An efficient synthesis of substituted 1,4-diazepines by a Pd catalyzed amination and sequential hydrogenation condensation

Article abstract of DOI:10.1016/j.cclet.2013.04.028

An efficient synthesis of substituted 1,4-diazepines is developed. The accessible intermediates have been obtained via Pd-catalyzed amination. The subsequent hydrogenation and intramolecular condensation sequences could be conducted successively in one po

Full text of DOI:10.1016/j.cclet.2013.04.028

Chinese Chemical Letters 24 (2013) 743–746
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
An efficient synthesis of substituted 1,4-diazepines by a Pd catalyzed amination
and sequential hydrogenation condensation
*
Xiao-Jian Wang, Yu-Lin Tian, Qing-Yang Zhang, Jian-Guo Qi, Da-Li Yin
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Active Substance Discovery and Druggability Evaluation, Institute of Materia
Medica, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100050, China
A R T I C L E I N F O
A B S T R A C T
Article history:
An efficient synthesis of substituted 1,4-diazepines is developed. The accessible intermediates have been
obtained via Pd-catalyzed amination. The subsequent hydrogenation and intramolecular condensation
sequences could be conducted successively in one pot without special operation. The mild and general
strategy enables the synthesis of various substituted 1,4-diazepines in high yields.
Received 20 March 2013
Received in revised form 9 April 2013
Accepted 16 April 2013
Available online 20 May 2013
ß 2013 Da-Li Yin. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
1,4-Diazepines
Pd-catalyzed amination
Hydrogenation
Intramolecular condensation
1. Introduction
carbonyl or ester substituted materials were also not tolerated
in the second amination–cyclization step.
Substituted 1,4-diazepines are an important class of pharma-
cologically active heterocyclic structure moieties which exist in
natural products [1] and clinical drugs, such as olanzapine [2] and
clozapine [3]. Most previously reported methods for the assembly
of 1,4-diazepine derivatives required multistep syntheses, which
suffer from difficulties in the preparation of intermediates, such as
amide or lactam, and introducing additional groups to the
heterocyclic scaffold to yield diverse molecules [4–7]. The harsh
conditions, purification after each step and low total yields make it
difficult to obtain such derivatives.
In recent years, metal-catalyzed amination methodology has
become an efficient tool to synthesize complex heterocycles [9,10].
During studies on heterocyclic syntheses and palladium catalyzed
amination [11–14], we envisioned a change from the starting
dihalobenzenes to o-bromonitrobenzenes according to our retro-
synthetic analysis, the limitation could be overcome and diverse
target molecules can be achieved. Herein, we report an efficient
and mild method for the synthesis of 1,4-diazepine derivatives.
More recently, Tsvelikhovsky and Buchwald developed a novel
and general method to provide access to 1,4-diazepine derivatives
that involve two steps of palladium-catalyzed, cross-coupling
reactions and subsequent intramolecular condensation [8]. This
method avoided almost all of the difficulties previously encoun-
tered in 1,4-diazepine synthesis. However, Buchwald’s method
still has some limitations in the availability of starting materials. o-
Bromochlorobenzene is commercially available, but others with
different substituents are rare, or difficult to prepare. The second
cross-coupling requires only one chloro-substituent in the
intermediate. Other halo substituents in the intermediate mole-
cules may cause selectivity problem. Obviously, additional
2. Experimental
Typical procedure for the preparation of 3a: A mixture of
PdCl2(PPh3)2, 2-bromonitrobenzene (1a) (1.3 mmol), 2-aminoben-
zophenone (2a) (1 mmol) and Cs2CO3 (5 mmol) in toluene (10 mL)
was stirred at 110 8C for 18 h under an argon atmosphere. After
removal of the solvent in vacuo, the residue was partitioned
between ethyl acetate and water. The product 3a was isolated
as an orange solid in 95% yield by silica gel chromatography
(PE/EA = 32/1).
Typical procedure for the preparation of 5a: 32 mg of 10% Pd/C
was added into a solution of 3a (1 mmol) in MeOH (5 mL). The
mixture was stirred under H2 at r.t. for 30 min and filtered. p-TSA
(5 mol %) was added to the filtrate and stirred for 5 min. The
mixture was concentrated and purified by silica gel chromatogra-
phy (PE/EA = 16/1) to give product 5a as a yellow solid in 93% yield.
* Corresponding author.
