Synthesis of aryl and heteryl 1,3,4-thiadiazinyl-phthalazine-1,4-dione derivatives via a multicomponent approach

Article abstract of DOI:10.1080/00397911.2011.604147

An expeditious one-pot method has been developed for the synthesis of aryl, heteryl thiadiazinyl-phthalazine-1,4-diones via a multicomponent approach. Reaction of phenacyl bromides with thiocarbohydrazide and phthalic anhydride afforded corresponding aryl thiadiazinyl-phthalazine-1,4-diones. Similarly, reaction of 3-(2-bromoacetyl)coumarins with thiocarbohydrazide and phthalic anhydride afforded required heteryl thiadiazinyl-phthalazine-1,4-diones under the same reaction conditions in excellent yields. The structure of all the synthesized compounds was confirmed from their analytical and spectral data.

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Synthesis of Aryl and Heteryl 1,3,4-
Thiadiazinyl-phthalazine-1,4-dione
Derivatives via a Multicomponent
Approach
Venkata Sreenivasa Rao Chunduru a & Vedula Rajeswar Rao a
a Department of Chemistry, National Institute of Technology,
Warangal, India
Accepted author version posted online: 13 Feb 2012.Version of
record first published: 07 Jan 2013.
To cite this article: Venkata Sreenivasa Rao Chunduru & Vedula Rajeswar Rao (2013): Synthesis of
Aryl and Heteryl 1,3,4-Thiadiazinyl-phthalazine-1,4-dione Derivatives via a Multicomponent Approach,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:7, 923-929
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Synthetic Communications1, 43: 923–929, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.604147
SYNTHESIS OF ARYL AND HETERYL
1,3,4-THIADIAZINYL-PHTHALAZINE-1,4-DIONE
DERIVATIVES VIA A MULTICOMPONENT APPROACH
Venkata Sreenivasa Rao Chunduru and Vedula Rajeswar Rao
Department of Chemistry, National Institute of Technology, Warangal, India
GRAPHICAL ABSTRACT
Abstract An expeditious one-pot method has been developed for the synthesis of aryl, heteryl
thiadiazinyl-phthalazine-1,4-diones via a multicomponent approach. Reaction of phenacyl bro-
mides with thiocarbohydrazide and phthalic anhydride afforded corresponding aryl
thiadiazinyl-phthalazine-1,4-diones. Similarly, reaction of 3-(2-bromoacetyl)coumarins with
thiocarbohydrazide and phthalic anhydride afforded required heteryl thiadiazinyl-phthalazine-
1,4-diones under the same reaction conditions in excellent yields. The structure of all the
synthesized compounds was confirmed from their analytical and spectral data.
Keywords 3-(2-Bromoacetyl)coumarins; one-pot reaction; phenacyl bromides; phthalic
anhydride; thiocarbihydrazide
INTRODUCTION
Phthalazine derivatives have been widely used as therapeutic agents because of
their anticonvulsant, vasorelaxant, anti-inflammatory, antipyretic, antihypertensive,
and bronchodilatory effects.[1–3] In derivatives of phthalazines, 2,3-dihydro-
phthalazine-1(4H), 4-diones are very important class of intermediates in the
synthesis of drug molecules such as the antihypertensive agent dihydralazine
(1,4-dihydrazinophthalazine).[4] Phthalazinediones are usually obtained by conden-
sation of appropriate phthalic acid derivatives such as esters or anhydrides with
hydrazine.[5]
Received May 15, 2011.
