NbCl5 as an efficient catalyst for the synthesis of 1,5-benzodiazepine derivatives

Article abstract of DOI:10.1080/00397910902752238

1,5-Benzodiazepine derivatives were synthesized in moderate to excellent isolated yields by the condensation reactions of o-phenylenediamine and ketones catalyzed by NbCl5 under mild conditions using n-hexane as solvent at 50°C. This method is simple and

Full text of DOI:10.1080/00397910902752238

This article was downloaded by: [The Aga Khan University]
On: 10 October 2014, At: 23:01
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
NbCl as an Efficient Catalyst
5
for the Synthesis of 1,5-
Benzodiazepine Derivatives
a
a
a
Shu-Tao Gao , Wei-Hua Liu , Jing-Jun Ma , Chun
a
Wang & Qian Liang
a
College of Sciences , Agricultural University of
Hebei , Baoding, China
Published online: 12 Aug 2009.
To cite this article: Shu-Tao Gao , Wei-Hua Liu , Jing-Jun Ma , Chun Wang
&
Qian Liang (2009) NbCl as an Efficient Catalyst for the Synthesis of 1,5-
5
Benzodiazepine Derivatives, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:18, 3278-3284, DOI:
10.1080/00397910902752238
To link to this article: http://dx.doi.org/10.1080/00397910902752238
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with

primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

1
Synthetic Communications , 39: 3278–3284, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902752238
NbCl as an Efficient Catalyst for the Synthesis
5
of 1,5-Benzodiazepine Derivatives
Shu-Tao Gao, Wei-Hua Liu, Jing-Jun Ma,
Chun Wang, and Qian Liang
College of Sciences, Agricultural University of Hebei, Baoding, China
Abstract: 1,5-Benzodiazepine derivatives were synthesized in moderate to excel-
lent isolated yields by the condensation reactions of o-phenylenediamine and
ketones catalyzed by NbCl under mild conditions using n-hexane as solvent at
5
ꢀ
5
0 C. This method is simple and effective with good yields.
5
Keywords: 1,5-Benzodiazepines, ketones, NbCl , o-phenylenediamines
INTRODUCTION
Benzodiazepines and their derivatives are very important compounds
because of their easy functionalization and potential pharmacological
properties. They are widely used as anticonvulsant, analgesic, hypnotic,
sedative, and antidepressive agents. Besides their biological properties,
benzodiazepine derivatives are also used as dyes for acrylic fibers. In
addition, 1,5-benzodiazepines are valuable synthons used for the
synthesis of other fused-ring compounds such as triazolo-, oxazino-,
[1]
oxadiazolo-, and furano-benzodiazepines. The preparation of 1,5-ben-
zodiazepines has received increasing attention in recent years. Until
now, comparatively few methods for their preparation had been reported in
the literature. These include condensation reactions of o-phenylenediamine
derivatives with a,b-unsaturated carbonyl compounds, b-haloketones, or
[2a]
[2b]
ketones promoted by BF ꢁ OEt ,
NaBH4,
polyphosphoric acid or
3
2
Received September 17, 2008.
Address correspondence to Chun Wang, College of Sciences, Agricultural
University of Hebei, Baoding 071001, Hebei Province, China. E-mail: wangc69@
yahoo.com.cn
3
278

