Efficient synthesis of imidazole-fused benzodiazepines using palladium-catalyzed intramolecular C-N bond formation reaction

Article abstract of DOI:10.1055/s-0032-1316828

An efficient three-step synthetic route to imidazole-fused benzodiazepines from imidazole-2-carbaldehyde is described. Application of intramolecular Buchwald-Hartwig cycloamination reaction in the final step is shown to be a convenient method for the synt

Full text of DOI:10.1055/s-0032-1316828

PAPER
▌85
paper
Efficient Synthesis of Imidazole-Fused Benzodiazepines Using Palladium-
Catalyzed Intramolecular C–N Bond Formation Reaction
Synthesis of Imidazole-Fused Benzodiazepines
Sudipta Mitra, Heena Darira, Partha Chattopadhyay*
Department of Chemistry, CSIR-Indian Institute of Chemical Biology, 4, Raja S. C. Mullick Road, Kolkata 700 032, India
Fax +91(33)24735197; E-mail: partha@iicb.res.in
Received: 07.11.2012; Accepted after revision: 26.11.2012
employing palladium-catalyzed intramolecular C–N bond
forming cyclization reaction.10–12 The copper- or palladi-
um-catalyzed intramolecular Buchwald–Hartwig aryl am-
ination reaction13 appeared particularly suitable for this
Abstract: An efficient three-step synthetic route to imidazole-
fused benzodiazepines from imidazole-2-carbaldehyde is de-
scribed. Application of intramolecular Buchwald–Hartwig cy-
cloamination reaction in the final step is shown to be a convenient
method for the synthesis of fused seven-membered diazacycles. The purpose. In continuation of these efforts, we became inter-
reactions proceeded smoothly with both aliphatic and aromatic
amines.
ested in applying this method in the synthesis of imidaz-
ole-fused benzodiazepines. To the best of our knowledge
Key words: palladium, catalysis, amination, cyclization, benzo-
diazepine
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 pres-
ence of anhydrous potassium carbonate in anhydrous
DMF at room temperature (Table 1).
There is a growing interest over the past few years in the
synthesis of nitrogen containing heterocycle-fused ben-
zazepines and benzodiazepines due to their crucial role as
main structural motif in many pharmacologically active
molecules. The clinical importance and commercial suc-
cess 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 me-
dicinal chemists to recognize them as privileged struc-
tures. Particularly, imidazobenzodiazepines1 and related
ligands interact selectively for a neuro-inhibitory, post-
synaptic GABAA receptor1f,g with high affinity. Accord-
ingly, they may act as agonists, partial agonists,1b and
antagonists. The therapeutic applications of benzodiaze-
pines 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 bio-
logical activities while others like telenzepine act as anti-
secretory 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 4859). Tetrahydro-
Table 1 Synthesis of N-Benzylated Imidazo-2-carbaldehydesa
N
Br
CHO
N
K2CO3, DMF
Br
N
+
CHO
R1
R2
R1
N
H
Br
R2
1
2a–c
3a–c
Entry R1
R2
Benzyl
bromide
Product Time
(h)
Yield
(%)b
1
2
3
H
H
2a
2b
2c
3a
3b
3c
16
17
16
95
92
94
OCH2O
OMe
H
a Reaction conditions: imidazole-2-carbaldehyde (1 equiv), 2-bromo-
benzyl bromide (1.2 equiv), K2CO3 (2 equiv), anhyd DMF (5
mL/mmol), r.t., 16–17 h.
imidazo[4,5,1-jk][l,4]benzodiazepin-2(1H)-thione,
as-
signed the acronym TIBO,1d,e is the first member of a
series of potent selective and noncompetitive inhibitors of
HIV-l reverse transcriptase.
b Isolated yield.
Despite the immense importance of imidazobenzodiaze-
pines, only a few groups1 have reported their synthesis.
These methods either require lengthy sequence of reac-
tions or harsh reaction conditions. For quite some time,
we have been engaged in the synthesis of several benzan-
nulated and dibenzannulated medium ring heterocycles
Imine formation with aliphatic and aromatic amines and
subsequent NaBH4 reduction in ethanol afforded the de-
sired amine precursors 4a–l in good yields (Table 2).
