Alum-catalyzed one-pot solventless synthesis of 1,5-benzodiazepines

Article abstract of DOI:10.1071/CH07316

Alum [KAl(SO₄)₂?12H₂O] was found to be an efficient, non-toxic, cheap, and environmentally benign catalyst for the synthesis of 1,5-benzodiazepines, in good to excellent yields, from the condensation of 1 mole of o-phenyle

Full text of DOI:10.1071/CH07316

Short Communication
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2008, 61, 159–162
Alum-Catalyzed One-Pot Solventless Synthesis
of 1,5-Benzodiazepines
Deepali Mahajan,A Tahira Naqvi,A Rattan Lal Sharma,A
and Kamal K. KapoorA,B
ADepartment of Chemistry, University of Jammu, Jammu-180006, India.
BCorresponding author. Email: k2kapoor@yahoo.com
Alum [KAl(SO4)2·12H2O] was found to be an efficient, non-toxic, cheap, and environmentally benign catalyst for the
synthesis of 1,5-benzodiazepines, in good to excellent yields, from the condensation of 1 mole of o-phenylenediamine
with 2 moles of ketone under solvent-free conditions.
Manuscript received: 8 September 2007.
Final version: 9 January 2008.
Table 1. Optimization of the amount of alum for the preparation of 1,5
Introduction
diazepines
Benzodiazepines are a class of drugs possessing hypnotic,[1]
anxiolytic, anticonvulsant, amnestic, and muscle relaxant prop-
erties. Different benzodiazepines are often used for the short-
term relief of severe, disabling anxiety or insomnia. They
serve as cholecystokinin A and B antagonists,[2] opioid recep-
tor ligands,[3] platelet-activating factor antagonists,[4] HIV
inhibitors,[5] as farnesyltransferase inhibitors,[6] and recently
they have been reported to show anti-leukaemic and anti-
platelet activity.[7] The synthesis of benzodiazepines has been
achieved by catalysts such as Zn[l-proline]2,[8] YbCl3,[9]
SbCl3–Al2O3,[10] BF3 etherate,[11] ionic liquids,[12] polystyrene
supported sulfonic acid,[13] and on ultrasound irradiation.[14]
However, these methods have one or more disadvantages such
as high temperature, moisture sensitivity of the reagent used,
prolonged reaction time, co-occurrence of side reactions, use
of stoichiometric amount of catalyst, harsh reaction conditions,
and complicated workup procedures. These facts provide the
necessary impetus to develop better and safer procedures for the
synthesis of benzodiazepines.
Entry
Mol-%
Amount alum [g]
Yield [%]
A
1
2
3
4
5
6
7
0
0
0.5
1.0
2.0
2.5
5.0
10.0
0.238
0.476
0.952
1.119
2.380
4.760
20
30
50
95
60
40
ANo reaction.
R1
R2
H
N
O
NH2
Alum
2
R2
ϩ
R2
80°C,
3 h
R1
N
2
NH2
R1
1
R
R
1 ϭ aryl or alkyl groups
2 ϭ alkyl group
Alum is employed in organic synthesis as a mild and efficient
Lewis acid.[15] It is also environmentally benign, non-polluting,
non-toxic, inexpensive, and safe. In our endeavour to develop a
greener protocol for the synthesis of pharmacologically active
benzodiazepines in one step from the cyclocondensation of
one equivalent of o-phenylenediamine with two equivalents of
ketone, we explored the usage of alum as a Lewis acid for this
purpose.
Scheme 1. Synthesis of 1,5-benzodiazepines.
conditions, the reaction was completed in 3 h (TLC), possibly
because of an increase in the surface area. To obtain optimum
concentration of alum for better yields, a set of experiments
was performed employing different concentrations of alum for a
reaction between 10 mmol of o-phenylenediamine and 20 mmol
of acetophenone in acetonitrile for 3 h; the results are shown in
Table 1. It is apparent from this table that just 2.5 mol-% of alum
was enough to push the reaction to completion. It was desir-
able for acetonitrile, being toxic, to be removed in view of the
development of a greener procedure. Towards this end, when
a mixture of o-phenylenediamine (10 mmol), acetophenone 1a
(20 mmol) and pulverized alum (2.5 mol-%) was heated, without
any solvent, in a round-bottom flask at 80◦C, complete conver-
sion into the desired product took 3 h as described in Scheme 1.
To benefit in terms of time economy, the reaction was subjected
Results and Discussion
When a mixture of o-phenylenediamine (10 mmol), acetophe-
none 1a (20 mmol), and crystalline alum (10 mol-%) was
refluxed in acetonitrile (50 mL) with stirring for 4.5 h, the
product was isolated in 40% yield by column chromatography
over silica gel and was found to be 2-methyl-2,4-diphenyl-2,3-
dihydro-1H-1,5-benzodiazepineasrevealedbycomparisonofits
spectroscopic and physical data with an authentic sample.[8,16]
When pulverized alum was used under the same reaction
© CSIRO 2008
10.1071/CH07316
0004-9425/08/020159