NbCl
5
as Efficient Catalyst
3279
Scheme 1. Equation of the reaction of o-phenylenediamine and ketones.
[
2c]
[2d]
SiO2, ceric ammonium nitrate (CAN), MgO=POCl , Yb(OTf)3,
[2e]
[2f]
3
2g,2h]
[
Al O =P O or AcOH under microwave conditions,
5
Amberlyst-15 in
[2j]
2
3
2
[
2i]
[2k]
ionic liquid,
1
CeCl ꢁ7H O=NaI supported on silica gel,
InBr3,
[2m]
and Sc(OTf) .
3
2
[
2l]
-butyl-3-methylimidazolium bromide ([bmim]Br),
3
However, many of these methodologies have shortcomings, such as long
reaction times, poor yields of the products, drastic reaction conditions,
occurrence of several side products, and expensive reagents.
More recently, NbCl has become a research focus as a Lewis acid
5
[
3–6]
catalyst in promoting various organic transformations.
with other Lewis acids, niobium(V) chloride has some advantages, such
Compared
[
5a,6]
as ease of handling, moisture stability, and low catalyst loading.
In continuing our endeavor to develop novel synthetic methodologies,
[7–10]
herein, we report a mild and efficient condensation reaction of o-phe-
nylenediamine and ketones catalyzed by NbCl under mild conditions
5
(
Scheme 1).
EXPERIMENTAL
Melting points were recorded on an electrothermal apparatus and are
1
uncorrected. H NMR (300 MHz) spectra were determined with a
Brucker Avance 300 spectrometer (CDCl -d ) using tetramethylsilane
3
6
ꢂ1
(TMS) as internal standard. Infrared (IR) spectra (cm ) were measured
with a WQF-510 spectrometer.
General Procedure
A mixture of o-phenylenediamine (5 mmol), ketone (12 mmol), and NbCl
ꢀ
5
(
10 mmol%) in n-hexane (5 mL) was stirred rapidly at 50 C for a certain
period of time (shown in Table 1) to complete the reaction (monitored by
thin-layer chromatography, TLC). After completion, the reaction mixture
was diluted with water (10 mL) and extracted with EtOAc (3 ꢃ 5 mL). The
extract was dried over anhydrous MgSO and evaporated under reduced
4
pressure. Then the crude product was subjected to column chromato-
graphy over silica gel using EtOAc–hexane (1:4) as eluent to afford pure

3280
S.-T. Gao et al.
Table 1. NbCl
5
-catalyzed synthesis of 1,5-benzodiazepines
Time Yield
ꢀ
Mp ( C)
[lit]
Mp ( C)
ꢀ
Entry
Ketone
Product
(h)
3
(%)
96
[
2a,2f]
a
CH
3
COCH
3
139–141
137–139
[
[
2a,2f]
2a,2f]
[11]
b
PhCOCH
3
6
4.5
5
91
90
95
88
150–151
138–139
138–140
142–144
151–152
c
d
e
f
CH COCH CH
3 2 3
137–138
CH
CH
3
COCH
CH
2
139–140
2
3
CH CH
3
2
CO
CH CH
[2a,2f]
5
144–145
118–120
2
3
CH
CH (CH3)2
3
COCH
2
[12]
5
90
87
85
118–119
[
2a,2b,2e]
g
4
.5
137–139 138–139
[
2a]
h
5
137–138
137–139
1
,5-benzodiazepine. All the products were fully characterized by IR and H
1
NMR spectroscopy and melting points, which were consistent with the
literature data.
Spectroscopic Data for Compounds
Entry 3a
1
H NMR (300 MHz, CDCl ) d : 1.35 (s, 6H), 2.22 (s, 2H), 2.38 (s, 3H),
.45 (br, 1H), 6.65–7.21 (m, 4H); IR (KBr) n: 3280, 1650, 1590 cm .
3
H
ꢂ1
3
Entry 3b
1
H NMR (300 MHz, CDCl ) d : 1.72 (s, 3H), 2.95 (d, 2H, J ¼ 0.17 Hz),
3
H
3
3
.12 (d, 2H, J ¼ 0.17 Hz), 3.38 (br, 1H), 6.80–7.72 (m, 14H); IR (KBr) n:
ꢂ1
350, 1645, 1592 cm
.

