4-Dimethylamino pyridine-promoted one-pot three-component regioselective synthesis of highly functionalized 4 H -thiopyrans via heteroannulation of β-oxodithioesters

Article abstract of DOI:10.1021/co200203e

A highly convergent and regioselective heteroannulation protocol for the synthesis of hitherto unreported highly substituted 2-amino-4-(aryl/alkyl)-5- (aroyl/heteroaroyl)-3-(cyano/carboalkoxy)-6-methylthio-4H-thiopyran derivatives has been developed. This

Full text of DOI:10.1021/co200203e

Research Article
pubs.acs.org/acscombsci
4-Dimethylamino Pyridine-Promoted One-Pot Three-Component
Regioselective Synthesis of Highly Functionalized 4H-Thiopyrans via
Heteroannulation of β-Oxodithioesters
Rajiv Kumar Verma, Girijesh Kumar Verma, Gaurav Shukla, Anugula Nagaraju, and Maya Shankar Singh*
Department of Chemistry (Centre of Advanced Study), Faculty of Science, Banaras Hindu University, Varanasi-221005, India
S
* Supporting Information
ABSTRACT: A highly convergent and regioselective heteroannulation
protocol for the synthesis of hitherto unreported highly substituted 2-
amino-4-(aryl/alkyl)-5-(aroyl/heteroaroyl)-3-(cyano/carboalkoxy)-6-
methylthio-4H-thiopyran derivatives has been developed. This one-pot
three-component domino coupling of β-oxodithioesters, aldehydes, and
malononitrile/ethyl or methyl cyanoacetate is promoted by 4-
dimethylamino pyridine (DMAP) in solvent (dichloromethane
(DCM)) as well as under solvent-free conditions. Systematic
optimization of reaction parameters identified that the three-
component coupling (3CC) protocol is tolerant to a wide array of functionality providing densely functionalized 4H-thiopyrans
in excellent yields. The merit of this cascade Knoevenagel condensation/Michael addition/cyclization sequence is highlighted by
its high atom-economy, excellent yields, and efficiency of producing three new bonds (two C−C and one C−S) and one
stereocenter in a single operation.
KEYWORDS: 4H-Thiopyrans, β-oxodithioesters, malononitrile, ethyl/methyl cyanoacetate, 4-dimethylaminopyridine,
regioselective heteroannulation
pyran derivatives are used as DNA dependent protein kinase
inhibitors.18 Several synthetic methods are available for the
synthesis of 4H-thiopyran derivatives. One such strategy
involves hetero Diels−Alder reaction of α, β-unsaturated
thioketones with activated dienophiles.19 Substituted 4H-
thiopyrans have been generated from a three-component
reaction of α,β-unsaturated ketone, Lawesson’s reagent, and
alkynes under microwave irradiation.20 In addition 4H-
thiopyrans have also been synthesized utilizing various 2-
cyanothioacetamide derivatives, malononitrile, and alde-
hydes21/dimethyl acetylenedicarboxylate derivatives.22 Re-
cently, an easy access to substituted 4H-thiopyran-4-ones
from α-alkenoyl-α-carbamoyl ketene-S,S-acetals has been
reported.23
Albeit the reported approaches are useful tools for the
synthesis of 4H-thiopyran derivatives, most of them suffer from
significant limitations such as harsh reaction conditions,
expensive catalysts/reagents, prolonged reaction times, and
multistep synthesis.20,24 Therefore, the discovery of more
general, efficient, rapid, and viable routes are highly desirable.
β-Oxodithioesters exhibit promising structural features as
versatile intermediates in organic synthesis, and their utility has
been well recognized.25 As a part of our current interest toward
the development of new MCRs26 for the synthesis of
INTRODUCTION
■
The strategies regarding the construction and cleavage of bonds
represent the central theme in organic synthesis. A major
challenge of modern synthesis is to design efficient cascades
that provide maximum structural diversity and complexity with
a minimum number of synthetic steps for the rapid generation
of functionalized molecules with interesting properties.1 One
approach to address this challenge involves the development of
eco-compatible, multicomponent procedures. Multicomponent
reactions2−4 (MCRs) have become important tools for the
rapid construction of molecules with predefined complexity and
diversity to find their applications in chemical biology and drug
discovery.5,6 MCRs have been investigated extensively in
organic and diversity oriented synthesis; primarily because of
their convergent nature, superior atom economy, and
straightforward experimental procedures.7 Solvent-free meth-
ods have several advantages over reactions in solvents. Thus,
solvent-free methods can be used to modernize classical
procedures by making them simpler, cleaner, safer (depending
on scale and exothermicity), and easier.8,9
Thiopyrans are targets for both synthetic and medicinal
chemists because of their various applications in medicinal,10,11
biological,12 and industrial fields.10 They constitute the core of
many natural products as well as serve as versatile building
blocks in organic synthesis.13 Thiopyrans are contained in
potent drug precursors for the synthesis of various bioactive
compounds such as tetrahydrodicranenone B,14 serricornin,15
thromoboxanes,16 and cyclopentanoids.17 Moreover, 4-oxothio-
Received: December 3, 2011
Revised: January 26, 2012
Published: January 27, 2012
© 2012 American Chemical Society
224
dx.doi.org/10.1021/co200203e | ACS Comb. Sci. 2012, 14, 224−230

ACS Combinatorial Science
Research Article
interesting heterocycles, recently, we reported the synthesis of
important scaffolds such as thiochromene-5-ones,27a chromene-
2-thiones,27b dihydropyrimidinones,27c and pyridopyrimidino-
nes27c utilizing β-oxodithioesters as one of the components.
Consequently, with the aim to devise a more general and
simple synthetic route for thiopyrans, herein we report the first
one-pot three-component regioselective synthesis of 4H-
thiopyran frameworks via domino coupling of β-oxodithioest-
ers, aldehydes, and malononitrile/ethyl or methyl cyanoacetate
promoted by DMAP in solvent (dichloromethane (DCM)) as
well as under solvent-free conditions in excellent yields.