160
D. Mahajan et al.
Table 2. Alum-catalyzed formation of 1,5-benzodiazepines
Yields are isolated yields. Melting points are uncorrected
Entry
Ketone 1
Product 2
Time [h]
Yield [%]
Obs. mp [◦C] (lit.)[8,16]
152–153 (150–152)
N
1
C6H5COMe 1a
3.0
95
N
H
2a
O
OCH3
N
A
2
3.0
93
OCH3
OCH3
N
H
1b
2b
Cl
O
N
Cl
3
3.5
92
162–163 (160–163)
1c
Cl
N
H
2c
O
OH
N
4
5.0
82
140–141 (137–139)
HO
1d
OH
N
H
2d
OMe
OMe
OCH3O
MeO
OCH3
N
MeO
A
OCH3
5
5.0
82
1e
OMe
N
H
MeO
2e
N
6
7
MeCOMe 1f
EtCOEt 1g
3.5
3.5
90
88
136–137 (137–139)
142–143 (145)
N
H
2f
N
N
H
2g
N
8
PriCOMe 1h
3.5
87
117–119 (118–120)
N
H
2h
(Continued)

Alum-Catalyzed Synthesis of 1,5-Benzodiazepines
161
Table 2. (Continued)
Product 2
Entry
9
Ketone 1
Time [h]
Yield [%]
88
Obs. mp [◦C] (lit.)[8,16]
140–142 (139–141)
N
EtCOMe 1i
3.5
N
H
2i
N
10
11
Cyclopentanone 1j
Cyclohexanone 1k
4.0
4.5
85
84
136–137 (137–138)
N
H
2j
N
135–136 (137)
N
H
2k
N
12
Cycloheptanone 1l
5.0
82
134–136 (135)
N
H
2l
AOil.
Alum
Alum
N
Alum
R
R
R
R
NH2
NH2
O
N
N
2
ϩ
R
N
H
3
4
R
Ϫ
R
R
H
N
N
Hϩ
N
N
R
Scheme 2. Proposed mechanism of the reaction.
to microwave irradiation (240 W) under solvent-free conditions
for 3 min with a pause after every 30 s; the yield of the product
dropped from 95 to 50%. Some decomposition to unidentified
tarry material was also observed.
4. The push by the NH lone pair of electrons of the enamine and
the pull caused by chelation of alum to the imine N atom facil-
itates the cyclization to a seven-membered ring as described in
Scheme 2.
A range of substrates such as substituted acetophenones,
dialkyl ketones, and cycloketones underwent reaction under sim-
ilarconditions, andtheresultsaredepictedinTable2.Thepresent
method thus provides a green alternative for the synthesis of
2,3-dihydro-1H-1,5-benzodiazepines from o-phenylenediamine
and ketones having hydrogens at the α-position, in the presence
of non-toxic, mild, non-polluting, and environmentally benign
alum.
Experimental
Melting points were measured in open capillaries on a Perfit
melting point apparatus and are uncorrected. IR spectra on KBr
disks were recorded on a Bruker-4800 infrared spectrometer.
NMR and electron-impact mass spectrometry (EI-MS) spec-
tra were recorded on Bruker AC-400 (400 and 100 MHz) and
JEOL D-300 mass spectrometers, respectively. Elemental anal-
1
yses were carried out with a Heraeus CHN rapid analyzer. H
Mechanism
and 13C NMR chemical shifts are reported in parts per million
from tetramethylsilane (TMS) as internal standard. All experi-
ments were performed in oven-dried glass apparatus. The alum
The most probable mechanism seems to be alum-catalyzed for-
mation of bis-imines 3 followed by tautomerism to the enamine

