2 ), 55.3 (OCH3 ), 112.4 (C), 113.2 (2 CH), 113.9 (CH), 115.0 (CH), 118.1 (CH), 121.0 (CH), 128.0 (CH), 129.2 (2 CH), 133.6 (CH), 136.4 (C), 145.4 (C), 147.5 (C), 159.5 (C).
MS (ESI): m /z = 372, 374 ([M + H+ ] for 79 Br and 81 Br), 394, 396 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C18 H18 BrN3 O: C, 58.08; H, 4.87; N, 11.29. Found: C, 58.28; H, 4.90; N, 11.40.
1-(2-Bromo-5-methoxybenzyl)-2-(benzylaminomethyl)-1H -imidazole (4f)
1-(2-Bromo-5-methoxybenzyl)-2-(benzylaminomethyl)-1H -imidazole (4f)
Yield: 0.36 g (74%); yellowish sticky mass; Rf
= 0.4 (EtOAc).
IR (neat): 2934, 2838, 1645, 1594, 1469, 1350, 1288, 1239, 1161, 1020, 738, 699 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.63 (s, 3 H), 3.79 (s, 2 H), 3.81 (s, 2 H), 5.23 (s, 2 H), 6.24 (d, J = 3.0 Hz, 1 H), 6.69 (dd, J = 3.0, 8.7 Hz, 1 H), 6.86 (d, J = 1.2 Hz, 1 H), 7.02 (d, J = 1.2 Hz, 1 H), 7.22–7.26 (m, 5 H), 7.46 (d, J = 9.0 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 44.9 (CH2 ), 49.4 (CH2 ), 53.1 (CH2 ), 55.1 (OCH3 ), 112.2 (C), 113.8 (CH), 114.3 (CH), 120.4 (CH), 126.7 (CH), 127.4 (CH), 128.0 (2 CH), 128.1 (2 CH), 133.2 (CH), 136.9 (C), 139.4 (C), 146.3 (C), 159.2 (C).
MS (ESI): m /z = 386, 388 ([M + H+ ] for 79 Br and 81 Br), 408, 410 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C19 H20 BrN3 O: C, 59.08; H, 5.22; N, 10.88. Found: C, 59.28; H, 5.19; N, 10.98.
1-(2-Bromo-5-methoxybenzyl)-2-(3,4-methylenedioxybenzylaminomethyl)-1H -imidazole (4g)
1-(2-Bromo-5-methoxybenzyl)-2-(3,4-methylenedioxybenzylaminomethyl)-1H -imidazole (4g)
Yield: 0.32 g (71%); pale brownish sticky mass; Rf
= 0.26 (EtOAc).
IR (neat): 2928, 1720, 1597, 1480, 1245, 1121, 1040, 930, 809, 739 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.65 (s, 3 H), 3.70 (s, 2 H), 3.80 (s, 2 H), 5.22 (s, 2 H), 5.92 (s, 2 H), 6.23 (d, J = 3.0 Hz, 1 H), 6.69–6.73 (m, 3 H), 6.79 (s, 1 H), 6.87 (d, J = 0.9 Hz, 1 H), 7.03 (d, J = 0.9 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 45.0 (CH2) , 49.6 (CH2) , 53.2 (CH2 ), 55.3 (CH3 ), 100.8 (CH2 ), 108.0 (CH), 108.6 (CH), 112.4 (C), 114.0 (CH), 114.5 (CH), 120.6 (CH), 121.2 (CH), 127.7 (CH), 133.4 (CH), 133.6 (C), 137.1 (C), 146.5 (C), 146.6 (C), 147.6 (C), 159.4 (C).
MS (ESI): m /z = 430, 432 ([M + H+ ] for 79 Br and 81 Br), 452, 454 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C20 H20 BrN3 O3 : C, 55.83; H, 4.68; N, 9.77. Found: C, 54.63; H, 4.64; N, 9.90.
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(isopropylaminomethyl)-1H -imidazole (4h)
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(isopropylaminomethyl)-1H -imidazole (4h)
Yield: 0.46 g (69%); pale yellowish sticky mass; Rf
= 0.28 (PE–EtOAc, 3:7).
