Acetylenic Ester Promoted Tandem Ring Opening of Dienyl Thiazolidin-4-ones and Cyclizations: A Facile and Chemoselective Synthesis of Functionalized Pyridine-2-carboxylates

Article abstract of DOI:10.1055/s-0036-1591721

Acetylenic ester promoted ring opening of dienyl-thiazolidin-4-ones and subsequent electrocyclization affords 5-phenyl-6-aryl pyridine-2-carboxylates in good to excellent yields.

Full text of DOI:10.1055/s-0036-1591721

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, 509–512
letter
509
en
B. Kuila et al.
Letter
Synlett
Acetylenic Ester Promoted Tandem Ring Opening of Dienyl
Thiazolidin-4-ones and Cyclizations: A Facile and Chemoselective
Synthesis of Functionalized Pyridine-2-carboxylates
Bilash Kuilaa
CO2Me
Kapil Kumarb
Dinesh Mahajanc
Prabhpreet Singhb
Gaurav Bhargava*a
S
R2
CO2Me
N
H
O
H
xylene
170 °C
OR1
H
O
R2
N
CO2R1
a Department of Chemical Sciences, I. K. Gujral Punjab Technical
University, Kapurthala, Punjab-144603, India
b Department of Chemistry, Guru Nanak Dev University, Amritsar,
Punjab 143005, India
c Drug Discovery Research Centre (DDRC), Translational Health
Sciences and Technology Institute (THSTI), Faridabad-121001,
India
R1 = Me, Et
2 = Ar
yield 78–91%
R
gaurav@ptu.ac.in
Received: 07.09.2017
Accepted after revision: 18.10.2017
Published online: 28.11.2017
as inhibitors of COX-1,15 HIV-RT,16 aldose reductase,17,18 bac-
terial enzyme MurB and YycG histidine kinase,19,20 as well
as having antidiabetic activity,21 antitubercular, antifungal,
and antihelmintic activities.21 Thiazolidin-4-ones have also
been explored as useful organic synthons of different
heterocycles.22
DOI: 10.1055/s-0036-1591721; Art ID: st-2017-d0712-l
Abstract Acetylenic ester promoted ring opening of dienyl-thiazoli-
din-4-ones and subsequent electrocyclization affords 5-phenyl-6-aryl
pyridine-2-carboxylates in good to excellent yields.
There are numerous reports on the acetylenic ester-
mediated synthesis of thiazolidin-4-ones using a variety of
thioamides and thioureas.22 However, there are few reports
exploring acetylenic ester mediated ring opening/transfor-
mations of 4-thiazolidinones. The present manuscript
demonstrates acetylenic ester mediated synthetic transfor-
mations of dienyl-thiazolidinones23 leading to a facile syn-
thesis of functionalized pyridine-2-carboxylates. In this
transformation, the dienyl-thiazolidinones 1a–h behave as
masked conjugated 2-azadienes and afford a facile and
chemoselective formation of pyridine-2-carboxylates medi-
ated by acetylenic esters in good to excellent yields.
The dienyl thiazolidin-4-ones 1a–h were prepared by
amidiolytic ring opening of 2-azetidinones-3-thiazolidin-4-
ones with sodium alkoxide in the corresponding alcohols
(Scheme 1).23 Crystallography data for 1a established the
trans conformation of the dienyl thiazolidin-4-one moi-
ety.23
Key words pyridine-2-carboxylate, dienyl-thiazolidin-4-one, acetylen-
ic ester, cyclization, 5,6-diarylpyridine
Functionalized pyridines having ester substituents at
their 2-position i.e., pyridine-2-carboxylates, are prominent
in biologically active molecules.1–3 Functionalized pyridine-
2-carboxylates have been identified as cholecystokinin
(CCK1) receptors, cannabinoid receptor type 1 (CB1), and
telomerase inhibitors.4 Similarly, 5,6-diaryl-2-pyridine-
carboxamides have been used as urotensin II receptor anta-
gonists and sphingosine-1-phosphate (S1P) receptor ago-
nists.5,6
Traditionally, [4+2] cycloadditions of acyclic 2-aza-
dienes have been used as a versatile method for the forma-
tion of functionalized pyridines, dihydropyridines, and
tetrahydropyridines.7–11 Barluenga et al. have explored the
synthesis of functionalized pyridines utilizing ethoxycar-
bonyl 2-aza-1,3-butadienes as starting materials.12 Meurer
et al. have reported the synthesis of different 5,6-diarylpyr-
idine carboxylates and carboxamides via cycloaddition of
azadiene phosphazene moieties and subsequently studied
their human CB1 inverse agonist activity.13 However, most
2-azadienes are found to be quite unstable and their syn-
thesis requires cumbersome experimental procedures.
Moreover, synthesis and cycloadditions of conjugated 2-
azadienes have been little explored.
R1
O
RO
N
R2
S
O
R2
N
NaOR, ROH
R = Me, Et
N
O
O
S
Scheme 1 Synthesis of dienyl thiazolidin-4-ones23
Thiazolidin-4-ones represent an important class of
heterocyclic compounds due to their diverse biological ac-
tivities.14 Thiazolidin-4-ones have activity profiles, acting
We started our investigations by attempting Diels–Alder
reactions of dienyl thiazolidin-4-one 1a with electron-defi-
cient dienophiles (such as methyl acrylate, methyl vinyl
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 509–512

