Synthesis of new 8-methoxy-4-methyl-3-(N-[2′-amino-(1′, 3′,4′)thia/oxa-diazol-5′-yl]-substituted methyl)-amino thiocoumarins

Article abstract of DOI:10.1080/10426500490474914

8-Methoxy-4-methyl-3-(N-[2′-amino-(1′, 3′,4′)thia/ oxa-diazol-5′-yl] substituted methyl)-amino thiocoumarins 6(a-f) and 7(a-f), were synthesized by using the unreported 8-methoxy-4-methyl-3-[N- (2′-oxo-2′-methoxy-1′-substituted ethan-1′-yl) amino thiocoumarins as key intermediates.

Full text of DOI:10.1080/10426500490474914

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Phosphorus, Sulfur, and Silicon and the Related
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SYNTHESIS OF NEW 8-METHOXY-4-METHYL-3-(N-[2′-
AMINO-(1′,3′,4′)THIA/OXA-DIAZOL-5′-YL]-SUBSTITUTED
METHYL)-AMINO THIOCOUMARINS
B. Prasanna a & G. V. P. Chandramouli a
a Department of Chemistry, National Institute of Technology, Warangal, A.P., India
Version of record first published: 16 Aug 2010.
To cite this article: B. Prasanna & G. V. P. Chandramouli (2004): SYNTHESIS OF NEW 8-METHOXY-4-METHYL-3-(N-[2′-AMINO-
(1′,3′,4′)THIA/OXA-DIAZOL-5′-YL]-SUBSTITUTED METHYL)-AMINO THIOCOUMARINS, Phosphorus, Sulfur, and Silicon and the
Related Elements, 179:10, 2059-2065
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Phosphorus, Sulfur, and Silicon, 179:2059–2065, 2004
ꢀC
Copyright Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500490474914
SYNTHESIS OF NEW
8-METHOXY-4-METHYL-3-(N-[2ꢀ-AMINO-
(1ꢀ,3ꢀ,4ꢀ)THIA/OXA-DIAZOL-5ꢀ-YL]-SUBSTITUTED
METHYL)-AMINO THIOCOUMARINS
B. Prasanna and G. V. P. Chandramouli
Department of Chemistry, National Institute of Technology,
Warangal, A.P., India
(Received October 3, 2003; accepted March 18, 2004)
8-Methoxy-4-methyl-3-(N-[2ꢁ-amino-(1ꢁ, 3ꢁ,4ꢁ)thia/oxa-diazol-5ꢁ-yl] sub-
stituted methyl)-amino thiocoumarins 6(a–f) and 7(a–f), were syn-
thesized by using the unreported 8-methoxy-4-methyl-3-[N-(2ꢁ-oxo-
2ꢁ-methoxy-1ꢁ-substituted ethan-1ꢁ-yl) amino thiocoumarins as key
intermediates.
Keywords: Aminoacids; amino thia/oxa-diazoles; 8-methoxy-4-methyl-
thiocoumarin
INTRODUCTION
Many derivatives of coumarins, such as EM 800, are known to be
Chromone prodrugs,1 which are useful as orally active nonsteroidal
antiestrogens2 and antitumor agents.3 Tazarotene, a substituted ben-
zothiopyran, is used for clinical evaluation of psoriasis.4,5 Tertatol
is another substituted benzothiopyran that is widely used against
hypertension.6,7
Inspired by these observations, and in continuation of our program of
synthesizing sulfur heterocycles,8 we designed the synthesis of a series
of a new 8-methoxy-4-methyl-3-(N-[2ꢁ-amino-(1ꢁ,3ꢁ,4ꢁ)thia/oxa-diazol-5ꢁ-
yl]-substituted methyl)-amino thiocoumarins 6(a–f) and 7(a–f) starting
from 6-methoxy-2-acetyl thiophenol.
Address correspondence to G. V. P. Chandramouli, Department of Chemistry; National
Institute of Technology, Warangal 506004, A.P., India. E-mail: gvpc@nitw.ernet.in
2059

