Synthesis of coumarin-substituted 1,3,4-thiadizine-2-thiones and 1,3-thiazoline-2-thiones

Article abstract of DOI:10.1080/00397911.2010.551698

Interaction of phenyl hydrazine/hydrazine with carbon disulfide in the presence of KOH affords the corresponding potassium salts of dithioformates. These in situ generated salts were reacted with different 3-(2-bromoacetyl) coumarins to yield N¹

Full text of DOI:10.1080/00397911.2010.551698

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Synthesis of Coumarin-Substituted
1,3,4-Thiadizine-2-thiones and 1,3-
Thiazoline-2-thiones
Venkata Sreenivasa Rao Chunduru a & Rajeswar Rao Vedula a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Accepted author version posted online: 27 Oct 2011. Version of
record first published: 26 Mar 2012
To cite this article: Venkata Sreenivasa Rao Chunduru & Rajeswar Rao Vedula (2012): Synthesis
of Coumarin-Substituted 1,3,4-Thiadizine-2-thiones and 1,3-Thiazoline-2-thiones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications1, 42: 2014–2021, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.551698
SYNTHESIS OF COUMARIN-SUBSTITUTED
1,3,4-THIADIZINE-2-THIONES AND
1,3-THIAZOLINE-2-THIONES
Venkata Sreenivasa Rao Chunduru and Rajeswar Rao Vedula
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
Abstract Interaction of phenyl hydrazine / hydrazine with carbon disulfide in the presence of
KOH affords the corresponding potassium salts of dithioformates. These in situ generated
salts were reacted with different 3-(2-bromoacetyl)coumarins to yield N1-phenyl-hydrazi-
necarbodithioic acid 2-oxo-2-(2-oxo-2H-chromen-3-yl)-ethyl ester (4a–c) and hydrazine-
carbodithioic acid 2-oxo-2-(2-oxo-2H-chromen-3-yl)-ethyl ester (7a–c) respectively.
Cyclocondensation of these compounds in the presence of an acid gave 3-(3-phenylamino-
2-thioxo-2,3-dihydro-thiazol-4-yl)-chromen-2-ones (5a–c) and 3-(2-thioxo-3,6-dihydro-2-
H-[1,3,4]thiadiazin-5-yl)-chromen-2-ones (8a–c) respectively.
Keywords 3-(2-Bromoacetyl)coumarin; one-pot synthesis; thiadiazine-2-thiones;
thiazoline-2-thiones
INTRODUCTION
Dithioformates are obtained by the reaction of carbon disulfide with amines or
hydrazines. Using dithioformates, various types of N- and S-containing heterocycles
have been synthesized. Among these heterocycles, 1,3,4-thiadiazines are biologically
active compounds. Many of these derivatives are important matrix metallo-
proteinase inhibitors.[1] They have shown excellent cardiotonic and hypertensive
activities.[2,3] They act as phosphodiesterase IV inhibitors, and these will be used
for treatment of tumors and Acquired Immune Deficiency Syndrome (AIDS).[4]
Received June 2, 2010.
Address correspondence to Rajeswar Rao Vedula, Department of Chemistry, National Institute of
Technology, Warangal 506 004, India. E-mail: vrajesw@yahoo.com
2014

1,3,4-THIADIAZINE-2-THIONES
2015
These derivatives may be used in agriculture as pesticides and insecticides.[5,6] Some
of these derivatives act as photographic magenta couplers.[7] Similarly, thiazolines
also act as dopamine b-monooxygenase (DBM) inhibitors.[8] They are also used as
antimicrobial agents.[9,10]
Coumarins are heterocyclic compounds, which are also known as benzo-2-
pyrone derivatives, and constitute an important group of natural products with vari-
ous biological activities.[11,12] The synthesis of coumarins and their derivatives have
attracted considerable attention from organic and medicinal chemists for many years
because of their wide range of medicinal applications such as antitumoral,
anti-inflammatory, antiviral, CNS active, and antioxidant activities.[13–15] Some of
coumarin derivatives have been known for their anti-HIV activities.[16–18] They were
also extensively used as photochromes with modulated fluorescence and laser
dyes.[19,20]
In view of the biological importance of coumarins, thiadiazines, and thiazoli-
dines, and in continuation of our earlier work on the synthesis of novel heterocyclic
systems,[21–23] in the present investigation an attempt has been made to synthesize
compounds containing coumarin: 1,3,4-thiadiazine-2-thione and 1,3-thiazoline-2-
thione. These compounds are expected to have enhanced biological activity and
might provide additional lead molecules for use in drug discovery.