RESULTS AND DISCUSSION
■
β-Oxodithioesters are not commercially sourced, and are
prepared according to reported procedures.25d,27b To the best
of our knowledge, there is no report on the synthesis of
pentasubstituted-4H-thiopyran derivatives from β-oxodithioest-
ers having aroyl/heteroaroyl groups at the 5-position and
methylthio group at 6-position of the ring. In our effort to
develop a new MCR for the synthesis of 4H-thiopyrans, we
devised a cascade strategy as outlined retrosynthetically in
Scheme 1.
Scheme 1. Retrosynthetic Pathways for the Synthesis of
Target 4H-Thiopyran Derivatives
On the basis of retrosynthetic analysis, we envisioned that
coupling of 1, 2, and 3 would lead to our desired thiopyran 4.
This strategy provided three new σ bonds and one stereogenic
center in a single operation through Knoevenagel condensa-
tion/Michael addition/intramolecular cyclization sequence. On
the basis of a proposed retrosynthetic scheme, a number of
starting materials are readily available for the synthesis of a
small combinatorial library of 4H-thiopyran derivatives (Figure
1).
Accordingly, 3-hydroxy-3-(p-methoxyphenyl)-prop-2-enedi-
thioate 1{1}, 2,4-dichlorobenzaldehyde 2{1}, and malononitrile
3{1} were selected as the substrates for reaction development.
Thus, to achieve our goal, test reactions between 1{1}, 2{1},
and 3{1} were performed by screening a variety of catalysts in
different solvents as well as under solvent-free conditions
(Table 1). Triethylamine (TEA) and K2CO3 could not trigger
the reaction even after 15 h of reflux in EtOH and CH3CN,
respectively (Table 1, entries 1 and 2), while DMAP in
refluxing dichloromethane provided the desired thiopyran 4{1,
1, 1} as exclusive product in 90% yield (Table 1, entry 3). With
DMAP base as good promoter in hand, next we intended to
optimize its loading, and it was found that the use of 20 mol %
of DMAP provided the best result (Table 1, entry 4). Reducing
the mol % of DMAP in the reaction increased the reaction time
and lowered the yield (Table 1, entry 5). However, a little β-
oxodithioester remained unreacted, so we enhanced the molar
ratio of aldehyde and malononitrile (1.1 equiv) to effect the
complete consumption of β-oxodithioester. No better yield was
obtained when the DMAP was increased to 1.0 equiv (Table 1,
entry 3). Next, to find the most suitable solvent for DMAP,
various solvents such as EtOH, THF, H2O, and CH3CN were
Figure 1. Diversity of Reagents.
screened (Table 1, entries 6−9). The results demonstrated that
DCM appeared to be the best choice for this transformation in
terms of reaction time and yield. Recently solvent-free reactions
have gained much attention in organic synthesis, so we decided
to carry out the reactions under solvent-free conditions. Thus,
the above test reaction was performed in the presence of 20
mol % of DMAP at different temperatures under solvent-free
conditions (Table 1, entries 10−12). It was found that 20 mol
% of DMAP at 70 °C provided the desired 4H-thiopyran in
90% yield as major product under solvent-free conditions
(Table 1, entry 11). Reducing the DMAP loading from 20 mol
% to 10 mol % led to a significant decrease in the yield (Table
1, entry 13). Interestingly, the use of 20 mol % of pyridine in
the model reaction did not give even a trace of the product
(Table 1, entry 14). Some other basic and acidic catalysts such
as piperidine, DBU, silica-H2SO4, and SnCl2·2H2O were also
investigated under solvent-free conditions, but results were not
satisfactory (Table 1, entries 15−18).
The above observations show the reaction proceeds well in
DCM in presence of 20 mol % of DMAP. The mild reaction
condition and clean TLC pattern are main advantages of the
reaction in refluxing DCM. The reaction under solvent-free
condition was faster and gives almost parallel yields, but some
225
dx.doi.org/10.1021/co200203e | ACS Comb. Sci. 2012, 14, 224−230

ACS Combinatorial Science
Research Article
a
Table 1. Optimization of Reaction Conditions for the Synthesis of 4H-Thiopyran
b
entry
catalyst
TEA
loading (mol %)
solvent
temp (°C)
time
15 h
yield (%)
1
100
100
100
20
10
20
20
20
20
20
20
20
10
20
20
20
20
20
EtOH
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
EtOH
THF
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
reflux
100
c
2
K2CO3
15 h
c
3
DMAP
2 h
90
92
82
75
72
70
80
88
90
80
78
c
4
DMAP
2 h
5
DMAP
8 h
6
DMAP
4.5 h
3.5 h
4.5 h
40 min
15 min
20 min
80 min
70 min
8 h
7
DMAP
8
DMAP
H2O
9
DMAP
CH3CN
none
10
11
12
13
14
15
16
17
18
DMAP
DMAP
none
70
DMAP
none
55
DMAP
none
70
pyridine
piperidine
DBU
DCM
none
reflux
70
4.5 h
6 h
40
20
15
none
70
SnCl2·2H2O
SiO2−H2SO4
none
70
10 h
none
70
12 h
c
a
b
Reaction of methyl-3-oxo-3-(p-methoxyphenyl)dithiopropionate 1{1}, 2,4-dichlorobenzaldehyde 2{1}, and malononitrile 3{1}. Isolated pure
c
yields. No desired product or complex TLC pattern.
color impurities were visible on TLC, which interferes with
purification of the product. Thus, most of the reactions have
been carried out in DCM.
Having identified the optimized conditions (DMAP 20 mol
%, DCM, 40 °C), we then explored the generality and synthetic
scope of this three-component coupling protocol by synthesiz-
ing a chemset 4 (Scheme 2). A wide range of β-oxodithioesters
our surprise, in case of phenylacetonitrile no reaction was
observed and the starting materials were completely uncon-
sumed, while cyanoacetamide and benzoyl acetonitrile showed
several very close spots on TLC plate that could not be isolated.
Notably, reaction with 2-hydroxybenzaldehyde and ferrocene
carboxaldehyde yielded only a Knoevenagel condensation
product. Thus, these observations limit the scope of this
reaction to some extent. To overcome the above problems, the
test reaction was performed under a variety of conditions, but
to no avail.