IR (neat): 3263, 2963, 2909, 1683, 1488, 1374, 1243, 1162, 1109, 1034, 929, 847, 733, 509 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 1.06 (d, J = 6.3 Hz, 6 H), 2.79–2.87 (m, 1 H), 3.80 (s, 2 H), 5.19 (s, 2 H), 5.96 (s, 2 H), 6.30 (s, 1 H), 6.85 (s, 1 H), 7.00 (d, J = 11.4 Hz, 2 H).
13 C NMR (75 MHz, CDCl3 ): δ = 22.7 (2 CH3 ), 43.6 (CH2 ), 48.5 (CH), 49.3 (CH2 ), 101.9 (CH2 ), 108.3 (CH), 112.8 (CH), 112.9 (C), 120.3 (CH), 127.6 (CH), 129.2 (C) 146.8 (C), 147.9 (C), 148.0 (C).
MS (ESI): m /z = 352, 354 ([M + H+ ] for 79 Br and 81 Br).
Anal. Calcd for C15 H18 BrN3 O2 : C, 51.15; H, 5.15; N, 11.93. Found: C, 51.35; H, 5.10; N, 11.81.
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(benzylaminomethyl)-1H -imidazole (4i)
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(benzylaminomethyl)-1H -imidazole (4i)
Yield: 0.41 g (68%); yellowish sticky mass; Rf
= 0.35 (PE–EtOAc, 3:7).
IR (neat): 3261, 2904, 2788, 1489, 1242, 1106, 1034, 925, 851, 751, 698, 493 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.81 (s, 2 H), 3.84 (s, 2 H), 5.17 (s, 2 H), 5.94 (s, 2 H), 6.26 (s, 1 H), 6.85 (s, 1 H), 7.02 (d, J = 5.1 Hz, 2 H), 7.27 (d, J = 5.7 Hz, 5 H).
13 C NMR (75 MHz, CDCl3 ): δ = 45.3 (CH2 ), 49.4 (CH2 ), 53.4 (CH2 ), 101.9 (CH2 ), 108.2 (CH), 112.8 (CH), 112.9 (C), 120.5 (C), 127.0 (2 CH), 127.7 (CH), 128.1 (2 CH), 128.4 (2 CH), 129.2 (C), 139.7 (C), 146.5 (C), 148.0 (C).
MS (ESI): m /z = 400, 402 ([M + H+ ] for 79 Br and 81 Br), 422, 424 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C19 H18 BrN3 O2 : C, 57.01; H, 4.53; N, 10.50. Found: C, 57.21; H, 4.50; N, 10.40.
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(phenylaminomethyl)-1H -imidazole (4j)
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(phenylaminomethyl)-1H -imidazole (4j)
Yield: 0.26 g (71%); white solid; mp 136–138 °C; Rf
= 0.75 (PE–EtOAc, 3:7).
IR (KBr): 1605, 1504, 1473, 1414, 1321, 1234, 1107, 1031, 926, 850, 751, 697, 515 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 4.30 (s, 2 H), 5.13 (s, 2 H), 5.95 (s, 2 H), 6.20 (s, 1 H), 6.67 (d, J = 7.8 Hz, 2 H), 6.74 (t, J = 6.9 Hz, 1 H), 6.88 (s, 1 H), 7.05 (d, J = 8.7 Hz, 2 H), 7.18 (t, J = 7.5 Hz, 2 H).
13 C NMR (75 MHz, CDCl3 ): δ = 41.1 (CH2 ), 49.5 (CH2 ), 101.9 (CH2 ), 108.0 (CH), 112.8 (CH), 112.9 (C), 113.1 (2 CH), 118.0 (CH), 120.8 (CH), 127.8 (CH), 128.4 (C), 129.1 (2 CH), 145.1 (C), 147.4 (C), 147.9 (C), 148.1 (C).
MS (ESI): m /z = 386, 388 ([M + H+ ] for 79 Br and 81 Br), 408, 410 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C18 H16 BrN3 O2 : C, 55.97; H, 4.18; N, 10.88. Found: C, 55.77; H, 4.13; N, 10.98.
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(4-methoxyphenylaminomethyl)-1H -imidazole (4k)
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(4-methoxyphenylaminomethyl)-1H -imidazole (4k)
Yield: 0.27 g (75%); brownish sticky mass; Rf
= 0.61 (PE–EtOAc, 3:7).
IR (neat): 2919, 2842, 1622, 1510, 1480, 1240, 1115, 1037, 930, 825, 754 cm–1 .
