Arylidene pyruvic acids motif in the synthesis of new thiopyrano[2,3-d]thiazoles as potential biologically active compounds

Article abstract of DOI:10.1515/hc-2014-0204

Novel rel-(5R,6S,7S)-2-oxo-5,7-diaryl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl-oxo-acetic acids were synthesized in 52-70% yields via regioselective and diastereoselective hetero-Diels-Alder reaction of 5-arylidene-4-thioxo-2-thiazolidinones with a series of arylidene pyruvic acids. The synthesized compounds were evaluated for anticancer activity in NCI60 cancer cell lines and for antiexudative activity on the carrageenan edema model in rats. Biological screening data led to identification of 3e as having moderate antitumor activity on the colon cancer HT-29 cell line and of 3b as having promising antiexudative effect.

Full text of DOI:10.1515/hc-2014-0204

Heterocycl. Commun. 2015; 21(1): 55–59
Andrii Lozynskyi, Borys Zimenkovsky, Ihor Nektegayev and Roman Lesyk*
Arylidene pyruvic acids motif in the synthesis
of new thiopyrano[2,3-d]thiazoles as potential
biologically active compounds
Abstract: Novel rel-(5R,6S,7S)-2-oxo-5,7-diaryl-3,5,6,7- Such derivatives may be considered as structures with
tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl-oxo-acetic ‘fixed’ thiazolidinone biophore in condensed heterosystems
acids were synthesized in 52–70% yields via regioselec- that allows to predict compounds’ pharmacological profile
tive and diastereoselective hetero-Diels-Alder reaction of saving and to extend the ‘structure-activity’ database. In
5
-arylidene-4-thioxo-2-thiazolidinones with a series of support of this view, thiopyrano[2,3-d]thiazoles with anti-
arylidene pyruvic acids. The synthesized compounds were cancer, antimycobacterial, and antitrypanosomal prop-
evaluated for anticancer activity in NCI60 cancer cell lines erties have been identified [5–15]. In continuation of our
and for antiexudative activity on the carrageenan edema research, the thiazolidinone moiety and a fragment of APAs
model in rats. Biological screening data led to identifica- were combined in a single heterocyclic system (Scheme 1).
tion of 3e as having moderate antitumor activity on the Herein, we report the synthesis and characterization of new
colon cancer HT-29 cell line and of 3b as having promising thiopyrano[2,3-d]thiazoles using APAs as dienophiles in
antiexudative effect.
hetero-Diels-Alder reactions.
Keywords: 5-arylideneisorhodanines; anticancer activity;
antiexudative activity; arylidene pyruvic acids; hetero-
Diels-Alder reaction; thiopyrano[2,3-d]thiazoles.
Results and discussion
Chemistry
DOI 10.1515/hc-2014-0204
Received December 11, 2014; accepted December 23, 2014
The synthesis of starting 5-arylidene-4-thioxo-2-thiazo-
lidinones (5-arylideneisorhodanines) 1a–d was accom-
plished by the reaction of 4-thioxo-2-thiazolidinone with
appropriate aldehydes in glacial acetic acid in the pres-
ence of a catalytic amount of fused sodium acetate [8, 10].
Same results were obtained for the reaction conducted
in ethanol in the presence of ethylenediaminediacetate
Introduction
Arylidene pyruvic acids (APAs) of a versatile structure have
been used as starting materials for the synthesis of a large
diversity of organic compounds [1]. In addition, this func-
tionality is associated with biological properties and is
present in a series of bioactive natural products [2–4]. Mean-
while, in our previous research, we obtained a number of
arguments in favor of the hypothesis of the pharmacological
potential of thiopyrano[2,3-d]thiazoles, synthetic precursors
to biologically active 5-aryl(heteryl)idene-4-thiazolidinones.
