A facile one pot synthesis of 2-aryl-4-[2H-2-oxo-[1]benzopyran-3-yl] 2,3-dihydro and 2,5-dihydro-1,5-benzothiazepines

Article abstract of DOI:10.1080/104265091001326

3-acetyl coumarins on condensation with various aromatic aldehydes in the presence of piperidine gave corresponding chalcones in a solid state under solvent free conditions. These chalcones are isolated and characterized. The insitu-formed chalcones (1) a

Full text of DOI:10.1080/104265091001326

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A Facile One Pot Synthesis
of 2-Aryl-4-[2H-2-oxo-
[1]benzopyran-3-yl] 2,3-
dihydro and 2,5-Dihydro-1,5-
benzothiazepines
V. Rajeswar Rao a & M. Madan Mohan Reddy a
a Department of Chemistry, National Institute of
Technology, Warangal, India
Published online: 16 Aug 2006.
To cite this article: V. Rajeswar Rao & M. Madan Mohan Reddy (2006) A Facile One Pot
Synthesis of 2-Aryl-4-[2H-2-oxo-[1]benzopyran-3-yl] 2,3-dihydro and 2,5-Dihydro-1,5-
benzothiazepines, Phosphorus, Sulfur, and Silicon and the Related Elements, 181:2,
461-471, DOI: 10.1080/104265091001326
To link to this article: http://dx.doi.org/10.1080/104265091001326
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Phosphorus, Sulfur, and Silicon, 181:461–471, 2006
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265091001326
A Facile One Pot Synthesis
of 2-Aryl-4-[2H-2-oxo-[1]benzopyran-3-yl] 2,3-dihydro
and 2,5-Dihydro-1,5-benzothiazepines
V. Rajeswar Rao
M. Madan Mohan Reddy
Department of Chemistry, National Institute of Technology, Warangal,
India
3-acetyl coumarins on condensation with various aromatic aldehydes in the
presence of piperidine gave corresponding chalcones in a solid state under sol-
vent free conditions. These chalcones are isolated and characterized. The in-
situ-formed chalcones (1) are also converted into corresponding 2-aryl-4-[2H-2-
oxo[1]benzopyran-3-yl]-2,3-dihydro (3) and 2,5-dihydro-1,5-benzothiazepines (4) in
one step by interacting with orthoamino thiophenol. Both the 2,3-dihydro (3) and
2,5-dihydrobenzothiazepines (4) have been converted into same tetrahydrobenzoth-
iazepine (5). Finally, the tetrahydrobenzo thiazepine (5) is converted into its acetyl
derivative (11). The structures of the title compounds have been confirmed on the
basis of their microanalytical, IR, 1 H NMR, and mass spectral data.
Keywords 3-acetylcoumarin; chalcone; benzothiazepine
INTRODUCTION
Immensechemotherapeutic applications of 1,5-benzothiazepine deriva-
tives such as diltiazem,1a,b clentiazem (TA-3090),2 anticoagulant,3
antiarteriosclerotic,4 antiischemic,5 antiatherosclerotic,6 antihyper-
tensive,7 and antidepressant8 etc. activity and their comparative study
with diazepams,9 and clobazam10 etc. interested us to synthesize a se-
ries of new 1,5-benzothazepines having substituents at the 2 and 4
positions.
The progress in the field of solid state organic reactions (SSOR) is
gaining significance both from the mechanistic and synthetic point of
view.11−14 There are a number of reports on the synthesis of chalcones
Received August 1, 2004; accepted March 1, 2005.
The authors are grateful to the Director, IICT, Hyderabad, and CDRI, Lucknow, for
providing spectral data.
Address correspondence to V. Rajeswar Rao, National Institute of Technology,
Department of Chemistry, Warangal 506004, India. E-mail: vrajesw@yahoo.com
461

