Regioselective synthesis of tetrahydrothiochromen-5-ones via a one-pot three-component solvent-free domino protocol

Article abstract of DOI:10.1021/ol201458q

A highly efficient one-pot three-component regioselective synthesis of 4-aryl-3-aroyl-2-methylsulfanyl-4,6,7,8-tetrahydrothiochromen-5-ones has been developed by annulation of β-oxodithioesters with aldehydes and cyclic 1,3-diketones under solvent-free co

Full text of DOI:10.1021/ol201458q

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3762–3765
Regioselective Synthesis of
Tetrahydrothiochromen-5-ones
via a One-Pot Three-Component
Solvent-Free Domino Protocol
Sushobhan Chowdhury, Ganesh Chandra Nandi, Subhasis Samai, and
Maya Shankar Singh*
Department of Chemistry, Faculty of Science, Banaras Hindu University,
Varanasi-221005, India
mssinghbhu@yahoo.co.in
Received May 30, 2011
ABSTRACT
A highly efficient one-pot three-component regioselective synthesis of 4-aryl-3-aroyl-2-methylsulfanyl-4,6,7,8-tetrahydrothiochromen-5-ones has
been developed by annulation of β-oxodithioesters with aldehydes and cyclic 1,3-diketones under solvent-free conditions promoted by P2O5. No
cocatalyst or activator is needed in this protocol. The merit of this process is highlighted by its high efficiency of producing three new bonds and a
stereocenter in one operation.
In the past decade, interest in green chemistry1 has
expanded, and it now encompasses wide areas of the
chemical enterprise and is an alternative way to reduce
drastic requirements for reactions. Their is a need for facile,
efficient, and nonpolluting synthetic procedures that reduce
the use of organic solvents and toxic reagents. For the
reasons of economy and pollution prevention, multicompo-
nent reactions2 (MCRs) have considerable ecological inter-
est as they address the fundamental principles of synthetic
efficiency and reaction design, arising from minimization of
waste, time, energy, and cost. Multicomponent reactions
involving a domino process3 with at least three different
substrates particularly performed under solvent-free
conditions4 have emerged as a powerful strategy for the
synthesis of chemically and biologically important organic
frameworks. This protocol allows molecular complexity
and diversity in a one-pot transformation and quite closely
approaches the concept of an ideal synthesis.
Molecules with a thiochromene framework not only are
important starting materials for numerous biologically
active compounds but also are widely present as key
(1) (a) Anastas, P.; Eghbali, N. Chem. Soc. Rev. 2010, 39, 301.
(b) Anastas, P. T.; Warner, J. C. In Green Chemistry: Theory and
Practice; Oxford University Press: New York, 1998, p. 30. (c) Ramachary,
D. B.; Kishor, M. J. Org. Chem. 2007, 72, 5056. (d) Leitner, W. Green
Chem. 2009, 11, 603.
€
(3) (a) D’Souza, D. M.; Kiel, A.; Herten, D. P.; Muller, T. J. J.
Chem.;Eur. J. 2008, 14, 529. (b) D’Souza, D. M.; Rominger, F.;
€
Muller, T. J. J. Angew. Chem., Int. Ed. 2005, 44, 153.
(4) (a) Tanaka, K.; Toda, F. Solvent-free Organic Synthesis; Wiley-
VCH: Weinheim, 2003. (b) Hernandez, J. G.; Juaristi, E. J. Org. Chem. 2010,
(2) (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, 2005. (b) Toure, B. B.; Hall, D. G.
Chem. Rev. 2009, 109, 4439. (c) Sunderhaus, J. D.; Martin, S. F. Chem.;
Eur. J. 2009, 15, 1300. (d) Ganem, B. Acc. Chem. Res. 2009, 42, 463.
(e) Padwa, A. Chem. Soc. Rev. 2009, 38, 3072. (f) Domling, A. Chem.
Rev. 2006, 106, 17. (g) Polshettiwar, V.; Varma, R. S. Chem. Soc. Rev.
2008, 37, 1546. (h) Shore, G.; Yoo, W. J.; Li, C. J.; Organ, M. Chem.;
Eur. J. 2010, 16, 126. (i) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed.
2005, 44, 1602. (j) Balamurugan, K.; Perumal, S.; Menendez, J. C.
ꢀ
75, 7107. (c) Li, S.; Wang, J. ÀX.; Wen, X.; Ma, X. Tetrahedron 2011, 67,
849. (d) Nelson, W. M. Green Solvents for ChemistryÀPerspectives and
Practice; Oxford University Press: Oxford, NY, 2003. (e) Sheldon, R. A.
