Investigation of various organocatalysts for improved and efficient one pot synthesis of 2,3-Dihydro-1H-1,5-benzodiazepines under solvent-free condition

Article abstract of DOI:10.14233/ajchem.2014.16440

A series of 2,3-dihydro-1H-1,5-benzodiazepines derivatives were synthesized by one-pot three-components condensation reaction of o-phenylenediamines with α,β-unsaturated carbonyl compounds and effect of various Br?nsted organo acids as catalyst was studie

Full text of DOI:10.14233/ajchem.2014.16440

Asian Journal of Chemistry; Vol. 26, No. 16 (2014), 5116-5120
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.16440
Investigation of Various Organocatalysts for Improved and Efficient One Pot
Synthesis of 2,3-Dihydro-1H-1,5-benzodiazepines Under Solvent-Free Condition
1
,†
2,†
3
2
2,*
3,*
YUHAO ZHAO , SHIKHA SHARMA , MINGHUA HUANG , AKSHDEEP SANDHAR , RAJESH K. SINGH and YANXU MA
1
2
School of Traditional Chinese Medicine, Capital Medical University, Beijing 100069, P.R. China
Department of Pharmaceutical Chemistry, Shivalik College of Pharmacy (Under Local Govt. Dept. Punjab) Nangal, Distt. Rupnagar- 140126,
Punjab, India
3
Department of Orthopedics, Beijing Traditional Chinese Medicine Hospital, Capital Medical University, Beijing 100010, P.R. China
*
Corresponding authors: E-mail: rksingh244@gmail.com; yizhangchaimen@gmail.com
Authors contributed equally this work
†
Received: 27 September 2013;
Accepted: 9 November 2013;
Published online: 28 July 2014;
AJC-15643
A series of 2,3-dihydro-1H-1,5-benzodiazepines derivatives were synthesized by one-pot three-components condensation reaction of
o-phenylenediamines with α,β-unsaturated carbonyl compounds and effect of various Brønsted organo acids as catalyst was studied.
Among the various organo acids screened, trifluoroacetic acid is versatile catalyst and the corresponding products were obtained in good
to excellent yield (84-94 %) under solvent-free condition.
Keywords: 1,5-Benzodiazepines, Organoacids, Trifluoroacetic acid, One pot, Solvent-free, Green chemistry.
and commercial availability. The evolution of organocatalysis
led to various valuable approaches, such as multicomponent
13
as well as domino and tandem reactions . In continuation with
INTRODUCTION
Benzodiazepines have gained great attention in the area
of synthetic medicinal chemistry and form an important compo-
nent of pharmacologically numerous bioactive compounds
which include anticonvulsants, antianxiety, analgesic, sedative,
antidepressive, hypnotic, antiinflammatory and muscle relaxant
our research for the exploration of various novel catalysts and
development of green procedure for the synthesis of various
14
heterocyclic and synthetic intermediates , in this study, we
have screened various readily available Brønsted organoacids
for their catalytic activity in the synthesis of 1,5-benzodia-
zepines (Table-1). The synthetic approach is outlined in
1
agents . In particular, 1,5-benzodiazepines are useful precur-
sors for the synthesis of fused ring benzodiazepine derivatives
2
such as triazolo, oxadiazolo, oxazino, furano benzodiazepines .
(
Scheme-I). Various aliphatic and aromatic acids have been
More recently their use has been extended to various diseases
such as cancer, viral infections (non-nucleoside inhibitors of
3
HIV-1 reverse transcriptase) and cardiovascular diseases .
used to catalyze the synthesis of 1,5-benzodiazepines, out of
which trifluoroacetic acid (TFA) came out to be the most
effective catalyst under solvent-free condition (Table-1).
Literature survey reveals the various catalysts and routes
for the synthesis of these compounds by condensation reaction
of o-phenylenediamines with α,β-unsaturated carbonyl
compounds in the presence of protic organic and inorganic
R1
H
R
NH2
NH2
O
TFA
R
N
R2
R1
4
-12
acids catalysts . However, majority of them suffer from
several limitations such as high temperature, long reaction time,
use of expensive reagents, low yields of products, high catalyst
loading, corrosive reagents, strongly acidic conditions and
further purification of products. Therefore development and
introduction of convenient and efficient methods for the prepa-
ration of 1,5-benzodiazepines is of practical importance and
is still in demand.