462
V. R. Rao and M. M. M. Reddy
derived from 3-acetyl coumarins.15−19 These procedures involve the re-
action of 3-acetyl coumarins with aromatic aldehydes in ethanol using
a catalytic amount of piperidine by refluxing for several hours. Of-
ten these procedures were tedious because of the low solubility of the
3-acetyl coumarins in ethanol and long reaction times. In view of these
SCHEME 1

A Facile One Pot Synthesis
463
limitations and in continuation of our interest on solvent free organic
reactions,20 herein we report a mild and highly efficient procedure
for the synthesis of chalcones derived from 3-acetyl coumarins using
a catalytic amount of piperidine under solvent free conditions in the
solid state. This procedure can be extended to other substituted het-
erocyclic chalcones. No solvent is needed as in the classical prepa-
ration of chalcones. The method is convenient, more economic, and
environmentally benign. The mild reaction conditions, operational sim-
ilarity, short reaction time, and excellent yields make the process more
versatile.
RESULTS AND DISCUSSION
The chalcones derived from 3-acetyl coumarins, i.e., 3-[1-oxo-3-
(substituted phenyl)-2-propenyl]-2H-1-benzopyran-2-ones (1), have
been reacted with 2-amino benzene thiol (2) in a mild acidic
medium using weakly acidified ethanol in an attempt primarily
to obtain the intermediates, but here attempts failed and the fi-
nal products 2-aryl-4-(2H-2-oxo-[1]-benzopyran-3-yl]-2,3-dihydro-1,5-
benzothiaze-pines (3) have been formed. When the chalcones (1) are
refluxed in ethanol containing 2-amino benzene thiol and piperidine
gave the corresponding 2-aryl-4-[2H-2-oxo-[1]benzopyran-2-one-3-yl]-
2,5-dihydro-1,5-benzothiazepines (4). Further, the sodium borohydride
reduction of the dihydrobenzothiazepine (3) provided the tetrahy-
drobenzothiazepine (5). The compound 5 is also formed by the reduction
of 3 with o-ATP (catalytic amount) in ethanol containing an acid. How-
ever, it is well known that o-ATP is contaminated with a little amount
of Di O-Aminophenyl Disulphide (DAPDS) (VI) due to its aerial oxida-
tion. Hence, the involvement of DAPDS in the reduction of 3 could not
be ruled out. Keeping this in view, 3 was also treated with DAPDS as
well as o-ATP in refluxing ethanol in the presence of an acid (HCl or
HBr). In all these cases compound 5 was obtained in good yields. The
reduction of 3 to 5 has been outlined in Scheme 2. Because reduction
is catalyzed by both o-ATP as well as DAPDS it may be suggested that
in the reduction of 3 with o-ATP/H⊕ in ethanol, the effective catalyst is
o-ATP. The nucleophilic addition of o-ATP to the initially formed car-
bocation 7 may result in the formation of 8, which may cleave to 5 and
1,2-benzothioquinone imine 9. The addition of ethanol to 9 may give rise
to another intermediate 10, which may in turn regenerate o-ATP with a
concomitant elimination of the corresponding carbonyl compound. The
compound 9 may now reenter the reductive cycle, which may continue
until 3 is completely reduced to 5. However, when DAPDS is used in
place of o-ATP, it may first undergo acid-catalyzed disproportionation

464
V. R. Rao and M. M. M. Reddy
SCHEME 2
to give 9 and o-ATP, which may catalyze the reduction as previously
described.
In conclusion it is worth mentioning that the present reductive
one-step conversion of 3 into 5 by using o-ATP or DAPDS in acidic
ethanol is quite significant as it constitutes a convenient access to
tetrahydro benzothiazepine derivatives (5). Also this procedure is
cheaper than the reduction of 3 to 5 by using NaBH4 as a reducing
agent.
The reduction of 4 with H2 using Pt resulted in the formation of
tetrahydro benzothiazepine derivative 5. The reduction product (5)

