Bromodimethylsulfonium bromide (BDMS)-catalyzed synthesis of 1,5-benzodiazepines using a multi-component reaction strategy

Article abstract of DOI:10.1055/s-0033-1338984

A new approach for the synthesis of multi-functionalized 15-benzodiazepines is developed starting from o-phenylenediamines, β-keto esters and aromatic aldehydes utilizing a one-pot, three-component strategy employing bromodimethylsulfonium bromide as the

Full text of DOI:10.1055/s-0033-1338984

LETTER
▌2601
letter
Bromodimethylsulfonium Bromide (BDMS)-Catalyzed Synthesis of
1,5-Benzodiazepines Using a Multi-Component Reaction Strategy
Synthesis of 1,5-Benzodiazepines
Satavisha Sarkar, Jugal Kishore Rai Deka, Jagadish P. Hazra, Abu T. Khan*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati 781039, India
Fax +91(361)2582349; E-mail: atk@iitg.ernet.in
Received: 14.08.2013; Accepted after revision: 08.09.2013
This work is dedicated to the late Dr. Uttara Debi who was compassionate and amicable in nature.
etate and p-toluenesulfonic acid (PTSA) as the catalyst,16a
but they were unable to synthesize 1,5-benzodiazepines
under these conditions. In 2008, they extended their ap-
proach to the synthesis of 1,5-benzodiazepines using
Abstract: A new approach for the synthesis of multi-functionalized
1,5-benzodiazepines is developed starting from o-phenylenedi-
amines, β-keto esters and aromatic aldehydes utilizing a one-pot,
three-component strategy employing bromodimethylsulfonium
bromide as the catalyst. The simple reaction procedure, good yields, o-phenylenediamine, aromatic aldehydes and β-keto esters
with pentafluorobenzoic acid as the catalyst.16b Although
Rodriguez et al. similarly established the synthesis of 1,4-
mild reaction conditions and applicability to a wide range of sub-
strates are some of the salient features of this protocol.
Key words: multi-component reactions, 1,5-benzodiazepines,
o-phenylenediamines, bromodimethylsulfonium bromide
diazepines using molecular sieves (4 Å), their strategy for
the synthesis of 1,5-benzodiazepines under identical con-
ditions failed.16c,d Our group has reported the synthesis of
1,5-benzodiazepines using 2,6-pyridinedicarboxylic acid
The benzodiazepine skeleton continues to generate inter- as an organocatalyst.16e Unfortunately, these protocols are
est from the pharmaceutical community.1 Indeed, the con- limited in scope due to the formation of side products, of-
cept of ‘privileged medicinal structures or scaffolds’ was ten lead to low yields, and require extended reaction
initially coined by Merck researchers during their work on times, high temperatures, inert atmospheric conditions or
benzodiazepines.2,3 They exhibit a broad spectrum of use expensive catalysts. Hence, there is scope for the
pharmacological properties, such as anti-inflammatory, development of new methodologies for the synthesis of
anticonvulsant, anti-anxiety, sedative, antidepressant, 1,5-benzodiazepine scaffolds.
hypnotic,1,4 antibiotic,5 anticancer6 and antiviral (HIV) ac-
We have reviewed the usefulness of bromodimethylsulfo-
tivities,7 and act as inhibitors of the HIV-1 capsid assem-
nium bromide (BDMS) as a catalyst as well as a brominat-
bly.8 Benzodiazepines have been developed as dyes for
ing reagent.17a Bromodimethylsulfonium bromide
acrylic fibers9 and have been used as starting materials for
displays efficient catalytic properties, as it is capable of
the preparation of triazole10a and oxadiazole10b derivatives.
generating hydrobromic acid (HBr) in situ, and acts as an
Multi-component reactions (MCRs) have emerged as a efficient pre-catalyst for several acid-catalyzed organic
powerful strategy to construct structurally complex and reactions.17b–d As part of our ongoing efforts to develop
functionally diverse multi-heterocyclic skeletons with ef- new synthetic protocols for the synthesis of biologically
ficient atom-economy.11
active heterocyclic compounds through multi-component
reactions, we have explored the utility of bromodimethyl-
sulfonium bromide as an efficient catalyst for the synthe-
sis of 1,5-benzodiazepine derivatives (Scheme 1).
