Regioselective synthesis of diltiazem analogue pyrazolo[4,3-c][1,5] benzothiazepines and antifungal activity

Article abstract of DOI:10.1080/10426501003713064

A dry media procedure has been developed for the synthesis of a series of new class of pyrazolo [4,3-c][1,5]benzothiazepines 6 under microwave irradiation using montmorillonite K10 as solid support. The catalyst can be recovered and reused. Thus, the procedure provides a simple and green synthetic methodology under environmentally friendly conditions. Antifungal screening of synthesized compounds has shown promising activity. Supplemental materials are available for this article. Go to the publishers online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/10426501003713064

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Regioselective Synthesis of
Diltiazem Analogue Pyrazolo[4,3-c]
[1,5]benzothiazepines and Antifungal
Activity
Anshu Dandia a , Ruby Singh a , Dharmendra Singh a , Ashok Laxkar a
& Asha Sivpuri b
a Centre of Advanced Studies, Department of Chemistry, University
of Rajasthan, Jaipur, India
b Department of Pathology, Durgapura, Jaipur, India
Version of record first published: 19 Nov 2010
To cite this article: Anshu Dandia, Ruby Singh, Dharmendra Singh, Ashok Laxkar & Asha Sivpuri
(2010): Regioselective Synthesis of Diltiazem Analogue Pyrazolo[4,3-c][1,5]benzothiazepines and
Antifungal Activity, Phosphorus, Sulfur, and Silicon and the Related Elements, 185:12, 2472-2479
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Phosphorus, Sulfur, and Silicon, 185:2472–2479, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426501003713064
REGIOSELECTIVE SYNTHESIS OF DILTIAZEM
ANALOGUE PYRAZOLO[4,3-c][1,5]BENZOTHIAZEPINES
AND ANTIFUNGAL ACTIVITY
Anshu Dandia,1 Ruby Singh,1 Dharmendra Singh,1
Ashok Laxkar,1 and Asha Sivpuri2
1Centre of Advanced Studies, Department of Chemistry, University of Rajasthan,
Jaipur, India
2Department of Pathology, Durgapura, Jaipur, India
A dry media procedure has been developed for the synthesis of a series of new class of pyrazolo
[4,3-c][1,5]benzothiazepines 6 under microwave irradiation using montmorillonite K10 as
solid support. The catalyst can be recovered and reused. Thus, the procedure provides a simple
and green synthetic methodology under environmentally friendly conditions. Antifungal
screening of synthesized compounds has shown promising activity.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Microwaves; montmorillonite; pyrazolo-benzothiazepines
INTRODUCTION
The development of a privileged heterocyclic scaffold is a rapidly emerging subject in
medicinal chemistry.1 The pyrazole unit is one of the core structures in a number of natural
products. Many pyrazole derivatives are known to exhibit a wide range of biological prop-
erties such as antihyperglycemic, analgesic, anti-inflammatory, antipyretic, antibacterial,
antifungal, hypoglycemic, sedative-hypnotic, antitumor, and anticoagulant activities.2–5
The 1,5-benzothiazepine class of compounds is important as calcium channel blockers of
proven utility such as diltiazem and clentiazem, and those in which the fused benzene
ring is substituted at various positions have been found to have enhanced pharmacological
properties.6,7 The incorporation of heterocyclic rings into prospective pharmaceutical can-
didates is a major tactic to gain activity and safety advantages. Although much work has
been directed toward the design and synthesis of fused-pyrazole derivatives,8–13 a search
of the literature revealed very few reports concerning fused pyrazolo-benzothiazepines14
having pyrazole fusion at various facets. Conventionally, the fusion of a pyrazole ring with
Received 18 November 2009; accepted 18 February 2010.
CSIR and U.G.C. New Delhi are gratefully acknowledged. R.S. is thankful to CSIR for the award of a
Research Associateship. We are also thankful to RSIC, CDRI, Lucknow, for the elemental and spectral analyses.
