Novel one-pot multicomponent synthesis of substituted 2,3-dihydro-2-(6-(4- hydroxy-6-methyl-2-oxo-2h-pyran-3-yl)-7h-[1,2,4]triazolo[3,4-b][1,3,4] thiadiazin-3-yl)phthalazine-1,4-diones and substituted 3-[3-(n′- benzylidene-hydrazino)-7h-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazin-6-yl]-4- hydroxy-6-methyl-pyran-2-ones

Article abstract of DOI:10.1080/00397911.2013.817584

A one-pot procedure has been developed for the synthesis of substituted 2,3-dihydro-2-(6-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7H-[1,2,4]triazolo[3, 4-b] [1,3,4]thiadiazin-3-yl)phthalazine-1,4-diones by reaction of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one, 4-amino-5-hydrazino-4H-[1, 2,4]triazole-3-thiol, and phthalic anhydrides in acetic acid medium. Similarly, a one-pot, three-component synthetic procedure has been developed for substituted 3-[3-(N¹-benzylidene-hydrazino)-7H-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazin-6-yl]-4-hydroxy-6-methyl-pyran-2-ones from 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one, 4-amino-5-hydrazino-4H-[1, 2,4]triazole-3-thiol, and various aromatic aldehydes in absolute ethanol and a few drops of glacial acetic acid.

Full text of DOI:10.1080/00397911.2013.817584

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Novel One-Pot Multicomponent
Synthesis of Substituted 2,3-Dihydro-2-
(6-(4-hydroxy-6-methyl-2-oxo-2H-
pyran-3-yl)-7H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazin-3-yl)phthalazine-1,4-
diones and Substituted 3-[3-(N′-
Benzylidene-hydrazino)-7H-[1,2,4]
Click for updates
triazolo[3,4-b][1,3,4]thiadiazin-6-yl]-4-
hydroxy-6-methyl-pyran-2-ones
Bade Thirupaiah a & Rajeswar Rao Vedula a
a Department of Chemistry , National Institute of Technology ,
Warangal , India
Published online: 27 Dec 2013.
To cite this article: Bade Thirupaiah & Rajeswar Rao Vedula (2014) Novel One-Pot Multicomponent
Synthesis of Substituted 2,3-Dihydro-2-(6-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7H-
[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-3-yl)phthalazine-1,4-diones and Substituted 3-[3-(N′-
Benzylidene-hydrazino)-7H-[1,2,4] triazolo[3,4-b][1,3,4]thiadiazin-6-yl]-4-hydroxy-6-methyl-pyran-2-
ones, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 44:4, 513-519, DOI: 10.1080/00397911.2013.817584
To link to this article: http://dx.doi.org/10.1080/00397911.2013.817584
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Synthetic Communications1, 44: 513–519, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.817584
NOVEL ONE-POT MULTICOMPONENT SYNTHESIS OF
SUBSTITUTED 2,3-DIHYDRO-2-(6-(4-HYDROXY-
6-METHYL-2-OXO-2H-PYRAN-3-YL)-7H-
[1,2,4]TRIAZOLO[3,4-b][1,3,4]THIADIAZIN-3-
YL)PHTHALAZINE-1,4-DIONES AND SUBSTITUTED
3-[3-(N’-BENZYLIDENE-HYDRAZINO)-7H-[1,2,4]
TRIAZOLO[3,4-b][1,3,4]THIADIAZIN-6-YL]-4-HYDROXY-
6-METHYL-PYRAN-2-ONES
Bade Thirupaiah and Rajeswar Rao Vedula
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
Abstract A one-pot procedure has been developed for the synthesis of substituted 2,3-
dihydro-2-(6-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7H-[1,2,4]triazolo[3,4-b] [1,3,4]-
thiadiazin-3-yl)phthalazine-1,4-diones by reaction of 3-(2-bromoacetyl)-4-hydroxy-6-
methyl-2H-pyran-2-one, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and phthalic
anhydrides in acetic acid medium. Similarly, a one-pot, three-component synthetic procedure
has been developed for substituted 3-[3-(N1-benzylidene-hydrazino)-7H-[1,2,4]triazolo
[3,4-b][1,3,4]thiadiazin-6-yl]-4-hydroxy-6-methyl-pyran-2-ones from 3-(2-bromoacetyl)-
4-hydroxy-6-methyl-2H-pyran-2-one, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and
various aromatic aldehydes in absolute ethanol and a few drops of glacial acetic acid.
Received March 23, 2013.
Address correspondence to Rajeswar Rao Vedula, Department of Chemistry, National Institute of
Technology, Warangal 506 004, India. E-mail: vrajesw@yahoo.com
513

