Copper catalysed cross-dehydrogenative coupling (CDC) reaction of 4-thiazolidinone with terminal alkyne

Article abstract of DOI:10.1016/j.tet.2018.10.068

Cross dehydrogenative coupling (CDC) strategy has been employed for C-alkynylation of 4-thiazolidinone with terminal alkyne under copper catalysis. Present reaction involves coupling of C(sp³) adjacent to sulfur of 4-thiazolidinone with C(sp) of terminal alkyne under CDC strategy is unprecedented to the best of our knowledge. Significant functional group tolerance, considerable yield and DFT study for mechanism make this synthetic task more interesting and compatible.

Full text of DOI:10.1016/j.tet.2018.10.068

Accepted Manuscript
Copper catalysed cross-dehydrogenative coupling (CDC) reaction of 4-thiazolidinone
with terminal alkyne
Mohammedumar M. Shaikh, Anuj P. Patel, Kishor H. Chikhalia
PII:
S0040-4020(18)31291-2
https://doi.org/10.1016/j.tet.2018.10.068
TET 29901
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 19 May 2018
Revised Date: 22 October 2018
Accepted Date: 25 October 2018
Please cite this article as: Shaikh MM, Patel AP, Chikhalia KH, Copper catalysed cross-dehydrogenative
coupling (CDC) reaction of 4-thiazolidinone with terminal alkyne, Tetrahedron (2018), doi: https://
doi.org/10.1016/j.tet.2018.10.068.
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ACCEPTED MANUSCRIPT
Copper catalysed Cross-Dehydrogenative Coupling (CDC)
reaction of 4-thiazolidinone with terminal alkyne
Mohammedumar M. Shaikh1, Anuj P. Patel1 and Kishor H. Chikhalia*2
1Department of Chemistry, School of Science, Gujarat University, Ahmedabad, Gujarat, India-
380009.
2Department of Chemistry, Veer Narmad South Gujarat University, Surat, Gujarat, India-395007.
E-mail: Chikhalia_kh@yahoo.com, Tel. No. 079-26300969
ꢀ GRAPHICAL ABSTRACT
ꢀ ABSTRACT
Cross dehydrogenative coupling (CDC) strategy has been employed for C-alkynylation of
4-thiazolidinone with terminal alkyne under copper catalysis. Present reaction involves coupling
of C(sp3) adjacent to sulfur of 4-thiazolidinone with C(sp) of terminal alkyne under CDC strategy
is unprecedented to the best of our knowledge. Significant functional group tolerance,
considerable yield and DFT study for mechanism make this synthetic task more interesting and
compatible.
ꢀ
Key words: Cross dehydrogenative coupling (CDC), sp3(C)-sp(C) bond, 4-thiazolidinone,
DFT study
ꢀ INTRODUCTION
Over the past few decades transition metal catalyzed cross coupling reactions have retain
their identity as revolutionary synthetic tool to streamline synthesis of numerous organic
molecules.1-4 Although classical cross coupling reactions were exclusively studied and widely
applied for coupling of C(sp2)-C(sp2), C(sp2)-C(sp), C(sp)-C(sp) and C(sp2)-X (X = hetero atom)
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it remains challenging for C(sp3)-C(sp) coupling due to some mechanistic aspects5. In order to
remove barriers of C(sp3)-C(sp) coupling, concept of oxidative coupling has arisen which enables
desired coupling through slightly different mechanistic route (Figure 1)6. However, oxidative
C(sp3)-C(sp) coupling reactions generally require either organometallic precursor or
prefunctionalized substrate5,7,8. In context to atom economy as well as green chemistry
perspectives, functionalization of C-H bond to install various organic motif through cross
dehydrogenative coupling (CDC) emerged as a promising pathway to construct carbon-carbon
bond without need of prefunctionalized substrate9-16. In the past few years, remarkable progress
has been achieved for the activation of relatively inert C(sp3)-H by employing CDC tactics17-20
.
Although in several cases late transition metal like palladium, platinum, ruthenium and rhodium
were used as heroic catalysts, nowadays, majority of chemists shifting their attention towards
utilization of inexpensive and non-toxic first row transition metal such as copper and iron were
reported to exhibits remarkable catalytic activity21-25. Alkyl group substituted with alkynyl
counterpart are of interest for pigment, pharmaceutical as well as material science industries26,27
.
Hence, development of methods for straight forward C-alkynylation of sp3 C-H carbon is an
emerging field of organic chemistry28-31. Beside few available other methods like nucleophilic as
well as electrophilic alkynylation to form sp3-sp carbon-carbon bond, radical mediated direct
installation of alkyne group is comparatively less explored18,32. However, copper/iron catalysed
CDC reactions have been widely investigated for oxidative functionalization of C(sp3)-H adjacent
to nitrogen or oxygen33-37, functionalization of C(sp3)-H adjacent to sulfur was comparatively less
reported38-41. Keeping this in mind and to continue our efforts in transition metal catalysed C-H
functionalization42-49, herein we report an efficient synthetic protocol for functionalization of
C(sp3)-H of 4-thiazolidinone with terminal alkyne to further explore C-alkynylation. We chose 4-
thiazolidinone because of its well known bioactive profile50-51 as well as our expertise in synthesis
and activation on it43,48. In past, we have reported C-alkynylation on same C-H bond of 4-
thiazolidinone through palladium catalysis48 (Figure 2) but here we are reporting alkynylation
through CDC pathway and further we have studied reaction possibilities through DFT study. We
have synthesised 4-thiazolidinones of hydrazines or hydrazides with different ketones via Schiff
base pathway. Slightly more acidic C-H bond adjacent to sulfur was chosen for functionalization
with terminal alkyne through CDC strategy. However, proposed pathway could not give
remarkable quantity of yield.
Figure -1: Oxidative coupling reaction for C(sp3)-C(sp) coupling5,7,8
.
