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

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. Patel¹and 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.^1-4Although 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 substrate^5,7,8. 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 substrate^9-16. In the past few years, remarkable progress

has been achieved for the activation of relatively inert C(sp³)-H by employing CDC tactics^17-20

.

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 activity^21-25. Alkyl group substituted with alkynyl

counterpart are of interest for pigment, pharmaceutical as well as material science industries^26,27

.

Hence, development of methods for straight forward C-alkynylation of sp³C-H carbon is an

emerging field of organic chemistry^28-31. 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 explored^18,32. However, copper/iron catalysed

CDC reactions have been widely investigated for oxidative functionalization of C(sp³)-H adjacent

to nitrogen or oxygen^33-37, functionalization of C(sp³)-H adjacent to sulfur was comparatively less

reported^38-41. Keeping this in mind and to continue our efforts in transition metal catalysed C-H

functionalization^42-49, 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 profile^50-51as well as our expertise in synthesis

and activation on it^43,48. 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) coupling^5,7,8

.

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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 Optimization^a

1a

2a

3a

Entry Catalyst

Oxidant

Solvent

^bYield

1

2

CuCl

CuI

DDQ

Toluene

31%

DDQ

BQ

Toluene

DCE

30%

35%

50%

40%

25%

60%

50%

20%

70%

3

CuOAc

CuBr

4

5

6

K₂S₂O₈

TBHP

DTBP

O₂(g)

TBHP

7

8

9

10

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11

^c12

13

CuBr

TBHP

-

Xylene

Acetonitrile

DCE

60%

50%

CuCl₂

Cu(OAc)₂

CuBr

Trace

15%

14

^d15

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 N₂gas.

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 alkynes^a

1(a-g)

2(a-g)

3 (a-h)

Where R₁= -NH-Ar or –NHCO-Ar

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O₂N

O

S

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 alkynes^a

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, -NO₂and -CF₃. After completion of substrate

examination we moved to propose plausible mechanistic pathway for proposed transformation.

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According to literature survey^52-63as 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 CuI^54,56-58. Earlier Kochi,

Kharasch and Minisci reveals some important secrets regarding reaction of Cu(I) with TBHP^57,58

.

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 TBHP^60,61. 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 A₉as an intermediate.

Therefore, we focused on the formation of A₉. The reaction energy profile of the radical pathway

is shown in Figure. Initially, Cu^IBr reacts with TBHP and oxidized to form Cu^IIBr(OH) (A₂) with

tBuO^.radical. Cu^IIBr(OH) then reacts with another molecule of TBHP to give intermediate

Cu^IIBr(OOtBu) (A₄) and H₂O via Ts1. On the other hand tBuO^.radical abstract a hydrogen

molecule from the reactant 1a to generate radical A₆through TS₂. The energy barrier for

abstraction of hydrogen was calculated to be 11.02 kcal mol^-1. Combining radical A₆with the

doublet A₅, compound A₉formed in conjunction with Cu^IBr. 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

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 CDCl₃as 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 literature^50,64,65, 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

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Article Doi

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

DOI: 10.1016/j.tet.2018.10.068

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