Zinc chloride-catalyzed one-pot, three-component synthesis of 5,8-dihydro-5,8-dioxo-4H-chromene derivatives

Article abstract of DOI:10.1002/jhet.849

An efficient zinc chloride-catalyzed one-pot synthesis of 5,8-dihydro-5,8-dioxo-4H-chromene derivatives have been achieved by the reaction of 2,5-dihydroxy-6-undecyl-1,4-bezoquinone, cyanothioacetamide, and aromaticaldehyde, in EtOH at room temperature. The structures of the products were characterized by IR, ¹H-NMR, mass spectra, and elemental analyses. Copyright

Full text of DOI:10.1002/jhet.849

March 2012
Zinc Chloride-Catalyzed One-Pot, Three-Component Synthesis of
5,8-Dihydro-5,8-dioxo-4H-chromene Derivatives
417
Vakiti Srinivas and Vedula Rajeswar Rao*
Department of Chemistry, National Institute of Technology, Warangal, Andhra Pradish, India
*E-mail: vrajesw@yahoo.com
Received September 3, 2010
DOI 10.1002/jhet.849
Published online 23 November 2011 in Wiley Online Library (wileyonlinelibrary.com).
An efficient zinc chloride-catalyzed one-pot synthesis of 5,8-dihydro-5,8-dioxo-4H-chromene deriva-
tives have been achieved by the reaction of 2,5-dihydroxy-6-undecyl-1,4-bezoquinone, cyanothioaceta-
mide, and aromaticaldehyde, in EtOH at room temperature. The structures of the products were
1
characterized by IR, H-NMR, mass spectra, and elemental analyses.
J. Heterocyclic Chem., 49, 417 (2012).
INTRODUCTION
development of new synthetic methods in heterocyclic
chemistry and multicomponent reactions [12,13], herein
we describe an efficient synthesis of 5,8-dihydro-5,8-
dioxo-4H-chromene derivatives via a three-component
reaction.
Mass screening program of natural product by the
National Cancer Institute has been identified the quinone
moiety as an important pharmacophoric element for cy-
totoxic activity [1,2]. Compounds containing the qui-
none group represent an important class of biologically
active molecules that are widespread in nature [3]. The
chemistry of quinones is largely dependent on the sub-
stituent being either on the quinonic or on adjacent
rings. This is reflected in their chemical reactivity, espe-
cially in heterocyclic quinones [4]. The efficiency of the
quinonic compounds in inhibiting cancer cell growth is
believed to stem from their participation in key cellular
redox mechanisms with consequent generation of highly
reactive oxygen species (ROS). The ROS turn out to
modify and degrade nucleic acids and proteins within
the cells [5,6].
RESULTS AND DISCUSSION
The one-pot, three-component condensation reactions
of embelin (1) with cyanothioacetamide (2) and aro-
matic aldehydes (3) in the presence of ZnCl2 in EtOH
at room temperature afforded corresponding 2-amino-4-
(substitutedphenyl)-5,8-dihydro-6-hydroxy-5,8-dioxo-7-un-
decyl-4H-chromene-3-carbothioamides (4) in good yields
(Scheme 1).
The mechanism of the reaction can be explained by
the fact that in the presence of Lewis acid, cyanothio-
acetamide 2 reacts with aldehyde 3 to afford intermedi-
ate 5 (Scheme 2). The intermediate 5 on reaction with
embelin can form another intermediate 6. Compound 6
on cyclization will give the product 4.
The compound 4a can also be prepared by alternative
stepwise method (Scheme 3). Involving condensation of
embelin with 5a resulted in the formation of 4a. The
compound 5a was prepared by following the literature
procedure [14]. The yields of the products are good in a
one-step process (85–93%). Compounds obtained by
both the methods were found to be identical by mixed
melting points measurements and co-TLC and spectral
data. The product 4 was shown to have quinone moiety
intact by its behavior toward Zn/AcOH in a reduction
and re-aerial oxidation test. The structures of 4a–i were
One of the most simple 1,4-benzoquinonic compound
isolated from natural sources is embelin (1). Compound
1 shows a diversity of relevant biological activities such
as chemopreventive effect against DENA/PB-induced
hepatocarcinogenesis in Wistar rats [7], antifertility
effects [8], and in vitro cytotoxic activity against B16
and XC cell lines [9]. In addition, recent studies have
shown that embelin is a fairly potent, nonpeptidic, cell-
permeable inhibitor of XIAP (X-linked inhibitor of apo-
ptosis protein), and it represents a promising lead com-
pound for designing an entirely new class of anticancer
agents that target the BIR3 domain of XIAP [10,11].
