A Sustainable, User-Friendly Protocol for the Pd-Free Sonogashira Coupling Reaction

Article abstract of DOI:10.1002/ejoc.201800827

We herein present a new catalytic system for the palladium-free Sonogashira coupling reaction. The catalytically active moiety is formed in situ, in a straightforward and user-friendly manner, by combining a widely available low-cost copper salt and an N-

Full text of DOI:10.1002/ejoc.201800827

A Journal of
Accepted Article
Title: A Novel, Sustainable, User-Friendly Protocol for the Pd-Free
Sonogashira Coupling Reaction
Authors: Aggeliki A Liori, Ioannis K Stamatopoulos, Argyro T
Papastavrou, Afroditi Pinaka, and Georgios C. Vougioukalakis
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800827
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10.1002/ejoc.201800827
European Journal of Organic Chemistry
FULL PAPER
A Novel, Sustainable, User-Friendly Protocol for the Pd-Free
Sonogashira Coupling Reaction
Aggeliki A. Liori,[a] Ioannis K. Stamatopoulos,[a] Argyro T. Papastavrou,[a] Afroditi Pinaka,[a] and
Georgios C. Vougioukalakis*[a]
Abstract: We herein present a new catalytic system for the palladium-
free Sonogashira coupling reaction. The catalytically-active moiety is
formed in situ, in a straightforward and user-friendly manner, by
combining a widely-available low-cost copper salt and an N-
heterocyclic carbene precursor. A series of N-heterocyclic carbene
ligand precursors with variable structural features, some of which are
novel, were tested and the reaction conditions were optimized. Using
the catalytic system with the optimum performance, the scope of the
alkyne and the aryl halide was probed. Aryl iodides readily react with
terminal alkynes, providing the coupling products in high to excellent
yields. The protocol is highly-efficient with alkynes bearing either alkyl
or aryl substituents, the latter having either electron-donating or
electron-withdrawing groups.
conjugated alkenyne moieties are moreover contained in many
intermediates or precursors used in the synthesis of non-linear
optical materials and polymers utilized in applications such as
molecular electronics.[5]
Scheme 1. The typical Sonogashira-Hagihara coupling reaction conditions.
Many modifications of the typical Sonogashira reaction have been
developed, including the use of other transition metals, ligands,
environmentally-friendly reaction media (ionic liquids, water, or
solvent-less), phase-transfer or even photochemical reaction
conditions.[5a] Microwave irradiation, combined with a phase-
transfer agent, has been also applied to the Sonogashira reaction
in the absence of a metal catalyst.[6] Successful examples using
water as the solvent have been reported under palladium, copper,
or iron catalysis.[7]
Numerous metal complexes, salts, or nanoparticles, based on
iron, cobalt, nickel, copper, indium, silver, gold, manganese or
ruthenium have been reported to catalyze the Sonogashira
coupling reaction, besides palladium.[8] The straightforward and
step-economical nature of some of these protocols makes them
ideal for industrial applications. Along these lines, the
replacement of noble transition metal catalysts with low-cost,
environmentally benign and abundant transition metal catalytic
Introduction
The Sonogashira reaction is known since 1975 and comprises a
powerful synthetic approach for the construction of C(sp)-C(sp2)
bonds.[1] Heck and Cassar independently reported the Pd-
catalyzed arylation and alkenylation of alkynes in the presence of
organic or inorganic bases in 1975.[2] Later on, Sonogashira and
Hagihara showed that the addition of a catalytic amount of
copper(I) iodide, as co-catalyst, induces a significant accelerating
effect in the reaction rate.[1] In the early days, reaction conditions
included Pd(0) as (pre)catalyst, triphenylphosphine as ligand and
copper iodide as co-catalyst, in a basic medium at temperatures
between 25oC and 100oC (Scheme 1). According to the generally-
accepted mechanism, a copper-acetylide species is generated in