Address correspondence to Anshu Dandia, Centre of Advanced Studies, Department of Chemistry, University
of Rajasthan, Jaipur -302004, India. E-mail: dranshudandia@yahoo.co.in
2472

REGIOSELECTIVE SYNTHESIS OF DILTIAZEM ANALOGUE
2473
X
SH
CHO
H3C
H3C
NH2
CH
O
Y
S
N
X
4
+
O
N
Y
N
Neat MW
N
N
C6H5
Y
2
C6H5
9
3
1
Mont.K10 MW
4
X
Y
Y
SH
NH2
CH3
CH3
N
N
CH
X
S
CH
H
X
N
N
O
N
O
7
C6H5
5
C6H5
Y
Y
H
N
X
S
X
CH3
CH3
S
N
N
H
N
N
N
C6H5
6
C6H5
8
y
Y = OCH3 (2a), Cl (2b) , H (2c)
X = H (4a), OCH3 (4b), CH3 (4c), Cl (4d), Br (4e) , OC2H5 (4f)
Scheme 1
a thiazepine nucleus requires a multistep procedure under harsh conditions with a tedious
isolation process, due to the formation of a mixture of products.
The use of microwave (MW) heating can dramatically cut down on reaction
time, increase product purity and yields, and allow precise control of reaction condi-
tions, all of which make it suited to meet the increased demands of high throughput
chemistry.1516 The reports concerning microwave-assisted rapid synthesis of fused
pyrazolo-benzothiazepines is not available. Hence, in continuation of our interest in
the synthesis of 1,5-benzothiazepines and annulated 1,5 benzothiazepines17 in a search
for better and improved cardiovascular drugs and to establish a structure–activity
relationship, we have investigated the reaction of benzylidene-pyrazolinones 3 with
aminothiophenol 4 under microwave irradiation. The results obtained showed the exclusive
formation of pyrazolo[4,3-c][1,5]benzothiazepine 6 instead of the other possible isomer
pyrazolo[3,4-b][1,5]benzothiazepine 8 (Scheme 1).
RESULTS AND DISCUSSION
Various inorganic solid supports, i.e., montmorillonite K10/montmorillonite KSF/
basic alumina, have been used to find the best medium (Table I). However, montmorillonite
K10 is the most adaptable support for synthesizing 6, since a comparatively higher yield
was achieved in a shorter time. The reaction has also been performed under neat conditions

2474
A. DANDIA ET AL.
Table I Comparative results obtained for the synthesis of pyrazolo[4,3-c][1,5]benzothiazepines 6a by reacting
3c and 4a
Time Tempa
Method (min)
Isolated Yield
(%)
Experiment
Support/solvent
(◦C)
Product
1
2
3
4
5
6
7
8
Ethanol + gl AcOH
ꢀ
420 Reflux
6
6
6
6
6
9c
15
82
90
80
76
89
Nil
12
Montmorillonite KSF
Montmorillonite K10
Basic alumina
MW
MW
MW
MW
MW
ꢀ
15
7
138
142
132
144
145
142
142
16
8
Montmorillonite K10 (MCR)
Neat (MCR)
Montmorillonite K10 (MCR)b
Montmorillonite K10 (MCR)b
8
7
Unchanged reactant
Traces of mixture
ꢀ
480
aFinal temperature is measured at the end of microwave irradiation by introducing a glass thermometer into
the reaction mixture in the beaker.
bThe reaction mixture was placed in a preheated oil bath.
under microwave irradiation, where 2-phenyl-benzothiazole 9 was formed exclusively in-
stead of the expected product pyrazolo[4,3-c][1,5]benzothiazepines 6. During the literature
survey, we came across one report18 in which pyrazolo[3,4-b][1,5]benzothiazepine 8 was
synthesized conventionally by the reaction of 3 with 4 using ethanol and glacial acetic
acid in lower yield. To check this possibility we have also carried out the same reaction
under identical conditions where an intractable mixture of product was formed. By tedious
isolation and chromatographic separation, the product was obtained in very low yield (15%)
and identified as 6, not 8 as reported earlier.18
The formation of 6 can be explained by involving the intermediacy of 5 instead of
7 as assumed by Fawi et al.18 The mechanistic pathway of the reaction of benzylidene-
pyrazolinones 3 with aminothiophenol 4 first involves the formation of intermediate Michael
adduct 5 via nucleophilic attack19 of the sulphydryl group on the β-carbon atom of the
double bond of 3, which is rendered electrophilic due to vinyl–carbonyl conjugation, which
is in agreement with the observations of several other workers, where they have mentioned
that when substituents are present in an α,β-unsaturated ketone, only the nucleophilic
addition of the mercapto group to the β-carbon atom takes place, followed by condensation
of the carbonyl group with the aromatic primary amine to give a seven-membered20–22
ring system leading to the formation of a new class of tricyclic ring system 6. Formation
of intermediate 5 is confirmed by its isolation during the course of the reaction. It is also
synthesized separately22 using isopropanol and their further conversion to final product,
which is found to be identical with compound 6 synthesized using montmorillonite KSF.
