An efficient alkynylation of 4-thiazolidinone with terminal alkyne under C-H functionalisation

Article abstract of DOI:10.1039/c6ra05015h

A method of palladium catalysed efficient alkynylation through the cross coupling reaction of terminal alkynes with the slightly more acidic C-H bonds of 4-thiazolidinone has been developed. This method allows the direct introduction of an ethynyl group into the 4-thiazolidinone moiety. Mild reaction conditions involving aerial oxidation and one pot synthesis make this reaction more efficient for the formation of sp³(C)-sp(C) bond.

Full text of DOI:10.1039/c6ra05015h

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An efficient alkynylation of 4-thiazolidinone with
terminal alkyne under C–H functionalisation†
Cite this: RSC Adv., 2016, 6, 50780
*
Mohammed Umar M. Shaikh, Sulochana S. Mudaliar and Kishor H. Chikhalia
A method of palladium catalysed efficient alkynylation through the cross coupling reaction of terminal
alkynes with the slightly more acidic C–H bonds of 4-thiazolidinone has been developed. This method
allows the direct introduction of an ethynyl group into the 4-thiazolidinone moiety. Mild reaction
conditions involving aerial oxidation and one pot synthesis make this reaction more efficient for the
formation of sp3(C)–sp(C) bond.
Received 25th February 2016
Accepted 10th May 2016
DOI: 10.1039/c6ra05015h
www.rsc.org/advances
it also requires halogenated precursor. From the above discus-
sion it is concluded that straightforward introduction of the
Introduction
alkyne group generally requires functionalised reactant mate-
rial such as unsaturation or halides. Hence efforts have been
diverted toward cross-coupling reactions involving activation of
unreactive C–H bonds under palladium catalysis, as this
procedure requires mild reaction conditions as well as a cheap,
readily available substrate and catalyst.17
Besides the problem discussed above regarding traditional
coupling, if acidic C–H bonds could be alkynylated directly,
then it would provide an excellent method with good potential
value.18–20 Based on the above concept, herein we report the
straightforward alkynylation of slightly more acidic C–H bonds
of 4-thiazolidinone with terminal acetylene using a palladium
catalyst without the need for any pre-functionalisation of the
substrate. Up to now this kind of work has mostly been carried
out via nucleophile–electrophile coupling pathways, but here
we are reporting the reaction that proceeds through a nucleo-
phile–nucleophile coupling strategy. In order to carry out the
desired coupling, substrate 4-thiazolidinone was synthesised
The development of transition metal catalysed reactions that
facilitate the activation of unreactive C–H bonds has achieved
considerable growth during the last two to three decades.1–7
A
major advantage of C–H functionalisation over traditional
organometallic reactions is that the C–H activation strategy not
only facilitates the synthesis of complex heterocycles in fewer
steps but also needs cheaper precursors than are typically found
in the case of traditional coupling i.e., that require halogenated
precursors. Based on these facts, direct functionalisation of
unreactive C–H bonds of heterocycles provides an interesting
approach in the world of synthetic chemistry. Conjugated
enynes are found to be excellent building blocks, mostly useful
as intermediates in natural products, optical materials, phar-
maceuticals, agrochemicals, etc. Furthermore, the excellent
reactivity of alkyne functionality toward metathesis, cycloaddi-
tion, addition reactions, etc.,8–10 encourages many researchers to
work in the direction of forming sp3–sp carbon–carbon bonds.
The generation of substituted alkyne functionality from clas-
sical cross-coupling or homo-coupling reactions generally
requires a reaction between a nucleophile and an electrophile in
the presence of a transition metal catalyst. Typical organome-
tallic reagents that are required as nucleophiles are B, Sn, Zn,
Mg, Si, etc.11 among which some are either expensive or toxic.
