Copper catalyzed cyanomethylation reaction of 4-thiazolidinone

Article abstract of DOI:10.1016/j.tetlet.2020.152601

An effective copper catalyzed Cross Dehydrogenative Coupling (CDC) reaction of 4-thiazolidinones with acetonitrile has been developed. The described strategy undergoes radical pathway by employing copper, oxidant and easily available acetonitrile as a cya

Full text of DOI:10.1016/j.tetlet.2020.152601

Journal Pre-proofs
Copper catalyzed cyanomethylation reaction of 4-thiazolidinone
Prakashsingh M. Chauhan, Mayur I. Morja, Manjoorahmed Asamdi, Kishor
H. Chikhalia
PII:
DOI:
Reference:
S0040-4039(20)31100-X
https://doi.org/10.1016/j.tetlet.2020.152601
TETL 152601
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
9 September 2020
20 October 2020
22 October 2020
Please cite this article as: Chauhan, P.M., Morja, M.I., Asamdi, M., Chikhalia, K.H., Copper catalyzed
cyanomethylation reaction of 4-thiazolidinone, Tetrahedron Letters (2020), doi: https://doi.org/10.1016/j.tetlet.
2020.152601
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Copper catalyzed cyanomethylation reaction
of 4-thiazolidinone
Prakashsingh M. Chauhana, Mayur I. Morjaa, Manjoorahmed Asamdib and Kishor H.
Chikhaliaa*
a Department of chemistry, Veer Narmad South Gujarat University, Surat, 395007, Gujarat, India. E-mail:
chikhalia_kh@yahoo.com; Tel: +91 9427155529
b Department of chemistry, Gujarat University, Ahmedabad, 380009, Gujarat, India.
Gujarat, India.
Graphical abstract:
R2
S
R1
N
R2
H
Cu,Oxidant
H
S
+
H
CN
N
Additives
O
R1
Air, 115°C 20h
O
CN
Where R1 = -NHAr or -NHCOAr
R2 = Aryl
Abstract:
An effective copper catalyzed Cross Dehydrogenative Coupling (CDC) reaction of 4-
thiazolidinones with acetonitrile has been developed. The described strategy undergoes radical
pathway by employing copper, oxidant and easily available acetonitrile as a cyanomethyl source.
Various cyanomethylated 4-thiazolidinone derivatives were obtained easily and conveniently in
moderate to good yield by employing this method. Substrate scope and optimization have been
carried out appropriately. Optimization was carried out through different oxidants, catalyst and
various additives.
Key words: 4-Thiazolidinones, Cross Dehydrogenative Coupling (CDC), Cyanomethylation,
Copper catalyst.
Introduction:
From green chemistry point of view as well as from atom economic approach, the direct C-H
functionalization methodology through cross dehydrogenative coupling (CDC) strategy or

oxidative coupling has emerged as an impressive and versatile tool in the construction of
carbon-carbon bond without any necessity of prefunctionalized substrate [1-10]. In the past few
decades, significant progress has been noticed for CDC reactions of relatively inert C(sp3)-H
bond [11-14]. Traditionally, C-H bond activation reactions have been achieved by employing
heavy transition elements like platinum, palladium, rhodium and ruthenium as heroic catalysts
with the generation of some stoichiometric amounts of metal salts as waste.
Nowadays, copper-catalyzed dehydrogenative coupling reactions have attracted more attention
owing to their lower cost and ease in handling [15-22]. Among them, the oxidative C(sp3)-H
activation of cheap and easily accessible acetonitrile has received great attention, as cyano group
can be easily converted into other reactive functional groups like esters, carboxylic acids,
amines, amides, tetrazoles, aldehydes and ketones etc.[23-24]. In addition to this, it plays an
important role in pharmaceuticals [25-26], bioactive molecules [27-28] and in synthesizing the
chemicals which owes unique character [29-30]. On the other hand,4-thiazolidinone scaffolds are
potentially useful constructs that display a wide range of fascinating biological activities such as
antimalarial [31], anti-HIV [32], anticancer [33], tuberculostatic [34], anti-inflammatory [35],
antiarrhythmic [36], anticonvulsant [37], and antihistaminic [38]. Some of the representative
nucleus is mentioned in Fig(1). In view of the pharmacological significance of 4-thiazolidinone
and importance of cyano group, as well as our continuous efforts regarding this type of molecule
[39-41],we were tempted to develop a novel heterocyclic building block which incorporates both
these units in the single molecular framework.
Acetonitrile (CH3CN) is a well recognized solvent and viewed as an inert chemical reagent. The
pKa value of acetonitrile is 31.3 in DMSO, so it is quite difficult to use it as pronucleophile.
Various approaches are available in which acetonitrile has been used directly as a
cyanomethylating agent by activating C(sp3)-H bond of methyl group. However, the direct
installation of cyano group through cyanomethylation reaction via radical pathways are less
explored [42-43] and also oxidative C-H functionalization nearby to the sulphur atom is less
reported [44-46]. Previously, Wei Zhang’s group has elegantly reported Cu-catalyzed
cyanomethylation of substituted tetrahydroisoquinolines with acetonitrile (sp3-sp3 coupling) but
it is beside to the N atom[47]. To the best of our knowledge, no examples have yet been
reported for the CDC reaction of 4-thiazolidinone and acetonitrile. Here, for the first time, we
have been reporting cyanomethylation of 4-thiazolidinone by making the use of copper catalyzed
CDC reaction in the presence of TBPB as an oxidant and Cs2CO3 as an additive. The required

