Cycloaddition reactions of cross-conjugated enaminones

Article abstract of DOI:10.1016/j.tet.2009.08.038

A detailed study on the cycloaddition reactions of cross-conjugated enaminones 1 and 9 with dimethyl acetylenedicarboxylate (DMAD) and ketenes is described. The reactions provide a variety of pyran (4, 11), pyran-2-one 14 and pyrrol-3-ylidene 8 derivative

Full text of DOI:10.1016/j.tet.2009.08.038

Tetrahedron 65 (2009) 8478–8485
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Cycloaddition reactions of cross-conjugated enaminones
,
a
a
b
Parvesh Singh a , Parul Sharma , Krishna Bisetty , Mohinder P. Mahajan
*
a Department of Chemistry, Durban University of Technology, Durban-4000, South Africa
b Department of Applied Chemistry, Guru Nanak Dev University, Amritsar 143001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 May 2009
Received in revised form 29 July 2009
Accepted 13 August 2009
Available online 19 August 2009
A detailed study on the cycloaddition reactions of cross-conjugated enaminones 1 and 9 with dimethyl
acetylenedicarboxylate (DMAD) and ketenes is described. The reactions provide a variety of pyran (4, 11),
pyran-2-one 14 and pyrrol-3-ylidene 8 derivatives having great pharmacological and medicinal signifi-
cance. Moreover, the preferred formation of product 8 over 7 has been explained on the basis of
molecular dynamics (MD) simulations performed on the intermediate 5 in the gas phase. The synthetic
potential of enaminones 9 has further been explored by treating them with Lawesson’s reagent (LR) and
trapping the in situ generated enaminothiones 16 with some acrylates 17 leading to the formation of
thiopyran derivatives 19. To the best of our knowledge, this is the first report in which cross-conjugated
enaminothiones 16 have been utilized in cycloaddition reactions.
Keywords:
Cycloaddition reactions
Cross-conjugated enaminones
DMAD
Ó 2009 Elsevier Ltd. All rights reserved.
Ketenes
1. Introduction
reactions,4 and reduction5 and oxidations,6 leading to the forma-
tion of various biologically and medicinally active compounds have
Development of synthetic methods for functionalized pyran and
pyran-2-one derivatives I (Fig. 1) is an important and interesting
research topic in organic chemistry, because these are not only
valuable materials in diverse organic synthesis, but also exhibit
important pharmaceutical activities. Therefore, many synthetic
methods for the synthesis of functionalized pyran and pyran-2-one
derivatives have been established.1 Moreover, enaminone systems
II (Fig. 1) represent versatile synthetic precursors that combine the
ambident nucleophilicity of enamines with the ambident electro-
philicity of enones. The presence of three nucleophilic and two
electrophilic sites II (Fig. 1) makes these systems highly susceptible
to the chemical reagents. For this reason a variety of their reactions
involving nucleophilic2 and electrophilic3 substitutions, photochemical
been explored in the literature. For example, pyrazolquina-
zolinones, belonging to class of antiallergenic and anti-
inflammatory agents,7 and triazoles, having biological activities
such as inhibition of growth, mobility of adhesion of cancerous cells
in rats,8 fungicidal,9 anticonvulsants10 and interference in the me-
tabolism of prostaglandins11 etc., can easily be synthesized using
enaminones as the starting materials. Pyrazoles, not only known as
potent insecticides12 and herbicides,13 but also as antitumour, anti-
inflammatory, antimicrobial, antipsychotic or analgesic agents,14
have also been prepared by the reactions of enaminones with hy-
drazine derivatives.15
Literature survey reveals that although the cycloaddition
reactions of simple enaminones II (Fig. 1) with some dienophiles
are reported, the cross-conjugated enaminones III (Fig. 1), despite
possessing immense synthetic value, have been much less ex-
plored in organic synthesis under Diels–Alder (DA) reaction con-
ditions.16 It has also been reported16 that despite the high
reactivity of sulfenes as dienophiles, they fail to react with open
chain enaminones III (Fig. 1) lacking substituents at the C-2 po-
sition. Recently, we have reported17 the successful cycloaddition
reactions of III (Fig. 1) with sulfene using ab initio and DFT cal-
culations, which clearly contradicts the earlier reported16 results,
and prompted us to explore the synthetic potential of cross-con-
jugated enaminones III (Fig. 1) with other dienophiles such as
DMAD and ketenes, reported herein. The selection of DMAD as
a dienophile has been made due to its versatile reactive nature
towards its reactions18 and considered to be significant in terms of
various regio- and stereochemical aspects associated with these
reactions.
..
.
.
Y
R'
O
. .
W
nucleophilic
sites
O
X
elcerophilic sites
O
I
R'
N
W = CO,CH
2
II
NHAr/N(CH3)2
R'
III
Figure 1.
* Corresponding author. Tel.: þ27 31 3732311; fax: þ27 31 2022671.
E-mail address: parveshguleria2006@yahoo.co.in (P. Singh).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.08.038

P. Singh et al. / Tetrahedron 65 (2009) 8478–8485
8479
O
2. Results and discussion
O
O
R2
N
H
OCH3
[4+2]
O
H
Ph
O
O
OCH3
OCH3
OCH3
OCH3
[1,3] H-shift
2.1. Cycloadditions of enaminones 1 and 9 with DMAD
+
Ph
O
H
HN
O
4
HN
The reaction of equimolar ratio of enaminones17 1a–c with
DMAD 2 in toluene at reflux for 13–15 h resulted in the formation of
a mixture of compounds, characterized as 4 and 7 or 8 in almost
equal proportions (Scheme 1, Table 1). The products 4a–c were
characterized as pyran derivatives on the basis of the spectroscopic
evidence and analytical data. For example, compound 4a in its 1H
OCH3
O
R2
R2
1
2
3
Ph
R2
C6 N7
O
H
O
R2
H
H
H
C3
C6 N7
C3
Ph
C5
Ph
C5
O
O
10
C
C9
11 OCH3
C9
15
O
C
spectrum, for example, exhibited two singlets at
two ester –OCH3 groups, a singlet at 5.87 for methine proton, one
doublet at
multiplets at
olefinic proton.
d 3.83 and 3.88 for
10
C
11
C
C
15
H3CO
d
H
H3CO
O
O
H
OCH3
6
d
7.61(J¼15.6 Hz) for trans olefinic proton along with
5
d
6.91–7.43 for 10 aromatic protons and a merged
X
-HOCH3
O
R2
O
Ph
Ph
N
N
R2
O
O
OCH3
O
H
O
O
OCH3
H2
OCH3
R2
H
O
H3CO
OCH3
7
O
O
O
OCH3
Toluene
O
HN
8
O
+
+
Ph
,
13-15h
Scheme 2.
NH
R2
Ph
N
R2
O
H
H
OCH3
Ph
1a-c
2
4
7
or
OCH3
OCH3
O
O
O
OCH3
O
O
O
Ph
R1
N
benzene/chloroform(40:60 v/v)
O
N
a. R2 = Ph
H
9a-c
,
N
3-4h
b. R2 = p-OCH3-Ph
c. R2 = p-tolyl
+
H
R2
O
OCH3
O
H
R1
H
8
10
H3CO
Scheme 1.
2
[1,3]-H shift
OCH3
OCH3
O
Table 1
Reactions of enaminones 1 with DMAD and ketenes
H
O
O
No.