(
EDDA). The APAs were synthesized by the reaction of a
corresponding aromatic aldehyde with a pyruvic acid in an
aqueous methanol solution of KOH [16]. The hetero-Diels-
Alder reaction of 2a–f with 5-arylidene-4-thioxo-2-thiazo-
lidinones 1a–d regioselectively and diastereoselectively
yielded a series of novel rel-(5R,6S,7S)-2-oxo-5,7-diaryl-
3
,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl-oxo-
acetic acids (Scheme 2).
The structure of the newly synthesized compounds
was confirmed by elemental analysis and spectroscopic
*
Corresponding author: Roman Lesyk, Department of
1
13
Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky data ( H NMR and C NMR). The stereochemical features
Lviv National Medical University, Pekarska 69, 79010 Lviv, Ukraine,
e-mail: dr_r_lesyk@org.lviv.net
of the above hetero-Diels-Alder reaction can be predicted.
In particular, we have observed that the use of APAs in the
Andrii Lozynskyi, Borys Zimenkovsky and Ihor Nektegayev:
[
4+2]-cyclocondensation with 5-arylideneisorhodanines
Department of Pharmaceutical, Organic and Bioorganic Chemistry,
Danylo Halytsky Lviv National Medical University, Pekarska 69,
7
leads to a pair of rel-(5R,6S,7S)-diastereomers. This claim
9010 Lviv, Ukraine
is based on the coupling constant values within the range
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6ꢀꢀꢀꢀꢁꢀA. Lozynskyi et al.: Arylidene pyruvic acids motif in the synthesis of new thiopyrano[2,3-d]thiazoles
Structure of target compounds
5-arylidene-4-thioxo-2-thiazolidinone
Arylidene pyruvic acid
H
N
S
H
S
N
COOH
O
O
O
H
O
HO OC
S
S
H
Ar
Ar
Bioactive thiopyrano [2,3-d]thiazoles
O
O
H
H
H
N
O
S
H
H
N
S
N
S
S
N
O
O
R
O
O
N
O
S
O
S
S
S
H
H
H
H
H
Ar
Ar
NHR
Ar
Ar
Antitrypanosomal activity
Anticancer and
Anticancer activity
Anticancer activity
antimycobacterial activity
N. Zelisko et al., 2012 [11]
D. Atamanyuk et al., 2013 [15]
A. Lozynskyi et al., 2014 [9]
R. Lesyk et al., 2006 [8]
Scheme 1ꢂBackground for target compounds synthesis.
R2
O
CHO
R2
OH
S
O
O
S
R1
HO
R1
O
NH
O
P2S
5
2a-c
S
NH
O
NH
O
S
O
Dioxane
S
S
A: AcOH, AcONa
or
B: EtOH, EDDA
AcOH, hydroquinone
NH
R1
S
1
1a: R = 3,4-diOMe
b: R = 4-OMe
1
O
1
1
1
1
3a: R1 = 3,4-diOMe ; R = H
2
c : R = 4-Cl
1
3b: R1 = 4-O Me; R2 = 3,4-diOMe
d: R = 4-Me
2
3
c: R1 = 4-OMe; R = H
3d: R = 4-Cl; R2 = OMe
1
O
2
R2
R2
2a: R = H
b: R = OMe
1
2
CHO
3e: R = 4-Me; R = OMe
f: R = 4-Me ; R = H
g: R = 4-Cl; R = H
CH3COCOOH
MeOH, KOH
OH
2
2
1
2
3
3
2
O
2c: R = 3,4-diOMe
1
2
Scheme 2ꢂSynthesis of 2-oxo-5,7-diaryl-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl-oxo-acetic acids.
of 10.4–10.8 Hz and the observed spectral patterns of the nih.gov) and evaluated for antitumor activity at 10-μꢀ
thiopyran fragment (triplet and two doublets at 4.18–4.85 concentration toward a panel of approximately 60 cancer
ppm), which show an axial-axial interaction of the 5-H, 6-H cell lines. The human tumor cell lines were represent-
and the 6-H, 7-H proton pairs. Importantly, a similar pattern ing leukemia, melanoma, lung, colon, central nervous
was observed earlier for cinnamic acids and their amides as system, ovarian, renal, prostate, and breast cancers. Anti-
dienophiles in the hetero-Diels-Alder reactions [9–11].