The amine precursor 4a was then used as model substrate
for the optimization of intramolecular cycloamination re-
action. Initially with the conditions used by Buchwald13a
(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
SYNTHESIS 2013, 45, 0085–0092
Advanced online publication: 06.12.2012
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0
3
9
-
7
8
8
1
1
4
3
7
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2
1
0
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DOI: 10.1055/s-0032-1316828; Art ID: SS-2012-N0903-OP
© Georg Thieme Verlag Stuttgart · New York

86
S. Mitra et al.
PAPER
Table 2 Synthesis of Imidazo N-Alkylated Amines 4a–la
Table 3 Optimization of the Cycloamination Reaction of 4a
HN R3
N
Entry Reaction conditions
Pd
Yield
(mol%)a (%)b
N
R3NH2
NaBH4
(1)
(2)
3a–c
c
1
2
3
4
Pd(PPh3)4, K2CO3, toluene, reflux, 16 h
10
10
10
10
–
–
–
R1
R2
Br
c
c
Pd2(dba)3, K2CO3, DMF, 120 °C, 17 h
Pd(OAc)2, K2CO3, DMF, 120 °C, 16 h
4a–l
Entry R1
R2
R3
Product Yield (%)b
Pd(OAc)2, (o-tol)3P, t-BuOK, toluene,
20
22
30
58
43
73d
70
67
35
43
35
30
56
reflux, 18 h
1
2
H
H
H
H
Ph
4a
4b
72
70
5
Pd(OAc)2, DPPF, K2CO3, toluene, reflux, 10
17 h
i-Pr
CH2
O
O
6
Pd(OAc)2, DPPF, t-BuOK, toluene, reflux, 10
18 h
3
H
H
4c
73
7
Pd2(dba)3, (±)-BINAP, t-BuOK, toluene, 10
reflux, 16 h
4
5
6
OMe
OMe
OMe
H
H
H
i-Pr
Ph
4d
4e
4f
77
75
74
8
Pd2(dba)3, (±)-BINAP, t-BuOK, toluene,
reflux, 17 h
6
Bn
CH2
O
O
9
Pd2(dba)3, (±)-BINAP, t-BuOK, toluene, 20
reflux, 16 h
7
OMe
H
4g
71
10
11
12
13
14
15
16
Pd2(dba)3, (±)-BINAP, t-BuOK, toluene, 30
reflux, 17 h
8
OCH2O
OCH2O
OCH2O
OCH2O
i-Pr
Bn
Ph
4h
4i
69
68
71
75
9
Pd2(dba)3, (±)-BINAP, t-BuOK, toluene, 40
reflux, 17 h
10
11
4j
Pd2(dba)3, (±)-BINAP, t-BuOK, DME,
reflux, 17 h
20
4-MeOC6H4
4k
CH2
O
O
Pd2(dba)3, (±)-BINAP, t-BuOK, 1,4-diox- 20
ane, reflux, 17 h
12
OCH2O
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.
Pd2(dba)3, (±)-BINAP, Cs2CO3, toluene, 20
reflux, 17 h
Pd2(dba)3, (o-tol)3P, t-BuOK, toluene,
reflux, 18 h
20
Pd2(dba)3, DPPF, t-BuOK, toluene, reflux, 20
18 h
product in the absence of a ligand (entries 2, 3). The reac-
tion 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 Cs2CO3, using other monodentate (tri-o-tol-
ylphosphine) or bidentate (DPPF) ligands and employing
different solvents (DME or 1,4-dioxane) proved less sat-
isfactory (entries 12–16).
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.
t-BuOK (2 equiv) as base, and toluene as solvent at reflux
to furnish 5a. Employing these conditions, other sub-
strates 4b–l were treated to afford 5b–l in 63–76% yield
(Table 4). A probable mechanism13b,c,14 of intramolecular
aryl amination for the synthesis of benzodiazepines is out-
lined in Scheme 1.
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′-dimethylethylene-
diamine, 10 mol%] and solvents like DMF (at 120 °C) or
toluene (reflux) also did not lead to the desired cyclic
product.