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B. Kuila et al.
Letter
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ketone, maleic anhydride, N-phenyl maleimides) as well as
electron-rich dienophiles (such as ethyl vinyl ether, tetra-
hydropyram, enamines etc.) in different solvents at differ-
ent temperatures (rt to 180 °C). However, all attempts to
achieve the desired reaction proved unsuccessful. Attempts
to use activated acetylenes with dienyl thiazolidin-4-one 1a
were also unsuccessful and resulted in the recovery of
starting material, even at elevated temperatures (up to
130 °C; Scheme 2). However, reaction of dienyl thiazolidin-
4-one 1a with different acetylenic esters at high tempera-
ture (170 °C and above) resulted in the formation of 6-(2,5-
dimethylphenyl)-5-phenylpyridine-2-carboxylate (3a) in
good yield (Scheme 3, Table 1; entry 3).
Table 1 Optimization of Reaction Conditions for the Synthesis of
Methyl 6-(2,5-Dimethylphenyl)-5-phenylpyridine-2-carboxylate (3a)
Entry
Alkynes
Solvent
Temp. (°C)
Time (h)a
Yield (%)b
1
2
–
toluene
xylene
xylene
xylene
xylene
xylene
xylene
xylene
xylenec
xylenec
xylenec
xylenec
dioxanec
DCEc
150
180
170
150
190
180
180
180
180
180
180
180
180
180
24
24
16
24
36
24
24
24
24
24
24
24
24
24
0
0
–
3
2a
2a
2b
2c
2d
2e
2f
91
40
0
4
5
6
39
52
48
0
7
8
RO
9
O
10
11
12
13
14
2g
2h
2i
0
R2OC
Diels–Alder reaction
R1
N
no reaction
0
+
rt to 180 °C
O
S
0
R2 = Me, OMe
2a
2a
5
R = Me, Et
R1 = Ar
8
RO
N
a Sealed tube was used.
CO2R3
O
b Isolated yield after purification.
c Starting material was recovered unreacted.
Diels–Alder reaction
up to 130 °C
R1
+
no reaction
O
S
R2
goes subsequent electrocyclization to yield final product 3a
at high temperature. The possible by-product of this reac-
tion, the acetylenic ester thioglycolic complex, was never
isolated, probably due to its unstable nature at elevated
temperature.
2 = CO2Me, Me, H
R = Me, Et
R1 = Ar
R
R3 = Me
Scheme 2 Attempted Diels–Alder cycloadditions of dienyl thiazolidin-
4-ones
With this encouraging outcome, we concentrated on
finding optimal reaction conditions. Several acetylenes
were found to be ineffective or less effective for tandem
ring opening and electrocyclization reaction leading to low
yields of pyridine ester 3 (Table 1, entries 6–8). Starting
material 1a did not afford any functionalized pyridine 3a
using unactivated acetylenes such as butyne-1,4-diol and
propargyl alcohol (entries 9–12). The reaction of dienyl thi-
azolidin-4-one 1a with methyl propiolate 2b was also not
successful (entry 5). However, the reaction of dienyl thiazo-
lidin-4-one 1a with activated acetylenes such as DMAD,
ethyl but-2-enoate, or ethyl-2-pentenoate resulted in the
formation of 5,6-diaryl pyridine-2-carboxylate 3a in fair to
good yields (entries 3–8). Best results in terms of yield for
the synthesis of 5,6-diaryl pyridine-2-carboxylate 3a were
observed with the use of DMAD as the activated acetylene
in xylene (entries 3 and 4). The reaction gave poor yields at
low temperature or with the use of other solvents such as
dioxane, 1,2-dichloroethane (DCE) etc. (entries 13 and 14).
The synthesis of 5,6-diaryl pyridine-2-carboxylate (3a)
is proposed to involve a ring opening of the functionalized
dienyl thiazolidin-4-one, resulting in generation of the
functionalized conjugated 2-azadeine in situ, which under-
S
Ph
R1
N
H
N
CO2Me
O
H
+
O
R2
H
O
3a
2a–i
1a
2a; R1 = CO2Me, R2 = CO2Me
2b; R1 = CO2Me, R2 = H
2c; R1 = CO2Et, R2 = Me
2d; R1= CO2Et, R2 = Et
2e; R1 = CO2Et, R2 = Ph
2f; R1 = CH2OH, R2 = CH2OH
2g; R1 = CH2OTBS, R2 = CH2OTBS
2h; R1 = CH2OTBS, R2 = H
2i; R1 = CH2CH2OH, R2 = H
Scheme 3 Synthesis of methyl 6-(2,5-dimethylphenyl)-5-phenyl-
pyridine-2-carboxylate 3a
After optimization of the reaction conditions, these tan-
dem ring opening and electrocyclizations were further ex-
plored by employing dienyl-thiazolidin-4-ones with differ-
ent substituents such as 4-methoxyphenyl, phenyl, 2-furyl
and 2 pyridyl at C-5 using DMAD and xylene as solvent at
170 °C (Scheme 4).24 All the reactions resulted in the forma-
tion of pyridine-2-carboxylates 3a–h in good yields (Table
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 509–512