1 H NMR (600 MHz, CDCl3 ): δ = 3.74 (s, 3 H), 4.29 (s, 2 H), 5.15 (s, 2 H), 5.96 (s, 2 H), 6.19 (s, 1 H), 6.63 (d, J = 9.0 Hz, 2 H), 6.76 (d, J = 9.0 Hz, 2 H), 6.87 (s, 1 H), 7.05 (d, J = 9.0 Hz, 2 H).
13 C NMR (150 MHz, CDCl3 ): δ = 42.1 (CH2 ), 49.6 (CH2 ), 55.7 (OCH3 ), 102.0 (CH2 ), 108.2 (CH), 112.8 (CH), 112.9 (C), 114.7 (4 CH), 120.7 (CH), 127.6 (CH), 128.4 (C) 141.6 (C), 145.5 (C), 148.0 (C), 148.2 (C), 152.6 (C).
MS (ESI): m /z = 416, 417 ([M + H+ ] for 79 Br and 81 Br), 438, 440 ([M + Na+ ] for 79 Br and 81 Br).
Anal. Calcd for C19 H18 BrN3 O3 : C, 54.82; H, 4.36; N, 10.09. Found: C, 54.72; H, 4.40; N, 10.19.
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(3,4-methylenedioxybenzylaminomethyl)-1H -imidazole (4l)
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(3,4-methylenedioxybenzylaminomethyl)-1H -imidazole (4l)
Yield: 0.28 g (73%); light brown solid; mp 138–140 °C; Rf
= 0.30 (PE–EtOAc, 3:7).
IR (KBr): 3250, 2960, 2899, 1680, 1500, 1340, 920, 840 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.70 (s, 2 H), 3.80 (s, 2 H), 5.15 (s, 2 H), 5.92 (s, 2 H), 5.95 (s, 2 H), 6.24 (s, 1 H), 6.72–6.85 (m, 4 H), 7.01 (d like, 2 H).
13 C NMR (75 MHz, CDCl3 ): δ = 45.0 (CH2 ), 49.4 (CH2 ), 53.2 (CH2 ), 100.8 (CH2 ), 101.9 (CH2 ), 107.9 (CH), 108.1 (CH), 108.6 (CH), 112.7 (CH), 112.8 (C), 120.5 (CH), 121.2 (CH), 127.7 (CH), 129.2 (C), 129.9 (C), 133.6 (C), 146.5 (C), 147.6 (C), 147.9 (C), 148.0 (C).
MS (ESI): m /z = 444, 446 ([M + H+ ] for 79 Br and 81 Br).
Anal. Calcd for C20 H18 BrN3 O4 : C, 54.07; H, 4.08; N, 9.46. Found: C, 54.29; H, 4.03; N, 9.56.
4,10-Dihydro-5H -imidazo[2,1-c ][1,4]benzodiazepines 5a–l; General Procedure
4,10-Dihydro-5H -imidazo[2,1-c ][1,4]benzodiazepines 5a–l; General Procedure
To a stirred solution of 4a –l (0.92–1.63 mmol, 1 equiv) in anhyd toluene (15 mL) were added t- BuOK (1.84–3.26 mmol, 2 equiv), (±)-BINAP (10 mol%), and Pd2 (dba)3 (10 mol%, Pd: 20 mol%). The reaction mixture was refluxed for 14–18 h under N2 atmosphere. After completion of the reaction (monitored by TLC, eluent: EtOAc), toluene was evaporated under vacuum, and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with H2 O (3 × 20 mL), followed by brine (30 mL), dried (Na2 SO4 ), filtered, and the solvent was evaporated under vacuum. The crude mass was purified by column chromatography over neutral alumina to afford the desired compounds 5a –l .
4,10-Dihydro-5H -phenylimidazo[2,1-c ][1,4]benzodiazepine (5a)
4,10-Dihydro-5H -phenylimidazo[2,1-c ][1,4]benzodiazepine (5a)
Yield: 0.21 g (73%); brownish sticky mass; Rf
= 0.51 (PE–EtOAc, 3:7).