Green Chem. 2005, 7, 267. (f) Corma, A.; Garcia, H. Chem. Rev. 2003,
103, 4307.
(5) (a) Hisio, M.; Ito, T.; Eliada, Y.; Nagaoka, K.; Nomiya, Y.
Japanese Patent No. 24984, 1970; Zh. Khim. 23N432P, 1966. (b) Kulikova,
L. K.; Klimenko, S. K.; Stolbova, T. V.; Kharchenko, V. G. Khim.;Farm. Zh.
1976, 73.
€
Tetrahedron 2011, 67, 3201. (k) Muschelknautz, C.; Frank, W.; Muller,
T. J. J. Org. Lett. 2011, 13, 2556.
r
10.1021/ol201458q
Published on Web 06/20/2011
2011 American Chemical Society

structural motifs in many natural products and are structu-
rally related to plant pigments like flavonoids and antho-
cyanins. The thiochromene derivatives exhibit tumorigenic,
antibacterial,5 and antifungal6 activities together with ap-
plications in dyes for chemical fibers.7 Furthermore, chro-
mene and thiochromene analogs of the HIV-1 protease
inhibitor Ritonavir have been prepared and are under
clinical trials.8 According to reports of some of the patents
they also act as modulators of the estrogen receptors.9 In
addition, 4H-thiochromenoapomorphines have been found
to possess a high dopamine receptor binding affinity.10
A thorough literature survey revealed that the reports for
the synthesis of thiochromones are limited11 and are mainly
prepared from substituted thiophenols.12,13 2-Trifluoro-
methyl thiochromones were synthesized by treating 2-mer-
captophenyl ketones with trifluoroacetic anhydride in THF
in the presence of triethylamine.14 Further, thiochromone
derivatives have been achieved by an organocatalytic domino
thia-Michael/aldol reaction.15 However, the above methods
suffer from drawbacks such as toxic organic solvents, costly
reagents, cumbersome experimental procedures, and lacking
generality. Therefore, more general, efficient, and viable
routes with operational simplicity for the synthesis of thio-
chromone derivatives are very much desirable and would be
of great relevance to both synthetic and medicinal chemists.
It is pertinent to note that P2O5 is a mild, cheap, biode-
gradable, and readily available reagent, which has recently
emerged as a powerful catalyst for various organic trans-
formations.16 Furthermore, we devised a straightforward,
versatile, and one-pot synthesis of heterocycles utilizing
P2O5 as a catalyst.17 P2O5 is not only a versatile stable acidic
enolizing agent but also a dehydrating reagent uniquely
suited for a one-pot transformation. To the best of our
knowledge, no report on the use of P2O5 as a catalyst for the
synthesis of thiochromones utilizing β-oxodithioesters is
known. As part of our ongoing research program on the
development of new protocols for the synthesis of hetero-
cycles via a one-pot multicomponent reaction,18 herein we
report, for the first time, a one-pot three-component syn-
thesis of thiochromone frameworks by the coupling of
β-oxodithioesters, aldehydes, and cyclic 1,3-diketones cata-
lyzed by P2O5 under solvent-free conditions.
Recently, β-oxodithioesters have received much attention
as a key intermediate in the synthesis of various important
bioactive frameworks such as dihydropyrimidinone,19 pyrido-
pyrimidinone,19 pyrazole,20 benzo[a]quinolizine-4-thione,21
and 2H-chromene-2-thione.22 Therefore, we became intri-
gued in scouting the use of β-oxodithioesters to develop a
more generalized synthetic strategy for the synthesis of
functionalized thiochromones. β-Oxodithioesters are synthe-
sized by reported methods23 in good yields (70À80%). Thus,
when β-oxodithioesters 1 were treated with aldehydes 2 and
cyclic 1,3-diketones 3 under solvent-free conditions in the
presence of P2O5 at 100 °C, the corresponding 4-aryl-3-aroyl-
2-methylsulfanyl-4,6,7,8-tetrahydrothiochromen-5-ones 4aÀt
were obtained in high yields (Scheme 1).
Scheme 1. Synthesis of Thiochromen-5-ones 4
(6) Wang, G.; Yang, G.; Ma, Z.; Tian, W.; Fang, B.; Linbo Li, L. Int.
J. Chem. 2010, 2, 19.
(7) (a) Tilak, B. D.; Vaidya, V. M. Tetrahedron Lett. 1963, 9, 487.
