Molecular iodine mediated one step synthesis of 3-substituted-6-(6- substituted-2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines

Article abstract of DOI:10.3184/030823410X12715064952719

Iodine mediated condensation of 3-acetyl-6-substitutedcoumarin (1) with 3-alkyl/aryl-4-amino-5-mercapto[1,2,4]triazoles (2) have been found to give 3-alkyl/aryl-6-(6-substituted-2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4] thiadiazines (3a-n) directly in one step. The reaction has also been carried out using microwave irradiation. This protocol is an improvement on reported methods as it occurs in a single step and avoids the use of highly lachrymatory molecular bromine.

Full text of DOI:10.3184/030823410X12715064952719

238 RESEARCH PAPER
APRIL, 238–240
JOURNAL OF CHEMICAL RESEARCH 2010
Molecular iodine mediated one step synthesis of 3-substituted-6-(6-
substituted-2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines
Anshu Jakhar and Jagdish K. Makrandi*
Department of Chemistry, Maharshi Dayanand University, Rohtak- 124001(Haryana), India
Iodinemediatedcondensationof3-acetyl-6-substitutedcoumarin(1)with3-alkyl/aryl-4-amino-5-mercapto[1,2,4]triazoles
(2)havebeenfoundtogive3-alkyl/aryl-6-(6-substituted-2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines
(3a–n) directly in one step. The reaction has also been carried out using microwave irradiation. This protocol is an
improvement on reported methods as it occurs in a single step and avoids the use of highly lachrymatory molecular
bromine.
Keywords: 6-(6-substituted-2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines, molecular iodine, 3-acetylcoumarin
Coumarins are a class of naturally occurring compounds that
exhibit diverse pharmacological activities. Enormous number
of compounds bearing coumarin system in their structure have
been synthesised and these derivatives have shown a remark-
ably broad spectrum of pharmacological activities and they
have been used as anticoagulant,1–3 antibacterial,4,5 antiviral,6,7
antitumor,8–11 bactericidal,12 fungicidal13 and anti-inflamma-
tory agents.14 Also, in recent times there are reports regarding
anti-HIV activity15–18 of coumarin derivatives. Coumarins
linked with nitrogen/nitrogen and sulfur heterocyclic units
at 3-position are well known to exhibit spasmolytic,19
uricosuric,19 anticancer20 and antitubercular activitiy.21
Few reports have appeared regarding the synthesis and
biological importance of variously substituted 2-oxochromen-
3-yl-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines.22–26 All these
methods involve the conversion of 3-acetylcoumarins into 3-
(2-bromoacetyl)coumarins prior to their reaction with vari-
ously substituted 4-amino-5-mercapto[1,2,4]triazoles, hence
the reaction takes place in two steps. The first step involves the
use of molecular bromine which is highly corrosive and
the bromoacetyl derivatives formed is quite lachrymatory.
We now report a highly efficient one-step synthesis of 3-alkyl/
aryl-6-(6-substituted-2-oxochromen-3-yl)-7H[1,2,4]
triazolo[3,4-b][1,3,4]thiadiazines by direct condensation of 3-
acetylcoumarins with 4-amino-3-alkyl/aryl-5-mercapto[1,2,4]
triazoles in the presence of molecular iodine. 4-Amino-5-
mercapto[1,2,4]triazole (1) was refluxed with 3-acetylcouma-
rin (2) in absolute ethanol in the presence of molecular iodine
in catalytic quantity. On working up the reaction mixture, a
colourless solid, m.p. 218–220 °C, was obtained in 65% yield.
Its IR spectra showed absorption at 1717 cm−1 due to the C=O
stretching frequency of the lactone ring of coumarin, absorp-
tion at 1604 cm−1 due to C=N stretching present in the ring
showing cyclic structure. In the 1H NMR spectra, it showed a
singlet for two protons at δ 4.20 was assigned to S–CH group
which further confirmed the cyclic structure. Based 2on the
above data, the compound was assigned the structure as (2-
oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines
(3a). The reaction between 4-amino-5-mercapto[1,2,4]triazole
(1) was refluxed with 3-acetylcoumarin (2) was also carried
out using microwave irradiations in dimethylformamide
(Scheme 1). The time required for the completion of the reac-
tion was found to be much shorter (100 s) as compared to time
under thermal conditions (4.0 h) and the required compounds
are obtained in better yields. Comparison of time and yield in
the thermal and microwave method is given in Table 1.
In conclusion, it can be stated that the present protocol
is highly efficient one and avoids the prior conversion of
3-acetylcoumarins into 3-(2-bromoacetyl)coumarins which
are quite lachrymatory and difficult to handle.