situ, which then transfers the acetylide moiety to palladium for the
desired coupling to occur, through a reductive elimination
pathway. Sonogashira coupling approaches are widely-applied in
the synthesis of pharmaceuticals, natural products and organic
materials with technological applications.[3] In natural product
synthesis, the Sonogashira reaction can be used as the key
coupling step to synthesize conjugated enynes or enediynes. It
can be also combined with transformations that convert the triple
bond into other functionalities, or with regioselective hetero-
annulation, leading to heterocyclic products.[4] Aryl-alkyne and
systems is
a
highly-attractive strategy, increasing the
sustainability of chemical transformations.[9,10]
The majority of ligands utilized in Pd-free, Cu(I)- or Cu(II)-
catalyzed Sonogashira coupling reactions contain nitrogen,
phosphorus, or oxygen donors. The most widely-used Cu-based
catalytic systems employ ethylenediamine, 1,10-phenathroline,
1,4-diphenyl-1,4-diazabuta-1,3-diene,
1,4-
diazabicyclo[2.2.2]octane (DABCO) or N,N’-dibenzyl-BINAM.[11]
In most cases, a large excess (up to 30%) of the multi-dentate
ligand is required.[12] Other synthetic protocols employ
multinuclear copper complexes bridged by N-donor ligands,
copper nanoparticles, microwave-assisted reactions, or Cu-
catalyzed Sonogashira couplings under blue LED light
irradiation.[13,14]
[a]
Aggeliki A. Liori, Dr. Ioannis K. Stamatopoulos, Argyro T.
Papastavrou, Dr. Afroditi Pinaka, Prof. Dr. Georgios C. Vougioukalakis*
Laboratory of Organic Chemistry
The use of N-heterocyclic carbenes (NHCs) in the rapidly-
evolving field of copper-catalyzed Sonogashira reaction has not
been investigated thoroughly, despite the wide utilization of this
ligand family in other useful transformations, such as in Heck
coupling and olefin metathesis.[15] This Cu-catalyzed approach
Department of Chemistry
National and Kapodistrian University of Athens
Panepistimiopolis, 15784 Athens, Greece
E-mail: vougiouk@chem.uoa.gr
Homepage: http://users.uoa.gr/~vougiouk
Supporting information for this article is given via a link at the end of the
document.
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10.1002/ejoc.201800827
European Journal of Organic Chemistry
FULL PAPER
has thus far resulted in only limited success, with only four
recently published reports.[16-18] In 2009, Biffis and co-workers
developed trinuclear NHC-coordinated copper complex 1 (Figure
1), compared its catalytic activity in the Sonogashira coupling
reaction with [Cu(Cl)(IPr)] (2) and showed that 1 is more
catalytically-efficient. A range of aryl iodides, bromides and
chlorides were successfully transformed into the corresponding
internal alkynes.[16,17] Whittlesey and co-workers have
synthesized another tri-nuclear copper complex, bearing a
tripodal NHC ligand and an isolated oxygen atom (3, Figure 1),
which also shows Sonogashira coupling efficiency.[18] Shulka and
co-workers prepared PS-Cu-NHC complex 4 (Figure 1), a
recyclable heterogeneous catalyst, and successfully utilized it in
Sonogashira coupling reactions as well.[19] In another recent work,
Tahsini and co-workers investigated the catalytic activity of a
series of copper bis-carbene mononuclear complexes (5, Figure
1) in Sonogashira couplings. These complexes efficiently catalyze
the coupling of aryl iodides with phenyl acetylene derivatives in
the presence of oxygen, while the reaction proceeds through a
radical mechanism.[20]
for the synthesis, purification and characterization of the
(pre)catalysts. Besides screening a number of low-cost, widely-
available copper sources, an extensive library of NHC precursors,
some of which are new, having different steric and electronic
properties, are evaluated. The most efficient catalytic system
comprises CuSO4•5H2Ο and a commercially-available NHC
precursor salt. This system couples a wide variety of terminal
alkynes (electron-poor aryl, electron-rich aryl, or alkyl) with both
electron-poor and electron-rich aryl iodides, in a highly-efficient
manner.