Strategies for the construction of 1,5-benzodiazepines are
generally based on the condensation reactions of o-phenyl-
enediamine with α,β-unsaturated carbonyl compounds,12
β-halo ketones,13 or ketones.12a,14 A cycloaddition ap- To develop suitable conditions, a trial reaction was per-
proach has also been explored using o-phenylenediamines formed with o-phenylenediamine (1 mmol), ethyl aceto-
and terminal alkynes.15
acetate (1 mmol) and 4-chlorobenzaldehyde (1 mmol)
using bromodimethylsulfonium bromide (5 mol%) in ace-
tonitrile as the solvent. Monitoring by TLC showed that,
Kita et al. reported the construction of 1,4-diazepines us-
ing ethylenediamine, aromatic aldehydes, methyl acetoac-
R1
NH2
O
O
BDMS (10 mol%)
HN
Ar
NH
R1
O
+
ArCHO
+
r.t. to 50 °C
OR
3
NH2
2
OR
1
4
Scheme 1 Bromodimethylsulfonium bromide (BDMS) catalyzed synthesis of substituted 1,5-benzodiazepine derivatives
SYNLETT 2013, 24, 2601–2605
Advanced online publication: 14.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338984; Art ID: ST-2013-D0779-L
© Georg Thieme Verlag Stuttgart · New York

2602
S. Sarkar et al.
LETTER
after five hours, there was no further change in the reac-
Table 2 Synthesis of 1,5-Benzodiazepine Derivatives Using Substi-
tion. After isolating the major product and analysis by tuted Aromatic Aldehydes, Ethyl Acetoacetate and o-Phenylenedi-
aminea
spectroscopic techniques, we identified it as the desired
product 4d (R = Et, R1 = H, Ar = 4-ClC6H4). To optimize
Entry
Ar
Product
Time (h) Yield (%)b
the conditions, similar reactions were executed with bro-
modimethylsulfonium bromide (5 mol%) in different sol-
vents such as ethanol, dichloromethane and 1,2-
dichloroethane (Table 1, entries 1–4), with 1,2-dichloro-
ethane being the most suitable. Catalysts including molec-
ular iodine, p-toluenesulfonic acid, trifluoroacetic acid
(TFA) and L-proline in 1,2-dichloroethane as the solvent
led to lower yields (Table 1, entries 7–10). The reaction
did not proceed at all in the absence of a catalyst (Table 1,
entry 11). Further experimentation established that bro-
modimethylsulfonium bromide (10 mol%) in 1,2-dichlo-
roethane was the optimal combination (Table 1, entry 5);
further increasing the amount of catalyst did not improve
the yield (Table 1, entry 6). From the above observations,
it is clear that bromodimethylsulfonium bromide plays a
specific role compared to other catalysts.
1
2
Ph
4a
4b
4c
4d
4e
4f
4.5
4
75
77
78
72
74
70
71
68
65
71
72
74
75
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-FC6H4
3-FC6H4
2-ClC6H4
2-O2NC6H4
2-naphthyl
2-furfuryl
2-thienyl
3-indolyl
3
4
4
4.5
4.5
5
5
6
7
4g
4h
4i
5
8
5
9
5
10
11
12
13
4j
4.5
4.5
5
4k
4l
Table 1 Optimization of the Reaction Conditions for the Synthesis
of 1,5-Benzodiazepine Derivativesa
Entry
Catalyst (mol%)
Solvent
Time (h) Yield (%)b
4m
4.5
a All the reactions were performed with o-phenylenediamine (1.0
mmol), ethyl acetoacetate (1.0 mmol) and different aromatic alde-
hydes (1.0 mmol).
1
2
BDMS (5)
BDMS (5)
BDMS (5)
BDMS (5)
BDMS (10)
BDMS (15)
I2 (10)
MeCN
EtOH
CH2Cl2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
12
12
6
38
25
35
64
72
72
64
25
20
27
–
b Yield of isolated product.