The assigned structures of 5b–l were determined on the
basis of their IR, H NMR, 13C NMR, mass spectra, and
1
elemental analysis. The 1H NMR spectrum of 5a consist-
ed of two singlets at δ = 4.95 and 4.86 for the benzylic
methylene protons and methylene protons attached to ni-
The optimized protocol for the palladium-catalyzed intra-
molecular aryl amination of 4a thus employs Pd2(dba)3
(10 mol%) as catalyst, (±)-BINAP (10 mol%) as ligand,
Synthesis 2013, 45, 85–92
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Imidazole-Fused Benzodiazepines
87
O
PPh2
PPh2
+
Pd
Pd
Pd2(dba)3
BINAP
Ph2
P
Pd(dba)
P
Ph2
R2
R1
R1
R2
N
N
Br
Ph2
P
N
N
N
R3
H
Pd(0)
N
R3
P
Ph2
reductive elimination
oxidative addition
R2
R1
R2
R1
Ph2
P
Ph2
P
(II) Pd
Pd (II)
Br
P
N
P
N
N
Ph2
H
R3
N
N
R3
N
t-BuOk
R2
R1
dehydrohalogenation
amine coordination
Ph2
P
(II) Pd
KBr + t-BuOH
Br
P
N
Ph2
H
N
R3
N
Scheme 1 Proposed mechanism for the synthesis of imidazobenzodiazepine
trogen of the aniline moiety, along with signals for eleven of benzodiazepines is highly desirable as this may lead to
aromatic protons (δ = 6.77–7.42). The 13C NMR spectrum a promising antidepressant drug. This finding opens up
showed signals assignable to 17 carbons in agreement the possibility of obtaining synthetically challenging
with the structure. The mass spectrum displayed a peak at imidazole-fused seven-membered benzoheterocycles.
m/z 262 for the [M + H]+ ion. The features of the 1H and
13C NMR spectra of compounds 5b–l were broadly simi-
lar 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.
Reactions at r.t. imply a temperature of 25 °C. Required reagents
were obtained from commercial sources and used without purifica-
tion. The solvents used were of technical grade, and freshly distilled
prior to use. All melting points were obtained on a laboratory melt-
ing point bath and are uncorrected. 1H (300 MHz, 600 MHz) and 13
C
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.
(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 stat-
ed 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.
In summary, we have established a straightforward effi-
cient 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
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 85–92

88
S. Mitra et al.
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Table 4 Synthesis of Imidazobenzodiazepines 5b–la
1-(2-Bromo-4,5-methylenedioxybenzyl)-1H-imidazole-2-carb-
aldehyde (3b)
N
Yield: 1.47 g (92%); white solid; mp 84–86 °C; Rf = 0.65 (PE–
EtOAc, 3:7).
Pd2(dba)3 (10 mol%; 20 mol% in Pd)
N
R3
N
4b–l
(
)-BINAP (10 mol%)
IR (KBr): 2908, 2842, 1681, 1626, 1478, 1412, 1249, 1110, 1036,
929, 858, 763, 681, 521 cm–1.
1H NMR (300 MHz, CDCl3): δ = 5.64 (s, 2 H), 5.99 (s, 2 H), 6.54
t-BuOK (2 equiv)
toluene, reflux
14–18 h
R2
5b–l
R1
(s, 1 H), 7.05 (s, 1 H), 7.20 (s, 1 H), 7.31 (s, 1 H), 9.87 (s, 1 H).
Entry
Substrate
Product
Time (h)
Yield (%)a
13C 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).
1
4b
4c
4d
4e
4f
5b
5c
5d
5e
5f
18
17
16
18
15
14
16
18
15
17
16
68
65
71
68
76
72
70
75
74
67
63
MS (ESI): m/z = 309, 311 ([M + H+] for 79Br and 81Br), 331, 333
2
([M + Na+] for 79Br and 81Br).
3
Anal. Calcd for C12H9BrN2O3: C, 46.63; H, 2.93; N, 9.06. Found: C,
46.85; H, 2.88; N, 9.18.
4
1-(2-Bromo-5-methoxybenzyl)-1H-imidazole-2-carbaldehyde
5
(3c)
Yield: 1.48 g (94%); white solid; mp 78–80 °C; Rf = 0.65 (PE–
6
4g
4h
4i
5g
5h
5i
EtOAc, 2:3).