A Facile One Pot Synthesis
465
SCHEME 3
obtained by this method was found indentical to the product that was
obtained by the reduction of 3 with either NaBH4, o-ATP, or DPDS
in ethanol containing an acid. This was further confirmed by Co-TLC,
m.p., and mixed m.p.s of these compounds.
The formation of 5 was further confirmed by the conversion into
the corresponding acetyl derivatives 11 using Ac2O and pyridine
(Scheme 3).
The structures of newly synthesized compounds were confirmed on
the basis of spectral and analytical data.
All the chalcones (1) displayed characteristic absorption bands in the
IR due to 1678 (α, β-unsaturated ketone) and 1740 5 (lactone C O).
1
The H NMR spectrum of Ia exhibited a characteristic multiplet for
three aromatic and two CH CH protons at 7.25–7.40. Another mul-
tiplet was observed for four aromatic protons at 7.60–7.70. The C4 pro-
ton of coumarin appeared as singlet at 8.5. All the cyclized compounds

466
V. R. Rao and M. M. M. Reddy
(3) displayed characteristic absorption bands due to C N and
lactone carbonyl at 1606 and 1705 cm−1, respectively. The absence
of an absorption band at 1678 cm−1 in compound 3 confirms that it
was cyclized. The 1H NMR spectra of 3a exhibited a characteristic
triplet for the CH S proton at 2.90 and a doublet for CH2 at
4.40. The remaining protons were observed in the usual regions. The
cyclized compound 4 exhibited -NH- absorptions in the region 3293
and lactone carbonyl at 1710 cm−1, respectively. The PMR spectrum of
4f displayed two characteristic doublets at 3.6 due to C2-H and an-
other at 6.75 due to C3-H. The C4 proton of coumarin appeared as
a singlet at 8.35. The remaining protons were observed in the usual
regions.
EXPERIMENTAL
All melting points were determined in open capillary tubes using a
sulphuric acid bath and were uncorrected. IR spectra (νmax, cm−1
)
were recorded on a Perkin-Elmer spectrophotometer. The 1H NMR
spectra were recorded on a Varian 200 MHz, and the chemical
shifts were recorded in δ (ppm) using TMS as an internal standard.
The mass spectra were scanned on a Jeol-JMS 300 spectrometer at
70 eV.
The 3-acetyl coumarins21 were prepared according to the literature
procedure.
3-[1-Oxo-3-(substituted
phenyl)-2-propenyl]-2H-1-benzopyran-2-ones (1)
A mixture 3-acetyl coumarin (0.01 mol) and appropriate aromatic alde-
hyde (0.01 mol) and 1 mL of piperidine was intimately ground for about
20 min while heating on a water bath at 45–50◦C. The grinding was con-
tinued for 10 more min, on completion of reaction as indicated by TLC,
the reaction mixture was treated with methanol. The resultant prod-
uct was filtered. The solids were recrystallized from suitable solvents
(80–93%); products were characterized by comparison with authenitic
samples (Table I).
2-Phenyl-4-(2H-2-Oxo-[1]-Benzopyran-3-Yl]-2,3-dihydro-1,5-
benzothiazepines (3)
General Procedure (One-Step Process)
A mixture of 3-acetyl coumarin (0.01 mol), appropriate aromatic alde-
hyde (0.01 mol) and 1 mL of piperidine was taken in a round-bottom