IR (neat): 1664, 1596, 1494, 1453, 1304, 1248, 1158, 1123, 1076, 748, 696 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 4.87 (s, 2 H), 4.95 (s, 2 H), 6.77 (d, J = 8.1 Hz, 2 H), 6.81–6.86 (m, 2 H), 6.95 (d, J = 0.9 Hz, 1 H), 7.16–7.22 (m, 2 H), 7.25–7.32 (m, 2 H), 7.35–7.42 (m, 2 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.4 (CH2 ), 49.5 (CH2 ), 115.0 (2 CH), 119.5 (CH), 120.0 (CH), 127.0 (CH), 127.1 (CH), 129.0 (CH), 129.2 (2 CH), 129.5 (CH), 130.5 (CH), 135.1 (C), 144.2 (C), 147.1 (C), 147.8 (C).
MS (ESI): m /z = 262 [M + H]+ .
Anal. Calcd for C17 H15 N3 : C, 78.13; H, 5.79; N, 16.08. Found: C, 78.33; H, 5.75; N, 16.20.
4,10-Dihydro-5H -isopropylimidazo[2,1-c ][1,4]benzodiazepine (5b)
4,10-Dihydro-5H -isopropylimidazo[2,1-c ][1,4]benzodiazepine (5b)
Yield: 0.25 g (68%); brownish sticky mass; Rf
= 0.32 (EtOAc).
IR (neat): 2969, 2928, 1675, 1598, 1491, 1456, 1375, 1315, 1275, 1170, 1122, 1051, 1010, 929, 742, 666 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 1.30 (d, J = 6.6 Hz, 6 H), 3.72–3.81 (m, 1 H), 4.33 (s, 2 H), 5.01 (s, 2 H), 6.84 (s, 1 H), 6.92 (s, 1 H), 7.00 (t, J = 6.6 Hz, 1 H), 7.22–7.36 (m, 3 H).
13 C NMR (75 MHz, CDCl3 ): δ = 21.0 (2 CH3 ), 47.2 (CH2 ), 49.8 (CH2 ), 52.2 (CH), 119.0 (CH), 121.2 (CH), 122.7 (CH), 126.5 (CH), 128.5 (CH), 129.6 (CH), 131.6 (C), 144.6 (C), 151.4 (C).
MS (ESI): m /z = 228 [M + H]+ .
Anal. Calcd for C14 H17 N3 : C, 73.98; H, 7.54; N, 18.49. Found: C, 73.76; H, 7.50; N, 18.60.
4,10-Dihydro-5H -(3,4-methylenedioxybenzyl)imidazo[2,1-c ][1,4]benzodiazepine (5c)
4,10-Dihydro-5H -(3,4-methylenedioxybenzyl)imidazo[2,1-c ][1,4]benzodiazepine (5c)
Yield: 0.23 g (65%); pale yellowish sticky mass; Rf
= 0.35 (EtOAc).
IR (neat): 1654, 1601, 1494, 1445,1247, 1124, 1038, 930, 46 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 4.25 (s, 2 H), 4.26 (s, 2 H), 5.14 (s, 2 H), 5.93 (s, 2 H), 6.75 (d, J = 7.8 Hz, 1 H), 6.87 (d, J = 14.7 Hz, 4 H), 7.05 (t, J = 7.3 Hz, 1 H), 7.21 (s, 1 H), 7.27 (s, 1 H), 7.36 (t, J = 7.5 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.5 (CH2 ), 52.9 (CH2 ), 58.3 (CH2 ), 100.9 (CH2 ), 108.1 (CH), 108.6 (CH), 119.2 (CH), 120.0 (CH), 121.8 (CH), 123.3 (CH), 126.9 (CH), 128.4 (CH), 129.8 (CH), 131.5 (C), 131.8 (C), 143.8 (C), 146.9 (C), 147.9 (C), 150.8 (C).
MS (ESI): m /z = 320 [M + H]+ , 342 [M + Na]+ .
Anal. Calcd for C19 H17 N3 O2 : C, 71.46; H, 5.37; N, 13.16. Found: C, 71.66; H, 5.41; N, 13.04.
4,10-Dihydro-5H -8-methoxy-5-isopropylimidazo[2,1-c ][1,4]benzodiazepine (5d)
4,10-Dihydro-5H -8-methoxy-5-isopropylimidazo[2,1-c ][1,4]benzodiazepine (5d)
Yield: 0.27 g (71%); yellowish sticky mass; Rf
= 0.27 (EtOAc).
