Simultaneous reduction of the nitro group and the azide group in o-nitrophenylazide induced by the TiCl4/Sm system: A novel synthesis of 2,3-dihydro-1H-1,5-benzodiazepines

Article abstract of DOI:10.1016/S0040-4039(00)01888-8

o-Nitrophenylazide was treated with the low-valent titanium reagent derived from the TiCl₄/Sm system to produce the intermediate 2 in situ, which was a 'living' double-anion and reacted readily with ketones containing active methyl or methylene groups to afford 2,3-dihydro-1H-1,5-benzodiazepines in moderate to high yields under mild and neutral conditions.

Full text of DOI:10.1016/S0040-4039(00)01888-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 73–75
Simultaneous reduction of the nitro group and the azide group in
o-nitrophenylazide induced by the TiCl /Sm system: a novel
4
synthesis of 2,3-dihydro-1H-1,5-benzodiazepines
a
a,b,
c
Weihui Zhong, Yongmin Zhang * and Xiaoyuan Chen
a
Department of Chemistry, Zhejiang University (Campus Xixi ), Hangzhou 310028, PR China
b
Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, PR China
c
Department of Chemistry, Hunan Jishou University, Jishou 416000, PR China
Received 10 August 2000; revised 9 October 2000; accepted 26 October 2000
Abstract—o-Nitrophenylazide was treated with the low-valent titanium reagent derived from the TiCl /Sm system to produce the
4
intermediate 2 in situ, which was a ‘living’ double-anion and reacted readily with ketones containing active methyl or methylene
groups to afford 2,3-dihydro-1H-1,5-benzodiazepines in moderate to high yields under mild and neutral conditions. © 2000
Elsevier Science Ltd. All rights reserved.
1
H-1,5-Benzodiazepine derivatives have attracted
preparation of 2,3-dihydro-1H-1,5-benzodiazepines us-
ing o-nitrophenylazide as the starting material.
strong interest due to their biological properties such as
anticonvulsant activity. The method for preparing this
1
kind of compound using o-phenylenediamines as start-
ing materials requires harsh conditions such as an acid
or base as catalyst, moderate to high thermal condi-
tions and prolonged reaction times, moreover, the
It is well known that low-valent titanium reagents have
an exceedingly high ability to promote reductive cou-
pling of carbonyl compounds. Many other functional
4
groups can also be reduced by these reagents. Our
2
,3
yields are relatively low. Here we wish to describe a
previous work has shown that the TiCl /Sm system can
4
5
new method induced by the TiCl /Sm system for the
induce reduction or coupling reactions. Nitro com-
4
Scheme 1.
Keywords: titanium tetrachloride; samarium; nitro group; azide; reductive cyclization; 2,3-dihydro-1H-1,5-benzodiazepine.
*
Corresponding author.
0
040-4039/01/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01888-8