511
B. Kuila et al.
Letter
Synlett
2). The acetylenic ester promoted tandem ring opening and
electrocyclization was found to be well tolerated by a vari-
ety of substituents on the dienyl thiazolidin-4-one. The
reaction of 2-[2-(2,5-dimethylphenyl)-4-oxo-thiazolidin-3-
yl]-5-phenyl-penta-2,4-dienoic acid methyl ester (1a) gave
the best yield of pyridine-2-carboxylate 3a (entry 1). 2-[(Fu-
ryl/pyridyl)-4-oxo-thiazolidin-3-yl]-5-phenyl-penta-2,4-di-
enoic acid methyl and ethyl esters 1d/1h on reaction with
DMAD afforded 6-furan-2-yl-5-phenyl-pyridine-2-carbox-
ylic acid alkyl ester (3d) and 3-phenyl[2,2′]bipyridinyl-6-
carboxylic acid alkyl ester (3h), respectively, in good yields
(entries 4 and 8).
singlets at δ = 2.25 and 1.83 ppm where assigned to the
methyl protons of the 2,5-dimethylphenyl group. 13C NMR
analysis demonstrated the presence of a carbonyl carbon at
δ = 166.0 ppm (CO of ester) and three aromatic carbons at δ
= 140.1, 146.2, and 158.6 ppm corresponding to C-4, C-2
and C-5 of the pyridine ring, respectively, as well as reso-
nances corresponding to the methyl ester at δ = 52.9 ppm
and two methyl carbons at δ = 19.1 and 20.8 ppm corre-
sponding to the 2,5-dimethylphenyl group (Figure 1).24–26
Ph
N
CO2Me
S
R2
N
H
O
H
DMAD, Xylene
Figure 1 6-(2,5-Dimethylphenyl)-5-phenylpyridine-2-carboxylate (3a)
O
170 °C
H
O
R1
R2
N
CO2R1
A plausible mechanism for the formation of alkyl 5,6-
disubstituted pyridine-2-carboxylates 3a–h is proposed to
involve an initial thia-Michael addition of sulfur from the
thiazolidin-4-one ring onto the acetylenic ester to provide a
dipolar complex 4. This is followed by an intramolecular
amidolytic ring opening of the thiazolidinone ring by
nucleophilic attack of the carbanion generated by initial
thia-Michael addition reaction and then a rearrangement to
yield the corresponding conjugated 2-azadiene 5. The con-
jugated 2-azadiene 5 subsequently undergoes electrocyclic
ring closure reaction at high temperature to yield pyridines-
2-ester 3 (Scheme 5).
3a; R1 = Me, R2 = 2,5-Me2C6H3
3b; R1 = Me, R2 = PhNO
1a; R1 = Me, R2 = 2,5-Me2C6H3
1b; R1 = Me, R2 = PhNO
3c; R1 = Me, R2 = 4-MeOC6H4
3d; R1 = Me, R2 = 2-furyl
1c; R1 = Me, R2 = 4-MeOC6H4
1d; R1 = Me, R2 = 2-furyl
3e; R1 = Et, R2 = 2,5-Me2C6H3
3f; R1 = Et, R2 = PhNO
3g; R1 = Et, R2 = 4-MeOC6H4
3h; R1 = Et, R2 = pyridyl
1e; R1 = Et, R2 = 2,5-Me2C6H3
1f; R1 = Et, R2 = PhNO
1g; R1 = Et, R2 = 4-MeOC6H4
1h; R1 = Et, R2 = pyridyl
Scheme 4 Synthesis of 5,6-diaryl pyridine-2-carboxylate 3a–h
Table 2 Synthesis of 5,6-Diaryl Pyridine-2-carboxylates 3a–h
Ph
H
Entry
S
R1
Me
Ar
2,5-dimethyl phenyl
Producta Yield (%)b
Ph
H
H
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
91
78
83
80
87
80
82
81
H
O
H
Ph
Ar
H
Ar
O
Me
Me
Me
Et
phenyl
N
RO
Ar
RO2C
NH
p-methoxy Phenyl
2-furyl
N
S
RO
O
S
O
1
5
CO2Me
CO2Me
2,5-dimethyl phenyl
phenyl
MeO2C
2a
CO2Me
Et
Ph
Ar
4
1g
1h
Et
p-methoxy Phenyl
2-pyridyl
3g
3h
Et
N
RO2C
a Xylene was used as solvent, reaction time 16 hours.
b Isolated yield after purification.
3
Scheme 5 Plausible mechanisms for the formation of 5,6-diaryl pyri-
dine-2-carboxylate 3a–h
The functionalized 5,6-disubstituted pyridine-2-car-
boxylates 3a–h, thus obtained were characterized on the
basis of spectroscopic analysis. For example, 6-(2,5-dimeth-
ylphenyl)-5-phenylpyridine-2-carboxylate (3a), showed a
In conclusion, we have demonstrated the acetylenic es-
ter promoted tandem ring opening and electrocyclization
of dienyl-thiazolidin-4-ones for the synthesis of pyridine-2-
carboxylates in good to excellent yields. The present meth-
odology represents a facile, chemoselective and metal-free
synthesis of substituted pyridines
1
molecular ion at m/z 318 in its mass spectrum.25 The H
NMR (300 MHz) spectrum of 3a showed two characteristic
doublets (J = 7.8 Hz) at δ = 7.88 and 8.19 ppm correspond-
ing to H3 and H4 of the pyridine ring. A singlet at δ =
4.00 ppm corresponded to the methyl ester, and two
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 509–512