1
Enaminones
Dienophile
DMAD
Product
Yield (%)
H
1a/1b/1c
4a/4b/4c
42/35/39
14a/14a
21/30
14d/14d
19/22
8a/8b/8c
45/39/32
15a/15b
69/62
15c/15d
66/70
N
H
R1
H
2
3
1a/1b
1a/1b
Chloro ketene
Phenyl ketene
a. R1 = Ph
b. R1 = p-OCH3-Ph
c. R1 = p-Cl-Ph
11
Scheme 3.
The plausible mechanism for the formation of products 4 in-
volves the initial formation of [4þ2] cycloadduct 3 as an in-
termediate that upon [1,3]-H shift gets transformed into 4 under
experimental conditions (Scheme 2). For 7 and 8, as depicted in
Scheme 2, it is assumed that the initial enamine type nucleophilic
Table 2
Reactions of enaminones 9 with DMAD and ketenes
No.
Enaminones
Dienophile
Product
Yield (%)
1
2
9a/9b/9c
9a/9b/9c
9a/9b/9c
9a/9b/9c
9a/9b/9c
DMAD
11a/11b/11c
14a/14/14c
14d/14e/14f
19a/19b/19c
19d/19e/19f
54/51/59
41/45/49
51/46/49
62/71/64
51/58/42
Chloroketene
Phenylketene
Methylacrylate
Acrylonitrile
3
attack of a-carbon of 1 at the acetylenic carbon of DMAD leads to
4a
5a
the formation of an intermediate 5 or its conformer 6 (obtained via
C5–C9 rotation), which upon stabilization by proton transfer and
cyclization by the nucleophilic attack of nitrogen N7 on C11 (of 5) or
C15 (of 6), leads to the formation of 7 or 8, respectively.
a
Cycloaddition reactions of 16 with acrylates.
On the other hand, heating of an equimolar mixture of enami-
nones22 9, having N,N-dimethylamine group at
b-position instead
formation of product 7 has been ruled out in this reaction and the
compound 8 is expected to be a preferred product on the basis of
molecular dynamics (MD) calculations performed on the in-
termediate 5 (A, Fig. 2) using AMBER program,19 as described in the
Computational section. The reason why we chose MD for these
studies was attributed to its extensive use by the modern chemists
to assess the most probable and bioactive conformation of peptides
by exploring their conformational profile.20
of aromatic amine, and 2 (DMAD) in a benzene/chloroform (40:60
v/v) mixture at reflux for 3–4 h led to the isolation of compounds
11, obtained presumably by the [1,3]-H shift of the initial [4þ2]
cycloadduct 10 formed as an intermediate (Scheme 3). The reaction
was found to be sluggish when refluxed in pure chloroform for
a longer period; on the other hand reaction in toluene resulted in
the formation of an intractable mixture from which no pure
product could be isolated. The structures of compounds 11a–c were
ascertained with the help of analytical data and spectroscopic ev-
idence provided in the Experimental section. The yields of the re-
actions described above are summarized in Table 2.
2.2. Computational section
The MD simulations (in the gas phase) have been performed on
intermediate 5 for 10 ns (see Section 4.2) at 400 K (to mimic ex-
perimental temperature). The most probable conformation has
Since we were unable to distinguish between products 7 and 8
on the basis of available spectral and analytical evidences, the

8480
P. Singh et al. / Tetrahedron 65 (2009) 8478–8485
Figure 2. A) Initial structure of 5 before MD run, B) Full optimized structure of most probable conformation of 5, C) Total energy profile for 10 ns trajectory of MD simulation (in gas
phase), D) Temperature profile for 10 ns trajectory (in gas phase).
been obtained out of 10,000 conformers using the PTRAJ module of
AMBER and was fully optimized at the Hartree–Fock (HF) energy
level (B, Fig. 2) with 6–31 g (d) basis set using the Gaussian pro-
gram.21 The thermodynamic parameters such as total energy
(C, Fig. 2) and temperature (D, Fig. 2) were plotted to measure the
quality of MD trajectories, and clearly reveal that the simulations
are relatively stable over the entire MD trajectories. A closer in-
spection of geometry B indicates an interatomic distance of 2.9 Å
between atoms N7 and C15, which is about 1.6 Å less than that
obtained between atoms N7 and C11 (4.5 Å), and could be a cause
for the favoured attack of N7 on C15 resulting in the preferential
formation of product 8. In addition, the measured dihedral angles
3.21 (N7–C6–C5–C9) and 61.17 (C6–C5–C9–C15) between N7 and
C15, and 3.21 (N7–C6–C5–C9), ꢀ117.31 (C6–C5–C9–C10) and ꢀ3.38
(C5–C9–C10–C11) between N7 and C11, clearly indicate a better
overlapping plane between atoms N7 and C15, and could be an-
other reason for the facile approach of N7 on C15. It is worth
mentioning that, although the interatomic distances obtained do
not correspond to the actual bond distances (1.4–1.5 Å), since the
present study has been done in the gas phase and not exactly
mimicking the experimental conditions, the preferred site of attack
could be ascertained on the basis of these findings. The reason for
choosing MD studies in the gas phase is associated with the high
cost involved, complexity and the time consuming nature of solvent
calculations in Amber.
cycloaddition reactions with enaminones 1 and 9 were thought to
be an interesting part of our current investigations. Thus, the
treatment of cross-conjugated enaminones 9 with chloro and
phenyl ketenes 12, generated in situ by the dropwise addition of
the corresponding acid chlorides to triethylamine (TEA) at 0 ꢁC
followed by careful column chromatography of the crude reaction
mixture led to the moderate yields (Table 1) of the products,
characterized as pyran-2-one derivatives 14. The formation of these
products presumably arises via elimination of –HN (CH3)2 from the
initial [4þ2] adduct 13 formed as an intermediate (Scheme 4).
O
O
O
R2
Hd
H
O
O
R2
H
R1
N
2
2
CH Cl , TEA
9
+
Ha
R1
H
0 ºC
O
R2
N
Hc
H
R1
H
H
12
Hb
Cl
1 = Ph
14a-f
13
a.
b.
c.
R
R
R
1 = p-OCH3-Ph
1 = p-Cl-Ph
R2 = Cl, Ph
R3
R2
O
O
N
R3
H
O
HN
Ph
O
O
CH Cl , TEA
2
2
H
+
12
o
+
0 C
Ph
H
H
R2
Ph
H
H
H
1a-b
H
H
14a,14d
15a-d
R
3 = Ph, p-OCH3-Ph
Scheme 4.
2.3. Cycloadditions of enaminones 1 and 9 with ketenes
The detailed spectroscopic features of pyranones 14a–f are de-
scribed in the Experimental Section; however, the salient features
are mentioned here. The compound 14a, for example, analyzed for
C13H9ClO2, exhibited a molecular ion peak at m/z 232 (Mþ) in the
Since ketenes are reported to be highly reactive dienophiles and
are extensively explored in heterocyclic synthesis,23 their

P. Singh et al. / Tetrahedron 65 (2009) 8478–8485
8481
mass spectrum and its IR spectrum (KBr) showed a strong ab-
sorption peak at 1696 cmꢀ1 due to
-unsaturated carbonyl group.
The 1H spectrum showed characteristic doublet at
6.12 (J¼7.2 Hz)
for olefinic proton Hc, a doublet at
6.61 (J¼16.2 Hz) for trans
olefinic proton Ha along with multiplets at 7.18–7.52 corre-
sponding to Hb and Hd merged with the aromatic protons.