Results and Discussion
Given that aerobic reaction conditions favor the Glaser/Hey
alkyne homocoupling (by)products,[21] all experiments were
conducted under an inert atmosphere. In order to probe and
optimize the cross-coupling reaction conditions, we chose the
coupling of p-iodonitrobenzene with phenylacetylene as the
model reaction. Initially, we tested a number of widely-available
copper sources (Table 1). Both copper(I) and copper(II) salts
catalyze the reaction, with the catalytic activity and selectivity
towards the desired Sonogashira coupling product being
dependent on the nature of the copper salt. Among all tested salts,
CuSO4•5H2O afforded the optimum results under the herein
studied conditions.
Table 1. Copper source optimization.
Homocoupling
Product (%)*
Entry
Copper Source
Product (%)*
1
2
3
4
5
6
7
8
Cu(NO3)2•3H2O
Cu(OAc)2•2H2O
Cu(OAc)2
CuCl2•2H2O
CuSO4•5H2O
CuCl2
26
38
52
48
59
44
38
44
6
6
7
5
8
5
CuCl
10
10
Figure 1: N-Heterocyclic carbene-based copper complexes as Sonogashira
catalysts.
CuI
Considering the lack of a detailed study on the catalytic activity of
simple, in-situ-prepared NHC/Cu-based catalytic systems in the
Sonogashira reaction, along with the wide availability, low-cost
and biocompatibility of copper, we herein report the development
of a sustainable, inexpensive, straightforward and user-friendly
protocol for this highly-useful transformation. This protocol can be
easily followed in any synthetic laboratory and requires a very
simple experimental setup, along with widely-available, stable
(pre)catalytic components. The in-situ formation of this new
catalytic system reduces the required effort, time and chemicals
*Yields calculated by GC/MS analysis
Experimental conditions: Cu salt 12 mol%, NHC precursor 25 12 mol%, 1-iodo-
4-nitrobenzene 0.5 mmol, phenylacetylene 0.6 mmol, K2CO3 1 mmol, solvent
DMF (3 mL), temperature = 125oC, reaction time 8h.
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10.1002/ejoc.201800827
European Journal of Organic Chemistry
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Table 2. Base optimization.
Table 4. (Pre)catalytic species’ loading optimization.
Product
(%)*
Homocoupling Product
(%)*
NHC
Precursor
25
Sonogashira
Product (%)*
Entry
Base
Homocoupling
Product (%)*
Entry
CuSO4•5H2O
1
2
3
4
K2CO3
Cs2CO3
KOH
59
43
50
32
8
6
8
8
1
2
3
4
5
6
5
15
10
20
10
12
20
33
41
36
56
59
81
9
7
10
10
20
12
20
5
tBuONa
16
8
*Yields calculated by GC/MS analysis
Experimental conditions: CuSO4•5H2O 12 mol%, NHC precursor 25 12 mol%,
1-iodo-4-nitrobenzene 0.5 mmol, phenylacetylene 0.6 mmol, base 1 mmol,
solvent DMF 3 mL, temperature = 125oC, reaction time 8h.
15
Table 3. Solvent optimization.
*Yields calculated by GC/MS analysis
Experimental conditions: copper source CuSO4•5H2O, NHC precursor 25, 1-
iodo-4-nitrobenzene 0.5 mmol, phenylacetylene 0.6 mmol, K2CO3 1 mmol,
solvent DMF (3 mL), temperature = 125oC, reaction time 8h.
Entry
Solvent
DMF
Product (%)*
Homocoupling Product (%)*
1
2
3
4
5
6
7
59
30
0
8
5
0
6
7
5
8
It is interesting to note that the preformed, well-defined copper
complex 8 affords lower Sonogashira product yields and inferior
product/byproduct (Glaser/Hey alkyne homocoupling) ratios in
comparison to the in-situ formed analogous catalytic system
based on NHC precursor 7 (Table 5) under identical conditions.
This finding suggests the formation of different and/or additional,
more active catalytic species in the case of the in-situ formed
system, in comparison to the well-defined one.