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Figure -2: Previous work
ꢀ RESULTS AND DISCUSSION
In order to get preliminary practical information, we began our study with 2-methyl-2-
phenyl-3-(phenylamino)thiazolidin-4-one (1a) and phenyl acetylene (2a) as a model reactants in
presence of DDQ as an oxidant along with CuBr catalyst in toluene for 8.0 hour at 90°C under air.
The result of this experiment indicate desired coupling product in moderate proportion (table 1,
entry no. 4). Hence, to get aimed product in satisfactory proportion we screened series of catalyst,
oxidant as well as solvent. Among tested catalysts, CuBr was found best compared to other like
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CuI, CuCl, CuOAc to transform proposed reaction (entry no. 1-4). Furthermore, utilization of
copper(II) catalysts instead of copper(I) could not work well and gives trace product (entry no. 13-
14). After catalyst, we have examined different oxidants and from the results we came to know
that tert-Butyl hydrogen peroxide (TBHP) was appeared to be best along with CuBr (entry no. 7).
Other tested oxidants like Benzoquinone (BQ), Di-ter-butylhydrogen peroxide (DTBP), 2,3-
Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), Potassium persulfate (K2S2O8), O2(g) (entry no.
5-9) were found to provide desired product in poor to moderate quantity. For solvents, DCE was
found as best among other tested solvents like xylene, toluene and acetonitrile (entry no. 7, 10-
12). Moreover proposed transformation could not found fruitful enough when performed under N2
(balloon) condition (entry no. 15). In addition, reaction without oxidant was found to provide trace
amount of yield (entry no. 16). In summary, catalytic system of CuBr and TBHP in DCE at 90°C
under air was chosen as optimized condition (entry no. 10).
Table 1: Reaction Optimizationa
1a
2a
3a
Entry Catalyst
Oxidant
Solvent
bYield
1
2
CuCl
CuI
DDQ
Toluene
31%
DDQ
DDQ
DDQ
BQ
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCE
30%
35%
50%
40%
25%
60%
50%
20%
70%
3
CuOAc
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
4
5
6
K2S2O8
TBHP
DTBP
O2(g)
TBHP
7
8
9
10
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11
c12
13
CuBr
CuBr
TBHP
TBHP
TBHP
TBHP
TBHP
-
Xylene
Acetonitrile
DCE
60%
50%
CuCl2
Cu(OAc)2
CuBr
Trace
Trace
15%
14
d15
DCE
DCE
16
CuBr
DCE
Trace
aReaction Condition: 1a: 1.0 mmol, 2a: 1.5 mmol, catalyst: 10 mol%, oxidant: 2.0 mmol, solvent:
5 ml per mmol, 8.0 hours, under air. bIsolated Yield. Cat 80°C. dunder N2 gas.
Having optimized condition in hand, we shifted our attention toward examination of
substrate scope. Initially, different 4-thiazolidinones (made from various phenylhydrazine or aryl
hydrazide with aromatic ketone via Schiff base route) were allowed to react with different
terminal aryl alkynes under optimized condition (table-2). Both electron withdrawing and
donating groups were found to tolerate employed optimized system in more or less proportion.
Although, synthesis of 3b, 3f, 3m, 3p, 3q and 3r took more time to complete whereas formation of
3g, 3h, 3n and 3o were completed in relatively short time with best yield.
Table 2: Scope for the reaction of various 4-thaizolidinone with different terminal alkynesa
1(a-g)
2(a-g)
3 (a-h)
Where R1 = -NH-Ar or –NHCO-Ar
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O2N
O
S
N
N
H
O
Br
b3m (65%)
aReaction Condition: 1a: 1.0 mmol, 2a: 1.5 mmol, catalyst: 10 mol%, oxidant: 2.0 mmol, solvent:
5 ml per mmol 8.0 hours, under air. bCompleted in 10 hours, cCompleted in 6.5 hours.
Interesting results were found when we used 4-thiazolidinone of aldehyde instead of
ketone (table-3). Two different products were obtained each with considerable quantity.
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Table 3: Scope for the reaction of 4-thaizolidinone with different terminal alkynesa
1
2
3
4
R
3
4
aReaction Condition: 1: 1.0 mmol, 2: 1.5 mmol, catalyst: 10 mol%, oxidant: 2.0 mmol, solvent: 5
ml per mmol, 8.0 hours, under air.
From table-2 and 3, it can be said that optimized condition exhibits considerable functional
group tolerance including –NH2, -OH, -X, -OR, -NO2 and -CF3. After completion of substrate
examination we moved to propose plausible mechanistic pathway for proposed transformation.
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According to literature survey52-63 as well as computational studies, we have proposed
following mechanistic pathway for claimed reaction (scheme-2). It is generally presumed that
decomposition of tert-butylhydrogenperoxide (tBuOOH) into t-butoxyl (tBuO.) and tert-
butylperoxyl (tBuOO.) radicals could be achieved by CuBr as well as CuI54,56-58. Earlier Kochi,
Kharasch and Minisci reveals some important secrets regarding reaction of Cu(I) with TBHP57,58
.
Kochi have proposed the emergence of copper peroxide complex (D) but could not figure out the
participation of tBuOO.59. Based on hydrogen atom transfer (HAT), Minisci suggested the
formation of tBuO. by the reaction of TBHP and Cu(I) which rapidly produces tBuOO. in
presence of TBHP60,61. The mechanism presented in scheme-2 thus reveals that the key
intermediate in such type of transformation is tBuOO. which react with Cu(I) to form copper
peroxide complex (D).
Scheme 1: Plausible Catalytic cycle
Mechanistically, CuBr (A) initiate the cycle by reacting with TBHP (tBuOOH) (B) and
molecular oxygen to afford (C) and (F). Obtained tBuOO-radical (F) react with 4-thiazolidinone
(1) to provide radical of 4-thiazoldinone (G) with elimination of tBuOOH which on reaction with
(C) to give another intermediate (D) and H2O (E). Later on (G) react with (D) to give another
intermediate (H) with removal of CuBr which on reaction with terminal alkyne (2) to produce
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copper actylide complex (I). Finally, reaction between intermediate (I) and (H) provide desired
coupling product (3).
ꢀ COMPUTATIONAL STUDY
For the better understanding of the feasibility and mechanistic pathway of the proposed
reaction we have performed the computational studies. The critical experimental results suggested
that the reaction proceed proposed radical pathway was the observation of A9 as an intermediate.
Therefore, we focused on the formation of A9. The reaction energy profile of the radical pathway
is shown in Figure. Initially, CuIBr reacts with TBHP and oxidized to form CuIIBr(OH) (A2) with
tBuO. radical. CuIIBr(OH) then reacts with another molecule of TBHP to give intermediate
CuIIBr(OOtBu) (A4) and H2O via Ts1. On the other hand tBuO. radical abstract a hydrogen
molecule from the reactant 1a to generate radical A6 through TS2. The energy barrier for
abstraction of hydrogen was calculated to be 11.02 kcal mol-1. Combining radical A6 with the
doublet A5, compound A9 formed in conjunction with CuIBr. Overall, from the above energy
profile we can say that the rate-determining step is hydrogen abstraction. Computational studies
results reveals that reaction proceed via radical pathway to form a crucial intermediate A9.
Table 5: Free energy profile of plausible mechanistic pathway
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TS2
4.35
TS2
TS1
2.00
TS1
11.02 kcal mol-1
N
S
O
1a
2.09 kcal mol-1
A2
tBuOOH
0.00
tBuOOH
N
Br Cu OH
-0.09
CuBr
-0.07
O
-6.67
Cu O
Br Cu OH
H20
-13.47
tBu
OtBu
Br
tBuOOH
-10.32
OtBu
A5
tBuO
-14.25
tBuO
A3
OtBu
Cu O
H20
Br
Cu O
Br
tBuO
Br Cu
A5
A4
tBuO OH
A1
NH
N
O
Br Cu OH
H3C
H3C
O
S
H
ButO O H
CH3
(TS-1)
(TS-2)
Reaction Coordinates
All calculations were performed with the Gaussian 09 package. The Kohn–Sham density
functional theory (DFT) was solved with the B3LYP functional and 6-31G+(d,p) basis sets were
chosen for all the atoms. The CPCM model was applied to account for solvent effects. Frequency
calculations at the same level of theory were also performed to verify the stationary points as
minima (no imaginary frequency) or transition states (one imaginary frequency). Transition states
were located by using the Berny algorithm. Intrinsic reaction coordinates (IRCs) were calculated
for the transition states to confirm that they indeed connected two relevant minima. All relative
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energies (corrected with zero point energy) and Gibbs free energies (at 298.15 K and 1 atm) are
reported in kcal mol-1. Geometries are displayed with Chemcraft.
ꢀ CONCLUSION
In conclusion, we have developed a CDC approach for C-alkynylation of C(sp3)-H using
4-thiazolidinones with terminal alkynes. Presented work contain an important idea regarding CDC
coupling of sp3(C-H) adjacent to sulfur atom which is hither to unreported as per our best
knowledge. Although, reported strategy shows considerable functional group tolerance but could
not increase yield in remarkable quantity and this might be limitation of this reaction. Current
work could be helpful for synthesis of other similar derivatives to functionalize relatively inert C-
H bond adjacent to sulfur with other C-H bond.
ꢀ EXPERIMENTAL SECTION
General comments: All starting materials were purchased from commercial suppliers and used
1
without further purification. All synthesized compounds were characterized by H NMR, 13C
NMR, HRMS as well as elemental analysis. Melting point and boiling point were obtained in
open capillaries on Veego electronic apparatus VMP-D (Veego Instrument Corporation, Mumbai,
1
13
India) and are uncorrected. H NMR and C NMR spectra were recorded on a Bruker400 MHz
1
model spectrometer using CDCl3 as a solvent and TMS as internal standard with H resonant
frequency of 400 MHz and 13C resonant frequency of 100 MHz. HRMS spectra were recorded on
1
13
XEVO G2-XS QTOF spectrophotometer. The chemical shifts of H NMR and C NMR were
reported as parts per million (ppm) downfield from TMS (Me4Si). The splitting patterns are
designated as follows; s, singlet; d, doublet; t, triplet; m, multiplet. Elemental analyses (C, H, N)
were performed using a Heraeus CarloErba 1180 CHN analyzer (Hanau, Germany).
1. General procedure for the synthesis of 1 :
According to literature50,64,65, reaction of different amine (hydrazine or hydrazide) with
different ketones in ethanol at refluxing temperature gives corresponding schiff base derivatives.
Later on, as per the literature, prepared Schiff bases on reaction with thioglycolic acid in DMF
results in the synthesis of 4-thiazolidinone.
2. Synthesis of 3 through CDC strategy:
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Synthesised 1 (1.0 mmol) was mixed with 2 (1.5 mmol) along with CuBr (10.0 mol%), TBHP
(30.0 mol%) in dichloroethane (10.0 ml) in a 25.0 ml glass tube. The reaction mixture was stirred
at 90°C for 8-10 hour under air until the reaction was completed (confirmed by TLC). Finally,
reaction mixture was cooled down at room temperature and poured into cold aqueous solution of
NaHCO3. Later on, reaction mixture was subjected to solvent extraction by adding 15-20 ml of
dichloromethane. Organic layer was then separated, dried (over anhydrous Na2SO4) and
concentrated under reduced pressure. Obtained residue was further purified by coloumn
chromatography to give desired product.
2-methyl-2-phenyl-3-(phenylamino)-5-(phenylethynyl)thiazolidin-4-one (3a), white
solid; Yield 70% (305 mg); mp 170-175 °C; 1H NMR (400 MHz, CDCl3) δ ppm: 7.58 (d, J = 4.8
Hz, 2H), 7.29 (m, 3H), 7.24-7.18 (m, 7H), 6.77 (dd, J1 = 6.0 Hz, J2 = 6.4 Hz, 1H), 7.62 (d, J= 5.2
Hz, 2H), 4.52 (s, 1H), 2.52 (s, 1H, D2O exchangeable), 2.07 (s, 3H); 13C NMR (100 MHZ,
CDCl3) δ ppm: 25.14, 40.01, 67.54, 75.73, 79.42, 115.47, 121.01, 123.80, 126.90, 128.12, 128.53,
128.59, 128.69, 129.28, 131.08, 141.76, 147.30, 179.42; Anal. Calcd. For C24H20N2OS: C: 74.97;
H: 5.24; N: 7.29; Found: C: 74.92; H: 5.29; N: 7.33; HRMS-ESI (m/z) calcd for C24H20N2OS [M
+ H]+ 384.1296, found 384.1292.
2-(4-methoxyphenyl)-2-methyl-5-(o-tolylethynyl)-3-((4-
(trifluoromethyl)phenyl)amino)thiazolidin-4-one (3b). white solid; Yield 65% (361 mg); mp
150-155 °C; 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.44-7.42 (m, 3H), 7.21-7.11 (m, 5H), 6.90
(d, J = 5.2 Hz, 2H), 6.57 (d, J = 5.2 Hz, 2H), 4.52 (s, 1H), 3.81 (s, 3H), 2.41 (s, 3H), 2.13 (s, 3H),
1.79 (s, 1H, D2O exchangeable); 13C NMR (100 MHZ, CDCl3) δ ppm: 20.73, 25.14, 40.01, 56.04,
66.99, 75.73, 80.63, 112.52, 124.12, 124.46, 124.93, 125.06, 125.64, 126.78, 127.97, 128.41,
129.24, 131.80, 137.33, 139.44, 152.24, 159.87, 179.42; Anal. Calcd. For C27H23F3N2O2S: C:
65.31; H: 4.67; N: 5.64; Found: C: 65.34; H: 4.70; F: 11.44; N: 5.64; HRMS-ESI (m/z) calcd for
C27H23F3N2O2S [M + H]+ 496.1432, found 496.1436.
5-((4-methoxyphenyl)ethynyl)-2-methyl-2-(p-tolyl)-3-(o-tolylamino)thiazolidin-4-one
(3c). Pale yellow solid; Yield 72% (367 mg); mp 182-185 °C; 1H NMR (400 MHz, DMSO-d6) δ
ppm: 7.53 (d, J = 6.4 Hz, 2H), 7.14-7.13 (m, 4H), 7.01-6.73 (m, 5H), 6.59 (d, J = 5.6 Hz, 1H),
4.52 (s, 1H), 3.81 (s, 3H), 2.41 (s, 3H), 2.38 (s, 3H), 2.17 (s, 3H), 1.97 (s, 3H), 1.79 (s, 1H, D2O
exchangeable); 13C NMR (100 MHZ, CDCl3) δ ppm: 17.35, 21.13, 25.14, 40.01, 56.04, 67.54,
75.73, 79.42, 114.65, 115.64, 115.74, 120.47, 125.52, 126.89, 127.20, 129.47, 130.57, 131.46,
136.27, 138.10, 146.29, 159.92, 179.42; Anal. Calcd. For C27H26N2O2S: C: 73.27; H: 5.92; N:
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6.33; Found: C: 73.24; H: 5.90; N: 6.36. HRMS-ESI (m/z) calcd for C27H26N2O2S [M + H]+
442.1715, found 442.1711.
5-((2-aminophenyl)ethynyl)-3-((2,6-dichlorophenyl)amino)-2-methyl-2-(p-
1
tolyl)thiazolidin-4-one (3d), Brown solid; Yield 77% (417 mg); mp 188-192 °C; H NMR (400
MHz, DMSO-d6) δ ppm: 7.19-7.16 (m, 5H), 7.08-7.04 (m, 3H), 6.67-6.64 (m, 2H), 6.53 (d, J =
5.6 Hz, 1H), 5.07 (s, 2H, D2O exchangeable), 4.52 (s, 1H), 2.45 (s, 1H, D2O exchangeable), 2.17
(s, 3H); 13C NMR (100 MHZ, CDCl3) δ ppm: 21.13, 25.14, 40.01, 70.93, 75.73, 82.71, 110.38,
111.93, 116.91, 122.29, 125.52, 127.75, 128.59, 119.47, 130.01, 131.43, 136.27, 138.10, 143.64,
149.41, 179.42. Anal. Calcd. For C25H21Cl2N3OS: C: 62.24; H: 4.39; N: 8.7; Found: C: 62.20; H:
4.40; N: 8.66. HRMS-ESI (m/z) calcd for C25H21Cl2N3OS [M + H]+ 481.0782, found 481.0787.
2-(4-fluorophenyl)-2-methyl-3-(o-tolylamino)-5-(o-tolylethynyl)thiazolidin-4-one (3e),
white solid; Yield 65% (318 mg); mp 160-165 °C; 1H NMR (400 MHz, CDCl3) δ ppm: 7.42 (d, J
= 4.8 Hz, 1H), 7.27-7.21 (m, 3H), 7.14-7.08 (m, 3H), 7.04-7.01 (m, 3H), 6.76 (dd, J1 = 6.0 Hz, J2
= 6.4 Hz, 1H), 6.69 (d, J = 6.0 Hz, 1H), 4.52 (s, 1H), 2.52 (s, 1H, D2O exchangeable), 2.38 (s,
3H), 2.27 (s, 3H), 2.06 (s, 3H); 13C NMR (100 MHZ, CDCl3) δ ppm: 17.35, 20.73, 25.14, 40.01,
66.99, 75.73, 80.63, 114.71, 115.74, 120.47, 124.83, 126.78, 126.89, 127.20, 128.41, 129.13,
129.24, 130.57, 131.80, 139.44, 139.77, 146.29, 165.20, 179.42; Anal. Calcd. For C26H23FN2OS:
C: 72.53; H: 5.38; N: 6.51; Found: C: 72.50; H: 5.40; N: 6.47. HRMS-ESI (m/z) calcd for
C26H23FN2OS [M + H]+ 430.1515, found 430.1511.
2-(4-methoxyphenyl)-2-methyl-3-(o-tolylamino)-5-((2-
(trifluoromethyl)phenyl)ethynyl)thiazolidin-4-one (3f), colourless oil; Yield 70% (408 mg); bp
< 200°C; 1H NMR (400 MHz, CDCl3) δ ppm: 7.53 (d, J = 6.0 Hz, 1H), 7.47 (d, J = 6.0 Hz, 1H),
7.31-7.20 (m, 4H), 7.04-7.00 (m, 2H), 6.89 (d, J = 6.4 Hz, 2H), 6.70 (dd, J1 = 5.6 Hz, J2 = 5.4 Hz,
1H), 6.40 (d, J = 6.4 Hz, 1H), 4.52 (s, 1H), 3.81 (s, 3H), 2.20 (s, 3H), 2.08 (s, 3H), 1.38 (s, 1H,
13
D2O exchangeable); C NMR (100 MHZ, CDCl3) δ ppm: 17.35, 25.14, 40.01, 56.04, 68.16,
75.73, 76.12, 112.52, 115.74, 120.47, 122.10, 124.01, 125.97, 126.89, 127.20, 127.97, 130.57,
130.75, 132.63, 132.64, 135.80, 137.33, 146.29, 159.87, 179.42; Anal. Calcd. For
C27H23F3N2O2S: C: 65.31; H: 4.67 N: 5.64; Found: C: 65.35; H: 4.70; N: 5.60. HRMS-ESI (m/z)
calcd for C27H23F3N2O2S [M + H]+ 496.1432, found 496.1435.
5-((4-methoxyphenyl)ethynyl)-2-methyl-3-(phenylamino)-2-(thiophen-2-
1
yl)thiazolidin-4-one (3g), colourless oil; Yield 77% (376 mg); bp 175-180°C; H NMR (400
MHz, CDCl3) δ ppm: 7.48 (d, J = 6.4 Hz, 2H), 7.18 (dd, J1 = 6.0 Hz, J2 = 6.2 Hz, 2H), 7.05-6.86
(m, 3H), 6.80-6.76 (m, 3H), 6.66 (d, J= 5.2 Hz, 2H), 4.52 (s, 1H), 3.79 (s, 3H), 2.47 (s, 1H, D2O
exchangeable), 2.17 (s, 3H); 13C NMR (100 MHZ, CDCl3) δ ppm: 29.61, 40.01, 56.04, 67.54,
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76.69, 79.42, 114.65, 115.47, 115.64, 121.01, 125.55, 126.38, 126.82, 129.20, 131.46, 147.36,
154.70, 159.92, 182.39; Anal. Calcd. For C23H20N2O2S2: C: 65.69; H: 4.79; N: 6.66; Found: C:
65.67; H: 4.77; N: 6.61. HRMS-ESI (m/z) calcd for C23H20N2O2S2 [M + H]+ 420.0966, found
420.0962.
2-(furan-2-yl)-2-methyl-5-(phenylethynyl)-3-((4-
(trifluoromethyl)phenyl)amino)thiazolidin-4-one (3h), brownish solid; Yield 80% (396 mg);
1
mp 185-190°C; H NMR (400 MHz, CDCl3) δ ppm: 7.49-7.42 (m, 4H), 7.32-7.20 (m, 4H), 6.58
(d, J = 5.4 Hz, 2H), 6.32-6.31 (m, 2H), 4.52 (s, 1H), 2.18 (s, 3H), 1.97 (s, 1H, D2O exchangeable);
13C NMR (100 MHZ, CDCl3) δ ppm: 23.83, 40.01, 67.54, 71.20, 79.42, 104.40, 111.71, 114.12,
123.80, 124.46, 125.06, 125.64, 128.53, 128.59, 131.08, 140.65, 152.24, 155.63, 182.39; Anal.
Calcd. For C23H17F3N2O2S: C: 62.44; H: 3.87; N: 6.33; Found: C: 62.40; H: 3.90; N: 6.30.
HRMS-ESI (m/z) calcd for C23H17F3N2O2S [M + H]+ 442.0963, found 442.0960.
N-(2-methyl-4-oxo-2-phenyl-5-(phenylethynyl)thiazolidin-3-yl)benzamide (3i), white
solid; Yield 65% (302 mg); mp 175-180°C; 1H NMR (400 MHz, CDCl3) δ ppm: 7.72 (d, J = 5.6
Hz, 2H), 7.46-7.45 (m, 3H), 7.39-7.21 (m, 8H), 6.63 (s, 1H), 4.52 (s, 1H), 2.17 (s, 3H); 13C NMR
(100 MHZ, CDCl3) δ ppm: 25.14, 40.01, 67.54, 76.90, 79.42, 123.80, 126.90, 128.12, 128.28,
128.48, 128.53, 128.59, 131.08, 132.03, 132.71, 141.76, 165.41, 180.41; Anal. Calcd. For
C25H20N2O2S: C: 72.79; H: 4.89; N: 6.79; Found: C: 72.76; H: 4.92; N: 6.75. HRMS-ESI (m/z)
calcd for C25H20N2O2S [M + H]+ 412.1245, found 412.1248.
N-(5-((2-aminophenyl)ethynyl)-2-(4-methoxyphenyl)-2-methyl-4-oxothiazolidin-3-yl)-
1
4-methylbenzamide (3j), brown solid; Yield 72% (383 mg); mp 163-168 °C; H NMR (400
MHz, CDCl3) δ ppm: 7.77 (d, J = 6.0 Hz, 2H), 7.37 (s, 1H), 7.29-7.24 (m, 4H), 7.19-6.99 (m, 4H),
6.67 (dd, J1 = 6.4 Hz, J2 = 6.2 Hz, 1H), 6.55 (d, J= 5.8 Hz, 1H), 5.41 (s, 2H, D2O exchangeable),
4.52 (s, 1H), 3.79 (s, 3H), 2.14 (s, 3H), 2.09 (s, 3H); 13C NMR (100 MHZ, CDCl3) δ ppm: 21.13,
25.14, 40.01, 56.04, 70.93, 76.90, 82.71, 110.30, 111.93, 112.52, 116.91, 127.97, 128.29, 128.80,
130.01, 131.25, 131.43, 137.33, 142.80, 149.41, 159.87, 165.41, 180.41; Anal. Calcd. For
C27H25N3O3S: C: 68.77; H: 5.34; N: 8.91; Found: C: 68.75; H: 5.39; N: 8.88. HRMS-ESI (m/z)
calcd for C27H25N3O3S [M + H]+ 471.1617, found 471.1620.
3-hydroxy-N-(5-((4-methoxyphenyl)ethynyl)-2-methyl-4-oxo-2-(p-tolyl)thiazolidin-3-
1
yl)benzamide (3k), yellow solid; Yield 70% (378 mg); mp 190-195 °C; H NMR (400 MHz,
CDCl3) δ ppm: 7.47-7.37 (m, 4H), 7.31-7.27 (m, 3H), 7.18-7.14 (m, 3H), 6.86 (d, J = 6.0 Hz,
1H), 6.86 (d, J = 5.8 Hz, 2H), 4.52 (s, 1H), 3.89 (s, 1H), 3.80 (s, 3H), 2.33 (s, 3H), 2.09 (s, 3H);
13C NMR (100 MHZ, CDCl3) δ ppm: 21.13, 25.14, 56.00, 67.54, 76.90, 79.92, 114.31, 114.65,
115.64, 120.70, 122.16, 125.52, 129.47, 130.49, 131.46, 133.27, 136.27, 138.10, 157.29, 159.92,
15

ACCEPTED MANUSCRIPT
165.80, 180.41. Anal. Calcd. For C27H24N2O4S: C: 68.63; H: 5.12; N: 5.93; Found: C: 68.60; H:
5.10; N: 5.95. HRMS-ESI (m/z) calcd for C27H24N2O4S [M + H]+ 472.1457, found 472.1459.
N-(2-(4-fluorophenyl)-2-methyl-4-oxo-5-(phenylethynyl)thiazolidin-3-yl)-4-
methoxybenzamide (3l), white solid; Yield 70% (359 mg); mp 180-185°C; 1H NMR (400 MHz,
CDCl3) δ ppm: 7.66 (d, J = 6.0 Hz, 2H), 7.39 (d, J = 6.2 Hz, 2H), 7.21-7.14 (m, 5H), 7.03-7.01
(m, 4H), 6.77 (s, 1H, D2O exchangeable), 4.52 (s, 1H), 3.81 (s, 3H), 2.16 (s, 3H); 13C NMR (100
MHZ, CDCl3) δ ppm: 25.14, 40.01, 56.04, 67.54, 76.90, 79.42, 113.17, 114.71, 123.80, 127.02,
128.53, 128.59, 128.99, 129.13, 131.08, 139.77, 162.98, 165.26, 165.41, 180.41; Anal. Calcd. For
C26H21FN2O3S: C: 67.81; H: 4.60; N: 6.08; Found: C: 67.85; H: 4.62; N: 6.10. HRMS-ESI (m/z)
calcd for C26H21FN2O3S [M + H]+ 460.1257, found 460.1253.
4-bromo-N-(2-methyl-2-(4-nitrophenyl)-4-oxo-5-(phenylethynyl)thiazolidin-3-
1
yl)benzamide (3m), yellow solid; Yield 65% (383 mg); mp 215-220°C; H NMR (400 MHz,
CDCl3) δ ppm: 8.11 (d, J = 5.8 Hz, 2H), 7.75 (d, J = 5.0 Hz, 2H), 7.59 (d, J = 5.6 Hz, 2H), 7.51
(m, 4H), 7.30 (dd, J1 = 5.0 Hz, J2 = 5.2 Hz, 1H), 7.22 (dd, J1 = 6.0 Hz, J2 = 5.8 Hz, 2H), 4.52 (s,
13
1H), 4.36 (s, 1H, D2O exchangeable), 2.19 (s, 3H); C NMR (100 MHZ, CDCl3) δ ppm: 25.14,
40.01, 67.54, 76.90, 79.42, 122.85, 123.80, 125.78, 127.96, 128.53, 128.59, 131.19, 132.05,
133.61, 144.26, 148.35, 165.41, 180.41; Anal. Calcd. For C25H18BrN3O4S: C: 55.98; H: 3.38 N:
7.83; Found: C: 55.95; H: 3.40; N: 7.80. HRMS-ESI (m/z) calcd for C25H18BrN3O4S [M + H]+
535.0201, found 535.0205.
4-chloro-N-(2-methyl-4-oxo-2-(thiophen-2-yl)-5-(o-tolylethynyl)thiazolidin-3-
1
yl)benzamide (3n), pale yellow solid, H NMR (400 MHz, CDCl3) δ ppm: 7.62 (d, J = 5.8 Hz,
2H), 7.38-7.36 (m, 3H), 7.18-7.09 (m, 4H), 6.95 (dd, J1 = 6.0 Hz, J2 =6.2 Hz, 1H), 7.84 (d, J = 6.2
Hz, 1H), 4.75 (s, 1H, D2O exchangeable), 4.52 (s, 1H), 2.36 (s, 3H), 2.16 (s, 3H); 13C NMR (100
MHZ, CDCl3) δ ppm: 20.73, 29.61, 40.01, 66.99, 77.21, 80.63, 124.83, 125.55, 126.38, 126.78,
126.82, 128.41, 128.76, 129.11, 129.24, 131.80, 132.57, 139.25, 139.44, 154.76, 165.41, 183.56;
Anal. Calcd. For C24H19ClN2O2S2: C: 61.73; H: 4.10; N: 6.00; Found: C: 61.70; H: 4.40; N:
6.04. HRMS-ESI (m/z) calcd for C24H19ClN2O2S2 [M + H]+ 466.0576, found 466.0573.
N-(5-((2-aminophenyl)ethynyl)-2-(furan-2-yl)-2-methyl-4-oxothiazolidin-3-
yl)benzamide (3o), pale yellow solid; Yield 75 % (358 mg); mp 205-210°C; 1H NMR (400 MHz,
CDCl3) δ ppm: 7.83 (d, J = 6.2 Hz, 2H), 7.44 (dd, J1 = 6.2 Hz, J2 = 6.4 Hz, 1H), 7.36-7.31 (m,
3H), 6.19 (d, 1H), 7.03 (dd, J1 = 5.4 Hz, J2 =5.2 Hz, 1H), 6.83 (s, 1H), 6.66 (dd, J1 = 6.0 Hz, J2 =
6.2 Hz, 1H), 6.52 (d, J = 6.0 Hz, 1H), 6.28 (dd, J1 = 5.8 Hz, J2 = 6.0 Hz, 1H), 6.13 (d, J = 5.6 Hz,
1H), 4.81 (s, 2H, D2O exchangeable), 4.52 (s, 1H), 2.10 (s, 3H); 13C NMR (100 MHZ, CDCl3) δ
ppm: 23.83, 40.01, 70.93, 72.14, 82.71, 104.40, 110.38, 111.71, 111.93, 116.91, 128.28, 128.48,
16

ACCEPTED MANUSCRIPT
130.01, 131.43, 132.03, 132.71, 140.65, 149.41, 155.63, 165.41, 183.5;. Anal. Calcd. For
C23H19N3O3S: C: 66.17; H: 4.59; N: 10.07; Found: C: 66.20; H: 4.62; N: 10.05. HRMS-ESI (m/z)
calcd for C23H19N3O3S [M + H]+ 417.1147, found 417.1142.
N-(2-methyl-2-(4-nitrophenyl)-4-oxo-5-(phenylethynyl)thiazolidin-3-yl)-4-
1
(trifluoromethyl)benzamide (3p), colourless solid; Yield 68% (393 mg); mp 225-230°C; H
NMR (400 MHz, CDCl3) δ ppm: 8.22 (d, J = 5.8 Hz, 2H), 7.85 (d, J = 5.6 Hz, 2H), 7.70-7.62 (m,
4H), 7.46 (d, J = 6.0 Hz, 2H), 7.25-7.24 (m, 4H), 4.52 (s, 1H), 2.10 (s, 3H); 13C NMR (100 MHZ,
CDCl3) δ ppm: 25.19, 40.01, 67.52, 76.90, 79.42, 122.85, 123.80, 124.46, 125.78, 126.48, 128.22,
128.53, 128.59, 131.08, 132.76, 136.66, 144.26, 148.35, 165.41, 180.41; Anal. Calcd. For
C26H18F3N3O4S: C: 59.43; H: 3.45; N: 8.00; Found: C: 59.45; H: 3.48; N: 7.98. HRMS-ESI (m/z)
calcd for C26H18F3N3O4S [M + H]+ 525.0970, found 525.0974.
N-(5-((4-methoxyphenyl)ethynyl)-2-methyl-4-oxo-2-phenylthiazolidin-3-yl)-4-
1
nitrobenzamide (3q), yellow solids; Yield 70% (388 mg); mp 180-185°C; H NMR (400 MHz,
CDCl3) δ ppm: 8.35 (d, J = 6.2 Hz, 2H), 8.00 (d, J = 6.0 Hz, 2H), 7.63 (d, J = 6.4 Hz, 2H), 7.30-
7.23 (m, 5H), 6.97 (d, J = 5.8 Hz, 2H), 6.05 (s, 1H), 4.52 (s, 1H), 3.79 (s, 3H), 2.10 (s, 3H); 13C
NMR (100 MHZ, CDCl3) δ ppm: 25.14, 40.01, 56.04, 67.54, 76.90, 79.42, 114.65, 115.64,
124.04, 126.90, 128.12, 128.69, 129.08, 131.46, 138.15, 141.76, 149.21, 159.92, 165.41, 180.41;
Anal. Calcd. For C26H21N3O5S: C: 64.05; H: 4.34; N: 8.62; Found: C: 64.07; H: 4.38; N: 8.60.
HRMS-ESI (m/z) calcd for C26H21N3O5S [M + H]+ 487.1202, found 487.1205.
N-(2-methyl-4-oxo-2-(p-tolyl)-5-((2-(trifluoromethyl)phenyl)ethynyl)thiazolidin-3-
1
yl)thiophene-2-carboxamide (3r), yellow oil, H NMR (400 MHz, CDCl3) δ ppm: 7.84 (d, J =
6.2 Hz, 1H), 7.63 (dd, J1 = 6.0 Hz, J2 = 6.2 Hz, 1H), 7.50 (d, J = 5.8 Hz, 1H), 7.42 (d, J = 5.8 Hz,
1H), 7.30- 7.10 (m, 8H), 4.52 (s, 1H), 2.33 (s, 3H), 2.04 (s, 3H); 13C NMR (100 MHZ, CDCl3) δ
ppm: 21.13, 25.14, 40.01, 68.16, 76.12, 76.90, 122.10, 124.01, 125.52, 125.97, 127.41, 129.02,
129.47, 130.05, 130.75, 132.63, 132.69, 135.80, 136.27, 138.10, 139.24, 156.02, 180.41; Anal.
Calcd. For C25H19F3N2O2S2: C: 59.99; H: 3.83; N: 5.60; Found: C: 59.96; H: 3.85; N: 5.63.
HRMS-ESI (m/z) calcd for C25H19F3N2O2S2 [M + H]+ 500.0840, found 500.08437.
2-phenyl-3-(phenylamino)-5-(phenylethynyl)thiazolidin-4-one (3s), white solid; Yield
1
35% (148 mg); mp 170-175 °C; H NMR (400 MHz, CDCl3) δ ppm: 7.43 (d, J = 6.4 Hz, 2H),
7.32-7.26 (m, 5H), 7.25-7.24 (m, 4H), 7.20 (d, J = 5.8 Hz, 2H), 6.79 (dd, J1 = 5.4 Hz, J2 = 5.2 Hz,
1H), 6.68 (d, J = 6.0 Hz, 2H), 6.23 (s, 1H), 4.52 (s, 1H), 2.91 (s, 1H, D2O exchangeable); 13C
NMR (100 MHZ, CDCl3) δ ppm: 67.94, 68.17, 115.64, 120.74, 123.80, 126.70, 127.74, 128.53,
128.59, 128.93, 129.08, 131.08, 139.96, 147.50, 179.81; Anal. Calcd. For C23H18N2OS: C: 74.57;
17

ACCEPTED MANUSCRIPT
H: 4.90; N: 7.56; O: 4.32; S: 8.65; Found: C: 74.60; H: 4.88; N: 7.58; O: 4.30; S: 8.64. HRMS-
ESI (m/z) calcd for C23H18N2OS [M + H]+ 370.1140, found 370.1144.
N-(4-oxo-2-phenyl-5-(phenylethynyl)thiazolidin-3-yl)benzamide (3t), white solid;
Yield 45% (203 mg); mp 185-190 °C; 1H NMR (400 MHz, CDCl3) δ ppm: 7.87 (d, J = 6.0 Hz,
2H), 7.50 (dd, J1 = 6.0 Hz, J2 = 5.8 Hz), 7.47 (d, J = 6.0 Hz, 2H), 7.44 (d, J = 5.8 Hz, 2H), 7.38-
7.28 (m, 5H), 7.27 (dd, J1 = 5.6 Hz, J2 = 5.4 Hz), 7.24 (d, J = 5.6 Hz, 2H), 5.93 (s, 1H), 5.51 (s,
1H, D2O exchangeable), 4.52 (s, 1H); 13C NMR (100 MHZ, CDCl3) δ ppm: 68.17, 68.66, 83.47,
123.80, 126.70, 127.74, 128.28, 128.48, 128.53, 128.59, 128.93, 131.08, 132.03, 132.71, 139.96,
160.65, 181.93; Anal. Calcd. For C24H18N2O2S: C: 72.34; H: 4.55; N: 7.03; Found: C: 72.30; H:
4.57; N: 7.05. HRMS-ESI (m/z) calcd for C24H18N2O2S [M + H]+ 398.1089, found 398.1085.
2-phenyl-3-(phenylamino)-2-(phenylethynyl)thiazolidin-4-one (4a), white solid; Yield
30% (127 mg); mp 210-215 °C; 1H NMR (400 MHz, CDCl3) δ ppm: 7.42-7.43 (m, 4H), 7.32 (d, J
= 6.0 Hz, 2H), 7.25 (dd, J1 = 5.6 Hz, J2 = 5.8 Hz, 1H), 7.25 (dd, J1 = 6.0 Hz, J2 = 5.8 Hz, 1H),
7.22 (d, J = 6.0 Hz, 2H), 7.19-6.69 (m, 5H), 4.34 (s, 1H, D2O exchangeable), 3.83-3.80 (d, J = 8.0
13
Hz, 2H); C NMR (100 MHZ, CDCl3) δ ppm: 35.81, 69.95, 79.06, 115.47, 121.01, 123.33,
127.00, 128.06, 128.51, 128.66, 129.28, 129.81, 131.41, 138.13, 147.36, 175.77; Anal. Calcd. For
C23H18N2OS: C: 74.57; H: 4.90; N: 7.56; Found: C: 74.55; H: 4.92; N: 7.53. HRMS-ESI (m/z)
calcd for C23H18N2OS [M + H]+ 370.1140, found 370.1145.
N-(4-oxo-2-phenyl-2-(phenylethynyl)thiazolidin-3-yl)benzamide (4b), white solid;
1
Yield 30% (135 mg); mp 225-230 °C; H NMR (400 MHz, CDCl3) δ ppm: 7.88 (d, J = 6.0 Hz,
2H), 7.49 (dd, J1 = 5.8 Hz, J2 = 5.6 Hz, 1H), 7.47 (d, J = 5.8 Hz, 2H), 7.45-7.44 (m, 4H), 7.40 (s,
1H, D2O exchangeable), 7.33 (d, J = 6.0 Hz, 2H), 7.27-7.25 (m, 5H), 3.70-3.67 (d, J = 8.0 Hz,
13
2H); C NMR (100 MHZ, CDCl3) δ ppm: 35.81, 69.95, 79.06, 123.33, 127.00, 128.06, 128.28,
128.48, 128.51, 128.66, 129.81, 131.41, s132.03, 132.71, 138.13, 165.41, 175.55; Anal. Calcd.
For C24H18N2O2S: C: 72.34; H: 4.55; N: 7.03; Found: C: 72.30; H: 4.59; N: 7.00. HRMS-ESI
(m/z) calcd for C24H18N2O2S [M + H]+ 398.1089, found 398.1085.
ꢀ ACKNOWLEDGEMENT
Authors are thankful to University Grant Commission, Delhi, India to provide financial assistance
under the scheme Maulana Azad National Fellowship program for present research work. Authors
are also thankful to Dr. N. K. Shah, Head of chemistry department to provide all necessary
facilities for present research work.
18

ACCEPTED MANUSCRIPT
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