However, the coupling of enaminones 1a–c with chloro and
phenyl ketenes, generated in situ as discussed above, resulted in the
isolation of a mixture of compounds 14 and 15 as depicted in
(Scheme 4). The amides 15a–d were obtained as major products
while the expected [4þ2] cycloadducts 14a, 14d were formed in
lower yields, as shown in Table 2.
3. Conclusion
a,b
d
In conclusion, a general and relevant study of the cycloaddition
reactions of cross-conjugated enaminones 1 and 9 with DMAD and
ketenes has been carried out, and a variety of pyran 4, 11 and pyran-
2-one 14 derivatives having great biological and medicinal signifi-
cance have been synthesized. Furthermore, the molecular dynamics
(MD) simulations (in the gas phase) have been performed on in-
termediate 5 to explain the preferred formation of five membered
product 8 over six membered product 7, expected to be thermo-
dynamically more stable. Additionally, unprecedented instantaneous
cycloaddition reactions of cross-conjugated enaminothiones, gen-
erated from the corresponding enaminones 9 using LR, with acry-
lates have been investigated, and a number of novel thiopyran
derivatives 19 have been prepared. Although cycloaddition of
simple enaminothiones is well explored in the literature, to our
knowledge, the cycloaddition reactions of cross-conjugated
enaminothiones were never previously investigated.
d
d
2.4. Cycloadditions of enaminothiones 16 with methyl
acrylate/acrylonitrile
Although a number of cycloaddition reactions involving acyclic
enaminothiones have been explored,24 there is not even a single
report concerning the engagement of cross-conjugated enamino-
thiones in cycloaddition reactions. This could probably be due to
their strong propensity to get polymerized under experimental
conditions. However, enaminones 9 on treatment with Lawessons’s
reagent25 (LR) in CH2Cl2 at 0 ꢁC, followed by trapping of the
resulting in situ generated enaminothiones 16 with methyl acry-
late/acrylonitrile 17, led to the formation of cycloadducts 19 in
moderate yields (Scheme 5, Table 2). The compounds obtained
were characterized as thiopyran derivatives on the basis of their
spectroscopic and analytical data and are presumably formed by
the elimination of dimethylamine from the [4þ2] adduct 18 gen-
erated as an intermediate (Scheme 5). The detailed features of these
compounds are described in the Experimental section; however,
the salient features are mentioned here. The compound 19a, for
example, analyzed for C15H14O2S, exhibited a molecular ion peak at
m/z 258 (Mþ) in the mass spectrum and its IR spectrum (KBr)
4. Experimental
4.1. General
Melting points were determined by the open capillary method
using Veego Precision Digital Melting Point apparatus (MP-D) and
are uncorrected. IR spectra were recorded on a Shimadzu D-8001
spectrophotometer. 1H NMR spectra were recorded in deuterated
chloroform with Bruker AC-E 300 (300 MHz) spectrometer using
TMS as internal standard. Chemical shift values are expressed as
ppm downfield from TMS and J values are in Hz. Splitting patterns
are indicated as s: singlet, d: doublet, t: triplet, m: multiplet and q:
quartet. 13C NMR spectra were also recorded on a Bruker AC-E 300
(75.0 MHz) spectrometer in a deuterated chloroform using TMS as
internal standard. Mass spectra were recorded on a Shimadzu
GCMS-QP-2000 mass spectrometer. Elemental analyses were per-
formed on a Heraus CHN-O-Rapid Elemental Analyzer. Column
chromatography was performed on silica gel (60–120) mesh or
a Harrison Research Chromatotron using 2 mm plates (Silica gel
PF254). CH2Cl2 was dried over phosphorous pentoxide and stored
over molecular sieves (4A). DMF-DMA26 and cross-conjugated
enaminones22 (9) were prepared according to the reported pro-
cedures. Phenylacetyl chloride was prepared from the corre-
sponding acid and thionyl chloride. Chloroacetyl chloride and
thionyl chloride were distilled before use. DMAD used for the cy-
cloadditions was commercially available.
showed a strong absorption peak at 1701 cmꢀ1 due to
saturated carbonyl group. The 1H spectrum showed characteristic
a,b-un-
singlet at
a doublet at
d
3.66 for methylene protons, a singlet at
d
d
3.81 for –OCH3,
6.93 and 7.04
6.42 (J¼6.6 Hz) for H1, two doublets at
d
(J¼15.6 Hz) corresponding to trans olefinic protons (H3 and H4).
Attempts were also made towards the isolation of stable enami-
nothiones 16 by stirring the corresponding enaminones 9 with LR
under similar reaction conditions, as discussed above, however, the
main spot formed during the reaction was found to be very un-
stable (TLC monitored) resulting in formation of a mixture of side
products, and thus nonseparation of the desired compound even
after careful column chromatography.
4.2. Computational methodology for MD
Ar
S
O
S
LR (2.0 eq.)
5 min
stir.
H
The MD calculations were carried out within the framework of
molecular mechanics, using all-atom AMBER 9.0 force field. The
initial 3D structure of intermediate 5 was prepared in Material
Studio (MS) ver 4.1,27 and was geometrically optimized using
Forcite module in MS. To perform the molecular mechanics cal-
culations, restrained electrostatic potential (RESP) atomic charges
consistent with the AMBER program were computed using GAFF
(General Amber Force Field) parameters.28 The system was then
minimized, in Sander, using 10,000 steps of steepest descent,
followed by a subsequent minimization using the conjugate gra-
dient algorithm. Subsequently, the structure was heated up to
400 K and was sufficient to enable the molecule to cross the po-
tential barriers of the different regions of the conformational
space. The molecular dynamics (MD) simulation was performed at
this temperature for 10 ns taking each snap shot at the interval of
1 ps. The PTRAJ module of AMBER 9.0 was used to calculate the
most probable conformer and thermodynamic properties of the
MD trajectory.
CH Cl
Ar
N
Ar
N
2
2
(in situ)
R2
30 min.
0 °C
9
16
N
H
+
R2
18
a. Ar = Ph
b. Ar = p-OCH3-Ph
c. Ar = p-Cl-Ph
17
R2 = -COOCH3, -CN
H
Ar
S
H
R2
19a-f
Scheme 5.
The prolonged heating (7 days) of 19 in toluene or xylene at
reflux with some highly reactive dienophiles such as N-phenyl-
maleimide (NPM), Maleic anhydride (MA) and Tetracyanoethylene
(TCNE) did not yield expected Diels–Alder bicycloadducts and the
starting materials were recovered. The observed reluctance of 19
p-electrons across
the ester or cyano group in 19, making these systems less reactive.
could probably be due to the delocalization of

8482
P. Singh et al. / Tetrahedron 65 (2009) 8478–8485
4.3. General procedure for cycloadditions between
enaminones 1 or 9 and DMAD
chromatography: EA/Hex (10:90), yielded 8b (39%) as light yellow
solid: mp 134–135 ꢁC; IR nmax (KBr): 1731, 1666 and 1510 cmꢀ1; 1H
NMR (CDCl3) d 3.85 (s, 3H, –OCH3), 3.90 (s, 3H, –OCH3), 6.79 (s, 1H,
Equimolar amounts of 1 and DMAD were heated at reflux in
toluene for 13–15 h. After completion of reaction (monitored by
TLC), the solvent was removed under reduced pressure and the
crude product was purified through silica gel column chromato-
graphy. The compounds 4 eluted first in column chromatography
while 8 were isolated later in higher percentage of ethyl acetate/
hexane mixture. The solid compounds 4 and 8, thus obtained, were
recrystallized from ethyl acetate (EA) and hexane (Hex) mixture in
ratio 1:9 and 2:8, respectively.