starting material 4-thiazolidinones were synthesized by the condensation reaction of various aryl
hydrazide with different aryl ketones through Schiff base formation followed by cyclization with
the help of thioglycolic acid. Slightly acidic C-H bond of the synthesized 4-thiazolidinones was
chosen for functionalization with acetonitrile through CDC strategy. In past, our research group
has developed C-alkynylation on the same C-H bond of 4-thiazolidinone through Cu catalyst and
CDC strategy [48].
O
S
Me
Me
Cl
N
N
N
N
O
H
NH
Me
N
F
N
O
S
O
Anti-HIV
NO2
O
Anticancer
O
H
H
MeO
C N
C N
N
O
S
O
Br
Antitubercular
OMe
N
Cl
N
O
O
N
HN
HN
H
Me
S
N N
S
O
S
O
O
Antiinflammatory
Antidepresant
Figure 1. Selected representative biologically active 4-thiazolidinone containing
molecules.

Scheme -1 Earlier work
Wei Zhang's Work
Cu, Base, [O]
N2, 120°C,20h
+
H
CN
N
Ph
N
Ph
CN
Present work
R1
O
R2
N
Cu, [O], Additives
R2
R1
O
+
N
H
CN
S
S
under air,115°C
20h
CN
1
NHAr or -NHCOAr
Aryl
Where R =
2
& R =
Results and Discussion
In order to validate our hypothesis and to get preliminary idea about preferred optimized reaction
condition, we strived with 2-methyl-2-phenyl-3-(phenyl amino) thiazolidin-4-one (1a) as a
model substrate, which was reacted with 10 ml of easily available acetonitrile (2a) in the
presence of oxidant along with catalyst and additive for 20 hour at 115°C under air atmosphere
as a model reaction (Table-1). To obtain the desired product in appropriate proportion, we
selected sequence of catalyst, oxidant as well as additives. Initially, we started with different
copper(I) catalyst such as CuCl, CuI & CuOAc respectively with oxidants like potassium
persulphate without any additive which gave the desired yield in very less proportion (Table-1,
entries1-3). Switching to CuBr catalyst with same oxidant and using Na2CO3, K2CO3 & NaHCO3
as an additive respectively increased the proportion of yield (Table-1, entries 4-6) and generated
the idea that catalyst CuBr suits the best among other. Moreover, to achieve yield in adequate
proportion, we exchanged oxidant potassium persulphate by TBHP and different additives like
K2CO3, Li2CO3, NAH and Cs2CO3 but still remarkable increase in the quantity of yield was not
observed. It was noticed that additive Cs2CO3 gave the best result compared to K2CO3, Li2CO3 &
NaH (Table-1, entries 7-10). To our delight, when oxidant TBPB was used in place of TBHP, the
yield was increased remarkably (Table-1, entry 11). Then, we shifted our attention and examined