7
4
W. Zhong et al. / Tetrahedron Letters 42 (2001) 73–75
Table 1. The preparation of 2,3-dihydro-1H-1,5-benzodi-
When MeOH (0.2 mL) was added to the solution of
intermediate 2, the brown–red color of the mixture
immediately turned into a yellow color to afford o-
phenylenediamine 4. However, if ketones were added to
the solution of 4 under similar conditions, no reaction
took place and no products 3 could be detected (entries
3a and 3i). Thus the intermediate 2 derived from o-
nitrophenylazide is more reactive than o-phenylene-
diamine.
azepines induced by the TiCl /Sm system
4
Entry
R
T (h)
Yield (%)a
78
3
3
3
3
3
3
3
3
3
3
3
3
a
a
b
c
d
e
f
g
h
i
Et
Et
n-Pr
n-Bu
n-C H
2
24
2
4
4
1
1
1
3
b
0
83
85
65
88
87
89
78
67
5
11
C H
6
5
p-MeC H
p-MeOC H
p-ClC H
p-BrC H
p-BrC H
m-NO C H
6
4
The structures of the products 3 were confirmed by IR,
6
4
1
8,9
H NMR, MS and elemental analysis. The IR spectra
6
4
−
1
of 3a–j exhibited a sharp band at ꢀ3350 cm (ꢀNH
stretching) and a medium absorption band at ꢀ1650
cm (CꢁN). The H NMR spectra of products 3a–d
derived from aliphatic ketones and o-nitrophenylazide
showed a two-proton singlet at lH ꢀ2.10 which is due
3
24
5
6
4
4
b
i
j
0
6
−
1
1
56
2
6
4
a
Isolated yields based on o-nitrophenylazide.
MeOH (0.2 mL) was added after the formation of the intermediate
b
1
to the methylene group. The H NMR spectra of the
2
. In this case, no products 3 could be detected.
corresponding products 3e–j showed a two-proton sin-
gle at lH ꢀ2.80 as for aromatic ketones. On the other
hand, in the mass spectra of the products 3a–j,
cyclic 1,5-benzodiazepine ions and benzimidazole ions
derived from the fragmentation and skeletal rearrange-
ment of the molecular ions were the main features
pounds and azide compounds can be easily reduced by
low-valent titanium or other reagents; however, they
6
are just reduced to the corresponding amines. Little
attention has been paid to reduction intermediates
derived from nitro or azide groups by treatment with
low-valent titanium reagents, which might induce some
reactions difficult to accomplish by other existing
methodologies. Recently, we reported the simultaneous
reduction of a nitro group and an SꢀS bond in bis(o-ni-
(
Table 1).
Ketones containing an active methylene group such as
cyclopentanone, cyclohexanone and 3-pentanone (en-
tries 3k–m) have been reacted with the intermediate 2
and gave the corresponding products 3 in low to mod-
erate yields (Scheme 2).
trophenyl)disulfides induced by the TiCl /Sm system
4
and its use in the synthesis of some heterocycles con-
7
taining nitrogen and sulfur. In order to extend the
application of the TiCl /Sm system, we tried the simul-
taneous reduction of a nitro group and an azide group
4
In summary, a series of 2,3-dihydro-1H-1,5-benzodi-
azepines was synthesized via reductive cyclization in-
in o-nitrophenylazide using the TiCl /Sm system. When
4
duced by the TiCl /Sm system of o-nitrophenylazide
4
o-nitrophenylazide 1 (1 equiv.) was added dropwise to
the low-valent titanium reagent (2.2 equiv.) prepared
from samarium powder (3 equiv.) and titanium tetra-
chloride (2.2 equiv.) in anhydrous THF under reflux,
the dark color of the solution gradually changed into a
brown–red color. The above phenomenon showed that
the nitro group and the azide group had been reduced
simultaneously by the low-valent titanium reagent to
form the intermediate 2 as a ‘living’ double-anion in
situ. When ketones containing active methyl groups
were treated with intermediate 2, the desired products
with ketones containing an active methyl or methylene
group. The advantages of our method are easily accessi-
ble starting materials, convenient manipulation and
moderate to high yields.
Acknowledgements
We are grateful to the National Natural Science Foun-
dation of China (Project No. 29872010) and the NSF of
Zhejiang province for financial support.
2
,3-dihydro-1H-1,5-benzodiazepines 3 were obtained in
good yields (Scheme 1).
Scheme 2.