RESULTS AND DISCUSSION
Humphlett et al.[24,25] prepared thiazoline-2-thiones by the reaction of
ammonium dithioformate and a -halo ketones. During the formation of thiazoline-
2-thiones, the intermediates formed are 4-hydroxy thiazolidine-2-thiones. On sub-
sequent dehydration, these gave thiazoline-2-thione. Later, Ege et al.[26] prepared
3-arylamino-1,3-thiazoline-2-thiones. Reaction of potassium (N-arylhydrazino)-
dithioformates with phenacyl halides gave the acylmethyl (hydrazino)thioformates.
On cyclization in acidic medium, these resulted in the formation of 3-arylamino-1,3-
thiazolin-2-thiones.
In this present study, we describe the preparation of 3-comarinyl-1,3-thiazoline-
2-thiones and 1,3,4-thiadiazine-2-thiones under mild and efficient conditions.
3-(2-Bromoacetyl)coumarins on reaction with phenyl hydrazine and carbondisulfide
gave the corresponding uncyclized compounds N1-phenyl-hydrazinecarbodithioic
acid 2-oxo-2-(2-oxo-2H-chromen-3-yl)-ethyl esters (4a–c). It is believed that reaction
between phenyl hydrazine and carbondisulfide led to the formation of s-potassium
(N-arylhydrazino)dithioformate. This salt was not isolated and was formed in situ.
On reaction with 3-(2-bromoacetyl)coumarins, the salt gave the uncyclized inter-
mediates (4a–c). These underwent cyclocondensation reaction catalyzed by an acid
to yield the 3-(3-phenylamino-2-thioxo-2,3-dihydro-thiazol-4-yl)-chromen-2-ones
(5a–c) (Scheme 1). On the other hand, reaction of 3-(2-bromoacetyl)coumarins with
hydrazine hydrate and carbondisulfide gave the corresponding uncyclized intermedi-
ates (7a–c). These intermediates (7a–c) under acidic conditions were cyclized to the
six-membered compounds 3-(2-thioxo-3,6-dihydro-2H-[1,3,4]thiadiazin-5-yl)-chromen-
2-ones (8a–c) (Scheme 2).
All the synthesized compounds were characterized by infrared (IR) and
1
NMR. In the H NMR spectra of 4 and 7, the methylene protons adjacent to

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V. S. R. CHUNDURU AND R. R. VEDULA
Scheme 1. Synthesis of 3-(3-phenylamino-2-thioxo-2,3-dihydro-thiazol-4-yl)-chromen-2-ones.
Scheme 2. Synthesis of 3-(2-thioxo-3,6-dihydro-2H-[1,3,4]thiadiazin-5-yl)-chromen-2-ones.
the sulfur atom appeared as two doublets. This nonequivalence can be explained
by the anisotropic effect caused by d orbitals of the sulfur atom.[27] The hydrogens
of CH2 were not equivalent, indicating the structure existed in the nonplanar con-
formation. Compound 5 can be readily distinguished from compound 8 by using
13C NMR spectral studies. In broad-band decoupled spectrum of 8a, there is a
characteristic singlet for S-CH2 carbon of the thiadiazine ring at d 26.0. This type
of singlet was absent in the case of 5. This clearly confirmed that structure 8 is a
six-membered thiadiazine-2-thione derivative and that the structure 5 is a five-
membered thiazoline-2-thione. The structures 5 and 8 were further confirmed from
the literature.[9,26]
CONCLUSION
In summary, we have prepared a five-membered cyclic product 3-(3-phenyl-
amino-2-thioxo-2,3-dihydro-thiazol-4-yl)-chromen-2-ones and a six-membered cyclic
product 3-(2-thioxo-3,6-dihydro-2H-[1,3,4]thiadiazin-5-yl)-chromen-2-ones through
novel ring-closing reactions. The advantages of this methodology are mild reaction
conditions, easy workup, clean reaction profile, shorter reaction time, and wide
range of substrate applicability.

