Synthesis of 1-H-1,5-benzodiazepines derivatives using SiO 2/ZnCl2

Article abstract of DOI:10.1002/hc.20674

A general and easy method for the synthesis of several 1-H-1,5- benzodiazepines using SiO₂/ZnCl₂ under solvent-free conditions is described. This efficient and improved method furnishes selectively and in good yields the correspondin

Full text of DOI:10.1002/hc.20674

Heteroatom Chemistry
Volume 22, Number 2, 2011
Synthesis of 1-H-1,5-Benzodiazepines
Derivatives Using SiO /ZnCl
2
2
Raquel G. Jacob,1 Ca´tia S. Radatz,1 Mariele B. Rodrigues,1 Diego
Alves,1 Gelson Perin,1 Eder J. Lenarda˜o,1 and Lucielli Savegnago2
1Instituto de Qu´ımica e Geocieˆncias, LASOL, Universidade Federal de Pelotas, UFPel,
96010–900 Pelotas, RS, Brazil
2Centro de Desenvolvimento Tecnolo´gico-CDTec, Universidade Federal de Pelotas, UFPel,
96010–900, Pelotas, RS, Brazil
Received 29 October 2010; revised 10 December 2010
1-H-1,5-benzodiazepines has been extended to vari-
ABSTRACT: A general and easy method for the
ous diseases such as cancer, viral infection, and car-
synthesis of several 1-H-1,5-benzodiazepines us-
diovascular disorders [2]. In addition, the derivatives
ing SiO2/ZnCl2 under solvent-free conditions is de-
of 1-H-1,5-benzodiazepines are used as intermedi-
scribed. This efficient and improved method fur-
ates in the synthesis of fused ring compounds [3] and
nishes selectively and in good yields the corresponding
are also used as dyes for acrylic fibers in photogra-
1-H-1,5-benzodiazepines derivatives starting from
phy [4]. Benzodiazepines are commonly synthesized
o-phenylenediamine and cyclic or acyclic ketones. The
by the condensation of o-phenylenediamine with
catalytic system was reused up four times, and the use
α,β-unsaturated carbonyl compounds [5], β-
ꢀ
C
of focused microwaves accelerates the reaction. 2011
haloketones [6], or principally with ketones [7]. In
Wiley Periodicals, Inc. Heteroatom Chem 22:180–185,
the procedures using ketones, many reagents have
2011; View this article online at wileyonlinelibrary.com.
been used, including BF3·OEt2 [7a], NaBH4 [7b],
DOI 10.1002/hc.20674
Ga(OTf)3 [7c], L-proline [7d], molecular iodine [7e],
acetic acid under microwave (MW) irradiation [7f],
ionic liquids [7g], among others [7h-o]. Many of
these processes have some limitations, such as long
reaction times, generation of by-products, harsh re-
INTRODUCTION
Benzodiazepines and their derivatives represent a
significant group of biologically active compounds
and exhibit a number of important biological prop-
erties, such as anticonvulsant, antianxiety, anti-
inflammatory, analgesic, hypnotic, antidepressive,
and sedative agents [1]. Their synthesis has been re-
ceiving much attention in the field of medicinal and
pharmaceutical chemistry [1]. Recently, the use of
action conditions, poor yields, and tedious work-up
procedures [7]. Therefore, the search for a better
catalyst for the synthesis of 1,5-benzadiazepines in
terms of mild reaction conditions, operational sim-
plicity, economic viability, and selectivity, continues
to attract the interest of synthetic organic chemists.
In this way, the use of heterogeneous catalysts,
such as solid-supported ones, has received consider-
able importance in organic synthesis because of their
ease of handling, enhanced reaction rates, greater se-
lectivity, simple workup, and recoverability of the
catalysts [8]. Indeed, as the reaction is heteroge-
neous in nature, the catalytic system can conve-
niently be separated by simple filtration. Among
various solid supports, silica is usually preferred
Correspondence to: Raquel G. Jacob; raquel.jacob@ufpel.edu.br.
Contract grant sponsor: CNPq.
Contract grant sponsor: CAPES.
Contract grant sponsor: FINEP.
Contract grant sponsor: FAPERGS/PRONEX.