2060
B. Prasanna and G. V. P. Chandramouli
RESULTS AND DISCUSSION
6-Methoxy-2-acetyl thiophenol 1 was prepared by acetylating 6-
methoxy thiophenol with acetyl chloride in anhydrous AlCl3 by
using dry DCM as solvent. The acetyl compound 1 was later re-
acted with chloroacetyl chloride by refluxing in dry acetone con-
taining anhydrous potassium carbonate in order to convert it
into the corresponding acetyl thio compounds 2. Upon further
treatment with substituted amino acid esters 3(a–e) in presence
of dry acetone containing anhydrous potassium carbonate, com-
ponds 2 produced a series of 2-acetyl-6-methoxy-1-[S-(1ꢁoxo-3ꢁ-aza-
4-substituted-5ꢁ-oxo-5ꢁ-methoxy-pent-1ꢁ–yl]-thiophenols 4(a–e). These
esters, when treated with NaOMe in dry methanol, in turn furnished
the desired 8-methoxy-4-methyl-3-[N-(2ꢁ-oxo-2ꢁ-methoxy-1ꢁ-substituted
ethan-1ꢁ-yl)]-amino thiocoumarins 5(a–e).
The esters 5(a–e), upon reaction with thiosemicarbazide and semi-
carbazide, produced a series of required thia/oxa diazole derivatives
6(a–e) and 7(a–e), respectively, as shown in Scheme 1.
By using methyl proline ester 3f in the place of the aminoacid esters,
and by carrying out same sequence of reactions b, c, and d, we got
another set products, 4f, 5f, 6f, and 7f, respectively, which are not shown
in the above scheme.
The structures of the compounds synthesized were established on the
basis of analytical and spectral data (Tables I–III). In the IR spectrum of
compound 4b, vibration bands at 3180 cm−1 and 1710 cm−1 correspond
to (CH3CO) group. The 1H NMR of the same compound contains signals
at 2.3 δ (d, 3H, CH3), 4.46 δ (s, 2H, CH2), 4.18 δ (q, 1H, CH), 3.74 δ (s,
3H, OMe), 4.28 δ (d, 3H, CO OCH3), 6.88–7.42 δ (m, 3H, Ar H). In
case of compound 5b, the signal for CH2 is absent. The absence of
this signal indicated in the participation of CH2 in the cyclization to
give rise to the thiocoumarin heterocycles. The mass spectrum of 5b
1
contains molecular ion peak of m/z 306. The H NMR spectra of the
compounds 6(a–f) and 7(a–f) show the absence of amino acid methyl
ester ( COOMe) group.
EXPERIMENTAL
All melting points were uncorrected. The elementary analysis was car-
ried out by CARRLO ERBA STUMENTOZOINE, Itali model, 1108, and
IR spectra (cm−1) were recorded on a PERKINE Elmer-282 instrument.
The 1H NMR spectra were recorded on a Varian 300 MHz spectrometer
using tetra methyl silane as an internal standard. Chemical shift values

Methyl Amino Thiocoumarins
2061
SCHEME 1 a) Anhydrous K2CO3: acetone, reflux; b) anhydrous K2CO3, ace-
tone; c) NaOMe, Methanol, reflux; d) NH2 NH CX NH2, ethanol, stirred at rt.
are expressed upon δ scale. Mass spectra were scanned on a Jeol-Jms-
300 spectrometer at 70 eV. The purity of the compound was monitored
by TLC performed on a silica gel plates (Merck) using ethylecetate and
petroleum ether.
2-Acetyl-6-methoxy-S-chloroacetyl Thiophenol 2
To a suspension of 2-acetyl-6-methoxy thiophenol 1 (1.82 g, 0.01 mol)
and anhydrous potassium carbonate (2.7 g, 0.02 mol) in dry acetone
(20 ml), chloro acetylchloride (1.13 g, 0.01 mol) was added. The result-
ing mixture was refluxed with stirring for 6 h. The progress of the reac-
tion was monitored by TLC. The reaction mixture was cooled, filtered,

