Solid support mediated chemo and regioselective synthesis of 3H-1,5-benzodiazepines from diversely substituted α-oxo ketene dithioacetals

Article abstract of DOI:10.1039/c3ra43347a

Solvent free, dry media supported synthesis of a series of 4-aryl/heteroaryl-2-methylthio-3H-1,5-benzodiazepines by chemo- and regioselective cyclization of substituted α-oxoketene dithioacetals with o-phenylenediamines is described. The X-ray crystallogr

Full text of DOI:10.1039/c3ra43347a

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Solid support mediated chemo and regioselective
synthesis of 3H-1,5- benzodiazepines from diversely
substituted a-oxo ketene dithioacetals3
Cite this: DOI: 10.1039/c3ra43347a
Received 29th April 2013,
Accepted 18th July 2013
Nutan Sharma, Tejpal Singh Chundawat, Subash Chandra Mohapatra
and Sunita Bhagat*
DOI: 10.1039/c3ra43347a
www.rsc.org/advances
Solvent free, dry media supported synthesis of a series of 4-aryl/
heteroaryl-2-methylthio-3H-1,5-benzodiazepines by chemo- and
regioselective cyclization of substituted a-oxoketene dithioacetals
with o-phenylenediamines is described. The X-ray crystallographic
studies confirmed the formation of the cyclized product.
and environmentally friendly methodology, we describe herein a
solid state approach for the rapid synthesis of 4-aryl-2-methylthio-
3H-1,5-benzodiazepines by chemo and regioselective cyclization of
a-oxo ketene dithioacetals with o-phenylenediamines 3a/3b
(Scheme 1). All the a-oxo ketene dithioacetals were synthesized
by a reported procedure.18 Solid phase reactions are of growing
interest19 because of their ease of execution and work-up, mild
reaction conditions, rate of reaction, selectivity, high yields, lack of
solvents and low cost in comparison to their homogeneous
counter parts.
The reaction has been performed under neat conditions by
varying different parameters which include solid supports such as
(i) acidic, basic or neutral aluminas, (ii) strongly acidic montmor-
illonite KSF, (iii) silica gel, and solvents such as toluene, ethanol,
xylene. From the results obtained it is obvious that basic alumina
(Table 1) is the most effective and simplest solid support for the
synthesis of 4a, since a comparatively higher yield is obtained in
shorter reaction time by this method. Consequently, we have used
same conditions to synthesize a series of aryl 4b–r (Table 2) and
heteroaryl substituted 4s–x (Table 3) 3H-1,5-benzodiazepines.
In order to compare the efficiency of various inorganic
supports, a model reaction between 1-(4-fluorophenyl)-3,3-bis
(methylthio)prop-2-en-1-one (2a) and o-phenylene diamine (3a)
Benzodiazepines1–4 have been the target of intense investigation in
medicinal chemistry and are now one of the most widely
prescribed class of psychotropics5 due to their remarkable central
nervous system (CNS) depressant activity. More recently, the area
of biological interest of 1,5-benzodiazepines6 has been extended to
various diseases such as cancer,7 viral infection (HIV)8 and
cardiovascular disorders.9 The 1,5-benzodiazepine core is indeed
a ‘‘privileged scaffold’’10 found in compounds active against a
variety of target types including peptide hormones such as
cholecystokinin (CCK),11 interleukin converting enzymes (ICE)12
and potassium blockers (Ik).9b Moreover, 1,5-benzodiazepines
derivatives are valuable synthons that can be exploited in the
synthesis of other fused ring compounds such as triazolo-,
oxadiazolo-, oxazino-, or furano-benzodiazepines.13 Thus, to
develop the synthetic strategy of this heterocyclic nucleus is of
current importance. In this context, we studied the reaction of
a-oxoketene dithioacetals with o-phenylenediamines and obtained
4-aryl-2-methylthio-3H-1,5-benzodiazepines in high yields.
4-Aryl-2-methylhio-3H-1,5-benzodiazepines have been reported
to be synthesized by the methylation of 1,5-benzodiazepin-2-
thione14,15 and by using o-phenylenediamine as starting materi-
als.16,17 However, the former afforded the desired products only in
the impure state, while the latter required high thermal conditions
and a prolonged reaction time (10 h). In view of the reported
limitations in the synthesis of 3H-1,5-benzodiazepines and
necessity for the development of a more efficient, convenient
Organic Synthesis Research Laboratory, Department of Chemistry, A.R.S.D. College,
University of Delhi, New Delhi-110021, India.
