Recyclable gallium(III) triflate-catalyzed [4+3] cycloaddition for synthesis of 2,4-disubstituted-3H-benzo[b][1,4]diazepines

Article abstract of DOI:10.1016/j.tetlet.2013.08.092

Simple and efficient Ga(OTf)₃-catalyzed [4+3] cycloaddition of 1,3-diarylpropynones and o-phenylenediamines is developed for the preparation of 2,4-disubstituted-3H-benzo[b][1,4]diazepines. The reaction has advantages of using a green solvent, generating a minimal amount of waste, and easy catalyst recycle.

Full text of DOI:10.1016/j.tetlet.2013.08.092

Tetrahedron Letters 54 (2013) 6178–6180
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Tetrahedron Letters
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Recyclable gallium(III) triflate-catalyzed [4+3] cycloaddition
for synthesis of 2,4-disubstituted-3H-benzo[b][1,4]diazepines
c,
Shi-Gang Huang a, Hai-Feng Mao a, Shao-Fang Zhou a, Jian-Ping Zou a,b, , Wei Zhang
⇑
⇑
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and Chemical Engineering, Suzhou University, 199 Renai Street, Suzhou, Jiangsu 215123, China
b Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, China
c Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple and efficient Ga(OTf)3-catalyzed [4+3] cycloaddition of 1,3-diarylpropynones and o-phenylenedi-
amines is developed for the preparation of 2,4-disubstituted-3H-benzo[b][1,4]diazepines. The reaction
has advantages of using a green solvent, generating a minimal amount of waste, and easy catalyst recycle.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 9 August 2013
Revised 22 August 2013
Accepted 24 August 2013
Available online 31 August 2013
Keywords:
Ga(OTf)3
Catalysis
[4+3] Cycloaddition
1,3-Diarylpropynones
2,4-Disubstituted-3H-
benzo[b][1,4]diazepines
Compounds containing privileged benzodiazepine ring system
have a wide range of pharmacological and biological activities.1
They have been used as analgesic, sedative, anticonvulsant, anti-
anxiety, antidepressive, hypnotic, and antiinflammatory agents.2
1,5-Benzodiazepines can be prepared by cyclization or cycloaddi-
CH2Cl2, EtOH, and EtOH/H2O. It was found that 95% EtOH is a good
choice of solvent (Table 1, entry 4). Reactions with different ratios
of substrates indicated that 1:1.5 of 1a:2a increased the yield to
71% (Table 1, entry 7). Increase of the reaction temperature to
¯
40 ôC further improved the yield to 78% (Table 1, entry 9), but
tion of o-phenylenediamines with 1,3-diketones,
alkenones, or b-haloketones.3 However, reactions of o-phenylen-
ediamines with
,b-conjugated alkynones are limited.4
a,b-conjugated
a
We have recently reported Ga(OTf)3-catalyzed [4+3] and
[4+2+1] cycloaddition reactions of o-phenylenediamines for the
synthesis of benzodiazepines (Scheme 1). The reaction of o-pheny-
lenediamines with o-hydroxychalcones5 or acetophenones6 both
Ar
H
N
R1
O
R1
NH2
NH2
[4+3]
Ar
OH
(a)
N
+
Ga(OTf)3
10 mol%
OH
afforded 2,3-dihydro-1H-benzo[b][1,4]diazepines (Scheme 1,
a
and b). The reaction of o-phenyl-enediamines with alkynoates
afforded 2,5-dihydro-1H-benzo[b]-[1,4]diazepines (Scheme 1, c).7
Introduced in this Letter is a new method for the synthesis of
2,4-disubstituted-3H-benzo[b]-[1,4]diazepines by [4+3] cycloaddi-
tion of o-phenylenediamines with 1,3-diarylpropynones.
The initial cycloadditions were carried out using equal molar
o-phenylenediamine 1a and 1,3-diphenylprop-2-yn-1-one 2a at
room temperature and in different solvents including CH3CN,
Ar
H
N
O
R1
R1
[4+2+1]
NH2
NH2
(b)
(c)
+
Ga(OTf)3
10 mol%
N
Ar
2 equiv
O
H
N
R1
R1
O
NH2
NH2
[4+2+1]
OR2
+
OR2
OR2
Scheme 1. [4+3] and [4+2+1] cycloadditions of o-phenylenediamines.
Ga(OTf)3
10 mol%
N
H
O
⇑
Corresponding authors.
E-mail addresses: jpzou@suda.edu.cn (J.-P. Zou), wei2.zhang@umb.edu
(W. Zhang).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.08.092

