A highly regioselective synthesis of 8-hydroxy-3-sulfanyl-7-undecyl-5H-[1, 2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione and its derivative

Article abstract of DOI:10.3184/030823410X12652161830635

Regioselective synthesis of novel 8-hydroxy-3-sulfanyl-7-undecyl-5 H-[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione (3) by condensation of 2-bromo-3,6-dihydroxy-5-undecyl-1,4-benzoquinone (bromoembelin) (1) with 4-amino-4 H-1,2,4-triazole-3,5-dit

Full text of DOI:10.3184/030823410X12652161830635

80 RESEARCH PAPER
FEBRUARY, 80–82
JOURNAL OF CHEMICAL RESEARCH 2010
A highly regioselective synthesis of 8-hydroxy-3-sulfanyl-7-undecyl-5H-
[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione and its derivatives
Srinivas Vakiti and Vedula Rajeswar Rao*
Department of Chemistry, National Institute ofTechnology, Warangal-506004, India
Regioselective synthesis of novel 8-hydroxy-3-sulfanyl-7-undecyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-
6,9-dione (3) by condensation of 2-bromo-3,6-dihydroxy-5-undecyl-1,4-benzoquinone (bromoembelin) (1) with
4-amino-4H-1,2,4-triazole-3,5-dithiol (2) in ethanol. Reaction of 3 with various alkyl, aralkyl and phenacyl halides
gave the corresponding thioethers (4).
Keywords: regioselective synthesis, 8-hydroxy-3-sulfanyl-7-undecyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione
The chemistry of quinones is of considerable interest since
this class of compounds include many natural products and
numerous important synthetic products.1,2 Addition of nitrogen
nucleophiles to benzo and naphthoquinones represents a
common synthetic route to many fused heterocyclic rings
which have been used as synthetic intermediates in medicinal
chemistry.3–6 Quinone derivatives may be toxic to cells by a
number of mechanisms7,8 including redox arylation, intercala-
tion, induction of DNA strand breaks, generation of free radicals
and alkylation via quinone methide formation.9 As a conse-
quence, the molecular framework of a large number of phar-
maceuticals and biological important compounds contains a
quinone moiety. Nowadays, their important pharmacological
activity is also attributed to the inhibition of special proteins,
such as bacterial topoisomerase, II-DNA gyrase (antibacterial),10
mammalian topoisomerases I and II (antitumor),11–12 and
HIV-1 integrase and proteinase (antiviral).13,14 Representative
examples of this class of compounds are well known antican-
cer drugs of the anthracycline series-doxorubicine and mito-
xanthrone. The action of which is believed to occur via
topoisomerase II inhibition.12
In connection15–17 with our research program directed toward
the synthesis of novel heterocyclic fused quinones and its
derivatives, we now report the regioselective synthesis of
novel 8-hydroxy-3-sulfanyl-7-undecyl-5H-[1,2,4]triazolo[3,4-
b][1,3,4]benzothiadiazole-6,9-dione (3) and its derivatives
4a–j. (Scheme 1).
Scheme 1
* Correspondent. E-mail: vrajesw@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2010 81
1H NMR δ (CDCl ) 0.85 (t, 3H, J = 5.2 Hz, end CH3), 1.23–1.28 (m,
18H, –(CH2)9–), 2.343 (t, 2H, J = 8 Hz, allylic CH2), 2.67 (s, 3H, SCH3),
8.84 (s, 1H, NH), 14.00 (s, 1H, OH). Anal. Calcd for C H28N4O S2: C,
55.02; H, 6.46; N, 12.83; S, 14.69. Found: C, 55.12; H,260 .49; N, 312.82;
S, 14.64%.
2-Bromo-3,6-dihydroxy-5-undecyl-1,4-benzoquinone (1) has
been prepared by the bromination of 2,5-dihydroxy-3-undecyl-
1,4-benzoquinone using NBS in CCl4.18 The 4-amino-4H-
1,2,4-triazole-3,5-dithiol (2) was prepared by condensation
of thiocarbohydrazide with carbon disulfide in pyridine.19
The cyclocondensation reaction between 1 and 2 leading
to the formation of 3 is highly regioselective. The reaction
between 1 and 2 may also expected to give o-quinonoid struc-
ture 5. Further formation of 5 could be ruled out by the fact
that the product failed to condense with o-phenylene diamine
to give phenazene derivative under different conditions. Both
the compounds 3 and 4 on reduction with Zn dust in acetic acid
gave a colourless solution which on aerial oxidation regained
the original colour providing evidence for the presence of
1,4-quinonoid structure.
