A facile synthesis of benzo[b][1,4]thiazepine derivatives by palladium acetate catalyzed reaction

Article abstract of DOI:10.1016/j.tetlet.2014.01.153

The preparation of steroid/nonsteroid fused benzo[b][1,4]thiazepines and 2-arylsubstituted benzo[b][1,4]thiazepines is described from Pd(OAc)₂ catalyzed reaction of steroidal/nonsteroidal β-halovinyl aldehydes and 2-aminothiophenols in DMF under heating condition.

Full text of DOI:10.1016/j.tetlet.2014.01.153

Accepted Manuscript
A facile synthesis of benzo[b][1,4]thiazepine derivatives by palladium acetate
catalyzed reaction
Partha Pratim Kaishap, Kommoori Shekarrao, Pallabi Saikia, Sanjib Gogoi,
Romesh C Boruah
PII:
S0040-4039(14)00220-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.153
TETL 44186
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 October 2013
29 January 2014
31 January 2014
Please cite this article as: Kaishap, P.P., Shekarrao, K., Saikia, P., Gogoi, S., Boruah, R.C., A facile synthesis of
benzo[b][1,4]thiazepine derivatives by palladium acetate catalyzed reaction, Tetrahedron Letters (2014), doi: http://
dx.doi.org/10.1016/j.tetlet.2014.01.153
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A facile synthesis of benzo[b][1,4]thiazepine derivatives by palladium acetate catalyzed
reaction
Partha Pratim Kaishap, Kommoori Shekarrao, Pallabi Saikia, Sanjib Gogoi,* Romesh C
Boruah*
* Corresponding author, Tel.: +91 3762372948; fax: +913762370011; skgogoi1@gmail.com; rc_boruah@yahoo.co.in
Medicinal Chemistry Division, North-East Institute of Science and Technology, Jorhat, Assam 785006, India
_______________________________________________________________________________________________________
Abstract
The preparation of steroid/nonsteroid fused benzo[b][1,4]thiazepines and 2-arylsubstituted
benzo[b][1,4]thiazepines
is described
from Pd(OAc)2 catalyzed
reaction of
steroidal/nonsteroidal β-halovinyl aldehydes and 2-aminothiophenols in DMF under heating
condition.
Keywords: Benzo[b][1,4]thiazepine, steroid, palladium acetate, β-bromovinyl aldehyde, 2-
aminothiophenol.
_______________________________________________________________________________________________________
The benzo[b][1,4]thiazepine moiety is a well known pharmacophore in medicinal chemistry.
Compounds bearing this moiety show different biological activities such as antiHIV, anticancer,
anticonvulsant, antianginal, antimicrobial, antifungal etc. They also act as angiotensin
converting enzyme inhibitors, calmodulin antagonists, bradykinin receptor agonists and Ca2+
antagonist.1 Some of the widely used benzo[b][1,4]thiazepine drugs are shown in Figure 1. The
first benzo[b][1,4]thiazepine derivative diltiazem (Figure 1) is used widely as an
antihypertensive drug due to its potent calcium channel blocking property. Similarly,
benzo[b][1,4]thiazepine derivative clentiazem is used clinically for its cardiovascular action,
quetiapine is used as an atypical antipsychotic agent and thiazesim is used as an antidepressant
(Figure 1).
It is known that fusion of a heterocyclic ring with the skeleton of a steroidal molecule alters
the activity of the molecule. Because of the remarkable biological activities of these steroids

fused with heterocycles, enormous efforts have been made by different research groups to
synthesize a wide variety of these heterosteroids.2
N
N
O
O
O
O
O
O
N
N
Cl
S
S
O
O
Diltiazem
(Calcium channel blocker)
Clentiazem
(Calcium channel blocker)
S
OH
O
N
N
N
O
N
S
N
Quetiapine
(Antipsychotic agent)
Thiazesim
(Antidepressant)
Figure 1:
Examples of some clinically used 1,5-benzothiazepine
derivatives
There are various synthetic methods reported in the literature for the synthesis of 2,4-
disubstituted benzo[b][1,4]thiazepine. For example, recently Willy B. et al. reported three-
component synthesis of 2,4-disubstituted benzo[b][1,5]thiazepines via coupling–addition–
cyclocondensation sequence.3 Nigam S. et al. reported the synthesis of 2,4-disubstituted
benzo[b][1,4]thiazepine by the reaction of 1-(benzo[d][1,3]dioxol-5-yl)-3-phenylpropane-1,3-
diones with o-aminothiophenol in pyridine.4 Moreover, there are several procedures reported for
the synthesis of 2,3-dihydro-substituted-benzo[b][1,4]thiazepine.5 But, to the best of our
knowledge synthesis of only 2-substituted benzo[b][1,4]thiazepine as well as steroid fused
benzo[b][1,4]thiazepines are rare in the literature. In last decade, β-halo-vinylaldehydes have
been used as a potential synthon for the synthesis of novel heterocycles.6 As a part of our
ongoing research on development of new methodology for the synthesis of novel heterocycles
including heterosteroids,7 herein, we report a simple and high yielding synthesis of steroid and
nonsteroid fused benzo[b][1,4]thiazepine as well as 2-substituted benzo[b][1,4]thiazepine
derivatives by palladium acetate catalyzed reaction of steroidal/nonsteroidal β-

