One-pot synthesis of 1,3,4-thiadiazin-5-yl-chromen-2-one derivatives via three-component reaction

Article abstract of DOI:10.1080/00397911.2010.540697

An expeditious, one-pot reaction has been described for the preparation of 1,3,4-thiadiazin-5-yl-chromen-2-one derivatives. These compounds were synthesized by the reaction of 3-(2-bromoacetyl)coumarin with thiocarbohydrazide and various carbonyl compounds. The newly synthesized compounds were characterized by infrared, ¹H NMR, and mass spectra. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.540697

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One-Pot Synthesis of 1,3,4-Thiadiazin-5-
yl-chromen-2-one Derivatives via Three-
Component Reaction
Venkata Sreenivasa Rao Chunduru a & Rajeswar Rao Vedula a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Accepted author version posted online: 21 Oct 2011. Version of
record first published: 25 Jan 2012
To cite this article: Venkata Sreenivasa Rao Chunduru & Rajeswar Rao Vedula (2012): One-Pot
Synthesis of 1,3,4-Thiadiazin-5-yl-chromen-2-one Derivatives via Three-Component Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:10, 1454-1460
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Synthetic Communications1, 42: 1454–1460, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.540697
ONE-POT SYNTHESIS OF 1,3,4-THIADIAZIN-5-YL-
CHROMEN-2-ONE DERIVATIVES VIA
THREE-COMPONENT REACTION
Venkata Sreenivasa Rao Chunduru and Rajeswar Rao Vedula
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
Abstract An expeditious, one-pot reaction has been described for the preparation of
1,3,4-thiadiazin-5-yl-chromen-2-one derivatives. These compounds were synthesized by
the reaction of 3-(2-bromoacetyl)coumarin with thiocarbohydrazide and various carbonyl
compounds. The newly synthesized compounds were characterized by infrared, 1H NMR,
and mass spectra.
Keywords 3-(2-Bromoacetyl)coumarin; one-pot synthesis; 1,3,4-thiadiazine; thiocarbo-
hydrazide
INTRODUCTION
1,3,4-Thiadiazines constitute an important class of heterocycles, which has
attracted much synthetic interest because of their wide range of biological activities.
Considerable attention has been focused on these compounds because many of these
derivatives are important matrix metalloproteinase inhibitors.[1] They show excellent
cardiotonic and hypertensive activities.[2,3] They act as phosphodiesterase(IV) inhibi-
tors. These can be used for treatment of tumors and acquired immune deficiency syn-
drome (AIDS).[4] The literature survey reveals that there are not many examples of
1,3,4-thiadiazines. These can be prepared by the reaction of thiosemicarbazide or
thiocarbohydrazide with a-halo ketones.[5] Some heteroaryl-1,3,4-thiadiazines have
been reported in the literature starting from phenacyl bromide or chloroacetic acid
and pyrazolyl-1-thiocarbonylhydrazide.[6]
Benzopyran-2-one (coumarin) and its derivatives have also found various med-
icinal applications such as antitumoral, anti-inflammatory, antiviral, central nevous
Received September 5, 2010.
Address correspondence to Rajeswar Rao Vedula, Department of Chemistry, National Institute of
Technology, Warangal 506 004, India. E-mail: vrajesw@yahoo.com
1454

1,3,4-THIADIAZINES
1455
Scheme 1. Synthesis of 1,3,4-thiadiazin-5-yl-chromen-2-one derivatives via one-pot, three-component
reaction. 6a: R1 ¼ H, R2 ¼ OMe; 6b: R2 ¼ H, R1 ¼ H; 6c: R1 ¼ Br, R2 ¼ Br; 6d: 5,6-benzo analog of 6a.
7a: R1 ¼ H, R2 ¼ H; 7b: R1 ¼ Br, R2 ¼ Br; 7c: 5,6-benzo analog of 7a. 8a: R1 ¼ H, R2 ¼ H; 8b: R1 ¼ H,
R2 ¼ Br; 8c: R1 ¼ Br, R2 ¼ Br; 8d: 5,6-benzo analog of 8a.
system, and antioxidant activities.[7–9] These derivatives have been found to be novel
lipid-lowering agents that possess moderate triglyceride-lowering activity.[10] Some
of the coumarin derivatives are known for their anti-HIV activities.[11–14]
In view of various biological activities of 1,3,4-thiadiazines and in continuation
of our earlier work on the synthesis of new heterocyclic compounds[15–18] with antici-
pated biological activities, we have investigated a practical approach for the syn-
thesis of heterocyclic compounds like 1,3,4-thiadiazines at the third position of
2H-benzopyran-2-one via a one-pot, three-component reaction under mild and
efficient conditions.