Contract grant number: 10/0005-1.
2011 Wiley Periodicals, Inc.
c
ꢀ
180

Synthesis of 1-H-1,5-Benzodiazepines Derivatives Using SiO2/ZnCl2 181
R1
R
TABLE 1 Reaction Conditions Optimization
H
N
O
H
N
NH2
NH2
SiO2/ZnCl2 (30%)
r.t. or MW at 50oC
NH2
R1
+
R1
SiO2 / Lewis acid
r.t. or 50oC
O
R
+
N
R
NH2
N
2a–h
3a–h
1
1
3a
2a
R = alkyl, aryl
R1 = alkyl
Entry Supported Lewis Acid Time (min.)
Yield (%)a,b
SCHEME 1 General scheme of the reaction.
1
2
3
4
5
6
7
8
None
150
60
40
20
20
80
11
20
69
74
73
85
91
75
80
89
FeCl3 (25%)
AlCl3 (25%)
ZnCl2 (25%)
ZnCl2 (30%)
ZnCl2 (10%)
ZnCl2 (25%)c
ZnCl2 (25%)d
since it displays many advantageous properties:
excellent stability (chemical and thermal), high-
surface area, good accessibility, and organic groups
can be robustly anchored to the surface, to pro-
vide catalytic centers [9]. Under this conception, our
group developed new protocols using SiO2/ZnCl2 as
a heterogeneous catalyst under solvent-free condi-
tions and MW irradiation for different organic re-
actions, including the synthesis of 1,2-disubstitued
benzimidazoles [10].
aYields are given for isolated products.
bReactions performed using o-phenylenediamine 1 (1.0 mmol),
dimethyl ketone 2a (2.5 equiv), and the catalyst (0.06 g).
cReaction was performed at 50◦C.
dReaction using 0.120 g of SiO2/ZnCl2.
Because the interesting application of 1-H-1,5-
benzodiazepines and in continuation to our studies
in the development of new and cleaner methods for
classical synthesis [10,11], we report herein the re-
sults of the preparation of 1-H-1,5-benzodiazepines
catalyzed by SiO2/ZnCl2 under solvent-free condi-
tions at room temperature, or under MW irradiation
(Scheme 1).
(Method A), o-phenylenediamine 1 (1.0 mmol) was
reacted with dimethyl ketone 2a (2.5 equiv) using
SiO2/ZnCl2 (30%) (0.06 g) at room temperature dur-
ing 20 min, affording 1,5-benzodiazepine 3a in 91%
yield.
To obtain an efficient protocol in terms of en-
ergy economy, we realized a study to reduce the
reaction time. Thus, the mixture was stirred under
different temperatures under MW irradiation. High
levels of consumption of the starting materials was
observed in these experiments, and the best result
was achieved after irradiation at 50◦C for 1.0 min,
giving the corresponding product 3a in 89% isolated
yield (Table 2, Method B).
To extend the scope of our methodology, the
possibility of performing the reaction with other ke-
tones was investigated under our two methodolo-
gies (Table 2). In most cases, the reaction proceeded
smoothly to give 1-H-1,5-benzodiazepines 3a–h in
good to excellent yields under both methods. Sym-
metrical alkylketones 2a and 2b were suitable sub-
strates for the reaction, and the respective products
were obtained in good to excellent yields (Table 2,
entries 1–4). It is interesting to note that, when we
used unsymmetrical ketones, such as 2-butanone 2c,
2-pentanone 2d, or 4-methyl-butan-2-one 2d as sub-
strates, the ring closure occurs selectively only from
one side of the carbon skeleton giving a single prod-
uct (Table 2, entries 5–10). Cyclic ketones such as
cyclopentanone and cyclohexanone reacted to give
the corresponding 1-H-1,5-benzodiazepines 3f and
3g in excellent yields (Table 2, entries 11–14). Reac-
tion of o-phenylenediamine 1 with acetophenone 2h
RESULTS AND DISCUSSION
Our initial studies have focused on the development
of an optimum set of reaction conditions. Thus, a
mixture of o-phenylenediamine 1 (1.0 mmol) and
dimethyl ketone 2a (2.5 equiv) was reacted with dif-
ferent silica-supported catalysts at room tempera-
ture, and the results are presented in Table 1. Dif-
ferent silica-supported catalysts (0.06 g) of Zn, Al,
Fe, as well as silica alone were tested, displaying a
moderated to good catalytic activity. The best result
was obtained using the catalytic system SiO2/ZnCl2
(25%), giving the desired 1,5-benzodiazepine 3a in
85% yield (Table 1, entry 4). To our satisfaction,
the use of a slight larger amount of ZnCl2 (30%)
yielded 91% of compound 3a after 20 min of re-
action at room temperature (Table 1, entry 5). Un-
fortunately, when the ZnCl2 ratio was reduced from
30% to 10% or the reaction temperature was in-
creased to 50◦C, a decrease in the yield of prod-
uct 3a was observed (Table 1, entries 6 and 7). A
reaction using a larger amount of catalytic system
(0.120 g) afforded product 3a in comparable yield
(Table 1, entries 5 vs. 8). In a optimized reaction
Heteroatom Chemistry DOI 10.1002/hc