S.-G. Huang et al. / Tetrahedron Letters 54 (2013) 6178–6180
6179
the reaction under reflux (78 °C) decreased the yield to 52%
Table 2 (continued)
(Table 1, entry 10). Increase of the reaction time from 10 to 24 h
gave the best yield of 92% (Table 1, entry 11). Reaction without cat-
Entry Propynone 2
Product 3
Yieldb (%)
O
OCH3
Table 1
Ga(OTf)3-catalyzed reactions of 1a and 2aa
Ph
N
H3CO
5
42
2e
O
NH2
N
N
3e
Ph
+
Ph
NH2
O
N
O
Ph
O
1a
Entry
2a
3a
N
Ph
6
7
8
94
45
97
1a:2a
Solvent
Ga(OTf)3 (mol %)
Time (h)
Yieldb (%)
2f
N
3f
Ph
Ph
1
2
3
4
5
6
7
8
1:1
1:1
1:1
1:1
CH3CN
CH2Cl2
EtOH
10
10
10
10
10
10
10
10
10
10
10
–
10
10
10
10
10
10
10
10
10
10
24
24
24
Trace
Trace
35
O
95% EtOH
50% EtOH
95% EtOH
95% EtOH
95% EtOH
95% EtOH
95% EtOH
95% EtOH
95% EtOH
95% EtOH
51
38
60
71
Ph
1:1
N
1:1.2
1:1.5
1:2
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
2g
72
N
3g
9
78c
52d
92
10
11
12
13
F
O
28
77
N
5
F
Ph
a
b
c
2h
Reactions at room temp.
Isolated yields.
40 °C.
N
3h
Ph
d
Reflux.
Br
O
H2N
Br
O
O
HN
9
92
86
Ph
Ph
Table 2
2i
Ga(OTf)3-catalyzed reactions of 1a and 2a–2ka
Ph
Ph
3i
R1
NO2
O
H2N
O
NH2
N
HN
NO2
R1
10
+
Ph
2j
NH2
N
Ph
3j
1a
2a-2k
3a-3k
O
H2N
Entry Propynone 2
Product 3
Yieldb (%)
N
O
Ph
Ph
Ph
11
92
O2N
N
2k
1
92
91
Ph
Ph
3k
O2N
N
3a
2a
a
Reaction conditions: 1 mmol 1a, 1.5 mmol 2, 10 mol % Ga(OTf)3, 25 °C for 24 h.
O
F
b
Isolated yield.
Ph
N
F
2
2b
alyst or with 5 mol % of catalyst gave product in 28% and 77%
yields, respectively (Table 1, entries 12 and 13). The effort of reac-
tion optimization revealed that the best condition for the cycload-
dition is to use 1:1.5 of 1a:2a with 10 mol % of Ga(OTf)3 in 95%
EtOH and at room temperature for 24 h.
To evaluate the generality and scope of the reaction, a series of
1,3-diarylpropynones 2 were employed for the cycloaddition reac-
tions. It was found that 1,3-diarylpropynones 2 bearing para-F and
para-Br on the 1-phenyl ring are favorable for the formation of
benzodiazepines 3 (Table 2, entries 2 and 3), whereas those bearing
electron-donating groups such as CH3, OCH3, and Ph are unfavor-
able (Table 2, entries 4, 5, and 7). Reactions of 1-furyl-3-phenylpro-
pynone 2f gave product 3f in 94% yield (Table 2, entry 6). Reactions
of ortho-substituted 1,3-diarylpropynones with Br and NO2 on the
1-phenyl ring only gave Michael addition products without cycli-
zation (Table 2, entries 9 and 10) except for the F-substituted sub-
strate 2h (Table 2, entry 8). Interestingly, we found that 2k with
N
3b
Ph
O
Br
Ph
N
Br
3
4
95
74
2c
N
Ph
Ph
3c
O
Ph
N
2d
N
3d