R2
Stirring, rt,
Solvent free
R1
N
R2
R = H, CH3
( )n
H
N
R
NH2
NH2
TFA
R
O
Stirring, rt,
Solvent free
N
( )n
n= 2,3
R = H, CH3
In recent years, lot of attention has been directed to green
synthesis by organocatalysts owing to their eco-friendliness
Scheme-I:Chemical reaction for the synthesis of substituted 1,5-benzo-
diazepines using trifluoroacetic acid (TFA)

Vol. 26, No. 16 (2014)
One Pot Synthesis of 2,3-Dihydro-1H-1,5-benzodiazepines Under Solvent-Free Condition 5117
TABLE-1
REACTION OF o-PHENYLENEDIAMINE WITH ACETO-
PHENONE PROMOTED BY VARIOUS BRONSTED ACIDS
and basified with ammonia solution. The precipitated solid
was separated, washed thoroughly with water and dried. The
residue was subjected to column chromatography to get the
pure 2,3-dihydro-1H-1,5-benzodiazepines (1-9).
Entry
Acids
Time (h)
12
Yield (%)
1
2
3
4
5
6
7
8
9
Malonic acid
Maleic acid
80
75
2
,2,4-Trimethyl-2, 3-dihydro-1H-1,5-benzodiazepine:
12
-1
Entry 2): IR (KBr, νmax, cm ): 3292 (NH), 2955 (Aromatic
(
Oxalic acid
12
70
1
CH), 1631 (Alkene C=C), 1474 (Aromatic C=C) H NMR
CDCl ): δ 1.3 (s, 6H, (2xCH ), δ 2.2 (s, 2H, -CH ), δ 2.4 (s,
3H, -CH ), δ 6.7-7.2 (m, 4H, ArH)
Anal. Calcd for C H N : C, 76.55; H, 8.57; N, 14.88;
Succinic acid
Formic acid
12
72
(
3
3
)
2
2
12
85
Trichloroacetic acid
Chloroacetic acid
Trifluoroacetic acid
Tartaric acid
Phthalic acid
Nicotinic acid
Cinnamic acid
Picric acid
12
90
3
12
88
12
16
2
12
94
Found: C, 76.51; H, 8.52; N, 14.92
,3-Dihydro-2-methyl-2,4-diphenyl-1H-1,5-benzodiaze-
12
67
2
10
11
12
13
14
15
16
17
18
12
70
-1
pine: (Entry 1): IR (KBr, νmax, cm ): 3277 (Sec N-H), 3061
Aromatic C-H), 2972 (Aliphatic C-H), 1559 (Aromatic C=C).
12
72
(
12
85
1
H NMR (CDCl ): δ1.8 (s, 3H, -CH ), δ 3 (d, 1H, -CH),
3
3
12
92
Benzoic acid
Ascorbic acid
Palmitic acid
Molybdic acid
Glycolic acid
12
78
δ 3.2 (d, 1H, -CH), δ 6.8-7.7 ( m, 14H, ArH).
Anal. Calcd for C H N : C, 84.58; H, 6.45; N, 8.97;
12
74
22
20
2
12
50
Found: C, 84.60; H, 6.42; N, 8.94.
,4-Dimethyl-2-ethyl-2,3-dihydro-1H-1,5-benzodiaze-
12
Very low
Very low
2
12
-1
pine: (Entry 3): IR (KBr, νmax, cm ): 3338 (Sec N-H), 3058
(
(
Aromatic C-H), 2968 (Aliphatic C-H), 1639 (C=N), 1472
Aromatic C=C), 1252 (C-N)
Recently, trifluoroacetic acid has emerged as a promising
catalyst for the synthesis of wide variety of reactions such as
1
1
Paal-Knorr Furan Synthesis , Meerwein-Ponndorf-Verley-
5
H NMR (CDCl
3
): δ 0.8 (t, 3H, -CH
), δ 2.2 (m, 2H, -CH
NH), δ 6.5-7.3 (m, 4H, ArH).