The reactions of 9 with DMAD were scrutinized by heating in
a benzene/chloroform (40:60) mixture for 3–4 h. A similar pro-
cedure, as discussed above for 8, was followed after completion of
the reaction.
H2), 7.01 (d, J¼9.0 Hz, 2H, ArH), 7.09 (d, J¼15.9 Hz, 1H, olefinic), 7.31
(d, J¼9.0 Hz, 2H, ArH), 7.38–7.56 (m, 5H, ArH), 7.69 (d, J¼15.9 Hz,
1H, olefinic), 8.02 (s,1H, H1); 13C NMR
d 53.0, 55.5,114.7,117.2,121.2,
121.7, 127.4, 128.4, 128.9, 130.8, 132.3, 134.2, 142.5, 143.4, 145.3,
160.0, 161.3, 166.6 and 185.9; MS (EI) m/z: 389 (Mþ). Calcd for
C23H19NO5: C, 70.94; H, 4.92; N, 3.60. Found: C, 71.02; H, 5.01; N,
3.57%.
4.3.6. [2-Oxo-4-(3-phenyl-acryloyl)-1-p-tolyl-1,2-dihydro-pyrrol-3-
ylidene]-acetic acid methyl ester (8c). Eluent for chromatography:
EA/Hex (10:90), yielded 8c (32%) as light yellow solid: mp 126–
127 ꢁC; IR nmax (KBr): 1730, 1667 and 1512 cmꢀ1 1H NMR (CDCl3)
;
d
2.42 (s, 3H, –CH3), 3.91 (s, 3H, –OCH3), 6.81–6.96 (m, 5H, 4ArH and
H2), 7.10 (d, J¼15.9 Hz, 1H, olefinic), 7.26–7.35 (m, 3H, ArH), 7.51 (d,
4.3.1. 4-Phenylamino-6-styryl-2H-pyran-2,3-dicarboxylic acid dimethyl
ester (4a). Eluent for chromatography: EA/Hex (5:95), yielded 4a
(42%) as yellow solid: mp 130–131 ꢁC; IR nmax (KBr): 1722 and
J¼8.4 Hz, 2H, ArH), 7.67 (d, J¼15.9 Hz, 1H, olefinic), 7.99 (s, 1H, H1);
13C NMR
d 21.2, 55.4, 114.5, 120.4, 125.9, 126.8, 129.1, 130.2, 130.3,
136.8, 139.7, 142.3, 143.2, 145.4, 158.9, 160.9, 161.2, 166.5 and 186.0;
MS (EI) m/z: 373 (Mþ). Calcd for C23H19NO4: C, 73.98; H, 5.13; N,
3.75. Found: C, 73.88; H, 5.02; N, 3.82%.
1612 cmꢀ1 1H NMR (CDCl3)
; d 3.83 (s, 3H, –OCH3), 3.88 (s, 3H,
–OCH3), 5.87 (s, 1H, –CH), 6.91–7.43 (m, 11H, 10H, ArH and 1H, ole-
finic), 7.61 (d, J¼15.6 Hz, 1H, olefinic), 7.63 (s, 1H, olefinic), 12.58 (d,
J¼12.7 Hz, 1H, –NH); 13C NMR
d
51.7, 52.4, 95.8, 107.2, 114.9, 117.3,
4.3.7. 4-Dimethylamino-6-styryl-2H-pyran-2,3-dicarboxylic acid di-
methyl ester (11a). Eluent for chromatography: EA/Hex (10:90),
yielded 11a (54%) as yellow solid: mp 164–165 ꢁC; IR nmax (KBr):
122.4,124.6,126.1,128.8,132.3,134.9,136.4,139.8,143.8,146.4,149.6,
165.6 and 169.2; MS (EI) m/z: 391 (Mþ). Calcd for C23H21NO5: C,
70.58; H, 5.41; N, 3.58. Found: C, 70.64; H, 5.38; N, 3.64%.
1718, 1618, 1544 and 1433 cmꢀ1 1H NMR (CDCl3)
; d 2.98 (s, 6H,
[–N(CH3)2]), 3.67 (s, 3H, –OCH3), 3.80 (s, 3H, –OCH3), 5.88 (s, 1H,
4.3.2. 4-(4-Methoxy-phenylamino)-6-styryl-2H-pyran-2,3-dicar-
boxylic acid dimethyl ester (4b). Eluent for chromatography: EA/Hex
(6:94), yielded 4b (35%) as golden yellow solid: mp 116–117 ꢁC; IR
–CH), 7.01 (d, J¼15.6 Hz, 1H, Ha), 7.26–7.50 (m, 5H, ArH), 7.53 (d,
J¼15.6 Hz, 1H, Hb), 7.73 (s, 1H, Hc); 13C NMR
d 43.5, 51.6, 52.9, 96.0,
104.5, 126.6, 127.8, 128.6, 129.2, 135.7, 140.2, 142.3, 153.3, 165.4 and
168.1; MS (EI) m/z: 343 (Mþ). Calcd for C19H21NO5: C, 66.46; H, 6.16;
N, 4.08. Found: C, 66.59; H, 6.11; N, 4.12%.
nmax (KBr): 1724 and 1612 cmꢀ1 1H NMR (CDCl3)
; d 3.77 (s, 3H,
–OCH3), 3.80 (s, 3H, –OCH3), 3.88 (s, 3H, –OCH3), 5.89 (s, 1H, –CH),
6.88 (d, J¼8.6 Hz, 2H, ArH), 7.02 (d, J¼8.6 Hz, 2H, ArH), 7.05 (d,
J¼15.7 Hz,1H, olefinic), 7.13–7.57 (m, 5H, ArH), 7.63 (d, J¼15.7 Hz, 1H,
olefinic), 7.64 (s, 1H, olefinic), 12.60 (d, J¼12.7 Hz, 1H, –NH); 13C NMR
4.3.8. 4-Dimethylamino-6-[2-(4-methoxy-phenyl)-vinyl]-2H-pyran-
2,3-dicarboxylic acid dimethyl ester (11b). Eluent for chromatogra-
phy: EA/Hex (10:90), yielded 11b (51%) as yellow crystalline solid:
mp 142–143 ꢁC; IR nmax (KBr): 1717, 1620, 1543 and 1433 cmꢀ1; 1H
d
51.8, 52.7, 55.5, 96.0, 107.4, 115.0, 118.6, 118.8, 124.9, 128.2, 128.8,
129.8, 132.5, 135.2, 141.2, 146.8, 147.1, 157.2, 165.5 and 169.0; MS (EI)
m/z: 421 (Mþ). Calcd for C24H23NO6: C, 68.40; H, 5.50; N, 3.32. Found:
C, 68.45; H, 5.43; N, 3.27%.
NMR (CDCl3)
d 3.01 (s, 6H, [–N(CH3)2]), 3.69(s, 3H, –OCH3), 3.80 (s,
3H, –OCH3), 3.82 (s, 3H, –OCH3), 6.89 (s, 1H, –CH), 6.92–7.48 (m, 5H,
4ArH and Ha), 7.54 (d, J¼16.1 Hz, 1H, Hb), 7.71 (s, 1H, Hc); 13C NMR
4.3.3. 6-Styryl-4-p-tolylamino-2H-pyran-2,3-dicarboxylic acid dimethyl
ester (4c). Eluent for chromatography: EA/Hex (5:95), yielded 4c
(39%) as light yellow solid: mp 122–123 ꢁC; IR nmax (KBr): 1726 and
d 43.8, 51.8, 52.7, 55.3, 89.9, 104.3, 126.5, 127.2, 128.1, 130.1, 134.8,
139.9, 143.5, 153.5, 165.4 and 168.4; MS (EI) m/z: 373 (Mþ). Calcd for
C20H23NO6: C, 64.33; H, 6.21; N, 3.75. Found: C, 64.49; H, 6.18; N,
3.72%.