From the above facts, we are interested in developing
newer synthetic methods for the construction of embelin
derivatives. As a part of our continuing interest in the
C
V
2011 HeteroCorporation

418
V. Srinivas and V. R. Rao
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Scheme 1. One-pot reaction of 2,5-dihydroxy-6-undecyl-1,4-bezoquinone, cyanothioacetamide, and aromatic aldehydes.
1
of the compounds was checked by TLC plates (E.Merek,
Mumbai, India). IR spectra (KBr) were recorded on a Bru-
kerWM-4(X) spectrometer (577model). 1H-NMR spectra were
recorded on a Bruker WM-400-MHz spectrometer in d ppm
using TMS as internal standard. The NH protons were
exchanged with D2O. Mass spectra (EI-MS) were determined
on a Perkin Elmer (SCIEX API-2000, ESI) at 12.5 eV.
General procedure synthesis of 2-amino-5,8-dihydro-6-
hydroxy-5,8-dioxo-4-ary-7-undecyl-4H-chromene-3-carbo-
thioamide (4). A mixture of 2,5-dihydroxy-6-undecyl-1,4-
bezoquinone (1 mmol), cyanothioacetamide (1 mmol) and aro-
matic aldehydes (1 mmol) and ZnCl2 (100 mg) in ethyl alco-
hol (10 mL) was stirred at room temperature for 5 h. Then the
reaction mixture was cooled and poured into cold water, and
the solid separated was filtered off. The crude product was
purified by recrystallization from ethanol to give 4.
confirmed from their analytical, IR, H–NMR, and mass
spectra.
The mass spectra of these compounds displayed molec-
ular ion peaks at the appropriate m/z values. The 1H-
NMR spectrum of 4a consists of a triplet for the end CH3
of alkyl group (d ¼ 0.87 ppm), a multiplet for A(CH2)9A
(d ¼ 1.20–1.30 ppm), a triplet for allylic CH2 (d ¼ 2.35
ppm), a singlet for the NMe2 (d ¼ 3.14 ppm), two dou-
blets for aromatic protons (d ¼ 6.71 ppm and d ¼ 7.98
ppm), a singlet for NH2 (d ¼ 7.35 ppm) and another sin-
glet to thioamide NH2 (d ¼ 7.45 ppm) protons, and a sin-
glet for the CH of pyran ring (d ¼ 8.68 ppm).
EXPERIMENTAL
Synthesis of 2-amino-4-(4-(dimethylamino)phenyl)-5,8-
dihydro-6-hydroxy-5,8-dioxo-7-undecyl-4H-chromene-3-car-
bothioamide (4a). An equimolar mixture of 2,5-dihydroxy-6-
undecyl-1,4-bezoquinone (1 mmol) and 2-cyano-3-(4-
Melting points were determined in open capillaries with a
‘‘cintex’’ melting point apparatus, Mumbai, India. Melting
points were uncorrected, and CHNS analysis was done by
Carlo Erba EA 1108 automatic elemental analyzer. The purity
Scheme 2. Mechanism of the reaction.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2012
Zinc Chloride-Catalyzed One-Pot, Three-Component Synthesis
of 5,8-Dihydro-5,8-dioxo-4H-chromene Derivatives
419
Scheme 3. Stepwise synthesis of 4a.
(dimethylamino)phenyl)prop-2-enethioamide (5a; 1 mmol) was
refluxed in ethanol in the presence of piperidine for 3 h. The
reaction mixture was cooled, and the solid separated was fil-
tered and recrystallised from ethanol.
ArH), 8.05 (s, 1H, CH of pyran ring), 9.68 (bs, 2H, NH2),
10.05 (bs, 2H, NH2). Anal. calcd. for C28H36N2O4S: C, 67.71;
H, 7.31; N, 5.64; S, 6.46. Found: C, 67.74; H, 7.34; N, 5.68;
S, 6.48%.