7
IR (KBr): 2863, 1683, 1569, 1476, 1412, 1339, 1259, 1159, 1044,
1018, 919, 879, 805, 745, 598 cm–1.
1H 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).
13C 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).
8
9
4j
5j
10
11
4k
4l
5k
5l
a Isolated yield.
MS (ESI): m/z = 295, 297 ([M + H+] for 79Br and 81Br).
Anal. Calcd for C12H11BrN2O2: 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)-1H-imidazole-2-carbaldehydes 3a–c; Gen-
eral 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 H2O (2 × 20 mL), dried (Na2SO4), fil-
tered, and concentrated. The crude residue was purified by column
chromatography over neutral alumina (EtOAc–PE, 3:1) to afford
the compounds 4a–l.
To a stirred solution of imidazole-2-carbaldehyde (1; 0.5 g, 5.2
mmol) in anhyd DMF (20 mL) was added K2CO3 (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 H2O (70 mL), and ex-
tracted with EtOAc (4 × 30 mL). The combined organic layers were
washed with H2O (40 mL), followed by brine (30 mL), dried
(Na2SO4), filtered, and the solvent was evaporated in vacuo. The
crude product was purified via column chromatography over neu-
tral alumina (EtOAc–PE, 1:9) to give 3a–c.
1-(2-Bromobenzyl)-2-(phenylaminomethyl)-1H-imidazole (4a)
Yield: 0.22 g (72%); brownish sticky mass; Rf = 0.38 (PE–EtOAc,
1:1).
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 (neat): 2923, 1685, 1601, 1501, 1436, 1315, 1262, 1216, 1105,
1026, 752 cm–1.
1H 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).
13C 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).
IR (KBr): 2846, 1678, 1465, 1411, 1337, 1294, 1244, 1155, 1024,
774, 664 cm–1.
1H 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).
13C 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 79Br and 81Br), 287, 289
MS (ESI): m/z = 342, 344 ([M + H+] for 79Br and 81Br).
([M + Na+] for 79Br and 81Br).
Anal. Calcd for C17H16BrN3: C, 59.66; H, 4.71; N, 12.28. Found: C,
59.86; H, 4.75; N, 12.18.
Anal. Calcd for C11H9BrN2O: C, 49.84; H, 3.42; N, 10.57. Found:
C, 49.64; H, 3.47; N, 10.67.
Synthesis 2013, 45, 85–92
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Synthesis of Imidazole-Fused Benzodiazepines
89
1-(2-Bromobenzyl)-2-(isopropylaminomethyl)-1H-imidazole
MS (ESI): m/z = 372, 374 ([M + H+] for 79Br and 81Br), 394, 396
([M + Na+] for 79Br and 81Br).
(4b)
Yield: 0.35 g (70%); yellowish sticky mass; Rf = 0.27 (PE–EtOAc,
3:7).
Anal. Calcd for C18H18BrN3O: C, 58.08; H, 4.87; N, 11.29. Found:
C, 58.28; H, 4.90; N, 11.40.
IR (neat): 2964, 2866, 1685, 1643, 1469, 1441, 1346, 1279, 1165,
1117, 1027, 747, 665 cm–1.
1H 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).
1-(2-Bromo-5-methoxybenzyl)-2-(benzylaminomethyl)-1H-im-
idazole (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.
1H 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).
13C 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).
13C 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 79Br and 81Br).
Anal. Calcd for C14H18BrN3: 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- methylenedioxybenzylaminometh-
MS (ESI): m/z = 386, 388 ([M + H+] for 79Br and 81Br), 408, 410
yl)-1H-imidazole (4c)
([M + Na+] for 79Br and 81Br).
Yield: 0.25 g (73%); yellowish sticky mass; Rf = 0.30 (PE–EtOAc,
3:7).
Anal. Calcd for C19H20BrN3O: C, 59.08; H, 5.22; N, 10.88. Found:
C, 59.28; H, 5.19; N, 10.98.
IR (neat): 2956, 2860, 1409, 1305, 1161, 1011, 846, 510 cm–1.
1H 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).
13C 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).