cancer assays were performed according to the NCI proto-
col, which is described elsewhere [17–19]. The compounds
were added at a single concentration, and the cell cultures
were incubated for 48 h. The results for each compound
are reported as the percentage of growth (GP%) of treated
Evaluation of anticancer activity in vitro
Synthesized rel-(5R,6S,7S)-2-oxo-5,7-diaryl-3,5,6,7-tetrahy- cells when compared with untreated control cells. The
dro-2H-thiopyrano[2,3-d]thiazol-6-yl-oxo-acetic
acids screening results are shown in Table 1.
3
e and 3c were selected by the National Cancer Institute
The tested compounds 3e and 3c did not show sig-
(
NCI) Developmental Therapeutic Program (www.dtp.nci. nificant activity in almost cancer cell lines. Nevertheless,
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A. Lozynskyi et al.: Arylidene pyruvic acids motif in the synthesis of new thiopyrano[2,3-d]thiazolesꢂꢁꢀꢀꢀꢂ57
Table 1ꢂCytotoxic activity of the tested compounds at concentration Table 2ꢂAntiexudative activity of the tested compounds on the car-
-
5
1
0 ꢃ against 60 cancer cell lines.
rageenan foot edema model in rats.
Test
Average Range of Most sensitive cell line
Test compound
Dose Cross section
Inhibition
of rat paw
edema (%)
compounds
growth
%)
growth growth (%) (cancer line/
(%) type)
(mg/kg)
of rat paw
(relative
(
units) over control
ꢁ
ꢁ
e
c
ꢄꢅ.ꢅꢆ
ꢅꢇ.ꢈꢅ– ꢅꢇ.ꢈꢅ (HT-ꢆꢄ/colon cancer)
ꢈꢉꢊ.ꢇꢇ 8ꢆ.8ꢈ (SK-MEL-ꢆ/melanoma)
ꢋꢋ.ꢇꢋ (UO-ꢇꢈ/renal cancer)
8ꢊ.ꢉꢆ– 8ꢄ.ꢊꢆ (SK-MEL-ꢆ/melanoma)
ꢈꢈꢌ.ꢉꢌ 8ꢊ.ꢉꢆ (TK-ꢈꢉ/renal cancer)
Control
–
ꢈꢉ
ꢄꢅ.ꢆ
ꢅ8.ꢊ
ꢋꢈ.ꢊ
8ꢄ.ꢌ
ꢋꢈ.ꢅ
8ꢋ.ꢉ
8ꢉ.ꢉ
–
ꢌꢌ.ꢊ
ꢌꢆ.ꢈ
ꢆꢋ.ꢊ
ꢌꢆ.ꢈ
ꢆꢄ.ꢊ
ꢇꢌ.8
Diclofenac sodium
ꢈꢉꢉ.ꢅ8
Ketorolac tromethamine
ꢈꢉ
ꢁa
ꢁb
ꢈꢉꢉ
ꢈꢉꢉ
ꢈꢉꢉ
ꢈꢉꢉ
8
8
ꢋ.ꢉꢉ (UO-ꢇꢈ/renal cancer)
ꢄ.ꢉꢊ (T-ꢌꢋ-D/breast cancer) ꢁd
ꢁg
slight in vitro cytostatic effect was observed in the growth of
SK-MEL-2 (melanoma), TK-10 and UO-31 (renal cancer), and providing novel rel-(5R,6S,7S)-2-oxo-5,7-diaryl-3,5,6,7-
T-47-D (breast cancer). Moreover, 3e possessed moderate tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl-oxo-acetic
effect on the colon cancer HT-29 cell line (GP% ꢁ=ꢁ 53.15%).
