Synthesis of 3-(3-(Phenacyl/Alkyl/Benzylthio)-[1,2,4]Triazolo[3,4-B][1,3,4] Thiadiazol-6-Yl)-2 H -Chromen-2-Ones

Article abstract of DOI:10.1080/10426507.2013.798790

Reaction of coumarin-3-carboxylic acid with 3,5-di mercapto-4-amino-s- triazole in POCl3to generate 3-(3-mercapto-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-6-yl)-2H-chromen-2-one (3). Reaction of 3 with different substituted phenacyl/benzyl/allyl bromides

Full text of DOI:10.1080/10426507.2013.798790

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Phosphorus, Sulfur, and Silicon and the Related
Elements
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http://www.tandfonline.com/loi/gpss20
Synthesis of 3-(3-(phenacyl/alkyl/benzylthio)-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-2H-
chromen-2-ones
Sreenu Pavurala a & Rajeswar rao Vedula a
a Department of Chemistry , National Institute of Technology , Warangal , India
Accepted author version posted online: 26 Jul 2013.
To cite this article: Phosphorus, Sulfur, and Silicon and the Related Elements (2013): Synthesis of 3-(3-(phenacyl/alkyl/
benzylthio)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-2H-chromen-2-ones, Phosphorus, Sulfur, and Silicon and the Related
Elements, DOI: 10.1080/10426507.2013.798790
To link to this article: http://dx.doi.org/10.1080/10426507.2013.798790
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Synthesis of 3-(3-(phenacyl/alkyl/benzylthio)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-
2H-chromen-2-ones
Sreenu Pavurala and Rajeswar rao Vedula*
Department of Chemistry, National Institute of Technology, Warangal, India
E-mail: vrajesw@yahoo.com
ABSTRACT
Reaction of coumarin-3-carboxylic acid with 3,5-di mercapto-4-amino-s-triazole in
POCl3 to gave 3-(3-mercapto-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-2H-chromen-2-one (3).
Reaction of 3 with different substituted phenacyl/benzyl/allyl bromides in anhydrous ethanol
gave corresponding 3-(3-(phenacyl/alkyl/benzylthio)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-6-
yl)-2H-chromen-2-ones 5. The structures of newly prepared compounds were confirmed from
their analytical and spectral data.
Graphical Abstract
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N
N
N
N
S
S
N
N
N N
N
O
O
O
S
R1
N
POCl3
(4)
R1-Br
HS
SH
HS
N
OH
Anhydrous ethanol
NH2
O
O
O
O
3
1
2
R1-Br
5 a
- j
(4)
Anhydrous ethanol
R1
S
N
N
N
S
N
O
O
6 a-j
Keywords: triazole, 1,3,4-thiadiazol, 1,2,4-triazole, phenacyl bromide, coumarin.
INTRODUCTION
The compounds having sulfur and nitrogen in a 5-membered ring system exhibit broad
range of biological properties1. Thiadiazole and its derivatives have various biological activities
such as anti-tuberculosis2, anticancer3, carbonicanhydrase-inhibiting effect4, antioxidant
properties5 and antimycobacterial6. When thiadiazole is fused with triazoles show antiviral7,
antitumor8, anthelmentic9 activities and the substituted triazolo thiadiazoles exhibit various
pharmacological activities such as herbicidal10, anti-HIV-1 effects11. 1,3,4-Thiadiazoles posses
various biological activities due to presence of =N–C–S moiety12.
Coumarins are very important heterocyclic systems used in drugs and dyes 13 . They are
usually available from natural sources such as secondary metabolite present in roots and leaves
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of many plant species14. Coumarins and their derivatives show a wide range of biological
activities such as HIV protease inhibition15, anticoagulant16, anti-inflammatory17 activity.
Prompted by the above observations and in continuation of our search for biologically
active nitrogen and sulfur containing heterocycles18-20, it was decided to synthesize these
heterocyclic coumarins.