RESULTS AND DISCUSSION
Condensation of various 3-(2-bromoacetyl)coumarins with thiocarbohydrazide
in 1.5–2 mL of acetone or acetophenone or salicylaldehyde gave the title products in
excellent yields. To reduce the side products, we have stirred the reaction mixture at
room temperature for about 30 min, followed by stirring at 50–55 ꢀC for about 1 h to
give the final products. The reaction path for the formation of products can be
explained by the S-acylation of thiocarbohydrazide with 1, followed by intramolecu-
lar cyclization to give coumarin substituted 2-hydrazino-6H-1,3,4-thiadiazines.
These underwent further condensation with carbonyl function of the solvent to give
the corresponding hydrazones 6, 7, and 8.
All the structures of newly synthesized compounds were confirmed by their
1
spectral data. The H NMR spectrum of compound 6a shows prominent peaks

1456
V. S. R. CHUNDURU AND R. R. VEDULA
Scheme 2. Two-step synthesis of 1,3,4-thiadiazin-5-yl-chromen-2-one derivatives.
for -CH3 at d 2.39, -CH2 of thiadiazine at d 3.87, and C-4 proton of coumarin at d
8.31. Similarly, 1H NMR spectrum of compound 8a shows prominent peaks at d 3.98
for -CH2 of thiadiazine and C-4 proton of coumarin at d 8.57. The 13CNMR spec-
trum of 6a also shows the peaks at d 14.5, 23.6, and 161.4 for methyl, CH2 of thia-
=
diazine, and C O of coumarin respectively. All the spectral data support the
formation of title products.
The structures of final products were also confirmed by synthesizing 6a and 8a
unambiguously. Reaction of equimolar mixture of 3-(2-bromoacetyl)coumarin,
thiocarbohydrazide in ethanol, and a catalytic amount of acetic acid gave 3-(2-hydra-
zino-6H-[1,3,4]thiadiazin-5-yl)-chromen-2-one 9. On reaction with 3 or 5 in ethanol
and a catalytic amount of piperidine, this gave the corresponding hydrazone 6a or
8a. The products obtained by both methods were found to be identical by mixed melt-
ing-point measurements, thin-layer chromatography (TLC), and spectral data.
CONCLUSION
In conclusion, we have developed an efficient, practical, one-pot synthesis
for the title compounds without application of any catalyst. This is a simple, mild,
inexpensive, and environmentally benign reaction. The biological activity of these
compounds is in progress.
EXPERIMENTAL
All the reagents and solvents were purchased from commercial sources
and were used without any further purification unless otherwise stated. 3-(2-
Bromoacetyl)coumarins[19] were prepared by literature procedure. Melting points
were determined in open capillaries with a Cintex melting-point apparatus
(Mumbai, India) and were uncorrected. CHNS analysis was done with a Carlo Erba
EA 1108 automatic elemental analyzer. The purity of the compounds was checked by
TLC plates (E. Merck Mumbai, India). Infrared (IR) spectra (KBr) were recorded
1
on a Bruker WM-4(X) spectrometer (577 model). H NMR spectra were recorded
on a Bruker WM-400 spectrometer in d ppm using tetramethylsilane as standard.
Mass spectra (EI-MS) were determined on Perkin Elmer (SCIEX API-2000, ESI)
at 12.5 eV.
General Procedure for the Synthesis of Compounds 6a–d, 7a–c, and
8a–d
3-(2-Bromoacetyl)coumarin (1 mmol), thiocarbohydrazide (1 mmol), and
1.5 mL of 3, 4, or 5 were taken in a conical flask and stirred at room temperature

1,3,4-THIADIAZINES
1457
for about 30 min. Then the reaction mixture was heated for about 1 h at 50–55 ꢀC
and cooled to room temperature; the solid separated was filtered, washed with
cooled methanol, and recrystallized from a suitable solvent.