1,3,4-THIADIAZINE-2-THIONES
2017
EXPERIMENTAL
All the reagents and solvents were pure, purchased from commercial sources,
and used without further purification unless otherwise stated. 3-(2-Bromoacetyl)-
coumarins[28] were prepared according to literature procedures. Melting points were
determined in open capillaries with a Cintex melting-point apparatus (Mumbai,
India) and were uncorrected. CHNS analysis was done on a Carlo Erba EA 1108
automatic elemental analyzer. The purity of the compounds was checked by
thin-layer chromatographic (TLC) plates (E. Merek Mumbai, India). IR spectra
1
(KBr) were recorded on a Bruker WM-4(X) spectrometer (577 model). H NMR
spectra were recorded on a Bruker WM-400 spectrometer in d ppm using tetra-
methylsilane (TMS) as standard. Mass spectra (EI-MS) were determined on a
Perkin-Elmer instrument (SCIEX API- 2000, ESI) at 12.5 eV.
General Procedure for the Synthesis of N1-Phenyl-hydrazine-,
Hydrazinecarbodithioic Acid 2-Oxo-2-(2-oxo-2H-chromen-3-yl)-ethyl
Esters 4a–c and 7a–c
Carbon disulfide (2 mmol) was added gradually with stirring to a solution of
phenyl hydrazine or hydrazine hydrate (2 mmol) in absolute ethanol (10 mL) at
0 ꢀC, followed by ice-cold potassium hydroxide (2 mmol) in absolute ethanol
(5 mL). After stirring at 0–5 ꢀC for 2 h, 3-(2-bromoacetyl)coumarin (2 mmol) was
added and stirred for about 1 h at 0–5 ꢀC. The solid obtained was filtered, washed
with water, and recrystallized from ethanol.
Data
N1-Phenyl-hydrazinecarbodithioic acid 2-oxo-2-(2-oxo-2H-chromen-3-
yl)-ethyl ester (4a). Yield 80%, mp 182–184 ꢀC. Color: light yellow; IR (KBr,
1
t
max): 3341, 3297, 1714, 1630, 1601, 1188; H NMR (400 MHz, DMSO-d6): d 3.38
(d, 1H of CH2, J ¼ 12.4 Hz), 4.05 (d, 1H of CH2, J ¼ 12 Hz), 6.65 (t, 1H, J ¼ 7.2 Hz,
Hz, ArH), 6.77 (d, 2H, J ¼ 7.6 Hz, ArH), 7.03 (t, 2H, J ¼ 8.4 Hz, ArH), 7.35–7.45 (m,
2H, ArH), 7.65 (t, 1H, J ¼ 8.4 Hz, ArH), 7.83 (d, 1H, J ¼ 8 Hz, ArH), 8.07 (s, 1H,
-NH, D2O, exchangeable), 8.16 (s, 1H, -NH, D2O, exchangeable), 8.31 (s, 1H, C-4
of coumarin). EI-MS 393 (100%) [M þ Na]þ. Anal. calcd. for C18H14N2O3S2: C,
58.36; H, 3.81; N, 7.56. Found: C, 58.29; H, 3.88; N, 7.50%.
N1-Phenyl-hydrazinecarbodithioic acid 2-(6-chloro-2-oxo-2H-chromen-
3-yl)-2-oxo-ethyl ester (4b). Yield 85%, mp 170–172 ꢀC. Color: light yellow; IR
1
(KBr, tmax): 3325, 3230, 1718, 1625, 1600, 1184; H NMR (400 MHz, DMSO-d6):
d 3.37 (d, 1H of CH2, J ¼ 12.4 Hz), 4.05 (d, 1H of CH2, J ¼ 12.4 Hz), 6.65 (t, 1H,
J ¼ 7.2 Hz, ArH), 6.75 (d, 2H, J ¼ 8 Hz, ArH), 7.03 (d, 2H, J ¼ 8.4 Hz, ArH) 7.50
(d, 1H, J ¼ 8.8 Hz, ArH), 7.67–7.70 (m, 1H, ArH), 8.0 (d, 1H, J ¼ 2.4 Hz, ArH),
8.15 (s, 2H, -NH, D2O, exchangeable), 8.31 (s, 1H, C-4 of coumarin). Anal. calcd.
for C18H13ClN2O3S2: C, 53.40; H, 3.24; N, 6.92. Found: C, 53.44; H, 3.18; N, 6.98%.