NbCl
5
as Efficient Catalyst
3281
Entry 3c
1
H NMR (300 MHz, CDCl ) d : 0.99 (t, 3H, J ¼ 7.0 Hz), 1.25 (t, 3H,
3
H
J ¼ 7.1 Hz), 1.68 (q, 2H, J ¼ 7.0 Hz), 2.14 (m, 2H), 2.32 (s, 3H), 2.70
(
1
q, 2H, J ¼ 7.1 Hz), 3.29 (br, 1H), 6.80–7.30 (m, 4H); IR (KBr) n: 3348,
ꢂ1
647, 1590 cm
.
Entry 3d
1
H NMR (300 MHz, CDCl ) d : 0.78–1.48 (m, 13H), 2.40 (s, 3H), 2.89
3
H
(
1
q, 1H, J ¼ 7.0 Hz), 3.72 (br, 1H), 6.68–7.41 (m, 4H); IR (KBr) n: 3348,
ꢂ1
655, 1592 cm
.
Entry 3e
1
H NMR (300 MHz, CDCl ) d : 0.83–1.52 (m, 14H), 2.33 (m, 2H), 2.93
3
H
(
1
q, 1H, J ¼ 7.0 Hz), 3.69 (br, 1H), 6.67–7.41 (m, 4H); IR (KBr) n: 3340,
ꢂ1
649, 1588 cm
.
Entry 3f
1
H NMR (300 MHz, CDCl ) d : 0.96–1.05 (m, 12H), 1.30 (s, 3H),
3
H
1
.49–1.50 (m, 2H), 1.67–1.75 (m, 1H), 2.04–2.25 (m, 3 H), 2.24 (d,
J ¼ 12.7 Hz, 2H), 6.62–6.65 (m, 1H), 6.85–6.90 (m, 2 H), 7.05–7.13 (m,
ꢂ1
1
H); IR (KBr) n: 3330, 1655, 1589 cm
.
Entry 3g
1
H NMR (300 MHz, CDCl ) d : 1.02–2.23 (m, 13H), 3.24 (m, 2H), 3.72
3
H
ꢂ1
(
br, 1H), 6.58–7.21 (m, 4H); IR (KBr) n: 3344, 1659, 1600 cm .
Entry 3h
1
H NMR (300 MHz, CDCl ) d : 0.92–2.32 (m, 17H), 3.21 (m, 2H), 3.70
3
H
ꢂ1
(
br, 1H), 6.5–7.16 (m, 4H); IR (KBr) n: 3340, 1648, 1600 cm .
RESULTS AND DISCUSSION
In our initial research, we studied the catalytic properties of NbCl for the
5
synthesis of 1,5-benzodiazepine using o-phenylenediamine and acetone as
substrates. The reaction was carried out using 5 mol% NbCl in CH Cl
2
5
2

3282
S.-T. Gao et al.
Table 2. Yield of reactions on different quantities of
a
catalyst
Catalyst quantity (mol %)
Yield (%)
0
2
5
7
0
5
—
17
42
60
86
83
1
1
a
The reaction time was 2 h.
ꢀ
as solvent at 40 C for 4 h to afford the corresponding 1,5-benzodiazepine in
42% yield. Encouraged by this result, we studied different reaction para-
meters to optimize the reaction conditions. The reaction was performed in
different solvents such as CH CN, CH Cl , C H OH, and n-hexane. Hex-
5
3
2
2
2
ane was found to be the best solvent in terms of yields and reaction time.
The reaction was also conducted in solvent-free conditions, but the yields
were not as good as to the yields obtained in n-hexane as solvent. Next, the
loading amount of NbCl was also optimized (Table 2). The results indi-
5
cated that 10 mol% of NbCl was sufficient to promote reaction. The opti-
5
mum yields of the product were obtained when a 1:2.4 ratio of o-
phenylenediamine to ketones was used. No products were obtained when
o-phenylenediamine was reacted with acetone under similar conditions in
the absence of the NbCl even after stirring for 24 h, thus highlighting
5
the role of the NbCl as a promoter. Any excess of NbCl beyond this load-
5
5
ing did not show any further increase in conversion and yield. Use of less
than the required catalyst loading resulted in poor yields.
Under the optimal reaction conditions, we investigated the reaction of a
series of symmetrical and unsymmetrical ketones with o-phenylenediamine
to get the corresponding 1,5-benzodiazepines (Table 1). In all cases, the reac-
tion could proceed efficiently and complete in 3–6 h with yields of 85–96%.
In conclusion, we have demonstrated here a new and efficient
procedure for the synthesis of 1,5-benzodiazepine derivatives catalyzed
by NbCl . The advantages of our protocol are easy workup, fast reaction
5
rates, mild reaction conditions, and good yields, which make the method
an attractive and a useful contribution to the present methodologies.
ACKNOWLEDGMENTS
This work was financially supported by the Natural Science Foundation
of the Agricultural University of Hebei (Nos. 2004-20 and 2005-18).