2062
B. Prasanna and G. V. P. Chandramouli
TABLE I Physical Properties and Analytical Data (Calc./Found%) of the
Compounds 4(a–f), 5(a–f), 6(a–f), and 7(a–f)
Comp.
Mol. formula
C14H17NO5S
m.p. (◦C)
123–125
C
H
N
O
S
4a
54.01/
53.94
55.37/
55.35
62.83/
62.78
62.71/
62.68
60.42/
60.39
56.96/
56.92
57.32/
57.30
58.62/
58.58
65.78/
65.72
65.39/
65.34
63.14/
63.10
61.24/
61.20
50.28/
50.24
51.71/
51.67
59.41/
59.38
59.59/
59.55
57.25/
57.22
54.53/
54.50
52.82/
52.80
54.20/
54.17
61.75/
61.71
61.73/
61.70
59.42/
59.40
56.97/
56.92
5.50/
5.45
5.89/
5.84
5.77/
5.72
5.49/
5.42
5.55/
5.52
5.68/
5.64
5.15/
5.11
5.57/
5.52
5.52/
5.49
5.25/
5.23
5.30/
5.26
5.74/
5.71
4.22/
4.20
4.63/
4.60
4.75/
4.72
4.57/
4.52
4.58/
4.55
4.84/
4.78
4.43/
4.38
4.85/
4.82
4.64/
4.60
4.73/
4.69
4.75/
4.73
5.06/
5.02
4.50/
4.46
4.30/
4.26
3.49/
3.45
6.36/
6.34
3.36/
3.34
4.15/
4.10
4.77/
4.72
4.56/
4.50
3.65/
3.63
6.63/
6.60
3.51/
3.48
4.20/
4.18
16.75/
16.72
16.08/
16.02
13.20/
13.16
15.11/
15.08
12.72/
12.68
14.96/
14.92
17.60/
17.57
16.86/
16.82
13.72/
13.68
15.65/
15.61
13.20/
13.17
15.63/
15.60
25.69/
26.54
24.30/
24.23
19.93/
19.90
18.16/
18.12
22.99/
22.94
23.71/
23.67
21.82/
21.78
20.82/
20.79
16.69/
16.65
15.16/
15.12
20.03/
19.92
19.19/
19.14
9.57/
10.30/
10.32
9.85/
9.80
7.99/
8.01
7.28/
7.26
7.68/
7.62
4b
4c
4d
4e
4f
C15H19NO5S
C21H23NO5S
C23H24N2O5S
C21H23NO6S
131–133
142–144
155–157
163–165
114–116
162–164
174–176
183–185
202–204
158–160
152–154
192–194
204–206
218–220
242–244
185–187
166–168
172–174
189–191
242–246
235–237
209–211
194–196
C
C
17H21NO5S
14H15NO4S
9.50/
9.52
5a
5b
5c
5d
5e
5f
10.93/
10.90
10.43/
10.40
8.36/
8.32
7.59/
7.52
8.03/
8.08
C15H17NO4S
21H21NO4S
C23H22N2O4S
21H21NO5S
C17H19NO4S
C
C
9.62/
9.58
6a
6b
6c
6d
6e
6f
C
14H14N4O2S2
15H16N4O2S2
19.18/
19.15
18.40/
18.42
15.11/
15.08
13.83/
13.78
14.56/
14.54
17.12/
17.08
10.07/
10.04
9.65/
9.61
7.85/
7.82
7.16/
7.11
7.55/
7.51
8.95/
8.91
9.51
9.18/
9.15
7.54/
7.50
6.90/
6.87
10.90/
10.86
8.54/
C
C21H20N4O2S2
C
C
C
23H21N5O2S2
21H20N4O3S2
17H18N4O2S2
8.50
7a
7b
7c
7d
7e
7f
C14H14N4O3S
15.08/
15.02
14.44/
14.41
13.72/
13.69
10.73/
10.70
15.08/
15.02
13.39/
13.34
C15H16N4O3S
C
21H20N4O3S
23H21N5O3S
C
C
21H20N4O4S2
C17H18N4O3S