IR (neat): 2966, 1644, 1607, 1499, 1428, 1267, 1166, 1043, 923, 817, 750 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 1.26 (d, J = 6.3 Hz, 6 H), 3.63–3.67 (m, 1 H), 3.77 (s, 3 H), 4.28 (s, 2 H), 4.98 (s, 2 H), 6.79–6.82 (m, 2 H), 6.86 (dd, J = 3.0, 8.7 Hz, 1 H), 6.91 (s, 1 H), 7.20 (d, J = 8.7 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 21.2 (2 CH3 ), 48.5 (CH2 ), 49.2 (CH2 ), 52.1 (CH), 55.3 (OCH3 ), 113.9 (CH), 114.1 (CH), 119.1 (CH), 122.9 (CH), 126.7 (CH), 133.9 (C), 144.3 (C), 144.8 (C), 155.2 (C).
MS (ESI): m /z = 258 [M + H]+ .
Anal. Calcd for C15 H19 N3 O: C, 70.01; H, 7.44; N, 16.33. Found: C, 69.81; H, 7.40; N, 16.45.
4,10-Dihydro-5H -8-methoxy-5-phenylimidazo[2,1-c ][1,4]benzodiazepine (5e)
4,10-Dihydro-5H -8-methoxy-5-phenylimidazo[2,1-c ][1,4]benzodiazepine (5e)
Yield: 0.22 g (68%); dark yellow solid; mp 98–100 °C; Rf
= 0.35 (PE–EtOAc, 3:7).
IR (KBr): 1588, 1496, 1429, 1365, 1304, 1273, 1237, 1211, 1153, 1081, 1036, 882, 841, 748, 695, 566 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.84 (s, 3 H), 4.77 (s, 2 H), 4.93 (s, 2 H), 6.72 (d, J = 8.1 Hz, 2 H), 6.79 (d, J = 9.6 Hz, 2 H), 6.94 (d, J = 8.4 Hz, 3 H), 7.17 (t, J = 7.6 Hz, 2 H), 7.28 (t like, J = 7.3 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.3 (CH2 ), 49.6 (CH2 ), 55.5 (OCH3 ), 114.0 (2 CH), 114.9 (CH), 115.3 (CH), 118.8 (CH), 120.1 (CH), 127.1 (CH), 129.2 (CH), 130.4 (CH), 136.4 (C), 139.3 (C), 144.4 (C), 147.9 (C), 158.3 (C).
MS (EI): m /z = 291.
Anal. Calcd for C18 H17 N3 O: C, 74.20; H, 5.88; N, 14.42. Found: C, 74.40; H, 5.92; N, 14.32.
4,10-Dihydro-5H -8-methoxy-5-benzylimidazo[2,1-c ][1,4]benzodiazepine (5f)
4,10-Dihydro-5H -8-methoxy-5-benzylimidazo[2,1-c ][1,4]benzodiazepine (5f)
Yield: 0.31 g (76%); pale brown solid; mp 88–90 °C; Rf
= 0.26 (EtOAc).
IR (KBr): 2922, 2808, 1501, 1450, 1375, 1255, 1206, 1149, 1046, 821, 700 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.77 (s, 3 H), 4.19 (s, 2 H), 4.31 (s, 2 H), 5.12 (s, 2 H), 6.86 (d like, 4 H), 7.17 (d, J = 8.7 Hz, 1 H), 7.23–7.33 (m, 3 H), 7.40 (d, J = 6.9 Hz, 2 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.4 (CH2 ), 53.7 (CH2 ), 55.4 (OCH3 ), 58.6 (CH2 ), 114.1 (CH), 114.2 (CH), 119.2 (CH), 120.9 (CH), 126.8 (CH), 127.3 (CH), 128.3 (2 CH), 128.4 (2 CH), 133.3 (C), 138.0 (C), 143.8 (C), 143.9 (C), 155.5 (C).
MS (ESI): m /z = 306 [M + H]+ , 328 [M + Na]+ .
Anal. Calcd for C19 H19 N3 O: C, 74.73; H, 6.27; N, 13.76. Found: C, 74.53; H, 6.23; N, 13.86.