1-(2-Bromo-5-methoxybenzyl)-2-(3,4-methylenedioxybenzyl-
aminomethyl)-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.
1H 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).
13C 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 = 400, 402 ([M + H+] for 79Br and 81Br).
Anal. Calcd for C19H18BrN3O2: 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)
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.
1H 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).
13C 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 = 430, 432 ([M + H+] for 79Br and 81Br), 452, 454
([M + Na+] for 79Br and 81Br).
Anal. Calcd for C20H20BrN3O3: 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-(isopropylamino-
methyl)-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.
1H 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).
MS (ESI): m/z = 338, 340 ([M + H+] for 79Br and 81Br), 360, 362
([M + Na+] for 79Br and 81Br).
Anal. Calcd for C15H20BrN3O: C, 53.26; H, 5.96; N, 12.42. Found:
C, 53.48; H, 5.92; N, 12.56.
13C 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).
1-(2-Bromo-5-methoxybenzyl)-2-(phenylaminomethyl)-1H-im-
idazole (4e)
Yield: 0.33 g (75%); white solid; Rf = 0.58 (PE–EtOAc, 2:3).
MS (ESI): m/z = 352, 354 ([M + H+] for 79Br and 81Br).
IR (KBr): 2927, 2845, 1688, 1600, 1471, 1286, 1160, 1056, 1019,
924, 865, 810, 748 cm–1.
1H 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).
13C 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).
Anal. Calcd for C15H18BrN3O2: 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-(benzylaminometh-
yl)-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.
© Georg Thieme Verlag Stuttgart · New York
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S. Mitra et al.
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1H 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).
13C 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).
Anal. Calcd for C20H18BrN3O4: 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
To a stirred solution of 4a–l (0.92–1.63 mmol, 1 equiv) in anhyd tol-
uene (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 re-
action mixture was refluxed for 14–18 h under N2 atmosphere. After
completion of the reaction (monitored by TLC, eluent: EtOAc), tol-
uene was evaporated under vacuum, and the mixture was extracted
with EtOAc (3 × 20 mL). The combined organic layers were
washed with H2O (3 × 20 mL), followed by brine (30 mL), dried
(Na2SO4), filtered, and the solvent was evaporated under vacuum.
The crude mass was purified by column chromatography over neu-
tral alumina to afford the desired compounds 5a–l.
MS (ESI): m/z = 400, 402 ([M + H+] for 79Br and 81Br), 422, 424
([M + Na+] for 79Br and 81Br).
Anal. Calcd for C19H18BrN3O2: 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-(phenylaminometh-
yl)-1H-imidazole (4j)
Yield: 0.26 g (71%); white solid; mp 136–138 °C; Rf = 0.75 (PE–
EtOAc, 3:7).
4,10-Dihydro-5H-phenylimidazo[2,1-c][1,4]benzodiazepine
IR (KBr): 1605, 1504, 1473, 1414, 1321, 1234, 1107, 1031, 926,
850, 751, 697, 515 cm–1.
(5a)
Yield: 0.21 g (73%); brownish sticky mass; Rf = 0.51 (PE–EtOAc,
3:7).
1H 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).
IR (neat): 1664, 1596, 1494, 1453, 1304, 1248, 1158, 1123, 1076,
748, 696 cm–1.
13C 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).
1H 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).
13C 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 = 386, 388 ([M + H+] for 79Br and 81Br), 408, 410
([M + Na+] for 79Br and 81Br).
Anal. Calcd for C18H16BrN3O2: C, 55.97; H, 4.18; N, 10.88. Found:
C, 55.77; H, 4.13; N, 10.98.
MS (ESI): m/z = 262 [M + H]+.
Anal. Calcd for C17H15N3: C, 78.13; H, 5.79; N, 16.08. Found: C,
78.33; H, 5.75; N, 16.20.
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(4-methoxyphenyl-
aminomethyl)-1H-imidazole (4k)
Yield: 0.27 g (75%); brownish sticky mass; Rf = 0.61 (PE–EtOAc,
3:7).
4,10-Dihydro-5H-isopropylimidazo[2,1-c][1,4]benzodiazepine
(5b)
IR (neat): 2919, 2842, 1622, 1510, 1480, 1240, 1115, 1037, 930,
825, 754 cm–1.