A Facile One Pot Synthesis
467
TABLE I Physical Data of Compounds (1a–j)
Yield
Compound∗
1a
RR1
R2R3
M.P.◦C
Reported
—
Time
20
Found
86
Reported
—
H
H
NO2
H
142–144
1b
1c
1d
1e
1f
H
Cl
H
NO2
H
212–214
228–230
204–206
252–254
281–282
188–190
252–254
281–283
242–244
—
—
25
30
25
22
30
25
24
22
20
93
88
92
93
91
94
90
80
86
—
—
—
—
75
70
—
50
—
Br
Br
Br
H
Br
Br
Br
H
H
H
H
Br
Br
H
H
H
H
—
N(CH3)2
H
—
N(CH3)2
H
>280
190
—
N(CH3)2
1g
1h
1i
Cl
H
CI
H
OH
H
H
>280
—
1j
Br
H
∗All compounds were recrystallized from methanol.
flask and intimately ground with glass rod for about 20 min while heat-
ing on a water bath at 45–50◦C. The grinding was continued for 10
more min; on completion of reaction as indicated by TLC, the reac-
tion mixture was treated with methanol or ethanol (20 mL) followed
by the addition of 1 mL of glacial acetic acid. The resultant reaction
mixture was treated with an equimolar quantity of 2-aminothiophenol
(0.01 mol) and refluxed for 5 h. The reaction mixture was cooled the
yellow solid formed was collected by filtration and recrystallized from
methanol (Table II).
2-Phenyl-4-[2H-2-oxo-[1]-benzopyran-3-Yl]-2,5-dihydro-1,5-
benzothiazepines (4)
General Procedure (One-Step Process)
A mixture of 3-acetyl coumarin (0.01 mol), an appropriate aro-
matic aldehyde (0.01 mol), and 1 mL of piperidine was taken in a
round-bottom flask and intimately ground with glass rod for about
20 min while heating on a water bath at 40–45◦C. The grinding

468
V. R. Rao and M. M. M. Reddy
TABLE II Physical Data of Compounds (3a–j)
Found (calc.) %
M.P. Yield
◦C
(%)
Mol. formula
(Mol. wt.)
Compound∗ RR1
H
R2R3
H
C
H
N
S
C26H22N2O2S
(426)
C24H16NClO2S
(417)
C24H16N2O4S
(428)
73.18 5.12 6.54 7.50
(73.21) (5.16) (6.57) (7.52)
68.95 3.83 3.31 7.64
(68.98) (3.86) (3.34) (7.67)
67.24 3.73 6.52 7.45
(67.28) (3.76) (6.54) (7.58)
3a
3b
H
H
H
H
H
Br
N(CH3)2 164–166 90
Cl
H
NO2
H
H
166–168 84
3c
3d
3e
3f
87–89
90–92
95–97
79
82 C26H20N2Br2O2S 53.41 3.42 4.75 5.46
Br N(CH3)2
(584)
C24H17NO3S
(399)
(53.44) (3.45) (4.79) (5.49)
(72.16) 4.26 3.48 8.00
72.12 (4.29) (3.51) (8.03)
H
H
H
OH
H
H
75
110–112 83
170–172 80
C26H21N2BrO2S 61.75 4.12 5.51 6.30
Br N(CH3)2
(505)
C24H15NBrClO2
S (496)
(61.79) (4.15) (5.54) (6.33)
49.96 3.00 2.80 6.42
(50.00) (3.04) (2.82) (6.45)
3g
3h
3i
H
Br
Br
Br
H
Cl
H
Cl
H
NO2
H
H
87–89
88 C24H14NBr2ClO2S 49.87 2.42 2.42 5.52
(577.5) (50.04) (2.43) (2.43) (5.57)
C24H15N2BrO4S 56.80 2.94 5.51 6.28
209–211 88
220–222 86
Br
H
(507)
C24H16NO2SBr
(462)
(56.80) (2.95) (5.52) (6.31)
62.30 3.44 3.00 6.88
(62.33) (3.46) (3.02) (6.92)
3j
Br
H
∗All compounds were recrystallized from methanol.
was continued for 10 minutes; on completion of the reaction as in-
dicated by TLC, the reaction mixture was treated with methanol or
ethanol (20 mL) followed by addition of 1 mL of piperidine. The re-
sultant mixture was treated with an equimolar quantity of ortho
aminothiophenol (0.01 mole) and refluxed for 9 h. The reaction mix-
ture was cooled, the excess a solvent was removed, and the residue
was poured onto crushed ice to give a pale yellow solid. The prod-
uct was filtered, washed with water, and recrystallized from methanol
(Table IV).
3-[2-(2-Chlorophenyl)-2,3,4,5-tetrahydro-
benzo[b][1,4]thiazepin-4-Yl]-chromen-2-One (5a)
from 3b
(i) Using o-ATP or DAPDS
A solution of 3b (0.001 mol) and o-ATP or DAPDS (0.0015 mol)
in ethanol (10 mL) and hydrochloric acid or hydrobromic acid
(4–5 drops) was refluxed for 10–12 h. The reaction mixture was then
cooled to r. t. and poured into aqueous NaHCO3 and extracted with