182 Jacob et al.
TABLE 2 Reaction of o−Phenylenediamine 1 with Ketones 2a–h Using SiO2/ZnCl2 as a Solid-Supported Catalyst
Entry
1
Ketone
Methoda
Time (min)
20
Product
Yield (%)b
mp (◦C) [Lit.]
A
91
139–140 [12]
O
H
N
N
2
3
2a
O
B
A
1.0
40
3a
89
80
142–144 [13]
H
N
N
4
5
2b
O
B
A
2.0
30
3b
94
93
138–140 [12]
140–142 [14]
H
N
N
6
7
2c
B
A
1.5
40
3c
H
N
91
94
O
N
8
9
2d
B
A
2.5
60
3d
93
60
119–120 [12]
O
H
N
N
10
11
2e
O
B
A
4.0
40
3e
87
85
138–140 [12]
135–137 [15]
H
N
N
12
13
2f
O
B
A
3.0
40
3f
93
90
H
N
N
14
15
2g
B
A
3.0
30
3g
96
97
149–151 [12]
H
N
O
N
16
2h
B
5.0
3h
95
aMethod A: Reactions are performed in the presence of ketone 2 (2.5 mmol) and o-phenylenediamine 1 (1.0 mmol) using 0.060 g of SiO2/ZnCl2
(30%) at room temperature. Method B: Reactions are performed in the presence of ketone 2 (2.5 mmol) and o-phenylenediamine 1 (1.0 mmol)
using 0.060 g of SiO2/ZnCl2 (30%) at 50◦C in a MW reactor.
bYields are given for isolated product.
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of 1-H-1,5-Benzodiazepines Derivatives Using SiO2/ZnCl2 183
TABLE 3 Reuse of Catalyst in the Synthesis of 1,5-
Benzodiazepine 3a
EXPERIMENTAL SECTION
General
H
Proton nuclear magnetic resonance spectra (1H
NMR) were obtained at 200 and 300 MHz on a
Bruker DPX-200 and 300 NMR spectrometer, re-
spectively. Spectra were recorded in CDCl3 solu-
tions. Chemical shifts are reported in ppm, refer-
enced to the solvent peak of CDCl3, or tetramethylsi-
lane (TMS) as the internal reference. Data are re-
ported as follows: chemical shift (δ), multiplicity,
coupling constant (J) in hertz, and integrated inten-
sity. Carbon-13 nuclear magnetic resonance spec-
tra (13C NMR) were obtained at 50 and 75 MHz on
a Bruker DPX-200 and 300 NMR spectrometer, re-
spectively. Spectra were recorded in CDCl3 solutions.
Chemical shifts are reported in ppm, referenced to
the solvent peak of CDCl3. Column chromatogra-
phy was performed using Merck Silica Gel (230–400
mesh) following the standard methods. Thin layer
chromatography (TLC) was performed using Merck
Silica Gel GF254, 0.25 mm thickness. For visualiza-
tion, TLC plates were either placed under ultraviolet
light, or stained with iodine vapor, or acidic vanillin.
The reactions were monitored by TLC for disappear-
ance of starting material.