512
B. Kuila et al.
Letter
Synlett
Funding Information
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Mura, U.; Cosconati, S.; Marinelli, M.; Novellino, E.; Sartini, S.;
La-Motta, C.; Settimo, F. D. Eur. J. Med. Chem. 2011, 46, 2797.
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The Board of Research in Nuclear Sciences (BRNS), India is thanked for
the Research Grant (Project No.2013/37C/11/BRNS/198). The Depart-
ment of Science and Technology (DST), India is also thanked for the
Research Grant (Project No. SB/FT/CS-079/2012).
)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591721.
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taking 1 as the limiting reactant. After completion of reaction,
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the pure product.
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ate (3a): White solid; 1H NMR (300 MHz, CDCl3): δ = 1.83 (s,
3 H), 2.25 (s, 3 H), 4.00 (s, 3 H), 6.91 (d, J = 7.8 Hz, 1 H), 6.98 (dd,
J = 7.8, 1.2 Hz, 1 H), 7.04 (s, 1 H), 7.10–7.15 (m, 2 H), 7.20–7.23
(m, 3 H), 7.88 (d, J = 7.8 Hz, 1 H), 8.19 (d, J = 7.8 Hz, 1 H); 13C
NMR (CDCl3): δ = 19.1, 20.8, 52.9, 123.7, 127.7, 128.1, 128.9,
129.1, 129.9, 130.9, 132.6, 134.9, 138.4, 139.0, 140.1, 146.2,
158.6, 166.0; LRMS: m/z = 318.2 [M+1]; HRMS: m/z calcd for
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C
21H20NO2 [MH+]: 318.1494; found: 318.1490.
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(3e): Yellow solid; 1H NMR (300 MHz, CDCl3): δ = 1.25 (t,
J = 7.8 Hz, 3 H), 1.85 (s, 3 H), 2.22 (s, 3 H), 4.23 (q, J = 7.8 Hz,
2 H), 6.94–7.05 (m, 3 H), 7.13–7.25 (m, 5 H), 7.89 (d, J = 7.5 Hz,
1 H), 8.16 (d, J = 7.5 Hz, 1 H); 13C NMR (CDCl3): δ = 15.5, 18.9,
20.8, 60.5, 123.7, 127.8, 128.3, 128.7, 129.9, 130.4, 131.0, 132.6,
135.2, 138.4, 139.1, 139.9, 146.2, 158.4, 165.7; LRMS: m/z = 332
[M+1]; HRMS: m/z calcd for C22H22NO2 [MH+]: 332.1651; found:
332.1655.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, 509–512