NbCl
5
as Efficient Catalyst
3283
REFERENCES
1
. (a) Essaber, M.; Baouid, A.; Hasnaoui, A.; Benharref, A.; Lavergne, J.-P.
Synthesis of new tri- and tetraheterocyclic systems: 1,3-Dipolar cycloaddition
of nitrile imines on 7-dimethyl-4-phenyl-3H-1,5-benzodiazepine. Synth.
Commun. 1998, 28, 4097–4104; (b) El-Sayed, A. M.; Abdel-Ghany, H.;
El-Saghier, A. M. M. A novel synthesis of pyrano[2,3-c]-, 1,3-oxazino[2,3-b]-,
1,2,4-triazolo[3,4-b]-, oxazolo[2,3-b]-, furo[3,2-c]-, and 3-substituted-[1,5]-
benzodiazepine-2-ones. Synth. Commun. 1999, 29, 3561–3572; (c) Xu, J. X.;
Wu, H. T.; Jin, S. Cycloaddition of benzoheteroazepine II reactions and con-
formations of cycloaddition 1,5-benzothiazepines and 1,5-benzodiazepines
with nitrile imine and nitrile oxides. Chin. J. Chem. 1999, 17, 84–91; (d) Zhang,
X. Y.; Xu, J. X.; Jin, S. Cycloaddition of benzoheteroazepine III reaction of
2,3-dihydro-lH-l,5-benzodiazepines with dichlorocarbene and stereostructures
of products. Chin. J. Chem. 1999, 17, 404–410; (e) Reddy, K. V. V.; Rao,
P. S.; Ashok, D. A facile synthesis of 2-benzoyl-6-hydroxy-3-methyl-5-
(2-substituted-2,3-dihydro-1H-1,5-benzodiazepine-4-yl) benzo [b] furans.
Synth. Commun. 2000, 30, 1825–1836.
2
. (a) Herbert, J. A. L.; Suschitzky, H. Syntheses of heterocyclic compounds,
Part XXIX: Substituted 2,3-dihydro-1H-1,5-benzodiazepines. J. Chem.
Soc., Perkin Trans. 1 1974, 2657–2661; (b) Morales, H. R.; Bulbarela, A.;
Contreras, R. New synthesis of dihydro- and tetrahydro-1,5-benzodiazepines
by reductive condensation of o-phenylenediamine and ketones in the presence
of sodium borohydride. Heterocycles 1986, 24, 135–139; (c) Jung, D. I.; Choi,
T. W.; Kim, Y. Y.; Kim, I. S.; Park, Y. M.; Lee, Y. G.; Jung, D. H. Synthesis
of 1,5-benzodiazepine derivatives. Synth. Commun. 1999, 29, 1941–1951; (d)
Varala, R.; Enugala, R.; Nuvula, S.; Adapa, S. R. Ceric ammonium nitrate
(
2
CAN) promoted efficient synthesis of 1,5-benzodiazepine derivatives. Synlett
006, 1009–1014; (e) Balakrishna, M. S.; Kaboudin, B. A simple and new
method for the synthesis of 1,5-benzodiazepine derivatives on a solid surface.
Tetrahedron Lett. 2001, 42, 1127–1129; (f) Curini, M.; Epifano, F.;
Marcotullio, M. C.; Rosati, O. Ytterbium triflate promoted synthesis of
1,5-benzodiazepine derivatives. Tetrahedron Lett. 2001, 42, 3193–3195; (g)
Kaboudin, B.; Navaee, K. Alumina=phosphorus pentoxide (APP) as an effi-
cient reagent for the synthesis of 1,5-benzodiazepines under microwave irra-
diation. Heterocycles 2001, 55, 1443–1446; (h) Pozarentzi, M.; Stephanatou,
J. S.; Tsoleridis, C. A. An efficient method for the synthesis of 1,5-benzodia-
zepine derivatives under microwave irradiation without solvent. Tetrahedron
Lett. 2002, 43, 1755–1758; (i) Yadav, J. S.; Reddy, B. V. S.; Eshwaraiah, B.;
Anuradha, K. Amberlyst-15: A novel and recyclable reagent for the synthesis
of 1,5-benzodiazepines in ionic liquids. Green Chem. 2002, 4, 592–594; (j)
Sabitha, G.; Reddy, G. S. K. K.; Reddy, K. B.; Reddy, N. M.; Yadav, J. S.
A new, efficient, and environmentally benign protocol for the synthesis of
1,5-benzodiazepines using cerium(III) chloride=sodium iodide supported on
silica gel. Adv. Synth. Catal. 2004, 346, 921–923; (k) Yadav, J. S.; Reddy,
B. V. S.; Kumar, S. P.; Nagaiah, K. Indium(III) bromide: A novel and effi-
cient reagent for the rapid synthesis of 1,5-benzodiazepines under solvent-free