Formation of intermediate 5 rules out the possibility of the formation of product 8.
In view of the immense utility of a green synthetic approach, and in order to develop
a facile procedure for the synthesis of 6, we have also carried out the improved synthesis
of key intermediates 3a–c in solvent-free conditions (neat) under microwave irradiation
by irradiating a mixture of p-substituted benzaldehyde 2a–c and 3-methyl-1-phenyl-2-
pyrazolin-5-one 1 for 1–2 min to give 3a–c. TLC studies indicated ∼100% conversion
of reactants and formation of a single product; therefore it was used as such for further
reaction with aminothiophenol 4. Hence, we extended this condition for one-pot synthesis
of 6 but surprisingly, the product isolated was identified as 2-phenyl-benzothiazole 9 instead
of the expected product 6, The formation of which can be explained by the mechanism
given in Scheme 2, which involved losses of pyrazolone moiety 1 from the intermediate 5.

REGIOSELECTIVE SYNTHESIS OF DILTIAZEM ANALOGUE
2475
Intramolecular nucleophilic attack by a lone pair of nitrogens on the electrophilic carbon
leads to the dihydro intramediate 11, which is readily oxidized to the corresponding 2-aryl-
benzothiazoles.
H
Ar
S
X
X
S
Y
5
1
+
9
N
H
NH2
10
11
Scheme 2
Further, an increasing number of organic compounds are formed by multicomponent
reactions that convert more than two adducts directly into their products by a one-pot
reaction.23 Hence, promoted by these observations and in continuation of our earlier in-
terest in multicomponent reactions under microwaves,24 we have also investigated this
reaction via the MCR of 1, 2, and 4 under microwave irradiation using montmorillonite
K10 and through a neat reaction. The results showed the formation of the pyrazolo[4,3-
c][1,5]benzothiazepines 6 under microwave irradiation coupled with inorganic supports
and the synthesis of 2-phenyl-benzothiazole 9 in neat conditions. However, the yield of
isolated product was comparatively low because it requires chromatographic separation.
Finally, in order to check the possible intervention of specific (non-thermal) mi-
crowave effects,25 the results obtained under microwave irradiation were compared to
conventional heating. The reaction in the case of compounds 6a has been carried out using
a preheated oil bath under the same conditions as under microwaves (time, temperature,
vessel, solid support). It has been found that reactants remained unchanged up to 7 min,
while traces of mixture of product were obtained when the reaction time was extended to
7–8 h (Table I).
Evaluation of the Antifungal Activity
The synthesized compounds were screened for antifungal activity against three
pathogenic fungi, namely Rhizoctonia Solani, which causes root rot of okra; Fusarium
oxysporum, which causes wilt of mustard; and Colletotrichum capsici, which causes leaf
spot and fruit rot of chilli using (i) the poison plate technique26 and (ii) the pot trial method.27
The results are summarized in Tables S1 and S2 (Supplemental Materials, available online).