copper (II) catalyst but the yield of the desired product was not increased (Table-1, entries 12-
13). Furthermore, Cu(OAc)2 with same additive and oxidant at 100 °C also fails to improve the
proportion of yield (Table-1, entry 14). Finally, carrying out the reaction without oxidant or
catalyst gave the yield in less proportion (Table-1, entries 15-16).
Table 1: Optimization of reaction conditionsa
O
O
[Cu] , oxidant
air, 115°C
NH
H
N
CN
H
H
NH
+
N
S
CN
S
1a
2a
3a
Entry
Catalyst
Oxidant
CH3CN
Additives bYield
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
TBHP
TBHP
TBHP
TBHP
TBPB
TBPB
TBPB
TBPB
-
-
1
2
CuCl
CuI
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10ml
10%
14%
Trace
31%
33%
25%
41%
40%
35%
58%
76%
40%
Trace
46%
10%
25%
-
-
3
CuOAc
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl2
Na2CO3
K2CO3
NaHCO3
K2CO3
Li2CO3
NaH
4
5
6
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
10
11
12
13
14
15
16
CuCl2.2H2O
Cu(OAc)2
CuBr
-
TBPB

aReaction Condition: 1a: (0.20 mmol), 2a: (10ml), catalyst: 10 mol%, oxidants: 3.0 equivalent &
b
Additives: 1.5 equivalent, 20 hours, under air. Isolated Yield.
With the optimized reaction condition in hand, to propose the generality of the transformation
(Table 2 and 3), we moved our attention towards investigation of substrate scope with respect to
coupling partner such as 2-methyl-2-phenyl-3-(phenylamino) thiazolidin-4-one (1a) with
acetonitrile (2a). Initially, diverse 4-thiazolidinones were permitted to react with less acidic
acetonitrile under optimized condition (Table-2). Both electron withdrawing and donating
groups were well tolerated under optimized reaction condition in more or less proportion.
Cyanomethylation of 4-thiazolidinone substrate without any substitution afforded 76 % yield
(Table-2, entry 3a). In addition, wide range of electron donating substituents present on R1 and
R2 aromatic ring of 4-thiazolidinone also generated good to higher yield (Table-2, entries 3b-3e).
Whereas, electron withdrawing substituents present on R1 and R2 of aromatic ring lowered the
desired yield (Table-2, entries 3f-3i). Furthermore, the scope of different 4-thiazolidinone
substrates of benzoylhydrazide were also examined under optimal condition (Table 3). It was
observed that unsubstituted compound afforded 74% yield (Table 3, entry 3aa). Herein, we also
noticed that both electron donating and withdrawing group played a crucial role for this
transformation. Electron donating group present on R1’ & R2’ of 4- thiazolidinone substrates of
benzoyl hydrazide could increase the yield (Table-3, entries 3ab-3ae) and electron withdrawing
group lowered the yield (Table-3, entries 3af-3ai). Next, we had examined the furan bearing 4-
thiazolidinone of benzoylhydrazide with the standard condition, which also generated good yield
(table 3, entry 3aj) but not in higher proportion. Since, pyridine nucleus possess good biological
acivity, reaction with pyridine containing 4-thiazolidinone was also conducted and related
product was afforded in good amount. (table 3, entry 3ak).
Table 2: Scope for the reaction of various 4-thaizolidinone of phenyl hydrazine.
R1
R1
O
O
CuBr,TBPB
NH
H
N
CN
H
H
NH
+
N
S
CN
air,115°C
S
R2
R2
3 (a-i)
1 (a-i)
2

H3CO
H3C
O
O
O
HN
HN
HN
N
CN
N
CN
N
CN
S
S
S
3c (80%)
3a (76%)
3b (78%)
F3C
O
O
O
HN
HN
N
N
S
CN
CN
HN
S
N
S
CN
H3CO
H3C
3e (76%)
3f (69%)
3d (77%)
O2N
O
O
O
HN
HN
N
CN
HN
N
CN
N
S
CN
S
S
O2N
F
3i (67%)
3h (64%)
3g (63%)