Scheme 2. Synthesis of Pentasubstituted-4H-Thiopyrans 4
The structures of all the thiopyran derivatives 4 were
1
deduced from their satisfactory elemental and spectral (IR, H,
13C NMR, and Mass) studies. The FT IR spectra of compounds
show a peak at 2100−2200 cm−1 for CN stretching and a
doublet for symmetric and antisymmetric stretching bands
1
around 3200−3300 cm−1 for NH2 groups. H NMR spectra
showed a sharp singlet in the range 4.59−5.74 ppm for the
proton present on C-4 and the sharp singlet around 2.30 ppm
for the methylthio group at the 6-position of the ring. The
presence of D2O exchangeable signal at 4.6−4.8 ppm can be
assigned to NH2 group at C-2 position. The shifting of this
signal to higher δ (6.5−6.6 ppm) in case of ethyl and methyl
cyanoacetate may be attributed to intramolecular hydrogen
bonding with ester functionality present at the C-3 position,
which further proved the formation of the expected skeleton.
The mass spectra of these compounds displayed molecular ion
peaks at the appropriate m/z values. Finally, the structure of
one representative compound 2-amino-6-methylthio-5-(thio-
phene-2-carbonyl)-4-thiophen-2-yl-4H-thiopyran-3-carbonitrile
4{4,11,1} was confirmed unambiguously by single crystal X-ray
1{1−7}, aldehydes (aromatic, heteroaromatic, and aliphatic)
2{1−17}, and malononitrile/cyanoacetic esters 3{1−3} were
well tolerated under the reaction conditions providing the
corresponding 4H-thiopyrans in excellent yields (Table 2).
Even extremely electron-rich aromatic β-oxodithioesters such as
1{4} and 1{5} proceeded smoothly (Table 2, entries 15−24).
However, in comparison to aromatic aldehydes, heterocyclic
and aliphatic aldehydes gave lower yields and required longer
reaction times.
To add further diversity to the thiopyran framework, reaction
of 1{1} and 2{1} with some other active cyano partners such as
phenyl acetonitrile, cyanoacetamide, and benzoyl acetonitrile
was also performed under optimized reaction conditions. To
226
dx.doi.org/10.1021/co200203e | ACS Comb. Sci. 2012, 14, 224−230

ACS Combinatorial Science
Research Article
Table 2. Scope Exploration: Variation of R1, R2, and R3 for
the Synthesis of Chemset 4
Scheme 3. Plausible Mechanism for the Formation of
Thiopyran 4
a
entry
R1
R2
R3
CN
product
yield (%)
b
1
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-OMeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
2-thienyl
2,4-Cl2C6H3
4-NO2C6H4
4-ClC6H4
4-MeC6H4
4-BrC6H4
4-OMeC6H4
4-NO2C6H4
4-NO2C6H4
4-OMeC6H4
C6H5
4{1,1,1}
4{1,7,1}
4{1,2,1}
4{1,16,1}
4{1,5,1}
4{1,15,1}
4{1,7,2}
4{2,7,1}
4{2,15,1}
4{2,10,1}
4{2,2,1}
4{3,7,1}
4{3,5,2}
4{3,10,3}
4{4,5,1}
4{4,11,1}
4{4,2,2}
4{4,13,1}
4{5,12,1}
4{5,9,1}
4{5,6,1}
4{5,14,1}
4(5,11,3}
4{5,9,2}
4{6,8,1}
4{6,3,1}
4{7,16,1}
4{7,17,1}
4{7,4,1}
92, 90
2
CN
93
91
87
88
84
92
90
82
88
3
CN
4
CN
5
CN
6
CN
7
CO2Me
CN
8
9
CN
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
CN
b
4-ClC6H4
4-NO2C6H4
4-BrC6H4
C6H5
CN
86, 85
b
CN
88, 89
CO2Me
CO2Et
CN
85
86
b
4-BrC6H4
2-thienyl
80, 80
2-thienyl
CN
78
84
70
76
81
80
65
81
2-thienyl
4-ClC6H4
Cyclohexyl
2-furyl
CO2Me
CN
2-thienyl
2-furyl
CN
2-furyl
3-NO2C6H4
4-FC6H4
CN
2-furyl
CN
2-furyl
n-heptane
2-thienyl
CN
2-furyl
CO2Et
CO2Me
CN
b
2-furyl
3-NO2C6H4
2-NO2C6H4
2-ClC6H4
4-MeC6H4
3-OHC6H4
3-ClC6H4
2,4-Cl2C6H3
81, 79
4-biphenyl
4-biphenyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
84
81
84
80
pathways I and II to furnish thiopyran 4 and pyran 5,
respectively. B1 undergoes regiospecific S-cyclization via route I
to give the desired thiopyran 4. The alternative O-cyclization of
B2 could lead to pyran 5 via route II. During our investigation,
we did not observe a trace of 5, and only 4 was obtained
exclusively. It should be emphasized that because of higher
nucleophilicity of sulfur, S-cyclization is more favorable over O-
cyclization making this protocol highly regioselective. The
above-mentioned regioselectivity has also been supported by
the presence of a peak corresponding to CO and absence of
CS peak in 13C NMR spectra of the thiopyrans.
CN
CN
CN
b
CN
85, 82
CO2Et
4{7,1,3}
87
a
b
Isolated yields under optimized conditions in DCM. Isolated yields
under solvent-free conditions.
diffraction (XRD) analysis (see the Supporting Information)
(Figure 2).28
CONCLUSION
■
In summary, a facile and efficient regioselective access to
hitherto unreported 2-amino-4-(aryl/alkyl)-5-(aroyl/heteroaro-
yl)-3-(cyano/carboalkoxy)-6-methylthio-4H-thiopyran deriva-
tives has been developed via direct annulation of β-
oxodithioesters with aldehydes and malononitrile promoted
by DMAP by 1−2 (C−S) and 3−4, 4−5 (C−C) bond
formation through domino Knoevenagel/Michael/cyclization
sequence. The versatility of the functionality such as amino,
cyano, carbonyl, and alkylthio groups make these compounds
promising candidates as precursors for further synthetic
transformations to meet the need of combinatorial chemistry,
chemical biology, and drug discovery. The simplicity of
execution, mild conditions, excellent yields, easy purification,
and high reactivity profile of DMAP make this protocol most
attractive for academic research and practical applications.
