"green synthesis" of benzothiazepine library of indeno analogues and their in vitro antimicrobial activity

Article abstract of DOI:10.2478/s11696-013-0496-4

A novel series of indeno-benzothiazepine derivatives was synthesised via a "green" route. Synthesis of these compounds involves the treatment of dinucleophiles such as 2-aminobenzenethiols with α,β-unsaturated ketones in poly(oxyethylene) (poly(ethylene g

Full text of DOI:10.2478/s11696-013-0496-4

Chemical Papers 68 (5) 719–724 (2014)
DOI: 10.2478/s11696-013-0496-4
SHORT COMMUNICATION
“Green synthesis” of benzothiazepine library of indeno analogues
and their in vitro antimicrobial activity
b
a
aAshok P. Acharya, Rahul D. Kamble, Snehalkumar D. Patil,
a
b
aShrikant V. Hese, Omprakash S. Yemul, Sudhakar G. Patil,
bShivshankar N. Halale, Bhaskar S. Dawane*
a
aSchool of Chemical Sciences, Swami Ramanand Teerth Marathwada University, Nanded (MS), India 431606
bMaharashtra Udayagiri Mahavidyalaya, Udgir (MS), India 413517
Received 2 March 2013; Revised 7 August 2013; Accepted 19 August 2013
A novel series of indeno-benzothiazepine derivatives was synthesised via a “green” route. Synthesis
of these compounds involves the treatment of dinucleophiles such as 2-aminobenzenethiols with
α,β-unsaturated ketones in poly(oxyethylene) (poly(ethylene glycol), PEG-400) catalysed by acetic
acid. The synthone α,β-unsaturated ketones were obtained by Claisen–Schmidt condensation of
indan-1-one with substituted pyrazole-2-carbaldehydes prompted by bleaching earth (pH 12.5) as
catalyst and PEG-400 as “green” reaction solvent. Screening of all the synthesised compounds for
antimicrobial activity revealed that most of these compounds exhibited moderate to significant
antimicrobial activity.
c
ꢀ 2013 Institute of Chemistry, Slovak Academy of Sciences
Keywords: indeno-benzothiazepine, PEG-400, bleaching earth, antimicrobial activity
The seven-membered heterocycle 1,5-benzothiaze-
pine is a versatile scaffold and it features in a num-
ber of well-known life-saving drugs such as CGP37157,
Clonazepam and Diltiazem (Cox & Matlib, 1993)
which have gained recognition for their multi-faceted
pharmacological and medicinal applications. 1,5-Ben-
zothiazepines are currently used as coronary vasodila-
tors and as antidepressants. In addition, the 1,5-
benzothiazepine moiety is a remarkable class of phar-
macophore, as compounds bearing this structural unit
possess a broad spectrum of biological activities such
as antitubercular (Upadhyay et al., 2012), anticonvul-
sant (De Sarro et al., 1995), Ca2+ channel antago-
nist (Kurokawa et al., 1997), antianginal (Miyata et
al., 1997), anti-HIV (Grandolini et al., 1999), squalene
synthase inhibitor (Yang et al., 2000), V2-arginine va-
sopressin receptor antagonist (Urbanski et al., 2003),
and HIV-1 reverse transcriptase inhibitor (Di Santo &
Costi, 2005).
tives in the field of pharmacological and medicinal
chemistry has stimulated interest in developing new
methodologies for their synthesis. In this respect, nu-
merous strategies have been reported including one-
pot to multi-step approaches using various catalysts
(Baag et al., 2007; El-Bayouki, 2013; Jain et al., 2011;
Prakash et al., 2005; Rao et al., 1995; Sindler-Kulyk &
Neckers, 1982; Yadav et al., 2002; Zhong et al., 2000).
However, some of these methods have one or more
drawbacks such as long reaction time, use of expen-
sive reagents, low yields, harsh reaction conditions,
effluent pollution, and tedious preparation procedure.