N
NH2
O
SiO2/ZnCl2 (30%)
M.W. at 50oC
+
NH2
N
1
3a
2a
Run
Reaction Time (h)
Yield (%)a
1b
2c
3c
4c
5c
1.0
1.0
1.0
1.5
2.5
89
88
88
85
79
aYields are given for isolated products.
bReactions performed using o-phenylenediamine 1 (1.0 mmol),
dimethyl ketone 2a (2.5 equiv), and SiO2/ZnCl2 (30%) (0.06 g).
cRecovered SiO2/ZnCl2 was used.
gave excellent yields of product 3h (Table 2, entries
15 and 16). The results depicted in Table 2 show
that the use of MW irradiation (Method B) is bet-
ter than conventional reaction (Method A), furnish-
ing the corresponding products in comparable yields
but in very short reaction time (Table 2, Method A vs.
Method B).
A reuse study of the catalyst was carried out
for the reaction presented in Table 3, according
Method B. After completion of the condensation
of dimethylketone with o-phenylenediamine, the re-
action mixture was diluted with ethyl acetate and
the catalyst was recovered by filtration. The solid-
supported catalyst was dried in an oven and reused
for subsequent experiments under similar reaction
conditions. The catalyst maintained its good level of
efficiency even after being reused four times (Table
3). The product 3a was obtained in 89, 88, 88, 85, and
79% yields after successive cycles. The observed fact
that yields of the product remained comparable in
these experiments, established the recyclability and
reusability of the catalyst without significant loss in
activity.
Preparation of Solid-Supported Catalyst
(SiO2/ZnCl2, 30%)
To a 100-mL beaker, silica gel 60 (7.0 g), ZnCl2
(3.0 g), and water (3.0 mL) were added. The suspen-
sion was stirred for 15 min at room temperature,
dried in an oven at 50◦C for 30 min, at 100◦C for ad-
ditional 30 min, and finally at 150◦C for 2 h. After this
procedure, the catalyst was cooled in a desiccator.
General Procedure for the Synthesis of 1-H-1,5-
Benzodiazepines 2a–h
Method A: To a mixture of appropriate ketone 2 (2.5
mmol) and o-phenylenediamine 1 (1.0 mmol), 0.060
g of SiO2/ZnCl2 (30%) was added and the whole
mixture was stirred at room temperature. The re-
action progress was followed by TLC. Method B: In a
10-mL glass vial equipped with a small magnetic stir-
ring bar, containing the appropriate ketone 2 (2.5
mmol) and o-phenylenediamine (1.0 mmol), 0.060 g
of SiO2/ZnCl2 (30%) was added and the vial was
tightly sealed with an aluminum/Teflon crimp top.
The mixture was then irradiated in a focused mi-
crowaves reactor (CEM) at 50◦C, using an irradia-
tion power of 200 W and pressure of 100 psi. After
stirring for the time indicated in Table 2, ethyl ac-
etate (10 mL) was added, and the organic solution
CONCLUSION
In conclusion, we have presented here an effi-
cient methodology for the synthesis of 1-H-1,5-
benzodiazepines in good yields by the condensation
of o-phenylenediamine with aryl, cyclic, or acyclic
ketones using SiO2/ZnCl2 as a solid-supported cata-
lyst. The catalytic system was reused up four times
without lost of activity. This clean protocol mini-
mizes the organic solvent and energy demands, as
well as, the reaction time could be reduced to a few
minutes using MW irradiation.
Heteroatom Chemistry DOI 10.1002/hc

184 Jacob et al.
was separated of the SiO2/ZnCl2 by filtration. The
solvent was evaporated under reduced pressure, and
the residue was purified by column chromatography
over silica gel eluting with hexanes/AcOEt 9:1 mix-
ture, yielding the products.