3
4
5
(4j, Table 2, entry 10). Furthermore, the reaction was also
carried out with heteroaromatic aldehydes such as furfu-
ral, thiophene 2-carboxaldehyde and indole 3-carboxalde-
hyde, giving moderate yields (4k–m, Table 2, entries 11–
13). Unfortunately, the reaction was unsuccessful with al-
iphatic aldehydes. When the reaction was carried out with
cyclohexanecarboxaldehyde, o-phenylenediamine and
ethyl acetoacetate, we isolated 2-cyclohexyl-1-(cyclohex-
ylmethyl)-1H-benzo[d]imidazole (5) (see the Supporting
Information) in 30% yield, instead of the desired 1,5-ben-
zodiazepine.
5
4.5
6
4.5
6
7
8
PTSA (10)
TFA (10)
12
9
12
12
24
10
11
L-proline (10)
No catalyst
Conducting the reaction of o-phenylenediamine and benz-
aldehyde with different acyclic β-keto esters such as
methyl acetoacetate or t-butyl acetoacetate gave the de-
a All the reactions were performed with o-phenylenediamine (1.0
mmol), ethyl acetoacetate (1.0 mmol) and 4-chlorobenzaldehyde (1.0
mmol).
b Yield of isolated product.
Having optimized the reaction conditions, we next exam-
ined the generality and scope of this reaction using ethyl
acetoacetate and o-phenylenediamine and various substi-
tuted aromatic aldehydes, which afforded the correspond-
ing products 4a–m in good to moderate yields (Table 2).18
Aromatic aldehydes with electron-donating substituents
such as methyl and methoxy groups generally gave better
yields (4b,c, Table 2, entries 2 and 3) compared to those
with electron-withdrawing substituents (4d–f, Table 2,
entries 4–6). We also performed the reaction with ortho-
and meta-substituted aldehydes (4g–i, Table 2, entries 7–
9), as well as with the sterically hindered naphthaldehyde
Figure 1 X-ray crystallographic structure of 4q (CCDC 952358)
Synlett 2013, 24, 2601–2605
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,5-Benzodiazepines
2603
sired products in good yields (4n,o, Table 3, entries 1 and
2), whereas allyl acetoacetate produced the corresponding
product in a slightly lower yield (4p, Table 3, entry 3).
Table 3 Reactions of Different β-Keto Esters with Benzaldehyde
and o-Phenylenediamine for the Synthesis of 1,5-Benzodiazepinesa
Entry
R
Product
Time (h) Yield (%)b
We successfully synthesized 1,5-benzodiazepine deriva-
tive 4q in 77% yield using the cyclic β-keto ester, ethyl 2-
oxocyclohexane carboxylate, o-phenylenediamine and
benzaldehyde. The product 4q was characterized by sin-
gle crystal X-ray diffraction (Figure 1).
1
2
3
Me
4n
4o
4p
4.5
5
72
74
68
t-Bu
CH2-CH=CH2
5
a All the reactions were performed with o-phenylenediamine (1.0 mmol),
benzaldehyde (1.0 mmol) and different β-keto esters (1.0 mmol).
b Yield of isolated product.
Extending the scope of this reaction by utilizing a disub-
stituted aromatic diamine furnished the desired product in
good yield (4r, 68%). However, mono-substituted di-
amines gave a mixture of two inseparable regioisomers in
approximately 6:4 ratios as determined by 1H NMR spec-
HN
NH
HN
NH
+
O
O
Cl
Cl
OEt
OEt
4s
4 h, 72% (overall yield)
4t
HN
NH
Cl
Cl
O
OEt
4r
5 h, 68%
HN
NH
HN
NH
+
O
O
OEt
OEt
5 h, 42% (overall yield)
4u
4v
Figure 2 Scope of 1,5-benzodiazepine derivatives with substituted diamines, benzaldehyde and ethyl acetoacetate
Me2S + HOBr
BDMS
HBr
H2O
H2N
NH
O
CHO
OR
A
NH2
NH2
R1
O
O
OR
3
2
1
H
H
N
N
O
HN
N
O
OR
R1
OR
B
H
HN
N
γ-adduct
O
tautomerization
H
H
R1
4
••
N
R1
OR
cyclization
HN
D
O
OR
R1
C
Scheme 2 A plausible mechanism for the formation of 1,5-benzodiazepine derivatives 4
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2601–2605

2604
S. Sarkar et al.
LETTER
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chloro substituent, we obtained a lower yield compared to
that with an electron-donating substituent (Figure 2).