4,10-Dihydro-5H -8-methoxy-5-(3,4-methylenedioxybenzyl)imidazo[2,1-c ][1,4]benzodiazepine (5g)
4,10-Dihydro-5H -8-methoxy-5-(3,4-methylenedioxybenzyl)imidazo[2,1-c ][1,4]benzodiazepine (5g)
Yield: 0.26 g (72%); pale yellow solid; mp 146–148 °C; Rf
= 0.36 (EtOAc).
IR (KBr): 1496, 1439, 1375, 1245, 1201, 1125, 1033, 925, 866, 813, 732, 640, 540 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.78 (s, 3 H), 4.16 (s, 2 H), 4.20 (s, 2 H), 5.10 (s, 2 H), 5.93 (s, 2 H), 6.74 (d, J = 7.8 Hz, 1 H), 6.84–6.90 (m, 6 H), 7.15 (d, J = 8.4 Hz, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.4 (CH2 ), 53.5 (CH2 ), 55.4 (OCH3 ), 58.3 (CH2 ), 100.8 (CH2 ), 107.9 (CH), 108.5 (CH), 114.1 (CH), 114.2 (CH), 119.2 (CH), 120.9 (CH), 121.7 (CH), 126.8 (CH), 131.9 (C), 133.3 (C), 143.7 (C), 143.8 (C), 146.8 (C), 147.8 (C), 155.5 (C).
MS (ESI): m /z = 350 [M + H]+ , 372 [M + Na]+ .
Anal. Calcd for C20 H19 N3 O3 : C, 68.75; H, 5.48; N, 12.03. Found: C, 68.97; H, 5.52; N, 11.91.
4,10-Dihydro-5H -7,8-methylenedioxy-5-isopropylimidazo[2,1-c ][1,4]benzodiazepine (5h)
4,10-Dihydro-5H -7,8-methylenedioxy-5-isopropylimidazo[2,1-c ][1,4]benzodiazepine (5h)
Yield: 0.31 g (70%); yellowish sticky mass; Rf
= 0.30 (EtOAc).
IR (neat): 2970, 2830, 1505, 1440, 1380, 1240, 1150, 1030, 940, 730 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 1.26 (d, J = 6.6 Hz, 6 H), 3.56–3.64 (m, 1 H), 4.27 (s, 2 H), 4.91 (s, 2 H), 5.93 (s, 2 H), 6.72 (s, 1 H), 6.82 (d, J = 9.0 Hz, 2 H), 6.91 (s, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 21.5 (2 CH3 ), 48.6 (CH2 ), 49.6 (CH2 ), 52.3 (CH), 101.3 (CH2 ), 103.7 (CH), 108.3 (CH), 119.1 (CH), 126.2 (C), 126.7 (CH), 143.2 (C), 144.6 (C), 145.8 (C), 148.3 (C).
MS (ESI): m /z = 272 [M + H]+ .
Anal. Calcd for C15 H17 N3 O2 : C, 66.40; H, 6.32; N, 15.49. Found: C, 66.18; H, 6.35; N, 15.60.
4,10-Dihydro-5H -7,8-methylenedioxy-5-benzylimidazo[2,1-c ][1,4]benzodiazepine (5i)
4,10-Dihydro-5H -7,8-methylenedioxy-5-benzylimidazo[2,1-c ][1,4]benzodiazepine (5i)
Yield: 0.34 g (75%); yellowish sticky mass; Rf
= 0.45 (EtOAc).
IR (neat): 1491, 1443, 1390, 1238, 1175, 1125, 1037, 932, 856, 750 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 4.19 (s, 2 H), 4.28 (s, 2 H), 5.05 (s, 2 H), 5.93 (s, 2 H), 6.75–6.88 (m, 4 H), 7.26–7.38 (m, 5 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.2 (CH2 ), 53.7 (CH2 ), 58.7 (CH2 ), 101.4 (CH2 ), 102.0 (CH), 108.3 (CH), 119.1 (CH), 125.5 (C), 126.6 (CH), 127.5 (CH), 128.4 (2 CH), 128.6 (2 CH), 137.8 (C), 143.3 (C), 143.7 (C), 145.2 (C), 148.4 (C).
MS (ESI): m /z = 320 [M + H]+ , 342 [M + Na]+ .
Anal. Calcd for C19 H17 N3 O2 : C, 71.46; H, 5.37; N, 13.16. Found: C, 71.66; H, 5.42; N, 13.06.