bromovinylaldehydes and 2-aminothiophenols using DMF as the solvent under heating
condition.
Table 1. Synthesis of benzo[b][1,4]thiazepine derivative 3aa
Entry
Pd catalyst (mol%)
PdCl2 (10 mol%)
Base
Solvent
DMSO
DMSO
DMF
Temp (oC)
120
Yield of 3a (%)b
1
2
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
58
70
78
52
78
75
56
0
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (10 mol%)
Pd(OAc)2 (5 mol%)
Pd(OAc)2 (5 mol%)
120
3
120
4
CH3CN
DMF
110
5
120
6
DMF
120
7
PdCl2(PPh3)2(10 mol%) Na2CO3
DMF
120
8
-
Na2CO3
Na2CO3
Na2CO3
DMF
120
9
Pd2(dba)3 (10 mol%)
Pd(OAc)2 (5 mol%)
DMF
120
27c
61d
10
DMF
120 (MW)
aAll reactions were run with 10 mol% of the PPh3 for 8 hours unless specified.
bYield of the isolated product.
cLigand PPh3 was not used
dReaction was run for 5 minutes under microwave irradiation (720 Watt, 14 bar)
We started the synthesis of 3a by the reaction of β-bromovinyl aldehyde 1a (1 mmol), 2-
aminothiophenol (2a, 1 mmol), palladium chloride (10 mol%), triphenylphosphine (10 mol%)
and Na2CO3 (1.2 mmol) in dimethylsulfoxide. To our delight, after heating the reaction mixture
for 8 hours at 120 oC, benzo[b][1,4]thiazepine derivative 3a was obtained in 58% yield (entry 1,
Table 1). This benzo[b][1,4]thiazepine derivative 3a was fully characterized by 1H NMR, 13C
NMR and mass spectroscopy. The 1H NMR of compound 3a exhibited a characteristic aromatic
singlet signal at δ 8.77 (1H) for the thiazepine ring proton near to nitrogen atom. At the same
time the 1H NMR of this compound showed four doublet signals at δ 6.91 (J = 6.8 Hz, 1H), 7.88
(J = 9.0 Hz, 1H), 8.14 (J = 8.4 Hz, 1H), 8.42 (J = 8.4 Hz, 1H), two triplet signals at δ 7.51 (J =
7.5 Hz, 1H), 7.65 (J = 7.5 Hz, 1H) and one singlet signal at δ 6.92 for the benzene rings protons.
13
The C NMR spectrum of 3a showed seventeen signals for carbons. The ESI mass spectra of
compound 3a exhibited [M+1]+ molecular ion peak at m/z = 294 [M+1]+. To determine the ideal

catalyst and solvent for the reaction we investigated this model reaction with some other
palladium catalysts and solvents (Table 1). The yield of desired product 3a increased to 70%
and decreased to 56% when Pd(OAc)2 and PdCl2(PPh3)2 were used respectively as the catalyst
(entries 2 and 7, Table 1). Further investigation on the solvent, it was found that DMF was the
most effective among the tested solvents and the yield of 3a was increased to 78% (entry 3,
Table 1), while there was sharp decrease in yield of 3a to 52% (entry 4, Table 1) when
acetonitrile was used. Then, we looked at the effect of catalyst loading on the yield of
compound 3a and we noticed that yield of 3a remained same when the quantity of Pd(OAc)2
was reduced to 5 mol% (entry 5, Table 1). The use of base K2CO3 in place of Na2CO3 decreased
the yield of compound 3a (entry 6, Table 1). In absence of Pd catalyst the reaction of 1a and 2a
did not afford compound 3a, instead it provided a complex mixture of products (entry 8, Table
1). Probably, in the absence of Pd catalyst and the presence of ortho-bromo group in the
aldehyde 1a facilitated side reactions such as coupling of amine group of 2a with the vinyl
halide 1a.8b In absence of the ligand PPh3, the Pd(OAc)2 catalyzed reaction of 1a and 2a under
heating condition (120 oC, 8 h) afforded low yield of the compound 3a (33%) in
dimethylsulfoxide (data not shown in Table 1). Use of phosphine-free palladium-catalyst such
as Pd2(dba)3 (10 mol%) afforded poor yield of the product 3a (27%) (entry 9, Table 1). Further,
we studied the influence of microwave irradiation on the reaction of 1a (1 mmol) and 2a (1
mmol) in presence of 5 mol% Pd(OAc)2, 10 mol% of PPh3, and Na2CO3 (2.0 mmol) using the
best solvent DMF. A substantial decrease in yield of 3a (61%) along with the formation of
complex mixture of products was observed in 5 minutes of reaction time (entry 10, Table 1).
With the optimized reaction condition in hand (entry 5, Table 1), the D-ring steroidal β-
bromovinyl aldehydes (1b-c) were tested under this condition with different substituted 2-
aminothiophenols (2a-c) to afford new benzo[b][1,4]thiazepine fused steroidal derivatives 3b-g
in 69-77% yields (entry 2-7, Table 2). Similarly, A-ring steroidal β-bromovinyl aldehyde 1d

reacted with 2-aminothiophenol (2a) to afford benzo[b][1,4]thiazepine fused steroidal derivative
3h in 70% yield (entry 8, Table 2). Moreover, nonsteroidal β-bromovinyl aldehydes such as 1e
and 1f reacted with 2-aminothiophenol (2a) to afford 2-substituted benzo[b][1,4]thiazepines in
72-76% yields (entry 9-10, Table 2). The known starting β-bromoformyl compounds 1a-f were
synthesized following known procedure.8
Table 2. Pd(OAc)2 catalyzed synthesis of benzo[ꢀ][1,4]thiazepine
Entry β-Bromovinyl aldehyde Aminothiophenol
Product
Yield
(%)a
Br
N
HS
CHO
1
78
S
H2N
H3CO
OCH3
1a
1b
2a
3a
Br
CHO
S
N
2a
72
2
3
AcO
AcO
3b
Cl
HS
S
1b
N
69
74
77
H2N
Cl
2b
3c
AcO
CF3
HS
S
N
4
5
1b
H2N
CF3
2c
AcO
3d
Br
CHO
2a
MeO
1c

2b
6
7
75
76
1c
1c
2c
H
H
70
H
H
2a
8
9
OHC
Br
N
H
H
S
H
H
1d
3h
Br
CHO
76
72
2a
S
N
1e
3i
Br
CHO
S
2a
10
Cl
N
Cl
1f
3j
aYield of the isolated product.
We proposed a plausible mechanism for this palladium catalyzed cyclization reaction which
is shown in Scheme 1. Oxidative addition of the vinylic halide group of 1 to Pd(0) and the
reaction of aldehyde group of 1 with arylamine produces an organopalladium imine
intermediate 4a. Intramolecular reaction of vinylic palladium with the thiol group of
intermediate 4a produces an eight-membered palladacyclic intermediate 4b which on
subsequent reductive elimination produces compound 3 and regenerates Pd(0).

X
S
Pd(0)
Pd(II)
CHO
N
1
3
SH
NH2
Pd S
2
X
H
S
Pd
N
4b
N
Na2CO3.HX
4a
Scheme 1.
3
Plausible mechanism of Pd-mediated formation of compound
In conclusion, a simple and efficient reaction for the synthesis of steroid/nonsteroid fused
benzo[b][1,4]thiazepines and 2-arylsubstituted benzo[b][1,4]thiazepines was developed using
Pd(OAc)2 as the catalyst in DMF solvent under heating condition. A wide variety of
steroidal/nonsteroidal β-bromovinyl aldehydes and 2-aminothiophenols undergo this reaction to
give good yields of benzo[b][1,4]thiazepine derivatives.
Acknowledgements
We are grateful to Director, CSIR-NEIST for his keen interests. This work was financially
supported by CSIR-OSDD (HCP-0001), CSIR-ACT (CSC0301) and CSIR-ORIGIN (CSC
0108) projects.
Supplementary Material
1
Supplementary data (general experimental procedure, characterization data, H NMR and 13C
NMR spectra for all compounds) associated with this article can be found, in the online version,
at http://.......
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Graphical Abstract
R
Br
S
Pd(OAc)2 (5 mol%),
PPh3 (10 mol%),
N
CHO
HS
+
H2N
R
Na2CO3, DMF,
120 oC, 8 h
MeO
MeO
(10 examples of steroidal and nonsteroidal
1,5-benzothiazepines, 69-78%)