Figure 2. ORTEP diagram of compound 4{4,11,1}.
On the basis of the above experimental results together with
the related reports, a plausible reaction scenario for this one-pot
three-component heteroannulation is outlined in Scheme 3. It
is conceivable that initially the aldehyde 2 undergoes DMAP
promoted Knoevenagel condensation with malononitrile 3 to
give adduct A, which acts as Michael acceptor. The enol form of
β-oxodithioester 1 attacks the Knoevenagel adduct A in a
Michael-type addition to produce an open chain azaketene type
intermediate B. Intermediate B may undergo intramolecular
cyclization via its two possible rotamers B1 and B2 through
EXPERIMENTAL PROCEDURES
■
General Information. All reagents were commercial and
purchased from Merck, Aldrich, and Fluka and were used as
received. 1H and 13C NMR spectra were recorded on JEOL AL
300 FT-NMR spectrometer. Chemical shifts are given as δ
227
dx.doi.org/10.1021/co200203e | ACS Comb. Sci. 2012, 14, 224−230

ACS Combinatorial Science
Research Article
value with reference to tetramethylsilane (TMS) as the internal
standard. The IR spectra were recorded on Varian 3100 FT-IR
spectrophotometer. Mass spectra were recorded on Thermo
LCQ Advantage Max Ion Trap Mass Spectrometer from
Central Drug Research Institute, Lucknow. The C, H, and N
analyses were performed from microanalytical laboratory with
an Exeter Analytical Inc. “Model CE-400 CHN Analyzer”. XRD
was measured on Xcalibur Oxford CCD Diffractometer. All the
reactions were monitored by TLC using precoated sheets of
residue thus obtained was purified by column chromatography
over silica gel using ethyl acetate/n-hexane (1:3) as eluent to
afford pure thiopyrans. Experimental Data of 4{1,1,1} is as
follows: Yellow solid, mp 136−137 °C. FT IR (KBr, cm−1):
3320, 3208, 2926, 2842, 2187, 1626, 1594, 1256, 1167, 843. 1H
NMR (300 MHz, CDCl3): δ 7.69 (d, J = 9.0 Hz, 2H, ArH),
7.45 (d, J = 8.4 Hz, 1H, ArH), 7.25−7.20 (m, 2H, ArH), 6.88
(d, J = 8.7 Hz, 2H, ArH), 5.18 (s, 1H, CH), 4.67 (s, 2H, NH2),
3.86 (s, 3H, OCH3), 2.28 (s, 3H, SCH3). 13C NMR (75 MHz,
CDCl3): δ 192.0, 164.1, 153.6, 137.6, 136.2, 134.2, 133.5, 131.5,
130.6, 129.6, 128.7, 127.8, 126.0, 117.4, 114.0, 75.3, 55.5, 43.4,
18.2. ESI MS (m/z): 463 (M++1); Anal. Calcd for
C21H16Cl2N2O2S2: C, 54.43; H, 3.48; N, 6.05%. Found: C,
54.34; H, 3.60; N, 5.44%.
silica gel G/UV-254 of 0.25 mm thickness (Merck 60F254
using UV light for visualization. Melting points were
)
determined with Buchi B-540 melting point apparatus and
̈
are uncorrected.
General Procedure for the Synthesis of β-Oxodi-
thioester 1{1-7}..27b Appropriate aryl/heteroaryl ketone (10
mmol) was added to a suspension of NaH (60% suspension in
mineral oil, 0.80 g, 20 mmol) in DMF/hexane solvent mixture
(1:4, 20 mL). After 30 min, dimethyl trithiocarbonate (10
mmol) was slowly added to the reaction mixture and stirred
well for 2 h. After completion of the reaction (monitored by
TLC), the reaction mixture was washed with hexane to remove
unreacted ketone and dimethyl trithiocarbonate. Reaction
mixture was acidified with 1 N HCl (20 mL) to get the β-
oxodithioester precipitated. The precipitated β-oxodithioester
was extracted with dichloromethane (2 × 20 mL) followed by
washing with brine (2 × 25 mL) and dried over anhydrous
sodium sulfate. The solvent was evaporated under vacuum, and
the residue obtained was purified by column chromatography
over silica gel using hexane as eluent to give the corresponding
β-oxodithioesters 1{1−7} in high yields. Experimental data of
ASSOCIATED CONTENT
■
S
* Supporting Information
Representative experimental procedures, analytical and spectral
data of chemset 4, single crystal XRD data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*Phone: +91-542-6702502. Fax: +91-542-2368127. E-mail:
mssinghbhu@yahoo.co.in.
Funding
This work was carried out under financial support from the
Council of Scientific and Industrial Research and the
Department of Science and Technology, New Delhi. R.K.V.
and G.S. are grateful to CSIR, New Delhi for a senior research
fellowship and junior research fellowship, respectively, and
G.K.V. and A.N. are thankful to the University Grants
Commission (UGC), New Delhi, for their junior research
fellowships.
ο
1{1} is as follows: Yellow solid, yield 73%, mp. 74−75 C. FT
IR (KBr, cm−1): 3430, 1603, 1582, 1545, 1503, 1430, 1232,
1180, 1052 1H NMR (300 MHz, CDCl3): δ 15.16 (s, 1H, OH),
7.86 (d, J = 8.7 Hz, 2H, ArH), 6.94 (d + s, J = 8.7 Hz, 3H, ArH
+ HOlefin), 3.87 (s, 3H, OCH3), 2.65 (s, 3H, SCH3). 13C NMR
(75 MHz, CDCl3): δ 215.5, 169.4, 162.7, 128.6, 126.1, 114.1,
107.0, 55.4, 16.9. FAB MS (m/z): 241 (M++1); Anal. Calcd for
C11H12O2S2: C, 54.97%; H, 5.03%. Found: C, 54.88%; H,
4.91%.
Notes
The authors declare no competing financial interest.