1614 cmꢀ1 1H NMR (CDCl3)
; d 2.33 (s, 3H, –CH3), 3.83 (s, 3H,
–OCH3), 3.89 (s, 3H, –OCH3), 5.91 (s, 1H, –CH), 6.92 (d, J¼8.8 Hz, 2H,
ArH), 7.02–7.58 (m, 8H, 7ArH and 1H, olefinic), 7.63 (d, J¼15.6 Hz,
1H, olefinic), 7.64 (s, 1H, olefinic), 12.57 (d, J¼12.9 Hz, 1H, –NH); 13C
4.3.9. 6-[2-(4-Chloro-phenyl)-vinyl]-4-dimethylamino-2H-pyran-
2,3-dicarboxylic acid dimethyl ester (11c). Eluent for chromatogra-
phy: EA/Hex (12:98), yielded 11c (59%) as light yellow solid: mp
NMR
d 21.0, 51.6, 52.5, 96.1, 107.3, 115.4, 117.9, 119.9, 122.6, 124.7,
127.2, 128.5, 129.1, 133.8, 139.3, 145.8, 147.2, 149.1, 165.3 and 168.9;
MS (EI) m/z: 405 (Mþ). Calcd for C24H23NO5: C, 71.10; H, 5.72; N,
3.45. Found: C, 71.19; H, 5.79; N, 3.38%.
133–134 ꢁC; IR nmax (KBr): 1717, 1619 and 1543 cmꢀ1 1H NMR
;
(CDCl3)
–OCH3), 6.88 (s, 1H, –CH), 6.91–7.10 (m, 3H, 2ArH and Ha), 7.24–7.75
(m, 4H, 2ArH, Hb and Hc); 13C NMR
43.7, 51.6, 52.7, 90.0, 104.5,
d 2.98 (s, 6H, [–N(CH3)2]), 3.67(s, 3H, –OCH3), 3.79 (s, 3H,
d
4.3.4. [2-Oxo-1-phenyl-4-(3-phenyl-acryloyl)-1,2-dihydro-pyrrol-3-
ylidene]-acetic acid methyl ester (8a). Eluent for chromatography:
EA/Hex (10:90), yielded 8a (45%) as light yellow solid: mp 142–
126.6, 127.5, 128.4, 131.2, 133.8, 138.5, 144.1, 153.1, 164.9 and 167.8;
MS (EI) m/z: 377 (Mþ). Calcd for C19H20NClO5: C, 60.40; H, 5.34; N,
3.71. Found: C, 60.51; H, 5.35; N, 3.67%.
143 ꢁC; IR nmax (KBr): 1731, 1666 and 1510 cmꢀ1 1H NMR (CDCl3)
;
d
3.90 (s, 3H, –OCH3), 6.78 (s,1H, H2), 6.84–6.99 (m, 4H, ArH), 7.11 (d,
J¼15.9 Hz,1H, olefinic), 7.18–7.53 (m, 6H, ArH), 7.67 (d, J¼15.9 Hz,1H,
olefinic), 8.01 (s, 1H, H1); 13C NMR
55.4, 114.6, 118.8, 120.5, 123.2,
4.4. General procedure for the reaction of enaminones 1 and
9 with ketenes
d
125.6,128.4,131.5,133.6,134.5,138.4,141.9,142.6,144.8,159.8,160.8,
166.3 and 185.6; MS (EI) m/z: 359 (Mþ). Calcd for C22H17NO4: C,
73.53; H, 4.77; N, 3.90. Found: C, 73.64; H, 4.82; N, 3.84%.
To a well-stirred solution of enaminones 1 or 9 (10 mmol) and
triethylamine (12 mmol) in dry methylene chloride (30 mL) was
added dropwise a solution of chloroacetyl chloride/phenyl acetyl
chloride in dry methylene chloride (30 mL) over a period of 0.5 h at
0 ꢁC. After completion of the reaction (TLC), the reaction mixture
was first washed with saturated sodium bicarbonate solution
4.3.5. [1-(4-Methoxy-phenyl)-2-oxo-4-(3-phenyl-acryloyl)-1,2-di-
hydro-pyrrol-3-ylidene]-acetic acid methyl ester (8b). Eluent for

P. Singh et al. / Tetrahedron 65 (2009) 8478–8485
8483
(2ꢂ25 mL) and water (2ꢂ50 mL) and the organic layer dried over
(m, 11H, 10ArH and 1 olefinic), 8.72 (d, J¼14.1 Hz, 1H, olefinic); 13
C
anhydrous sodium sulfate. Removal of solvent under reduced
pressure yielded the crude product, which was purified by silica gel
column chromatography using a mixture of ethyl acetate and
hexane.
NMR d 50.1, 112.5, 113.9, 121.8, 126.5, 128.6, 129.5, 131.2, 132.6, 135.7,
138.4, 143.7, 159.8, 170.8 and 188.2; MS (EI) m/z: 325 (Mþ). Calcd for
C19H16ClNO2: C, 70.05; H, 4.95; N, 4.30. Found: C, 70.13; H, 4.89; N,
4.27%.
4.4.1. 3-Chloro-6-styryl-pyran-2-one (14a). Eluent for chromato-
graphy: EA/Hex (5:95), yielded 14a (41%) as pale yellow solid: mp
4.4.8. 2-Chloro-N-(4-methoxy-phenyl)-N-(3-oxo-5-phenyl-penta-
1,4-dienyl)-acetamide (15b). Eluent for chromatography: EA/Hex
(8:92), yielded 15b (62%) as white solid: mp 190–191 ꢁC; IR nmax
152–153 ꢁC; IR nmax (KBr): 1710 cmꢀ1
;
1H NMR (CDCl3)
d
6.12 (d,
J¼7.2 Hz, 1H, Hc), 6.61 (d, J¼16.2 Hz,1H, Ha), 7.18–7.52 (m, 7H, 5ArH,
(KBr): 1710 and 1673 cmꢀ1; 1H NMR (CDCl3)
d 3.82 (s, 3H, –OCH3),
Hb and Hd); 13C NMR
d
104.6, 117.8, 120.7, 127.5, 128.9, 129.7, 135.1,
3.91 (s, 2H, –CH2), 5.33 (d, J¼14.5 Hz, 1H, olefinic), 6.88 (d,
J¼15.9 Hz, 1H, olefinic), 6.99 (d, J¼8.8 Hz, 2H, ArH), 7.19–7.61 (m,
8H, 7ArH and 1 olefinic), 8.75 (d, J¼14.4 Hz, 1H, olefinic); 13C NMR
136.0, 140.6, 158.1 and 158.4; MS (EI) m/z: 232 (Mþ). Calcd for
C13H9ClO2: C, 67.11; H, 3.90. Found: C, 67.24; H, 3.99%.
d
50.2, 112.4, 114.3, 122.4, 125.8, 129.4, 129.9, 132.1, 132.9, 134.6,
4.4.2. 3-Chloro-6-[2-(4-methoxy-phenyl)-vinyl]-pyran-2-one
(14b). Eluent for chromatography: EA/Hex (5:95), yielded 14b
(45%) as yellow solid: mp 160–161 ꢁC; IR nmax (KBr): 1710 cmꢀ1; 1H
137.4, 144.1, 159.8, 171.0 and 188.1; MS (EI) m/z: 355 (Mþ). Calcd for
C20H18ClNO3: C, 67.51; H, 5.10; N, 3.94. Found: C, 67.63; H, 5.17; N,
3.99%.
