A one-pot transition-metal-free tandem process to 1,4-benzodiazepine scaffolds

Article abstract of DOI:10.1055/s-0032-1317781

An efficient and practical method for the synthesis of 1,4-benzodiazepines is reported. This methodology offers a transition-metal-free tandem process in one pot. This process is applicable to the construction of a wide variety of 1,4-benzodiazepines and other tricyclic systems with high potential biological and pharmacological activities. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317781

PAPER
▌111
paper
A One-Pot Transition-Metal-Free Tandem Process to 1,4-Benzodiazepine
Scaffolds
One-Pot Synthesis of Benzodiazepines
Yanqiu Li,a,1 Chunjing Zhan,a,1 Bingchuan Yang,a Xiaoqun Cao,*b Chen Ma*a,c
a
School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, P. R. of China
b
Department of Chemical Engineering, Taishan Medical University, Taian, P. R. of China
c
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, P. R. of China
Fax +86(531)88564464; E-mail: chenma@sdu.edu.cn
Received: 31.08.2012; Accepted after revision: 16.11.2012
To date, several methods have been reported for the syn-
thesis of these 1,4-benzodiazepine scaffolds.16 Wang et al.
described the synthesis of these tricyclic compounds in
chlorobenzene using ortho-substituted benzoic acids and
Abstract: An efficient and practical method for the synthesis of
1,4-benzodiazepines is reported. This methodology offers a transi-
tion-metal-free tandem process in one pot. This process is applica-
ble to the construction of a wide variety of 1,4-benzodiazepines and
other tricyclic systems with high potential biological and pharmaco- benzene-1,2-diamine in the presence of copper.17 Joshua
logical activities.
and co-workers reported the synthesis of a tricyclic lactam
by coupling 2,5-dibromonitrobenzene with anthranilic
acid via multiple steps.18 Diao and Ma developed a new
copper-catalyzed strategy to construct these compounds
from ortho-substituted aryl bromides and primary
amines.19 However, these procedures suffer from some
disadvantages such as complex manipulation20 and the
use of transition metal catalyst.21 Additionally, to the best
of our knowledge, fused pyridazinobenzodiazepines have
not been reported. We believe these to be valuable inter-
mediates in medicinal chemistry.
Key words: 1,4-benzodiazepines,
one-pot reaction, transition-metal-free tandem process
pyridazinobenzodiazepines,
The synthesis of heterocycles2 is currently regarded as one
of the primary challenges in medicinal chemistry. 1,4-
Benzodiazepines have received considerable attention be-
cause of their biological activities such as antidepressant,3
anti-inflammatory,4 antagonist,5 antimicrobial,6 anti-HIV
agents,7 and antihypertensive8 activities. The 1,4-benzodi-
azepine moiety is also a pivotal intermediate for the pro-
duction of the medicines, which are currently marketed
including olanzapine, clozapine, and viramune (Figure
1).9 Pyridazinone derivatives still play an important role
in medicinal chemistry owing to their biological activi-
ties,10 including antimicrobial,11 pesticide,12 analgesic,13
herbicidal,14 and anticancer15 activities.
Herein, we report an effective metal-free process for the
synthesis of 1,4-benzodiazepines and fused pyridazino-
benzodiazepines. Substituted benzenes 2 and N-substitut-
ed 2-aminobenzamides 1 were used as substrates in the
presence of cesium carbonate (Scheme 1). 2-Aminobenz-
amide (1a) and 4,5-dichloro-2-(tetrahydro-2H-pyran-2-
yl)pyridazin-3(2H)-one (4) as substrates, sodium hydride
as the base, and DMF as the solvent were used to synthe-
size the fused pyridazinobenzodiazepine 5 (Scheme 2).