According, to our literature survey,16b,e a plausible mech-
anism for this conversion is depicted in Scheme 2. It is
proposed that o-phenylenediamine (1) reacts with β-keto
ester (2) to form enaminoester A in the presence of bro-
modimethylsulfonium bromide at room temperature,
which is a very characteristic reaction of carbonyl com-
pounds in the presence of an acid catalyst.
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I.; Hucke, O.; Kawai, S. H.; Lacoste, J.-E.; Landry, S.;
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We have isolated intermediate A, and it was evident from
the NMR spectrum of the major product isolated after 15
minutes that compound A was formed during the first step
of this transformation. Next, intermediate A reacts with
the aromatic aldehyde 3 under reflux conditions to form
imine-enaminoester intermediate B. This intermediate,
stabilized by an intramolecular hydrogen bonding interac-
tion, can provide the 1,5-benzodiazepine derivative
through a γ-selective C–C bond forming reaction. Thus
imine-enaminoester B tautomerizes into intermediate C
which undergoes cyclization to give D. This intermediate
D undergoes a 1,5-H shift to form the final product 4, the
γ adduct, which is stabilized by intramolecular H-bond-
ing.
(9) Harris, R. C.; Straley, J. M. US Pat., 1,537,757, 1968 Chem.
Abstr., 1970, 73, 100054w.
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VCH: Weinheim, 2005.
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Procopio, A. Tetrahedron Lett. 2011, 52, 4827; and
references cited therein. (b) Goswami, S.; Hazra, A.; Jana, S.
J. Heterocycl. Chem. 2009, 46, 861. (c) Feng, S.-E.; Xu, F.;
Shen, Q. Chin. J. Chem. 2008, 26, 1163.
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Corma, A.; Iborra, S.; Santos, L. L. Chem. Eur. J. 2009, 15,
8834.
In summary, we have devised a simple synthetic protocol
for the synthesis of 1,5-benzodiazepine derivatives from
o-phenylenediamine, β-keto esters and aromatic alde-
hydes catalyzed by bromodimethylsulfonium bromide,
via a one-pot multi-component reaction. Bromodimethyl-
sulfonium bromide acts as a pre-catalyst and generates
hydrobromic acid in situ, which plays a vital role in the
synthesis of the 1,5-benzodiazepine derivatives. The ad-
vantage of this protocol is the use of readily available
starting materials without the need for an inert atmo-
sphere.
Acknowledgments
S.S. is thankful to CSIR, New Delhi, India for her research fellow-
ship. The authors gratefully acknowledge the DST, New Delhi, for
providing the XRD facility under the FIST program and CIF, IITG
for the NMR facility. J.K.R.D and J.P.H are thankful to the Depart-
ment of Chemistry, IIT Guwahati, for the opportunity to work as
summer interns. We are also thankful to the referees for their va-
luable comments and suggestions.
(15) (a) Shobha, D.; Chari, M. A.; Selvan, S. T.; Oveisi, H.;
Mano, A.; Mukkanti, K. J. Org. Chem. 2012, 77, 4484.
(b) Maiti, G.; Kayal, U.; Karmakar, R.; Bhattacharya, R. N.
Tetrahedron Lett. 2012, 53, 1460.
(16) (a) Fujioka, H.; Murai, K.; Kubo, O.; Ohba, Y.; Kita, Y. Org.
Lett. 2007, 9, 1687. (b) Murai, K.; Nakatani, R.; Kita, Y.;
Fujioka, H. Tetrahedron 2008, 64, 11034. (c) Sotoca, E.;
Constantieux, T.; Rodriguez, J. Synlett 2008, 1313.
