A one-pot synthetic strategy for construction of the dibenzodiazepine skeleton via a transition metal-free process

Article abstract of DOI:10.1039/c4ob00871e

A one-pot transition metal-free methodology for constructing pharmacologically active dibenzodiazepine derivatives was developed. Fluoro-, bromo- and nitro-substituted aryl aldehydes were applied to this reaction efficiently. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ob00871e

Organic &
Biomolecular Chemistry
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PAPER
A one-pot synthetic strategy for construction
of the dibenzodiazepine skeleton via a transition
metal-free process†
Cite this: Org. Biomol. Chem., 2014,
12, 6895
Shuai Fang,a Xiaoyi Niu,a Zeyuan Zhang,a Yan Sun,a Xiaomeng Si,a Cuicui Shan,a
Lei Wei,a Aiqing Xu,a Lei Fenga and Chen Ma*a,b
Received 30th April 2014,
Accepted 13th July 2014
A one-pot transition metal-free methodology for constructing pharmacologically active dibenzodiazepine
derivatives was developed. Fluoro-, bromo- and nitro-substituted aryl aldehydes were applied to this
reaction efficiently.
DOI: 10.1039/c4ob00871e
www.rsc.org/obc
Introduction
In the past 50 years, dibenzodiazepines and their structural
analogues have attracted significant attention because of
their efficient pharmacological activity. Clozapine 1 has been a
listed drug for treating schizophrenia since 1982.1 Compounds
2 and 3 exhibited good affinity to the D1-like subtype of dopa-
mine receptors.2,3 Compound 4 revealed a high RXR antagon-
istic activity and good pharmacokinetic properties (Fig. 1).4
Other pharmacologically active dibenzodiazepine derivatives
were also reported abundantly in previous literature.5
Since the first synthesis of dibenzodiazepine derivatives by
Schmutz in 1964,6 limited progress has been made. Tra-
ditional paths universally depended on lactam or amide inter-
mediates,7,8 and dibenzodiazepines and their structural
analogues were obtained through multi-step or metal-catalysed
reactions (Scheme 1). In recent years, a few novel methods
have been established. Buchwald developed a skilful method
that contained two steps of palladium-catalysed cross-coupling
reaction and subsequent intramolecular condensation.9
However, the reactant is difficult to prepare, and utilization of
a metal catalyst and ligand is not economical. Yin and Liang
also developed synthetic methods to obtain dibenzodiaze-
pines, respectively.10,11 Similarly, transition metal catalysts
played key roles in their systems. Thus, it is necessary to
provide a concise, general and efficient protocol for combining
dibenzodiazepine derivatives.
Fig. 1 Pharmacologically active dibenzodiazepine derivatives.
Scheme 1 Traditional methods for preparing dibenzodiazepine
derivatives.
aKey Laboratory of Special Functional Aggregated Materials, Ministry of Education,
School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100,
P. R. China
bState Key Laboratory of Bioactive Substance and Function of Natural Medicines,
Herein, we report a one-pot, transition metal-free method
to produce dibenzodiazepine derivatives. N-(2-Aminophenyl)-
4-methylbenzenesulfonamide derivatives and 2-fluorobenz-
aldehyde derivatives acted as substrates.
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union
Medical College, Beijing, 100050, P. R. China. E-mail: chenma@sdu.edu.cn
†Electronic supplementary information (ESI) available: The NMR spectra of all
synthesized new compounds. See DOI: 10.1039/c4ob00871e
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Table 2 The reaction of N-(2-aminophenyl)-4-methylbenzenesulfon-
amide derivatives 5 and 2-substituted aryl aldehydes 6a
Results and discussion
N-(2-Aminophenyl)-4-methylbenzenesulfonamide 5a was pre-
pared according to literature procedures.12 To optimize the
reaction conditions, N-(2-aminophenyl)-4-methylbenzenesulfon-
amide 5a and 2-fluorobenzaldehyde 6a were used as model
substrates (Table 1). The effect of bases was investigated, and
Cs2CO3 showed the best efficiency in this reaction (entry 6).