E-mail: sunitabhagat28@rediffmail.com
Electronic supplementary information (ESI) available: Data and spectral copies of
3
1H, 13C NMR for target compounds. X-ray crystallographic data of compound 4c.
CCDC 920827. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3ra43347a
Scheme 1 Chemoselective cyclization for the synthesis of 3H-1,5-benzodiaze-
pines.
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Table 1 Optimization of reaction conditionsa
Table 3 Synthesis of various heterocyclic benzodiazepine derivativesa
Entry
Medium
T (uC)
Time (h)
Yieldb (%)
Entry
1
Substrate (R)
2j,
Diamine
3a
Product (4s–x)
4s
Yieldb(%)
82
1
2
3
4
5
6
7
8
Montmorillonite KSF
Silica Gel
90
90
90
90
90
100
90
4
4
4
4
4
4
4
4
5
42
45
60
92
90
70c
5
60
62
58
Acidic Alumina
Neutral Alumina
Basic Alumina
Basic Alumina
Basic Alumina
—
Toluene
Ethanol
Xylene
2
3
2j,
3b
3a
4t
85
70
90
9
10
11
reflux
reflux
reflux
8
10
24
2k,
4u
a
The reactions were performed using a-oxo ketene dithioacetal 2a (1
mmol), amine 3a (1.5 mmol) and inorganic solid support (1 g).
b
c
Yield of the isolated product after column chromatography. 0.5 g
4
2k,
3b
4v
72
of basic alumina was used.
5
6
2l,
2l,
3a
3b
4w
4x
75
80
was performed at 90 uC for 4 h (Table 1). The yield of the product
4a was lowest when highly acidic montmorillonite KSF was used
as a solid support (entry 1) in comparison to silica gel and acidic
Table 2 Synthesis of various aromatic benzodiazepine derivativesa
a
The reactions were performed using a-oxo ketene dithioacetal 2 (1
b
mmol), amine 3 (1.5 mmol) and basic alumina (1 g). Yield of the
isolated product after column chromatography.
alumina which gave 42% and 45% yield respectively (entries 2,3).
When neutral alumina was used it led to the formation of 4a in
60% yield (entry 4). It is highly notable that the reaction of 2a and
3a gave the highest yield of 92% in basic alumina as an inorganic
support (entry 5). To the best of our knowledge this is the first
example in which 3H-1,5-benzodiazepine has been obtained
directly and efficiently from 2a and 3a by using basic alumina
as the reaction medium in the absence of any solvent. It was
noticed that when the temperature of the reaction was increased
from 90 uC to 100 uC, it had no significant effect on the yield of the
product 4a and almost comparable yield of 90% was obtained
(entry 6). Reducing the amount of solid support from 1 g to 0.5 g
adversely decreased the yield of 4a to 70% which was anticipated
due to improper adsorption of the reactants on a solid support
(entry 7). However in the absence of a solid support, the reactants
remained almost unchanged during the course of reaction with a
negligible yield of 5% (entry 8).
Entry Substrate (2a–i)
Diamine Product (4a–r) Yieldb(%)
1
2
3
4
5
6
7
8
2a, R1 = F, R2 = H
2a, R1 = F, R2 = H
2b, R1 = Cl, R2 = H
2b, R1 = Cl, R2 = H
2c, R1 = Br, R2 = H
2c, R1 = Br, R2 = H
2d, R1 = CF3, R2 = H
2d, R1 = CF3, R2 = H
2e, R1 = Cl, R2 = Cl
2e, R1 = Cl, R2 = Cl
2f, R1 = CH3, R2 = H
2f, R1 = CH3, R2 = H
2g,R1= OCH3, R2 = H
2g,R1= OCH3, R2 = H
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
3a
3b
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
92
94
85
87
88
89
88
87
80
82
85
90
78
77
80
82
85
83
9
10
11
12
13
14
15
16
17
18
2h, R1 = H, R2 = OCH3 3a
2h, R1 = H, R2 = OCH3 3b
2i, R1 = F, R2 = OCH3 3a
2i, R1 = F, R2 = OCH3 3b
a
The reactions were performed using a-oxo ketene dithioacetal 2 (1
We also carried out the cyclization reaction of 2a and 3a in
toluene, ethanol and xylene (entries 9–11), in order to compare
b
mmol), amine 3 (1.5 mmol) and basic alumina (1 g). yield of the
isolated product after column chromatography.
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with organic solvents. It shows that, reactions performed in these
solvents proceeded much more slowly and gave lower yields
compared to the reaction using basic alumina as a solid support.
These results clearly show the advantage of a solid support such as
basic alumina over high boiling and hazardous solvents.