acids. Two tested compounds display slight antitumor
activity against melanoma, renal, and breast cancers
cell lines. The preliminary results of antiexudative activ-
ity on the carrageenan foot edema model in rats allowed
identifying the active compound 3b with effect level
Antiexudative activity
For antiexudative tests, adult male and female rats weighing comparable to that of diclofenac sodium or ketorolac
1
40–150 g were used. The carrageenan-induced hind paw tromethamine.
edema in rats was produced using the method of Winter
et al. [20]. Diclofenac sodium (10 mg/kg) and ketorolac
tromethamine (10 mg/kg) were used as reference com-
pounds. Carrageenan solution (1.0% in sterile 0.9% NaCl Experimental
solution) was injected subcutaneously into the subplanar
region of the hind paw (in volume of 0.1 mL to each paw) 1 h Chemistry
after administration of the test compound. The synthesized
compounds were intraperitoneally injected (1 h before car- All materials were purchased from commercial sources and used
without purification. Melting points were measured in open capil-
rageenan) in a dose 100 mg/kg. Control rats only received
lary tubes and are uncorrected. Elemental analyses were performed
a solution of 0.5% carboxymethylcellulose with one drop
1
using Perkin-Elmer 2400 CHN analyzer. The H NMR (400 MHz) and
of Tween-80. The hind paw volume was measured with
an electronic onkograph immediately before and 4 h after
1
3
C NMR (100 MHz) spectra were recorded on Varian Gemini 400 or
Bruker 125 in DMSO-d using tetramethylsilane as internal standard.
6
carrageenan injection. The effect of the test compounds The purity of all obtained compounds was checked by thin-layer
on decreasing paw edema was compared with control rats. chromatography.
The starting compounds, 2,4-thiazolidinedione [21] and 4-thi-
The antiexudative activity was expressed as a decrease in
oxo-2-thiazolidinone [22], were obtained as described previously.
rat paw edema and is given in percentage (Table 2).
5
-Arylidene-4-thioxo-2-thiazolidinones 1a–d were prepared by Kno-
Among tested compounds, 3b was found to be the
evenagel condensation using method A or B.
most active. It decreased carrageenan-induced edema on
4
2.1%. This value is comparable with the effect of refer- Method A:ꢂA mixture of 4-thioxo-2-thiazolidinone (10 mmol), appro-
priate substituted benzaldehyde (10 mmol), and sodium acetate
10 mmol) in glacial acetic acid (10 mL) was heated under reflux for
ence compounds. For other derivatives, 3a, 3d, and 3g,
(
moderate antiexudative activity was observed.
2
0 min in water bath (100°C). The solid product was collected by fil-
tration and used without further purification.
Method B:ꢂA mixture of 4-thioxo-2-thiazolidinone (10 mmol) and
appropriate substituted benzaldehyde (10 mmol) in ethanol in the
presence of catalytic amount of EDDA was heated under reflux for 10
Conclusions
5
-Arylideneisorhodanines and APAs undergo regioselec- min. The solid product was collected by filtration and used without
tive and diastereoselective hetero-Diels-Alder reaction, further purification.
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8ꢀꢀꢀꢀꢁꢀA. Lozynskyi et al.: Arylidene pyruvic acids motif in the synthesis of new thiopyrano[2,3-d]thiazoles
General procedure for hetero-Diels-Alder reaction afford- (d, 2H, J ꢁ=ꢁ 8.1 Hz, arom.), 7.35 (d, 2H, J ꢁ=ꢁ 8.7 Hz, arom.), 7.59 (d, 2H, J ꢁ=ꢁ
1
3
8
.1 Hz, arom.), 11.45 (s, 1H, NH); C NMR: δ 192.8, 171.6, 171.0, 165.8,
ing 3a–g
1
43.5, 141.3, 133.4, 132.8, 132.0, 131.4, 121.2, 116.9, 109.5, 55.8, 51.2, 45.3,
4
1.5, 23.3. Anal. Calcd for C H NO S : C, 59.85; H, 4.34; N, 3.17. Found:
22 19 5 2
A mixture of appropriate 5-arylidene-4-thioxo-2-thiazolidinone (5
mmol), APA (5.5 mmol), and a catalytic amount of hydroquinone (2–3
mg) in 15 mL of glacial acetic acid was heated under reflux for 4–7 h
and then lef overnight at room temperature. The resultant solid
product was collected by filtration, washed with water, methanol
C, 59.83; H, 4.33; N, 3.18.