2-Methyl-2,4-diisobutyl-2,3-dihydro-1-H-1,5-ben-
zodiazepine (3e). White solid: mp 119–120◦C. 1H
NMR (300 MHz, CDCl3): 0.91–1.03 (m, 12H), 1.33
(s, 3H), 1.46–1.59 (m, 2H), 1.69–1.81 (m, 1H), 2.11–
2.31 (m, 3H), 2.46 (d, 2H, J = 7.5), 6.67–6.72 (m, 1H),
6.94–6.99 (m, 2H), 7.12–7.17 (m, 1H). 13C NMR (75
MHz, CDCl3): 22.45, 22.72, 24.18, 24.91, 25.06, 26.35,
28.14, 43.25, 51.71, 51.84, 71.10, 121.52, 121.58,
125.32, 127.08, 137.77, 140.50, 174.32. IR (KBr)
(cm−1): 3396, 1635, 1597. MS (EI): m/z (% relative
intensity) = 272 (M+, 6), 215 (100), 173 (32), 133
(32), 92 (7), 77 (5), 65 (4).
2,2,4-Trimethyl-2,3-dihydro-1-H-1,5-benzodiaze-
pine (3a). White solid: mp 139–140◦C. 1H NMR (300
MHz, CDCl3): 1.34 (s, 6H), 2.22 (s, 2H), 2.36 (s, 3H),
2.97 (br s, 1H, NH), 6.70–6.72 (m, 1H), 6.95–7.01 (m,
2H), 7.11–7.15 (m, 1H). 13C NMR (75 MHz, CDCl3):
29.78, 30.41, 45.02, 68.34, 121.67, 122.02, 125.43,
126.74, 137.84, 140.68, 172.37. IR (KBr) (cm−1):
3288, 1631, 1595. MS (EI): m/z (% relative intensity)
= 188 (M+, 37), 173 (100), 133 (64), 77 (6), 65 (11).
10-Spirocyclopentane-1,2,3,9,10,10a-hexahydro-
benzo[b]cyclopenta[e][1,4] diazepine (3f). Yellow
2,2,4-Triethyl-3-methyl-2,3-dihydro-1-H-1,5-
benzodiazepine (3b). Yellow solid: mp 142–144◦C.
1H NMR (300 MHz, CDCl3): 0.77 (t, 3H, J = 7.4),
0.88 (t, 3H, J = 7.5), 0.93 (d, 3H, J = 7.0), 1.22
(t, 3H, J = 7.4), 1.30–1.38 (q, 2H, J = 7.4), 1.51–
1.59 (m, 2H), 2.48–2.56 (m, 2H), 2.78–2.85 (q, 1H,
J = 7.0), 3.62 (br s, 1H, NH), 6.59 (d, 1H, J =
8.0), 6.72 (t, 1H, J = 8.0), 6.95 (t, 1H, J = 8.0).
7.32 (d, 1H, J = 8.0). 13C NMR (75 MHz, CDCl3):
7.29, 7.84, 11.56, 12.31, 28.01, 28.38, 35.69, 46.05,
60.31, 117.50, 117.95, 126.68, 132.24, 132.75, 139.03,
173.74. IR (KBr) (cm−1): 3288, 1635, 1600. MS (EI):
m/z (% relative intensity) = 244 (M+, 10), 215 (100),
147 (65), 92 (7). 77 (9), 65 (6).
1
solid: mp 138–140◦C. H NMR (300 MHz, CDCl3):
1.26–1.85 (m, 8H), 2.11–2.25 (m, 4H), 2.37–2.49 (m,
2H), 2.78–2.86. (m, 1H), 3.99 (br s, 1H, NH), 6.63 (d,
1H, J = 7.9), 6.79 (t, 1H, J = 8.4), 6.95 (t, 1H, J =
7.9), 7.94 (d, 1H, J = 8.4). 13C NMR (50 MHz, CDCl3):
23.50, 24.10, 24.30, 28.80, 33.40, 38.50, 39.20, 56.40,
67.30, 118.60, 119.30, 126.90, 133.10, 139.20, 143.80,
178.20. IR (KBr) (cm−1): 3338, 1641, 1604. MS (EI):
m/z (% relative intensity) = 240 (M+, 36), 211 (100),
183 (24), 145 (54), 132 (55), 91 (25), 77 (21), 65 (27).