E-mail address: yindali@imm.ac.cn (D.-L. Yin).
1001-8417/$ – see front matter ß 2013 Da-Li Yin. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.04.028

744
X.-J. Wang et al. / Chinese Chemical Letters 24 (2013) 743–746
Table 1
Pd-catalyzed amination of 2-bromo nitrobenzenes and 2-aminobenzophenone under different reaction conditionsa.
[TD$INLE]
Entry
Catalyst
Ligand
Solvent
Temp. (8C)
Yieldb (%)
1
2
3
4
5
6
7
PdCl2(PPh3)2
Pd(dba)3
–
DMF
120
120
110
120
110
110
120
50
43
32
55
95
84
77
dppf
dppf
dppf
–
Toluene
Pd(OAc)2
Toluene
PdCl2
Toluene
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Toluene
–
1,4-Dioxane
N-Methyl pyrrolidinone
–
a
Reaction conditions: 1a (2.5 mmol), 2a (3 mmol), Pd catalyst (0.25 mmol), ligand (0.3 mmol), Cs2CO3 (7 mmol), solvent (10 mL), 110–120 8C, 18 h.
Isolated yields.
b
Table 2
The hydrogenation and intramolecular condensation conditions.
[TD$INLE]
Entry
Hydrogenation
Pd/C (10 g %) hydrogenation in methanol, r.t. for 30 min
Intramolecular condensation
Yieldc (%)
1a
2b
3
Dioxane, 4 A MS, reflux for 4 h
25
80
93
˚
Dioxane, p-TSA, reflux for 1 h
Filtrate, p-TSA, r.t. 5 min
a
˚
4 A MS 200 mg.
b
c
p-TSA 5 mol%.
Isolated yields.
Table 3
The preparation of various 1,4-diazepine derivatives.a
[DT$INLE]
R1
O
NH2
N
O2N
Br
R2
R2
i
iii
+
N
X
R1
X
H
1
2
5
Entry
R1
R2
X
5
Yieldb (%)
1
2
H
H
H
H
H
H
F
CH
CH
CH
N
b
c
d
e
f
90.3
92.2
92.3
95.1
85.3
82.1
93.1
91.3
94.2
93.3
95.2
OCH3
CF3
H
3
4c
5
Cl
CH
CH
CH
CH
CH
CH
N
6
COOCH3
g
h
i
7
–CH3
–CH3
–CH3
–CH3
–CH3
H
8
F
9
OCH3
CF3
H
j
10
11
k
l
a
Reagents and conditions: (i) 1 (2.5 mmol), 2 (3.0 mmol), PdCl2(PPh3)2 (0.25 mmol), Cs2CO3 (7 mmol), toluene (10 mL), 110–120 8C, 18 h. (ii) 10% Pd/C methanol, r.t., 30 min.
(iii) p-TSA (5 mol %), r.t. 5 min.
b
Isolated total yield after column chromatography of the products.
c
Reaction was carried out with 25 mmol of 1.

X.-J. Wang et al. / Chinese Chemical Letters 24 (2013) 743–746
745
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3. Results and discussion
We initially conducted the reaction using 2-aminobenzophe-
none 1a and 2-bromonitrobenzenes 2a as substrate in the presence
of PdCl2(PPh3)2, Cs2CO3 at 120 8C in DMF under an argon
atmosphere. However, a complicated mixture was observed,
which contained the desired product 3a in only 50% yield
(Table 1, entry 1). Different catalysts, ligands and solvents were
then screened for the cross-coupling of 2-bromonitrobenzene and
2-aminodibenzophenone. Reactions conducted utilizing Pd2(dba)3,
Pd(OAc)2 and PdCl2 with ligand 1,10-bis(diphenylphosphino)fer-
rocene (dppf) gave 3a in low yields (Table 1, entries 2–4). The best
result was obtained using PdCl2(PPh3)2 as catalyst, and toluene as
solvent, which gave product 3a in 95% yield (Table 1, entry 5),
whereas the same reaction in 1,4-dioxane gave 3a in 84% yield, and
in N-methylpyrrolidone gave 77% yield (Table 1, entries 6 and 7,
respectively).
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therapeutic use in schizophrenia, Drugs 40 (1990) 722–747.
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These results indicated the coupling reaction proceeded
smoothly and consistently within the planned reaction sequence.
After the optimized reaction conditions were established, subse-
quent hydrogenation generated the corresponding amine com-
pound which is difficult to isolate due to its unstable properties.