Scheme 1
* Correspondent. E-mail: jkmakrandi_chem@rediffmail.com

JOURNAL OF CHEMICAL RESEARCH 2010 239
Table 1 Comparison of time and yield under thermal and
CH2CH2CH3), 2.55–2.59 (t, 2H, CH2CH CH3), 4.17 (s, 2H, SCH ),
7.37–7.41 (m, 2H, H5′, 6′), 7.65–7.73 (m, 22H, H7′, 8′), 8.44 (s, 1H, H4′)2.
6-(6-Methyl-2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (3e): M.p. 158–161 °C. IR (KBr) (cm−1): 1720 (C=O),
1605 (C=N), 1560 (C=C), 1496 (C–N). 1H NMR (DMSO-d6): δ 2.44
(s, 3H, CH3), 4.12 (s, 2H, SCH2), 7.31–7.49 (m, 3H, H5′, 7′, 8′), 8.27
(s, 1H, H4’), 8.68 (s, 1H, H3). Anal. Calcd for C14H10N O2S : C, 56.36;
H, 3.37; N, 18.78. Found: C, 56.24; H, 3.26; N, 18.914%.
microwave methods
Comp. R1
R2
Thermal method MW irradiation
%Yield/Time (h) %Yield/Time (s)
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
H
CH3
C2H5
C3H7
H
CH3
C2H5
C3H7
2-OHC6H4
3-CH3C6H4
4-ClC6H4
2-OHC6H4
3-CH3C6H4 CH3
4-ClC6H4 CH3
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
65/4.0
59/4.5
60/5.0
63/4.0
65/3.5
64/3.0
67/3.0
66/3.5
75/5.0
70/7.5
80/6.0
87/1.5
75/4.0
85/3.0
82/100
83/90
81/90
82/80
80/70
78/75
81/60
83/65
88/20
82/30
88/35
92/20
83/25
90/30
3-Methyl-6-(6-methyl-2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine (3f): M.p. 120–122 °C. IR (KBr) (cm−1): 1728
(C=O), 1617 (C=N), 1565 (C=C), 1502 (C–N). 1H NMR (DMSO-d6):
δ 2.46 (s, 3H, CH ), 2.58 (s, 3H, CH ), 4.12 (s, 2H, SCH2), 7.29–7.42
(m, 3H, H5′, 7′, 8′),3 8.29 (s, 1H, H4’)3. Anal. Calcd for C H12N4O S:
C, 57.68; H, 3.87; N, 17.93. Found: C, 57.58; H, 3.76; N,1158.02%.2
3-Ethyl-6-(6-methyl-2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine (3g): M.p. 112–114 °C. IR (KBr) (cm−1): 1722
(C=O), 1610 (C=N), 1570 (C=C), 1495 (C–N). 1H NMR (DMSO-d6):
δ 1.42–1.45 (t, 3H, CH2CH3, J = 8.64 Hz), 2.47 (s, 3H, CH3), 3.07–
3.12 (q, 2H, CH CH3, J = 8.64 Hz), 4.20 (s, 2H, SCH2), 7.27–7.32
(m, 3H, H5′, 7′, 8′)2, 8.32 (s, 1H, H4’). Anal. Calcd for C H14N4O S:
C, 58.88; H, 4.32; N, 17.16. Found: C, 58.84; H, 4.20; N,1167.31%.2
6-(6-Methyl-2-oxochromen-3-yl)-3-n-propyl-7H[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazine (3h): M.p. 150–152 °C. IR (KBr) (cm−1):
1721 (C=O), 1614 (C=N), 1568 (C=C), 1501 (C–N). 1H NMR
(DMSO-d6): δ 1.01–1.05 (t, 3H, CH2CH CH ), 1.80–1.89 (h, 2H,
CH2CH CH3), 2.49 (s, 3H, CH ), 2.88–2.952(t, 23H, CH2CH CH ), 4.06
(s, 2H, 2SCH2), 7.29–7.44 (m,3 3H, H5′, 7′, 8′), 8.29 (s, 1H, 2H4’)3. Anal.
Calcd for C H N4O S : C, 59.98; H, 4.73; N, 16.45. Found: C, 59.84;
H, 4.56; N,1176.1663%. 2
6-(2-Oxochromen-3-yl)-3-(2-hydroxyphenyl)-7H[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazine (3i): M.p. 275–279 °C (lit.24 282–284 °C).
IR (KBr) (cm-1): 1720 (C=O), 1606 (C=N), 1552 (C=C), 1505 (C–N).