RESULTS AND DISCUSSION
We have synthesized 3-(3-(phenacyl/alkyl/benzyl thio)-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazol-6-yl)-2H-chromen-2-ones via a two-step process. In the first step, coumarin-3-
carboxylic acid (1) was reacted with 4-amino-4H-[1,2,4]triazole-3,5-dithiol (2) in POCl3 . In the
second step the intermediate was further reacted with different substituted phenacyl / benzyl/
alkyl bromides (4) in anhydrous ethanol under reflux condition for 4-6 h to gave the
corresponding thio ethers (5). All the thio ethers prepared were new compounds. This is a
regioselective S-alkylation. The alkylation of (3) with phenacyl/ benzyl/ alkyl bromides may
result in different types of products such as N-alkylated, S-alkylated products and a mixture of
both. In the present investigation, a mixture of products is not formed (as evidenced by TLC).
The formation of S-alkylated products have been explained in preference to N-alkylated
products as due to high nucleophilicity of thiol group21. The formation of these S-alkylated
products was confirmed by spectral data.
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Scheme-1
The compound 3 showed in its IR spectrum characteristic peaks for SH at 2922 cm-1 and
lactone carbonyl at 1710 cm-1. In the 1H-NMR (DMSO-d6) spectrum , the compound 3 showed a
characteristic singlet at δ 2.79 for SH and coumarin C-4 proton appeared as singlet at δ 7.25.
The remaining aromatic protons were observed in the usual aromatic region. In the mass
spectrum the compound 3 exhibited [M+H]+ ion at m/z 303.
The compound 5a was characterized by analytical and spectral data. In the IR spectrum it
exhibited a lactonyl carbon band at 1720 cm-1 , C=O stretching frequency at 1681 cm-1, C=N
stretching frequency at 1610 cm-1 respectively.
1
The H NMR spectrum of 5a showed –S- CH2 protons at δ 4.90, aromatic proton
chemical shifts appeared in the region δ 7.46-8.04 as a multiplet and the C-4 proton of
coumarin resonated at δ 8.97 as a singlet.
13
The C NMR spectrum of 5a showed carbon chemical shift for -CH2- at δ 40.3 , the
lactone carbonyl carbon resonated at δ 160.8 and carbonyl carbon signal appeared at most
downfield δ 192.8 . The mass spectrum showed a molecular ion peak at m/z 421.
EXPERIMENTAL
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All the reagents and solvents were pure, purchased from commercial sources, and were
used without further purification unless otherwise stated. Melting points were determined in
open capillaries with a “Cintex” melting point apparatus (Mumbai, India) and were uncorrected.
CHN analytical data acquired by Carlo Erba EA 1108 automatic elemental analyzer. The
compounds purity was checked by TLC plates (E. Merck, Mumbai, India) . IR spectra (KBr)
1
were recorded on a Bruker WM-4(X) spectrometer (577 model). H NMR spectra were recorded
on a Bruker WM-400 spectrometer in δ ppm using TMS as standard. Mass spectra (EI-MS) were
determined on Perkin Elmer (SCIEX API- 2000, ESI) at 12.5 eV. The Supplemental Materials
contains sample 1H and 13C NMR spectra for 5a and 5d (Figures S 1 – S 3)
General Procedure for preparation of compound (3)
A mixture of coumarin-3-carboxylic acid 1(1mmol), 4-amino-4H-[1,2,4]triazole-3,5-dithiol
2 (1mmol) and POCl3 (10 mL) was heated under reflux for 4 h. Excess POCl3 was removed
under reduced pressure. The concentrated mass was cooled and poured into ice to yield a solid
product which on washing with NaHCO3 followed by water and recrystallization from ethanol
gave the title compound.
General Procedure for preparation of compounds (5a-j)
A mixture of 3-(3-mercapto-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-2H-chromen-2-
one 3 (1mmol) and appropriate phenacyl/ benzyl/ allyl bromide 4 was refluxed for 4-6 h in
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anhydrous ethanol. The reaction mixture was cooled and the solid separated was filtered, washed
thoroughly with water and recrystallized from methanol to get the title compounds.