Moreover, preparation of such organometallic reagents involves
air sensitive and multistep reactions. Substituted enynes can
also be synthesised by the Stephens–Castro reaction,12 Sono-
gashira coupling,13 Heck alkynylation,14 Heck–Sonogashira–
Cassar coupling,15 etc. All these reactions require either a co-
catalyst in addition to palladium or organometallic precur-
sors. Sonogashira–Hagihara coupling16 was also developed, but
Department of Chemistry, School of Science, Gujarat University, Ahmedabad 380009,
Gujarat, India. E-mail: Chikhalia_kh@yahoo.com; Tel: +91 79 26300969
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra05015h
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routinely. The slightly more acidic proton of the synthesised 4- backed silica gel was used for TLC (silica gel 60 F254 grade,
thiazolidinone moiety was chosen for functionalisation with Merck DC) and spots were visualised by UV light. Column chro-
terminal acetylene by employing palladium catalysis. However, matography was performed on silica gel LC 60A (70–200 micron).
the same reaction also might be applicable to the other
substrate with an acidic C–H bond, but here we choose the 4-
thiazolidinone molecule because of its well reported excellent
biological prole and also because synthesis of this molecule
requires a cheap and easily available substrate.21–24
2. Instrumental
All synthesised compounds were characterised by H NMR, 13C
NMR, mass spectroscopy as well as by elemental analysis. A Veego
electronic apparatus VMP-D (Veego Instruments Corporation,
Mumbai, India) was used for checking the melting point in open
capillaries and the results are uncorrected. Varian Gemini 200
1
Experimental section
1. Reagents and materials
1
MHz and Avans 300 MHz model spectrometers were used for H
NMR and 13C NMR spectra, respectively. DMSO-d6 was used as the
All reactions except the coupling reaction were carried out under solvent and TMS as the internal standard with 200 MHz and 300
nitrogen atmosphere. 1,4-Dioxane and toluene were dried over Na MHz resonant frequencies of 1H NMR and 13C NMR, respectively.
with benzophenone-ketyl intermediate as an indicator. Solutions Chemical shis were recorded as parts per million (ppm) down-
1
and solvents that are moisture and air sensitive were transferred eld from TMS for H NMR and 13C NMR. Splitting patterns are
through a stainless-steel cannula or syringe. All chemicals were designated as follows: d, doublet, s, singlet, t, triplet, dd, double
received from appropriate suppliers. Analytical grade solvents were doublet, m, multiplet. A Heraeus CarloErba 1180 CHN analyser
used. Reactions were monitored routinely by TLC. Aluminium- (Hanau, Germany) was used for elemental analysis.
Table 1 Reaction optimizationa
Entry
Catalyst
Ligand
Base
Solvent
Yieldb
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd2(dba)3
Pd(dppf)Cl2
Pd(PPh3)2Cl2
PdCl2
Brettphos
Xphos
Xphos
Xphos
Xphos
KOAc
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Toluene
Trace
Trace
34%
45%
40%
60%
37%
20%
31%
21%
48%
56%
16%
14%
Trace
28%
15%
45%
20%
18%
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Xphos
Brettphos
Xantphos
t-Bu brettphos
Dppf
Josiphos
Sphos
—
Xphos
Xphos
Xphos
9
10
11
12
13
14
15
16
17
18
19
20
KOAc
LiOtBu
KOtBu
Xphos
Xphos
Xphos
Xphos
Cs2CO3
Cs2CO3
Cs2CO3
DMF
THF
a
Catalyst: 1.5 mol%, ligand: 3 mol%, 4-thiazolidinone 1.0 mmol, terminal acetylene: 1.0 mmol, base: 2.5 mmol, solvent: 5 ml per mmol, 1 atm. O2.
Isolated yields.
b
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dioxane (2.0 ml) was slowly added using a syringe pump at 60
ꢀC. The temperature was then raised to 90 ꢀC. Aer completion
of the reaction, the reaction mixture was poured into cold
aqueous sodium bicarbonate solution and then ltered through
a pad of celite, eluting with dichloromethane. The ltrate was
concentrated and the residue was puried by using column
chromatography in order to get the desired product.29 The yield
was 55–60%.
3. Preparation of Schiff base substrates
The corresponding hydrazide (isonicotinic acid hydrazide or
nicotinic acid hydrazide) or aryl amine with different aryl
aldehydes was reacted at reux temperature using ethanol as
a solvent according to the literature without any modica-
tion.25,26 The progress of the reaction was continuously moni-
tored using TLC. Aer completion of the reaction, the reaction
mixture was poured into cold water so that solid precipitates of
Schiff base came out. Other Schiff base derivatives were
prepared from the corresponding aryl amine and aryl aldehyde.