A Facile One Pot Synthesis
469
TABLE III Physical Data of Compounds (4a–f)
Found (calc.) %
M.P. Yield
◦C
(%)
Mol. formula
(Mol. wt.)
Compound∗ RR1 R2R3
C
H
N
S
4a
4b
4c
H
H
H
H
H
H
H
Cl
H
NO2
H
OH
H
H
206–208 75
118–120 68
177–179 76
C24H16NClO2S 68.94 3.82 3.30 7.62
(417)
C24H16N2O4S
(428)
(68.98) (3.86) (3.35) (7.66)
67.25 3.72 6.50 7.45
(67.28) (3.76) (6.54) (7.48)
72.12 4.24 3.48 8.00
(72.16) (4.29) (3.51) (8.03)
C
24H17NO3S
(399)
4d
4e
4f
160–162 76 C26H21N2BrO2S 61.75 4.12 5.50 6.60
(505) (61.79) (4.15) (5.54) (6.33)
24H15NBrClO2S 57.96 3.00 2.79 6.40
Br N(CH3)2
H
Br
H
H
H
H
H
H
Cl
H
H
210–212 74
150–152 78
C
(496)
26H22N2O2S
(426)
(58.02) (3.04) (2.82) (6.45)
73.16 5.13 6.52 7.49
(73.21) (5.16) (6.57) (7.52)
C
N(CH3)2
5a
11a
Cl
H
Cl
H
95–96
75
C
24H18NClO2S 68.62 4.30 3.30 7.61
(419) (68.65) (4.32) (3.34) (7.64)
132–134 90
C
26H20NClO3S 67.57 4.33 3.00 6.91
(67.60) (4.36) (3.03) (6.94)
∗All compounds were recrystallized from methanol.
CH2Cl2 (2 × 15 mL). The organic layer was washed with water
(2 × 15 mL) and dried (MgSO4). The mass obtained was crystallized
from hexane.
(ii) Using NaBH4
A solution of 0.001 mol of compound 3b and 0.001 mol of NaBH4 in 30
mL of anhydrous ethanol was refluxed for 8 h. During this time the yel-
low color of the starting material disappeared. After decomposing the
complex by adding few drops of acetic acid, the alcohol was removed
in vacuum. The product (5b) was treated with H2O and extracted with
ether. The solvent was removed to leave a solid; the solid was recrys-
tallized from n-hexane.
Synthesis of 3-[2-(2-Chlorophenyl)-2,3,4,5-tetrahydro-
benzo[b][1,4] thiazepin-4-yl]-chromen-2-one (5a) by the
Reduction of 4a
The compound 4a (0.001 mol) in acetic acid (10 mL) was hydrogenated
at atmospheric pressure and r. t. during 24 h using a platinum cat-
alyst (from 0.1 g of PtO2). The reaction mixture was filtered and the

470

A Facile One Pot Synthesis
471
filtrate was removed in vacuum to give 5. This was recrystallized from
n-hexane.
3-[5-Acetyl-2-(2-chlorophenyl)-2,3,4,5-tetrahydrobenzo[b][1,4]
thiazepin-4-yl]chromen-2-one (11a)
A solution of 5a (0.001 mol) in dry Ac2O (3 mL) and pyridine (0.1 mL)
was refluxed for 2–3 h, cooled to r.t., and kept for 24 h at r.t., and poured
into ice-cold water. The solid obtained was filtered, washed with water,
and crystallized from ethanol to afford 11a.
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