Synthesis of 3-[3-(2-oxo-2-phenyl-ethylsulfanyl)-[1,2,4]triazolo[3,4- b] [1,3,4]
thiadiazol-6-yl]-chromen-2-one (5a)
Yellow solid, yield 78%, 4h, m.p. 194-196 oC. IR (KBr, cm-1): υ 1720 ( lactone carbonyl
1
carbon of coumarin), 1681 (C=O), 1610 (C=N), 1567 (C=C). H NMR (400 MHz, DMSO-d6): δ
4.90 (s, 2H, -SCH2CO–), 7.46-7.60 (m, 4H, ArH ), 7.67 (t, 1H, J=7.2Hz, ArH), 7.82 (t, 1H, J=
7.8Hz, ArH), 7.99–8.04 (m, 3H, ArH), 8.97 (s, 1H, C-4 of coumarin). 13C NMR (400 MHz,
DMSO-d6 δ ppm): 40.3, 116.3, 117.0, 118.1, 125.3, 125.6, 128.3, 128.7, 130.7, 133.7, 135.1,
143.4, 150.0, 151.7, 154.3, 158.9, 160.9, 193.1. EI-MS 421 [M+H]+. Anal. calcd. For
C20H12N4O3S2: C, 57.13; H, 2.88; N, 13.32; Found: C, 57.10; H, 2.82; N, 13.19.
Synthesis of 3-{3-[2-(4-bromo-phenyl)-2-oxo-ethylsulfanyl]-[1,2,4] triazolo[3,4-
b][1,3,4]thiadiazol-6-yl}-chromen-2-one (5b)
o
Yellow solid, yield 79%, 4h, m.p. 207-209 C. IR (KBr, cm-1): υ 1722 (lactone carbonyl
1
carbon of coumarin), 1684 (C=O), 1609 (C=N), 1584 (C=C). H NMR (400 MHz, DMSO-d6): δ
4.85 (s, 2H, -SCH2CO–), 7.47-7.61 (m, 2H, ArH ), 7.76 (d, 2H, J=8.4 Hz, ArH), 7.82 (t, 1H,
J=7.8 Hz, ArH), 7.93 (t, 1H, J=9 Hz, ArH), 8.03 (d, 2H, J=8 Hz, ArH), 8.96 (s, 1H, C-4 of
coumarin). 13C NMR (400 MHz, DMSO-d6 δ ppm): 40.4, 116.2, 116.8, 118.0, 125.2, 127.8,
130.3, 130.7, 131.7, 134.1, 135.1, 150.0, 151.5, 154.3, 158.8, 160.8, 192.4. EI-MS 499 [M]+.
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Anal. calcd. For C20H11BrN4O3S2: C, 48.10; H, 2.22; N, 11.22; Found: C, 48.14; H, 2.20;
N,11.18
Synthesis of 3-{3-[2-(4-chloro-phenyl)-2-oxo-ethylsulfanyl]-[1,2,4] triazolo[3,4-b]
[1,3,4]thiadiazol-6-yl}-chromen-2-one (5c)
o
Yellow solid, yield 76%, 4h, m.p. 210-212 C. IR (KBr, cm-1): υ 1723 (lactone carbonyl
1
carbon of coumarin), 1698 (C=O), 1609 (C=N), 1566 (C=C). H NMR (400 MHz, DMSO-d6): δ
4.86 (s, 2H, -SCH2CO–), 7.46-7.62 (m, 4H, ArH ), 7.82 (t, 1H, J=7.2Hz, ArH), 7.99–8.04 (m,
13
3H, ArH), 8.96 (s, 1H, C-4 of coumarin). C NMR (400 MHz, DMSO-d6 δ ppm): 40.3, 116.2,
116.8, 118.0, 125.2, 128.8, 130.2, 130.6, 133.8, 135.0, 138.6, 150.0, 151.5, 154.3, 158.8, 160.8,
192.2. EI-MS 455 [M+H]+. Anal. calcd. For C20H11ClN4O3S2: C, 52.80; H, 2.44; N, 12.32
Found: C, 52.76; H, 2.40; N, 12.28.