162
D. Mahajan et al.
(Qualigens Fine Chemicals) used was a commercial reagent.
SISCO silica was used as an adsorbent for TLC (0.5-mm thick
plates). The visualization of spots was effected by exposure to
iodine vapour and 5% 2,4-dinitrophenyl hydrazine in ethanol
containing a few drops of conc. H2SO4. Column chromato-
graphy was performed over silica gel (60–120 mesh) with graded
solvent systems of ethyl acetate/n-hexane. The solvents were
dried before use as per established procedures.
Spirocycloheptan-6,7,8,9,10,10a,11,12-
octahydrobenzo[b]cyclohepta[e][1,4]diazepine 2l
Pale yellow solid. δH (CDCl3, 400 MHz) 7.35–6.60 (m, 4H),
3.62 (br s, 1H), 2.90–2.35 (m, 3H), 1.95–0.95 (m, 20H). δC
(CDCl3, 100 MHz) 22.5, 23.2, 26.4, 28.5, 28.7, 29.5, 29.8, 30.1,
38.6, 40.9, 54.5, 72.4, 121.2, 121.5, 125.6, 127.7, 137.5, 139.7,
179.2. νmax(KBr)/cm−1 3325, 1630, 1600. Calc. for C20H28N2
(296.4580): C 81.0, H 9.5, N 9.4. Found: C 81.1, H 9.5, N 9.5%.
m/z 296 (M+).
General Procedure for the Synthesis of Substituted
Benzodiazepines
References
A mixture of o-phenylenediamine (1.08 g, 10 mmol), ketone
(20 mmol), and pulverized alum (1.19 g, 2.5 mol-%) was heated
in round-bottom flask at 80◦C until completion of reaction (3.0–
5.0 h) as revealed by TLC. The reaction mixture was diluted
with ethyl acetate (70 mL) and filtered. The filtrate was washed
with brine (2 × 25 mL), dried over anhydrous Na2SO4, the
ethyl acetate was distilled off under reduced pressure, and the
residue was directly charged on a small silica gel column (ethyl
acetate/n-hexane) to afford pure the benzodiazepines (82–95%).
[1] L. O. Randall, B. Kappel, S. Garattini, E. Mussini, L. O. Randall,
Benzodiazepines 1973, pp. 27 (Raven Press: New York, NY).
[2] M. G. Bock, R. M. Dipardo, B. E. Evans, K. E. Rittle, W. L. Whitter,
D. F. Veber, P. S. Anderson, R. M. Freidinger, J. Med. Chem. 1989, 32,
13. doi:10.1021/JM00121A004
[3] D. Romer, H. H. Buschler, R. C. Hill, R. Maurer, T. J. Petcher,
H. Zeugner, W. Benson, E. Finner, W. Milkowski, P. W. Thies, Nature
1982, 298, 759. doi:10.1038/298759A0
[4] E. Kornecki, Y. H. Erlich, R. H. Lenox, Science 1984, 226, 1454.
doi:10.1126/SCIENCE.6150550
[5] (a) M. J. Kukla, H. J. Breslin, C. J. Diamond, P. P. Grous, C. Y. Ho,
M. Mirands, J. D. Rodgers, R. G. Sherrill, E. De Clercq, J. Med. Chem.
1991, 34, 3187. doi:10.1021/JM00115A007
Physical and Spectroscopic Data for Selected Products
2-Methyl-2,4-diphenyl-2,3-dihydro-1H-1,5-
benzodiazepine 2a
(b) K. A. Parker, C. A. Coburn, J. Org. Chem. 1992, 57, 97.
doi:10.1021/JO00027A019
Yellow crystals. δH (CDCl3, 400 MHz) 7.60–7.55 (m, 4H),
7.0–6.55 (m, 3H), 3.40 (br s, 1H), 3.20 (d, 1H, J 12.8), 2.90 (d,
1H, J 12.8), 1.85 (s, 3H). δC (CDCl3, 100 MHz) 29.7, 42.9, 73.3,
78.5, 121.2, 121.4, 121.6, 125.2, 126.1, 126.8, 126.9, 127.8,
127.9, 128.1, 128.5, 129.5, 137.9, 139.5, 139.9, 142.5, 147.5,
167.5. νmax(KBr)/cm−1 3325, 1636, 1598. Calc. for C22H20N2
(312.4166): C 84.6, H 6. 5, N 9.0. Found: C 84.5, H 6.5, N 8.6%.
m/z 312 (M+).
[6] C. Z. Ding, R. Batorsky, R. Bhide, H. J. Chao, Y. Cho, S. Chong,