2-Amino-4-(4-(dimethylamino)phenyl)-5,8-dihydro-6-hydroxy-
5,8-dioxo-7-undecyl-4H-chromene-3-carbothioamide (4a). Brown
solid, yield 85%, m.p. 199–200ꢀC; IR (KBr) m: 3288 (NH2
stretching of CSNH2), 3152 (NH2), 1612 (quinone C¼¼O),
2-Amino-5,8-dihydro-6-hydroxy-4-(4-methoxyphenyl)-5,8-dioxo-
7-undecyl-4H-chromene-3-carbothioamide (4e). Light yellow
solid, yield 85%, m.p. 176–177ꢀC; IR (KBr) m: 3396 (NH2
stretching of CSNH2), 3315 (NH2), 1641 (quinone C¼¼O),
1
1
1376 (C¼¼S) cmꢁ1; H-NMR (400 MHz, DMSO-d6) (d ppm):
1257 (C¼¼S) cmꢁ1; H-NMR (400 MHz, DMSO-d6) (d ppm):
0.87 (t, 3H, end CH3), 1.20–1.30 (m, 18H, A(CH2)9A), 2.35
(t, 2H, allylic CH2), 3.14 (s, 6H, NMe2), 6.71 (d, 2H, J ¼ 6.9
Hz, ArH), 7.98 (d, 2H, J ¼ 6.67Hz, ArH), 7.35 (bs, 2H, NH2),
7.45 (bs, 2H, NH2), 8.68 (s, 1H, CH of pyran ring). EI-MS m/
z 525 (Mþ); Anal. calcd. for C29H39N3O4S: C, 66.26; H, 7.48;
N, 7.99; S, 6.10. Found: C, 66.29; H, 7.51; N, 7.94; S, 6.12%.
2-Amino-5,8-dihydro-6-hydroxy-5,8-dioxo-4-phenyl-7-undecyl-
4H-chromene-3-carbothioamide (4b). Black solid, yield 89%,
m.p. 187–188ꢀC; IR (KBr) m: 3329 (NH2 stretching of
CSNH2), 3210 (NH2), 1620 (quinone C¼¼O), 1370 (C¼¼S)
0.84 (t, 3H, end CH3), 1.22–1.30 (m, 18H, A(CH2)9A), 2.35
(t, 2H, allylic CH2), 3.86 (s, 3H, p-OCH3), 7.14 (d, 2H, J ¼
6.6Hz, ArH), 7.97 (d, 2H, J ¼ 6.3Hz, ArH), 8.06 (s, 1H, CH
of pyran ring), 9.48 (bs, 2H, NH2), 9.98 (bs, 2H, NH2). Anal.
calcd. for C28H36N2O5S: C, 65.60; H, 7.08; N, 5.46; S, 6.25.
Found: C, 65.63; H, 7.00; N, 5.44; S, 6.28%.
2-Amino-5,8-dihydro-6-hydroxy-4-(2-hydroxyphenyl)-5,8-dioxo-
7-undecyl-4H-chromene-3-carbothioamide (4f). Brown solid,
yield 89%, m.p. 189–190ꢀC; IR (KBr) m: 3435 (NH2 stretching
of CSNH2), 3291 (NH2), 1611 (quinone C¼¼O), 1359 (C¼¼S)
cmꢁ1
;
1H-NMR (400 MHz, DMSO-d6) (d ppm): 0.83 (t, 3H,
cmꢁ1 1H-NMR (400 MHz, DMSO-d6) (d ppm): 0.85 (t, 3H,
;
end CH3), 1.22–1.30 (m, 18H, A(CH2)9A), 2.35 (t, 2H, allylic
CH2), 7.30–7.55 (m, 5H, ArH), 8.18 (s, 1H, CH of pyran
ring). Anal. calcd. for C27H34N2O4S: C, 67.19; H, 7.10; N,
5.80; S, 6.64. Found: C, 67.16; H, 7.14; N, 5.84; S, 6.61%.
2-Amino-4-(4-chlorophenyl)-5,8-dihydro-6-hydroxy-5,8-dioxo-
7-undecyl-4H-chromene-3-carbothioamide (4c). Black solid,
yield 90%, m.p. 208–209ꢀC; IR (KBr) m: 3330 (NH2 stretching
of CSNH2), 3215 (NH2), 1624 (quinone C¼¼O), 1366 (C¼¼S)
end CH3), 1.20–1.30 (m, 18H, A(CH2)9A), 2.35 (t, 2H, allylic
CH2), 7.40–7.48 (m, 2H, ArH), 7.78–7.80 (m, 1H, ArH), 7.98
(d, 1H, J ¼ 6 Hz, ArH), 8.98 (s, 1H, CH of pyran ring), 9.80
(bs, 2H, NH2), 10.30 (bs, 2H, NH2). Anal. calcd. for
C27H34N2O5S: C, 65.04; H, 6.87; N, 5.62; S, 6.43. Found: C,
65.00; H, 6.85; N, 5.65; S, 6.47%.
2-Amino-5,8-dihydro-6-hydroxy-4-(4-hydroxyphenyl)-5,8-dioxo-
7-undecyl-4H-chromene-3-carbothioamide (4g). Green solid,
yield 93%, m.p. 171–172ꢀC; IR (KBr) m: 3422 (NH2 stretching
of CSNH2), 3242 (NH2), 1612 (quinone C¼¼O), 1369 (C¼¼S)
cmꢁ1 1H-NMR (400 MHz, DMSO-d6) (d ppm): 0.83 (t, 3H,
;
end CH3), 1.22–1.30 (m, 18H, A(CH2)9A), 2.35 (t, 2H, allylic
CH2), 7.52–7.65 (m, 4H, ArH), 8.45 (s, 1H, CH of pyran
ring). Anal. Calcd. for C27H33ClN2O4S: C, 62.72; H, 6.43; N,
5.42; S, 6.20. Found: C, 62.70; H, 6.47; N, 5.45; S, 6.24%.