Methyl Amino Thiocoumarins
2063
TABLE II IR and 1H NMR Spectral Data of the Compounds 5(a–f)
Comp.
IR (cm−1
)
m/z (M+1
292
)
1H NMR (δ ppm)
5a
1680 (
S
C
O), 1710
2.22 (s, 3H, CH3), 3.62 (s, 3H,
(CO),3240(NH)
OCH3), 3.90 (s, 3H, CO OCH3),
4.20 (s, 2H, CH2), 6.96–7.40 (m,
3H, Ar H), 12.16 (s, 1H, NH)
1.34 (d, 3H, CH3), 2.59 (s, 3H, CH3),
4.30 (q, 1H, CH), 6.88–7.42 (m,
3H, Ar H), 12.38 (s, 1H, NH)
2.32 (s, 3H, CH3), 3.74 (s, 3H,
OCH3), 4.12 (s, 3H, CO OCH3),
4.14 (t, 1H, CH), 4.32 (d, 2H,
CH2), 6.90–7.46 (m, 8H, Ar H)
2.12 (s, 3H, CH3), 3.3 (d, 2H, CH2),
3.64 (s, 3H, OCH3), 4.26 (s, 3H,
CO OCH3), 4.36 (t, 1H, CH),
5.20 (s, 1H, Indole-H), 6.92–7.52,
(m, 7H, Ar H), 12.12 (s, 1H, NH)
2.34 (s, 3H, CH3), 3.64 (s, 3H,
OCH3), 4.00 (s, 1H, CH), 4.26 (s,
3H, CO OCH3), 3.32 (d, 2H,
CH2), 6.94–7.42 (m, 7H, Ar H),
10.42 (s, 1H, OH), 12.14 (s, 1H,
NH)
5b
5c
1680 (
S
C
O), 1705
306
382
(
CO), 3254 ( NH)
1690 (
S C O), 1710
(
CO), 3242 (NH)
5d
5e
1692 (
S
C
O), 1704
421
408
(CO), 3320 (NH)
1694 (
(CO), 3140 (NH), 3520
OH)
S C O), 1705
(
5f
1690 (
S
C
O), 1704
332
2.10–2.18 (m, 6H, (CH2)3), 2.36 (s,
3H, CH3), 3.64 (s, 3H, OCH3),
4.12 (t, 1H, CH), 4.30 (s, 3H,
CO OCH3), 7.12 (m, 3H, Ar H),
12.14 (s, 1H, NH)
(
CO)
the inorganic residue was washed with acetone, and the solvent was
removed on a rotavapor. By the addition of water to the residue, the
title compound was obtained as an oil, which was purified by column
chromatography (EtOAc/petroleum ether 1:9). Yield, 70–74%.
2-Acetyl-6-methoxy-1-[S-(1ꢀ-oxo-3ꢀ-aza-4ꢀ-substituted-5ꢀ-
oxo-5ꢀ-methoxy-pent -1ꢀ-yl]-thiophenols 4(a–e) and 4f
A mixture of 3(a–f) (0.01 mol), 2-Acetyl-6-methoxy-S-chloroacetyl thio-
phenol 2 (0.01 mol), and anhydrous K2CO3 (2.7 g; 0.02 mol) in 25 ml of
dry acetone was refluxed with stirring for 8 h. The progress of the reac-
tion was monitored by TLC. The reaction mixture was cooled, filtered,
the inorganic residue was washed with acetone, and the solvent was
removed on a rotavapor. The addition of water to the residue gave the
title compounds as precipitates, which were collected by filtration. They
were washed with water and crystallized from ethanol. Yield, 60–72%.