K2CO3 was equally efficient as Cs2CO3 (entry 5) but a stronger
base like NaOH did not favor the reaction (entry 2). Higher
yields were obtained with the increase of temperature (entries
4–6). The solvents were screened as well. NMP and DMSO gen-
erated moderate yields, but the reaction in toluene failed to
form the product (entries 8–10). Molecular sieves 4 Å had a
strong effect on the reactions (entries 6 and 7). Herein, entry 6
was the best condition.
Substrate
Entry
1
5
6
Product
Yieldb/%
75
5a
With the optimized conditions in hand, the scope of the
reaction was tested. Initially, the reaction of N-(2-amino-
phenyl)-4-methylbenzenesulfonamide 5a and 2-fluorobenz-
aldehyde derivatives 6 was investigated (Table 2). A variety of
electron deficient 2-halo- and 2-nitro-substituted aryl alde-
hydes were detected and discovered to work efficiently
(Table 2, entries 1–3). To our delight, the coupling of 2-bromo-
benzaldehyde derivatives with 5a took place in the absence of
a transition metal (entries 2, 10).13 Although the nitro group
has rarely been utilized as a leaving group,14 a moderate yield
was obtained from the reaction of N-(2-aminophenyl)-
4-methylbenzenesulfonamide 5a and 2-nitrobenzaldehyde 6c
(entries 3, 11). All substrates worked well with moderate yields.
Moreover, 2-fluorobenzaldehyde 6 with electron-withdrawing
groups (entries 4–8, 12–15 and 18) generated better yields than
those with electron-donating groups (entries 16, 19). Sub-
sequently, the scope of N-(2-aminophenyl)-4-methylbenzene-
2
3
5a
5a
7a
7a
54c
63
4
5a
74
5
6
7
8
9
5a
5a
5a
5a
5b
69
72
67
81
72
sulfonamide derivatives
5 was screened. N-(2-Amino-4,5-
Table 1 Optimization of reaction conditionsa
Entry
Solvent
Base
T/°C
Time/h
Yieldb/%
1
2
3
4
5
6
7
8
9
DMF
DMF
DMF
DMF
DMF
DMF
DMF
NMP
Toluene
DMSO
Cs2CO3
NaOH
120
120
120
130
130
130
130
130
Reflux
130
2
2
2
2
3
3
3
3
3
3
57
41
55
64
K2CO3
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
10
11
5b
5b
7g
7g
45c
69
70
75
63c
58
Trace
65
10
a Reaction conditions: N-(2-aminophenyl)-4-methylbenzenesulfonamide
5a (1.0 equiv.), 2-fluorobenzaldehyde 6a (1.3 equiv.) and a base
(3.0 equiv.), under a nitrogen atmosphere, 4 Å molecular sieves.
b Isolated yields. c Reaction without 4 Å molecular sieves.
12
5b
63
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dimethylphenyl)-4-methylbenzenesulfonamide 5b and N-(2-
amino-5-methylphenyl)-4-methylbenzenesulfonamide 5c1 were
also applicable to this reaction. The ratio of isomers 7m and
7n is in accordance with the ratio of reactants 5c1 and 5c2.
Table 2 (Contd.)
Conclusions
We provide a one-pot synthetic strategy to construct dibenzo-
diazepine derivatives via a transition metal-free procedure.
This tandem process could work well with a wide range of
2-fluoro-, 2-bromo- and 2-nitro-substituted aryl aldehydes. The
application of this reaction system in pharmaceuticals and
industry is in progress.