Data
3-f2-[N!-(1-Phenyl-ethylidene)-hydrazino]-6H-[1,3,4]thiadiazin-5-ylg-
chromen-2-one (6a). Recrystallization: (CHCl3 þ MeOH); color: yellow solid;
yield 72%; mp 178–180 ꢀC; IR (KBr, tmax, cmꢁ1): 1602 (C N), 1732 (C O), 3105
=
=
1
(NH); H NMR (400 MHz, DMSO-d6): d 2.39 (s, 3H, -CH3), 3.87 (s, 2H, -CH2 of
thiadiazine), 7.41–7.48 (m, 5H, ArH), 7.67 (t, 1H, J ¼ 7.6 Hz, ArH), 7.87 (m, 3H,
7.6 Hz, ArH), 8.31 (s, 1H, C-4 of coumarin), 11.71 (s, 1H, -NH, D2O, exchangeable);
13C NMR (CDCl3 d ppm): 14.5, 23.6, 116.1, 118.8, 123.5, 125.0, 126.2, 128.4, 129.4,
129.4, 132.8, 138.2, 141.5, 144.6, 153.5, 157.5, 159.3, 161.4; EI-MS 377 [M þ H]þ.
Anal. calcd. for C20H16N4O2S: C, 63.81; H, 4.28; N, 14.88. Found: C, 63.76; H,
4.21; N, 14.83%.
8-Methoxy-3-f2-[N!-(1-phenyl-ethylidene)-hydrazino]-6H-[1,3,4]thiadiazin-
5-ylg-chromen-2-one (6b). Recrystallization: (CHCl3 þ MeOH); color: yellow
solid; yield 75%; mp 184–186 ꢀC; IR (KBr, tmax, cmꢁ1): 1607 (C N), 1714 (C O),
=
=
1
3105 (NH); H NMR (400 MHz, DMSO-d6): d 2.46 (s, 3H, -CH3), 3.92 (s, 2H,
-CH2 of thiadiazine), 3.94 (s, 3H, OMe), 7.35–7.44 (m, 6H, ArH), 7.85 (d, 2H,
J ¼ 7.6 Hz, ArH), 8.36 (s, 1H, C-4 of coumarin), 11.55 (s, 1H, -NH, D2O, exchange-
able). Anal. calcd. for C21H18N4O3S: C, 62.05; H, 4.46; N, 13.78. Found: C, 62.01;
H, 4.40; N, 13.82%.
6,8-Dibromo-3-f2-[N!-(1-phenyl-ethylidene)-hydrazino]-6H-[1,3,4]thiadiazin-
5-ylg-chromen-2-one (6c). Recrystallization: (CHCl3 þ MeOH); color: yellow
solid; yield 75%; mp 172–174 ꢀC; IR (KBr, tmax, cmꢁ1): 1602 (C N), 1732 (C O),
=
=
1
3103 (NH); H NMR (400 MHz, DMSO-d6): d 2.39 (s, 3H, -CH3), 3.86 (s, 2H,
-CH2 of thiadiazine), 7.75–7.95 (m, 5H, ArH), 8.12–8.23 (m, 2H, ArH), 8.26 (s,
1H, C-4 of coumarin), 11.75 (s, 1H, -NH, D2O, exchangeable). Anal. calcd. for
C20H14Br2N4O2S: C, 44.97; H, 2.64; N, 10.49. Found: C, 44.93; H, 2.61; N, 10.42%.
3-f2-[N!-(1-Phenyl-ethylidene)-hydrazino]-6H-[1,3,4]thiadiazin-5-ylg-
benzo[f]chromen-3-one (6d). Recrystallization: (CHCl3 þ MeOH); color: yellow
solid; yield 71%; mp 194–196 ꢀC; IR (KBr, tmax, cmꢁ1): 1585 (C N), 1716 (C O),
=
=
1
3159 (NH); H NMR (400 MHz, DMSO-d6): d 2.40 (s, 3H, -CH3), 3.93 (s, 2H, -
CH2 of thiadiazine), 7.41–7.43 (m, 3H, ArH), 7.65 (t, 2H, J ¼ 6.8 Hz, ArH), 7.75–
7.86 (m, 3H, ArH), 8.09 (d, 1H, J ¼ 8.0 Hz), 8.26 (d, 1H, J ¼ 8.0 Hz), 8.65 (s, 1H,
C-4 of coumarin), 9.01 (s, 1H, ArH), 11.75 (s, 1H, -NH, D2O, exchangeable). Anal.
calcd. for C24H18N4O2S: C, 67.59; H, 4.25; N, 13.14. Found: C, 67.52; H, 4.21; N,
13.10%.