10-Spirocyhexane-2,3,4,10,11,11a-hexahydro-1H-
dibenzo[b,e][1,4]diazepine (3g). Yellow solid: mp
1
135–137◦C. H NMR (200 MHz, CDCl3): 1.16–1.96
2,4-Diethyl-2-methyl-2,3-dihydro-1-H-1,5-benzo-
diazepine (3c). Yellow solid: mp 138–140◦C. 1H
NMR (200 MHz, CDCl3): 0.96 (t, 3H, J = 7.4), 1.19–
1.32 (m, 6H), 1.58–1.71 (m, 2H), 2.21–2.37 (m, 2H),
2.69–2.81 (q, 2H, J = 7.4), 3.76 (br s, 1H, NH), 6.72–
6.79 (m, 1H), 6.91–7.08 (m, 2H), 7.32–7.38 (m, 1H).
13C NMR (50 MHz, CDCl3): 8.60, 10.70, 26.60, 35.60,
35.80, 42,30, 70.60, 121.90, 125.50, 126.10, 127.20,
137.90, 140.70, 175.70. IR (KBr) (cm−1): 3331, 1637,
1594. MS (EI): m/z (% relative intensity) = 216 (M+,
16), 187 (100), 145 (24), 133 (26), 77 (6), 65 (6).
(m, 14H), 2.32 (t, 2H, J = 6.2), 2.44–2.66 (m, 1H),
3.87 (br s, 1H, NH), 6.51–6.64 (m, 1H), 6.69–6.75 (m,
2H), 6.89–7.09 (m, 1H). 13C NMR (50 MHz, CDCl3):
21.80, 21.70, 23.50, 24.50, 25.30, 33.50, 34.40, 39.30,
40.80, 52.40, 63.10, 121.30, 121.60, 126.30, 129.70,
138.10, 142.60, 178.80. IR (KBr) (cm−1): 3406, 1637,
1595. MS (EI): m/z (% relative intensity) = 268 (M+,
17), 225 (100), 169 (15), 145 (54), 132 (44), 92 (9),
77 (18), 65 (9).
2-Methyl-2,4-dipropyl-2,3-dihydro-1-H-1,5-benz-
odiazepine (3d). Yellow solid: mp 140–142◦C. 1H
NMR (200 MHz, CDCl3): 0.89–1.05 (m, 6H), 1.25 (s,
3H), 1.32–1.61 (m, 4H), 1.63–1.82 (m, 2H), 2.08–2.24
(m, 2H), 2.47–2.57 (m, 2H), 3.32 (br s, 1H, NH), 6.65–
6.74 (m, 1H), 6.91–6.99 (m, 2H), 7.01–7.18 (m, 1H).
13C NMR (50 MHz, CDCl3): 13.76, 14.35, 17.26, 19.59,
27.33, 42.16, 44.46, 45.52, 70.52, 121.47, 121.51,
125.18, 126.75, 137.75, 140.39, 174.91. IR (KBr)
(cm−1): 3331, 1635, 1597. MS (EI): m/z (% relative
intensity) =/m/z: 244 (M+, 11), 201 (100), 161 (13),
133 (16), 87 (3), 77 (9), 65 (7).
2-Methyl-2,4-diphenyl-2,3-dihydro-1-H-1,5-benz-
odiazepine (3h). White solid: mp 149–151◦C. 1H
NMR (300 MHz, CDCl3): 1.76 (d, 3H, J = 4.3), 2.97
(dd, 1H, J = 13.0, 4.4), 3.14 (dd, 1H, J = 13.0, 4.4),
3.52 (br s, 1H, NH), 6.82–6.86 (m, 1H), 7.03–7.09 (m,
2H), 7.17–7.39 (m, 7H), 7.56–7.62 (m, 4H). 13C NMR
(75 MHz, CDCl3): 29.85, 43.05, 73.68, 121.39, 121.62,
125.39, 126.30, 127.04, 127.99, 128.27, 128.58,
129.70, 138.03, 139.55, 140.06, 147.57, 167.65. IR
(KBr) (cm−1): 3452, 1633, 1597. MS (EI): m/z (% rel-
ative intensity) = 312 (M+, 6), 297 (16), 194 (100),
103 (17), 77 (14).
Heteroatom Chemistry DOI 10.1002/hc

Synthesis of 1-H-1,5-Benzodiazepines Derivatives Using SiO2/ZnCl2 185
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Kita, Y.; Fujioka, H. Tetrahedron 2008, 64, 11034. (o)
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Heteroatom Chemistry DOI 10.1002/hc