Address correspondence to Vedula Rajeswar Rao, Department of Chemistry, National Institute of
Technology, Warangal 506004, India. E-mail: vrajesw@yahoo.com
923

924
V. S. R. CHUNDURU AND V. R. RAO
Moreover, these compounds have attracted considerable attention because
they exhibit interesting chemiluminescence phenomena,[6] they have pronounced
dienophilic properties,[7] and they can be used as precursors for the preparation of
benzocyclobutene-1,2-diones, which, in turn, represent useful synthons.[8] Similarly,
heterocycles containing a phthalazine moiety also show some pharmacological and
biological activities.[9–11] Some examples are [1,2,3]triazolo[4,5-g]phthalazine-4,
9-diones,[12] pyrazolo[1,2-b]phthalazines,[13,14] and [5,6]benza-3a,7a-diazaindanes.[15]
1,3,4-Thiadiazines were biologically active compounds. Many of these deriva-
tives were important matrix metalloproteinase inhibitors.[16] They have shown excel-
lent cardiotonic and hypertensive activities.[17,18] They act as phosphodiesterase IV
inhibitors and may be used for treatment of tumors and acquired immune deficiency
syndrome (AIDS).[19] These derivatives may be used in agriculture as pesticides and
insecticides.[20] Some of these derivatives act as photographic magenta couplers.[21]
Based on these results and as a part of our research program in the synthesis of
novel heterocyclic systems,[22–24] we report the synthesis of a novel heterocyclic
system, 1,3,4-thiadiazinyl-phthalazine-1,4-dione, via multicomponent approach.
RESULTS AND DISCUSSION
Reaction of an equimolar mixture of phenacyl bromide, thiocarbohydrazide,
and phthalic anhydride in anhydrous ethanol and a catalytic amount of acetic acid
at 60–65 ꢀC gave
a novel bicyclic ring system, 2,3-dihydro-2-(5-aryl-6H-
1,3,4-thiadiazin-2-yl)phthalazine-1,4-diones (4a–f), in good yields (Scheme 1). In this
one-pot reaction, two heterocyclic ring systems (thiadiazine and phthalazine-1,4-
dione) were developed simultaneously. In the formation of products, it is believed
that the thiocarbohydrazide first reacts with phenacyl bromide to give an uncyclized
intermediate by the elimination of HBr, which further undergoes cyclization by elim-
inating water to give hydrazino-thiadiazine derivative. This, on reaction with phtha-
lic anhydride, gave 1,3,4-thiadiazinyl-phthalazine-1,4-dione in good yields. The
structure of the compounds was confirmed from their analytical and spectral data.
For example, the infrared (IR) spectrum of compound 4b showed two strong
absorption peaks at 3233 cmꢁ1 and 1663 cmꢁ1 for NH and amide carbonyl respect-
ively. The 1H NMR spectrum of compound 4b showed sharp singlets at d 2.35 and d
3.95 for methyl and methelene of thiadiazine, respectively. A broad singlet at for NH
is also observed at d 8.76, which is exchangeable with D2O. These spectral data
clearly prove the structures of the products 4a–f.
Scheme 1. Synthesis of 2,3-dihydro-2-(5-aryl-6H-1,3,4-thiadiazin-2-yl)phthalazine-1,4-diones. 4a: R ¼ Cl;
4b: R ¼ Me; 4c: R ¼ OMe; 4d: R ¼ H; 4e: R ¼ NO2; and 4f: R ¼ Ph.

PHTHALAZINE-1,4-DIONE DERIVATIVES
925
Scheme 2. One-pot synthesis of 2,3-dihydro-2-(5-(2-oxo-2H-chromen-3-yl)-6H-1,3,4-thiadiazin-2-
yl)phthalazine-1,4-diones. 6a: R1 ¼ R2 ¼ H; 6b: 5,6-benzoanalouge of 6a; 6c: R1 ¼ H, R2 ¼ Cl; 6d:
R1 ¼ R2 ¼ Cl; and 6e: R1 ¼ R2 ¼ Br.