4,10-Dihydro-5H -7,8-methylenedioxy-5-phenylimidazo[2,1-c ][1,4]benzodiazepine (5j)
4,10-Dihydro-5H -7,8-methylenedioxy-5-phenylimidazo[2,1-c ][1,4]benzodiazepine (5j)
Yield: 0.28 g (74%); pale yellow solid; mp 140–142 °C; Rf
= 0.42 (PE–EtOAc, 3:7).
IR (KBr): 1597, 1492, 1382, 1299, 1227, 1192, 1120, 1038, 929, 864, 757, 691 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 4.72 (s, 2 H), 4.91 (s, 2 H), 6.02 (s, 2H), 6.74–6.84 (m, 5 H), 6.95 (s, 2 H), 7.19 (t, J = 7.3 Hz, 2 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.1 (2 CH2 ), 101.8 (CH2 ), 109.1 (CH), 109.9 (CH), 114.2 (CH), 119.1 (CH), 119.9 (CH), 127.0 (CH), 128.7 (C), 129.2 (CH), 140.7 (C), 144.1 (C), 146.2 (C), 147.6 (C), 148.7 (C).
MS (ESI): m /z = 306 [M + H]+ .
Anal. Calcd for C18 H15 N3 O2 : C, 70.81; H, 4.95; N, 13.76. Found: C, 70.61; H, 4.90; N, 13.88.
4,10-Dihydro-5H -7,8-methylenedioxy-5-(4-methoxyphenyl)imidazo[2,1-c ][1,4]benzodiazepine (5k)
4,10-Dihydro-5H -7,8-methylenedioxy-5-(4-methoxyphenyl)imidazo[2,1-c ][1,4]benzodiazepine (5k)
Yield: 0.27 g (67%); yellowish sticky mass; Rf
= 0.48 (EtOAc).
IR (neat): 1729, 1619, 1506, 1384, 1241, 1123, 1036, 931, 825, 755, 666 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 3.75 (s, 3 H), 4.80 (s, 2 H), 4.90 (s, 2 H), 5.98 (s, 2 H), 6.70–6.80 (m, 7 H), 6.97 (s, 1 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.3 (CH2 ), 50.0 (CH2 ), 55.6 (OCH3 ), 101.7 (CH2 ), 108.8 (CH), 109.2 (CH), 114.6 (2 CH), 117.2 (2 CH), 119.8 (CH), 126.5 (CH), 128.0 (C), 142.1 (C), 142.2 (C), 144.0 (C), 145.6 (C), 148.7 (C), 153.6 (C).
MS (ESI): m /z = 336 [M + H]+ .
Anal. Calcd for C19 H17 N3 O3 : C, 68.05; H, 5.11; N, 12.53. Found: C, 68.27; H, 5.08; N, 12.43.
4,10-Dihydro-5H -7,8-methylenedioxy-5-(3,4-methylenedioxybenzyl)imidazo[2,1-c ][1,4]benzodiazepine (5l)
4,10-Dihydro-5H -7,8-methylenedioxy-5-(3,4-methylenedioxybenzyl)imidazo[2,1-c ][1,4]benzodiazepine (5l)
Yield: 0.21 g (63%); yellow solid; mp 182–184 °C; Rf
= 0.31 (EtOAc).
IR (KBr): 2895, 2834, 1615, 1490, 1442, 1384, 1246, 1165, 1116, 1036, 930, 861, 729, 675 cm–1 .
1 H NMR (300 MHz, CDCl3 ): δ = 4.16 (s, 4 H), 5.03 (s, 2 H), 5.93 (s, 4 H), 6.75–6.88 (m, 7 H).
13 C NMR (75 MHz, CDCl3 ): δ = 49.1 (CH2 ), 53.5 (CH2 ), 58.4 (CH2 ), 100.9 (CH2 ), 101.3 (CH2 ), 101.9 (CH), 108.0 (CH), 108.3 (CH), 108.6 (CH), 119.1 (CH), 121.8 (CH), 125.5 (C), 126.8 (CH), 131.6 (C), 143.3 (C), 143.6 (C), 145.2 (C), 146.9 (C), 147.9 (C), 148.3 (C).
MS (ESI): m /z = 364 [M + H]+ .
Anal. Calcd for C19 H15 N3 O4 : C, 65.32; H, 4.33; N, 12.03. Found: C, 65.52; H, 4.30; N, 12.15.