General Procedure for the Synthesis of Highly
Substituted 2-Amino-6-methylthio-4H-thiopyrans De-
rivatives 4. Method A. To a mixture of β-oxodithioester 1
(1.0 mmol), aldehyde 2 (1.1 mmol), and malononitrile (or
cyanoacetates) 3 (1.1 mmol) in dichloromethane (10 mL), 4-
dimethylaminopyridine (20 mol %, 0.2 mmol, 0.024 g) was
added. The reaction mixture was heated at reflux with constant
stirring until the completion of the reaction (monitored by
TLC). The reaction mixture was cooled to room temperature,
and the solvent was evaporated under vacuum. The contents
were dissolved in chloroform (20 mL) and washed with water
(1 × 20 mL) followed by brine (1 × 20 mL). The organic layer
was dried over anhydrous Na2SO4, and the solvent was
evaporated under vacuum. The residue thus obtained was
purified by column chromatography over silica gel using ethyl
acetate/n-hexane (1:3) as eluent to afford pure thiopyrans.
Method B. A mixture of β-oxodithioester 1 (1.0 mmol),
aldehyde 2 (1.1 mmol), and malononitrile (or cyanoacetates) 3
(1.1 mmol) was heated in the presence of DMAP (20 mol %,
REFERENCES
■
(1) (a) Schreiber, S. L. Target-Oriented and Diversity-Oriented
Organic Synthesis in Drug Discovery. Science 2000, 287, 1964−1969.
(b) Multicomponent Reactions; Zhu, J.-P., Bienayme, H., Eds.; Wiley-
VCH: Weinheim, Germany, 2005; p 1499. (c) Trost, B. M. Atom
Economy-A Challenge for Organic Synthesis: Homogeneous Catalysis
Leads the Way. Angew. Chem., Int. Ed. Engl. 1995, 34, 259−281.
(d) Tietze, L. F. Domino Reactions in Organic Synthesis. Chem. Rev.
1996, 96, 115−136.
(2) (a) Domling, A. Recent Developments in Isocyanide Based
Multicomponent Reactions in Applied Chemistry. Chem. Rev. 2006,
106, 17−89. (b) D’Souza, D. M.; Muller, T. J. J. Multicomponent
Syntheses of Heterocycles by Transition-Metal Catalysis. Chem. Soc.
Rev. 2007, 36, 1095−1108. (c) Cariou, C. C. A.; Clarkson, G. J.;
Shipman, M. Rapid Synthesis of 1,3,4,4-Tetrasubstituted Beta-Lactams
from Methyleneaziridines using a Four-Component Reaction. J. Org.
Chem. 2008, 73, 9762−9764. (d) Pedro, M. P. G; Pedro, M. S. D. C.;
Montalbano, F.; Candeias, N. R. Boronic Acids and Esters in the
Petasis-Borono Mannich Multicomponent Reaction. Chem. Rev. 2010,
110, 6169−6193. (e) Artemev, A. V.; Gusarova, N. K.; Malysheva, S.
F.; Mamatyuk, V. I.; Gatilov, Y. V.; Ushakov, I. A.; Trofimov, B. A.
One-Pot Atom-Economic Synthesis of Thioselenophosphinates via a
New Multicomponent Reaction of Secondary Phosphanes with
Elemental Sulfur, Selenium, and Amines. Eur. J. Org. Chem. 2010,
6157−6160. (f) Banfi, L.; Basso, A.; Giardini, L.; Riva, R.; Rocca, V.;
Guanti, G. Tandem Ugi MCR/Mitsunobu Cyclization as a Short,
ο
0.2 mmol, 0.024 g) at 70 C. After completion of the reaction
(monitored by TLC), the contents was dissolved in chloroform
(20 mL) and washed with water (1 × 20 mL) followed by brine
(1 × 20 mL). The organic layer was dried over anhydrous
Na2SO4, and the solvent was evaporated under vacuum. The
228
dx.doi.org/10.1021/co200203e | ACS Comb. Sci. 2012, 14, 224−230

ACS Combinatorial Science
Research Article
Protecting-Group-Free Route to Benzoxazinones with Four Diversity
Points. Eur. J. Org. Chem. 2011, 100−109.
Chem. 2010, 12, 206−214. (d) Jiang, B.; Tu, S.-J.; Kaur, P.; Wever, W.;
Li, G. Four-Component Domino Reaction Leading to Multi-
functionalized Quinazolines. J. Am. Chem. Soc. 2009, 131, 11660−
11661. (e) Chen, Z.; Wu, J. Efficient Generation of Biologically Active
H-pyrazolo[5,1-a]isoquinolines via Multicomponent Reaction. Org.
Lett. 2010, 12, 4856−4859.
(3) (a) Staben, S. T.; Blaquiere, N. Four-Component Synthesis of
Fully Substituted 1,2,4-Triazoles. Angew. Chem., Int. Ed. 2010, 49,
325−328. (b) Yue, T.; Wang, M.-X.; Wang, D.-X.; Masson, G.; Zhu, J.
Catalytic Asymmetric Passerini-Type Reaction: Chiral Aluminum-
Organophosphate-Catalyzed Enantioselective Alpha-addition of Iso-
cyanides to Aldehydes. J. Org. Chem. 2009, 74, 8396−8399.
(c) Trofimov, B. A.; Andriyankova, L. V.; Belyaeva, K. V.; Malkina,
A. G.; Nikitina, L. P.; Afonin, A. V.; Ushakov, I. A. C2-
Functionalization of 1-Substituted Imidazoles with Aldehydes and
Electron-Deficient Acetylenes: A Novel Three-Component Reaction.
Eur. J. Org. Chem. 2010, 1772−1777. (d) Ma, N.; Jiang, B.; Zhang, G.;
Tu, S.-J.; Wever, W.; Li, G. New Multicomponent Domino Reactions
(MDRs) in Water: Highly Chemo-, Regio- and Stereoselective
Synthesis of Spiro{[1,3]dioxanopyridine}-4,6-diones and Pyrazolo-
[3,4-b]pyridines. Green Chem. 2010, 12, 1357−1361. (e) Ruijter, E.;
Scheffelaar, R.; Orru, R. V. A. Multicomponent Reaction Design in the
Quest for Molecular Complexity and Diversity. Angew. Chem., Int. Ed.
2011, 50, 6234−6246.
(8) (a) Tanaka, K. Solvent-free Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2003. (b) Hernandez, J. G.; Juaristi, E. Green
́
Synthesis of α,β- and β,β-Dipeptides under Solvent-Free Conditions. J.