Anal. calcd for C13
Found: C, 77.25; H, 8.88; N, 14.01
1-Spirocyclocyclohexane-2,3,4,10,11,11a-hexahydro-
H-dibenzo[b,e][1,4]diazepine: (Entry 4): IR (KBr, νmax
3
), δ 1.3 (brs, 6H, 2x-
1
Aldol reactions of enolizable aldehydes , Pictet-Spengler
6
CH
3
), δ 1.7 (q, 2H, -CH
2
2
), δ 3.3 (brs, 1H,
17
18
reaction , Claisen rearrangement and cross-coupling reac-
1
9,20
18 2
H N : C, 77.18; H, 8.97; N, 13.85;
tions . Trifluoroacetic acid is the simplest stable perfluori-
nated carboxylic acid chemical compound, with the formula
1
3 2
CF CO H. It is a strong carboxylic acid due to the influence
1
,
of the electronegative trifluoro methyl group. Trifluoroacetic
acid is almost 100,000-fold more acidic than acetic acid. Using
extremely acidic compounds in an organic synthesis allows
better manipulations of end products in a reaction. Trifluoro-
acetic acid is also less oxidizing than sulfuric acid but more
readily available in anhydrous from than many other acids.
Because of its interesting properties, such as low toxicity,
solubility in water and organic solvents and strength, trifluoro-
acetic acid is considered to be a special reagent for highly
-1
cm ): 3278 (Sec. NH), 3059 (Aromatic CH), 2858 (Alkane
CH), 1634 (Imine C=N), 1481 (Aromatic C=C), 751 (ortho
substituted oop).
1
H NMR (CDCl
): δ 1.2-1.9 (m, 16H, -CH ), δ 2.3-2.6
3 2
(
m, 3H, -CH), δ 4.5 (1H, br, NH), δ 6.8-7.9 (m, 4H, ArH).
Anal. Calcd for C18 : C, 80.55; H, 9.01; N, 10.44;
Found: C, 80.62; H, 9.05; N, 10.54
0-Spirocycloheptan-6,7,8,9,10,10a,11,12-octahy-
drobenzo[b]cyclohepta[e][1,4]diazepine: (Entry 5): IR (KBr,
24 2
H N
1
21
sensitive microsequencing of proteins as well as a special
-
1
22
ν
(
max, cm ): 3266 (Sec N-H), 2916 (Aromatic C-H), 2972
Aliphatic C-H), 1633 (Alkene C=C), 1484 (Aromatic C=C).
catalyst for promotion of numerous organic reactions .
EXPERIMENTAL
1
H NMR (CDCl
NH, 1H), δ 2.6 (m, 2H, -CH
m, 4H, ArH).
Anal. calcd for C20
3 2
): δ 1.5-2.4 (m, 20H, -CH ), δ 2.4 (s,
All the chemicals were purchased from commercial
suppliers. The melting points were determined on Veego-
programmable melting point apparatus (microprocessor based)
2
), δ 2.8 (m, 1H, -CH), δ 6.6-7.4
(
H
28
2
N : C, 81.03; H, 9.52; N, 9.45;
1
and are uncorrected. H NMR spectra were obtained using
Found: C, 81.15; H, 9.56; N, 9.54
,2,4-Trimethyl-2,3-dihydro-8-methyl-1H-1,5-benzo-
Brucker AC-400 F, 400 MHZ spectrometer. IR spectra were
obtained with Perkin Elmer 882 Spectrum and RXI, FT-IR.
Elemental analyses for C, H and N were performed on Thermo-
flash EA-1112 CHNS-OAnalyzer. Reactions were monitored
and the homogeneity of the products was checked by TLC.
All chemicals were dried and freshly prior to use according to
standard procedure.
2
-1
diazepine:(Entry 6): IR (KBr, νmax, cm ): 3454 (sec. NH),
924 (Aromatic CH), 2853 (Alkane CH), 1437 (Aromatic
C=C), 1236 (C-N), 946 (1,2,4-substituted oop)
2
1
H NMR (CDCl
), δ 2.3 (s, 3H,-CH
CH), δ 6.5-7.0 (m, 3H, ArH).