NMR (CDCl3)
d
3.82 (s, 3H, –OCH3), 6.13 (d, J¼7.2 Hz,1H, Hc), 6.63 (d,
J¼16.1 Hz,1H, Ha), 7.02 (d, J¼8.6 Hz, 2H, ArH), 7.28 (d, J¼16.1 Hz,1H,
4.4.9. N-(3-Oxo-5-phenyl-penta-1,4-dienyl)-2,N-diphenyl-acetamide
(15c). Eluent for chromatography: EA/Hex (10:90), yielded 15c
(66%) as pale yellow solid: mp 180–182 ꢁC; IR nmax (KBr): 1706 and
Hb), 7.31 (d, J¼8.6 Hz, 2H, ArH), 7.46 (d, J¼7.2 Hz, 1H, Hd); 13C NMR
d
55.3, 104.7, 117.7, 119.9, 124.4, 127.8, 129.5, 133.9, 135.8, 145.2, 157.9
and 158.3; MS (EI) m/z: 262 (Mþ). Calcd for C14H11ClO3: C, 64.01; H,
1674 cmꢀ1; 1H NMR (CDCl3)
d
3.56 (s, 2H, –CH2), 5.27 (d, J¼14.4 Hz,
4.22. Found: C, 64.12; H, 4.18%.
1H, olefinic), 6.79 (d, J¼15.9 Hz, 1H, olefinic), 6.84–7.48 (m, 15H,
ArH), 7.51 (d, J¼15.6 Hz, 1H, olefinic), 8.80 (d, J¼14.1 Hz, 1H, ole-
4.4.3. 3-Chloro-6-[2-(4-chloro-phenyl)-vinyl]-pyran-2-one
(14c). Eluent for chromatography: EA/Hex (5:95), yielded 14c (49%)
as yellow solid: mp 143–144 ꢁC; IR nmax (KBr): 1709 cmꢀ1; 1H NMR
finic); 13C NMR
d 41.8, 112.3, 114.2, 122.2, 127.0, 127.5, 128.3, 129.0,
129.5, 130.8, 131.5, 134.0, 135.1, 139.6, 141.4, 141.8, 161.3, 170.5 and
188.4; MS (EI) m/z: 367 (Mþ). Calcd for C25H21NO2: C, 81.72; H, 5.76;
N, 3.81. Found: C, 81.64; H, 5.82; N, 3.77%.
(CDCl3)
d
6.28 (d, J¼7.2 Hz, 1H, Hc), 6.63 (d, J¼16.2 Hz, 1H, Ha), 7.21
(d, J¼16.2 Hz, 1H, Hb), 7.22–7.57 (m, 5H, 4ArH and Hd); 13C NMR
d
106.3,126.4,128.8,129.3,131.2,132.4,133.8,136.2,140.2,158.5 and
4.4.10. N-(4-Methoxy-phenyl)-N-(3-oxo-5-phenyl-penta-1,4-di-
enyl)-2-phenyl-acetamide (15d). Eluent for chromatography: EA/
Hex (10:90), yielded 15d (70%) as pale white solid: mp 174–175 ꢁC;
158.6; MS (EI) m/z: 267 (Mþ). Calcd for C13H8Cl2O2: C, 58.46; H,
3.02. Found: C, 58.55; H, 3.11%.
IR nmax (KBr): 1706 and 1677 cmꢀ1 1H NMR (CDCl3)
; d 3.54 (s, 2H,
4.4.4. 3-Phenyl-6-styryl-pyran-2-one (14d). Eluent for chromato-
graphy: EA/Hex (5:95), yielded 14d (51%) as yellow solid: mp 178–
–CH2), 3.82 (s, 3H, –OCH3), 5.25 (d, J¼14.4 Hz, 1H, olefinic), 6.73 (d,
J¼15.9 Hz, 1H, olefinic), 6.88–7.53 (m, 14H, ArH), 7.53 (d, J¼15.6 Hz,
179 ꢁC; IR nmax (KBr): 1710 cmꢀ1
;
1H NMR (CDCl3)
d
6.29 (d,
J¼6.9 Hz, 1H, Hc), 6.67 (d, J¼15.9 Hz, 1H, Ha), 7.26–7.93 (m, 12H,
10ArH, Hb and Hd); 13C NMR
105.8, 118.5, 125.8, 125.9, 127.4, 128.1,
1H, olefinic), 8.78 (d, J¼14.4 Hz, 1H, olefinic); 13C NMR
d 41.7, 55.4,
112.5, 114.3,122.2, 125.5, 126.2, 127.1, 127.9, 128.5, 129.1, 130.7, 132.9,
133.3, 138.8, 140.5, 141.8, 160.9, 169.8 and 188.3; MS (EI) m/z: 397
(Mþ). Calcd for C26H23NO3: C, 78.57; H, 5.83; N, 3.52. Found: C,
78.65; H, 5.89; N, 3.43%.
d
128.3, 128.5, 128.9, 129.2, 129.3, 135.1, 140.2, 158.5 and 161.2; MS
(EI) m/z: 274 (Mþ). Calcd for C19H14O2: C, 83.19; H, 5.14. Found: C,
83.28; H, 5.11%.
4.5. General procedure for the reaction of cross-conjugated
enaminothiones 16 with methyl acrylate/acrylonitrile
4.4.5. 6-[2-(4-Methoxy-phenyl)-vinyl]-3-phenyl-pyran-2-one
(14e). Eluent for chromatography: EA/Hex (6:94), yielded 14e
(46%) as yellow crystalline solid: mp 169–170 ꢁC; IR nmax (KBr):
To a well-stirred solution of enaminothiones 16, prepared after
stirring LR (30 mmol) with enaminones 9 (10 mmol) in dry CH2Cl2
at 0 ꢁC for 30 min, was added methyl acrylate/acrylonitrile
(12 mmol) and stirred for 5 min. After completion (TLC), the re-
action mixture was washed with water (2ꢂ50 mL) and extracted
using CH2Cl2 (3ꢂ50 mL). The evaporation of solvent under reduced
pressure resulted in crude mixture that was purified through silica
gel column chromatography yielding reddish solid compounds,
which were recrystallized using chloroform/hexane mixture (1:5).
1709 cmꢀ1; 1H NMR (CDCl3)
d
3.82 (s, 3H, –OCH3), 6.30 (d, J¼6.9 Hz,
1H, Hc), 6.64 (d, J¼16.1 Hz, 1H, Ha), 7.01 (d, J¼8.5 Hz, 2H, ArH), 7.25–
7.99 (m, 9H, 7ArH, Hb and Hd); 13C NMR
55.3, 105.6, 117.8, 123.4,
d
125.2, 126.8, 127.3, 128.3, 129.1, 129.4, 130.5, 133.2, 134.8, 140.3,
158.7 and 160.8; MS (EI) m/z: 304 (Mþ). Calcd for C20H16O3: C,
78.93; H, 5.30. Found: C, 78.85; H, 5.26%.
4.4.6. 6-[2-(4-Chloro-phenyl)-vinyl]-3-phenyl-pyran-2-one
(14f). Eluent for chromatography: EA/Hex (5:95), yielded 14f (49%)
as pale yellow solid: mp 183–184 ꢁC; IR nmax (KBr): 1709 cmꢀ1
;
1H
4.5.1. 6-Styryl-2H-thiopyran-3-carboxylic acid methyl ester (19a).
Eluent for chromatography: EA/Hex (5:95), yielded 19a (62%) as
reddish brown solid: mp 122–123 ꢁC; IR nmax (KBr): 1701 cmꢀ1; 1H
NMR (CDCl3)
d
6.29 (d, J¼7.2 Hz, 1H, Hc), 6.62 (d, J¼15.9 Hz, 1H, Ha),
7.33–7.70 (m, 11H, 9ArH, Hb and Hd); 13C NMR
d
106.2, 126.2, 127.0,
128.3, 128.4, 128.5, 129.1, 129.4, 133.6, 133.9,134.8, 135.1, 140.1, 158.2
and 161.1; MS (EI) m/z: 308 (Mþ). Calcd for C19H13ClO2: C, 73.91; H,
4.24. Found: C, 73.98; H, 4.27%.
NMR (CDCl3)
J¼6.6 Hz, 1H), 6.93 (d, J¼15.6 Hz, 1H), 7.04 (d, J¼15.6 Hz, 1H), 7.24–
7.48 (m, 6H, 5ArH and 1 olefinic); 13C NMR
24.1, 52.1, 114.1, 115.7,
d 3.66 (s, 2H, –CH2), 3.81 (s, 3H, –OCH3), 6.42 (d,
d
122.1,125.4, 126.5, 128.7, 133.3, 135.9, 141.5, 145.8 and 166.5; MS (EI)
m/z: 258 (Mþ). Calcd for C15H14O2S: C, 69.74; H, 5.46. Found: C,
69.83; H, 5.38%.
4.4.7. 2-Chloro-N-(3-oxo-5-phenyl-penta-1,4-dienyl)-N-phenyl-
acetamide (15a). Eluent for chromatography: EA/Hex (8:92), yiel-
ded 15a (69%) as pale white solid: mp 164–165 ꢁC; IR nmax (KBr):
1710 and 1672 cmꢀ1; 1H NMR (CDCl3)
d
3.92 (s, 2H, –CH2), 5.37 (d,
4.5.2. 6-[2-(4-Methoxy-phenyl)-vinyl]-2H-thiopyran-3-carboxylic
J¼14.4 Hz, 1H, olefinic), 6.87 (d, J¼15.9 Hz, 1H, olefinic), 7.27–7.63
acid methyl ester (19b). Eluent for chromatography: EA/Hex (5:95),

8484
P. Singh et al. / Tetrahedron 65 (2009) 8478–8485
yielded 19b (71%) as reddish solid: mp 131–132 ꢁC; IR nmax (KBr):
1697 cmꢀ1 1H NMR (CDCl3)
3.65 (s, 2H, –CH2), 3.82 (s, 3H,
(e) Rousset, S.;Abarbri, M.; Thibonnet, J.; Parrain, J. L.; Duchene, A. Tetrahedron Lett.
2003, 44, 7633–7636; (f) Downs, J. R.; Grant, S. P.; Townsend, J. D.; Schady, D. A.;
Pastine, S. J.; Embree, M. C.; Metz, C. R.; Pennington, W. T.; Bailey Walsch, R. D.;
Beam, C. F. Can. J. Chem. 2004, 82, 659–664; (g) Gerus, I. I.; Tolmachova, N. A.;
Vdovenko, S. I.; Froehlich, R.; Haufe, G. Synthesis 2005, 8, 1269–1278.
2. (a) Hegde, S. G.; Jones, C. R. J. Heterocycl. Chem. 1993, 30, 1501–1508; (b) Stuyter,
M. A. T.; Pandit, U. K.; Speckaamp, W. N.; Huismon, H. O. Tetrahedron Lett. 1966,
3, 87–90; (c) Derbyshire, P. A.; Hunter, G. A.; Mcnab, M.; Monahan, L. C. J. Chem.
Soc., Perkin Trans. 1 1993, 2017–2025; (d) Braibante, M. E. F.; Braibante, H. S.;
Missio, L.; Andricopula, A. Synthesis 1994, 898–900; (e) Singh, K.; Singh, J.;
Singh, H. Tetrahedron 1998, 54, 935–942.
;
d
–OCH3), 3.84 (s, 3H, –OCH3), 6.38 (d, J¼6.6 Hz, 1H), 6.83 (d,
J¼15.6 Hz, 1H, olefinic), 6.88 (d, J¼8.7 Hz, 2H ArH), 7.01 (d,
J¼15.6 Hz, 1H, olefinic), 7.22–7.25 (m,1H, olefinic), 7.41 (d, J¼8.7 Hz,
2H, ArH); 13C NMR
d 24.1, 51.9, 55.3, 114.2, 115.6, 121.3, 125.1, 128.5,
129.0, 134.3, 135.6, 143.2, 160.1 and 166.4; MS (EI) m/z: 288 (Mþ).
Calcd for C16H16O3S: C, 66.64; H, 5.59. Found: C, 66.78; H, 5.66%.
3. (a) Al-Omran, F.; Al-Awadi, N.; Abdel-Khalik, M. M.; Kaul, K.; El-Khair, A. A.;
Elnagdi, M. H. J. Chem. Res., Synop. 1997, 38, 8401–8445; (b) Al-Omran, F.;
Al-Awadi, N.; El-Khair, A. A.; Elnagdi, M. H. Org. Prep. Proced. Int. 1997, 29,
285–292; (c) Satyanarayana, J.; Ila, H.; Junjappa, H. Synthesis 1991, 10, 889–890;
(d) Hasenknopf, B.; Lehn, J.-M. Helv. Chim. Acta 1996, 79, 1643–1650; (e) Livoreil,
A.; Sauvage, J.-P.; Armaroli, N.; Balzani, V.; Flamigni, L.; Ventura, B. J. Am. Chem.
Soc.1997,119,12114–12124; (f) Kepe, V.; Kocevar, M.; Polanc, S. J. Heterocycl. Chem.
1996, 33, 1707–1710; (g) Strah, S.; Stanovnik, B. J. Heterocycl. Chem. 1997, 34,
263–267.
4. Blache, Y.; Chavignon, O.; Sinibaldi, M. E.; Troin, A.; Gueiffier, A.; Teulade, J. C.;
Troin, Y.; Gramain, J. C. Heterocycles 1994, 38, 1241–1248.
5. (a) San Martin, R.; de Marigorta, E. M.; Dominguez, E. Tetrahedron 1994, 50,
2255–2264; (b) Bartoli, G.; Cimarelli, C.; Palmieri, G. J. Chem. Soc., Perkin Trans. 1
1994, 537–543.
4.5.3. 6-[2-(4-Chloro-phenyl)-vinyl]-2H-thiopyran-3-carboxylic acid
methyl ester (19c). Eluent for chromatography: EA/Hex (5:95),
yielded 19c (64%) as reddish solid: mp 115–116 ꢁC; IR nmax (KBr):
1699 cmꢀ1 1H NMR (CDCl3)
; d 3.63 (s, 2H, –CH2), 3.81 (s, 3H,
–OCH3), 6.37 (d, J¼6.6 Hz, 1H), 6.81 (d, J¼15.6 Hz, 1H, olefinic), 7.02
(d, J¼15.6 Hz, 1H, olefinic), 7.10–7.39 (m, 5H, 4ArH and 1 olefinic);
13C NMR
d 23.9, 53.1, 114.1, 119.6, 122.1, 124.7, 126.5, 127.9, 130.1,
134.8, 143.2, 152.4 and 166.1; MS (EI) m/z: 292 (Mþ). Calcd for
C15H13ClO2S: C, 61.53; H, 4.48. Found: C, 61.43; H, 4.53%.