3-[2-(N!-Isopropylidene-hydrazino)-6H-[1,3,4]thiadiazin-5-yl]-chromen-
2-one (7a). Recrystallization: (CHCl3 þ MeOH); color: yellow solid; yield 70%; mp
1
172–174 ꢀC; IR (KBr, tmax, cmꢁ1): 1572 (C N), 1718 (C O), 3138 (NH); H NMR
(400 MHz, DMSO-d6): d 2.08 [s, 6H, -(CH3)2], 3.86 (s, 2H, -CH2 of thiadiazine),
7.70–7.83 (m, 4H, ArH), 8.55 (s, 1H, C-4 of coumarin), 9.08 (s, 1H, -NH, D2O,
=
=

1458
V. S. R. CHUNDURU AND R. R. VEDULA
exchangeable); EI-MS 315 [M þ H]þ. Anal. calcd. for C15H14N4O2S: C, 57.31; H,
4.49; N, 17.82. Found: C, 57.27; H, 4.45; N, 17.77%.
6,8-Dibromo-3-[2-(N!-isopropylidene-hydrazino)-6H-[1,3,4]thiadiazin-5-
yl]-chromen-2-one (7b). Recrystallization: (CHCl3 þ MeOH); color: yellow solid;
yield 77%; mp 160–162 ꢀC; IR (KBr, tmax, cmꢁ1): 1572 (C N), 1723 (C O), 3154
=
=
1
(NH); H NMR (400 MHz, DMSO-d6): d 2.08 [s, 6H, -(CH3)2], 3.81 (s, 2H, -CH2
of thiadiazine), 8.19 (d, 1H, J ¼ 2.4 Hz, ArH), 8.22 (d, 1H, J ¼ 2.4 Hz, ArH), 8.69
(s, 1H, C-4 of coumarin), 9.08 (s, 1H, -NH, D2O, exchangeable). Anal. calcd. for
C15H12Br2N4O2S: C, 38.16; H, 2.56; N, 11.87. Found: C, 38.11; H, 2.51; N, 11.82%.
3-[2-(N!-Isopropylidene-hydrazino)-6H-[1,3,4]thiadiazin-5-yl]-benzo[f]
chromen-3-one (7c). Recrystallization: (CHCl3 þ MeOH); color: yellow solid;
yield 75%; mp 194–194 ꢀC; IR (KBr, tmax, cmꢁ1): 1570 (C N), 1720 (C O), 3157
=
=
1
(NH); H NMR (400 MHz, DMSO-d6): d 1.67 (s, 6H, -(CH3)2), 3.82 (s, 2H, -CH2
of thiadiazine), 8.11–8.30 (m, 4H, ArH), 8.52–8.54 (m, 2H, ArH), 8.60 (s, 1H, C-4
of coumarin), 9.13 (s, 1H, -NH, D2O, exchangeable). Anal. calcd. for C19H16N4O2S:
C, 62.62; H, 4.43; N, 15.37. Found: C, 62.57; H, 4.40; N, 15.31%.
3-f2-[N!-(2-Hydroxy-benzylidene)-hydrazino]-6H-[1,3,4]thiadiazin-5-ylg-
chromen-2-one (8a). Recrystallization: (MeOH þ AcOH); color: yellow solid;
yield 80%; mp 200–202 ꢀC; IR (KBr, tmax, cmꢁ1): 1602 (C N), 1725 (C O), 3152
=
=
1
(NH), 3427 (OH); H NMR (400 MHz, DMSO-d6): d 3.98 (s, 2H, -CH2 of thiadia-
zine), 7.35–7.56 (m, 4H, ArH), 7.68 (d, 2H, J ¼ 8.8 Hz, ArH), 7.86 (d, 2H, J ¼ 7.6 Hz,
=
ArH), 8.35 (s, 1H, N C-H), 8.57 (s, 1H, C-4 of coumarin), 10.25 (s, 1H, -NH, D2O,
exchangeable), 11.32 (s, 1H, -OH, D2O, exchangeable). EI-MS 379 [M þ H]þ. Anal.
calcd. for C19H14N4O3S: C, 60.31; H, 3.73; N, 14.81. Found: C, 60.28; H, 3.70; N,
14.76%.
6-Bromo-3-f2-[N!-(2-hydroxy-benzylidene)-hydrazino]-6H-[1,3,4]thiadiazin-
5-ylg-chromen-2-one (8b). Recrystallization: (MeOH þ AcOH); color: yellow
solid; yield 76%; mp 190–192 ꢀC; IR (KBr, tmax, cmꢁ1): 1608 (C N), 1734
=
1
=
(C O), 3209 (NH), 3345 (OH); H NMR (400 MHz, DMSO-d6): d 4.08 (s, 2H,
-CH2 of thiadiazine), 7.40–7.58 (m, 6H, ArH), 7.70 (s, 1H, ArH), 7.90 (s, 1H,
=
-N C-H), 8.50 (s, 1H, C-4 of coumarin), 10.32 (s, 1H, -NH, D2O, exchangeable).