1H NMR (DMSO-d6): δ 4.14 (s, 2H, SCH2), 6.90–7.72 (m, 7H,
H5′, 6′, 7′, 8′, 3′′, 4′′, 5′′), 8.15-8.17 (dd, 1H, H6′′, J = 1.6 and 8.08 Hz), 8.42
(s, 1H, H4’), 11.57 (s, 1H, OH).
6-(2-Oxochromen-3-yl)-3-(3-methylphenyl)-7H[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine (3j): M.p. 245–246 °C. IR (KBr) (cm−1): 1718
(C=O), 1614 (C=N), 1570 (C=C), 1501 (C–N). 1H NMR (DMSO-d6):
δ 2.44 (s, 3H, CH3) 4.17 (s, 2H, SCH ), 7.31–7.44 (m, 4H,
H5′, 6′, 7′, 8′),7.67–7.72 (m, 2H, H4′′, 5′′), 7.80–7.821 (dd, 1H, H , J = 1.64
and 7.68 Hz), 7.88 (s, 1H, H2′′), 8.39 (s, 1H, H4’). Ana6l′.′Calcd for
C H N O2S requires: C, 64.15; H, 3.76; N, 14.96. Found: C, 64.03;
H2,03.1542;4N, 15. 22%.
CH3
Experimental
General procedure
All the melting points were determined in open capillary tubes
using liquid paraffin bath and are uncorrected. IR spectra (KBr) were
1
recorded in Perkin-Elmer spectrophotometer, H NMR on Bruker
Avance II 400 MHz spectrometer and elemental analysis on Perkin-
Elmer 2400 CHN elemental analyser. All the solvents were distilled
and dried according to the literature procedures.
The 4-amino-3-alkyl/aryl-5-mercapto[1,2,4]triazoles27,28 and 3-
acetylcoumarin29 were prepared according to literature procedures.
Synthesis of 3-alkyl/aryl-6-(6-substituted-2-oxochromen-3-yl)-7H
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazines (3a–n); general procedure
1. Under thermal conditions
A mixture of 4-amino-5-mercapto[1,2,4]triazole (5 mmol), 3-acetyl-
coumarin (5 mmol) and I2 (0.42 mmol) in absolute ethanol (25 mL)
was refluxed on the water bath in a 100 mL round bottom flask. The
progress of the reaction was checked on TLC. The reaction mixture
was cooled and poured on crushed ice when solid separates out. The
solid was filtered under suction, washed with water and recrystallised
from DMF–ethanol (2:3).
3-(4-Chlorophenyl)-6-(2-oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazine (3k): M.p. 224–227 °C (lit.24 226–228 °C). IR
(KBr) (cm−1): 1722 (C=O), 1608 (C=N), 1565 (C=C), 1495 (C–N). 1H
NMR (DMSO-d6): δ 4.15 (s, 2H, SCH2), 7.38–7.47 (m, 4H, H5′, 6′, 7′, 8′),
7.65–7.72 (m, 2H, H3′′, 5′′), 8.02–8.04 (m, 2H, H ) 8.35 (s, 1H, H4’).
3-(2-Hydroxyphenyl)-6-(6-methyl-2-oxochr2o′′,m6′′en-3-yl)-7H[1,2,4]
triazolo[3,4-b][1,3,4] thiadiazine (3l): M.p. >250 °C. IR (KBr)
(cm−1): 1721 (C=O), 1607 (C=N), 1562 (C=C), 1503 (C–N). 1H NMR
(DMSO-d6): δ 2.58 (s, 3H, CH3), 4.24 (s, 2H, SCH ), 7.22–7.43 (m,
3H, H5′, 7′, 8′), 7.92–8.28 (m, 3H, H3′′, 4′′, 5′′), 8.24–8.226 (dd, 1H, H6′′,
J = 1.64 and 8.12 Hz), 8.48 (s, 1H, H ), 11.42 (s, 1H, OH). Anal.
Calcd for C H N4O S: C, 61.52; H, 3.641’; N, 14.35. Found: C, 61.35;
H, 3.32; N, 2104.1543%. 3
6-(6-Methyl-2-oxochromen-3-yl)-3-(3-methylphenyl)-7H[1,2,4]
triazolo[3,4-b][1,3,4] thiadiazine (3m): M.p. 211–213 °C. IR (KBr)
(cm−1): 1726 (C=O), 1615 (C=N), 1568 (C=C), 1501 (C–N). 1H NMR
(DMSO-d6): δ 2.44 (s, 6H, 2×CH3), 4.26 (s, 2H, SCH2), 7.30–7.42
(m, 3H, H5′, 7′, 8′), 7.50–7.52 (m, 2H, H4′′, 5′′), 7.82–7.84 (dd, 1H, H6′′,
J = 1.60 and 7.64 Hz), 7.87 (s, 1H, H2′′), 8.40 (s, 1H, H4’). Anal. Calcd
for C H N O2S requires: C, 64.93; H, 4.15; N, 14.42. Found:
C, 64.2716;1H6 ,43.97; N, 14. 62%.