Me
N
H
N
S
N
N
H
N
O
N
Cl
R2
R1
Y
X
N
N
Cs2CO3, DMF
150 °C
R2
H
+
N
H
N
NH2
N
R1
O
Me
1
2
3
olanzapine
X = F, Cl
Y = F, Cl, NO2
clozapine
O
N
H
N
Scheme 1 One-pot synthesis of 1,4-benzodiazepines
N
N
O
H
N
N
Cl
Cl
N
N
NH2
N
NaH, DMF
80 °C
THP
viramune
+
NH
NH2
THP
O
Figure 1 Structures of olanzapine, clozapine and viramune
O
O
1a
4
5
Scheme 2 One-pot synthesis of a pyridazinobenzodiazepine
SYNTHESIS 2013, 45, 0111–0117
Advanced online publication: 30.11.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1317781; Art ID: SS-2012-H0697-OP
© Georg Thieme Verlag Stuttgart · New York

112
Y. Li et al.
PAPER
Initially, the 2-aminobenzamide (1a) and 2,3-difluoroben-
zonitrile (2e) were chosen as models to determine the op-
timized conditions. As shown in Table 1, the reaction
temperature, base, and solvent were investigated. The pre-
liminary study was conducted using K2CO3 as the base
and DMF as the solvent at room temperature for 48 hours,
but the desired product 3d was not obtained. Increasing
the temperature to 150 °C led to the desired product in
30% yield (Table 1, entry 2). Next, the reaction was car-
ried out using various bases, and Cs2CO3 provided the
highest yields (Table 1, entries 1–4). When strong base
such as NaH or t-BuOK was used in the reaction, no de-
sired 3d was obtained (Table 1, entries 1, 4, 7, and 8). Fi-
nally, the solvents DMF and DMSO were investigated
using Cs2CO3 as the base (Table 1, entries 3 and 6). To our
delight, the desired product 3d was obtained in 54% yield
when DMF was used.
Table 1 Reaction Conditions and Yields for the Synthesis of 3d
O
O
NH
F
F
NH2
Cs2CO3, DMF
150 °C
+
N
NH2
H
CN
2e
NC
1a
3d
Entry
Base
Solvent Temp (°C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
NaH
DMF
DMF
DMF
150
150
150
150
150
150
150
150
8
0
K2CO3
12
8
30
54
0
Cs2CO3
t-BuOK DMF
12
12
6
K2CO3
DMSO
DMSO
28
52
0
The optimized conditions (Table 1, entry 3) were applied
to a variety of compounds 2, and the results are summa-
rized in Table 2. As observed in Table 2, the reaction pro-
ceeded well with substituted benzenes and N-substituted
2-aminobenzamides to give a range of 1,4-benzodiaze-
pines.22 When 1 was reacted with benzenes containing
electron-withdrawing groups (halogen, nitro, cyano, and
trifluoromethyl), the corresponding products 3 were gen-
erated in moderate to good yields (Table 2, entries 1–6, 8,
and 11). Moreover, the reaction was also applied to 2-
fluoro-1-methyl-3-nitrobenzene (2g) bearing an electron-
donating group, affording the desired product 3f in 67%
yield (Table 2, entry 7). Further, 2-amino-N-methylbenz-
Cs2CO3
t-BuOK DMSO
NaH DMSO
12
8
0
amide (1b) possessing an electron-donating group was re-
acted with 2e under the same conditions to afford the
corresponding product 3i in excellent yield (Table 2, entry
11).