J. Gullo-Brown, P. Guo, S. H. Kim, F. Lee, K. Leftheris, A. Miller,
T. Mitt, M. Patel, B. A. Penhallow, C. Ricca, W. C. Rose, R. Schmidt,
W. A. Slusarchyk, G. Vite, N.Yan, V. Manne, J. T. Hunt, J. Med. Chem.
1999, 42, 5241. doi:10.1021/JM990391W
[7] R. Ramajayam, R. Giridhar, R. M.Yadav, R. Balaraman, H. Djabalah,
D. Shum, C. Radu, Eur. J. Med. Chem. in press. doi:10.1016/
J.EJMECH. 2007.11.023
[8] V. Sivamurugan, K. Deepa, M. Palanichamy, V. Murugesan, Synth.
Commun. 2004, 34, 3833. doi:10.1081/SCC-200034752
[9] J. Wu, F. Xu, Z. Zhou, Q. Shen, Synth. Commun. 2006, 36, 457.
doi:10.1080/00397910500383527
2-Methyl-2,4-di(4-hydroxyphenyl)-2,3-dihydro-
1H-1,5-benzodiazepine 2d
[10] B. A. Ganai, S. Kumar, C. S. Andotra, K. K. Kapoor, Synth. Commun.
2006, 36, 803. doi:10.1080/00397910500451456
[11] X. L. Wang, X. F. Zheng, R. H. Liu, J. Reiner, J. B. Chang,Tetrahedron
2007, 63, 3389. doi:10.1016/J.TET.2007.02.002
[12] D. V. Jarikote, S. A. Siddiqui, R. Rajagopal, D. Thomas, R. J. Lahoti,
K.V. Srinivasan,TetrahedronLett. 2003, 44, 1835. doi:10.1016/S0040-
4039(03)00096-0
Yellow solid. δH (CDCl3, 400 MHz) 7.45–6.95 (m, 12H), 4.20
(br s, 1H), 2.8 (s, 2H), 1.65 (s, 3H). νmax(KBr)/cm−1 3345, 1635,
1510. Calc. for C22H20N2O2 (344.4154): C 76.7, H 5.9, N 8.1.
Found: C 76.8, H 5.8, N 8.2%. m/z 344 (M+).
2-Methyl-2,4-di(2,4,6-trimethoxyphenyl)-2,3-dihydro-
1H-1,5-benzodiazepine 2e
[13] V. Polshettiwar, R. S. Varma, Tetrahedron Lett. 2008, 49, 397.
[14] K. P. Guzen, R. Cella, H. A. Stefani, Tetrahedron Lett. 2006, 47, 8133.
doi:10.1016/J.TETLET.2006.09.043
[15] J.Azizian,A.A. Mohammadi,A. R. Karimi, M. R. Mohammadizadeh,
J. Org. Chem. 2005, 70, 350. doi:10.1021/JO049138G
[16] (a) M. S. Balakrishna, B. Kaboudin,Tetrahedron Lett. 2001, 42, 1127.
doi:10.1016/S0040-4039(00)02168-7
Viscous oil. δH (CDCl3, 400 MHz) 7.35–6.20 (m, 8H), 3.55–
3.15 (m, 9H), 4.10 (br s, 1H), 2.60 (s, 2H), 1.50 (s, 3H).
νmax(KBr)/cm−1 3320, 2960, 1495. Calc. for C28H33N2O6
(492.5751): C 68.3, H 6.5, N 5.7. Found: C 68.3, H 6. 6, N 5.5%.
m/z 492 (M+).
(b) M. Curini, F. Epifano, M. C. Marcotullio, O. Rosati, Tetrahedron
Lett. 2001, 42, 3193. doi:10.1016/S0040-4039(01)00413-0
(c) J. Wu, F. Xu, Z. Zhou, Q. Shen, Synth. Commun. 2006, 36, 457.
doi:10.1080/00397910500383527
(d) M. Pozarentzi, J. S. Stephanatou, C. A. Tsoleridis, Tetrahedron
Lett. 2002, 43, 1755. doi:10.1016/S0040-4039(02)00115-6
(e) B. M. Reddy, P. M. Sreekanth, Tetrahedron Lett. 2003, 44, 4447.
doi:10.1016/S0040-4039(03)01034-7
2,4-Diethyl-2-methyl-2,3-dihydro-1H-1,5-
benzodiazepine 2i
Yellow solid. δH (CDCl3, 400 MHz) 7.30–6.75 (m, 4H), 3.20
(br s, 1H), 2.65 (q, 2H, J 7.0), 2.30 (s, 3H), 2.15 (m, 2H), 1.75
(q, 2H, J 6.9), 1.20 (t, 3H, J 7.0), 1.00 (t, 3H, J 6.9). δC (CDCl3,
100 MHz) 35.6, 35.7, 42.1, 70.5, 121.9, 125.4, 126.0, 127.0,
137.8, 140.8, 175.5. νmax(KBr)/cm−1 3330, 1638, 1605. Calc.
for C14H20N2 (216.3087): C 77.7, H 9.3, N 13.0. Found: C 77.7,
H 9.4, N 13.0%. m/z 216 (M+).
(f) D. V. Jarikote, S. A. Siddiqui, R. Rajagopal, T. Daniel, R. J. Lahoti,
K. V. Srinivasan, Tetrahedron Lett. 2003, 44, 1835. doi:10.1016/
S0040-4039(03)00096-0