With the established optimal conditions (Table 1, entry 5), we
explored the scope of a-oxo ketene dithioacetals 2(a–l) with
o-phenylenediamines 3a/3b. As shown in Table 2, the reaction was
tolerant towards a variety of a-oxo ketene dithioacetals (2) bearing
different substituents at R1 and R2. When an electron-withdrawing
group was used as R1, then reaction was well implemented to form
intriguing cyclized products 4a–h in 87–94% yields (entries 1–8).
Whereas placement of electron-withdrawing groups at both R1
and R2 resulted in 80–82% yield (entry 9–10). When an electron-
donating group was used as R1 then products 4k–n were obtained
in 77–90% yields (entries 11–14), and a comparable yield of 4o, 4p
was obtained when R2 was used as electron-donating group
(entries 15–16). Furthermore, When R1 was used as electron-
withdrawing and R2 was used as electron donating in the same
compound then the yield was 85% and 83% respectively (entries
17–18).
Scheme 2 Plausible mechanism for synthesis of 3H,1-5 benzodiazepines.
[M + 1] at 285 corresponds to the molecular mass of the
compound. Additionally, the structures of the synthesized novel
3H-1,5-benzodiazepine derivatives (4) have been confirmed by the
single crystal X-ray diffraction analysis of compound 4c (Fig. 1).
On the basis of above experimental results, a plausible
mechanism involving the enamine–imine tautomeric intermediate
is depicted as shown in Scheme 2. The mechanism involves
substitution of one of the thiomethyl groups of ketene dithioacetal
2 by one of the amino groups of reactant 3a/3b resulting in
formation of intermediate 4A at first. This intermediate can either
be converted into ketene aminal 520 (Scheme 1), or tautomerise to
the imine form 4B. 4B is likely to exist in an anti-configuration due
to steric stability and undergo cyclocondensation yielding 4. This
mechanism can also best interpret the results reported in the
literature;21 especially the reaction between ketene dithioacetals
and 2-aminothiophenol22 or 2-aminophenol22 in the presence of
sodium, and guanidine22 or hydrazine.22
We further employed the same protocol to examine its scope
for the reaction of o-phenylenediamine 3a/3b with a-oxoketene
dithioacetals bearing heterocyclic rings as R (Table 3). Using
benzofuran as R afforded the products in 82% and 85% yield
(entries 1–2) respectively. However when pyridine, thiophene were
used as heteroaryl substituents, the corresponding products 4u–x
were obtained in 70–80% yield. (entries 3–6).
Structural assignments have been made on the basis of IR, 1H
NMR, 13C NMR and mass spectra. IR spectra of the products 4a–x
did not reveal characteristic ketocarbonyl absorption peaks in the
range 1675–1670 cm21 and also, absorption of primary amino
groups (two bands in the region 3450–3150 cm1) were absent. On
another hand, the copresence of an absorption at around 1585–
1600 cm21 u(CLN), and C–H stretching frequencies in the range
2920–2930 cm21 were observed.
Conclusions
In conclusion, we have developed an efficient, green methodology
for the synthesis of 3H,1-5 benzodiazepines. The advantages such
as (i) no requirement of additional reagent/catalyst, (ii) non-
inflammable and nontoxic reaction medium, (iii) high yields, (iv)
excellent chemo and regioselectivity, (v) virtually no waste
generation, and (vi) ease of product isolation/purification fulfil
the triple bottom line philosophy of green chemistry and make the
present methodology environmentally benign. Furthermore, the
methylthio group can be explored for the synthesis 2-amino-4-aryl-
3H-1,5-benzodiazepine analogues of biological importance.
1
In the H NMR spectra, absorptions as singlets at d 3.30–3.60
(s, 2H) and d 2.40–2.50 (s, 3H), were characterized for methylene
protons between two imine bonds and one methyl proton of SCH3
in 4a–x. Formation of the final compound 4a was further
confirmed on the basis of 13C NMR and mass spectra. In the
mass spectrum of 4a, the appearance of molecular ion peaks, m/z,
Acknowledgements
The authors are thankful to Department of Science and
Technology (DST) women scientist scheme (WOS-A) for
financial support and USIC, University of Delhi for providing
instrumentation facilities. TJ, NS are thankful to UGC for SPF
and DST for INSPIRE Fellowship. Dr S.C. Mohapatra is
thankful to Dr D.S. Kothari postdoctoral fellowship No- F.4-
2/2006(BSR) 13-215/2008(BSR).
Fig. 1 Ortep diagram of compound 4c.
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