514
B. THIRUPAIAH AND R. R. VEDULA
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resource(s):
Full experimental and spectral details.]
Keywords 4-Amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol; 3-(2-bromoacetyl)-4-hydroxy-
6-methyl-2H-pyran-2-one; 2,3-dihydrophthalazine-1,4-dione; Schiff base; triazolothiadiazine
INTRODUCTION
Multicomponent reactions have recently emerged as valuable tools in the
preparation of structurally diverse chemical libraries of drug-like heterocyclic com-
pounds.[1] Multicomponent reactions are well known to be selective, efficient,
atom-economical, time-saving, and easy to perform while requiring readily available
starting materials.[2] The [1,2,4]triazolo[3,4-b][1,3,4]thiadiazines possess antimicro-
bial activities.[3] The [1,2,4]triazolo[3,4-b][1,3,4]thiadiazine system is reported to
possess significant antibacterial, antifungal, herbicidal, and anthelmintic activities.[4,5]
[1,2,4]Triazolo[3,4-b][1,3,4]thiadiazine[6] is reported to show a broad spectrum of
pharmacological properties such as antitubercular,[7] diuretics,[8] and hypoglycaemic[9]
activities. 3,6-Disubstituted-7H-s-trizolo[3,4-b][1,3,4]thiadiazine derivatives were
prepared by condensing 4-amino-5-mecapto-3-alkyl=aryl-1,2,4-triazoles with substituted
a-halocarbonyl compounds.[10,11] Phthalazine has played a unique role in the design
and synthesis of novel biologically active compounds, serving as anticonvulsant,[12]
vasorelaxant,[13] anti-HIV,[14] PDE3=PDE4 inhibitory agents,[15] antiasthamatic,[16]
leishmanicidal,[17] and antidiabetic.[18] We designed the synthesis of novel substituted
1,2,4-triazolothiadiazine derivatives starting from bromodehydroacetic acid and 4-
amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol.
RESULTS AND DISCUSSION
4-Amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol (parpald) is a substrate for the
synthesis of diverse N,S-heterocycles by multicomponent reactions (MCRs). Most
interestingly, the outcomes of the final products from the MCRs involving 4-amino-5--
hydrazino-4H-[1,2,4]triazole-3-thiol are substrated dependent. Therefore, a one-pot,
three-component synthesis of triazolo thiadiazin-3-yl phthalazine1,4-dione was per-
formed with excellent yields. In this method, thiadiazine and 2,3-dihydrophthalazine-
1,4-dione rings were formed in one pot. Reaction of an equimolar mixture of
3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-one, 4-amino-5-hydrazino-4H-[1,2,
4]triazole-3-thiol, and phthalic anhydride in acetic acid gave the final products of
2,3-dihydro-2-(6-(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7H-[1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazin-3-yl)phthalazine-1,4-dione derivatives 4a and b (Scheme 1).
Similarly, reaction of an equimolar mixture of 3-(2-bromoacetyl)-4-hydroxy-
6-methyl-2H-pyran-2-one, 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol, and various
aromatic aldehydes in absolute ethanol and few drops of glacial acetic acid gave the final
products of 3-[3-(N1-benzylidene-hydrazino)-7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-
yl]-4-hydroxy-6-methyl-pyran-2-one derivatives 6 (Scheme 2). The reaction time along
with the yields of the products are given in Table 1.
A plausible mechanism for the formation of products 4 and 6 is proposed in
Scheme 2. In the first step, elimination of HBr from 1 and 2 will give an intermediate

ONE-POT MULTICOMPONENT SYNTHESIS
515
Scheme 1. Synthetic approach to compounds 4 and 6.
oxonium ion A. The nitrogen of NH2 of the ring attacks on the protonated corbonyl
carbon followed by loss of water molecule to give the intermediate C. This undergoes
cyclocondensation with phthalic anhydride to give an end product. Then C reacts
with carbocation of araldehyde to give an intermediate F. On loss of water molecule
and loss of proton, this gives the title products 6.
All the structures of newly synthesized compounds have been confirmed by
their spectral data. The infrared (IR) spectrum ofꢀc1ompound 4a showed promineꢀn1t
peaks at 1720 cmꢀ1 for –C O of lactone, 1641 cm for –C O of amide, 3260 cm
for –NH, and 3434 cmꢀ1 for –OH, whereas the 1H NMR spectrum of compound 4a
showed characteristic singlets for CH3 of pyran at d 2.31, CH2 of thiadiazine at d
4.47, CH of pyran at d 6.15, NH at d 10.30, and OH at d 12.84 ppm. Similarly,
the IR spectrum of compound 6a showed prominent peaks at 1738 cmꢀ1 for
=
=
–C O of lactone, 3230 cmꢀ1 for –NH, and 3435 cmꢀ1 for –OH. The 1H NMR spec-
=
trum of compound 6a showed charecteristic singlets for CH3 of pyran at d 2.22,
=
Ar-OCH3 at d 3.86, CH2 of thiadiazine at d 4.48, CH of pyran at d 6.15, Ar-CH N
at d 8.25, NH at d 10.77, and OH at d 12.90 ppm. All these spectral data clearly con-
firm the formation of products 4a and b and 6a–j.
CONCLUSION
In conclusion, we have developed a facile and efficient one-pot, three-
component protocol for the synthesis of novel substituted [1,2,4]triazolo-
[3,4-b][1,3,4]thiadiazin derivatives. This reaction proceeded smoothly in good to
excellent yields. In all cases, the products can be purified by simple recrystallization.
EXPERIMENTAL
All the chemicals used in this work were purchased from commercial
sources. Melting points were determined with an Electrothermal-9100 apparatus.

516
B. THIRUPAIAH AND R. R. VEDULA
Scheme 2. Reaction mechanism of final compounds 4 and 6.
The purity of the compounds was checked by thin-layer chromatography (TLC)
plates (E. Merck Mumbai, India). IR spectra (KBr) were recorded on a Perkin-
1
Elmer 100 S spectrometer. H NMR spectra were recorded on a Bruker WM-400

ONE-POT MULTICOMPONENT SYNTHESIS
517
Table 1. Synthesis of final products (4 and 6)
Entry
R1
R2
R3
R4
Product
Time (h)
Yield (%)
1
2
H
Br
H
H
Br
H
Br
H
Br
—
—
—
—
—
—
—
—
—
—
4a
4b
6a
6b
6c
6d
6e
6f
8
9
9
8
9
8
8
9
9
9
9
9
75
80
75
80
78
75
85
75
70
65
75
70
3
H
OCH3
Br
Cl
4
H
H
5
H
H
6
H
H
N(CH3)2
OCH3
H
7
H
OCH3
NO2
OCH3
H
8
H
9
H
OH
OH
OH
H
6g
6h
6i
10
11
12
OH
H
H
OH
H
6j
1
spectrometer in d ppm using tetramethylsilane (TMS) as the standard. H and 13C
NMR spectra were obtained in dimethylsulfoxide (DMSO) using TMS as reference
standard (d in parts per million, J in hertz). Electron ionization mass spectra
(EI-MS) were determined on a Perkin-Elmer instrument (SCIEX API-2000, ESI)
at 12.5 eV.
General Procedure for the One-Pot Synthesis of 2,3-Dihydro-2-(6-
(4-hydroxy-6-methyl-2-oxo-2H-pyran-3-yl)-7H-[1,2,4]-triazolo
[3,4-b][1,3,4]thiadiazin-3-yl)phthalazine-1,4-dione (4a)
An equimolar mixture of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-
2-one (1.0 mmol), 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol (1.0 mmol), and
phthalic anhydride (1.0 mmol) was taken in glacial acetic acid. The reaction mixture
was heated at 80 ꢁC for about 8 h and cooled to room temperature. The solid
obtained was filtered, washed with water, and recrystallized from ethanol. Light
yellow solid (0.318 g, 75%); mp 209–211 ꢁC; IR (KBr) (tmax=cmꢀ1): 3434, 3260,
1
1720, 1641; H NMR (400 MHz, DMSO-d6) 2.31 (s, 3H, CH3), 4.47 (s, 2H, CH2),
6.15 (s, 1H, CH), 7.62 (d, 2H, J ¼ 7.2 Hz, ArH), 7.78 (d, 2H, J ¼ 7.6 Hz, ArH),
10.30 (s, 1H, NH), 12.84 (s, 1H, OH). 13C NMR (400 MHz, DMSO-d6) 22.1, 25.3,
99.3, 102.0, 121.2, 127.9, 128.7, 133.5, 136.1, 142.5, 149.4, 161.0, 164.4, 174.5. Mass
spectrum m=z: 425 (M þ H). Anal. calcd. for C18H12N6O5S: C, 50.94; H, 2.85; N,
19.80; Found: C, 50.90; H, 2.80; N, 19.75.
General Procedure for the One-Pot Synthesis of 4-Hydroxy-3-f3-
[N1-(4-methoxy-benzylidene)-hydrazino]-7H-[1,2,4]triazolo[3,4-b]
[1,3,4]thiadiazin-6-ylg-6-methyl Pyran-2-one (6a)
Equimolar mixture of 3-(2-bromoacetyl)-4-hydroxy-6-methyl-2H-pyran-2-
one (1.0 mmol), 4-amino-5-hydrazino-4H-[1,2,4]triazole-3-thiol (1.0 mmol), and
4-methoxybenzaldehyde (1.0 mmol) was taken in absolute ethanol containing
a catalytic amount of acetic acid. The reaction mixture was heated at 60–65 ꢁC for
about 9 h and cooled to room temperature. The solid obtained was filtered, washed

518
B. THIRUPAIAH AND R. R. VEDULA
with water, and recrystallized from ethanol. Yellow solid (0.309 g, 75%); mp
204–206 ꢁC; IR (KBr) (tmax=cmꢀ1): 3435, 3230, 1738; 1H NMR (400 MHz,
DMSO-d6) 2.22 (s, 3H, CH3), 3.86 (s, 3H, OCH3), 4.48 (s, 2H, CH2), 6.12 (s, 1H,
CH), 6.97 (d, 2H, J ¼ 8.4 Hz, ArH), 7.55 (d, 2H, J ¼ 8.8 Hz, ArH), 8.25 (s, 1H,
CH), 10.46 (s, 1H, NH), 12.90 (s, 1H, OH). 13C NMR (400 MHz, DMSO-d6)
22.2, 24.9, 55.2, 108.7, 114.2, 114.4, 124.9, 127.3, 127.8, 130.8, 144.0, 149.6, 153.3,
160.1, 164.3, 174.9. Mass spectrum m=z: 411 (M-H). Anal. calcd. for C18H16N6O4S:
C, 52.42; H, 3.91; N, 20.38. Found: C, 52.36; H, 3.96; N, 20.34.
ACKNOWLEDGMENT
The authors are thankful to the director of the National Institute of
Technology, Warangal, A. P., India, for providing financial support and facilities.
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