6. (a) Tabakovic, I. Electrochim. Acta 1995, 40, 2809--2813; (b) Dominguez, E.;
Ibeas, E.; de Maigorta, E. M.; Palacios, J. K.; SanMartin, R. J. Org. Chem. 1996, 61,
5435–5439.
4.5.4. 6-Styryl-2H-thiopyran-3-carbonitrile (19d). Eluent for chro-
matography: EA/Hex (8:92), yielded 19d (51%) as a brown solid: mp
107–108 ꢁC; IR nmax (KBr): 2224 cmꢀ1; 1H NMR (CDCl3)
d 3.51 (s, 2H,
7. Vogt, B. R.. U.S. Patent 4,112,098, 1978; (CA 92: 146801).
8. Kohn, E. C.; Liotta, A. J. Natl. Cancer Inst. 1990, 82, 54–61.
–CH2), 6.37 (d, J¼6.6 Hz, 1H), 6.81 (d, J¼15.6 Hz, 1H, olefinic), 6.89–
9. Nielsen, F. E.; Pedersen, E. B.; Begtrip, M. Liebigs Ann. Chem. 1984, 11, 1848–1859.
10. Meier, R. Eur. Patent Appl. EP229, 011, 1987; (CA 107: 198336h).
11. Biagi, G.; Ferreti, M.; Livi, O.; Scartoni, V.; Lucacchini, A.; Mazzoni, M. Farmaco
Ed. Sci. 1986, 41, 388–400.
6.99 (m, 3H, ArH), 7.00 (d, J¼15.6 Hz, 1H, olefinic), 7.10–7.46 (m, 3H,
2ArH and 1H olefinic); 13C NMR
d 26.1, 114.5, 119.5, 121.5, 123.9,
127.6, 129.0, 130.7, 135.6, 139.4, 142.1 and 160.3; MS (EI) m/z: 225
(Mþ). Calcd for C14H11NS: C, 74.63; H, 4.92; N, 6.22. Found: C, 74.77;
H, 5.02; N, 6.14%.
12. Parlok, J. J. J. Heterocycl. Chem. 1998, 35, 1493–1499.
13. (a) Frinkelstein, B. L.; Strok, C. J. J. Pesticide Sci. 1997, 50, 324–332; (b) Schallner, O.;
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Marongiu, M. E. Eur. J. Med. Chem. 1998, 33, 375–382; (b) Tsuji, K.; Nakamurana,
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45, 987–995; (c) Nauduri, D.; Reddy, G. Chem. Pharm. Bull. 1998, 46, 1254–1260;
(d) Gajare, A. S.; Bhawsar, S. B.; Shingare, M. S. Indian J. Chem. 1997, 6, 321–322;
(e) Wise, L. D.; Butler, D. E.; Dewald, H. A.; Lustgarten, D. M.; Pattison, I. C.;
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Med. Chem. 1987, 30, 1807–1812; (f) Brune, K. Med. Toxicol. 1986, 1, 1–9.
15. Olivera, R.; SanMartin, R.; Dominguez, E. J. Org. Chem. 2000, 65, 7010–7019.
16. Bargagna, A.; Schenone, P.; Bondavalli, F.; Longobardi, M. J. Heterocycl. Chem.
1982, 19, 257–261.
17. Singh, P.; Bisetty, K.; Mahajan, M. P. S. Afr. J. Chem. 2009, 62, 47–55.
18. (a) Kinzel, O. D.; Ball, R. G.; Donghi, M.; Maguire, C. K.; Muraglia, E.; Pesci, S.;
Rowley, M.; Summa, V. Tetrahedron Lett. 2008, 49, 6556–6558; (b) Ram, R. N.;
Kumar, N. Tetrahedron 2008, 64, 10267–10271; (c) Katoh, N.; Nakahata, T.;
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19. Case, D. A.; Darden, T. A.; Cheatham, T. E.; Simmerling, C. L.; Wang, J.; Duke, R.
E.; Luo, R.; Merz, K. M.; Pearlman, D. A.; Crowley, M.; Walker, R. C.; Zhang, W.;
Wang, B.; Hayik, S.; Roitberg, A.; Seabra, G.; Wong, K. F.; Paesani, F.; Wu, X.;
Brozell, S.; Tsui, V.; Gohlke, H.; Yang, L.; Tan, C.; Mongan, J.; Hornak, V.; Cui, G.;
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University of California: San Francisco, 2006.
4.5.5. 6-[2-(4-Methoxy-phenyl)-vinyl]-2H-thiopyran-3-carbonitrile
(19e). Eluent for chromatography: EA/Hex (10:90), yielded 19e
(58%) as a brown solid: mp 118–119 ꢁC; IR nmax (KBr): 2225 cmꢀ1
;
1H NMR (CDCl3)
d 3.47 (s, 2H, –CH2), 3.82 (s, 3H, –OCH3), 6.35 (d,
J¼6.6 Hz, 1H), 6.80 (d, J¼15.6 Hz, 1H, olefinic), 6.85 (d, J¼8.7 Hz, 2H,
ArH), 7.01 (d, J¼15.6 Hz, 1H, olefinic), 7.25–7.30 (m, 1H, olefinic),
7.43 (d, J¼8.7 Hz, 2H, ArH); 13C NMR
d 26.0, 55.3, 114.3, 119.0, 120.3,
124.6, 128.6, 128.8, 130.1, 135.6, 140.1, 143.4 and 160.5; MS (EI) m/z:
255 (Mþ). Calcd for C15H13NOS: C, 70.56; H, 5.13; N, 5.49. Found: C,
70.45; H, 5.21; N, 5.43%.
4.5.6. 6-[2-(4-Chloro-phenyl)-vinyl]-2H-thiopyran-3-carbonitrile
(19f). Eluent for chromatography: EA/Hex (10:90), yielded 19f
(42%) as a brown solid: mp 126–127 ꢁC; IR nmax (KBr): 2225 cmꢀ1
;
1H NMR (CDCl3)
J¼15.6 Hz, 1H, olefinic), 6.89–7.10 (m, 3H, 2ArH and 1H olefinic),
7.17–7.49 (m, 3H, 2ArH and 1H olefinic); 13C NMR
26.2, 114.6,
d
3.49 (s, 2H, –CH2), 6.36 (d, J¼6.6 Hz, 1H), 6.83 (d,
d
118.9, 120.8, 123.7, 125.6, 128.9, 132.4, 136.1, 138.2, 143.1 and 160.3;
MS (EI) m/z: 259 (Mþ). Calcd for C14H10ClNS: C, 64.73; H, 3.88; N,
5.39. Found: C, 64.65; H, 3.99; N, 5.45%.
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Acknowledgements
The authors are grateful to CSIR, New Delhi, for financial support
under Grant No. 01(1872/03/EMR-II) and to the Department of
Chemistry, GNDU, Amritsar, and RSIC (CDRI), Lucknow, for assis-
tance with spectral data. Financial assistance from the National
Research Foundation (NRF) and the Centre for Research Manage-
ment and Development (CRMD), DUT, for a postdoctoral fellowship
is gratefully acknowledged.
21. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Stratmann, R. E.; Burant,
J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas,
O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B. C.; Pomelli, C.;
Adamo, S.; Clifford; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Moro-
kuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavchari, K.; Foresman, J. B.; Cio-
slowski, J.; Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M. P.; Gill, M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E.
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