We have investigated the intramolecular condensation conditions
without purification of compound 4a. To our delight, 5a could be
obtained in 93% yield after 5 min at r.t. by adding catalytic amounts
of p-TSA to the filtrate, where 10% Pd/C had been removed (Table 2
entry 3).
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nation, Angew. Chem. Int. Ed. 47 (2008) 6338–6361.
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containing indoles from o-fluoronitrobenzenes, Org. Lett. 11 (2009) 637–639.
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diones using titanium(IV) chloride and triethylsilane, Tetrahedron Lett. 52 (2011)
6827–6830.
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deficient heteroaromatic amines with heteroaryl halides, Synth. Commun. 43
(2012) 456–463.
[15] Compound 5a: 1H NMR (300 MHz, CD3Cl): d 7.710 (d, 2H, J = 5.4 Hz), 7.404 (m,
3H), 7.323 (m, 2H), 7.014 (m, 3H), 6.918 (m, 1H), 6.779 (m, 1H), 6.704 (m, 1H),
4.975 (s, 1H). 13C NMR (100 MHz, CDCl3): d 169.49, 154.45, 142.60, 141.32,
140.85, 132.19, 131.94, 129.93, 128.67, 127.96, 127.56, 126.81, 124.17, 122.42,
119.70. HRMS (m/z) (M+H): Calcd. for C19H14N2: 271.123, found: 271.1233. Mp
129–131 8C. IR (KBr): 3350, 1609, 1571, 1445, 1283, 960. Compound 5b: 1H NMR
(300 MHz, CD3Cl): d 7.69 (d, 1H, J = 6.6 Hz), 7.44 (m, 3H), 7.38 (td, 1H, J = 7.8 Hz,
J = 1.5 Hz), 7.01 (m, 2H), 6.93 (m, 2H), 6.77 (d, 1H, J = 4.5 Hz), 6.72 (dd, 1H,
J = 7.8 Hz, J = 2.7 Hz), 6.63 (m, 1H), 4.97 (s, 1H). 13C NMR (100 MHz, CDCl3): d
170.58, 160.97, 158.58, 154.50, 142.05 (J = 9 Hz), 140.90, 138.64, 132.15
(J = 6 Hz), 130.26, 129.64, 128.01, 127.45, 122.60, 120.08 (J = 9 Hz), 119.69,
114.58 (J = 23 Hz), 112.88 (J = 23 Hz). HRMS (m/z) (M+H): Calcd. for
With optimized reaction conditions established, we examined
the scope of the method for the assembly of 1,4-diazepine
derivatives. A variety of substitutions on the o-bromonitroaro-
matic ring was tolerated, including electron-withdrawing (Table 3,
entries 3, 6, and 10) and electron-donating groups (Table 3, entries
2 and 9), as well as with fluoro substitution on the aromatic ring
(Table 3, entries 1 and 8) and with 2-bromo-3-nitropyridine
(Table 3, entries 4 and 11). It is noteworthy that the chloro
substituent and the carboxylic ester group remained intact in the
reactions and gave products in high yields (Table 3, entries 5 and
6). The two step sequence to substituted 1,4-diazepines gave yields
ranging from 82% to 95%, which corresponds to a yield of 90% to
98% over each step of the sequence. Furthermore, the reaction
could be scaled up to gram amounts without any problem [15].
C
19H13FN2: 289.1136, found: 289.1142. Mp 103–105 8C. IR (KBr): 3352, 1613,
1466, 1216, 1107, 866. Compound 5c: 1H NMR (300 MHz, CD3Cl): d 7.70 (d, 2H,
J = 7.8 Hz), 7.43 (m, 3H), 7.37 (m, 1H), 6.99 (d, 1H, J = 7.5 Hz), 6.89 (m, 2H), 6.74 (d,
1H, J = 7.5 Hz), 6.60 (s, 2H), 3.77 (s, 3H). 13C NMR (100 MHz, CDCl3): d 170.00,
156.61, 155.03, 141.67, 141.29, 135.77, 132.15, 131.94, 129.97, 129.58, 127.94,
127.44, 122.28, 120.24, 119.51, 113.13, 112.55, 55.59. HRMS (m/z) (M+H): Calcd.