Org. Chem. 2010, 75, 7107−7111. (c) Li, S.; Wang, J.-X.; Wen, X.; Ma,
X. Mild and Efficient Barbier Allylation Reaction Mediated by
Magnesium Powder Under Solvent-free Conditions. Tetrahedron
2011, 67, 849−855.
(9) (a) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.;
Machado, P. Solvent-Free Heterocyclic Synthesis. Chem. Rev. 2009,
109, 4140−4182. (b) Choudhary, G.; Peddinti, R. K. An Expeditious,
Highly Efficient, Catalyst-free and Solvent-free Synthesis of Nitro-
amines and Nitrosulfides by Michael Addition. Green Chem. 2011, 13,
276−282. (c) Iliescu, S.; Ilia, G.; Plesu, N.; Popa, A.; Pascariu, A.
Solvent and Catalyst-free Synthesis of Polyphosphates. Green Chem.
2006, 8, 727−730. (d) Yan, S.; Chen, Y.; Liu, L.; He, N.; Lin, J. Three-
Component Solvent-Free Synthesis of Highly Substituted Bicyclic
Pyridines Containing a Ring-Junction Nitrogen. Green Chem. 2010, 12,
2043−2052.
(10) (a) Ingall, A. H. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, U.K., 1984; Vol.
3, p 885, and previous references cited therein. (b) Mayer, R.; Broy,
W.; Zahradnik, R. Monocyclic Sulphur Containing Pyrones. Adv.
Heterocycl. Chem. 1967, 8, 219−276 , and previous references cited
therein. (c) Hepworth, J. D.; Gabbutt, C. D.; Heron, B. M. In
Comprehensive Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon, Oxford, U.K., 1996; Vol. 5, p 325.
(11) (a) Sun, X.; Wong, J. R.; Song, K.; Hu, J.; Garlid, K. D.; Chen, L.
B. AA1, a Newly Synthesized Monovalent Lipophilic Cation, Expresses
Potent in vivo Antitumor Activity. Cancer Res. 1994, 54, 1465−1471;
(b) Bertenshaw, D. E.; Getman, D.; Heintz, R. M.; Talley, J. J.; Reed,
K. L.; Chruschiel, R. A.; Clare, M. Cyclic Sulfone Containing
Retroviral Protease Inhibitors. PCT Int. Appl. WO 9414793 A1
19940707, 1994. Chem. Abstr. 1994, 123, 169509;(c) Britton, J. E.;
Fang, J.; Heyer, D.; Miller, A. B.; Navas-III, F.; Smalley Jr, T. L.;
Zuercher, W. J.; Kalamreddy, S. R. A Preparation of Derivatives of
Cycloalkylidene and (Thio)pyranylidene, Useful as Estrogen Receptor
Modulators. PCT Int. Appl. WO 2005012220 A2 20050210, 2005.
Chem. Abstr. 2005, 142, 219151.
(12) (a) Daniel, D.; Rene, R. Study of nitro derivatives with
biological interest.XXXVII. Some pyran analogs of nitrobenzofurans
and nitronaphthofurans. Eur. J. Med. Chem. 1984, 19, 477−479;
(b) Sawaki, M.; Iwataki, I.; Hirono, Y.; Ishikawa, H.; Wakai, A.; Asada,
M. Japanese Patent 75129565, 1978. Chem. Abstr. 1978, 89, 43112.
(c) Herrinton, P. M.; Owen, C. E.; Gage, J. R. Iodination and Metal
Halogen Exchange of Aromatic Compounds: An Improved Prepara-
tion of a Key Oxazolidinone Antibiotic Intermediate. Org. Process Res.
Dev. 2001, 5, 80−83.
(13) (a) Ingall, A. H. In Comprehensive Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, U.K., 1996; Vol. 5, p 501. (b) Vedejs, E.; Krafft, G. A. Cyclic
Sulfides in Organic Synthesis. Tetrahedron 1982, 38, 2857−2881.
(14) Casy, G.; Taylor, R. J. K. The Synthesis of 2,3-Disubstituted
Cyclopentenones Using the Ramberg-Baecklund Reaction in Con-
junction with Organocopper Chemistry. Tetrahedron 1989, 45, 455−
466.
(4) (a) Duan, X.-H.; Liu, X.-Y.; Guo, L.-N.; Liao, M.-C.; Liu, W.-M.;
Liang, Y.-M. Palladium-Catalyzed One-Pot Synthesis of Highly
Substituted Furans by a Three-Component Annulation Reaction. J.
Org. Chem. 2005, 70, 6980−6983. (b) Wei, H.-L.; Yan, Z.-Y.; Niu, Y.-
N.; Li, G.-Q.; Liang, Y.-M. New Light on an Old Story: Facile and
Efficient Synthesis of 1,3-Diaryl-5-spirohexahydropyrimidines via a Six-
Molecule, Three-Component Mannich-Type Reaction. J. Org. Chem.
2007, 72, 8600−8603. (c) Cui, S.-L.; Wang, J.; Wang, Y.-G. Copper-
Catalyzed Multicomponent Reaction: Facile Access to Novel
Phosphorus Amidines. Org. Lett. 2008, 10, 1267−1269. (d) Shen,
Z.-L.; Xu, X.-P.; Ji, S.-J. Bronsted Base-Catalyzed One-Pot Three-
Component Biginelli-Type Reaction: An Efficient Synthesis of 4,5,6-
Triaryl-3,4-dihydropyrimidin-2(1H)-one and Mechanistic Study. J.
Org. Chem. 2010, 75, 1162−1167. (e) Guan, X.-Y.; Yang, L.-P.; Hu, W.
Cooperative Catalysis in Multicomponent Reactions: Highly Enantio-
selective Synthesis of γ-Hydroxyketones with a Quaternary Carbon
Stereocenter. Angew. Chem., Int. Ed. 2010, 49, 2190−2192. (f) Floch,
́
C. L.; Gall, E. L.; Leonel, E.; Koubaa, J.; Martens, T.; Retailleau, P. A
Cobalt-Catalyzed Multicomponent Approach to Novel 2,3-Di- and
2,2,3-Trisubstituted 3-Methoxycarbonyl-γ-butyrolact-ones. Eur. J. Org.
Chem. 2010, 5279−5286.