These results encouraged us to test this one-pot reaction with
3-(2-bromoacetyl)coumarin in place of phenacyl bromides. Reaction of an equimolar
mixture of 3-(2-bromoacetyl)coumarin, thiocarbohydrazide, and phthalic anhydride in
anhydrous ethanol and catalytic amount of acetic acid at 60–65ꢀC also gave a novel tri-
cyclic ring system, 2,3-dihydro-2-(5-(2-oxo-2H-chromen-3-yl)-6H-1,3,4-thiadiazin-2-
yl)phthalazine-1,4-diones (6a–e), in good yields (Scheme 2). The IR spectrum of com-
pound 6a showed absorption peaks at 3443 cmꢁ1, 1729 cmꢁ1, and 1680 cmꢁ1 attributed
to NH, lactone carbonyl, and amide carbonyl, respectively. The 1H NMR spectrum of
compound 6a also showed sharp singlets at d 3.96 and d 8.25 for methylene of thiadia-
zine ring and C-4 proton of comarin and a broad singlet is observed at d 8.33 for NH,
which is exchangeable with D2O.
In conclusion, we have developed a one-pot reaction for the synthesis of aryl
and heteryl 1,3,4-thiadiazinyl-phthalazine-1,4-dione derivatives via a multicompo-
nent approach using readily available starting materials. These highly functionalized
derivatives may be of interest for pharmaceutical purposes yet to be explored.
EXPERIMENTAL
All the reagents and solvents were pure, purchased from commercial
sources, and used without further purification unless otherwise stated.
3-(2-Bromoacetyl)coumarins[25] were prepared according to literature procedure.
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. Merck Mumbai,
India). IR spectra (KBr) were recorded on a Bruker Optics (model Tensor 27) spec-
1
trometer. H NMR spectra were recorded on a Bruker WM-400 spectrometer in d
ppm using tetramethylsilane (TMS) as standard. Mass spectra (ESI-MS) were
determined on a Perkin-Elmer (SCIEX API-2000, ESI) at 12.5 ev.
General Procedure for the Synthesis of Aryl and Heteryl
1,3,4-Thiadiazinyl-phthalazine-1,4-diones
An equimolar mixture of phenacyl bromide or 3-(2-bromoacetyl)coumarin,
thiocarbohydrazide, and phthalic anhydride was taken in anhydrous ethanol

926
V. S. R. CHUNDURU AND V. R. RAO
containing a catalytic amount of acetic acid. The reaction mixture was heated at
60–65 ꢀC for about 2–3 h and cooled to room temperature. The yellow solid obtained
was filtered, washed with water, and recrystallized from aqueous ethanol.
2-(5-(4-Chlorophenyl)-6H-1,3,4-thiadiazin-2-
yl)-2,3-dihydrophthalazine-1,4-dione (4a)
Yield 70%; mp 271–273 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3423 (NH), 1656
1
=
=
(amide, ꢁC O), 1597 (ꢁC N); H NMR (400 MHz, CDCl3): d 3.74 (s, 2H, CH2),
7.40–7.67 (m, 4H, ArH), 7.71–7.88 (m, 4H, ArH), 8.74 (s, 1H, NH, D2O exchange-
able); ESI-MS 370 [Mþ]; 13C NMR (CDCl3 þ DMSO-d6): 22.6, 109.8, 116.3, 121.6,
125.2, 128.1, 129.0, 130.7, 131.0, 136.5, 137.2, 139.1, 149.2, 157.9, 167.4. Anal. calcd.
for C17H11ClN4O2S: C, 55.06; H, 2.99; N, 15.11, Found: C, 54.96; H, 2.94; N,
15.15%.
2,3-Dihydro-2-(5-p-tolyl-6H-1,3,4-thiadiazin-2-
yl)phthalazine-1,4-dione (4b)
Yield 78%; mp > 300 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3232 (NH), 1663
1
=
=
(amide, ꢁC O), 1598 (ꢁC N); H NMR (400 MHz, CDCl3): d 2.35 (s, 3H, Me),
3.95 (s, 2H, CH2), 7.14–7.18 (m, 2H, ArH), 7.60–7.88 (m, 6H, ArH), 8.76 (s, 1H,
NH, D2O exchangeable). Anal. calcd. for C18H14N4O2S: C, 61.70; H, 4.03; N,
15.99, Found: C, 61.59; H, 3.94; N, 15.88%.