Anal. calcd. for C19H13BrN4O3S: C, 49.90; H, 2.87; N, 12.25. Found: C, 49.86; H,
2.81; N, 12.20%.
6,8-Dibromo-3-f2-[N!-(2-hydroxy-benzylidene)-hydrazino]-6H-[1,3,4]-
thiadiazin-5-ylg-chromen-2-one
(8c). Recrystallization:
(MeOH þ AcOH);
color: yellow solid; yield 79%; mp 164–166 ꢀC; IR (KBr, tmax, cmꢁ1): 1602
1
=
=
(C N), 1716 (C O), 3195 (NH), 3395 (OH); H NMR (400 MHz, DMSO-d6): d
4.14 (s, 2H, -CH2 of thiadiazine), 7.31–7.39 (m, 2H, ArH), 7.72–7.86 (m, 3H,
=
ArH), 8.12 (s, 1H, ArH), 8.34 (s, 1H, -N C-H), 8.68 (s, 1H, C-4 of coumarin),
10.23 (s, 1H, -NH, D2O, exchangeable), 10.79 (s, 1H, -OH, D2O, exchangeable).
Anal. calcd. for C19H12Br2N4O3S: C, 42.56; H, 2.26; N, 10.45. Found: C, 42.51;
H, 2.21; N, 10.41%.
3-f2-[N!-(2-Hydroxy-benzylidene)-hydrazino]-6H-[1,3,4]thiadiazin-5-ylg-
benzo[f]chromen-3-one (8d). Recrystallization: (MeOH þ AcOH); color: yellow

1,3,4-THIADIAZINES
1459
solid; yield 76%; mp 188–190 ꢀC; IR (KBr, tmax, cmꢁ1): 1602 (C N), 1732 (C O),
3143 (NH), 3383 (OH); 1H NMR (400 MHz, DMSO-d6): d 4.05 (s, 2H, -CH2 of thia-
=
=
=
diazine), 7.62–7.90 (m, 7H, ArH), 8.10 (s, 1H, -N C-H), 8.24 (d, 1H, J ¼ 9.2 Hz,
ArH), 8.48–8.60 (m, 2H, ArH), 8.75 (s, 1H, C-4 of coumarin), 10.45 (s, 1H, -NH,
D2O, exchangeable), 11.46 (s, 1H, -OH, D2O, exchangeable). Anal. calcd. for
C23H16N4O3S: C, 64.47; H, 3.76; N, 13.08. Found: C, 64.42; H, 3.71; N, 12.97%.
General Procedure for the Synthesis of 3-(2-Hydrazino-6H-[1,3,4]-
thiadiazin-5-yl)-chromen-2-one (9)
3-(2-Bromoacetyl)coumarin (1 mmol), thiocarbohydrazide (1 mmol) are taken
in 5 mL of anhydrous ethanol, refluxed for about 1 h. The yellow solid obtained
on cooling was filtered, washed with methanol, and recrystallized.
Recrystallization: (CHCl3 þ MeOH); yellow solid; yield 70%; mp 139–141 ꢀC;
IR (KBr, tmax, cmꢁ1): 1607 (C N), 1709 (C O), 3316 (NH), 3466 (NH2); 1H
NMR (400 MHz, DMSO-d6): d 4.01 (s, 2H, -CH2 of thiadiazine), 7.34–7.50 (m,
2H, ArH), 7.70 (m, 1H, ArH), 7.89 (d, 1H, J ¼ 7.2 Hz, ArH), 8.37 (s, 1H, C-4 of cou-
marin), 10.01 (s, 1H, -NH, D2O, exchangeable), 12.0 (s, 2H, -NH2, D2O, exchange-
able); EI-MS 275 [M þ H]. Anal. calcd. for C12H10N4O2S: C, 52.54; H, 3.67; N,
20.43. Found: C, 52.50; H, 3.62; N, 20.49%.
=
=
General Procedure for the Synthesis of Compounds 6a and 8a
from 3-(2-Hydrazino-6H-[1,3,4]thiadiazin-5-yl)-chromen-2-one 9
A mixture of compound 9 (1 mmol), 3 or 5 (1.2 mmol) in 5 mL of anhydrous
ethanol, and one or two drops of piperidine was refluxed for about 1 h. The solid
obtained was cooled, filtered, washed with methanol, and recrystallized.
ACKNOWLEDGMENTS
The authors are thankful to the director, National Institute of Technology,
Warangal, for providing facilities. One of the authors (C.H.V.S.R.) is thankful to
the director for awarding an institute fellowship.
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