Synthesis of 3-(3-(2-(4-nitrophenyl)-2-oxoethylthio)-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazol-6-yl)-2H-chromen-2-one (5d)
o
Yellow solid, yield 75%, 5h, m.p. 221-222 C. IR (KBr, cm-1): υ 1718 (lactone carbonyl
carbon of coumarin), 1698 (C=O), 1608 (C=N), 1566 (C=C), 1347 (NO2 ) . 1H NMR (400 MHz,
DMSO-d6): δ 4.92 (s, 2H, -SCH2CO–), 7.48-7.56 (m, 2H, ArH ), 7.82 (d, 1H, J=7.6Hz, ArH),
8.03 (d, 1H, J=7.6Hz, ArH), 8.22 (d, 2H, J=8.8Hz ArH), 8.35 (d, 2H, J=8.8Hz ArH) 8.96 (s, 1H,
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C-4 of coumarin ). EI-MS 466 [M+H]+. Anal. calcd. For C20H11N5O5S2: C, 51.61; H, 2.38; N,
15.05; Found: C, 51.54; H, 2.35; N, 15.12.
Synthesis of 3-(3-(2-oxo-2-p-tolylethylthio)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-6-
yl)- chromen-2-one (5e)
Yellow solid, yield 80%, 4h, m.p. 190-192 oC. IR (KBr, cm-1): υ 1721 (lactone carbonyl
carbon of coumarin), 1698 (C=O), 1605 (C=N), 1564(C=C). 1H NMR (400 MHz, DMSO-d6): δ
2.37 (s, 3H, CH3), 4.85 (s, 2H, -SCH2CO–), 7.34 (d, 2H, J=8.0Hz, ArH ), 7.46-7.60 (m, 2H,
ArH), 7.82–7.93 (m, 3H, ArH), 8.03 (d, 1H, J=8Hz, ArH), 8.96 (s, 1H, C-4 of coumarin). Anal.
calcd. For C21H14N4O3S2: C, 58.05; H, 3.25; N, 12.89; Found: C, 58.10; H, 3.28; N, 12.85.
Synthesis of 3-(3-(2-(4-methoxyphenyl)-2-oxoethylthio)- [1,2,4]triazolo [3,4-b]
[1,3,4]thiadiazol-6-yl)-2H-chromen-2-one (5f)
Yellow solid, yield 84%, 4h, m.p. 205-207 oC. IR (KBr, cm-1): υ 1723 (lactone carbonyl
1
carbon of coumarin), 1676 (C=O), 1598 (C=N), 1564 (C=C). H NMR (400 MHz, DMSO-d6): δ
3.84 (s, 3H, OCH3), 4.83 (s, 2H, -SCH2CO–), 7.04-7.06 (d, 2H, J=8.8Hz ArH ), 7.46-7.56 (m,
2H, ArH), 7.82 (s, 1H, ArH), 7.96–8.03 (m, 3H, ArH), 8.96 (s, 1H, C-4 of coumarin). Anal.
calcd. For C21H14N4O4S2: C, 55.99; H, 3.13; N, 12.44; Found: C, 55.91; H, 3.16; N, 12.48.
Synthesis of 3-(3-(2-(biphenyl-4-yl)-2-oxoethylthio)-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazol-6-yl)-2H-chromen-2-one (5g)
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o
Yellow solid, yield 75%, 5h, m.p. 207-209 C. IR (KBr, cm-1): υ 1722 (lactone carbonyl
1
carbon of coumarin), 1697 (C=O), 1603 (C=N), 1565 (C=C). H NMR (400 MHz, DMSO-d6): δ
4.92 (s, 2H, -SCH2CO–), 7.44-7.55 (m, 5H, ArH ), 7.75 (d, 2H, J= 8 Hz, ArH), 7.83 (t, 3H, J=
8.6 Hz, ArH), 8.02 (d, 1H, J= 8 Hz, ArH), 8.08 (d, 2H, J= 8.4 Hz, ArH), 8.99 (s, 1H, C-4 of
coumarin). 13C NMR (400 MHz, DMSO-d6 δ ppm): 40.4, 116.2, 116.9, 118.0, 125.2, 126.8,
126.9, 128.4, 129.0, 129.1, 130.6, 133.9, 135.0, 138.6, 150.0, 151.6, 154.3, 158.9, 160.8, 192.7.
Anal. calcd. For C26H16N4O3S2: C, 62.89; H, 3.25; N, 11.28; Found: C, 62.77; H, 3.28; N, 11.24.