The yield of the reaction is 80–85%.
Result and discussion
To reach the desired goal, we rst checked the feasibility of our
experimental result using phenyl acetylene 1a and N-(4-oxo-2-
phenylthiazolidin-3-yl) isonicotinamide (INH) 2a as model
reactants to gain a preliminary understanding so that we could
optimize the reaction conditions for a more efficient synthetic
route under mild conditions. Our preliminary inspection was
carried out with the catalyst Pd(OAc)2, with dppf as ligand,
Cs2CO3 as base and 1,4-dioxane as solvent at 90ꢀ using O2 as
oxidant. However, the result we got was an inadequate yield of
the desired product with the concomitant formation of other
byproducts. Hence, to achieve satisfactory formation of 3a we
screened a series of ligands, catalysts, bases and solvents to
ensure the viability of the proposed coupling phenomenon. The
optimum results are summarized in Table 1. Consequently,
through several different experiments, it was observed that in
the presence of Pd(OAc)2, the cross-coupling of 1a and 2a could
4. General procedure for the synthesis of 4-thiazolidinone
An oven dried at-bottomed ask previously equipped with
a magnetic stir bar was charged with Schiff base (0.01 mol) and
thioglycolic acid (0.01 mol) in dry toluene as solvent.27,28 The
system was modied by using a Dean–Stark apparatus in order
to remove the water molecules formed azeotropically during the
reaction. The reaction mixture was heated at reuxing temper-
ature. Aer the completion of the reaction, the mixture was
poured into a cold aqueous sodium bicarbonate solution in
order to remove unreactive thioglycolic acid. The crude product
was ltered, washed with distilled water and puried by crys-
tallisation. The reaction gives a yield of 80–85%.
5. Typical procedure for palladium catalysed coupling of 4-
thiazolidinone with terminal alkyne
4-Thiazolidinone (1.0 mmol), ligand (2.0 mol%), base (2.5 produce the desired product 3a at 65% yield, whereas other
mmol) and a palladium catalyst (1.0 mol%) in 1,4-dioxane were palladium catalysts were less effective compared with Pd(OAc)2.
stirred in an oven dried at-bottom ask which was equipped Replacement of Pd(OAc)2 by Pd(dppf)Cl2 and Pd(Ph3P)2Cl2
with a condenser under nitrogen atmosphere. Aer stirring for provides a considerable yield compared to the use of Pd(OAc)2.
30 minutes at room temperature, the ask was vacuumed and Moreover, the results obtained by employing Pd2(dba)3 and
relled with O2. Then the ow of O2 was maintained at 1 ml Pd(PPh3)4 catalysts were considered to show them to be inap-
minÀ1. Terminal acetylene 2a (1.0 mmol) dissolved in 1,4- propriate as Pd precursors. In addition, to prevent homo
Fig. 1 Phosphine ligands.
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Table 2 Scope for the reaction of 4-thiazolidinone with different terminal alkynesa
Entry
Product
R1
R2
Yieldb
1
2
3
4
5
6
7
3a
3b
3c
3d
3e
3f
–H
–H
60%
65%
65%
67%
67%
67%
70%
2-CH3
4-CH3
2-NO2
2-NO2
2-OCH3
3-NO2
2-CH3
4-CH3
2-NO2
2-OCH3
2-OCH3
4-N(CH3)2
3g
Entry
Product
R1
R2
Yieldb
8
9
10
11
3h
3i
3j
–H
–H
60%
65%
65%
70%
2-CH3
4-CH3
4-OCH3
2-CH3
4-CH3
4-OCH3
3k
Entry
Product
R1
R2
Yieldb
12
13
14
3l
3m
3n
2-NO2
4-NO2
2-CH3
–H
–H
2-CH3
62%
65%
67%
a
Reaction condition: Pd(OAc)2: 1.0 mol%, xphos: 2.0 mol%, Cs2CO3: 2.5 mmol, 4-thiazolidinone: 1.0 mmol, phenyl acetylene: 1.0 mmol. 1,4-
dioxane: 5 ml per mmol, 1 atm. O2. b Isolated yield.
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coupling of phenyl acetylene, phenyl acetylene dissolved in 1,4-
dioxane was added slowly using a syringe pump.