N1-Phenyl-hydrazinecarbodithioic
chromen-3-yl)-2-oxo-ethyl ester (4c). Yield 85%, mp 110–112 ꢀC. Color: light
acid
2-(6,8-dibromo-2-oxo-2H-

2018
V. S. R. CHUNDURU AND R. R. VEDULA
1
yellow; IR (KBr, tmax): 3426, 1719, 1648, 1606, 1189; H NMR (400 MHz, DMSO-
d6): d 3.38 (d, 1H of CH2, J ¼ 12.4 Hz), 4.03 (d, 1H of CH2, J ¼ 12 Hz), 6.66 (t, 1H,
J ¼ 7.2 Hz, ArH), 6.74 (d, 2H, J ¼ 7.6 Hz, ArH), 7.04 (t, 2H, J ¼ 8.4 Hz, ArH), 8.16
(s, 2H, ArH), 8.20 (s, 2H, -NH, D2O, exchangeable), 8.29 (s, 1H, C-4 of coumarin).
Anal. calcd. for C18H12Br2N2O3S2: C, 40.93; H, 2.29; N, 5.30. Found: C, 40.98; H,
2.32; N, 5.35%.
Hydrazinecarbodithioic acid 2-oxo-2-(2-oxo-2H-chromen-3-yl)-ethyl
ester (7a). Yield 79%, mp 188–190 ꢀC. Color: light yellow; IR (KBr, tmax): 3311,
1
3302, 3199, 1716, 1625, 1606, 1199; H NMR (400 MHz, DMSO-d6): d 3.15 (d,
1H of CH2, J ¼ 12 Hz), 3.80 (d, 1H of CH2, J ¼ 12 Hz), 5.07 (s, 2H, -NH2, D2O,
exchangeable), 7.39–7.47 (m, 2H, ArH), 7.67 (t, 1H, J ¼ 8.4 Hz, ArH), 7.84 (s, 1H,
-NH, D2O, exchangeable), 7.90 (d, 1H, J ¼ 8.4 Hz, ArH), 8.35 (s, 1H, C-4 of
coumarin). EI-MS 317 (75%) [M þ Na]þ. Anal. calcd. for C12H10N2O3S2: C,
48.97; H, 3.42; N, 9.52. Found: C, 48.91; H, 3.47; N, 9.58%.
Hydrazinecarbodithioic acid 2-(6-bromo-2-oxo-2H-chromen-3-yl)-2-
oxo-ethyl ester (7b). Yield 82%, mp 180–182 ꢀC. Color: light yellow; IR (KBr,
1
t
max): 3340, 3296, 1712, 1629, 1610, 1188; H NMR (400 MHz, DMSO-d6): d 3.15
(d, 1H of CH2, J ¼ 12.4 Hz), 3.79 (d, 1H of CH2, J ¼ 12 Hz), 5.06 (s, 2H, -NH2,
D2O, exchangeable), 7.51 (d, 1H, J ¼ 8.8 Hz ArH), 7.69–7.72 (m, 1H, ArH), 7.90
(s, 1H, -NH, D2O, exchangeable), 8.08 (d, 1H, J ¼ 2.8 Hz, ArH), 8.35 (s, 1H, C-4
of coumarin). Anal. calcd. for C12H9BrN2O3S2: C, 38.61; H, 2.43; N, 7.51. Found:
C, 38.65; H, 2.47; N, 7.55%.