W. Zhong et al. / Tetrahedron Letters 42 (2001) 73–75
75
References
8. General procedure: TiCl (0.25 mL, 2.2 mmol) was added
4
dropwise using a syringe to a stirred suspension of Sm
powder (0.45 g, 3 mmol) in freshly distilled dry THF (20
mL) at room temperature under a nitrogen atmosphere.
After the completion of addition, the mixture was refluxed
for 2 h. The suspension of the low-valent titanium reagent
formed was cooled to room temperature and a solution of
o-nitrophenylazide 1 (1 mmol) in anhydrous THF (2 mL)
was added. The deep blue color of the solution changed
into a brownish red within 5–10 min. Then ketone (2.2
mmol) in anhydrous THF (2 mL) was added slowly. After
stirring at 60°C for a given time (Table 1, the reaction was
monitored by TLC), the reaction was quenched with dis-
tilled water (10 mL) and extracted with ether (3×30 mL).
The organic phase was washed with brine (15 mL) then
1
. Chimirri, A. Farmaco 1991, 46(1, Suppl.), 289. (Chem.
Abstr. 1991, 115, 8753m).
. (a) Orlov, V. D.; Desenko, S. M.; Kolos, N. N. Khim.
2
Geterotsikl. Soedin. 1984, 126 (Russ) (Chem. Abstr. 1984,
1
00, 209761h). (b) El-Sayed, A. S.; Haggag, B.; El-Bay-
ouki, K. A. M. Orient. J. Chem. 1987, 3, 66 (Chem. Abstr.
988, 108, 5910e). (c) Mishriky, N.; Haggag, B.; Latif, N.
Egypt J. Chem. 1991, 32, 679. (d) Insuasty, B.; Abonia, R.;
Quiroga, J.; Meier, H. J. Heterocycl. Chem. 1993, 30, 229.
. (a) Rao, P. S.; Venkataratnam, R. V. Synth. Commun.
991, 21, 1811. (b) Herbert, J. A. L.; Suschitzky, H. J.
Chem. Soc., Perkin Trans. 1 1974, 2657. (c) Reddi, P. S.;
Ratnam, C. V.; Rao, N. V. S. Indian J. Chem. 1972, 10,
1
3
1
982. (d) Morales, H. R.; Bulbarela, A.; Contreras, R.
dried with anhydrous MgSO . The solvent were removed
4
Heterocycles 1986, 24, 135.
. For reviews, see: (a) McMurry, J. E. Acc. Chem. Res.
under reduced pressure to give the crude product which
was purified by preparative thick layer chromatography
using ethyl acetate and cyclohexane (1:6) as eluant.
4
1974, 7, 281. (b) McMurry, J. E. Acc. Chem. Res. 1983, 16,
4
05. (c) McMurry, J. E. Chem. Rev. 1989, 89, 1513. (d)
9. Typical physical data of compounds are listed. Compound
3c, 2,4-dibutyl-2,3-dihydro-2-methyl-1H-1,5-benzodiazepine
Oil. wmax: 3350 (NH), 2980, 2850, 1475, 1380 (CH , CH ),
Lenoir, D. Synthesis 1989, 883. (e) F u¨ rstner, A.; Bog-
danovi, B. Angew. Chem., Int. Ed. 1996, 35, 2443.
. (a) Wang, J. Q.; Zhang, Y. M. Synth. Commun. 1995, 25,
3
2
−
1
5
1650 (CꢁN) cm . l : 7.23–6.46 (4H, m, ArH), 3.02 (1H,
H
3545. (b) Zhou, L. H.; Zhang, Y. M. Synth. Commun.
1998, 28, 3249. (c) Zhou, L. H.; Zhang, Y. M. Tetrahedron
2000, 56, 2953. (d) Zhou, L.; Zhang, Y. J. Chem. Res.(S)
1999, 27. (e) Zhou, L.; Zhang, Y. Synth. Commun. 1999,
29, 533.
br s, NH), 2.44 (2H, t, J=6.5 Hz, CH ), 2.06 (2H, s,
2
+
CH ), 1.75–0.75 (19H, m, alkyl-H). m/z (%): 272 (M ,
2
13.4), 215 (100), 174 (29.7) and 132 (30.7). Anal.
C H N . Calcd C, 79.36; H, 10.36; N, 10.28. Found C,
18
28
2
79.44; H, 10.23; N, 10.09%. Compound 3i, 2,4-di(4%-bro-
2a
6
. (a) Huang, Y.; Zhang, Y. M.; Wang, Y. L. Synth. Com-
mun. 1997, 27, 1059. (b) Bosch, I.; Costa, A. M.; Martin,
M.; Urpi, F.; Vilarrasa, J. Org. Lett. 2000, 2, 397 and
references cited therein.
. Zhong, W. H.; Chen, X. Y.; Zhang, Y. M. Synth. Com-
mun. 2000, 30, in press.
mophenyl)-2,3-dihydro-2-methyl-1H-1,5-benzodiazepine
152–154°C. wmax: 3350 (NH), 2960, 2830, 1465, 1375 (CH ,
3
−
1
CH ), 1645 (CꢁN) cm . l : 7.73–6.65 (12H, m, ArH),
2
H
3.40 (1H, br s, NH), 2.81 (2H, s, CH ), 1.58 (3H, s, CH ).
2
+
3
+
+
7
m/z (%): 472 (M +4, 9.0), 470 (M +2, 13.7), 468 (M ,
7.0), 275 (49), 274 (100), 273 (55.4) and 272 (98.2).
.
.