Screening studies regarding a ligand revealed that the
phosphine ligand is most suitable in the event of this trans-
formation. As shown in Table 1, the yield decreased when we
used a bidentate ligand such as xantphos, dppf. Thus, to obtain
a better result we subsequently shied our attention toward
sterically hindered monodentate phosphine ligands like xphos,
josiphos, sphos, brettphos, and t-bu brettphos, as mentioned in
Table 1. The effect of these ligands on the reaction was exam-
ined under the same reaction conditions in order to check the
potential of each of these ligands. From these studies we found
that sphos and josiphos provide decent yield, while brettphos
and t-bu brettphos offer moderate yields, whereas xphos gives
a better yield under the same reaction condition. From these
attempts, we conclude that by employing a xphos ligand with
Pd(OAc)2 in 1,4-dioxane at 90 ꢀC, an excellent yield could be
obtained from among all the possibilities (Fig. 1).
Fig. 2 Plausible mechanism.
As discussed in Table 1, the base has played a critical role in
this reaction. Among the screened bases, Cs2CO3 was found to
be most fruitful base among the other bases that were examined
under similar reaction conditions. Replacement of Cs2CO3 by
K2CO3 provided a poor yield, whereas an alkoxide base such as
LiOtBu gives a moderate yield, but when LiOtBu was replaced
with another alkoxy base such as KOtBu the yield obtained was
poor. Also, a literature survey revealed the fact that utilization of
Cs2CO3 tolerates the functional group more widely than other
bases in this kind of transformation.
Aer inspection of the effect of the base's role, the effect of
solvent was studied in great detail. Based on various parame-
ters, an appropriate solvent was chosen. We had subsequently
screened 1,4-dioxane, THF, DMF and toluene as solvents and
examined their effects on the resultant yield. However, we found
that among all the mentioned solvents 1,4-dioxane offered the
highest yield. Our results suggest that on increasing the polarity
of the solvent, e.g. when THF and DMF were used instead of 1,4-
dioxane, a lower yield was obtained, and when a nonpolar
solvent such as toluene was used instead of 1,4-dioxane, a lower
yield was acquired.
Aer completion of the effective examination of the various
parameters of the desired reaction, we turned our attention to
checking the possibility of the same reaction with other
substrates (e.g., various 4-thiazolidinone derivatives as well as
various terminal alkynes) producing a viable catalytic system
based on optimized conditions (Table 2).
The results obtained indicated that the examined catalytic
system was suitable for a wide range of substrates. Moreover,
this catalytic system tolerates a wide range of functional groups,
including –OCH3, –CH3, –CONH, –N(CH3)2 and –NO2. Further-
more, this catalyst system failed when the substrate contains –X
(halogen) and –NH2 groups because if any halogen or –NH2
group were there, the palladium catalyst would react with it rst
instead of reacting with the acidic –CH2 group. In such a situa-
tion we further need to include some additives to improve the
employed catalytic system, with the anticipation of getting the
desired product.
Based on a study of the cross-coupling reaction and a litera-
ture survey, the plausible mechanism was suggested in
following scheme (Fig. 2).
The mechanism consists of (I) removal of the AcOH molecule
on the reaction between the terminal alkyne with the base,
producing a palladium acetate complex (II). Again removal of
the AcOH molecule takes place when the palladium complex
reacts with the 4-thiazolidinone moiety, forming a new palla-
dium complex (III). Elimination of palladium due to trans-
metallation gives Pd0 along with the desired product (IV). The
reaction between oxygen and the eliminated AcOH yields an
AcOÀ ion which further reacts with Pd0 to give Pd(OAc)2.
Conclusion
In conclusion, herein we have demonstrated a feasible, effective
and extensive method for a palladium catalysed cross-coupling
reaction to generate a new C–C bond between sp3 (C–H) and sp
(C–H) by using the acidic C–H bond of 4-thiazolidinone and the
C–H bond of a terminal alkyne group. The signicance of the
proposed reaction is that this kind of cross-coupling reaction
has hitherto not been reported. However, a similar type of
coupling can be carried out by using cross-dehydrogenative
coupling. Furthermore, the proposed catalytic system is
capable of tolerating various functional groups, which makes
this method more feasible for academic as well as industrial
research.
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