2,3-Dihydro-2-(5-(4-methoxyphenyl)-6H-1,3,4-thiadiazin-2-
yl)phthalazine-1,4-dione (4c)
Yield 78%; mp 282–284 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3446 (NH), 1665
(amide, ꢁC O), 1595 (ꢁC N); 1H NMR (400 MHz, CDCl3): d 3.90 (s, 3H,
OMe), 4.0 (s, 2H, CH2), 6.59–6.66 (m, 2H, ArH), 6.96–6.98 (m, 3H, ArH),
8.07–8.10 (m, 3H, ArH), 8.30 (s, 1H, NH, D2O exchangeable). Anal. calcd. for
C18H14N4O3S: C, 59.01; H, 3.85; N, 15.29, Found: C, 58.95; H, 3.80; N, 15.22%.
=
=
2,3-Dihydro-2-(5-phenyl-6H-1,3,4-thiadiazin-2-yl)phthalazine-1,
4-dione (4d)
Yield 71%; mp 222–224 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3420 (NH), 1656
1
=
=
(amide, ꢁC O), 1601 (ꢁC N); H NMR (400 MHz, CDCl3): d 3.77 (s, 2H, CH2),
7.44–7.46 (m, 4H, ArH), 7.71–7.86 (m, 5H, ArH), 8.86 (s, 1H, NH, D2O exchange-
able). Anal. calcd. for C17H12N4O2S: C, 60.70; H, 3.60; N, 16.66, Found: C, 60.65;
H, 3.49; N, 16.58%.
2,3-Dihydro-2-(5-(4-nitrophenyl)-6H-1,3,4-thiadiazin-2-
yl)phthalazine-1,4-dione (4e)
Yield 69%; mp 234–236 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3428 (NH), 1658
1
=
=
(amide, ꢁC O), 1597 (ꢁC N); H NMR (400 MHz, CDCl3): d 4.03 (s, 2H, CH2),

PHTHALAZINE-1,4-DIONE DERIVATIVES
927
7.89–7.92 (m, 4H, ArH), 8.29–8.31 (m, 4H, ArH), 8.97 (s, 1H, NH, D2O exchange-
able). Anal. calcd. for C17H11N5O4S: C, 53.54; H, 2.91; N, 18.36, Found: C, 53.50;
H, 2.87; N, 18.30%.
2-(5-Biphenyl-4-yl-6H-[1,3,4]thiadiazin-2-yl)-2,3-dihydro-phthalazine-
1,4-dione (4f)
Yield 76%; mp 251–253 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3427 (NH), 1649
1
=
=
(amide, ꢁC O), 1606 (ꢁC N); H NMR (400 MHz, CDCl3): d 3.80 (s, 2H, CH2),
7.45–7.83 (m, 13H, ArH), 8.95 (s, 1H, NH, D2O exchangeable). Anal. calcd. for
C23H16N4O2S: C, 66.97; H, 3.91; N, 13.58, Found: C, 66.91; H, 3.87; N, 13.51%.
2,3-Dihydro-2-(5-(2-oxo-2H-chromen-3-yl)-6H-1,3,4-thiadiazin-2-
yl)phthalazine-1,4-dione (6a)
Yield 73%; mp 206–208 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3443 (NH), 1729
(lactone, ꢁC O), 1680 (amide, ꢁC O), 1602 (ꢁC N); 1H NMR (400 MHz,
CDCl3): d 3.96 (s, 2H, CH2), 7.36–7.39 (m, 2H, ArH), 7.60–7.63 (m, 2H, ArH),
7.74–8.05 (m, 4H, ArH), 8.25 (s, 1H, C4 of comarin), 8.33 (s, 1H, NH, D2O
exchangeable); 13C NMR (CDCl3-d6): 23.9, 111.2, 114.5, 116.4, 117.8, 124.6,
126.8, 128.3, 128.8, 131.2, 132.6, 134.0, 134.8, 138.5, 142.5, 143.6, 152.2, 158.8,
163.2, 166.8. ESI-MS 405 [M þ H]. Anal. calcd. for C20H12N4O4S: C, 59.40; H,
2.99; N, 13.85, Found: C, 59.34; H, 2.91; N, 13.79%.