Substrate
Entry
13
5
6
Product
Yieldb/%
69
5b
Experimental
General information
14
5b
73
N-(2-Aminophenyl)-4-methylbenzenesulfonamide 5a, N-(2-amino-
4,5-dimethylphenyl)-4-methylbenzenesulfonamide 5b and
N-(2-amino-5-methylphenyl)-4-methylbenzenesulfonamide 5c1
were prepared according to literature procedures.12 Other
chemicals were commercially available and were used without
further purification. All reactions were monitored by thin-layer
chromatography (TLC). 1H NMR spectra were recorded on a
Bruker Avance 400 or 300 spectrometer at 400 or 300 MHz,
using DMSO-d6 as the solvent and tetramethylsilane (TMS) as
the internal standard. 13C NMR spectra were run on the same
instrument at 100 or 75 MHz. Melting points were determined
on an XD-4 digital micro melting point apparatus. HRMS
15
16
17
5b
78
5b
40
5c1, 5c2
73d
spectra were determined on
(Agilent).
a Q-TOF6510 spectrograph
General experimental procedure for starting material 5a
1,2-Phenylenediamine (54 mmol) was dissolved in dry DCM,
cooled to 0 °C and Et3N (50 mmol) was added followed by
p-toluenesulphonyl chloride (50 mmol). The reaction mixture
was stirred at 0 °C for 30 min and then at room temperature
for 3 h. The reaction was quenched by the addition of water,
the organic matter was extracted with CHCl3 (50 mL × 2), dried
and concentrated to obtain the crude product, which was
further purified by a short pad silica gel column chromato-
graphy to obtain N-tosylated o-phenylenediamine (ref. 12). A
similar procedure was employed for N-(2-amino-4,5-dimethyl-
phenyl)-4-methylbenzenesulfonamide 5b and N-(2-amino-5-
methylphenyl)-4-methylbenzenesulfonamide 5c2.
18
5c1, 5c2
67d
19
5a
35e
General experimental procedure for 7a
A mixture of N-(2-aminophenyl)-4-methylbenzenesulfonamide
5a (1.0 mmol), 2-fluorobenzaldehyde 6a (1.3 mmol), Cs2CO3
(3 mmol) and 4 Å molecular sieves in DMF (6 mL) was stirred
at 130 °C under a nitrogen atmosphere, and TLC monitored
the end of the reaction. After the mixture was cooled, water
was added. The solution was extracted with ethyl acetate
(20 ml × 3). The combined organic phase was dried with
a Reaction conditions: 5 (1.0 equiv.), 6 (1.3 equiv.) and a base (3.0 equiv.), under
a nitrogen atmosphere. b Isolated yields. c Reaction conditions: Cs2CO3, DMF,
145 °C, 4 Å molecular sieves, 3 h. d The ratios were obtained using NMR.
e Reaction time: 4 h.
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MgSO4 and the solvent was removed in vacuo to obtain the 21.54; HRMS calcd for C21H15F3N2O2S (M + H)+ 417.0806;
residue. The residue was purified by column chromatography found: 417.0883.
on silica gel to afford 7a.
7,8-Dimethyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine
(7g).
5-Tosyl-5H-dibenzo[b,e][1,4]diazepine (7a). White solid Pale yellow solid (72%). Mp 164–167 °C. 1H NMR (400 MHz,
1
(75%). Mp 155–157 °C. H NMR (300 MHz, DMSO-d6): δ 8.03 DMSO-d6): δ 8.09 (s, 1H), 7.70–7.67 (m, 1H), 7.54 (d, J = 4.2 Hz,
(s, 1H), 7.75–7.70 (m, 1H), 7.61–7.53 (m, 3H), 7.50–7.41 (m, 2H), 7.49 (d, J = 7.9 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 7.24 (s,
3H), 7.32–7.26 (m, 3H), 7.18 (d, J = 9.0 Hz, 2H), 2.39 (s, 3H); 1H), 7.14 (d, J = 8.2 Hz, 2H), 7.03 (s, 1H), 2.38 (s, 3H), 2.25 (s,
13C NMR (75 MHz, DMSO-d6): δ 158.94, 144.02, 143.97, 140.81, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 158.52,
136.06, 133.35, 132.99, 131.05, 131.00, 130.46, 130.08, 129.75, 144.31, 142.18, 141.21, 138.37, 137.49, 136.63, 133.21, 131.86,
129.41, 129.18, 128.50, 128.32, 127.09, 21.04; HRMS calcd for 131.69, 131.20, 130.81, 130.55, 130.14, 129.57, 129.48, 127.62,
C20H16N2O2S (M + H)+ 349.0932; found: 349.0994.