Hydrazinecarbodithioic acid 2-(6,8-dibromo-2-oxo-2H-chromen-3-yl)-2-
oxo-ethyl ester (7c). Yield 83%, mp 190–192 ꢀC. Color: light yellow; IR (KBr,
1
t
max): 3311, 3201, 1734, 1631, 1556, 1178; H NMR (400 MHz, DMSO-d6): d 3.14
(d, 1H of CH2, J ¼ 12.4 Hz), 3.81 (d, 1H of CH2, J ¼ 12.4 Hz), 5.09 (s, 2H, -NH2,
D2O, exchangeable), 7.94 (s, 1H, -NH, D2O, exchangeable), 8.21 (s, 1H, ArH),
8.24 (s, 1H, ArH), 8.33 (s, 1H, C-4 of coumarin). Anal. calcd. for C12H8Br2N2O3S2:
C, 31.88; H, 1.78; N, 6.20. Found: C, 31.84; H, 1.73; N, 6.24%.
General Procedure for the Synthesis of 3-(3-Phenylamino-
2-thioxo-2,3-dihydro-thiazol-4-yl)-chromen-2-ones 5a–c and
3-(2-Thioxo-3,6-dihydro-2H-[1,3,4]thiadiazin-5-yl)-chromen-
2-ones 8a–c
Compounds 4a–c or 7a–c (1 mmol) was taken in absolute ethanol (10 mL) with
one or two drops of concentrated HCl and refluxed for 2–3 h. After completion of
the reaction, it was cooled to room temperature, and the yellow solid obtained
was filtered and recrystallized from ethanol.
Data
3-(3-Phenylamino-2-thioxo-2,3-dihydro-thiazol-4-yl)-chromen-2-one (5a).
Yield 75%, mp 180–182 ꢀC. Color: yellow; IR (KBr, tmax): 3325, 1701, 1604, 1560,
1114; 1H NMR (400 MHz, DMSO-d6): d 6.47 (d, 2H, J ¼ 8.4 Hz, ArH), 6.74

1,3,4-THIADIAZINE-2-THIONES
2019
(t, 1H, J ¼ 7.6 Hz, ArH), 7.01–7.05 (m, 3H, 2H, ArH and 1H, thiazoline), 7.11–7.17
(m, 2H, ArH), 7.32 (d, 1H, J ¼ 7.6 Hz, ArH), 7.39–7.43 (m, 1H, ArH), 8.01 (s, 1H,
-NH, D2O, exchangeable), 8.05 (s, 1H, C-4 of coumarin). 13C NMR (75 MHz,
DMSO-d6): 110.2, 110.9, 113.0, 116.6, 119.2, 120.5, 120.8, 128.9, 130.4, 137.2,
138.0, 142.6, 145.6, 149.2, 157.2, 186.5. EI-MS 391 (100%) [M þ K]þ. Anal. calcd.
for C18H12N2O2S2: C, 61.34; H, 3.43; N, 7.95. Found: C, 61.38; H, 3.47; N, 7.91%.
6-Chloro-3-(3-phenylamino-2-thioxo-2,3-dihydro-thiazol-4-yl)-chromen-
2-one (5b). Yield 77%, mp 194–196 ꢀC. Color: yellow; IR (KBr, tmax): 3350, 1716,
1600, 1577, 1114; 1H NMR (400 MHz, CDCl3): d 6.65 (d, 2H, J ¼ 7.6 Hz, ArH), 6.98
(t, 1H, J ¼ 7.6 Hz, ArH), 7.22–7.29 (m, 4H, 3H, ArH and 1H, thiazoline), 7.44 (s, 1H,
-NH, D2O, exchangeable), 7.51 (d, 2H, J ¼ 9.2 Hz, ArH), 8.22 (s, 1H, C-4 of cou-
marin). 13C NMR (75 MHz, DMSO-d6): 110.3, 110.8, 113.1, 115.6, 119.3, 120.5,
121.1, 128.4, 130.6, 136.2, 138.1, 143.6, 145.9, 148.2, 156.2, 186.1. Anal. calcd.
C18H11ClN2O2S2: C, 55.88; H, 2.87; N, 7.24. Found: C, 55.85; H, 2.86; N, 7.29%.