Reaction of 2-bromo-3,6-dihydroxy-5-undecyl-1,4-benzo-
quinone (1) with 4-amino-4H-1,2,4-triazole-3,5-dithiol (2)
in ethanol afforded the 8-hydroxy-3-sulfanyl-7-undecyl-
5H-[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione
(3). Condensation of 3 with various alkyl, aralkyl and phenacyl
halides in DMF yielded the corresponding thioethers (4)
respectively. The formation of 4 is highly selective S-
alkylation reaction. The alkylation of 3 with alkyl, aralkyl and
phenacyl halides may result in the formation of different types
of products like O-alkylated, N-alkylated and S-alkylated.
No mixtures of products were formed. In our case, only one
product was observed (as evidenced by TLC). This formation
of S-alkylated products has been explained in preference to
the two other alkylated product is due to high nucleophilicity
of thiol group. The S-alkylated products were confirmed by
spectral data.
3-Ethylsulfanyl-8-hydroxy-7-undecyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]
benzothiadiazole-6,9-dione (4b): Yield 89%, m.p. 158–159 °C. IR:
1
νmax 1466 (C=C), 1559 (–C=N–), 1609 (–C=O), 3208 (OH) cm−1. H
NMR δ (CDCl3) 0.84 (t, 3H, J = 6.4 Hz, end CH3), 1.23–1.30 (m,
18H, –(CH ) –), 2.43 (t, 2H, J = 6.8 Hz, allylic CH2), 2.55 (t, 3H,
J = 5.6 Hz, 2C9H3 of ethyl), 3.25 (q, 2H, J = 7.2 Hz, CH of ethyl), 14.16
(s, 1H, OH). Anal. Calcd for C21H N4O S2: C, 55.297; H, 6.71; N,
12.43; S, 14.23. Found: C, 55.92; H,360 .67;3N, 12.40; S, 14.20%.
3-Allylsulfanyl-8-hydroxy-3-sulfanyl-7-undecyl-5H-[1,2,4]triazolo
[3,4-b][1,3,4]benzothiadiazole-6,9-dione (4c): Yield 91%, m.p. 127–
128 °C. IR: νmax 1459 (C=C), 1558 (–C=N–), 1616 (–C=O), 3268
(OH) cm−1. 1H NMR δ (CDCl3) 0.83 (t, 3H, J = 8 Hz, end CH ), 1.23–
1.28 (m, 18H, –(CH )9–), 2.42 (t, 2H, J = 8 Hz, allylic CH2),33.92 (d,
J = 7.2 Hz, 2H, S-C2H ), 5.14 (d, J = H , HA, J = 9.6 Hz, HA of allyl
group), 5.30 (d, J = HX2, HB, J = 16.8 Hz,XH of allyl group), 5.93–6.04
(m, 1H, HX). Anal. Calcd for C H N4OBS : C, 57.12; H, 6.54; N,
12.11; S, 13.86. Found: C, 57.10;22H,360 .51;3N2, 12.00; S, 13.83%.
3-Benzylsulfanyl-8-hydroxy-7-undecyl-5H-[1,2,4]triazolo[3,4-b]
[1,3,4]benzothiadiazole-6,9-dione (4d): Yield 93%, m.p. 76–77 °C.
IR: νmax 1455 (C=C), 1495 (–C=N–), 1628 (–C=O), 3302 (OH), 3437
(NH) cm−1. 1H NMR δ (CDCl3) 0.83 (t, 3H, J = 8 Hz, end CH ), 1.23–
1.28 (m, 18H, –(CH2) –), 2.41 (t, 2H, J = 8 Hz, allylic CH2),34.51 (s,
2H, S–CH2), 7.25–7.393 (m, 5H, ArH). Anal. Calcd for C26H N4O3S2:
C, 60.91; H, 6.29; N, 10.93; S, 12.51. Found: C, 60.87; H,325.64; N,
12.51; S, 11.46%.