2-Amino-5,8-dihydro-6-hydroxy-5,8-dioxo-4-p-tolyl-7-undecyl-
4H-chromene-3-carbothioamide (4d). Green solid, yield 91%,
m.p. 162–163ꢀC; IR (KBr) m: 3357 (NH2 stretching of
CSNH2), 3288 (NH2), 1640 (quinone C¼¼O), 1291 (C¼¼S)
cmꢁ1 1H-NMR (400 MHz, DMSO-d6) (d ppm): 0.84 (t, 3H,
;
end CH3), 1.18–1.30 (m, 18H, A(CH2)9A), 2.28 (t, 2H, allylic
CH2), 6.96 (d, 2H, J ¼ 6Hz, ArH), 7.95 (d, 2H, J ¼ 6.6Hz,
ArH), 8.10 (s, 1H, CH of pyran ring), 9.48 (bs, 2H, NH2),
9.95 (bs, 2H, NH2). Anal. calcd. for C27H34N2O5S: C, 65.04;
H, 6.87; N, 5.62; S, 6.43. Found: C, 65.10; H, 6.89; N, 5.65;
S, 6.40%.
2-Amino-5,8-dihydro-6-hydroxy-4-(3,4,5-trimethoxyphenyl)-
5,8-dioxo-7-undecyl-4H-chromene-3-carbothioamide (4h). Yellow
solid, yield 91%, m.p. 197–198ꢀC; IR (KBr) m: 3393 (NH2
cmꢁ1
;
1H NMR (400 MHz, DMSO-d6) (d ppm): 0.83 (t, 3H,
end CH3), 1.22–1.30 (m, 18H, A(CH2)9A), 2.25 (t, 2H, allylic
CH2), 2.46 (s, 3H, p-CH3), 7.24 (d, 2H, ArH), 7.78 (d, 2H,
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V. Srinivas and V. R. Rao
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stretching of CSNH2), 3260 (NH2), 1633 (quinone C¼¼O),
Acknowledgments. The authors thank the University Grants
Commission New Delhi (F.No. 32-201/2006 (SR)) for financial
support.
1
1335 (C¼¼S) cmꢁ1; H-NMR (400 MHz, DMSO-d6) (d ppm):
0.83 (t, 3H, end CH3), 1.22–1.30 (m, 18H, A(CH2)9A), 2.35
(t, 2H, allylic CH2), 3.85 (s, 3H, OCH3), 3.91 (s, 6H, OCH3),
7.44 (s, 2H, ArH), 8.15 (s, 1H, CH of pyran ring), 9.64 (bs,
2H, NH2), 10.17 (bs, 2H, NH2). Anal. calcd. for
C30H40N2O7S: C, 62.91; H, 7.04; N, 4.89; S, 5.60. Found: C,
62.74; H, 7.00; N, 4.86; S, 5.64%.
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5,8-dioxo-7-undecyl-4H-chromene-3-carbothioamide (4i). Brown
solid, yield 92%, m.p. 177–178ꢀC; IR (KBr) m: 3405 (NH2
stretching of CSNH2), 3306 (NH2), 1689 (quinone C¼¼O),
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1343 (C¼¼S) cmꢁ1; H-NMR (400 MHz, DMSO-d6) (d ppm):
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0.82 (t, 3H, end CH3), 1.10–1.23 (m, 18H, A(CH2)9A), 2.31
(t, 2H, allylic CH2), 7.74–7.80 (m, 2H, ArH), 7.85–7.90 (m,
1H, ArH), 8.13 (d, 1H, ArH), 8.32 (d, 1H, ArH), 8.60 (d, 1H,
ArH), 9.81 (s, 1H, CH of pyran ring), 9.95 (bs, 2H, NH2),
10.38 (bs, 2H, NH2). Anal. calcd. for C31H36N2O5S: C, 67.86;
H, 6.61; N, 5.11; S, 5.84. Found: C, 67.88; H, 6.58; N, 5.14;
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CONCLUSIONS
We find a novel zinc chloride-catalyzed one-pot
method for the synthesis of 5,8-dihydro-5,8-dioxo-4H-
chromene derivatives. This method has an advantage of
one-step, easy work-up, milder reaction conditions, and
good yields.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet