Green synthesis of benzopyran-annulated thiopyrano[2,3-b ]thiochromen-5(4 H)-ones by domino Knoevenagel-hetero-Diels-Alder reaction

Article abstract of DOI:10.1055/s-0030-1258261

Benzopyran-annulated thiopyrano[2,3-b]thiochromen-5(4H)-ones have been synthesized by the domino Knoevenagel-hetero-Diels-Alder (DKHDA) reaction of 4-hydroxydithiocoumarin with O-allylated salicylaldehyde and O-propargylated salicylaldehyde in aqueous medium. The reaction requires only a single step operation and is highly regio- and stereoselective providing potentially bioactive polycyclic heterocycles in high yields. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1258261

PAPER
4043
Green Synthesis of Benzopyran-Annulated Thiopyrano[2,3-b]thiochromen-
5(4H)-ones by Domino Knoevenagel–Hetero-Diels–Alder Reaction
Domino
K
noevena
.
gel–Hetero-D
C
iels–Alde
r
Reac
.
tion Majumdar,* Abu Taher, Sudipta Ponra
Department of Chemistry, University of Kalyani, Kalyani 741235, W. B., India
E-mail: kcm_ku@yahoo.co.in
Received 5 August 2010; revised 11 August 2010
sized indole- and thiochromen-annulated [6,6]-fused
Abstract: Benzopyran-annulated thiopyrano[2,3-b]thiochromen-
5(4H)-ones have been synthesized by the domino Knoevenagel–
hetero-Diels–Alder (DKHDA) reaction of 4-hydroxydithiocou-
marin with O-allylated salicylaldehyde and O-propargylated salicyl-
aldehyde in aqueous medium. The reaction requires only a single
step operation and is highly regio- and stereoselective providing po-
tentially bioactive polycyclic heterocycles in high yields.
thiopyranobenzopyran derivatives using DKHDA reac-
tion,14a,f,g which are difficult to prepare by usual radical
cyclization and Claisen rearrangement.15
Thieno[2,3-b]benzopyran-4-one skeleton has been used
as an intermediate for the synthesis of a series of antipsy-
chotic drugs.16 Similarly, pharmacophores containing a
chromone moiety show biological activity and many of
them also have useful medicinal applications.17 There are
reports on the synthesis of thieno[2,3-b]thiochromen-4-
one18 and thiochromone-annulated [6,5]-fused benzofu-
rothiopyran derivatives.19 But no such reports of thio-
chromone-annulated [6,6]-fused benzopyranothiopyran
derivatives are known, except our preliminary report.14g
Key words: aqueous medium, domino Knoevenagel–hetero-Diels–
Alder reaction, stereoselective, regioselective, 4-hydroxydithiocou-
marin
Recently, there is a flurry of activities in the development
of newer synthetic methods for the construction of com-
plex molecules from simple substrates following the prin-
ciple of ‘green chemistry’.1 The main principles of green
chemistry are avoidance of toxic reagents, reduction of
waste, and responsible utilization of resources.2 Recently,
the development of solvent-free syntheses3 or replace-
ment of toxic or hazardous solvents with environmentally
benign solvents4 is one of the main areas of green chemis-
try. In modern organic chemistry water,5 ionic liquid,6
fluorous,7 supercritical media,8 and polyethylene glycol9
have been used as alternative reaction solvents. The use of
water as an environmentally benign and economically fa-
vorable alternative of organic solvents has developed a
highly active field of research in synthetic chemistry and
catalysis.10 Water is environment friendly, nontoxic, non-
flammable, and ubiquitous in nature.5a,b,11 A number of re-
actions including Diels–Alder reaction have been carried
out in aqueous media.
In continuation of our interest in the synthesis of annulat-
ed [6,6]-fused thiopyranobenzopyran derivatives14a,f,g and
in order to explore the utility of this methodology we be-
came interested to synthesize thiochromone-annulated
[6,6]-fused thiopyranobenzopyran derivatives using 4-hy-
droxydithiocoumarin and O-allylated/crotylated salicylal-
dehydes in environmentally benign water medium. The
results are reported here.
The required precursors 2a–f were prepared in high yields
by refluxing various substituted salicylaldehydes 1a–e
with allyl bromide or crotyl bromide in the presence of an-
hydrous potassium carbonate and a catalytic amount of
NaI in anhydrous acetone at room temperature.20 Other
precursors 3a–g were prepared in high yields and purity
by the reaction of substituted salicylaldehydes 1a–g and
propargyl bromide in the presence of anhydrous potassi-
Hetero-Diels–Alder reaction is one of the most important
synthetic tools for the construction of heterocycles as well
as natural products. A number of heterocyclic compounds
have been prepared by domino Knoevenagel–hetero-
Diels–Alder (DKHDA) reaction.12 Tietze and co-workers
have extensively utilized this reaction for the synthesis of
tetracyclic compounds containing a pyran ring using un-
saturated aromatic and aliphatic aldehydes with several
1,3-dicarbonyl compounds.13 There are several reports on
the intramolecular DKHDA reaction with alkenes and
alkynes.14 The methodology is useful for the construction
of annulated [6,6]-fused pyranobenzopyran or thiopyra-
nobenzopyran derivatives.13,14 Recently, we have synthe-
OH
O
R3
a R1 = R2 = R3 = H
b R1 = Br, R2 = R3 = H
c R1 = Me, R2 = R3 = H
d R1 = t-Bu, R2 = R3 = H
e R1 = Cl, R2 = Me, R3 = H
f R1 = R2 = H, R3 = Me
CHO
R2
CHO
R2
(i)
R1
R1
2a–f
1a–e
a R1 = R2 = H
OH
O
b R1 = Br, R2 = H
c R1 = Me, R2 = H
d R1 = t-Bu, R2 = H
e R1 = Cl, R2 = Me
f R1 = OMe, R2 = H
g R1 = Cl, R2 = H
CHO
R2
CHO
R2
(i)
R1
R1
1a–g
3a–g
SYNTHESIS 2010, No. 23, pp 4043–4050
Advanced online publication: 17.09.2010
DOI: 10.1055/s-0030-1258261; Art ID: Z20110SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0
Scheme 1 Reagents and conditions: (i) allyl/crotyl bromide, anhyd
K2CO3, anhyd acetone, NaI, reflux, (ii) propargyl bromide, anhyd
K2CO3, DMF, r.t.

4044
K. C. Majumdar et al.
PAPER
O
O
CHO
CHO
OH
S
O
O
O
S
O
H
H
3a
2a
(i)
(i)
S
S
S
S
5h
4a
5a
Scheme 2 Reagents and conditions: (i) reflux in H2O.
um carbonate in anhydrous DMF at room temperature21 3a–g were determined from their elemental analyses and
(Scheme 1).
spectroscopic data. The characteristic peaks for 5h–n in
the 1H NMR spectra appear as AB quartets for the OCH2
protons between d = 4.62 and 4.94 followed closely by
singlets for the SCH= protons at d = 5.99–6.57. The cor-
responding carbon signal for the OCH2, SCH=, and C=O
groups of compound 5h in the 13C NMR spectra appear at
d = 69.7, 109.4, 177.1, respectively.
The O-allylsalicylaldehyde (2a) was used first as a model
substrate in order to study the DKHDA reactions of 4-hy-
droxydithiocoumarin (4a) with O-allyl/crotylsalicylalde-
hydes 2a–f and O-propargylsalicylaldehydes 3a–g.14g
According to the published procedure,14a the hetero-
Diels–Alder reaction of 4a and 2a was carried out in re-
fluxing acetic acid and triethylamine and the final product
5a was obtained in 85% yield after 4 hours. Very recently,
Table 1 Influence of Catalyst, Solvent, and Base on the DKHDA
we have reported the DKHDA reaction of the alkynes in Reaction of 4a with 3aa
water medium.14f,g Therefore, it was decided to try this re-
Entry
Lewis acid
(mol%)
Solvent
Base
Yield
(%)
action on alkenes in water medium. Accordingly, the re-
action of 4a and 2a in refluxing water instead of acetic
acid and triethylamine was carried out for 4 hours and to
our delight the product 5a was obtained in 84% yield.
Similarly, the DKHDA reactions of 4-hydroxydithiocou-
marin (4a) with O-propargylated salicylaldehydes 3a–g
were carried out14g in aqueous medium under refluxing
condition (Scheme 2).
1
2
–
H2O
–
80
58
49
65
35
32
29
45
60
34
28
23
CuI (20)
CuI (30)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
H2O
–
3
H2O
–
4
H2O
Et3N
5
MeOH
MeCN
1,4-dioxane
toluene
H2O
Et3N
In the case of the DKHDA reaction of 4-hydroxydithio-
coumarin (4a) with O-propargylated salicylaldehydes 3a–g,
the optimized condition was standardized through a series
of experiments, where the influences of Lewis acid, base,
and solvents were examined in the reaction (Table 1).
Table 1, entry 3 reveals that increasing the amount of cat-
alyst decreases the yield of the product. The reason may
be due to the coordination of soft sulfur atom22 with the
d10 copper ions, which prevents the hetero-Diels–Alder
reaction and thereby decreasing the yield of the product.
Highest yield of the final product was obtained when the
reaction was carried out in refluxing aqueous medium in
the absence of any catalyst.
6
Et3N
7
Et3N
8
Et3N
9
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
(NH4)2HPO4
10
11
12
MeOH
MeCN
1,4-dioxane
a All reactions were carried out for 4 h.
The reaction is highly regio- and stereoselective. The re-
action of 4-hydroxydithiocoumarin (4a) with O-allylsali-
cylaldehyde (2a) give only the cis-annulated [6,6]-fused
thiopyrano benzopyran derivative 5a. The structure and
stereochemistry of the product 5a was determined by
spectral analysis and single crystal X-ray diffraction23
(Figure 1).
To extend the utility of this methodology, DKHDA reac-
tion was carried out for other O-allylated/crotylated and
O-propargylated salicylaldehydes 2b–f and 3b–g with 4-
hydroxydithiocoumarins 4a,b (Table 2). The structures of
the products obtained by the reaction of 4-hydroxydithio-
coumarin (4a) with O-propargylated salicylaldehydes
Figure 1 Single crystal X-ray structure of compound 5a
Synthesis 2010, No. 23, 4043–4050 © Thieme Stuttgart · New York

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Domino Knoevenagel–Hetero-Diels–Alder Reaction
4045
Table 2 DKHDA Reaction of 4a,b with 2a–f and 3a–g in Aqueous Mediuma
O
R3
O
R1
R1
R1
CHO
R1
CHO
R2
O
R2
O
OH
S
O
O
H
R2
R2
3a–g
2a–f
H2O, reflux
H
R3
H2O, reflux
X
S
S
S
S
S
5h–n
4a X = H
4b X = Cl
5a–g
Entry
1
4
Aromatic aldehyde
Product
Yield (%)b
O
O
O
4a
4a
4a
2a
5a
5b
5c
H
84
82
74
CHO
H
S
S
Br
O
O
O
2
3
2b
H
Br
CHO
H
S
S
S
O
O
O
H
2c
H
CHO
S
O
O
O
H
4
4a
2d
5d
73
H
CHO
S
S
S
S
Cl
O
O
O
5
6
7
4a
4a
4b
2e
5e
5f
65
70
72
H
H
Cl
CHO
H
S
O
O
O
2f
CHO
H
S
O
O
S
O
H
2c
5g
CHO
H
Cl
S
Synthesis 2010, No. 23, 4043–4050 © Thieme Stuttgart · New York

4046
K. C. Majumdar et al.
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Table 2 DKHDA Reaction of 4a,b with 2a–f and 3a–g in Aqueous Mediuma (continued)
O
R3
O
R1
R1
R1
CHO
R1
CHO
R2
O
R2
O
OH
S
O
O
H
R2
R2
3a–g
2a–f
H2O, reflux
H
R3
H2O, reflux
X
S
S
S
S
S
5h–n
4a X = H
4b X = Cl
5a–g
Entry
8
4
Aromatic aldehyde
Product
Yield (%)b
O
O
O
4a
4a
4a
3a
5h
5i
80
79
75
CHO
S
S
Br
O
O
O
O
9
3b
Br
CHO
S
S
S
O
O
10
3c
5j
CHO
S
O
O
S
O
O
O
O
11
4a
3d
5k
72
CHO
S
S
S
S
Cl
O
12
13
14
4a
4a
4a
3e
5l
O
69
76
77
Cl
CHO
S
MeO
O
O
3f
5m
5n
MeO
CHO
S
Cl
O
O
S
3g
Cl
CHO
a All reactions were carried out in refluxing aqueous medium for 4 h.
b Isolated yields.
Synthesis 2010, No. 23, 4043–4050 © Thieme Stuttgart · New York

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Domino Knoevenagel–Hetero-Diels–Alder Reaction
4047
H
O
S
O
O
S
O
O
S
O
path a
or
H
S
S
S
OH
S
O
6
7
8
CHO
H2O
+
reflux
S
4a
2 and 3
O
S
O
O
O
S
path b
S
S
9a
9
exo pathway
endo pathway
O
O
O
O
O
O
H
H
or
H
H
S
S
S
S
S
S
5h (obtained)
10 (not obtained)
5a (obtained)
Scheme 3 Probable mechanism of DKHDA reaction
It is notable that the DKHDA reaction of 4-hydroxydithio- stereochemistry of the final products depends on the exo-
coumarins 4 with O-allylated/crotylated salicylaldehydes and endo-orientation of the dienophiles in the transition
2a–f occurs in the absence of any base (Et3N) or catalyst states. The intermediate 9 may undergo rotation around
(EDDA) and reaction with unactivated alkynes 3a–g oc- the single bond to assume the structure 9a, which may
curs without the help of a Lewis acid/catalyst. The reason then undergo cyclization via endo-selectivity of the hetero
may perhaps be explained by considering the presence of Diels–Alder reaction to give the product 5a. The reaction
soft sulfur atom in the diene moiety of the substrates. The does not proceed via exo-pathway to give the product 10
sulfur atom may offer itself a reactive center and is more perhaps due to the sp2-geminal effect of 1,3-allylic
polarizable compared to other heteroatoms. Moreover, strain.24
there are empty d-orbitals at the sulfur atom having a
In conclusion, we have developed a mild, efficient, regio-
and stereoselective protocol for the synthesis of benzo-
pyran-annulated thiopyranothiochromen-5(4H)-ones by
matching symmetry with that of the p-orbitals of the acet-
ylene moiety for interaction.14f
The stereochemistry of the final product and the mecha- domino Knoevenagel–hetero-Diels–Alder reaction of 4-
nism of the reaction are depicted in Scheme 3. Initially, hydroxydithiocoumarin with alkenes and alkynes. This
Knoevenagel condensation between 4-hydroxydithiocou- protocol conforms to several green chemistry principles.
marin (4a) and O-allylated 2 or O-propargylated salicyl- Green aspects of this reaction include: (i) water is used as
aldehyde 3 occurs to give the heterodiene intermediate. a reaction medium, which is benign, safe, and easily avail-
There is a possibility for the formation of two heterodiene able, avoiding the use of conventional volatile organic
intermediates (intermediates 6 and 9) giving two products, solvents; (ii) the reaction is highly atom economic – only
angularly-fused product 7 (when O-allylated salicylalde- water is the by-product; (iii) no additive or base is re-
hyde is used) or 8 (when O-propargylated salicylaldehyde quired; and (iv) the reaction occurs in a single-step opera-
is used) or linearly fused 5a or 10 (when O-allylated sali- tion.
cylaldehyde is used) and 5h (when O-propargylated sali-
cylaldehyde is used). But only linearly fused products 5a
Melting points were determined in open capillaries and are uncor-
and 5h were isolated, which show that the reactions pro-
ceed via path ‘b’. This selectivity may be attributed to the
presence of the sulfur atom. High polarizability and soft-
ness of sulfur atom make the HOMO-LUMO energy gap
smaller when thiocarbonyl group of thioester acts as a het-
erodiene than that of the carbonyl group of a,b-unsaturat-
ed ketone system and thus the reaction follows via path ‘b’
to afford the linearly fused products. In the case of the
DKHDA reaction with O-allylated salicylaldehydes, the
rected. IR spectra were recorded on a Perkin–Elmer L 120-000A
spectrometer on KBr disks. 1H NMR and 13C NMR spectra were re-
corded on a Bruker DPX-300, Bruker DPX-400, or Bruker DPX-
500 spectrometer in CDCl3 with TMS as internal standard. CHN
values were recorded on 2400 series II CHN Perkin–Elmer analyz-
er. Mass spectra and HRMS were recorded on a QTOF Micro YA
263 instrument at the Indian Association for the Cultivation of
Science, Kolkata. Silica gel [(60–120, 230–400 mesh), Rankem,
India] was used for chromatographic separation. Silica gel G [CDH,
Synthesis 2010, No. 23, 4043–4050 © Thieme Stuttgart · New York

4048
K. C. Majumdar et al.
PAPER
(India)] was used for TLC. Petroleum ether (PE) used refers to the
fraction boiling between 60–80 °C.
5d
Yield: 73%; colorless solid; mp 175–177 °C.
IR (KBr): 1225, 1506, 1598, 2926 cm–1.
Compounds 5a–n; General Procedure
1H NMR (500 MHz, CDCl3): d = 1.11 (s, 9 H), 2.40–2.42 (m, 1 H),
2.93 (dd, J = 2.6, 12.3 Hz, 1 H), 3.36 (t, J = 12.2 Hz, 1 H), 4.31 (dd,
J = 1.8, 11.2 Hz, 1 H), 4.54 (dd, J = 1.8, 11.2 Hz, 1 H), 5.14 (d,
J = 3.7 Hz, 1 H), 6.70 (d, J = 8.2 Hz, 2 H), 7.08 (dd, J = 1.7, 8.5 Hz,
1 H), 7.46 (d, J = 7.9 Hz, 1 H), 7.52 (t, J = 7.9 Hz, 1 H), 7.57–7.60
(m, 1 H), 8.58 (d, J = 7.9 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 26.9, 30.1, 31.3 (3 C), 33.2, 34.0,
69.7, 115.7, 121.0, 124.8, 124.9, 125.9, 127.4, 128.2, 129.5, 130.1,
131.3, 136.0, 143.5, 150.1, 150.2, 177.3.
A mixture of 4-hydroxydithiocoumarin 4a,b (0.26 mmol) and O-al-
lylsalicylaldehyde 2a–f (0.26 mmol) or O-propargylsalicylaldehyde
3a–g (0.26 mmol) was refluxed in H2O (7 mL) for 4 h. After com-
pletion of the reaction as monitored by TLC, the reaction mixture
was cooled and diluted with H2O (25 mL). The mixture was extract-
ed with EtOAc (3 × 25 mL). The combined organic extracts were
washed with brine (2 × 20 mL) and dried (Na2SO4). The resulting
crude product obtained after removal of the solvent was purified by
column chromatography over silica gel (60–120 mesh) using PE–
EtOAc mixture as eluent to give compounds 5a–n (Table 2).
MS: m/z = 394 (M+).
Anal. Calcd for C23H22O2S2: C, 70.02; H, 5.62. Found: C, 70.21; H,
5.57.
5a
Yield: 84%; colorless solid; mp 210–212 °C.
IR (KBr): 1221, 1514, 1600, 2931 cm–1.
5e
1H NMR (400 MHz, CDCl3): d = 2.42–2.45 (m, 1 H), 2.94 (ddd,
J = 1.2, 4.0, 12.0 Hz, 1 H), 3.35 (t, J = 12.0 Hz, 1 H), 4.34 (dd,
J = 1.6, 11.2 Hz, 1 H), 4.59 (dd, J = 2.0, 11.2 Hz, 1 H), 5.15 (d,
J = 3.6 Hz, 1 H), 6.68 (d, J = 7.6 Hz, 1 H), 6.73–6.79 (m, 2 H), 7.06
(t, J = 7.6 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 1 H), 7.53 (t, J = 8.0 Hz, 1
H), 7.56–7.59 (m, 1 H), 8.57 (dd, J = 1.2, 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 26.8, 29.9, 33.1, 69.8, 116.3,
121.1, 121.9, 124.8, 127.4, 127.9, 128.0, 129.2, 129.7, 130.0, 131.4,
136.1, 150.5, 152.6, 177.1.
Yield: 65%; colorless solid; mp 174–176 °C.
IR (KBr): 1256, 1494, 1611, 2922 cm–1.
1H NMR (400 MHz, CDCl3): d = 1.95 (s, 3 H), 2.84–2.89 (m, 1 H),
2.91 (d, J = 5.2 Hz, 1 H), 3.16 (dd, J = 8.8, 12.0 Hz, 1 H), 4.15 (dd,
J = 4.0, 15.2 Hz, 1 H), 4.21 (dd, J = 2.0, 11.2 Hz, 1 H), 5.11 (d,
J = 5.6 Hz, 1 H), 6.66 (d, J = 9.2 Hz, 1 H), 7.11 (d, J = 8.8 Hz, 1 H),
7.48 (d, J = 8.0 Hz, 1 H), 7.53 (dd, J = 1.2, 7.6 Hz, 1 H), 7.60 (dt,
J = 1.2, 7.6 Hz, 1 H), 8.46 (dd, J = 1.2, 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 17.2, 33.5, 35.9, 38.1, 69.2, 115.1,
124.4, 125.2, 127.1, 127.7, 127.9, 129.6, 131.2, 131.5, 134.9, 135.6,
136.6, 150.7, 155.4, 177.5.
HRMS: m/z calcd for C19H14O2S2 [M + H]+: 339.0508; found:
339.0547.
MS: m/z = 386 (M+).
5b
Yield: 82%; colorless solid; mp 213–215 °C.
IR (KBr): 1224, 1518, 1603, 2923 cm–1.
Anal. Calcd for C20H15ClO2S2: C, 62.08; H, 3.91. Found: C, 62.23;
H, 3.83.
1H NMR (500 MHz, CDCl3): d = 2.40–2.44 (m, 1 H), 2.94 (ddd,
J = 1.5, 4.1, 12.3 Hz, 1 H), 3.28 (t, J = 12.2 Hz, 1 H), 4.33 (dd,
J = 1.8, 11.3 Hz, 1 H), 4.56 (dd, J = 2.1, 11.3 Hz, 1 H), 5.11 (d,
J = 3.3 Hz, 1 H), 6.66 (d, J = 8.5 Hz, 1 H), 6.76 (s, 1 H), 7.17 (dd,
J = 1.8, 8.5 Hz, 1 H), 7.48 (d, J = 8.1 Hz, 1 H), 7.54 (t, J = 7.1 Hz,
1 H), 7.59 (dd, J = 1.3, 8.2 Hz, 1 H), 8.57 (dd, J = 1.3, 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 26.8, 29.7, 33.1, 69.8, 113.2,
118.2, 124.1, 124.8, 127.2, 127.6, 129.7, 129.9, 130.9, 131.5, 131.7,
136.1, 151.1, 151.9, 176.9.
5f
Yield: 70%; colorless solid; mp 190–192 °C.
IR (KBr): 1215, 1511, 1598, 2925 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.50 (d, J = 6.4 Hz, 3 H), 2.06 (d,
J = 10.4 Hz, 1 H), 3.67 (dd, J = 6.4, 10.5 Hz, 1 H), 4.47 (d, J = 11.4
Hz, 1 H), 4.56 (d, J = 11.4 Hz, 1 H), 5.20 (s, 1H), 6.68 (d, J = 7.4
Hz, 1 H), 6.73 (d, J = 7.3 Hz, 1 H), 6.76 (d, J = 8.6 Hz, 1 H), 7.07
(t, J = 7.6 Hz, 1 H), 7.46 (d, J = 7.8 Hz, 1 H), 7.52 (t, J = 7.5 Hz, 1
H), 7.58 (t, J = 7.5 Hz, 1 H), 8.57 (d, J = 7.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 18.9, 29.7, 35.6, 37.0, 66.8, 116.1,
121.1, 122.3, 124.9, 127.4, 127.8, 127.9, 129.0, 129.6, 130.7, 131.3,
136.2, 151.3, 153.2, 177.0.
MS: m/z = 416, 418 (M+).
Anal. Calcd for C19H13BrO2S2: C, 54.68; H, 3.14. Found: C, 54.89;
H, 3.10.
MS: m/z = 352 (M+).
5c
Yield: 74%; colorless solid; mp 153–155 °C.
IR (KBr): 1243, 1518, 1608, 2923 cm–1.
Anal. Calcd for C20H16O2S2: C, 68.15; H, 4.58. Found: C, 68.39; H,
4.61.
1H NMR (400 MHz, CDCl3): d = 2.11 (s, 3 H), 2.59–2.66 (m, 1 H),
2.88–2.98 (m, 2 H), 4.10 (dd, J = 9.6, 11.6 Hz, 1 H), 4.29 (d,
J = 11.2 Hz, 1 H), 4.40 (dd, J = 5.6, 9.6 Hz, 1 H), 6.28 (s, 1 H), 6.75
(d, J = 8.0 Hz, 1 H), 6.88 (d, J = 8.0 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1
H), 7.55 (d, J = 7.6 Hz, 1 H), 7.62 (t, J = 8.0 Hz, 1 H), 8.41 (d,
J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 20.9, 29.2, 39.7, 41.7, 71.3, 116.6,
124.7, 125.7, 126.5, 126.6, 127.7, 128.1, 129.2, 129.3, 131.4, 131.7,
135.9, 149.1, 152.5, 178.6.
5g
Yield: 72%; colorless solid; mp 204–206 °C.
IR (KBr): 1239, 1494, 1627, 2919 cm–1.
1H NMR (400 MHz, CDCl3): d = 2.11 (s, 3 H), 2.59–2.62 (m, 1 H),
2.92–2.98 (m, 2 H), 4.11 (t, J = 10.5 Hz, 1 H), 4.26 (d, J = 11.2 Hz,
1 H), 4.40 (dd, J = 5.2, 9.2 Hz, 1 H), 6.23 (s, 1 H), 6.75 (d, J = 8.0
Hz, 1 H), 6.89 (d, J = 7.6 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 2 H), 8.34
(d, J = 7.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 17.2, 33.5, 35.9, 38.0, 69.2, 115.1,
124.4, 125.2, 127.1, 127.7, 127.9, 129.5, 131.2, 131.5, 134.9, 135.6,
136.6, 150.7, 155.3, 177.5.
MS: m/z = 352 (M+).
Anal. Calcd for C20H16O2S2: C, 68.15; H, 4.58. Found: C, 68.01; H,
4.65.
MS: m/z = 386 (M+).
Synthesis 2010, No. 23, 4043–4050 © Thieme Stuttgart · New York

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Domino Knoevenagel–Hetero-Diels–Alder Reaction
4049
Anal. Calcd for C20H15ClO2S2: C, 62.08; H, 3.91. Found: C, 62.25;
H, 3.85.
Anal. Calcd for C20H13ClO2S2: C, 62.41; H, 3.40. Found: C, 62.56;
H, 3.37.
5h
5m
Yield: 80%; colorless solid; mp 212–214 °C (Lit.14g mp 212–214
°C).
Yield: 76%; colorless solid; mp 182–184 °C.
IR (KBr): 743, 1160, 1601, 2932 cm–1.
The spectral data were in accordance with the reported values.
1H NMR (400 MHz, CDCl3): d = 3.61 (s, 3 H), 4.62 (d, J = 12.0 Hz,
1 H), 4.91 (d, J = 11.6 Hz, 1 H), 5.41 (s, 1 H), 5.99 (s, 1 H), 6.09 (d,
J = 2.8 Hz, 1 H), 6.62 (dd, J = 2.8, 8.8 Hz, 1 H), 6.78 (d, J = 8.8 Hz,
1 H), 7.50–7.55 (m, 2 H), 7.62 (t, J = 7.2 Hz, 1 H), 8.49 (d, J = 7.6
Hz, 1 H).
5i
Yield: 79%; colorless solid; mp 238–240 °C.
IR (KBr): 741, 1158, 1614, 2921 cm–1.
1H NMR (500 MHz, CDCl3): d = 4.65 (d, J = 11.8 Hz, 1 H), 4.93 (d,
J = 11.7 Hz, 1 H), 5.42 (s, 1 H), 6.08 (s, 1 H), 6.57 (s, 1 H), 6.71 (d,
J = 8.6 Hz, 1 H), 7.18 (dd, J = 2.3, 8.6 Hz, 1 H), 7.52–7.58 (m, 2 H),
7.63 (t, J = 7.8 Hz, 1 H), 8.52 (d, J = 8.1 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 35.9, 55.6, 72.8, 108.9, 111.4,
111.8, 117.3, 121.3, 125.1, 127.8, 129.0, 129.6, 130.6, 130.9, 131.7,
135.6, 146.3, 148.1, 153.7, 176.9.
MS: m/z = 366 (M+).
MS: m/z = 413, 415 (M+).
Anal. Calcd for C20H14O3S2: C, 65.55; H, 3.85. Found: C, 65.76; H,
3.81.
Anal. Calcd for C19H11BrO2S2: C, 54.95; H, 2.67. Found: C, 54.79;
H, 2.76.
5n
5j
Yield: 77%; colorless solid; mp 224–226 °C.
Yield: 75%; colorless solid; mp 208–210 °C.
IR (KBr): 744, 1158, 1608, 2923 cm–1.
IR (KBr): 738, 1158, 1603, 2925 cm–1.
1H NMR (400 MHz, CDCl3): d = 4.65 (d, J = 11.6 Hz, 1 H), 4.93 (d,
J = 11.6 Hz, 1 H), 5.41 (s, 1 H), 6.08 (s, 1 H), 6.44 (s, 1 H), 6.76 (d,
J = 8.4 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 1 H), 7.52–7.79 (m, 3 H), 8.52
(d, J = 8.0 Hz, 1 H).
1H NMR (500 MHz, CDCl3): d = 2.13 (s, 3 H), 4.63 (d, J = 11.8 Hz,
1 H), 4.92 (d, J = 11.8 Hz, 1 H), 5.41 (s, 1 H), 6.00 (s, 1 H), 6.28 (s,
1 H), 6.73 (d, J = 8.2 Hz, 1 H), 6.87 (d, J = 7.9 Hz, 1 H), 7.52–7.57
(m, 2 H), 7.63 (t, J = 8.0 Hz, 1 H), 8.52 (dd, J = 1.3, 8.0 Hz, 1 H).
13C NMR (100 MHz): d = 20.8, 35.8, 72.8, 108.9, 116.8, 121.7,
125.1, 125.2, 127.2, 127.8, 128.2, 129.7, 130.1, 130.6, 131.0, 131.7,
135.8, 146.1, 151.9, 176.9.
MS: m/z = 370 (M+).
Anal. Calcd for C19H11ClO2S2: C, 61.53; H, 2.99. Found: C, 61.34;
H, 2.92.
MS: m/z = 350 (M+).
Acknowledgment
Anal. Calcd for C20H14O2S2: C, 68.54; H, 4.03. Found: C, 68.29; H,
4.14.
We thank the CSIR (New Delhi) and DST (New Delhi) for financial
assistance. Two of us (A.T. and S.P.) are grateful to the CSIR (New
Delhi) for a Senior and a Junior Research Fellowship. We also thank
the DST (New Delhi) for providing Bruker NMR spectrometer (400
MHz) and Perkin–Elmer CHN Analyzer under its FIST program.
5k
Yield: 72%; colorless solid; mp 206–208 °C.
IR (KBr): 742, 1157, 1600, 2924 cm–1.
1H NMR (500 MHz, CDCl3): d = 1.11 (s, 9 H), 4.63 (d, J = 11.8 Hz,
1 H), 4.90 (d, J = 11.6 Hz, 1 H), 5.46 (s, 1 H), 6.03 (s, 1 H), 6.50 (d,
J = 1.1 Hz, 1 H), 6.76 (d, J = 8.5 Hz, 1 H), 7.09 (dd, J = 2.0, 8.4 Hz,
1 H), 7.52–7.56 (m, 2 H), 7.64 (m, 1 H), 8.51 (dd, J = 1.1, 8.0 Hz, 1
H).
13C NMR (100 MHz, CDCl3): d = 31.3 (3 C), 34.0, 36.0, 72.6,
109.1, 116.3, 121.7, 122.0, 124.5, 125.1, 125.7, 127.8, 129.3, 130.5,
130.8, 131.7, 135.6, 143.2, 145.7, 151.8, 177.3.
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Yield: 69%; colorless solid; mp 168–170 °C.
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Synthesis 2010, No. 23, 4043–4050 © Thieme Stuttgart · New York

4050
K. C. Majumdar et al.
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Synthesis 2010, No. 23, 4043–4050 © Thieme Stuttgart · New York