1H 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).
13C 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).
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.
1H 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).
13C 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 = 416, 417 ([M + H+] for 79Br and 81Br), 438, 440
MS (ESI): m/z = 228 [M + H]+.
([M + Na+] for 79Br and 81Br).
Anal. Calcd for C14H17N3: C, 73.98; H, 7.54; N, 18.49. Found: C,
73.76; H, 7.50; N, 18.60.
Anal. Calcd for C19H18BrN3O3: C, 54.82; H, 4.36; N, 10.09. Found:
C, 54.72; H, 4.40; N, 10.19.
4,10-Dihydro-5H-(3,4-methylenedioxybenzyl)imidazo[2,1-
c][1,4]benzodiazepine (5c)
1-(2-Bromo-4,5-methylenedioxybenzyl)-2-(3,4-methylene-
dioxybenzylaminomethyl)-1H-imidazole (4l)
Yield: 0.28 g (73%); light brown solid; mp 138–140 °C; Rf = 0.30
(PE–EtOAc, 3:7).
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.
1H 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).
13C 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).
IR (KBr): 3250, 2960, 2899, 1680, 1500, 1340, 920, 840 cm–1.
1H 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).
13C 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 = 320 [M + H]+, 342 [M + Na]+.
MS (ESI): m/z = 444, 446 ([M + H+] for 79Br and 81Br).
Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C,
71.66; H, 5.41; N, 13.04.
Synthesis 2013, 45, 85–92
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of Imidazole-Fused Benzodiazepines
91
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).
(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]+.
IR (neat): 2966, 1644, 1607, 1499, 1428, 1267, 1166, 1043, 923,
817, 750 cm–1.
1H 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).
13C 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).
Anal. Calcd for C20H19N3O3: 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)
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.
1H 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).
13C 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 = 258 [M + H]+.
Anal. Calcd for C15H19N3O: 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]ben-
zodiazepine (5e)
Yield: 0.22 g (68%); dark yellow solid; mp 98–100 °C; Rf = 0.35
(PE–EtOAc, 3:7).
MS (ESI): m/z = 272 [M + H]+.
Anal. Calcd for C15H17N3O2: C, 66.40; H, 6.32; N, 15.49. Found: C,
66.18; H, 6.35; N, 15.60.
IR (KBr): 1588, 1496, 1429, 1365, 1304, 1273, 1237, 1211, 1153,
1081, 1036, 882, 841, 748, 695, 566 cm–1.
1H 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).
13C 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).
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.
1H 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).
13C 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 (EI): m/z = 291.
Anal. Calcd for C18H17N3O: C, 74.20; H, 5.88; N, 14.42. Found: C,
74.40; H, 5.92; N, 14.32.
MS (ESI): m/z = 320 [M + H]+, 342 [M + Na]+.
4,10-Dihydro-5H-8-methoxy-5-benzylimidazo[2,1-c][1,4]ben-
Anal. Calcd for C19H17N3O2: C, 71.46; H, 5.37; N, 13.16. Found: C,
71.66; H, 5.42; N, 13.06.
zodiazepine (5f)
Yield: 0.31 g (76%); pale brown solid; mp 88–90 °C; Rf = 0.26
(EtOAc).
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): 2922, 2808, 1501, 1450, 1375, 1255, 1206, 1149, 1046,
821, 700 cm–1.
1H 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).
IR (KBr): 1597, 1492, 1382, 1299, 1227, 1192, 1120, 1038, 929,
864, 757, 691 cm–1.
13C 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).
1H 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).
13C 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]+, 328 [M + Na]+.
Anal. Calcd for C19H19N3O: C, 74.73; H, 6.27; N, 13.76. Found: C,
74.53; H, 6.23; N, 13.86.
MS (ESI): m/z = 306 [M + H]+.
Anal. Calcd for C18H15N3O2: C, 70.81; H, 4.95; N, 13.76. Found: C,
70.61; H, 4.90; N, 13.88.
4,10-Dihydro-5H-8-methoxy-5-(3,4-methylenedioxybenzyl)im-
idazo[2,1-c][1,4]benzodiazepine (5g)
Yield: 0.26 g (72%); pale yellow solid; mp 146–148 °C; Rf = 0.36
(EtOAc).