2064
B. Prasanna and G. V. P. Chandramouli
TABLE III IR and 1H NMR Spectral Data of the Compounds 6(a–f) and
7(a–f)
Comp.
IR cm−1
(m/z) M+1
333
1H NMR(δ ppm)
6a
1680 (C O),
3242 (NH),
3415 (NH2)
1684 (C O),
3140 (NH),
3412 (NH2)
1682 (C O),
3142 (NH),
3416 (NH2)
1690 (C O),
3145
(indole-NH),
3244 (NH),
3418 (NH2)
1692 (C O),
3140 (NH),
3412 (NH2),
3560 ( OH)
1690 (C O),
3412 (NH2)
2.32 (s, 3H, CH3), 2.48 (s, 2H, CH2),
3.82 (s, 3H, OCH3), 7.30–7.36 (m, 3H, Ar H)
9.8 (s, 2H, NH2), 12.2 (s, 1H, NH)
6b
6c
6d
347
425
462
2.14 (d, 3H, CH3), 2.36 (s, 3H, CH3),
2.42 (q, 1H, CH), 3.84 (s, 3H, OCH3), 7.32–7.38
(m, 3H, Ar H), 9.6 (s, 2H, NH2), 12.8 (s, 1H, NH)
2.30 (s, 3H, CH3), 2.54 (t, 1H, CH), 3.14 (d, 2H, CH2),
3.84 (s, 3H, OCH3), 7.34–7.36
(m, 8H, Ar H), 9.6 (s, 2H, NH2), 12.1 (s, 1H, NH)
2.32 (s, 3H, CH3), 2.58 (t, 1H, CH), (d, 2H, CH2),
3.42 3.86 (s, 3H, OCH3), 4.68 (s, 1H, CH), 5.12
(s, 1H, indole H), 6.94–7.42 (m, 7H, Ar H),
9.4 (s, 2H, NH2), 11.4 (s, 1H, NH)
6e
441
2.36 (s, 3H, CH3), 2.48 (t, 1H, CH), 3.40 (d, 2H, CH2),
3.86 (s, 3H, OCH3), 6.92–7.40 (m, 7H, Ar H),
9.4 (s, 2H, NH2), 10.8 (s, 1H, OH), 12.6 (s, 1H, NH)
6f
375
303
333
409
446
2.10 (t, 1H, CH), 2.22–2.26 (complex multiplet
pattern, 6H, (CH2)3), 2.32 (s, 3H, CH3), 3.86 (s, 3H,
OCH3), 6.92–7.24 (m, 3H, Ar H), 2.42 (s, 2H, NH2)
2.30 (s, 3H, CH3), 2.54 (s, 2H, CH2), 3.80
(s, 3H, OCH3), 7.34–7.92 (m, 3H, Ar H),
9.92 (s, 2H, NH2), 12.42 (s, 1H, NH)
2.10 (d, 3H, CH3), 2.22 (s, 3H, CH3), 2.48 (q,
2H, CH2), 8.88 (s, 3H, OCH3), 7.52–7.58 (m, 3H,
Ar H), 9.6 (s, 2H, NH2), 12.24 (s, 1H, NH)
2.33 (s, 3H, CH3), 2.52 (t, 1H, CH), 3.12 (d, 2H, CH2),
3.86 (s, 3H, OCH3), 6.92–7.38 (m, 8H, Ar H),
9.72 (s, 2H, NH2), 12.51 (s, 1H, NH)
7a
7b
7c
7d
1682 (C O),
3180 (NH),
3412 (NH2)
1688 (C O),
3142 (NH),
3414 (NH2)
1686 (C O),
3240 (NH),
3412 (NH2)
1692 (C O),
3182 (NH),
3415 (NH2)
2.32 (s, 3H, CH3), 2.56 (t, 1H, CH), 3.46 (d, 2H, CH2),
3.86 (s, 3H, OCH3), 5.62 (s, 1H, indole-H),
6.92–7.30 (m, 7H, Ar H), 9.4 (s, 2H, NH2),
12.3 (s, 1H, NH)
7e
7f
1688 (C O),
3240 (NH),
3412 (NH2),
3540 ( OH)
1690 (C O),
3415 (NH2)
423
357
2.46 (t, 1H, CH), 2.48 (s, 3H, CH3), 3.46 (d, 2H, CH2),
3.88 (s, 3H, OCH3), 6.94–7.42 (m, 7H, Ar H),
9.7 (s, 2H, NH2), 10.6 (s, 1H, OH), 12.3 (s, 1H, NH)
2.10 (t, 1H, CH), 2.26–2.32 (complex multiplet
pattern, 6H, (CH2)3), 2.34 (s, 3H, CH3), 3.84
(s, 3H, OCH3), 6.92–7.32 (m, 3H, Ar H),
9.8 (s, 2H, NH2)

Methyl Amino Thiocoumarins
2065
8-Methoxy-4-methyl-3-[N-(2ꢀ-oxo-2ꢀ-methoxy-1ꢀ-
substituted Ethan-1ꢀ-yl)]-amino Thiocoumarins 5(a–e)
and 5f
To a stirred solution of 4(a–f) (0.001 mol) in dry methanol (15 ml) was
added dropwise a solution of sodium methoxide (0.01 mol) in methanol
(5 ml). The reaction mixture was refluxed for 3 h followed by removal
of methanol under reduced pressure. The resultant precipitate was ob-
tained by addition of water. The residue was filtered, washed with water,
dried, and crystallized from ethanol. Yield, 58–64%.
8-Methoxy-4-methyl-3-(N-[2ꢀ-amino-(1ꢀ,3ꢀ,4ꢀ)thia/oxa-
diazol-5ꢀ-yl]-substituted methyl)-amino Thiocoumarins
6(a–f) and 7(a–f)
A mixture of 5(a–f) (0.001 mol) and thiosemicarbazide or semicarbazide
(0.001 mol) in dry ethanol (20 ml) was stirred at room temperature for
5 h. The reaction mixture was poured into ice-cold water. The precip-
itated solids were collected and recrystallized from chloroform. Yield,
56–60%.
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