6,8-Dibromo-3-(3-phenylamino-2-thioxo-2,3-dihydro-thiazol-4-yl)-chromen-
2-one (5c). Yield 76%, mp 168–170 ꢀC. Color: yellow; IR (KBr, tmax): 3350, 1716,
1
1600, 1577, 1116; H NMR (400 MHz, DMSO-d6): d 6.51 (d, 2H, J ¼ 7.6 Hz, ArH),
6.77 (t, 1H, J ¼ 7.6 Hz, ArH), 7.12 (t, 2H, J ¼ 8.4 Hz, ArH), 7.39 (s, 1H, thiazoline),
7.96 (s, 1H, ArH), 8.20 (s, 1H, ArH), 8.32 (s, 1H, C-4 of coumarin), 9.37 (s, 1H, -NH,
D2O, exchangeable). Anal. calcd. for C18H10Br2N2O2S2: C, 42.37; H, 1.98; N, 5.49.
Found: C, 42.34; H, 1.96; N, 5.45%.
3-(2-Thioxo-3,6-dihydro-2H-[1,3,4]thiadiazin-5-yl)-chromen-2-one (8a).
Yield 73%, mp 200–202 ꢀC. Color: yellow; IR (KBr, tmax): 3323, 1701, 1620, 1604,
1107; 1H NMR (400 MHz, DMSO-d6): d 3.98 (s, 2H, S-CH2), 7.71 (d, 2H, J ¼ 2.4 Hz,
Hz, ArH), 7.91 (d, 2H, J ¼ 2.4, ArH), 8.16 (s, 1H, C-4 of coumarin), 10.28 (s, 1H,
-NH, D2O, exchangeable). EI-MS 277 (100%) [M þ H]þ. 13C NMR (75 MHz,
DMSO-d6): 26.0, 110.1, 116.5, 121.5, 124.7, 131.1, 137.3, 141.2, 145.3, 149.6,
157.7, 189.3. Anal. calcd. for C12H8N2O2S2: C, 52.16; H, 2.92; N, 10.14. Found:
C, 52.11; H, 2.96; N, 10.17%.
6-Bromo-3-(2-thioxo-3,6-dihydro-2H-[1,3,4]thiadiazin-5-yl)-chromen-2-one
(8b). Yield 76%, mp 194–196 ꢀC. Color: yellow; IR (KBr, tmax): 3172, 1728, 1616,
1
1587, 1116; H NMR (400 MHz, DMSO-d6): d 3.98 (s, 2H, S-CH2), 7.52–7.57 (m,
1H, ArH), 7.73–7.75 (m, 1H, ArH), 8.03 (d, 1H, J ¼ 2.4 Hz, ArH), 8.42 (s, 1H,
C-4 of coumarin), 13.48 (s, 1H, -NH, D2O, exchangeable). 13C NMR (75 MHz,
DMSO-d6): 26.3, 116.3, 118.3, 122.1, 124.8, 128.9, 132.9, 143.3, 144.4, 153.9,
159.2, 189.8. Anal. calcd. for C12H7BrN2O2S2: C, 40.57; H, 1.99; N, 7.89. Found:
C, 40.54; H, 1.96; N, 7.81%.
6,8-Dibromo-3-(2-thioxo-3,6-dihydro-2H-[1,3,4]thiadiazin-5-yl)-chromen-
2-one (8c). Yield 76%, mp 216–216 ꢀC. Color: yellow; IR (KBr, tmax): 3172, 1728,
1
1616, 1587, 1116; H NMR (400 MHz, DMSO-d6): d 3.98 (s, 2H, S-CH2), 8.17 (d,
1H, J ¼ 2.4 Hz, ArH), 8.24 (d, 1H, J ¼ 2 Hz, ArH), 8.39 (s, 1H, C-4 of coumarin),
13.50 (s, 1H, -NH, D2O, exchangeable). Anal. calcd. for C12H6Br2N2O2S2:C,
33.20; H, 1.39; N, 6.45. Found: C, 33.24; H, 1.35; N, 6.49%.

2020
V. S. R. CHUNDURU AND R. R. VEDULA
ACKNOWLEDGMENTS
The authors are thankful to the director, NIT, Warangal, for providing the
facilities. One of the authors (C. H. V. S. R.) is thankful to the director for awarding
an institute fellowship.
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