3284
S.-T. Gao et al.
conditions. Synthesis 2005, 480–484; (l) Jarikote, D. V.; Siddiqui, S. A.;
Rajagopal, R.; Daniel, T.; Lahoti, R. J.; Srinivasan, K. V. Room temperature
ionic liquid promoted synthesis of 1,5-benzodiazepine derivatives under
ambient conditions. Tetrahedron Lett. 2003, 44, 1835–1838; (m) De, S. K.;
Gibbs, R. A. Scandium(III) triflate as an efficient and reusable catalyst for
synthesis of 1,5-benzodiazepine derivatives. Tetrahedron Lett. 2005, 46,
1811–1813.
3
4
5
. Wang, R.; Li, B. G.; Huang, T.-K.; Shi, L.; Lu, X.-X. NbCl -catalyzed
5
one-pot Mannich-type reaction: Three-component synthesis of b-amino
carbonyl compounds. Tetrahedron Lett. 2007, 48, 2071–2073.
. Sudo, Y.; Arai, S.; Nishida, A. Facile and regioselective dealkylation of
alkyl aryl ethers using niobium(V) pentachloride. Eur. J. Org. Chem. 2006,
3, 752–758.
. (a) Andrade, C. K. Z.; Azevedo, N. R. Niobium(V) chloride–mediated allyla-
tion of aldehydes: Scope and stereoselectivity. Tetrahedron Lett. 2001, 42,
5
6473–6476; (b) Andrade, C. K. Z.; Azevedo, N. R.; Oliveira, G. R. NbCl :
A novel Lewis acid in allylation reactions. Synthesis 2002, 928–936; (c)
Andrade, C. K. Z.; Oliveira, G. R. Allylation of aldimines promoted by
NbCl . Tetrahedron Lett. 2002, 43, 1935–1937.
5
6
7
. Andrade, C. K. Z.; Matos, R. A. F. Niobium pentachloride–mediated
nucleophilic additions to cyclic N-acyliminium ions. Synlett. 2003, 1189–
1191.
. Ma, J. J.; Zhou, X.; Zang, X. H.; Wang, C.; Wang, Z.; Li, J. C.; Li, Q. A
green and efficient synthesis of 9-aryl-3,4,5,6,7,9-hexahydroxanthene-1,8-
dione using task-specific ionic liquid as dual catalyst and solvent. Aus.
J. Chem. 2007, 60, 146–148.
8
9
. Wang, C.; Ma, J. J.; Zhou, X.; Zang, X. H.; Wang, Z.; Gao, Y. J.; Cui, P. L.
1-n-Butyl-3-methylimmidazolium tetrafluoroborate promoted green synthesis
of 5-arylidene barbituric acids and thiobarbituric acids derivatives. Synth.
Commun. 2005, 35 (21), 2759–2764.
. Ma, J. J.; Zang, X. H.; Zhou, X.; Wang, C.; Li, J. C.; Li, Q. One-pot synthesis
of 3,4-dihydropyrimidin-2 (1H)-ones catalyzed by acidic ionic liquid. Indian
J. Chem. Sec. B 2007, 46, 2045–2048.
1
1
1
0. Ma, J. J.; Gao, S. T.; Li, Z.; Tang, R. X.; Liu, H. Y.; Wang, C.; Gao, Y.
Synthesis of 5-arylmethylidene-2-thio-4-thiazolidinone derivatives catalyzed
by alkaline ionic liquid. Chin. J. Org. Chem. 2008, 28 (2), 339–342.
1. Yi, W. B.; Cai, C. Ytterbium perfluorooctanesulfonate–catalyzed synthesis of
1,5-benzodiazepine derivatives in fluorous solvents. Synth. Commun. 2007,
37, 3827–3833.
2. Yadav, J. S.; Reddy, B. V. S.; Praveenkumar, S.; Nagaiah, K.; Lingaiah, N.;
Saiprasad, P. S. Ag 40: A novel and recyclable heteropoly acid for the
synthesis of 1,5-benzodiazepines under solvent-free conditions. Synthesis
004, 901–904.
3
PW12O
2