(5) (a) Sunderhaus, J. D.; Dockendorff, C.; Martin, S. F. Applications
of Multicomponent Reactions for the Synthesis of Diverse
Heterocyclic Scaffolds. Org. Lett. 2007, 9, 4223−4226. (b) Haurena,
C.; Gall, E. L.; Sengmany, S.; Martens, T.; Troupel, M. A Straight-
forward Three-Component Synthesis of α-Amino Esters Containing a
Phenylalanine or a Phenylglycine Scaffold. J. Org. Chem. 2010, 75,
2645−2650.
(6) (a) Willy, B.; Muller, T. J. J. Regioselective Three-Component
Synthesis of Highly Fluorescent 1,3,5-Trisubstituted Pyrazoles. Eur. J.
Org. Chem. 2008, 4157−4168. (b) Heravi, M. M.; Baghernejad, B.;
Oskooie, H. A.; Hekmatshoar, R. A Novel and Facile Synthesis of 2-
(Cyclohexylamino)-6,7-dihydro-3-aryl-1H-indol-4(5H)-ones via a
One-pot Multicomponent Reaction. Tetrahedron Lett. 2008, 49,
6101−6103. (c) Adib, M.; Sheikhi, E.; Kavoosi, A.; Bijanzadeh, H.
R. Synthesis of 2-(Alkylamino)-5-{alkyl[(2-oxo-2H-chromen-3-yl)-
carbonyl]amino}-3,4-furandicarboxylates using a Multicomponent
Reaction in Water. Tetrahedron 2010, 66, 9263−9269. (d) Chen,
W.-B.; Wu, Z.-J.; Pei, Q.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C.
Highly Enantioselective Construction of Spiro[4H-pyran-3,3′-oxin-
doles] Through a Domino Knoevenagel/Michael/Cyclization Se-
quence Catalyzed by Cupreine. Org. Lett. 2010, 12, 3132−3135.
(7) (a) Ganem, B. Strategies for Innovation in Multicomponent
Reaction Design. Acc. Chem. Res. 2009, 42, 463−472. (b) Toure, B. B.;
Hall, D. G. Natural Product Synthesis Using Multicomponent
Reaction Strategies. Chem. Rev. 2009, 109, 4439−4486. (c) Zhou,
H.; Zhang, W.; Yan, B. Use of Cyclohexylisocyanide and Methyl 2-
Isocyanoacetate as Convertible Isocyanides for Microwave-Assisted
Fluorous Synthesis of 1,4-Benzodiazepine-2,5-dione Library. J. Comb.
(15) Ward, D. E.; Jheengut, V.; Beye, G. E. Thiopyran Route to
Polypropionates: An Efficient Synthesis of Serricornin. J. Org. Chem.
2006, 71, 8989−8992.
(16) (a) McDonald, B. P.; Steele, R. W.; Sutherland, J. K.; Leslie, B.
W.; Brewster, A. Synthetic Approaches to Thiathromboxanes. Part 2.
Synthesis of Structural Isomers of Thiathromboxane A2. J. Chem. Soc.,
Perkin Trans 1 1988, 675−679. (b) Casy, G.; Lane, S.; Taylor, R. J. K.
Preparation of Thiathromboxane Analogs and Formal Total Synthesis
229
dx.doi.org/10.1021/co200203e | ACS Comb. Sci. 2012, 14, 224−230

ACS Combinatorial Science
Research Article
of Dithiathromboxane A2 Based on Conjugate Addition Reactions of
Thiin-4-ones. J. Chem. Soc., Perkin Trans 1 1986, 1397−1404.
(17) McAllister, G. D.; Taylor, R. J. K. The Synthesis of
Polyoxygenated, Enantiopure Cyclopentene Derivatives Using the
Ramberg-Backlund Rearrangement. Tetrahedron Lett. 2001, 42, 1197−
1200.
(18) Hollick, J. J.; Golding, B. T.; Hardcastle, I. R.; Martin, N.;
Richardson, C.; Rigoreau, L. J. M.; Smith, G. C. M.; Griffin, R. J.
Pyranone, Thiopyranone, and Pyridone Inhibitors of Phosphatidyli-
nositol 3-Kinase Related Kinases. Structure-Activity Relationships for
DNA-Dependent Protein Kinase Inhibition, and Identification of the
First Potent and Selective Inhibitor of the Ataxia Telangiectasia
Mutated Kinase. J. Med. Chem. 2007, 50, 1958−1972.
(19) Saito, T.; Takekawa, K.; Takahashi, T. The First Catalytic,
Highly Enantioselective Hetero-Diels-Alder Reaction of Thiabuta-
dienes. Chem. Commun. 1999, 1001−1002.
(20) Barthakur, M. G.; Chetia, A.; Boruah, R. C. Microwave-
Promoted One-Pot Synthesis of 4H-Thiopyrans from α,β-Unsaturated
Ketones via a Three-Component Reaction. Tetrahedron Lett. 2006, 47,
4925−4927.
(21) (a) Cherepanov, I. A.; Savin, E. D.; Frolova, N. G.; Shishkova,
M. O.; Godovikov, I. A.; Suponitsky, K. Y.; Lyssenko, K. A.; Kalinin, V.
N. 4H-Thiopyrans Bearing a Mesoionic Ring. Mendeleev Commun.
2009, 19, 320−321. (b) Zhang, X.; Li, X.; Fan, X.; Wang, X.; Li, D.;
Qu, G.; Wang, J. Ionic Liquid Promoted Preparation of 4H-Thiopyran
and Pyrimidine Nucleoside-Thiopyran Hybrids Through One-Pot
Multicomponent Reaction of Thioamide. Mol. Diversity 2009, 13, 57−
61. (c) Fan, X.; Wang, X.; Zhang, X.; Li, X.; Qu, G. MWI-Promoted
Preparation of 4H-Thiopyran Derivatives Through One-Pot Multi-
component Reactions. J. Chem. Res. 2007, 693−695.
(22) Deryabina, T. G.; Demina, M. A.; Belskaya, N. P.; Bakulev, V. A.
Reaction of 3-Aryl-2-cyanothioacrylamides with Dimethyl Acetylene-
carboxylate, Methyl Propiolate, and N-phenylmaleimide. Russ. Chem.