21.53, 19.31, 19.25; HRMS calcd for C22H20N2O2S (M + H)+
1-Fluoro-5-tosyl-5H-dibenzo[b,e][1,4]diazepine (7b). White 377.1245; found: 377.1382.
solid (74%). Mp 160–162 °C. 1H NMR (400 MHz, DMSO-d6):
3-Bromo-7,8-dimethyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine
δ 8.14 (s, 1H), 7.78–7.73 (m, 1H), 7.48–7.38 (m, 5H), 7.34–7.25 (7h). Pale yellow solid (63%). Mp 164–167 °C. 1H NMR
(m, 5H), 2.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 160.64 (400 MHz, DMSO-d6): δ 7.88 (s, 1H), 7.79–7.77 (m, 1H), 7.71 (s,
(d, J = 252.0 Hz, 1C), 152.65 (d, J = 7.0 Hz, 1C), 144.79, 144.45, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.30–7.25 (t, 3H), 7.17 (d, J =
143.58 (d, J = 4.0 Hz, 1C), 136.44, 135.03 (d, J = 10.0 Hz, 1C), 8.1 Hz, 2H), 7.04 (s, 1H), 2.38 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H);
133.64, 131.49, 130.41, 130.19, 129.13, 128.81, 127.61, 126.68 13C NMR (100 MHz, DMSO-d6): δ 157.46, 144.57, 142.03,
(d, J = 3.0 Hz, 1C), 119.24 (d, J = 12.0 Hz, 1C), 116.83 (d, J = 138.71, 137.79, 136.27, 133.20, 132.63, 132.41, 132.04, 130.78,
21.0 Hz, 1C), 21.55; HRMS calcd for C20H15FN2O2S (M + H)+ 130.70, 130.26, 129.65, 127.65, 125.93, 21.54, 19.32, 19.28;
367.0838; found: 367.0895.
HRMS calcd for C22H19BrN2O2S (M + H)+ 455.0423; found:
3-Bromo-5-tosyl-5H-dibenzo[b,e][1,4]diazepine (7c). White 455.0487.
solid (69%). Mp 166–167 °C. 1H NMR (300 MHz, DMSO-d6):
2-Bromo-7,8-dimethyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine
δ 7.99 (s, 1H), 7.84–7.81 (m, 1H), 7.77 (d, J = 1.8 Hz, 1H), 7.56 (7i). Pale yellow solid (69%). Mp 266–267 °C. 1H NMR
(d, J = 8.4 Hz, 1H), 7.52–7.42 (m, 3H), 7.33–7.26 (m, 3H), 7.19 (400 MHz, DMSO-d6): δ 7.88 (d, J = 2.3 Hz, 1H), 7.87 (s, 1H),
(d, J = 8.1 Hz, 2H), 2.39 (s, 3H); 13C NMR (75 MHz, DMSO-d6): 7.82 (d, J = 2.3 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.30 (d, J =
δ 157.92, 144.22, 143.89, 141.63, 135.74, 132.89, 132.76, 8.2 Hz, 1H), 7.24 (s, 1H), 7.18–7.16 (d, J = 8.3 Hz, 1H), 7.17 (d,
132.34, 132.03, 131.27, 130.11, 129.86, 129.69, 128.58, 128.55, J = 8.1 Hz, 2H), 7.04 (s, 1H), 2.38 (s, 3H), 2.25 (s, 3H), 2.21 (s,
127.13, 125.74, 21.05; HRMS calcd for C20H15N2O3S (M + H)+ 3H); 13C NMR (100 MHz, DMSO-d6): δ 156.90, 144.51, 141.90,
427.0038; found: 427.0066.