(b) Tilak, B. D.; Jain, S. K. Indian J. Chem. 1969, 7, 17.
(8) (a) Kaye, P. T.; Musa, M. A.; Nchinda, A. T.; Nocanda, X. W.
Synth. Commun. 2004, 34, 2575. (b) Kaye, P. T. S. Afr. J. Chem. 2004, 57,
545.
(9) (a) Kaltenbach, R. F.; Robinson, S. P.; Trainor, G. L. U.S. Patent
2005/0267183 A1, December 1, 2005. (b) Zhang, X.; Sui, Z. U.S. Patent
2006/0020018 A1, January 26, 2006.
(10) Attila Sipos, A.; Toth, M.; Mueller, F. K. U.; Lehmann, J.;
Berenyi, S. Monatsh. Chem. 2009, 140, 473.
(11) (a) Katoaka, T.; Tomoto, A.; Shimizu, H.; Hori, M. J. Chem.
Soc., Perkin Trans. 1 1983, 2913. (b) Banzatti, C.; Mellini, P.; Salvadori,
P. Gazz. Chim. Ital. 1987, 117, 259. (c) Kaye, P. T. S. Afr. J. Sci. 2004,
100, 545.
ꢀ
(12) (a) Rasolofonjatovo, E.; Treguier, B.; Provot, O.; Hamze, A.;
Morvan, E.; Brion, J. -D.; Alami, M. Tetrahedron Lett. 2011, 52, 1036.
(b) Kenny, R. S.; Mashelkar, U. C.; Rane, D. M.; Bezawada, D. K.
Tetrahedron 2006, 62, 9280.
(13) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006, 128,
10354.
Initially, a mixture of 3-oxo-3-phenyldithiopropionic
acid methyl ester 1a (1.0 mmol), 4-nitrobenzaldehyde 2c
(14) (a) Usachev, B. I.; Shafeev, M. A.; Sosnovskikh, V. Y. Russ.
Chem. Bull. Int. Ed. 2006, 55, 504. (b) Usachev, B. I.; Sosnovskikh, V. Y.;
€
Shafeev, M, A.; Roschenthaler, G. -V. Phosphorus, Sulfur, Silicon 2005,
180, 1315.
(18) (a) Samai, S.; Nandi, G. C.; Kumar, R.; Singh, M. S. Tetrahe-
dron Lett. 2009, 50, 7096. (b) Samai, S.; Nandi, G. C.; Singh, P.; Singh,
M. S. Tetrahedron 2009, 65, 10155. (c) Nandi, G. C.; Samai, S.; Singh,
M. S. Synlett 2010, 1133. (d) Samai, S.; Nandi, G. C.; Singh, M. S.
Tetrahedron Lett. 2010, 51, 5555.
(19) Nandi, G. C.; Samai, S.; Singh, M. S. J. Org. Chem. 2010, 75,
7785.
(20) Peruncheralathan, S.; Khan, T. A.; Ila, H.; Junjappa, H. J. Org.
Chem. 2005, 70, 10030.
(21) Roy, A.; Nandi, S.; Ila, H.; Junjappa, H. Org. Lett. 2001, 3, 229.
(22) Verma, R. K.; Verma, G. K.; Raghuvanshi, K.; Singh, M. S.
Tetrahedron 2011, 67, 584.
(23) Samuel, R.; Asokan, C. V.; Suma, S.; Chandran, P.; Retnamma,
S.; Anabha, E. R. Tetrahedron Lett. 2007, 48, 8376.
(15) Rios, R.; Sunden, H.; Ibrahem, I.; Zhao, G. -L.; Eriksson, L.;
Cordova, A. Tetrahedron Lett. 2006, 47, 8547.
(16) (a) Massah, A. R.; Dabagh, M.; Shahidi, S.; Naghash, H. J.;
Momeni, A. R.; Aliyan, H. J. Iran. Chem. Soc. 2009, 6, 405. (b) Hajipour,
A. R.; Zarei, A.; Ruoho, A. E. Tetrahedron Lett. 2007, 48, 2881.
(c) Eshghi, H.; Rahimizadeh, M.; Saberi, S. Chin. Chem. Lett. 2008,
19, 1063. (d) Zarei, A.; Hajipour, A. R.; Khazdooz, L.; Mirjalili, B. F.;
Zahmatkesh, S. J. Mol. Catal. A: Chem. 2009, 301, 39.
(17) (a) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahe-
dron 2009, 65, 7129. (b) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S.