=
=
=
2,3-Dihydro-2-(5-(3-oxo-3H-benzo[f]chromen-2-yl)-6H-
1,3,4-thiadiazin-2-yl)phthalazine-1,4-dione (6b)
Yield 75%; mp 152–154 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3424 (NH), 1715
(lactone, ꢁC O), 1655 (amide, ꢁC O), 1595 (ꢁC N); 1H NMR (400 MHz,
CDCl3): d 4.11 (s, 2H, CH2), 7.44–8.12 (m, 10H, ArH), 8.75 (s, 1H, C4 of comarin),
9.0 (s, 1H, NH, D2O exchangeable). ESI-MS 454 [Mþ]. Anal. calcd. for
C24H14N4O4S: C, 63.43; H, 3.11; N, 12.33, Found: C, 63.37; H, 3.18; N, 12.27%.
=
=
=
2-(5-(6-Chloro-2-oxo-2H-chromen-3-yl)-6H-1,3,4-thiadiazin-2-
yl)-2,3-dihydrophthalazine-1,4-dione (6c)
Yield 69%; mp 185–187ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3426 (NH), 1735
1
=
=
=
(lactone, ꢁC O), 1660 (amide, ꢁC O), 1601 (ꢁC N); H NMR (400 MHz, CDCl3): d
3.84 (s, 2H, CH2), 7.38–7.59 (m, 4H, ArH), 7.69–8.01 (m, 2H, ArH), 8.13 (d, 1H, J¼ 2.8 Hz,
Hz, ArH), 8.96 (s, 1H, C4 of comarin), 10.44 (s, 1H, NH, D2O exchangeable). Anal. calcd.
for C20H11ClN4O4S: C, 54.74; H, 2.53; N, 12.77, Found: C, 54.68; H, 7.94; N, 12.70%.
2-(5-(6,8-Dichloro-2-oxo-2H-chromen-3-yl)-6H-1,3,4-thiadiazin-2-
yl)-2,3-dihydrophthalazine-1,4-dione (6d)
Yield 72%; mp 182–184 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3225 (NH), 1742
1
=
=
=
(lactone, ꢁC O), 1666 (amide, ꢁC O), 1595(ꢁC N); H NMR(400 MHz, CDCl3):d

928
V. S. R. CHUNDURU AND V. R. RAO
3.96 (s, 2H, CH2), 7.38–7.59 (m, 4H, ArH), 7.87 (d, 1H, J ¼ 2.8 Hz, ArH), 8.13 (d,
1H, J ¼ 2.4 Hz, ArH), 8.96 (s, 1H, C4 of comarin), 9.78 (s, 1H, NH, D2O, exchange-
able). Anal. calcd. for C20H10Cl2N4O4S: C, 50.75; H, 2.13; N, 11.84, Found: C,
50.69; H, 2.10; N, 11.79%.
2-(5-(6,8-Dibromo-2-oxo-2H-chromen-3-yl)-6H-1,3,4-thiadiazin-2-
yl)-2,3-dihydrophthalazine-1,4-dione (6e)
Yield 75%; mp 168–170 ꢀC; yellow; IR (KBr, tmax, cmꢁ1): 3432 (NH), 1719
(lactone, ꢁC O), 1647 (amide, ꢁC O), 1597 (ꢁC N); 1H NMR (400 MHz,
CDCl3): d 3.84 (s, 2H, CH2), 7.46–7.60 (m, 3H, ArH), 7.81 (d, 1H, J ¼ 7.6 Hz,
ArH), 8.15–8.18 (m, 2H, ArH), 8.25 (s, 1H, C4 of comarin), 10.46 (s, 1H, NH,
D2O, exchangeable). Anal. calcd. for C20H10Br2N4O4S: C, 42.73; H, 1.79; N, 9.97,
Found: C, 42.68; H, 1.75; N, 9.92%.
=
=
=
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 M. H. R. D. for an institute fellowship.
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