140.42, 138.64, 137.90, 136.34, 135.95, 133.37, 133.32, 132.66,
2-Fluoro-5-tosyl-5H-dibenzo[b,e][1,4]diazepine (7d). White 131.89, 130.84, 130.27, 129.71, 127.64, 122.42, 21.54, 19.30,
solid (72%). Mp 173–175 °C. 1H NMR (400 MHz, DMSO-d6): 19.28; HRMS calcd for C22H19BrN2O2S (M + H)+ 455.0423;
δ 7.96 (s, 1H), 7.58–7.56 (m, 2H), 7.50–7.42 (m, 4H), 7.32–7.26 found: 455.0486.
(m, 3H), 7.19 (d, J = 8.3 Hz, 2H), 2.38 (s, 3H); 13C NMR
1-Fluoro-7,8-dimethyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine
(100 MHz, DMSO-d6): δ 162.08 (d, J = 273.0 Hz, 1C), 157.92, (7j). Pale yellow solid (73%). Mp 179–181 °C. 1H NMR
144.60, 144.28, 137.64 (d, J = 3.0 Hz, 1C), 136.32, 133.76, (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.75–7.71 (m, 1H), 7.43 (t,
133.19 (d, J = 8.0 Hz, 1C), 133.10 (d, J = 9.0 Hz, 1C), 131.62, J = 9.2 Hz, 1H), 7.36–7.31 (m, 3H), 7.22 (d, J = 7.8 Hz, 3H), 7.05
130.34, 130.06, 129.12, 127.63, 120.56 (d, J = 23.0 Hz, 1C), (s, 1H), 2.39 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H); 13C NMR
117.15(d,
J
=
24.0 Hz, 1C), 21.54; HRMS calcd for (100 MHz, DMSO-d6): δ 160.58 (d, J = 251.0 Hz, 1C), 151.63 (d,
J = 8.0 Hz, 1C), 144.66, 143.49, 142.07, 138.79, 137.93, 136.49,
C20H15FN2O2S (M + H)+ 367.0838; found: 367.0848.
2-Bromo-5-tosyl-5H-dibenzo[b,e][1,4]diazepine (7e). White 134.77 (d, J = 10.0 Hz, 1C), 131.77, 130.98, 130.33, 129.33,
solid (67%). Mp 195–197 °C. 1H NMR (300 MHz, DMSO-d6): 127.63, 126.67 (d, J = 3.0 Hz, 1C), 119.38 (d, J = 12.0 Hz, 1C),
δ 7.97 (s, 1H), 7.93–7.87 (m, 2H), 7.50–7.43 (m, 4H), 7.33 (d, J = 116.64 (d, J = 20.0 Hz, 1C), 21.55, 19.32, 19.27; HRMS calcd for
8.1 Hz, 2H), 7.29–7.26 (m, 1H), 7.19 (d, J = 8.4 Hz, 2H), 2.39 (s, C22H19FN2O2S (M + H)+ 395.1151; found: 395.1123.
3H); 13C NMR (75 MHz, DMSO-d6): δ 157.37, 144.17, 143.75,
7,8-Dimethyl-5-tosyl-2-(trifluoromethyl)-5H-dibenzo[b,e][1,4]-
140.05, 135.80, 135.73, 133.02, 132.62, 132.17, 131.09, 129.88, diazepine (7k). Pale yellow solid (78%). Mp 188–190 °C.
129.62, 128.63, 127.12, 122.11, 21.06; HRMS calcd for 1H NMR (400 MHz, DMSO-d6): δ 8.07–8.03 (m, 3H), 7.71 (d, J =
C20H15BrN2O2S (M + H)+ 427.0038; found: 427.0027.