EXPERIMENTAL
Melting points were determined on a Toshniwal apparatus. Thin layer chromatogra-
phy on silica gel “G” coated plates using benzene:ethyl acetate (8:2) as eluent was used
for monitoring the progress of the reactions. IR spectra (KBr) were recorded on a Magna
1
FT IR-550 spectrophotometer, and H NMR and 13C NMR spectra were recorded on a
Bruker DRX-300 using CDCl3 at 300.15 and 75.47, respectively. TMS was used as the
internal reference. Mass spectra of representative compounds were recorded on a Kratos
50 mass spectrometer at 70 eV. The microwave-assisted reactions were carried out in a
commercial multimode MW oven equipped with inverter technology and also attached
with a magnetic stirrer and reflux condenser, operating at 1000W generating 2450 MHz

2476
A. DANDIA ET AL.
frequency. 5-Substituted-2-aminobenzenethiols (4a–e) were prepared by the method in the
literature.28
Synthesis of 4-Benzylidene-5-methyl-2-phenyl-2,4-dihydro-pyrazol-
3-one 3a
Classical thermal method. An equimolar mixture (0.01 mol) of 3-methyl-1-
phenyl-2-pyrazolin-5-one 1 and p-methoxybenzaldehyde 2a in absolute ethanol (20 mL)
was taken in a conical flask. Aqueous 4% KOH solution was added dropwise at room
temperature with continuous stirring. The color of the solution changed to blue within
10 min, and the solution became blurred with suspension of particles, then ice cold HCl
was added. This was kept for 3–4 h. The solid thus obtained was filtered, dried, and
crystallized from methanol to give cream-colored crystals of 3a, mp 119◦C, yield 80%.
Neat reaction. A neat equimolar mixture (0.01 mol) of 1 and 2a was irradiated
inside a microwave oven until the completion of reaction for 1–2 min (monitored by TLC).
The resulting solid mass was dissolved in methanol, and cream-colored crystals separated
out, which were found to be pure as indicated by TLC. For analytical purposes, the product
was further recrystallized from ethanol.
3a: Mp 119◦C, yield ∼93%. IR (cm−1): 1600 (C C), 1680 (C O) cm−1. 1H NMR
(CDCl3): δ 2.12 (s, 3H, CH3), 3.93 (s, 3H, OCH3), 4.93 (s, 1H, methine proton), 6.92–7.11
(m, 9H, Ar-H).
Investigation of the Reaction of 3 with 4 Under Different
Reaction Conditions
Reaction in isopropanol. 2-Aminothiophenol 4a (2 mmol) was added drop-
wise to a solution of 4-benzylidene-5-methyl-2-phenylpyrazolin-3-one 3c (2 mmol) in
isopropanol (20 mL) with stirring. After being stirred for 2–4 h, the reaction mixture was
cooled in an ice bath. The resulting crystals were collected and recrystallized from iso-
propanol to afford colorless crystals identified as 3-(2-amino-phenylthio)-3-pyrazoliones
5, mp 134–135◦C, yield 62%.
IR (cm−1): 3500–3350 (NH2 asym. and sym), 1685 (C O), 1595 (C N). 1H NMR
(CDCl3) Diastereomeric ratio (3:1) δ 2.06/2.01 (s, 3H, CH3), 4.08/3.88 (d, 1H, J = 11.7
Hz), 4.69/4.48 (d, 1H, J = 11.7 Hz), 5.03–5.08 (bs, 2H, NH2 exchangeable with D2O),
7.77–7.30 (Ar-CH, m). 13C NMR 17.7 (CH3), 39.9 (S-CH), 51.21(CH), 115.4, 118.6, 120.6,
122.9, 124.9, 125.8, 126.2, 126.9, 128.2, 130.1, 140.3, 142.2, 144.8, 155.8 (C N), 174.6
(C O); Anal. Calcd. for C23H21N3OS : C, 71.29; H,5.46; N,10.84; Found: C, 71.08; H,
5.42; N, 10.79.
Neat condition. Equimolar quantities of 3c and 4a were gently mixed and irra-
diated inside the microwave oven for an appropriate time (TLC). Upon completion of the
reaction, the mixture was cooled, and the product was extracted from methanol to give 9a.
The compounds 9b and 9c were prepared in same manner as described above.