The most convenient method for the synthesis of these
compounds involves the treatment of dinucleophiles
such as 2-aminobenzenethiols with α,β-unsaturated
ketones in PEG-400.
Liquid polymers or low melting polymers have re-
cently emerged as alternative “green” solvent sys-
tems with unique properties such as thermal stabil-
ity, commercial availability, non-volatility, immiscibil-
The importance of 1,5-benzothiazepine deriva-
*Corresponding author, e-mail: bhaskardawane@rediffmail.com; rdkamble143@gmail.com

720
A. P. Acharya et al./Chemical Papers 68 (5) 719–724 (2014)
Table 1. Characterisation data of compounds IIIa–IIIj prepared by using PEG-400
Compound
R
Time/min
130
Yield/%
93
M.p./◦C
204–206
IIIa
IIIb
IIIc
145
135
88
91
192–194
196–198
IIId
IIIe
120
162
95
90
210–212
180–182
IIIf
155
125
85
93
170–173
164–166
IIIg
IIIh
IIIi
140
180
92
86
152–154
142–144
IIIj
170
90
156–158
ity with a number of organic solvents and recycla-
bility. Poly(ethylene glycol) (PEG) (Dawane et al.,
2010a, 2010b) is one of the “green” solvents and,
as included in an environmentally benign protocol,
it was applied in many reactions (Chen et al., 2005;
Chobe et al., 2012, 2013; Konda et al., 2011). Keeping
these observations in view and within the framework
of “Green Chemistry”, PEG-400-prompted reactions
(Chandrasekhar et al., 2002, 2003; Heldebrant & Jes-
sop, 2003) have attracted attention of organic chemists
due to the versatile advantages of these reactions such
as solvating ability, aptitude to act as a phase-transfer
catalyst, negligible vapour pressure, easy recyclability,
eco-friendly nature and easy work-up of the reaction
mixture.
basic nature and thermal stability; it was used as a
catalyst in some reactions (Ballini et al., 2001).
Prompted by these versatile applications, a novel
series of indeno-benzothiazepine viz. 11-[substituted-
phenyl)-1-phenyl-1H-pyrazol-4-yl]-12H-10-thia-5-aza-
dibenzo[a,g]azulenes (IIIa–IIIj) derivatives was syn-
thesised using PEG-400 as a “green” solvent and
bleaching earth as a catalyst (pH 12.5).
Melting points were determined in an open capil-
lary tube and are uncorrected. The chemical solvents
used were purified prior to use. Bleaching earth was
a gift from Supreme Silicones (Pune, India). Comple-
tion of the reaction was monitored by thin layer chro-
matography (TLC) on a pre-coated sheet of silica gel
G using iodine vapour for detection. IR spectra (in
KBr pellets) were recorded on a Shimadzu FTIR 8401
spectrophotometer. 1H NMR spectra (400 MHz) of
compounds dissolved in dimethyl sulphoxide (DMSO-
Recently, bleaching earth (known also as bleaching
clay) was found to exhibit unique physical and chem-
ical properties such as shape selectivity, acidic and

A. P. Acharya et al./Chemical Papers 68 (5) 719–724 (2014)
721
Fig. 1. Two-step synthesis of indeno-benzothiazepine derivatives IIIa–IIIj. Reaction conditions: i) PEG-400, bleaching earth (pH
12.5), 60–80◦C, 1–2 h; ii) PEG-400, AcOH, 60–80◦C, 2–3 h; for hetaryl or aryl substituent R, see Table 1.
d6) were recorded using a Bruker Avance spectrome-
ter and tetramethylsilane (TMS) as an internal stan-
dard. Mass spectra were recorded on a GC–MS Shi-
madzu QP2010 Plus spectrometer (EI mode). Ele-
mental analyses were performed on a Carlo Erba 106
Perkin–Elmer 240 analyser.
solid product thus obtained was filtered, washed with
water (2 × 5 mL), and recrystallised from aqueous
acetic acid to afford a pure product (IIIa–IIIj). The
PEG-400 was recovered from water by direct distil-
lation and re-used for a second run by charging the
same substrates.