Tetrahedron Lett. 2009, 50, 7220. (c) Kumar, R.; Raghuvanshi, K.;
Verma, R. K.; Singh, M. S. Tetrahedron Lett. 2010, 51, 5933. (d) Verma,
G. K.; Raghuvanshi, K.; Verma, R. K.; Dwivedi, P.; Singh, M. S.
Tetrahedron 2011, 67, 3698.
Org. Lett., Vol. 13, No. 14, 2011
3763

(1.0 mmol), and dimedone 3a (1.0 mmol) was heated at
100 °C under solvent-free conditions in the presence of
different catalysts such as p-TSA, InCl3, KF-Alumina,
piperidine, SiO2, and P2O5 (20 mol % each) separately.
p-TSA, InCl3, KF-Alumina, piperidine, and SiO2 did
catalyze the reaction to furnish the desired product 4c
albeit in low yields (Table 1, entries 1À5). To our delight,
P2O5 gave the desired thiochromone 4c in 90% yield
(Table 1, entry 6). Encouraged by this result, we then
focused on optimizing the reaction conditions.
one-pot Knoevenagel condensation/Michael addition/
cyclization cascade reaction under the optimal conditions.
Representative results are shown in Table 2.
Table 2. Exploration of the Substrate Scope for the Synthesis
of 4
time
(h)
yielda
(%)
entry
R1
C6H5
R2
R3
4a
4b
4c
4d
4e
4f
C6H5
Me
H
1.75
1.5
82
86
90
87
83
84
82
75
82
83
74
80
82
72
74
78
80
74
82
76
C6H5
4-FC6H4
C6H5
4-NO2C6H4
2,4-Cl2C6H3
3-NO2C6H4
4-BrC6H4
Me
Me
Me
Me
Me
Me
H
1.5
C6H5
1.5
Table 1. Optimization of Reaction Conditions for the Synthesis
of 4a
C6H5
1.5
C6H5
2.0
yieldb
(%)
4g
4h
4i
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
2-thienyl
2-thienyl
2-thienyl
2-thienyl
3-pyridyl
3-pyridyl
2-furyl
4-ClC6H4
1.75
2.5
catalyst
(mol %)
temp
time
(h)
2-OMeC6H4
3-NO2C6H4
4-BrC6H4
entry
(°C)
1.5
1
p-TSA (20)
InCl3 (20)
KF-Alumina (20)
Piperidine (20)
SiO2 (20)
100
100
100
100
100
100
100
100
100
80
4
45
30
20
35
40
90
60
76
88
35
45
87
25
4j
Me
Me
H
1.75
2.0
2
6
4k
4l
2-ClC6H4
3
5
3-NO2C6H4
4-Cl-3-FC6H3
3-NO2C6H4
2,4-Cl2C6H3
4-BrC6H4
1.75
1.5
4
2.5
4
4m
4n
4o
4p
4q
4r
4s
4t
Me
Me
H
5
2.0
6
P2O5 (20)
1.5
3
2.0
7
P2O5 (10)
H
1.75
1.75
2.0
8
P2O5 (15)
2.5
1.5
4
2-furyl
4-NO2C6H4
4-MeC6H4
4-CF3C6H4
3-OHC6H4
Me
Me
Me
Me
9
P2O5 (25)
2-furyl
10
11
12
13
P2O5 (20)
2-furyl
1.75
2.5
P2O5 (20)
90
3
2-furyl
P2O5 (20)
120
80
1.5
4
a Isolated pure yields.
H3PO4 (40)
a Reaction of 3-oxo-3-phenyldithiopropionic acid methyl ester 1a
(1.0 mmol), 4-nitrobenzaldehyde 2c (1.0 mmol), and dimedone 3a (1.0
mmol) under solvent-free conditions. b Isolated pure yields.
Notably, a wide range of β-oxodithioesters 1aÀe,
aromatic aldehydes 2aÀm, and cyclic 1,3-diketones 3a,b
were well tolerated and proceeded smoothly under the
optimized reaction conditions. However, unfortunately,
when some aliphatic aldehydes (acetaldehyde, propio-
naldehyde, and isobutyraldehyde) and cyclic 1,3-diketones
The P2O5 loading was subsequently examined (entries
6À9), and it was found that 20 mol % of P2O5 provided the
maximum yield in minimum time (Table 1, entry 6). We
immediately undertook a study to examine the effects of
temperature on this transformation. The results demon-
strated that 100 °C appeared to be the optimum tempera-
ture for this transformation (Table 1, entries 6 and 10À12).