EtOH
Dioxane
DMAc
NMP
54
38
29
36
Et3N
With regards to the structural variation of the NHCs utilized, the
increased yield of the homocoupling (by)product in the case of
ortho- and para- MeO-substituted 21 and 23, in comparison to the
meta-substituted 22, can be attributed to the increased electron
density transfer to the nitrogen atom of the imidazolinium ring in
the case of 21 and 23. Moreover, the increased Sonogashira
product yield in the case of meta- and para-substituted NHC salts
22 and 23, in comparison to the ortho-substituted NHC precursor
21, most probably originates from the decreased steric hindrance
adjacent to the carbenic center of the NHCs in the case of NHC
salts 22 and 23. Furthermore, there is no clear correlation
between the saturated or unsaturated backbone of the
imidazolinium or imidazolium ring, respectively, as well as
between the symmetrical or unsymmetrical nature of the NHC
substituents with the corresponding catalytic activity. The highest
Sonogashira product yield (59%) and optimum product/byproduct
ratio (59/7) from all herein-studied NHC precursors were obtained
with the symmetrical carbene 25 (Table 5). The corresponding
NHC precursor having an unsaturated imidazolinium ring (24,
Table 5) provides significantly lower product yield and
product/byproduct ratio.
Finally, although the coupling of p-iodonitrobenzene with phenyl
acetylene is feasible in the absence of an NHC precursor
(Sonogashira/homocoupling product yield is 28%/7% under
identical to the NHC screening reaction conditions), both the
Sonogashira product yield and the Sonogashira/homocoupling
product ratio is significantly inferior, in comparison to the
conditions employing an NHC precursor as well. That is, in the
reaction of p-iodonitrobenzene, the addition of NHC salts
significantly improves the Sonogashira product yields and
DMSO
*Yields calculated by GC/MS analysis
Experimental conditions: CuSO4•5H2O 12 mol%, NHC precursor 25 12 mol%,
1-iodo-4-nitrobenzene 0.5 mmol, phenylacetylene 0.6 mmol, base 1 mmol,
solvent 3 mL, temperature = 125oC, reaction time 8h.
After determining the optimum copper source, we studied the
effect of base. As shown in Table 2, the best results were obtained
with K2CO3. With regards to the solvent, polar aprotic solvents are
the most commonly-used media for the Sonogashira reaction.
This was confirmed in the case of the herein-developed protocol
as well, with the most efficient solvent being DMF (Table 3).
Moreover, reaction temperatures in the range of 100oC are typical
for the copper-catalyzed Sonogashira coupling reaction. Our
studies showed that the herein-reported catalytic system exerts
its highest efficiency at 125oC. Finally, we investigated the impact
of the (pre)catalytic species’ loading. The best results were
obtained with 20 mol% copper and NHC precursor loading
(copper/NHC precursor 1:1, entry 6, Table 4). Use of other
copper/NHC precursor ratios does not improve the desired
product yield (Table 4).
The in situ-generated NHC ligands’ influence on the reaction
outcome was then studied thoroughly, by employing a series of
NHC precursors having variable steric and electronic
characteristics. Besides the known from the literature NHC
precursor salts 6-7, 9 and 18-31 (Table 5), novel, unsymmetrical
NHC precursors 10-17 (Table 5) were also synthesized and
utilized.
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10.1002/ejoc.201800827
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decreases the yield of the alkyne dimer (byproduct). Even more
importantly, no Sonogashira product was generated in the
absence of an NHC precursor with the other organohalides
studied (both aromatic and aliphatic).
Table 5. NHC precursors and the well-defined Cu complex studied, along with the corresponding Sonogashira and homocoupling (by)product yields.
Experimental conditions: CuSO4•5H2O 20%, NHC precursor 20%, K2CO3 1 mmol, 1-iodo-4-nitrobenzene 0.5 mmol, phenylacetylene 0.6 mmol, solvent DMF 3 mL,
temperature =125oC, reaction time 8h.
Having determined the optimum catalytic system and reaction
conditions, we examined the organohalide and alkyne reaction
scope. Aryl iodides bearing electron withdrawing groups react
with phenylacetylene affording the cross-coupling product in very
good GC and isolated yields (entries 1 and 8, Table 6).