(d) Sotoca, E.; Allais, C.; Constantieux, T.; Rodriguez, J.
Org. Biomol. Chem. 2009, 7, 1911. (e) Lal, M.; Basha, R. S.;
Sarkar, S.; Khan, A. T. Tetrahedron Lett. 2013, 54, 4264.
(17) (a) Choudhury, L. H.; Parvin, T.; Khan, A. T. Tetrahedron
2009, 65, 9513. (b) Khan, A. T.; Parvin, T.; Choudhury, L.
H. J. Org. Chem. 2008, 73, 8398. (c) Khan, A. T.; Basha, R.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
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iotSrat
ungIifoop
r
t
References and Notes
(1) (a) Randall, O.; Kappel, B. In Benzodiazepines; Garattini,
S.; Mussini, E.; Randall, L. O., Eds.; Raven Press: New
York, 1973, 27. (b) Schütz, H. In Benzodiazepines;
Springer: Heidelberg, 1982.
(2) Evans, B. E.; Rittle, K. E.; Bock, M. G.; DiPardo, R. M.;
Freidinger, R. M.; Whitter, W. L.; Lundell, G. F.; Veber, D.
F.; Anderson, P. S. J. Med. Chem. 1988, 31, 2235.
(18) 1,5-Benzodiazepines; General Procedure
In an oven-dried 25 mL round-bottomed flask was added the
Synlett 2013, 24, 2601–2605
© Georg Thieme Verlag Stuttgart · New York

LETTER
requisite o-phenylenediamine (1.0 mmol) and β-keto ester
Synthesis of 1,5-Benzodiazepines
2605
1158, 1455, 1618, 1637, 2923, 3415, 3467 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 1.28 (t, J = 7.2 Hz, 3 H, -CH3), 2.54
(dd, J = 14, 4.4 Hz, 1 H, -CH2), 2.70 (dd, J = 14, 9.2 Hz, 1
H, -CH2), 3.7 (br s, 1H, -NH), 4.1–4.2 (m, 2 H, -OCH2), 4.61
(s, 1 H, =CH), 4.85 (dd, J = 9.2, 4 Hz, 1 H, -CH), 6.76–6.79
(m, 1 H, Ar-H), 6.85–6.94 (m, 1 H, Ar-H), 6.96–7.05 (m, 2
H, Ar-H), 7.28–7.32 (m, 1 H, Ar-H), 7.32–7.39 (m, 4 H,
Ar-H), 10.24 (s, 1 H, -NH). 13C NMR (100 MHz, CDCl3):
δ = 14.75, 40.52, 59.05, 65.33, 82.42, 121.01, 121.80,
122.74, 125.19, 126.29 (2 C), 128.18, 129.03 (2 C), 130.11,
138.11, 145.07, 158.83, 170.52.HRMS (ESI): m/z [M + H]+
calcd for C19H20N2O2: 309.1598; found: 309.1594. Anal.
Calcd for C19H20N2O2: C, 74.00; H, 6.54; N, 9.08. Found: C,
74.06; H, 6.59; N, 9.02.
(1.0 mmol) in DCE (3 mL). Next, bromodimethylsulfonium
bromide (10 mol%) was added and the mixture was stirred at
r.t. After 15 min, the aromatic aldehyde (1.0 mmol) was
added and the mixture was heated at 55 °C for the
appropriate amount of time. Following completion (TLC),
the solvent was removed on a rotary evaporator. The residue
was extracted with CH2Cl2 (2 × 10 mL), washed with H2O
(10 mL) and dried over anhydrous Na2SO4. The solution was
filtered, concentrated in vacuo and the residue purified by
column chromatography (EtOAc–hexane, 5:95) to provide
the 1,5-diazepine product.
(Z)-Ethyl 2-(4-Phenyl-4,5-dihydro-1H-benzo[b][1,4]-
diazepin-2(3H)-ylidene)acetate (4a)
Yield: 0.213 g (75%); yellow solid; mp 73–77 °C. IR (KBr):
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2601–2605

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