for C20H16N2O: 301.1335, found: 301.1339. Mp 149–152 8C. IR (KBr): 3349, 2400,
1666, 1501, 1328, 1243, 1117, 960. Compound 5d: 1H NMR (300 MHz, CD3Cl): d
7.70 (d, 2H, J = 6.9 Hz), 7.56 (s, 1H), 7.41 (m, 3H), 7.27 (m, 2H), 6.97 (m, 2H), 6.74
(t, 2H, J = 7.5 Hz), 5.12 (s, 1H). 13C NMR (100 MHz, CDCl3): d 170.85, 153.40,
145.85, 140.77, 140.72, 132.38, 132.36, 130.41, 129.62, 128.07, 127.50, 126.01,
125.98, 123.51, 123.47, 122.93, 119.99, 119.85. HRMS (m/z) (M+H): Calcd. for
4. Conclusion
In conclusion, we have developed an efficient and convenient
synthesis of 1,4-diazepine derivatives via Pd-catalyzed amination,
hydrogenation and intramolecular condensation sequences. The
conditions of the coupling and cyclization have been fully
investigated. The efficiency and substituent tolerance of these
procedures have been demonstrated by synthesizing a number of
functionalized 1,4-diazepine derivatives. Considering the short
steps and mild conditions for the synthesis, together with the
inexpensive starting material and catalytic system, this method
provides an expansion on the substrate scope of Buchward’s
strategy, as well as an alternative route for the synthesis of 1,4-
diazepine derivatives.
C
20H13F3N2: 339.1104, found: 339.1105. Mp 129–131 8C. IR (KBr): 3267, 2400,
1607, 1445, 1325, 1123, 1074, 960, 751. Compound 5e: 1H NMR (300 MHz,
CD3Cl): 7.95 (d, 1H, J = 4.8 Hz), 7.68 (d, 2H, J = 7.5 Hz), 7.56 (d, 1H,
d
J = 7.8 Hz), 7.38 (m, 3H), 7.29 (t, 1H, J = 7.5 Hz), 7.01 (m, 2H), 6.92 (m, 1H),
6.83 (d, 1H, J = 5.1 Hz Hz), 6.19 (s, 1H). 13C NMR (100 MHz, CDCl3): d 171.06,
153.39, 152.01, 145.05, 140.80, 136.52, 135.24, 132.51, 132.30, 130.27, 129.64,
128.01, 127.13, 122.32, 120.40, 119.98. HRMS (m/z) (M+H): Calcd. for C18H13N3:
272.1182, found: 272.1187. Mp 183–186 8C. IR (KBr): 3277, 2380, 1703, 1454,
1227, 1021, 960. Compound 5f: 1H NMR (300 MHz, CD3Cl): d 7.67 (d, 2H,
J = 6.9 Hz), 7.42 (m, 3H), 7.30 (m, 2H), 6.95 (m, 3H), 6.76 (d, 1H, J = 8.1 Hz),
6.61 (d, 1H, J = 8.1 Hz). 13C NMR (100 MHz, CDCl3): d 170.78, 154.18, 119.84,
141.75, 141.40, 140.71, 132.30, 130.39, 129.67, 129.09, 128.13, 128.04, 127.34,
126.40, 122.71, 120.58. HRMS (m/z) (M+H): Calcd. for C19H14ClN2: 305.0840,
found: 305.0845. Mp 191–193 8C. IR (KBr): 3274, 2336, 1601, 1423, 1255, 1064,
960. Compound 5g: 1H NMR (400 MHz, CD3Cl): d 7.98 (s, 1H), 7,60 (m, 3H), 7.42–
7.52 (m, 3H), 7,35 (t, 1H, J = 5.4 Hz), 7.03 (m, 1H), 7.01 (m, 1H), 6.79 (d, 1H,
J = 7.6 Hz), 6.73 (d, 1H, J = 7.6 Hz), 5.21 (s, 1H). 13C NMR (100 MHz, CDCl3): d
166.552, 153.289, 147.334, 140.777, 132.660, 132.477, 132.344, 130.495,
130.320, 130.045, 129.641, 128.398, 128.036, 127.399, 126.095, 122.809,
Acknowledgment
This work was financially supported by National Natural
Science Foundation of China (No. 81102322).