Using inorganic solid supports. An equimolar mixture of 3b (0.01 mol)
and 4a (0.01 mol) was adsorbed on inorganic solid supports (4 g) (montmorillonite
K10/montmorillonite KSF/basic alumina) via a methanolic solution (5 mL). The dry, free-
flowing powder was kept in the microwave oven and irradiated at a power output of 90%
(640 watts) for the time indicated in Table I. After completion of the reaction (monitored
by TLC), the recyclable inorganic solid support was separated by filtration after eluting the

REGIOSELECTIVE SYNTHESIS OF DILTIAZEM ANALOGUE
2477
Table II Physical and analytical data of compounds 6a–i and 9a–c
Compound
X
Y
Time (min)
Mp (◦C)
Yielda (%)
Rfb
6a
6b
6c
6d
6e
6f
6g
6h
6i
H
H
H
Cl
6
7
8
9
8
7
6
7
7
6
7
7
122
112
102
109
92
90
80
85
80
82
88
80
76
89
89
87
90
.81
.72
.76
.82
.79
.81
.88
.75
.71
.83
.82
.79
OCH3
OC2H5
Cl
Br
CH3
Cl
CH3
H
OCH3
H
OCH3
OCH3
OCH3
OCH3
Cl
Cl
OCH3
Cl
98
124
128
105
220
210
112
9a
9b
9c
OCH3
H
aYield of the isolated products.
bUsing solvent system benzene:ethylacetate (8:2).
product with methanol. The solvent was evaporated to give crystals, which are identified
as pyrazolo[4,3-c][1,5]benzothiazepine 6a, and which were crystallized from methanol.
All other compounds 6b–i were similarly prepared using montmorillonite K10 as the
solid support under microwave irradiation (Table II).
Multicomponent reaction (MCR).
MCR in neat condition. An equimolar mixture (0.01mol) of 1, benzaldehyde
2b, and 2-aminothiophenol 4a was irradiated at 640 watts until the completion of the
reaction (TLC). The light brown, sticky solid mass that was obtained was triturated with
pet ether and crystallized with methanol to give pale yellow, shiny crystals of compounds
2-arylbenzenthiazole 9a.
MCR using solid supports. An equimolar mixture of (0.001 mol) 1, 2c, and
4a was adsorbed on an inorganic solid support (2 g) such as montmorillonite K10 via a
methanolic solution and swirled for a while, followed by removal of the solvent under
gentle vacuum. The dry powder thus obtained was placed on an alumina bath and irradiated
in microwave oven at power output of 90% (640 watt) for 8 min (TLC) listed in Table I. The
product was extracted with methanol and identified as pyrazolo[4,3-c][1,5]benzothiazepine
6a after using column chromatography.
1
Compound 6a. H NMR (CDCl3) δ 2.07 (s, 3H, CH3), 4.91(s, 1H, methine proton),
6.92–7.51 (m, 14H, Ar-H), 8.26 (bs, 1H, NH). IR (KBr)/cm−1 3350(NH), 1601 (C N);
Analysis calcd for C23H19N3S; C, 74.77; H, 5.18; N, 11.37; S, 8.68. Found C, 74.52; H,
5.16; N, 11.33; S, 8.64. Mass (m/z) 369 (M+, 3.47%), 331 (3.9%), 300 (43.4%), 275 (4.1%),
210 (100%), 114 (18.95), 72(6.4%).
1
Compound 6b. H NMR (CDCl3) δ 2.08 (s, 3H, CH3), 4.91 (s, 1H, methine
proton), 6.99–7.59, (m, 13H, Ar-H), 8.16 (bs, 1H, NH). IR (KBr)/cm−1 3352 (NH), 1600
(C N); Analysis calcd for C23H17Cl2N3S; C, 68.39; H, 4.49; N, 10.40; S, 7.94. Found C,
68.15; H, 4.47; N, 10.43, S, 7.91. Mass (m/z) 403 (M+, 25%), 326 (100%), 270 (29%)
etc. 13C NMR (CDCl3) δ7.1 (CH3), 34.2 (methine carbon), 106.8, 119.1, 118.2, 122.8.
124.9, 126.8. 128.2, 129.8, 130.3, 131.2, 138.8, 139.5, 141.8, 145.8, 148.3 (aromatic and
other ring carbons) 154.3 (C N).