The antimicrobial activities of compounds IIIa–
IIIj against Escherichia coli, Salmonella typhi, Staphy-
lococcus aureus and Bacillus subtilis (bacteria) and
Aspergillus niger, Aspergillus flavus and Penicillium
chrysogenum (fungi) (all obtained from the Insti-
tute of Microbial Technology (IMTech), Chandigarh,
India) were determined using the agar-well diffu-
sion method. Penicillin (25 g mL−1) and nystatin
(25 g mL−1) were used as reference drugs for antibac-
terial and antifungal activity, respectively. DMSO
(1 vol. %) was used as a control.
α,β-Unsaturated ketones (IIa–IIj) were prepared
as follows: a mixture of indan-1-one (1 mmol), substi-
tuted hetaryl- or aryl-aldehyde (1 mmol), and a cat-
alytic amount of bleaching earth (10 mole %, pH 12.5)
in PEG-400 (20 mL) was stirred at 60–80◦C for 1–
2 h. After completion of the reaction (monitored by
TLC), the mixture was filtered to separate the cata-
lyst and the filtrate was poured into a beaker contain-
ing ice-cold water (100 mL) under stirring. The solid
product thus obtained was filtered, washed with water
(2 × 20 mL), dried and recrystallised from ethanol to
afford the corresponding α,β-unsaturated ketone (IIa–
IIj).
A new series of 11-[(substituted-phenyl)-1-phenyl-
1H-pyrazol-4-yl]-12H-10-thia-5-aza-dibenzo[a,g]azul-
enes (IIIa–IIIj) (indeno-benzothiazepine derivatives)
was synthesised in two steps. Thus, α,β-unsaturated
ketones IIa–IIj were prepared by Claisen–Schmidt
condensation of indan-1-one with various hetaryl- or
aryl-aldehydes Ia–Ij in the presence of a catalytic
amount of bleaching earth (10 mass %, pH 12.5)
and PEG-400 as a “green” reaction solvent. It is as-
sumed that bleaching earth abstracts one proton in
the C-2 position of indan-1-one to produce a carban-
ion which serves as nucleophile in the subsequent re-
action with an aldehyde, followed by dehydration to
afford α,β-unsaturated ketone (known mechanism of
Claisen–Schmidt condensation). The ubsequent reac-
tion of IIa–IIj with 2-aminothiophenol (addition of a
thiol group to the double bond of α,β-unsaturated ke-
tone and the subsequent intramolecular cycloconden-
sation of amine with ketone) in PEG-400 as a “green”
reaction solvent and a catalytic amount (a few drops)
of acetic acid afforded the desired IIIa–IIIj (Fig. 1).
The chemical structures of the newly synthesised
1
compounds were confirmed by IR, H NMR and mass
spectral data (Table 2). The IR spectra exhibited
the relevant bands in the region of 3350–3440 cm−1
(O—H stretching vibrations) and 1610–1650 cm−1