3-p-Nitrobenzylsulfanyl-8-hydroxy-7-undecyl-5H-[1,2,4]triazolo
[3,4-b][1,3,4]benzothiadiazole-6,9-dione (4e): Yield 90%, m.p. 132–
133 °C. IR: νmax 1466 (C=C), 1523 (–C=N–), 1602 (–C=O), 3345
1
(OH) cm−1. H NMR δ (CDCl3) 0.83 (t, 3H, J = 5.2 Hz, end CH ),
1.23–1.28 (m, 18H, –(CH2) –), 2.31 (t, 2H, J = 8 Hz, allylic CH32),
4.58 (s, 2H, S–CH2), 7.65–97.72 (m, 2H, ArH), 8.15–8.18 (m, 2H,
ArH). Anal. Calcd for C26H31N5O5S : C, 56.00; H, 5.60; N, 12.56; S,
11.50. Found: C, 56.10; H, 5.64; N,212.51; S, 11.46%.
Experimental
Melting points were determined in open capillaries with a Cintex
melting point apparatus, Mumbai, India. Melting points uncorrected
and CHNS analysis was done by Carlo Erba EA 1108 automatic
elemental analyser. The purity of the compounds was checked by TLC
plates (E.Merek, Mumbai, India), IR spectra (KBr) were recorded on
8-Hydroxy-3-(2-oxo-2-phenyl-ethylsulfanyl)-7-undecyl-5H-
[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione (4f): Yield 92%,
m.p. 145–146 °C. IR: νmax 1458 (C=C), 1526 (–C=N–), 1615, 1617
1
(–C=O), 3147 (OH) cm−1. H NMR δ (CDCl3) 0.83 (t, 3H, J = 8 Hz,
1
end CH ), 1.23–1.28 (m, 18H, –(CH )9–), 2.35 (t, 2H, J = 8 Hz, allylic
CH ), 23.93 (s, 2H, S–CH2), 7.43–72.58 (m, 5H, ArH), 14.00 (s, 1H,
OH2). Anal. Calcd for C H N4O4S2: C, 59.98; H, 5.97; N, 10.36; S,
11.86. Found: C, 59.94;2H7 , 352.94; N, 10.31; S, 11.89%.
a BrukerWM-4(X) spectrometer (577model). H NMR spectra were
recorded on a Bruker WM-400 MHz spectrometer in δ ppm using
TMS as internal standard. The NH and OH protons were exchanged
with D2O. Mass spectra (EI-MS) were determined on a Perkin Elmer
(SCIEX API-2000, ESI) at 12.5eV.
8-Hydroxy-3-(2-oxo-2-p-tolyl-ethylsulfanyl)-7-undecyl-5H-[1,2,4]
triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione (4g): Yield 89%,
m.p. 140–141 °C. IR: νmax 1457 (C=C), 1516 (–C=N–), 1610 (quino-
8-hydroxy-3-sulfanyl-7-undecyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]
benzothiadiazole-6,9-dione
1
noid –C=O), 1654 (–C=O), 3412 (OH), 3740 (NH) cm−1. H NMR
A mixture of 2-bromo-3,6-dihydroxy-5-undecyl-1,4-benzoquinone
(3.73 g, 0.01 mol) and 4-amino-4H-1,2,4-triazole-3,5-dithiol (1.48 g,
0.01 mol) in ethanol (20 mL) and few drops of pyridine was refluxed
for 4 hours. After completion of reaction the mixture was cooled and
poured over crushed ice. The solid thus, separated was filtered, dried
and recrystallised from methanol.
δ (CDCl3) 0.83 (t, 3H, J = 8 Hz, end CH3), 1.23–1.28 (m, 18H,
–(CH2)9–), 2.35 (t, 2H, J = 8 Hz, allylic CH2), 2.77 (s, 3H, p-CH ),
2.89 (s, 2H, S–CH ), 7.37–7.48 (m, 4H, ArH). Anal. Calcd f3or
C H N O4S : C, 60.262; H, 6.18; N, 10.10; S, 11.56. Found: C, 60.61;
H2,86.3144;4N, 120.14; S, 11.59%.