rel-(5R,6S,7S)-[7-(4-Methylphenyl)-5-phenyl-2-oxo-3,5,6,7-
tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl)]oxo-acetic acid (3f):ꢂ
1
Yield 56%; mp 182–184°C (EtOH); H NMR: δ 2.25 (s, 3H, CH ), 4.24
3
(5–10 mL), diethyl ether, and crystallized from acetic acid or ethanol.
(
d, 1H, J ꢁ=ꢁ 10.6 Hz, 7-H), 4.56 (t, 1H, J ꢁ=ꢁ 10.6 Hz, 6-H), 4.98 (d, 1H,
J ꢁ=ꢁ 10.6 Hz, 5-H), 7.11 (d, 2H, Jꢀ=ꢀ8.7 Hz, arom.), 7.13 (d, 2H, Jꢀ=ꢀ8.7 Hz,
rel-(5R,6S,7S)-[7-(3,4-Dimetoxyphenyl)-5-phenyl-2-oxo-3,5,6,7-
tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl]oxo-acetic acid (3a):ꢂ
Yield 60%; mp 192–194°C (AcOH); H NMR: δ 3.71 (s, 3H, OCH ), 3.72
arom.), 7.29–7.35 (m, 3H, arom.), 7.42 (d, 2H, J ꢁ=ꢁ 7.2 Hz, arom.), 11.48 (s,
13
1
H, NH); C NMR: δ 196.6, 170.4, 160.4, 137.2, 135.8, 135.3, 129.2, 128.8,
1
3
128.5, 128.2, 126.6, 120.0, 108.1, 54.5, 47.9, 45.5, 20.7. Anal. Calcd for
C H NO S : C, 61.30; H, 4.16; N, 3.40. Found: C, 61.31; H, 4.15; N, 3.41.
(
s, 3H, OCH ), 4.21 (d, 1H, J ꢁ=ꢁ 10.8 Hz, 7-H), 4.64 (t, 1H, J ꢁ=ꢁ 10.8 Hz,
3
2
1
17
4 2
6
-H), 5.00 (d, 1H, J ꢁ=ꢁ 10.8 Hz, 7-H), 6.69 (d, 1H, J ꢁ=ꢁ 8.1 Hz, arom.), 6.82
(
t, 1H, J ꢁ=ꢁ 7.5 Hz, arom.), 6.86 (s, 1H, arom.), 7.27–7.36 (m, 3H, arom.),
rel-(5R,6S,7S)-[7-(4-Chlorophenyl)-5-phenyl-2-oxo-3,5,6,7-
tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl)oxo-acetic acid (3g):ꢂ
1
3
7
.44 (d, 2H, J ꢁ=ꢁ 7.5 Hz, arom.), 11.47 (s, 1H, NH); C NMR: δ 192.6, 172.6,
1
1
70.8, 165.6, 145.2, 141.9, 137, 131.6, 130.4, 128.9, 128.5, 121.4, 119.2, 115.4,
09.2, 6.11, 6.23, 55.5, 48.6, 42.1. Anal. Calcd for C H NO S : C, 57.76;
1
Yield 70%; mp 178–180°C (EtOH); H NMR: δ 4.27 (d, 1H, J ꢁ=ꢁ 10.8 Hz,
2
2
19
6
2
7-H), 4.47 (t, 1H, J ꢁ=ꢁ 10.8 Hz, 6-H), 4.86 (d, 1H, J ꢁ=ꢁ 10.8 Hz, 5-H), 7.21
H, 4.19; N, 3.06. Found: C, 57.77; H, 4.20; N, 3.07.