4,10-Dihydro-5H-7,8-methylenedioxy-5-(4-methoxyphenyl)im-
idazo[2,1-c][1,4]benzodiazepine (5k)
IR (KBr): 1496, 1439, 1375, 1245, 1201, 1125, 1033, 925, 866, 813,
732, 640, 540 cm–1.
1H 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).
13C 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
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.
1H 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).
13C 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
© Georg Thieme Verlag Stuttgart · New York
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S. Mitra et al.
PAPER
(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]+.
(h) Anzini, M.; Valenti, S.; Braile, C.; Cappelli, A.; Vomero,
S.; Alcaro, S.; Ortuso, F.; Marinelli, L.; Limongelli, V.;
Novellino, E.; Betti, L.; Giannaccini, G.; Lucacchini, A.;
Daniele, S.; Martini, C.; Ghelardini, C.; Di Cesare, Mannelli.
L.; Giorgi, G.; Mascia, M. P.; Biggio, G. J. Med. Chem.
2011, 54, 5694.
Anal. Calcd for C19H17N3O3: C, 68.05; H, 5.11; N, 12.53. Found: C,
68.27; H, 5.08; N, 12.43.
(2) Wright, W. B.; Brabander, H. J.; Greenblatt, E. N.; Day, I.
P.; Hardy, R. A. J. Med. Chem. 1978, 21, 1087.
(3) Selnick, H. G.; Liverton, N. J.; Baldwin, J. J.; Butcher, J. W.;
Claremon, D. A.; Elliotte, J. M.; Freidinger, R. M.; King, S.
A.; Libby, B. E.; Mcintyre, C. J.; Pribush, D. A.; Remy, D.
C.; Smith, G. R.; Tebben, A. J.; Jurkiewicz, N. K.; Lynch, J.
J.; Salata, J. J.; Sanguinetti, M. C.; Siegal, P. K. S.;
Slaughter, D. E.; Vyas, K. J. Med. Chem. 1997, 40, 3865.
(4) Albright, J. D.; Feich, M. F.; Santos, E. G. D.; Dusza, J. P.;
Sum, F. W.; Venkatesan, A. M.; Coupet, J.; Chan, P. S.; Ru,
X.; Mazandarani, H.; Bailey, T. J. Med. Chem. 1998, 41,
2442.
(5) Castro, J. L.; Broughton, H. B.; Russell, M. G. N.; Rathbone,
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Smith, A. J.; Marshall, G. R.; Matassa, V. G. J. Med. Chem.
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10, 314.
4,10-Dihydro-5H-7,8-methylenedioxy-5-(3,4-methylenedioxy-
benzyl)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.
1H 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).
13C 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 C19H15N3O4: C, 65.32; H, 4.33; N, 12.03. Found: C,
65.52; H, 4.30; N, 12.15.
(7) Nicholson, A. N.; Stone, B. M.; Clarke, C. H. Br. J. Clin.
Pharmacol. 1977, 4, 567.
(8) Eltze, M.; Gönne, S.; Riedel, R.; Schlotke, B.; Schudt, C.;
Simon, W. A. Eur. J. Pharmacol. 1985, 112, 211.
(9) (a) De Clercq, E. Farmaco 2001, 56, 3. (b) De Clercq, E.
Farmaco 1999, 54, 26.
(10) Neogi, A.; Majhi, T. P.; Mukhopadhyay, R.; Chattopadhyay,
P. J. Org. Chem. 2006, 71, 3291; and the references cited
therein.
Acknowledgment
S.M. thanks Council of Scientific and Industrial Research (CSIR)
for providing a senior research fellowship (SRF). Thanks are also
due to Dr. B. Achari, Former Emeritus Scientist, IICB, for valuable
suggestions.
(11) Mitra, S.; Banerjee, T. S.; Hota, S. K.; Bhattacharya, D.;
Das, S.; Chattopadhyay, P. Eur. J. Med. Chem. 2011, 46,
1713; and the references cited therein.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
(12) Adhikary, N. D.; Chattopadhyay, P. Eur. J. Org. Chem.
2011, 7346.
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Synthesis 2013, 45, 85–92
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