8.2 Hz, 1H), 7.32–7.28 (m, 3H), 7.19 (d, J = 8.1 Hz, 2H), 7.07 (s,
5-Tosyl-2-(trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepine (7f). 1H), 2.39 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H); 13C NMR (100 MHz,
White solid (81%). Mp 181–183 °C. 1H NMR (400 MHz, DMSO- DMSO-d6): δ 157.24, 144.67, 144.52, 141.89, 138.88, 138.11,
d6): δ 8.15 (s, 1H), 8.08 (d, J = 5.9 Hz, 2H), 7.75 (d, J = 8.9 Hz, 136.30, 132.15, 131.89 (d, J = 3.0 Hz, 1C), 130.64, 130.37,
1H), 7.50–7.45 (m, 3H), 7.34–7.28 (m, 3H), 7.22 (d, J = 8.3 Hz, 129.75 (q, 1C), 129.71, 128.25, 127.63, 124.00 (d, J = 269.0 Hz,
2H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 158.20, 1C), 21.55, 19.32, 19.29; HRMS calcd for C23H19F3N2O2S
144.82, 144.67, 144.28, 136.32, 133.37, 131.99, 131.83, 131.57, (M + H)+ 445.1119; found: 445.1202.
130.43, 130.28, 130.03 (q, J = 3.0, 33.0 Hz, 1C), 129.28, 129.16,
3-Methoxy-7,8-dimethyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine
128.29 (d, J = 4.0 Hz, 1C), 127.61, 123.94 (d, J = 271.0 Hz, 1C), (7l). Pale yellow solid (40%). Mp 137–138 °C. 1H NMR
6898 | Org. Biomol. Chem., 2014, 12, 6895–6900
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(400 MHz, DMSO-d6): δ 7.80 (s, 1H), 7.47 (d, J = 8.6 Hz, 1H),
7.28 (d, J = 8.2 Hz, 2H), 7.22 (s, 1H), 7.14 (d, J = 8.9 Hz, 2H),
7.13–7.10 (m, 1H), 7.01 (s, 1H), 7.00 (s, 1H), 3.85 (s, 3H), 2.37
(s, 3H), 2.25 (s, 3H), 2.21 (s, 3H); 13C NMR (100 MHz, DMSO-
d6): δ 163.13, 157.91, 144.28, 142.54, 142.52, 138.34, 137.10,
136.49, 132.36, 132.01, 130.71, 130.08, 129.52, 127.69, 124.74,
115.45, 56.32, 21.54, 19.35, 19.27; HRMS calcd for
C23H22N2O3S (M + H)+ 407.1424; found: 407.1484.
2 J. Su, H. Tang, B. A. McKittrick, D. A. Burnett, H. Zhang,
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5 For recent reviews of the pharmacological activity of
dibenzodiazepines, see: (a) A. V. Joshua, S. K. Sharma,
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4234.
7-Methyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine (7m1) and
8-methyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine (7m2) (1 : 2).
1
Pale yellow solid (73%). H NMR (400 MHz, DMSO-d6): δ 7.99,
7.95 (d, 1H), 7.70 (m, 1H), 7.56–7.50 (m, 3H), 7.34–7.28 (m,
3H), 7.22–7.16 (m, 3H), 7.06 (s, 1H), 2.37, 2.34 (d, 3H), 2.30 (s,
3H); 13C NMR (100 MHz, DMSO-d6): δ 159.63, 158.61, 144.42,
144.39, 144.18, 142.11, 141.37, 141.07, 139.64, 138.75, 136.61,
136.57, 133.49, 133.38, 133.32, 131.63, 131.58, 131.39, 131.19,
130.91, 130.85, 130.60, 130.50, 130.21, 129.61, 129.56, 129.52,
129.17, 128.81, 127.59, 21.53, 20.89, 20.76; HRMS calcd for
C21H18N2O2S (M + H)+ 363.1162; found: 363.1192.