(
d, 2H, J ꢁ=ꢁ 8.4 Hz, arom.), 7.29–7.31 (m, 5H, arom.), 7.38 (d, 2H, J ꢁ=ꢁ 7.2
1
3
Hz, arom.), 11.40 (s, 1H, NH); C NMR: δ 193.2, 171.3, 171.4, 162.6, 140.1,
39.8, 133.3, 129.5, 120.2, 115.6, 109.8, 55.7, 50.2, 45.1, 41.2. Anal. Calcd
for C H ClNO S : C, 55.62; H, 3.27; N, 3.24. Found: C, 55.61; H, 3.28;
rel-(5R,6S,7S)-[5-(3,4-Dimetoxyphenyl)-7-(4-methoxyphenyl)-2-
oxo-3,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl]oxo-acetic
1
2
0
14
4 2
1
acid (3b):ꢂYield 52%; mp 184–186°C (EtOH); H NMR: δ 3.74 (s, 3H,
N, 3.25.
OCH ), 3.75 (s, 3H, OCH ), 3.86 (s, 3H, OCH ), 4.17 (d, 1H, J ꢁ=ꢁ 10.4 Hz,
3
3
3
7
-H), 4.48 (t, 1H, J ꢁ=ꢁ 10.4 Hz, 6-H), 4.77 (d, 1H, J ꢁ=ꢁ 10.4 Hz, 5-H), 6.85
(
d, 1H, J ꢁ=ꢁ 8.4 Hz, arom.), 6.96 (s,1H, arom.), 7.04 (d, 1H, J ꢁ=ꢁ 8.4 Hz,
Cytotoxic activity against malignant human tumor cells
arom.), 7.09 (d, 2H, J ꢁ=ꢁ 8.0 Hz, arom.), 7.58 (d, 2H, J ꢁ=ꢁ 8.0 Hz, arom.),
1.25 (s, 1H, NH); 1 C NMR: δ 196.5, 170.8, 170.5, 161.3, 160.6, 158.6,
3
1
1
48.8, 135.9, 132.7, 129.5, 127.3, 121.1, 115.0, 111.5, 108.2, 55.6, 55.4, 54.9, Anticancer in vitro assay was performed on the human tumor cell
7.8, 45.1. Anal. Calcd for C H NO S : C, 56.66; H, 4.34; N, 2.87. Found: lines panel derived from nine neoplastic diseases, in accordance
4
2
3
21
7 2
C, 56.65; H, 4.33; N, 2.88.
with the protocol of the Drug Evaluation Branch, National Can-
cer Institute, Bethesda, MD, USA [17–19]. Tested compounds were
-5
rel-(5R,6S,7S)-[7-(4-Methoxyphenyl)-5-phenyl-2-oxo-3,5,6,7- added to the culture at a single concentration (10 ꢀ), and the
tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl]oxo-acetic acid (3c):ꢂ cultures were incubated for 48 h. End point determinations were
1
Yield 69%; mp 186–188°C (EtOH); H NMR: δ 3.75 (s, 3H, OCH ), 4.18 made with a protein binding dye, sulforhodamine B. Results for
3
(
1
d, 1H, J ꢁ=ꢁ 10.4 Hz, 7-H), 4.49 (t, 1H, J ꢁ=ꢁ 10.4 Hz, 6-H), 4.85 (d, 1H, J ꢁ=ꢁ each tested compound were reported as the GP% of the treated
0.4 Hz, 5-H), 6.80 (d, 2H, J ꢁ=ꢁ 8.4 Hz, arom.), 7.09 (d, 2H, J ꢁ=ꢁ 8.4 Hz, cells when compared with the untreated control cells. GP% was
arom.), 7.29–7.37 (m, 3H, arom.), 7.39 (d, 2H, J ꢁ=ꢁ 7.2 Hz, arom.), 11.29 (s, evaluated spectrophotometrically vs. controls not treated with test
1
3
1
1
H, NH); C NMR: δ 193.51, 171.43, 171.65, 167.32, 145.19, 142.88, 139.22, agents.