8-Hydroxy-3-[2-(4-methoxy-phenyl)-2-oxo-ethylsulfanyl]-7-
undecyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione
(4h): Yield 93%, m.p. 168–169 °C. IR: νmax 1512 (C=C), 1562
8-Hydroxy-3-sulfanyl-7-undecyl-5H-[1,2,4]triazolo[3,4-b][1,3,4]
benzothiadiazole-6,9-dione (3):Yield 90%, m.p. 197–198 °C. IR: ν
1486 (C=C), 1522 (–C=N–), 1603, 1622 (–C=O), 2916 (SH), 33m0a5x
1
(–C=N–), 1660 (–C=O), 3385 (OH), 3732 (NH) cm−1. H NMR δ
1
(OH) cm−1. H NMR δ (CDCl ) 0.87 (t, 3H, J = 5.2 Hz, end CH3),
(CDCl ) 0.83 (t, 3H, J = 8 Hz, end CH3), 1.23–1.28 (m, 18H, –(CH2)9–),
2.35 (t3, 2H, J = 8 Hz, allylic CH2), 3.85 (s, 3H, O–CH3), 2.89 (s, 2H,
S–CH ), 7.06–7.20 (m, 4H, ArH). Anal. Calcd for C28H34N4O5S2: C,
58.93;2H, 6.00; N, 9.82; S, 11.24. Found: C, 58.97; H, 6.10; N, 9.85;
S, 11.29%.
1.23–1.28 (m, 18H, –(CH2)9–), 13.62 (s, 1H, SH), 2.50 (t, 2H, J = 6.8 Hz,
allylic CH2), 8.85 (s, 1H, NH), 14.00 (s, 1H, OH). EI-MS 422 (M+).
Anal. Calcd for C19H26N4O3S : C, 54.00; H, 6.20; N, 13.26; S, 15.18.
Found: C, 53.94; H, 6.15; N, 212.82; S, 15.12%.
3-[2-(4-Chloro-phenyl)-2-oxo-ethylsulfanyl]-8-hydroxy-7-undecyl-
5H-[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione (4i):
Yield 90%, m.p. 123–124 °C. IR: νmax 1523 (C=C), 1562 (–C=N–),
Reaction of 3 with alkyl, aralkyl and phenacyl halides (4); general
procedure
1
1622 (–C=O), 3325 (OH) cm−1. H NMR δ (CDCl3) 0.83 (t, 3H, J =
Compound 3 (0.01 mol) was dissolved in a mixture of dimethyl
formamide (10 mL) and anhydrous ethanol (10 mL) and appropriate
alkyl, aralkyl and phenacyl halides (0.01 mol) was added. The reac-
tion mixture was refluxed for 3–4 hours at 80–90 oC, and then cooled;
the solid separated was filtered, dried and recrystallised from suitable
solvent to give the corresponding thioethers.
8-Hydroxy-3-methylsulfanyl-7-undecyl-5H-[1,2,4]triazolo[3,4-b]
[1,3,4]benzothiadiazole-6,9-dione (4a):Yield 92%, m.p. 112–113 °C.
IR: νmax 1517 (C=C), 1565 (–C=N–), 1604 (–C=O), 3274 (OH) cm–1.
5.2 Hz, end CH3), 1.23–1.28 (m, 18H, –(CH2)9–), 2.35 (t, 2H, J = 8 Hz,
allylic CH2), 4.39 (s, 2H, S–CH2), 7.62–7.68 (m, 4H, ArH), 14.02 (s,
1H, OH). Anal. Calcd for C27H31ClN4O S2: C, 56.38; H, 5.43; N, 9.74;
S, 11.15. Found: C, 56.34; H, 5.47; N, 49.81; S, 11.18%.
3-[2-(4-Bromo-phenyl)-2-oxo-ethylsulfanyl]-8-hydroxy-7-undecyl-
5H-[1,2,4]triazolo[3,4-b][1,3,4]benzothiadiazole-6,9-dione (4j):
Yield 92%, m.p. 152–153 °C. IR: νmax 1521 (C=C), 1562 (–C=N–),
1622 (–C=O), 3317 (OH), 3601 (NH) cm−1. 1H NMR δ (CDCl3) 0.83

82 JOURNAL OF CHEMICAL RESEARCH 2010
4
5
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(t, 3H, J = 8 Hz, end CH ), 1.23–1.28 (m, 18H, –(CH2)9–), 2.35 (t, 2H,
J = 8 Hz, allylic CH2), 43.42 (s, 2H, S–CH2), 7.76–7.96 (m, 4H, ArH),
14.02 (s, 1H, OH). Anal. Calcd for C27H31BrN4O4S2: C, 52.34; H, 5.04;
N, 9.04; S, 10.35. Found: C, 52.38; H, 5.12; N, 9.14; S, 10.39%.
6
7
This work was supported by grant from UGC, New Delhi for
the sanction of project (F.No. 32-201/2006 (SR)) is gratefully
acknowledged.
8
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Received 21 November 2009; accepted 7 January 2010
Paper 090881 doi: 10.3184/030823410X12652161830635
Published online: 1 March 2010
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