2478
A. DANDIA ET AL.
1
Compound 6c. H NMR (CDCl3) δ 2.07 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 3.94 (s,
3H, OCH3), 4.85 (s, 1H, methine proton), 7.16–7.97, (m, 12H, Ar-H), 8.25 (bs, 1H, NH). IR
(KBr)/cm−1 3353 (NH), 1604 (C N); Analysis calcd for C25H23N3O2S; C, 69.91; H, 5.40;
N, 9.78. Found C, 70.11; H, 5.42; N, 9.75. Mass (m/z) 429 (M+ 82.2%), 411 (100%), 377
(66.5%), 308 (2.1%), 211 (12.4%).13C NMR (CDCl3) δ7.3 (CH3), 36.7 (methine carbon),
55.3 (OCH3), 56.2 (OCH3), 104.98, 118.1, 119.2, 123.8. 125.9, 126.8. 127.2, 128.6, 130.9,
131.9, 137.3, 138.9, 142.8, 147.1, 149.20 (aromatic and other ring carbons) 155.3 (C N).
1
Compound 6d. H NMR (CDCl3) δ 1.28 (t, 3H, J = 7Hz,) 2.07 (s, 3H, CH3),
3.79 (s, 3H, OCH3), 4.02 (q, 2H, J = 7Hz), 4.85 (s, 1H, methine proton), 7.26–7.97, (m,
12H, Ar-H), 8.26 (bs, 1H, NH). IR (KBr)/cm−1 3352 (NH), 1602 (C N); Analysis calcd
for C26H25N3O2S; C, 70.40; H, 5.68; N, 9.47. Found C, 70.19; H, 5.70; N, 9.45. 13C NMR
(CDCl3) δ7.4 (CH3), 15.2 (CH3), 35.2 (methine carbon), 55.6 (OCH3), 59.7 (OCH2), 105.2,
114.8, 115.3, 117.6. 118.6. 119.2, 123.1. 126.9, 128.2, 130.8 134.2, 138.2, 138.8, 140.5,
146.8, 150.7, 152.4, 159.2 (aromatic and other ring carbons).
1
Compound 6e. H NMR (CDCl3) δ 2.12 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.89 (s,
1H, methine proton), 7.23–7.70, (m, 12H, Ar-H), 8.19 (bs, 1H, NH). IR (KBr)/cm−1 3350
(NH), 1600 (C N); Analysis calcd for C24H20ClN3OS; C, 66.43; H, 4.65; N, 9.68.Found
C, 66.64; H, 4.67; N, 9.71.
1
Compound 6f. H NMR (CDCl3) δ 2.09 (s, 3H, CH3), 3.76 (s, 3H, OCH3), 4.83 (s,
1H, methine proton), 7.20–7.69 (m, 12H, Ar-H), 8.17 (bs, 1H, NH). IR (KBr)/cm−1 3352
(NH), 1601 (C N); Analysis calcd for C24H20BrN3OS; C, 60.25; H, 4.21; N, 8.78. Found
C, 60.03; H, 4.23; N, 8.75.
1
Compound 6g. H NMR (CDCl3) δ 2.05 (s, 3H, CH3), 3.93 (s, 3H, CH3), 4.82 (s,
1H, methine proton), 7.22–7.81, (m, 12H, Ar-H), 8.20 (bs, 1H, NH). IR (KBr)/cm−1 3350
(NH), 1603 (C N); Analysis calcd for C24H20ClN3S; C, 68.97; H, 4.82; N, 10.53. Found
C, 68.75; H, 4.84; N, 10.50.
1
Compound 6h. H NMR (CDCl3) δ 2.08 (s, 3H,CH3), 4.91 (s, 1H, methine proton),
7.19–7.59, (m, 12H, Ar-H), 8.16 (bs, 1H, NH). IR (KBr)/cm−1 3355 (NH), 1605 (C N);
Analysis calcd for C23H17Cl2N3S; C, 63.02; H, 3.91; N, 9.59. Found, C, 63.25; H, 3.93; N,
9.56.
1
Compound 6i. H NMR (CDCl3) δ 1.98 (s, 3H,CH3), 2.12 (s, 3H,CH3), 3.72 (s,
3H, OCH3), 4.89 (s, 1H, methine proton), 7.23–7.70, (m, 12H, Ar-H), 8.19 (bs, 1H, NH).
IR (KBr)/cm−1 3350 (NH), 1601 (C N); Analysis calcd for C25H23N3OS; C, 72.61; H,
5.61; N, 10.16. Found, C, 72.84; H, 5.63; N, 10.12.
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