33.54, 131.54, 129.74, 121.18, 117.76, 111.56, 56.44, 55.73, 49.65, 41.22.
Anal. Calcd for C H NO S : C, 59.00; H, 4.01; N, 3.28. Found: C, 59.02;
2
1
17
5 2
Acknowledgments: We thank Dr. V. L. Narayanan from
the Drug Synthesis and Chemistry Branch, National Can-
cer Institute, Bethesda, MD, USA, for in vitro evaluation of
anticancer activity.
H, 4.02; N, 3.27.
rel-(5R,6S,7S)-[7-(4-Chlorophenyl)-5-(4-methoxyphenyl)-2-oxo-
3
,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl]oxo-acetic acid
1
(
3d):ꢂYield 65%; mp 192–194°C (EtOH); H NMR: δ 3.73 (s, 3H, OCH ),
3
4.17 (t, 1H, J ꢁ=ꢁ 10.4 Hz, 6-H), 4.38 (d, 1H, J ꢁ=ꢁ 10.4 Hz, 7-H), 4.94 (d, 1H,
J ꢁ=ꢁ 10.4 Hz, 5-H), 6.79 (d, 2H, J ꢁ=ꢁ 8.0 Hz, arom.), 7.19 (d, 2H, J ꢁ=ꢁ 8.4 Hz,
arom.), 7.25 (d, 2H, J ꢁ=ꢁ 8.0 Hz, arom.), 7.29 (d, 2H, J ꢁ=ꢁ 8.4 Hz, arom.),
1
3
References
1
1
1.29 (s, 1H, NH); C NMR: δ 192.4, 172.6, 170.6, 164.1, 141.5, 139.8, 131.5,
30.6, 129.4, 128.6, 118.2, 114.2, 107.8, 55.8, 5.2, 46.7, 43.8. Anal. Calcd
for C H ClNO S : C, 54.60; H, 3.49; N, 3.03. Found: C, 54.61; H, 3.48; [1] Shiri, M.; Heravi, M.; Soleymnifard, B. Arylidene pyruvic acids
2
1
16
5 2
N, 3.02.
(APAs) in the synthesis of organic compounds. Tetrahedron
012, 68, 6593–6650.
2
rel-(5R,6S,7S)-[5-(4-Methoxyphenyl)-7-(4-methylphenyl)-2-oxo- [2] Montalban, A. G.; Boman, E.; Chang, C.-D.; Conde Ceide, S.;
3
,5,6,7-tetrahydro-2H-thiopyrano[2,3-d]thiazol-6-yl]oxo-acetic acid
Dahl, R.; Dalesandro, D.; Delaet, N. G. J.; Erb, E.; Ernst, J. T.;
Gibbs, A.; et al. The design and synthesis of nowel α-ketoamide-
based p3ꢍMAP kinase inhibitors. Bioorg. Med. Chem. Lett.
2008, 18, 1772–177ꢍ.
1
(
3e):ꢂYield 55%; mp 172–174°C (EtOH); H NMR: δ 2.26 (s, 3H, CH ),
3
3
.72(s, 3H, OCH ), 4.19 (d, 1H, J ꢁ=ꢁ 10.4 Hz, 7-H), 4.49 (t, 1H, J ꢁ=ꢁ 10.4 Hz,
3
6
-H), 4.86 (d, 1H, J ꢁ=ꢁ 10.4 Hz, 5-H), 6.88 (d, 2H, J ꢁ=ꢁ 8.7 Hz, arom.), 7.12
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