Synthesis of 3-(3-(benzylthio)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-2H-
chromen-2-one (5h)
o
Red solid, yield 73%, 5h, m.p. 225-227 C. IR (KBr, cm-1): υ 1705 (lactone carbonyl
carbon of coumarin), 1603 (C=N), 1562 (C=C). 1H NMR (400 MHz, DMSO-d6): δ 4.50 (s, 2H, -
SCH2–), 7.22-7.33 (m, 5H, ArH ), 7.53 (d, 1H, J=7.6Hz, ArH), 7.60 (d, 1H J=8.4Hz, ArH), 7.82
(d, 1H, J=7.2Hz, ArH), 8.14 (d, 1H, J=8.0Hz ArH), 9.13 (s, 1H, C-4 of coumarin). Anal. calcd.
For C19H12N4O2S2: C, 58.15; H, 3.08; N, 14.28; Found: C, 58.18; H, 3.12; N, 14.32.
Synthesis of 3-(3-(3-nitrobenzylthio)-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazol-6-yl)-2H-
chromen-2-one (5i)
o
Red solid, yield 70%, 6h, m.p. 232-234 C. IR (KBr, cm-1): υ 1708(lactone carbonyl
1
carbon of coumarin), 1606 (C=N), 1563 (C=C), 1344 (NO2 ). H NMR (400 MHz, DMSO-d6): δ
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4.46 (s, 2H, -SCH2-), 7.53-7.64 (m, 4H, ArH ), 7.82 (s, 1H, ArH), 8.02 (d, 1H, J=6.0Hz ArH),
8.12–8.17 (m, 2H, ArH), 9.09 (s, 1H, C-4 of coumarin). Anal. calcd. For C19H11N5O4S2: C,
52.17; H, 2.53; N, 16.01; Found: C, 52.14; H, 2.58; N, 16.12.
Synthesis of 3-(3-(allylthio)-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-yl)-2H-chromen-
2-one (5j)
Red solid, yield 72%, 6h, m.p. >300 oC. IR (KBr, cm-1): υ 1708 (lactone carbonyl carbon
1
of coumarin), 1605 (C=N), 1562 (C=C). H NMR (400 MHz, DMSO-d6): δ 3.92 (d, 2H, J=7.2
Hz, -SCH2-), 5.13 (d, 1H, J=8.8 Hz, CH2 of allyl proton), 5.23 (d, 1H, J= 8 Hz, CH2 of allyl
proton), 5.99 (m, 1H, CH of allyl proton), 7.99–8.04 (m, 4H, ArH), 8.64 (s, 1H, C-4 of
coumarin). EI-MS 343 [M+H]+. Anal. calcd. For C15H10N4O2S2: C, 52.62; H, 2.94; N, 16.36;
Found: C, 52.58; H, 2.92; N, 16.31.
CONCLUSION
In conclusion we have developed an efficient regioselective approach for the synthesis of
3-(3-(phenacyl/alkyl/benzylthio)-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazol-6-yl)-2H-chromen-2-
ones in a simple procedure. The yields of the products are good in this synthesis.
AKNOWLEDGEMENT
We are thankful to CSIR-New Delhi for providing the financial assistance and to the
Director of NIT-Warangal for research facilities.
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N
N
N
N
N
S
S
N
N
N N
N
O
O
O
S
R1
POCl3
(4)
R1-Br
HS
SH
HS
N
OH
Anhydrous ethanol
NH2
O
O
O
O
3
1
2
R1-Br
5 a
- j
(4)
Anhydrous ethanol
R1
S
N
N
N
S
N
O
O
6 a-j
R1
5f
R1
5a Phenacyl
p-Methoxy phenacyl
p-Phenyl phenacyl
Benzyl
5b p-Bromo phenacyl 5g
5c p-Chloro phenacyl 5h
5d p-Nitro phenacyl
5e p-Methyl phenacyl 5j
5i
m-Nitro benzyl
Allyl
Scheme-1: Synthesis of 3-(3-(phenacyl/alkyl/benzylthio)-[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazol-6-yl)-2H-chromen-2-ones
Supplemental Materials
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Figure S 1: 13C NMR of 5a
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Figure S 2: 1H NMR of 5a
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Figure S 3: 1H NMR of 5d
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