Iodobenzene and aryl iodides having electron donating
substituents react in low to very good yields (entries 4, 7 and 9,
Table 6). Electron-poor aryl bromides are less reactive (entries 2
and 12, Table 6), while electron-rich aryl bromides are not reactive
at all with phenylacetylene (entries 5 and 6, Table 6). Aryl
chlorides do not react with phenylacetylene as well, even when
they bear electron withdrawing substituents (entry 3, Table 6). Our
protocol is highly-efficient with heterocyclic aryl iodides such as 3-
iodopyridine (entry 11, Table 6).
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Terminal alkynes bearing aryl substituents with electron-
withdrawing groups react almost quantitatively with p-
iodonitrobenzene, whereas with p-iodoanisole they react in low
yields (entries 8 and 9, Table 7). These low yields, in the case of
p-iodoanisole, originate from the competing formation of the
Glaser/Hey alkyne homocoupling product.
Table 6. Aryl halide Sonogashira reaction scope.
Table 7. Terminal alkyne Sonogashira reaction scope.
Sonogashira Coupling Product
% GC Yield (Isolated Yield)
Entry
R
X
1
2
3
4
5
6
7
8
9
NO2
NO2
NO2
OMe
OMe
Me
I
Br
Cl
I
81 (77)
32
trace
70 (67)
trace
trace
75 (71)
65
Cross-Product %
NMR Yield (Isolated
Yield) R=NO2
Cross-Product %
NMR Yield (Isolated
Yield) R=OMe
Entry
1
Y
Br
Br
I
41
28
H
2
3
97
84
CF3
NH2
I
81 (77)
70 (67)
I
19
4
5
6
82
89
99
99
10
79*
11
12
87 (84)
56 (51)
86 (80)
9 monosubstituted
7
8
9
99
99
1
Experimental conditions: CuSO4•5H2O 20 mol%, NHC precursor 25 20mol%,
aryl halide 0.5 mmol, phenylacetylene 0.6 mmol, K2CO3 1 mmol, solvent DMF
3 mL, temperature =125 oC, reaction time 8h.
98 (92)
99 (94)
*Depending on the workup conditions, a small percentage gets hydrolyzed to
the corresponding acid.
16
We then extensively studied the Sonogashira reaction scope with
regards to the alkyne, by coupling p-iodonitrobenzene or p-
iodoanisole with alkyl- or aryl-substituted terminal alkynes having
variable steric and electronic characteristics (Table 7). The bulky,
tert-butylacetylene reacts in very good to excellent yields (entry 2)
with both p-iodonitrobenzene and p-iodoanisole, while 1-pentyne
reacts in low to moderate yields (entry 1) most probably due to its
low boiling point. Both tert-butylacetylene and 1-pentyne provide
better yields with the electron-poor p-iodonitrobenzene. Aryl-
substituted terminal alkynes bearing electron donating groups at
the phenyl ring react in excellent to quantitative yields (entries 4-
7, Table 7), against both p-iodonitrobenzene and p-iodoanisole,
with the reactions of p-iodoanisole being slightly more efficient. It
is worth mentioning that even the cross-coupling of an ortho-
substituted, sterically-hindered alkyne proceeds efficiently, as
shown in entry 6 (Table 7).
Experimental conditions: CuSO4•5H2O 20 mol%, NHC precursor 25 20mol%, 1-
iodo-4-nitrobenzene or p-iodoanisole 0.5 mmol, terminal alkyne 0.6 mmol,
K2CΟ3 1 mmol, solvent DMF 3 mL, temperature = 125 oC, reaction time 8h.