11-[(Substituted-phenyl)-1-phenyl-1H-pyrazol-4-
yl]-12H-10-thia-5-aza-dibenzo[a,g]azulenes (IIIa–IIIj)
were prepared as follows: a mixture of α,β-unsaturated
ketones (IIa–IIf ) (1 mmol), 2-aminothiophenol
(1 mmol), PEG-400 (20 mL), and acetic acid (3–4
drops) was heated at 60–80◦C for 2–3 h (see Table 1
for specific reaction time). After completion of the re-
action (monitored by TLC), the reaction mixture was
cooled and poured into ice-cold water (100 mL). The
—
—
O
—
(C N). The absence of bands corresponding to C
—
stretching vibrations at 1660–1695 cm−1 indicates the
intramolecular cyclisation of α,β-unsaturated ketone
with 2-aminothiophenol to afford a seven-membered
indeno-benzothiazepine ring. The presence of α,β-
unsaturated sulphide bond in the 1,5-benzothiazepine
ring is confirmed by the signals at δ = 149 and δ = 152

722
A. P. Acharya et al./Chemical Papers 68 (5) 719–724 (2014)
Table 2. Spectral data of newly prepared compounds
Compound
Spectral data
IR, ν˜/cm−1): 1230 (C—N), 1500–1542 (C
C
), 1692 (C O), 2924 (C—H), 3059 (H—C
)
aryl
—
—
—
IIa
—
aryl
1H NMR (400 MHz, DMSO-d6), δ: 3.51 (s, 3H, OCH3) 4.32 (s, 2H, CH2), 6.93 (d, 1H, Haryl), 7.05 (d, 6H, Haryl),
—
7.11 (t, 4H, Haryl), 7.32 (t, 1H, Haryl), 7.51 (d, 2H, Haryl), 8.41 (s, 1H, C CH)
—
13C NMR (400 MHz, DMSO-d6), δ: 34 (CH2), 58 (OCH3), 130, 138, 142 (Cpyrazole ), 130–155 (Caryl) 190 (C O)
—
—
MS, m/z: 392 (M+
)
For C26H20N2O2 (Mr = 392.45) wi/mass % calculated: C, 79.57; H, 5.14; N, 7.14; O, 8.15; found: C, 79.58; H, 5.16;
N,7.12; O, 8.16
IR, ν˜/cm−1: 736 (C—Cl), 1250 (C—S), 1501–1600 (C
C
), 1610 (C
)
—
—
Nthiazepine), 3061 (H—Caryl
—
IIIa
—
aryl
1H NMR (DMSO-d6), δ: 5.43 (s, 2H, CH2), 6.77 (d, 2H, Haryl), 6.91–7.26 (m, 6H, Haryl), 7.32 (t, 4H, Haryl), 7.43
(t, 2H, Haryl), 7.51 (d, 2H, Haryl), 7.55 (s, 1H, Hpyrazole), 8.23 (s, 2H, Haryl
)
13
—
—
—
C NMR (400 MHz, DMSO-d6), δ: 114 ( C—S), 124 (C N), 128–148 (Caryl), 130, 138, 142 (Cpyrazole ), 148–156
—
(Cthiazepine
)
MS, m/z: 502 (M+
)
For C31H20ClN3S (Mr = 502.03) wi/mass % calculated: C, 74.17; H, 4.02; Cl, 7.06; N, 8.37; S, 6.39; found: C, 74.14;
H, 4.05; Cl, 7.02; N, 8.36; S, 6.41
—
—
Nthiazepine), 2935 (C—H), 3095 (H—Caryl
—
IIIb
IIIc
IIId
IR, ν˜/cm−1: 1240 (C—S), 1580–1600 (C
C
), 1632 (C
)
—
aryl
1H NMR (400 MHz, DMSO-d6), δ: 1.07 (s, 3H, CH3) 5.31(s, 2H, CH2), 6.57 (d, 2H, Haryl), 6.73–7.08 (m, 6H,
Haryl), 7.22 (t, 4H, Haryl), 7.34 (t, 2H, Haryl), 7.58 (s, 1H, Hpyrazole), 7.63 (d, 2H, Haryl), 8.14 (s, 2H, Haryl