Table-3: Substrate scope of 4-thiazolidinones of benzoyl hydrazide
'
R1
'
R1
O
O
O
O
H
H
H
CuBr,TBPB
HN
HN N
N
CN
CN
S
+
S
air,115°C
R2'
R2'
1a (a-k)
2
3a (a-k)
O
O
O
O
O
O
H3CO
H3C
HN
N
HN
HN
CN
N
CN
N
CN
S
S
S
3ab (78%)
3aa (74%)
O
3ac (79%)
O
O
O
O
O
CF3
HN
N
HN
HN
CN
N
CN
N
S
CN
S
S
H3CO
H3C
3af (68%)
3ae (81%)
3ad (77%)
O
O
O
O
O
O
Cl
HN
N
HN
N
CN
HN
N
CN
CN
S
S
S
F
O2N
3ai (69%)
3ah (64%)
3ag (70%)
O
O
O
O
N
HN
N
HN
N
CN
CN
S
S
O
3ak (71%)
3aj (76%)

From Table-2 and 3, it can be said that optimized condition exhibits considerable functional
group tolerance including -OH, -X, -OR, -NO2 and -CF3.
On the basis of experimental results and literature survey [49-51], a plausible mechanism has
been proposed for compound 3a. Initially, formation of active Cu (II) species A along with tert-
butoxy radical or benzoate radical takes place through oxidation of CuBr by tert-butyl peroxy
benzoate (TBPB) under the thermal condition. Then less acidic C(sp3)-H bond of acetonitrile
was abstracted by tert-butoxy or benzoate radical and generated cyanomethyl radical active
species B, concominant elimination of tBuOH of PhCOOH. Then coordination-directed insertion
of slightly acidic C-H bond of 4-thiazolidinone 1a with Cu (II) active species generated the
metallacycle intermediate C with simultaneous formation of tBuOH or PhCOOH. After the
formation of active species B and C, the formation of complex D takes place, which is followed
by the free radical addition of species B & C. Finally, the desired cyanomethylated coupling
product 3a was obtained by the reductive elimination with regeneration of Cu (I) species again.
Control experiment:
To get insight in the reaction pathway, control experiments were carried out for compound 1a
and 1aa. When radical scavenger like 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added
during cyanomethylation of 4-thaizolidinone under standard optimized condition for 20 h and
the results revealed that cyanomethylation was fully inhibited since the compounds 3a and 3aa
were not obtained. Therefore, a single-electron-transfer (SET) pathway was considered and
presumed that cyanomethyl radical might act as an intermediate.
NH
H
TEMPO (3eq)
N
N
H
+
CN
S
N
Standard Condition
O
S
O
CN
1a
2
3a, NR

TEMPO (3eq)
H
H
N
N
+
H
CN
Standard Condition
N
N
O
O
S
S
O
O
NC
1aa
2
3aa, NR
Plausible Mechanism:
O
N
Ph
S
O
O
O
Cu(II)
O
1a
(Or Cu(ll)OtBu)
Ph
O
A
TBPB
PhCOOH
(Or tBuOH )
CH3CN
2a
tBuO
(Or PhCOO )
N
S
O
C
Cu(I)
Cu(II)
tBuOH
CH2CN
(Or PhCOOH )
B
N
S
O
CH2CN
Cu(III)
S
NC
3a
N
O
D
Figure-2. Plausible mechanism for cyanomethylation

Conclusion:
We have developed an efficient and prominent Cu catalysed cyanomethylation of C(sp3)-H
using diverse 4-thiazolidinones with acetonitrile. This methodology represents the cross
dehydrogenative coupling (CDC) of C(sp3)-H of 4-thiazolidinones adjacent to sulphur atom and
C(sp3)-H bond of acetonitrile. One pot synthesis, functional group tolerance and favourable in
terms of atom economy make this protocol more interesting and promising. This strategy
tolerates wide range of functional group and provides new example/insight into C-H
functionalisation. This study would become more helpful in synthesizing other analogue
derivatives which required functionalization of relatively inert C-H bond adjacent to sulphur
atom.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Acknowledgment
Authors are thankful to IISER-Pune and IIT-Mumbai for the spectral analysis. The authors
express their gratitude to Head of Chemistry Department Prof. N. B. Patel, Veer Narmad South
Gujarat University, Surat to provide necessary lab facilities. Mr. Prakashsingh M. Chauhan is
also thankful to SHODH (ScHeme Of Developing high quality research), Gujarat, India for
financial assistsance.

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