Mechanistic Insights
An important issue concerning the use of copper salts as catalysts
in palladium-free Sonogashira reactions is the possible presence
of palladium impurities. In this regard, Novak and co-workers have
published a work on the influence of palladium traces on the
copper-catalyzed Sonogashira reaction.[22] More specifically, they
showed that palladium concentration of even ppb levels can
significantly increase the catalytic activity of a copper-based
catalytic system. To verify copper catalysis in our system, we
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10.1002/ejoc.201800827
European Journal of Organic Chemistry
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examined the catalytic activity of four different CuSO4•5H2O
sources, from different producers, including a new batch having
the highest possible commercially-available purity (99.999%), in
the reaction of Table 1, entry 5. Our study afforded almost
identical results in all cases, with variations within our protocol’s
experimental error.
On a different note, copper catalysis in the Sonogashira cross-
coupling reaction is often associated with the presence of radical
species. To probe the possible involvement of free radicals in our
protocol, we performed two types of benchmark reactions.
Experiments carried out in the presence of (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO), one of the most widely-
utilized radical scavenger, showed only a very slight decrease of
the coupling product yield, suggesting the absence of radical
species in the main reaction pathway.[23] Moreover, experiments
carried out in the presence of the radical initiator
azobisisobutyronitrile (AIBN) did not show an enhanced catalytic
activity of our system, again excluding the intervention of free
radical species in the main cross-coupling route.[24]
iodides, bearing either electron-withdrawing or electron-donating
substituents, react in good to excellent yields with
phenylacetylene, while aryl bromides are less reactive and aryl
chlorides do not react at all. With regards to the different terminal
alkynes studied, the protocol is highly efficient with both alkyl- and
aryl-substituted alkynes, bearing either electron donating or
electron withdrawing moieties, in most cases providing excellent
or quantitative yields with p-iodonitrobenezene and p-iodoanisole.
Experimental Section
General Remarks. All chemicals were obtained from commercial sources
and were used without any further purification. Solvents were purified
according to published procedures,[31] distilled and stored under argon
over 3Å molecular sieves. 1H, 13C and 19F NMR spectra were recorded
with a Varian Mercury 200MHz spectrometer. NMR spectroscopic data is
given in the order: chemical shift, multiplicity (s: singlet, br. S: broad singlet,
d: doublet, t: triplet, q: quartet, m: multiplet), coupling constant in Hertz (Hz),
and number of protons. HRMS spectra were recorded in a QTOF maxis
Impact (Bruker) spectrometer with Electron Spray Ionization (ESI). The
GC-MS spectra were recorded with a Shimandzu R GCMS-QP2010 Plus
Chromatograph Mass Spectrometer using a MEGAR (MEGA-5, F.T:
0.25μm, I.D.: 0.25mm, L: 30m, Tmax: 350 oC, Column ID# 11475) column.
The course of the reactions and the separation of the formed products was
followed with either GC-MS or thin layer chromatography (TLC), using
aluminium sheets (0.2 mm) coated with silica gel 60 with fluorescence
material that absorbs at 254 nm (silica gel 60 F254). The purification of the
products was carried out by flash column chromatography, using silica gel
60 (230-400 mesh).
Additionally, we performed a number of blank experiments in the
reaction
of
phenylacetylene
with
aryl
iodides
(p-
iodonitrobenezene and p-iodoanisole). All experiments carried
out without a copper source showed that the reaction does not
proceed in absence of copper. Finally, experiments carried out by
using only the inorganic base did not afford any cross-coupled
product at all.[25]
The generally-accepted copper(I)-catalyzed Sonogashira
coupling mechanism involves formation of the copper acetylide,
oxidative addition to the organohalide and, eventually, reductive
elimination of the cross-coupled product.[26-28] The current
mechanistic understanding concerning copper(II) catalytic
systems involves reduction of copper(II) to copper(I) by the
solvent or the ligand (usually amines), followed by the mechanism
proposed for copper(I) systems.[29] The transient formation of
yellow solids in the reaction mixture of copper-catalyzed
Sonogashira couplings has been attributed to intermediate
copper acetylides.[30] In the course of our experiments we
observed that the reaction mixtures very often turned yellow,
during the first minutes of the reaction, a fact we also believe is
due to the transient formation of copper acetylides.