120.019, 119.592, 51.968. HRMS (m/z) (M+H): Calcd. for
C21H17O2N2,
329.1284, found 329.1286. Mp 159–162 8C. IR (KBr): 3285, 1238, 1078, 1054,
975, 730. Compound 5h: 1H NMR (400 MHz, CD3Cl): d 7.60 (d, 2H, J = 8 Hz), 7.29
(m, 2H), 7.19 (m, 2H), 7.02 (m, 3H), 6.91 (t, 1H, J = 7.2 Hz), 6.77 (d, 1H, J = 8 Hz),
6.69 (d, 1H, J = 6.8 Hz), 4.97 (s, 1H). 13C NMR (100 MHz, CDCl3): d 169.36, 154.39,
142.62, 140.95, 140.12, 138.49, 132.18, 131.82, 129.54, 128.64, 127.59, 126.57,
124.10, 122.32, 119.67, 119.66, 21.38. HRMS (m/z) (M+H): Calcd. for C20H16N2:
References
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746
X.-J. Wang et al. / Chinese Chemical Letters 24 (2013) 743–746
285.1386, found: 285.1386. Mp 168–170 8C. IR (KBr): 3347, 1577, 1466, 1238,
Compound 5k: 1H NMR (400 MHz, CD3Cl): d 7.60 (d, 2H, J = 8 Hz), 7.55 (m,
1H), 7.31 (m, 1H), 7.21 (m, 5H), 7.05 (m, 1H), 6.95 (m, 1H), 6.75 (m, 2H), 5.11
(s, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): d 170.67, 153.36, 145.84, 140.91,
140.75, 137.91, 132.41, 132.24, 129.64, 128.87, 127.58, 125.90, 125.87, 123.27,
123.24, 122.87, 119.94, 119.78, 21.42. HRMS (m/z) (M+H): Calcd. for C21H15F3N2:
353.1260, found: 353.1264. Mp 180–183 8C. IR (KBr): 3309, 2740, 1637, 1325,
1076, 960, 751. Compound 5l: 1H NMR (400 MHz, CD3Cl): d 7.93 (d, 1H, J = 4 Hz),
7.55 (m, 3H), 7.31 (t, 1H, J = 7.6 Hz), 7.21 (d, 2H, J = 7.6 Hz), 6.98 (m, 2H), 6.91 (m,
1H), 6.84 (m, 1H), 5.91 (s, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3): d 170.93,
153.31, 151.96, 144.88, 140.62, 138.00, 136.36, 135.32, 132.42, 132.35, 129.68,
128.74, 127.17, 122.31, 120.37, 120.02, 21.42. HRMS (m/z) (M+H): Calcd. for
876. Compound 5i: 1H NMR (400 MHz, CD3Cl): d 7.59 (d, 2H, J = 7.6 Hz), 7.29 (m,
1H), 7.20 (m, 2H), 7.03 (m, 2H), 6.94 (m, 1H), 6.78 (d, 1H, J = 8 Hz), 6.71 (m, 1H),
6.62 (m, 1H), 4.92 (s, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3): d 170.43,
160.92, 158.53, 154.43, 142.14, 140.53, 138.66, 138.06, 132.01 (J = 17 Hz), 129.62,
128.69, 127.46, 122.49, 120.11, 119.65, 114.40 (J = 24 Hz), 112.61 (J = 23 Hz),
21.36. HRMS (m/z) (M+H): Calcd. for C20H15FN2: 303.1292, found: 303.1296. Mp
145–148 8C. IR (KBr): 3345, 1620, 1487, 1220, 1113, 960. Compound 5j: 1H NMR
(400 MHz, CD3Cl): d 7.60 (d, 2H, J = 7.6 Hz), 7.31 (m, 1H), 7.19 (d, 2H, J = 7.6 Hz),
7.02 (m, 1H), 6.91 (t, 1H, J = 7.6 Hz), 6.88 (s, 1H), 6.77 (d, 1H, J = 8 Hz), 6.65 (m,
2H). 13C NMR (100 MHz, CDCl3): d 169.87, 156.60, 154.98, 141.80, 140.20, 138.47,
135.80, 132.19, 131.83, 129.59, 128.65, 127.51, 122.23, 120.18, 119.48, 112.93,
112.44, 55.59, 21.38. HRMS (m/z) (M+H): Calcd. for C21H18N2O: 315.1492, found
315.1495. Mp 178–180 8C. IR (KBr): 3300, 1567, 1433, 1203, 1103, 982.
C
19H15N3: 286.1339, found: 286.1347. Mp 175–177 8C. IR (KBr): 3223, 2246,
1667, 1411, 1227, 1021, 960.