Table 2 Synthesis of 1,4-Benzodiazepines 3a
O
H
R1
N
Y
R2
Cs2CO3, DMF
150 °C
N
R2
H
+
NH2
X
N
R1
O
X = F, Cl
Y = F, Cl, NO2
1
2
3
Entry 1
R1
H
2
Time (h)
Product 3
Yield (%)b
O
F
NH
NH
1
1a
2a
7
3a
68
F
F
NO2
N
H
O
NO2
Cl
Cl
2
3
1a
H
H
2b
2c
7
3b
3c
56
51
N
H
Cl
O
F
F
NH
1a
7.5
NC
CN
N
H
Synthesis 2013, 45, 111–117
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Benzodiazepines
113
Table 2 Synthesis of 1,4-Benzodiazepines 3a (continued)
O
H
N
R1
Y
R2
Cs2CO3, DMF
150 °C
N
R2
H
+
NH2
X
N
R1
O
X = F, Cl
Y = F, Cl, NO2
1
2
3
Entry 1
R1
H
2
Time (h)
Product 3
Yield (%)b
O
Cl
NH
NH
4
5
1a
2d
2e
5.5
6.5
3c
60
NC
NO2
CN
CF3
Cl
N
H
O
F
F
1a
H
3d
54
N
H
CN
NC
NH
O
Cl
Cl
6
7
1a
1a
H
H
2f
6
3e
3f
47
67
F3C
N
H
O
NH
F
2g
5.5
N
NO2
H
O
Cl
NH
NH
NH
8
1a
1a
1a
H
H
H
2h
2i
6
3g
3h
3h
60
Cl
NO2
N
H
O
F
9
6
trace
trace
NO2
N
H
O
Cl
10
2j
6.5
NO2
N
H
O
Me
F
F
N
11
1b
Me
2e
5
3i
90
N
H
CN
NC
a Reaction conditions: 1 (1 mmol), 2 (1.2 mmol), Cs2CO3 (3 mmol), DMF (10 mL), 150 °C, 5–7.5 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 111–117

114
Y. Li et al.
PAPER
As shown in Table 2, the reactant with nitro group (Table
2, entries 9 and 10) could afford 3h,21,22a but their yields
were much lower than the substrates having a strong
electron-donating group. The tricyclic product 3h was ob-
tained only in trace amounts and was confirmed by
HRMS analysis. Conversely, the mono-substituted prod-
uct 8 was mainly obtained (Scheme 3).
O
NH2
O
O2N
NH
NH2
Cs2CO3, DMF
150 °C
+
NO2
NH2
1a
X
2i,j
8
X = F, Cl
Figure 2 Single crystal X-ray structure of 3i
Scheme 3 Reaction of 1a with 2i and 2j
In summary, we have developed a simple and efficient ap-
proach for the synthesis of 1,4-benzodiazepines in moder-
ate to good yields. The prominent features of this
methodology are mild and metal catalyst-free reaction
conditions. On the basis of the related work, a facile method
was discovered for assembling 2-(tetrahydro-2H-pyran-2-
yl)-5,11-dihydro-1H-benzo[e]pyridazino[4,5-b][1,4]di-
azepine-1,10(2H)-dione in high yield. Importantly, this
method has high potential uses in the synthesis of biolog-
ically relevant compounds. Further investigation for
broadening the application of this methodology is current-
ly underway in our laboratory.
After the synthesis of 1,4-benzodiazepines 3, this method-
ology was explored for the preparation of fused
pyridazinobenzodiazepines 5. Thus, 4,5-dichloro-2-
(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (4) could
be employed to construct 2-(tetrahydro-2H- pyran-2-yl)-
5,11-dihydro-1H-benzo[e]pyridazino[4,5-b][1,4]diazepine-
1,10(2H)-dione (5) in the presence of cesium carbonate in
DMF at 120 °C in 54% yield. By comparison of various
reaction conditions, we found that NaH in DMF at 80 °C
was the most efficient system, giving the tricyclic product
5 in 84% yield (Scheme 2).
Based on the experimental results, a proposed reaction
mechanism of the one-pot formation of 3i is outlined in
Scheme 4. The reaction of 1b with 2e yielded compound
6 by nucleophilic aromatic substitution. The next step was
the formation of intermediate 7. Finally, intermediate 7
underwent an intramolecular nucleophilic displacement
of halogen anion by a nitrogen anion to yield compound
3i. To support this mechanism, the structure of 3i was un-
ambiguously proved by single crystal X-ray analysis (Fig-
ure 2).