2. Under microwave irradiations
A
mixture of 4-amino-5-mercapto[1,2,4]triazole (1 mmol), 3-
acetylcoumarin (1 mmol) and I2 (0.042 mmol) in DMF (5 mL) was
taken in a loosely stoppered 20 mL round bottom flask and was irradi-
ated in a Samsung Trio CE1031LFB microwave oven at 160 °C and
400 W for 100 s. The completion of reaction was checked on TLC.
The reaction mixture was diluted with ice cold water (20 mL), when
a solid separated out which was filtered, washed with water and
recrystallized from DMF–ethanol (2:3).
The physical and spectral data of the compounds 3a–n are as
follows:
6-(2-Oxochromen-3-yl)-7H[1,2,4]triazolo[3,4-b][1,3,4]thiadiazine
(3a): M.p. 218–220 °C (lit.24 216–218 °C). IR (KBr) (cm−1): 1717
(C=O), 1604 (C=N), 1549 (C=C), 1494 (C–N). 1H NMR (DMSO-d6):
δ 4.20 (s, 2H, SCH2), 7.40–7.44 (m, 2H, H5′, 6′), 7.69–7.75 (m, 2H,
H
), 8.47 (s, 1H, H4’), 8.71 (s, 1H, H3).
76′, 8-′(2-Oxochromen-3-yl)-3-methyl-7H[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (3b): M.p. 244–246 °C (lit.24 250–252 °C). IR (KBr)
(cm−1): 1715 (C=O), 1620 (C=N), 1578 (C=C), 1506 (C–N). 1H NMR
(DMSO-d6): δ 2.59 (s, 3H, CH ), 4.11 (s, 2H, SCH2), 7.40–7.44
(m, 2H, H5′, 6′), 7.69–7.75 (m, 2H,3H7′, 8′), 8.43 (s, 1H, H4’).
3-(4-Chlorophenyl)-6-(6-methyl-2-oxochromen-3-yl)-7H[1,2,4]
triazolo[3,4-b][1,3,4] thiadiazine (3n): M.p. 244–246 °C. IR (KBr)
(cm−1): 1720 (C=O), 1609 (C=N), 1560 (C=C), 1502 (C–N). 1H NMR
(DMSO-d6): δ 2.44 (s, 3H, CH ), 4.14 (s, 2H, SCH2), 7.32–7.51
6-(2-Oxochromen-3-yl)-3-ethyl-7H[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (3c): M.p. 208–210 °C (lit.24 211–213 °C). IR (KBr)
(cm−1): 1725 (C=O), 1606 (C=N), 1563 (C=C), 1510 (C–N). 1H NMR
(DMSO-d6): δ 1.43–1.47 (t, 3H, CH CH3, J = 8.60 Hz), 3.05–3.10
(q, 2H, CH2CH3, J = 8.60 Hz), 4.225 (s, 2H, SCH2), 7.41–7.45
(m, 2H, H5′, 6′), 7.70–7.75 (m, 1H, H7′), 7.78–7.80 (m, 1H, H8′), 8.51
(s, 1H, H ).
(m, 5H, H5′, 7′, 8′, 3′′ and 5′′), 8.01–8.033(m, 2H, H
) 8.29 (s, 1H, H4’).
Anal. Calcd for C H N O SCl: C, 58.75; H2,′′3an.d260′′; N, 13.70. Found:
C, 58.53; H, 2.95;2N0 ,1133.4922%.
6-(2-O4x′ochromen-3-yl)-3-n-propyl-7H[1,2,4]triazolo[3,4-b][1,3,4]
thiadiazine (3d): M.p. 196–199 °C (lit.24 198–200 °C). IR (KBr)
(cm−1): 1721 (C=O), 1611 (C=N), 1564 (C=C), 1493 (C–N). 1H NMR
(DMSO-d6): δ 0.98–1.00 (t, 3H, CH2CH2CH3), 1.66–1.75 (h, 2H,
The authors thank RSIC-SAIF, Punjab University, Chandigarh
for recording IR, NMR and microanalysis of the compounds.
A.J. also thanks UGC New Delhi for financial support.

240 JOURNAL OF CHEMICAL RESEARCH 2010
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Received 4 February 2010; accepted 13 April 2010
Paper 100991 doi: 10.3184/030823410X12715064952719
Published online: 30 April 2010
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