2-Bromo-7-methyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine (7n1)
and
2-bromo-8-methyl-5-tosyl-5H-dibenzo[b,e][1,4]diazepine
(7n2) (1 : 2). Pale yellow solid (67%). 1H NMR (300 MHz,
DMSO-d6): δ 7.96, 7.92 (d, 1H), 7.81–7.74 (m, 2H), 7.55–7.52
(m, 1H), 7.37–7.30 (m, 3H), 7.25–7.15 (m, 3H), 7.08 (s, 1H),
2.39, 2.36 (d, 3H), 2.32 (s, 3H); 13C NMR (75 MHz, DMSO-d6):
δ 157.78, 157.05, 144.15, 144.12, 143.55, 141.71, 141.49,
141.41, 139.46, 138.52, 135.79, 135.76, 132.76, 132.67, 132.52,
132.20, 131.99, 131.92, 131.34, 130.91, 130.89, 130.42, 130.36,
130.24, 130.19, 129.24, 128.77, 128.40, 127.14, 125.60, 125.54,
21.04, 20.40, 20.28; HRMS calcd for C21H17BrN2O2S (M + H)+
441.0267; found: 441.0294.
6 (a) F. Hunziker, F. Künzle, O. Schindler and J. Schmutz,
Helv. Chim. Acta, 1964, 47, 1163–1172; (b) F. Hunziker,
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249; (c) F. Hunziker, E. Fischer and J. Schmutz, Helv. Chim.
Acta, 1967, 50, 1588–1599.
7 For reviews of the synthesis of dibenzodiazepines (and
their derivatives) via lactam intermediates, see:
(a) R. A. Smits, H. D. Lim, B. Stegink, R. A. Bakker,
I. J. P. de Esch and R. Leurs, J. Med. Chem., 2006, 49, 4512–
4516; (b) L. Wang, G. M. Sullivan, L. A. Hexamer,
L. A. Hasvold, R. Thalji, M. Przytulinska, Z.-F. Tao, G. Li,
Z. Chen, Z. Xiao, W.-Z. Gu, J. Xue, M.-H. Bui, P. Merta,
P. Kovar, J. J. Bouska, H. Zhang, C. Park, K. D. Stewart,
H. L. Sham, T. J. Sowin, S. H. Rosenberg and N.-H. Lin,
J. Med. Chem., 2007, 50, 4162–4176; (c) Y. Liao,
B. J. Venhuis, N. Rodenhuis, W. Timmerman, H. Wikström,
E. Meier, G. D. Bartoszyk, H. Böttcher, C. A. Seyfried and
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(d) R. S. Kalhapure, B. P. Patil, M. N. Jadhav, L. A. Kawle
and S. B. Wagh, Eur. J. Chem., 2011, 8, 1747–1749.
1-(Benzyloxy)-5-tosyl-5H-dibenzo[b,e][1,4]diazepine (7o).
Pale yellow solid (35%). Mp 155–157 °C. 1H NMR (400 MHz,
DMSO-d6): δ 8.16 (s, 1H), 7.64 (t, J = 8.2 Hz, 1H), 7.44–7.10 (m,
14H), 7.09 (d, J = 8.0 Hz, 1H), 5.26–5.17 (m, J = 25.48, 12.0 Hz,
2H), 2.39 (s, 3H); 13C NMR (100 MHz, DMSO-d6): δ 158.08,
155.82, 145.08, 144.47, 143.89, 136.98, 136.69, 134.34, 134.11,
131.14, 130.21, 129.87, 129.01, 128.57, 127.37, 128.19, 128.07,
127.61, 122.16, 119.85, 113.78, 70.78, 21.53; HRMS calcd for
C27H22N2O3S (M + H)+ 455.1424; found: 455.1474.
Acknowledgements
8 For reviews of the synthesis of dibenzodiazepines (and
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We are grateful to the National Science Foundation of China
(no. 21172131) and State Key Laboratory of Bioactive Substance
and Function of Natural Medicines, Institute of Materia
Medica, Chinese Academy of Medical Sciences and Peking
Union Medical College (no. GTZK201405) for financial support
of this research.
Notes and references
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