During the course of the reaction, water probably reacts
with P2O5 to form H3PO4, which may catalyze the reac-
tion. Thus, to check the efficacy of H3PO4, the above
model reaction was further investigated in the presence
of H3PO4 (10 mol %, 20 mol %, and 40 mol %) separately.
Phosphoric acid did catalyze the reaction to form the
desired thiochromone albeit in low yield (Table 1, entry
13), while the major product formed was characterized as a
xanthene derivative. Thus, the best yield, cleanest reaction,
and most facile workup were achieved employing 20 mol %
of P2O5 at 100 °C under solvent-free conditions. The
starting materials were completely consumed to afford
the desired compound that was highly visible on TLC
under UV light. Control experiments verified that the
reaction does not proceed in the absence of P2O5.
To generate a small library of functionalized thiochro-
men-5-ones 4, we next utilized a variety of substrates to
explore the synthetic scope and generality of this accelerated
Figure 1. ORTEP diagram of compound 4b.
Org. Lett., Vol. 13, No. 14, 2011
3764

generate adduct A, which acts as a Michael acceptor. The
enol form of β-oxodithioester 1 attacks Knoevenagel
adduct A in a Michael-type addition to produce an open
chain intermediate B. Intermediate B may undergo intra-
molecular cyclization via its two possible rotamers B1 and
B2 through pathways I and II to furnish thiochromone 4
and chromone C, respectively. B1 undergoes regiospecific
S-alkylation via route I followed by dehydration to give the
desired thiochromone 4. The alternative O-alkylationofB2
could lead to chromone C via route II. During our
investigation, we did not observe a trace of C, and 4 was
obtained exclusively. It should be emphasized that S-alky-
lation is more favorable than O-alkylation making the
protocol highly regioselective.
Scheme 2. Plausible Mechanism for the Formation of Thio-
chromen-5-one 4
In summary, we have developed a mild, efficient, and
versatile annulation protocol for densely functionalized
thiochromone derivatives involving β-oxodithioesters, al-
dehydes, and cyclic 1,3-diketones under solvent-free con-
ditions via a one-pot multicomponent domino reaction in
high yields. To the best of our knowledge, this is the first
report of thiochromone synthesis via ring annulation of
β-oxodithioesters utilizing P2O5, which acts as a catalyst as
well as a dehydrating agent in the same transformation. It
is worth mentioning that in the course of our reactions
three new bonds (two CÀC and one CÀS) and one
stereocenter are formed in one operation. Importantly,
this method is suitable to library generation, diversity-
oriented synthesis, and drug discovery, which makes the
methodology more attractive for organic synthesis.
Furthermore, it can be considered as environmentally
friendly, since it requires the use of neither solvent nor
metal-containing catalysts.
(Indane-1,3-dione and meldrum acid) were utilized under
the optimized reaction conditions, it led to mixture of
several very close spots on the TLC plate, which could
not be isolated, thus, limiting the scope of this reaction to
some extent.
The structures of all the newly synthesized compounds
were deduced from their satisfactory elemental and spectral
1
(IR, H, 13C NMR, and MS) studies. The mass spectra
of these compounds displayed molecular ion peaks at the
appropriate m/z values. Finally, the structure of one
representative compound 3-benzoyl-4-(4-fluorophenyl)-2-
methylsulfanyl-4,6,7,8-tetrahydrothio-chromen-5-one 4b
was confirmed unambiguously by the X-ray single crystal
diffraction analysis (see the Supporting Information)
(Figure 1).24
Although we have not established the mechanism of the
reaction experimentally, a plausible reaction scenario for
the domino cyclocondensation is outlined in Scheme 2.
The first step is believed to be the Knoevenagel condensa-
tion between the aldehyde 2 and cyclic 1,3-diketone 3 to
Acknowledgment. We gratefully acknowledge the gen-
erous financial support from the Council of Scientific and
Industrial Research(CSIR) and theDepartmentofScience
and Technology (DST), New Delhi. S.C. is thankful to
the University Grants Commission (UGC), New Delhi
for a junior research fellowship, and S.S. and G.C.N.
are grateful to CSIR, New Delhi for their senior research
fellowship.
Supporting Information Available. Full experimental
1
details; analytical and spectroscopic data (copies of H
and 13C NMR for compounds 4aÀt); X-ray data and
structure for compound 4b (CIF). This material is avail-
able free of charge via the Internet at http://pubs.acs.org.
(24) Crystallographic data for compound 4b have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication no. CCDC 819852. These data can be obtained free of
charge at www.ccdc.cam.ac.uk.
Org. Lett., Vol. 13, No. 14, 2011
3765