2-Amino-N-methylbenzamide (1b)23 and 4,5-dichloro-2-(tetra-
hydro-2H-pyran-2-yl)pyridazin-3(2H)-one (4)24 were prepared ac-
cording to literature procedures. All other commercial reagents
were used without further purification. Petroleum ether (PE) refers
to the fraction boiling in the 60–90 °C range. All the reactions were
conducted under N2 atmosphere and monitored by TLC. Melting
points were determined on an XD-4 digital micro melting point ap-
1
paratus. H NMR spectra were recorded at 300 MHz on a Bruker
Avance 300 spectrometer with TMS as the internal standard and
CDCl3 or DMSO-d6 as solvent. 13C NMR spectra were obtained on
a Bruker Avance 300 (75 MHz) spectrometer with TMS as the in-
ternal standard and CDCl3 or DMSO-d6 as solvent. 19F NMR spec-
tra were obtained in DMSO-d6 on a Bruker Avance 300 (282 MHz)
spectrometer. High-resolution mass spectra (HRMS) were obtained
on a Q-TOF6510 spectrograph (Agilent). Single crystal X-ray dif-
fraction were performed on a Rigaku RAXIS-SPIDER IP diffrac-
tometer at 50 kV and 20 mA and data collection was performed at
273(2) K by using graphite monochromated MoKα radiation (λ =
0.71073 Å).
MeHN
O
O
F
F
H
N
F
NHMe
base
– HF
+
NH2
1b
NC
NC
2e
6
–
O
Me
NC
MeN
O
N
F
2-Amino-N-methylbenzamide (1b)
H
base
– H+
N
To a solution of 2-nitrobenzoic acid (1.0 g, 6 mmol) in MeOH (15
mL) was slowly added concd H2SO4 (2 mL) at r.t. over 15 min.
Then, the mixture was refluxed, and the end of the reaction was
monitored by TLC (eluent: PE–EtOAc, 5:1, v/v). The reaction mix-
ture was cooled to r.t. Brine (50 mL) was added and the mixture was
extracted with CH2Cl2 (2 × 30 mL). The combined organic phases
were dried (MgSO4). The solvent was removed under vacuum to af-
ford a residue. A mixture of the residue and aq MeNH2 (20 mL) was
refluxed for 2 h. After cooling, brine (50 mL) was added and the
mixture was extracted with EtOAc (3 × 30 mL). The combined or-
ganic phases were dried (MgSO4) and the solvent was removed un-
– F–
N
H
NC
7
3i
Scheme 4 A proposed reaction mechanism
Synthesis 2013, 45, 111–117
© Georg Thieme Verlag Stuttgart · New York

PAPER
One-Pot Synthesis of Benzodiazepines
115
der vacuum to afford an orange solid. The solid was stirred with 12
M HCl (20 mL) at 55 °C. SnCl2 (2.84 g, 15 mmol) was slowly added
to the mixture and the resulting solution was stirred at 100 °C for 15
min. After cooling to r.t., white crystals separated out. The crude
product was washed with aq 1 M NaOH (30 mL) and extracted with
CH2Cl2 (2 × 30 mL). The combined organic phases were dried
(MgSO4) and concentrated. The crude product was purified by re-
crystallization from EtOAc (20 mL) to afford the desired product 1b
as a white solid (0.62 g, 69%); mp 75.0–76.3 °C (Lit.23 mp 76–78
°C).
(m, 1 H), 7.21 (s, 2 H), 6.95–6.92 (dd, J = 0.6, 8.4 Hz, 1 H), 6.74–
6.68 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 166.12, 150.05, 148.48, 145.72,
134.10, 129.66, 128.85, 120.43, 119.42, 116.80, 116.07, 115.39,
107.03, 105.60.
HRMS (ESI): m/z [M + H+] calcd for C14H9N3O: 236.0818; found:
236.0839.
8-(Trifluoromethyl)-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one
(3e)21c
Yield: 97 mg (47%); white crystals; mp 205.1–207.0 °C (Lit.21c mp
200–202 °C).
11-Oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-6-carbo-
nitrile (3d); Typical Procedure
1H NMR (300 MHz, DMSO-d6): δ = 9.94 (s, 1 H), 7.96–7.94 (d, J =
2.7 Hz, 1 H), 7.92 (s, 1 H), 7.77–7.72 (m, 2 H), 7.27–7.22 (m, 1 H),
6.80–6.77 (d, J = 7.2 Hz, 1 H), 6.64–6.60 (m, 1 H), 6.46 (s, 1 H).
To a solution of 2-aminobenzamide (1a; 100 mg, 0.74 mmol) in an-
hyd DMF (10 mL) were added 2,3-difluorobenzonitrile (2e; 124
mg, 0.89 mmol) and Cs2CO3 (723 mg, 2.22 mmol) at r.t. under a dry
N2 atmosphere. The resulting solution was stirred at 150 °C, and the
progress of the reaction was monitored by TLC (eluent: PE–EtOAc,
5:1, v/v). The mixture was diluted with brine (100 mL) and extract-
ed with EtOAc (3 × 30 mL). The combined organic layers were
dried (MgSO4), filtered, and concentrated in vacuo. Purification of
the residue by flash column chromatography (PE–EtOAc, 8:1, v/v)
afforded the desired product 3d; yield: 94 mg (54%); pale yellow
crystals; mp 191.8–193.2 °C.
13C NMR (75 MHz, DMSO-d6): δ = 167.56, 150.18, 139.28, 132.81,
2
128.85, 128.84, 127.52, 126.64 (q, JC,F = 32.2 Hz), 126.50 (q,
3JC,F = 3.75 Hz), 123.41 (q, 1JC,F = 270.8 Hz), 124.43 (q, 3JC,F = 3.38
Hz), 116.81, 114.97, 113.52.
19F NMR (282 MHz, DMSO-d6): δ = –60.75.
HRMS (ESI): m/z [M + H+] calcd for C14H9F3N2O: 279.0740;
found: 279.1576.
1H NMR (300 MHz, DMSO-d6): δ = 8.14–8.11 (dd, J = 0.9, 8.4 Hz,
1 H), 7.96–7.93 (dd, J = 1.5, 8.1 Hz, 1 H), 7.89–7.86 (dd, J = 0.9,
8.7 Hz, 1 H), 7.58–7.52 (m, 1 H), 7.37–7.32 (m, 1 H), 7.20 (s, 2 H),
6.97–6.94 (dd, J = 0.6, 8.4 Hz, 1 H), 6.75–6.70 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 165.60, 150.02, 149.16, 143.64,
134.15, 129.29, 128.91, 125.78, 116.86, 116.44, 116.21, 116.16,
105.56, 101.36.
6-Methyl-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (3f)
Yield: 111 mg (67%); orange crystals; mp 136.1–138.2 °C.
1H NMR (300 MHz, DMSO-d6): δ = 11.26 (s, 1 H), 8.72 (s, 1 H),
8.19–8.16 (d, J = 8.7 Hz, 1 H), 7.66––7.63 (d, J = 8.1 Hz, 1 H),
7.33–7.26 (dd, J = 7.5, 15.6 Hz, 1 H), 7.01–6.98 (d, J = 8.4 Hz, 1
H), 6.79–6.73 (dd, J = 7.5, 11.7 Hz, 2 H), 5.78 (s, 1 H), 2.48 (s, 3 H).
13C NMR (75 MHz, DMSO-d6): δ = 168.00, 149.94, 147.95, 135.49,
134.47, 133.59, 127.47, 125.97, 124.04, 122.01, 117.79, 117.19,
114.77, 22.22.
HRMS (ESI): m/z [M + H+] calcd for C14H9N3O: 236.0818; found:
236.0814.
8-Fluoro-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (3a)21c
Yield: 115 mg (68%); orange crystals; mp 219.6–222.3 °C (Lit.21c
mp 222–223 °C).
HRMS (ESI): m/z [M + H+] calcd for C14H12N2O: 225.1022; found:
225.1032.
8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (3g)3,22
Yield: 108 mg (60%); pale yellow crystals; mp 231.2–232.8 °C
(Lit.3 mp 232–233 °C).
1H NMR (300 MHz, DMSO-d6): δ = 7.90–7.87 (dd, J = 1.2, 9.3 Hz,
1 H), 7.81–7.73 (m, 2 H), 7.31–7.23 (m, 2 H), 7.08 (s, 2 H), 6.92–
6.90 (d, J = 7.5 Hz, 1 H), 6.72–6.66 (m, 1 H).
1H NMR (300 MHz, DMSO-d6): δ = 7.95–7.94 (dd, J = 2.1, 8.4 Hz,
1 H), 7.91–7.88 (dd, J = 1.5, 8.1 Hz, 1 H), 7.80–7.77 (d, J = 8.4 Hz,
1 H), 7.46–7.42 (dd, J = 2.1, 8.4 Hz, 1 H), 7.33–7.27 (m, 1 H), 7.14
(s, 2 H), 6.94–6.91 (dd, J = 0.6, 8.4 Hz, 1 H), 6.72–6.67 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 164.02, 149.43, 140.78, 133.35,
132.25, 129.51, 128.51, 125.45, 120.38, 116.62, 115.94, 111.51,
106.30.
13C NMR (75 MHz, DMSO-d6): δ = 163.46, 159.74 (d, 1JC,F = 239.2
3
Hz), 148.63, 148.62 (d, JC,F = 15.8 Hz), 137.73, 132.60, 127.89,
119.50 (d, 3JC,F = 10.5 Hz), 116.06, 115.41, 112.18 (d, 2JC,F = 24.0
Hz), 106.08 (d, 4JC,F = 2.2 Hz), 98.79 (d, 2JC,F = 28.5 Hz).
19F NMR (282 MHz, DMSO-d6): δ = –115.77.
HRMS (ESI): m/z [M + H+] calcd for C13H9FN2O: 229.0772; found:
229.0764.
HRMS (ESI): m/z [M + H+] calcd for C13H9ClN2O: 245.0476;
found: 245.0480.
6-Chloro-5H-dibenzo[b,e][1,4]diazepin-11(10H)-one (3b)3,22
Yield: 101 mg (56%); orange crystals; mp 120.9–122.9 °C.
10-Methyl-11-oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diaze-
pine-9-carbonitrile (3i)
Yield: 166 mg (90%); white crystals; mp 141.5–143.0 °C.
1H NMR (300 MHz, DMSO-d6): δ = 7.94–7.91 (dd, J = 1.5, 8.1 Hz,
1 H), 7.77–7.74 (dd, J = 0.9, 8.1 Hz, 1 H), 7.51–7.48 (dd, J = 0.9,
8.1 Hz, 1 H), 7.43–7.41 (d, J = 7.8 Hz, 1 H), 7.38–7.28 (m, 1 H),
7.16 (s, 2 H), 6.94–6.92 (d, J = 7.5 Hz, 1 H), 6.73–6.68 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 164.02, 149.43, 140.78, 133.35,
132.25, 129.51, 128.51, 125.45, 120.38, 116.62, 115.94, 111.51,
106.30.
1H NMR (300 MHz, DMSO-d6): δ = 7.92–7.89 (dd, J = 1.5, 7.8 Hz,
1 H), 7.42–7.35 (m, 3 H), 7.20–7.17 (dd, J = 8.1 Hz, 1 H), 7.14–7.08
(m, 1 H), 6.99–6.96 (dd, J = 0.9, 8.1 Hz, 1 H), 6.06 (s, 1 H), 3.53 (s,
3 H).
13C NMR (75 MHz, DMSO-d6): δ = 169.39, 157.31, 153.99, 143.20,
131.41, 128.73, 126.62, 123.83, 120.62, 120.35, 119.24, 118.42,
115.01, 108.46, 26.16.
HRMS (ESI): m/z [M + H+] calcd for C13H9ClN2O: 245.0476;
found: 245.0476.
HRMS (ESI): m/z [M + H+] calcd for C15H11N3O: 250.0975; found:
250.0993.
11-Oxo-10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine-8-carbo-
nitrile (3c)
From 2c, yield: 89 mg (51%); from 2d, yield: 104 mg (60%); pale
yellow crystals; mp 186.1–188.2 °C.
1H NMR (300 MHz, DMSO-d6): δ = 8.37–8.36 (d, J = 0.9 Hz, 1 H),
7.95–7.91 (m, 2 H), 7.86–7.82 (dd, J = 1.5, 8.4 Hz, 1 H), 7.36–7.30
2-[(2-Nitrophenyl)amino]benzamide (8)
From 2i, yield: 113 mg (60%); from 2j, yield: 104 mg (55%);
orange crystals; mp 201.3–203.2 °C.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 111–117

116
Y. Li et al.
PAPER
1H NMR (300 MHz, DMSO-d6): δ = 11.22 (s, 1 H), 8.14–8.11 (dd,
J = 1.2, 8.4 Hz, 2 H), 7.75–7.72 (dd, J = 1.2, 7.8 Hz, 1 H), 7.60–7.43
(m, 5 H), 7.15–7.10 (m, 1 H), 7.02–6.96 (m, 1 H).
13C NMR (75 MHz, DMSO-d6): δ = 170.00, 139.65, 139.26, 135.91,
135.53, 131.41, 129.13, 126.25, 124.39, 122.23, 120.05, 119.47,
117.88.
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HRMS (ESI): m/z [M + H+] calcd for C13H11N3O3: 258.0834; found:
258.0886.
2-(Tetrahydro-2H-pyran-2-yl)-5,11-dihydro-1H-benzo[e]pyr-
idazino[4,5-b][1,4]diazepine-1,10(2H)-dione (5)
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ran-2-yl)pyridazin-3(2H)-one (4; 196 mg, 0.89 mmol) and NaH
(60%, 89 mg, 2.22 mmol) at r.t. under a dry N2 atmosphere: The
mixture was stirred for 2 h at 80 °C and then quenched with brine
(100 mL).The precipitated crude product was purified by recrystal-
lization from EtOAc (20 mL) to afford the desired product 5 as an
orange solid; yield: 194 mg (84%); orange crystals; mp 271.8–
273.2 °C.
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1H NMR (300 MHz, DMSO-d6): δ = 9.81 (s, 1 H), 7.72–7.69 (dd,
J = 1.0, 9.2 Hz, 2 H), 7.61–7.66 (s, 1 H), 7.33–7.29 (m, 1 H), 7.11–
7.09 (d, J = 8.0 Hz, 1 H), 6.87–6.83 (dd, J = 7.6, 15 Hz, 1 H), 5.84–
5.81 (dd, J = 1.9,10.8 Hz, 1 H), 3.96–3.93 (d, J = 11.0 Hz, 1 H),
3.61–3.54 (m, 1 H), 2.10–2.00 (m, 1 H), 1.94–1.91 (d, J = 12.0 Hz,
1 H), 1.71–1.60 (m, 2 H), 1.51–1.46 (m, 2 H).
13C NMR (75 MHz, DMSO-d6): δ = 167.11, 156.02, 146.05, 134.84,
133.64, 132.88, 128.67, 122.62, 121.68, 120.72, 120.50, 83.22,
67.92, 28.35, 25.12, 22.75.
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HRMS (ESI): m/z [M + H+] calcd for C16H16N4O3: 313.1295; found:
313.1291.
Acknowledgment
We are grateful to the National Science Foundation of China (No.
21172131) and the State Key Laboratory of Natural and Biomimetic
Drugs of Peking University (No. K20090205) for financial support
of this research.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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