Bull. 2005, 54, 2880−2889.
(c) Samai, S.; Nandi, G. C.; Singh, P.; Singh, M. S. L-Proline: An
Efficient Catalyst for the One-Pot Synthesis of 2,4,5-Trisubstituted and
1,2,4,5-Tetrasubstituted Imidazoles. Tetrahedron 2009, 65, 10155−
10161. (d) Nandi, G. C.; Samai, S.; Singh, M. S. First InCl3-Catalyzed,
Three-Component Coupling of Aldehydes, β-Naphthol, and 6-Amino-
1,3-dimethyluracil to Functionalized Naphthopyranopyrimidines.
Synlett 2010, 1133−1137. (e) Kumar, R.; Raghuvanshi, K.; Verma,
R. K.; Singh, M. S. Application of Cyclic-1,3-diketones in Domino and
Multicomponent Reactions: Facile Route to Highly Functionalized
Chromeno[2,3-d]pyrimidinones and Diazabenzo[b]fluorenones under
Solvent-Free Conditions. Tetrahedron Lett. 2010, 51, 5933−5936.
(f) Samai, S.; Nandi, G. C.; Chowdhury, S.; Singh, M. S. L-Proline
Catalyzed Synthesis of Densely Functionalized Pyrido[2,3-d]-
pyrimidines via Three-Component One-Pot Domino Knoevenagel
Aza-Diels-Alder Reaction. Tetrahedron 2011, 67, 5935−5941.
(27) (a) Chowdhury, S.; Nandi, G. C.; Samai, S.; Singh, M. S.
Regioselective Synthesis of Tetrahydrothiochromen-5-ones via a One-
Pot Three-Component Solvent-Free Domino Protocol. Org. Lett.
2011, 13, 3762−3765. (b) Verma, R. K.; Verma, G. K.; Raghuvanshi,
K.; Singh, M. S. An Expedient Route to Highly Functionalized 2H-
Chromene-2-thiones via Ring Annulation of β-Oxodithioesters
Catalyzed by InCl3 under Solvent-Free Conditions. Tetrahedron
2011, 67, 584−589. (c) Nandi, G. C.; Samai, S.; Singh, M. S. Biginelli
and Hantzsch-Type Reactions Leading to Highly Functionalized
Dihydropyrimidinone, Thiocoumarin, and Pyridopyrimidinone Frame-
works via Ring Annulation with β-Oxodithioesters. J. Org. Chem. 2010,
75, 7785−7795.
(28) Crystal data for 4{4,11,1}: C16H12N2OS4, Yellow, M = 376.56,
monoclinic, space group P21/c, a = 8.6868(3), b = 12.0610(3), c =
16.5857(3) Å, V = 1737.5 Å3, μ = 0.55 mm−1, Z = 4, T = 293 K, F000
=
776, R = 0.0374, wR2 = 0.1216. The CCDC deposition number:
CCDC 836399.
(23) Liu, J.; Fu, X.; Zhou, Y.; Zhou, G.; Liang, Y.; Dong, D. Facile
and Divergent Synthesis of Substituted Pyridine-2,4(1H,3H)-diones
and 4H-Thiopyran-4-ones from α-Alkenoyl-α-carbamoyl Ketene-S,S-
acetals. Aus. J. Chem. 2010, 63, 1267−1271.
(24) (a) Boaz, N. W.; Fox, K. M. Synthesis of 2,6-Diaryl-4H-
thiopyran-4-ones. J. Org. Chem. 1993, 58, 3042−3045. (b) Bloxham, J.;
Dell, C. P. Reaction of 3-Aryl-2-cyanothioacrylamides with Electron-
deficient Alkynes: Synthesis of 4-Aryl-4H-thiopyrans. J. Chem. Soc.,
Perkin Trans. 1 1994, 989−993.
(25) (a) Singh, O. M.; Devi, N. S.; Thokchom, D. S.; Sharma, G. J.
Novel 3-Alkanoyl/Aroyl/Heteroaroyl-2H-chromene-2-thiones: Syn-
thesis and Evaluation of their Antioxidant Activities. Eur. J. Med.
Chem. 2010, 45, 2250−2257. (b) Singh, O. M.; Devi, N. S. Application
of β-Oxodithioesters in Domino and Multicomponent Reactions:
Facile Route to Dihydropyrimidines and Coumarins. J. Org. Chem.
2009, 74, 3141−3144. (c) Samuel, R.; Chandran, P.; Retnamma, S.;
Sasikala, K. A.; Sridevi, N. K.; Anabha, E. R.; Asokan, C. V. Alkylation
of Aryl 3-Oxopropanedithioate and 3-Amino-1-aryl-3-thioxo-1-prop-
anones as an Effective Tool for the Construction of Differently
Substituted Thiophenes and Annulated Thiophenes. Tetrahedron
2008, 64, 5944−5948. (d) Samuel, R.; Asokan, C. V.; Suma, S.;
Chandran, A.; Retnamma, S.; Anabha, E. R. A Facile Method for the
Synthesis of Substituted 2-Ylidene-1,3-oxathioles from Acetophenones.
Tetrahedron Lett. 2007, 48, 8376−8378. (e) Peruncheralathan, S.;
Khan, T. A.; Ila, H.; Junjappa, H. Regioselective Synthesis of 1-Aryl-
3,4-substituted/annulated-5-(methylthio)pyrazoles and 1-Aryl-3-
(methylthio)-4,5-substituted/annulated Pyrazoles. J. Org. Chem.
2005, 70, 10030−10035.
(26) (a) Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. An Efficient
One-Pot Synthesis of Tetrahydrobenzo[a]xanthene-11-one and
Diazabenzo[a]anthracene-9,11-dione Derivatives under Solvent Free
Condition. Tetrahedron 2009, 65, 7129−7134. (b) Nandi, G. C.;
Samai, S.; Kumar, R.; Singh, M. S. Atom-efficient and Environment-
Friendly Multicomponent Synthesis of Amidoalkyl Naphthols
Catalyzed by P2O5. Tetrahedron Lett. 2009, 50, 7220−7222.
230
dx.doi.org/10.1021/co200203e | ACS Comb. Sci. 2012, 14, 224−230