C NMR(400 MHz, DMSO-d6) δ: 22 (CH3), 118 ( C—S), 125 (C N), 130, 138, 142 (Cpyrazole ), 130–155 (Caryl),
)
13
—
—
—
—
148–156(Cthiazepine
)
EIMS, m/z: 482 (M+
)
For C32H23N3S (Mr = 481.61) wi/mass % calculated: C, 79.80; H, 4.81; N, 8.72; S, 6.66; found: C, 79.76; H, 4.82;
N, 8.70; S, 6.63
IR, ν˜/cm−1: 1240 (C—S), 1581–1600 (C
—
—
Nthiazepine), 3061 (H—Caryl
—
C
), 1610 (C
)
—
aryl
1H NMR (400 MHz, DMSO-d6), δ: 3.73 (s, 3H, OCH3), 5.30 (s, 2H, CH2), 6.47 (d, 2H, Haryl), 6.71–7.01 (m, 6H,
Haryl), 7.22 (t, 4H, Haryl), 7.47 (t, 2H, Haryl), 7.53(d, 2H, Haryl), 7.58 (s, 1H, Hpyrazole), 8.43 (s, 2H, Haryl
C NMR (400 MHz, DMSO-d6), δ: 53 (OCH3), 117 ( C—S), 123 (C N), 132, 135, 140 (Cpyrazole ), 138–151
)
13
—
—
—
—
(Caryl), 149–158 (Cthiazepine
EIMS, m/z: 482 (M+
)
)
For C31H20N3OS (Mr = 482.58) wi/mass % calculated: C, 77.16; H, 4.18; N, 8.71; O, 3.32; S, 6.64; found: C, 77.05;
H, 4.20; N, 8.73; O, 3.33; S, 6.60
IR, ν˜/cm−1: 1305 (C—S), 1535 (N—O), 1506–1602 (C
1H NMR (400 MHz, DMSO-d6), δ: 5.42 (s, 2H, CH2), 6.52 (d, 2H, Haryl), 6.61–7.01 (m, 7H, Haryl), 7.32 (t, 4H,
C
), 1608 (C
)
—
—
—
Ndiazepine), 3083 (H—Caryl
—
aryl
Haryl), 7.47 (t, 2H, Haryl), 7.51 (d, 2H, Haryl), 7.63 (s, 1H, Hpyrazole), 8.43 (s, 2H, Haryl
)
13
—
—
—
C NMR (400 MHz, DMSO-d6), δ: 115 ( C—S), 122 (C N), 128, 135, 141 (Cpyrazole ), 142–150 (Caryl), 152–160
—
(Cthiazepine
)
EIMS, m/z: 512 (M+
)
For C31H20N4O2S (Mr = 512.58) wi/mass % calculated: C, 75.14; H, 4.27; N, 14.13; O, 6.46; found: C, 75.18; H,
4.30; N, 14.15; O, 6.44
—
—
Nthiazepine), 3080 (H—Caryl
—
IIIe
IIIg
IR, ν˜/cm−1: 1235 (C—S), 1570–1602 (C
C
), 1610 (C
)
—
aryl
1H NMR (400 MHz, DMSO-d6), δ: 5.41 (s, 2H, CH2), 6.22–7.56 (m, 10H, Haryl), 8.32 (s, 1H, NH ), 9.71 (s, 1H,
OH)
EIMS, m/z: 354 (M+
)
For C23H18N2O2 (Mr = 354.40) wi/mass % calculated: C, 77.95; H, 5.12; N, 7.90; O, 9.03; found: C, 77.96; H, 5.10;
N, 7.80; O, 9.20
IR, ν˜/cm−1: 1245 (C—S), 1581–1600 (C
—
—
Nthiazepine), 3061 (H—Caryl), 3380 (OH)
—
C
), 1610 (C
—
aryl
1H NMR (400 MHz, DMSO-d6), δ: 1.71 (s, 3H, CH3), 5.40 (s, 2H, CH2), 6.28–6.61 (m, 5H, Haryl), 6.71–7.80 (m,
8H, Haryl), 9.90 (s, 1H, OH)
13
—
—
—
C NMR (400 MHz, DMSO-d6), δ: 18 (CH3), 21 (CH3), 116 ( C—S), 124 (C N), 131, 135, 140 (Cpyrazole ),
—
136–159 (Caryl), 158–165 (Cthiazepine
EIMS, m/z: 371 (M+
)
)
For C23H17NO2S (Mr = 371.45) wi/mass % calculated: C, 74.37; H, 4.61; N, 3.77; O, 8.61; S, 8.63; found: C, 74.35;
H, 4.62; N, 3.73; O, 8.63; S, 8.60
IR, ν˜/cm−1: 732 (C—Cl), 1580–1600 (C
C
), 1608 (C
)
—
—
Nthiazepine), 3085 (H—Caryl
—
IIIh
—
aryl
1H NMR (400 MHz, DMSO-d6), δ: 3.83 (s, 3H, OCH3), 5.45 (s, 2H, CH2), 6.63 (d, 1H, Haryl), 6.78 (s, 1H, Haryl),
6.83(d, 1H, Haryl), 6.96 (t, 1H, Haryl), 7.06 (m, 2H, Haryl), 7.12–7.25 (m, 5H, Haryl) 9.82 (s, 1H, OH)
EIMS, m/z: 359 (M+
)
For C22H14ClNS (Mr = 358.12) wi/mass % calculated: C, 73.42; H, 3.92; Cl, 9.85; N, 3.89; S, 8.91; found: C, 73.45;
H, 3.93; Cl, 9.94; N, 3.91; S, 8.90

A. P. Acharya et al./Chemical Papers 68 (5) 719–724 (2014)
723
Table 2. (continued)
Compound
Spectral data
IR, ν˜/cm−1: 1230 (C—S), 1570–1605 (C
C
), 1620 (C
—
—
Nthiazepine), 3025 (H—Caryl), 3415 (OH)
—
IIIi
—
aryl
1H NMR (400 MHz, DMSO-d6), δ: 5.3 (s, 2H, CH2), 6.46–6.88 (m, 4H, Haryl), 7.04–7.12 (m, 4H, Haryl), 9.83 (s,
1H, OH)
EIMS, m/z: 341 (M+
)
For C22H15NOS (Mr = 340.23) wi/mass % calculated: C, 77.39; H, 4.43; N, 4.10; O, 4.69; S, 9.39; found: C, 77.4;
H, 4.41; N, 4.11; O, 4.67; S, 9.40
—
—
Nthiazepine), 3046 (H—Caryl
—
IIIj
IR, ν˜/cm−1: 1244 (C—S), 1530 (N—O), 1520–1600 (C
C
), 1636 (C
)
—
aryl
1H NMR (400 MHz, DMSO-d6), δ: 5.26 (s, 2H, CH2), 7.39–7.61 (m, 12H, Haryl
EIMS, m/z: 370 (M+
)
)
For C22H14N2O2S (Mr = 369.01) wi/mass % calculated: C, 71.33; H, 3.81; N, 7.56; O, 8.64; S, 8.66; found: C, 71.30;
H, 3.82; N, 7.55; O, 8.63; S, 8.67
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(C-2 and C-3 atoms of 1,5-benzothiazepine moiety)
in 13C NMR spectra. In addition, the corresponding
molecular ion peak (M+) was observed in the mass
spectra for all compounds IIIa–IIIj, thus supporting
their proposed structure.
The results of antimicrobial testing are sum-
marised in Fig. 2. In comparison with antibacterial
penicillin as a standard, compounds IIIa, IIIb, IIId–
IIIf, and IIIh were found to be active against Es-
cherichia coli. Compounds IIId and IIIf–IIIh also ex-
hibited activity against Salmonella typhi. Compounds
IIIa, IIId, IIIf, and IIIg showed comparatively good
activity against Bacillus subtilis, while IIIa, IIIc–IIIe,
and IIIg were active against Staphylococcus aureus.
Regarding antifungal activity, some reduction in the
growth of Aspergillus niger (compounds IIIc, IIIe, IIIf,
IIIi, and IIIj) and Aspergillus flavus (compounds IIIb,
IIIe, IIIg, and IIIh) was observed in comparison with
the standard nystatin. By contrast, compounds IIIa,
IIIe, IIIg and IIIh were inactive against Penicillium
chrysogenum.
Acknowledgements. The authors wish to express their
thanks to UGC SAP Award no. (F.3-36/2011 (SAP-II) and to
UGC for the teacher fellowship under the FDP scheme. RDK
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