Anal. calcd for C13
Found: C, 77.22; H, 8.91; N, 13.93
,3-Dihydro-2,8-dimethyl-2,4-diphenyl-1H-1,5-
3 3
): δ 1.2 (s, 6H, -CH ), δ 1.35 (s, 3H,
-CH
3
3
), δ 2.3 (d, 1H, -CH), δ 2.3(d, 1H,
-
General procedure for the preparation of 2,3-dihydro-
H-1,5-benzodiazepines: To a solution of o-phenylenediamine
10 mmol) in trifluoroacetic acid (1 mmol, 10 mol %), various
18 2
H N : C, 77.18; H, 8.97; N, 13.85;
1
(
2
-1
ketones (22 mmol) were added while shaking and kept stirred
at room temperature for 12 h.After completion of the reaction
benzodiazepine: (Entry 7): IR (KBr, νmax, cm ): 3335 (Sec.
NH), 3057 (Aromatic CH), 2969 (Alkene CH), 2858 (Alkane
CH), 1612 (Imine C=N), 1493 (Aromatic C=C), 1328 (C-N),
[
3
monitored by TLC using CHCl and MeOH (4.5:0.5 mL) as
eluent], the reaction mixture was then poured into crushed ice
7
58 (ortho substituted oop).

5
118 Zhao et al.
Asian J. Chem.
1
14e
H NMR (CDCl ): δ 1.75 (s, 3H, -CH
3
3
), δ 2.6 (s, 3H,
respectively which has already been reported . Picric acid
also found to give excellent yield of 92 % but due to toxicity
of picric acid as it was not safe especially in the absence of
solvent, this catalyst was not explored further for the synthesis
of 1,5-benzodiazepines. It is interesting to mention that using
molybdic acid and glycolic acid, the yield of the product was
very low (Table -1, entry 17 and 18).At last, we found trifluoro-
acetic acid as the best catalyst for further synthesis of various
substituted 1,5-benzodiazepines. Slight excess of acetophe-
none was found to be advantageous. Hence, molar ratio of o-
phenylenediamine to ketone was kept to be (1:2.2 mmol).
Encouraged by these results, a wide variety of ketones were
treated with o-phenylendiamine using trifluoroacetic acid
under the optimized conditions to afford the corresponding
1,5-benzodiazepines (Table-2) in good to excellent yields. Both
of the linear and cyclic ketones reacted with the diamines
containing electron donating group on aromatic rings, without
any significant difference, to give the corresponding 1,5-benzo-
diazepine derivatives in quantitative yields. No reaction was
observed when o-phenylenediamine was treated with ketone
under similar conditions in the absence of a catalyst.
-
CH
3
), δ 2.9 (d, 1H, -CH), δ 3.1 (d, 1H, -CH), δ 7.2-7.9 (m,
4H, ArH), δ 2.6 (br, 1H, NH).
Anal. calcd for C23 : C, 84.63; H, 6.79; N, 8.58;
Found: C, 84.68; H, 6.84; N, 8.45
1-Spirocyclocyclohexane-2,3,4,10,11,11a-hexahydro-
-methyl-1H-dibenzo[b,e][1,4]diazepine: (Entry 8): IR
1
22 2
H N
1
8
-
1
(
(
KBr, νmax, cm ): 3351 (Sec. NH), 2930 (Alkene CH), 2857
Alkane CH), 1633 (Imine C=N), 1484 (Aromatic C=C)
1
H NMR (CDCl
), δ 3 (t, 1H,-CH), δ 7.3-7.9 (m, 3H, ArH).
Anal. calcd for C19 : C, 80.80; H, 9.28; N, 9.92;
Found: C, 80.86; H, 9.34; N, 9.98.
0-Spirocycloheptan-6,7,8,9,10,10a,11,12-octahydro-
-methylbenzo[b]cyclo hepta [e] [1,4]diazepine: (Entry 9):
3
): δ 1.7-2.5 (m, 18H, -CH
2
), δ 3.0 (s,
3
H, -CH
3
26 2
H N
1
8
-1
IR (KBr, νmax, cm ): 3327 (Sec N-H), 3060 (Aromatic C-H),
922 (Alkene C-H), 2852 (Aliphatic C-H), 1617 (Alkene
C=C), 1492 (Aromatic C=C)
2
1
H NMR (CDCl
), δ 3.1 (br, 1H, -NH), δ 3.1 (s, 1H, -CH), δ 6.5-7.1 (m,
H,-CH).
Anal. calcd for C19
Found: C, 81.29; H, 9.79; N, 9.15.
3
): δ 1.6 (m, 22H, -CH
2
), δ 2.2 (s, 3H,
-
CH
3
3
H
26
2
N : C, 81.24; H, 9.74; N, 9.02;
The proposed mechanism of the reaction (Scheme-II)
involves an intramolecular imine enamine cyclization promoted
by organoacid. A role of Brønsted organoacids has been
proposed to activate the carbonyl group of substituted ketones
by activating oxygen atom which ultimately enhances the
electrophilicity of the ketones and leads to reduction in reaction
time.Amine of o-phenylenediamine attacks activated carbonyl
group of ketone giving the intermediate diimine A. A 1,3-
hydrogen shift of the attached methyl group then occurs which
require catalytic amount of Brønsted acid as proton source
forming isomeric enamine B, which cyclized to afford seven
membered benzodiazepine rings.
RESULTS AND DISCUSSION
In search for an efficient catalyst among various catalysts
and the best experimental condition, we have studied efficacy
of chosen various organocatalysts (10 mol %) by taking o-
phenylenediamine and acetophenone (1:2.2) as model reaction.
We found that trifluoroacetic acid was the most effective
catalyst for the synthesis of 1,5-benzodiazepine (Table-1, entry
8
) than other acid catalysts which furnished the product in
lower yields.Apart from trifluoroacetic acid, chloroacetic acid
and trichloroacetic acid has given high yield of 88 % and 90 %,
H
O
R
R
NH2
1,3- hydrogen
shift
R
CH3
N
N
N
N
CH3
CH3
Organoacids
R
R
NH2
H
CH2
CH2
O
H
H
CH3
RCOO--H
A, Diimine
R
RCOO--H
R
R
H
N
Intramolecular imine
enamine cyclization
N
CH3
CH3
CH2
N
H
N
R
R
RCOO
B, Enamine
Scheme-II: Proposed mechanism for Bronsted organoacids catalyzed reaction

Vol. 26, No. 16 (2014)
One Pot Synthesis of 2,3-Dihydro-1H-1,5-benzodiazepines Under Solvent-Free Condition 5119
TABLE-2
CONDENSATION OF o-PHENYLENEDIAMINE WITH VARIOUS KETONES CATALYZED BY TFA
lit.
m.p. (°C)
Entry
Diamine
Ketone
Product
Yield (%)
Time (h)
m.p. (°C)
149-150
H
N
Ph
NH2
O
6
1
94
12
151-152
NH2
Ph
N
Ph
H
N
NH2
NH2
O
6
2
92
87
12
138-139
138-139
137-139
N
H
N
NH2
NH2
O
6
3
12
137-138
N
O
NH2
NH2
H
N
7
4
89
12
137-138
138-139
N
O
NH2
NH2
H
N
7
5
92
12
133-134
136-137
N
H
N
H C
NH2
H C
3
3
O
7
6
7
90
92
12
12
126-128
127-128
NH2
N
H
N
Ph
H C
NH2
NH2
H C
3
3
O
8
91-92
92-93
Ph
N
Ph
O
H C
NH2
NH2
H
N
3
H C
3
8
8
89
12
140-142
142-143
N
O
H C
NH2
3
H
N
H3C
8
9
85
12
121-122
124-125
NH2
N

5
120 Zhao et al.
Asian J. Chem.
6
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efficient and selective catalyst among various acids screened
for the synthesis of 1,5-benzodiazepines under solvent-free
conditions. The work out is easy, no solvent is required, reaction
condition are mild and yield are excellent. These advantages
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acid as catalyst.
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The authors gratefully acknowledged Dr. D.N. Prasad,
Principal and Management Committee, Shivalik College of
Pharmacy, Nangal, India for constant encouragement and
support. The research is supported by Capital Application
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