6180
S.-G. Huang et al. / Tetrahedron Letters 54 (2013) 6178–6180
Table 3
Table 4
Cycloaddition of diamines 1 and 2aa
Recycling of Ga(OTf)3 catalysta
Yieldb (%)
Br
Entry
Diamine 2
Product 3
NH2
Ph
Ph
N
O
10mol%
Ga(OTf)3
NH2
NH2
N
1
NH2
92
47
+
N
3a
Ph
O
1a
95% EtOH
Ph
N
3c
Br
2c
Ph
1a
NH2
Ph
O
NH
Yieldb (%)
2
3
Round
Time (h)
NH2
1b
Ph
HN
Ph
Ph
1
2
3
4
5
6
7
8
9
10
24
24
24
24
24
24
24
24
24
24
95
96
96
94
95
95
95
94
96
95
3l
NH2
N
N
NH2
93
1c
Ph
Ph
3m
NH2
NH2
N
4
5
6
96
89
72
1d
N
3n
a
The reactions were performed at 25 °C.
Ph
Ph
b
Isolated yield.
NH2
NH2
N
minimal waste disposal, the catalyst Ga(OTf)3 can be easily sepa-
rated from the product simply by filtration and can be reused with-
out further treatment for at least 10 times.
Cl
Cl
N
3o
1e
Ph
NH2
NH2
Ph
N
Acknowledgments
O2N
O2N
N
Ph
Ph
1f
J.P.Z. thanks the National Natural Science Foundation of China
for financial support (No. 20772088, 21172163) and A Project
Funded by the Priority Academic Program Development of Jiangsu
Higher Education Institutions.
3p
O
O
N
NH2
NH2
Ph
Ph
7
47
N
Ph
1g
3q
Supplementary data
a
Reaction conditions: 1 mmol 1, 1.5 mmol 2, 10%mol Ga(OTf)3, 25 °C for 24 h.
Isolated yield.
b
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.08.
092.
para-NO2 substituted 1-phenyl afforded imine 3k (Table 2, entry
11). It may attribute to the para-NO2 on the 1-phenyl ring which
made the carbonyl group more electrophilic.
References and notes
The scope and limitations of the reaction of diamines 1 were also
explored. The reaction of ethylenediamine 1b with 2a only gave Mi-
chael addition product 3l (Table 3, entry 2). Among the substituted
o-phenylenediamines 1, those with electron-donating groups such
as CH3 are favorable for the cycloaddition (Table 3, entries 3 and 4).
Weak electron-withdrawing groups such as Cl have little effect on
yield (Table 3, entry 5). However, those bearing a strong electron-
withdrawing group such as NO2 and carbonyl afforded products
with significantly reduced yield (Table 3, entries 6 and 7).
The catalyst reusability was also investigated. A mixture of o-
phenylenediamine 1a (1 mmol), 1-(4-bromophenyl)-3-phenyl-
prop-2-yn-1-one 2c (1 mmol), and Ga(OTf)3 (0.1 mmol) in 3 mL
of 95% EtOH was stirred at room temperature for 24 h. After com-
pletion of the reaction as monitored with TLC, product 3c was pre-
cipitated out from the reaction solvent while Ga(OTf)3 was left in
the solution. After the product was collected by filtration, the cat-
alyst in the filtrate was directly used for the next reaction without
further treatment. This process was repeated ten times and the cat-
alyst maintained good and consistent activity (Table 4).
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In summary, a simple and efficient method for the preparation
of 2,4-disubstituted-3H-benzo[b][1,4]diazepines by Ga(OTf)3-cata-
lyzed [4+3] cycloaddition of o-phenylenediamines with 1,3-diaryl-
propynones has been developed. The reactions are conducted in
95% EtOH at room temperature. In addition to mild reaction condi-
tions, simple manipulations, using renewable green solvent, and
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