General procedure for the Sonogashira coupling reactions. A dry
Schlenk tube equipped with a magnetic stirrer is loaded under argon with
CuSO4•5H2O (20 mol%, 0.1 mmol), the NHC precursor (20 mol%, 0.1
mmol), K2CO3 (2 mmol), the aryl halide (0.5 mmol) and dry DMF (3 mL).
The terminal alkyne (0.6 mmol) is then added and the reaction mixture is
sealed under an argon atmosphere. The Schlenk tube is transferred in a
preheated oil bath (125oC) and the reaction mixture is stirred for 8h. Then,
the reaction mixture is cooled to room temperature and transferred in a
250 mL separating funnel with 50 mL of H2O. The mixture is extracted with
ethyl acetate (3X15mL). The organic layers are combined, washed with
brine (15 mL) and dried over MgSO4. The dry organic layer is filtered and
the solvent is removed in a rotary evaporator. Products are separated with
column chromatography using a CH2Cl2/n-hexane 2/8 mixture.
The preparation of the novel NHC ligand precursors was carried out
according to published procedures[32] and is discussed in the Supporting
Information of the article.
Conclusions
A novel, sustainable, user-friendly catalytic protocol for the
copper-based, palladium-free Sonogashira coupling reaction was
developed. The catalytic system is formed in-situ in
Acknowledgements
a
straightforward manner, by using widely-available, low-cost,
stable pre-catalytic species: a copper salt, an NHC ligand
precursor and an inorganic base. The reaction conditions were
optimized and the impact of the NHCs’ stereochemical and
electronic features influence on the reaction outcome was
investigated by screening a series of NHC ligand precursors
bearing a variety of functional groups. Some of the studied NHC
precursors have not been reported in the literature before. The
cross-coupling reaction scope with regards to both the
organohalide and the alkyne was investigated thoroughly. Aryl
The authors acknowledge the contribution of COST Action CA15106 (C-H
Activation in Organic Synthesis – CHAOS).
Keywords: copper • N-heterocyclic carbenes • catalysis • cross coupling
• Sonogashira coupling • alkynes • organohalides
[1]
[2]
K. Sonogashira, Y. Tohda, N. Hagihara, Tetrahedron Lett, 1975, 16,
4467-4470.
a) H. Dieck, F. Heck, J. Organomet. Chem., 1975, 93, 259–263, b) L.
Cassar, J. Organomet. Chem., 1975, 93, 253-257.
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10.1002/ejoc.201800827
European Journal of Organic Chemistry
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[3]
Saejueng P, C. G. Bates, D. Venkataraman, Synthesis, 2005, 10, 1706-
1712.
[15] G. C Vougioukalakis, R. H. Grubbs, Chem. Rev 2010, 110, 1746-1787.
[16] F. Lazreg, F. Nahra, C. S. J. Cazin, Coord. Chem. Rev. 2015, 293-264,
48-79.
[4]
[5]
D. Wang, S. Gao, Org. Chem. Front. 2014, 1, 556-566.
a) M. Karak, L. C. A. Barbosa, G. C. Hargaden, RSC Adv., 2014, 4,
53442–53466, b) The Chemistry of Triple-Bonded Functional Groups;
Patai, S.; Rappoport, Z., Eds.; Wiley: New York, 1983, c) Brandsma, L.
Preparative Acetylenic Chemistry, 2 ed.;Elsevier: New York, 1988, d)
Stang, P. J.; Diederich, F.Modern Acetylene Chemistry; VCH: New York,
1995, e) T. F. Rutledge, Acetylenic Compounds: Preparation and
Substitution Reactions; Reinhold Book Corp: New York, 1968.
N. E. Leadbeater, M. Marco, B. J. Tominack, Org. Let. 2003, 5, 3919-
3922.
[17] a) A. Biffis, C. Tubaro, E. Scattolin, M. Basato, G. Papini, C. Santini, E.
Alvarez, S. Conejero, Dalton Trans, 2009, 7223-7229, b) C. Tubaro, A.
Biffis, E. Scattolin, M. Basato, Tetrahedron 2008, 64, 4187-4195.
[18] C. E. Ellul, G. Reed, M. F. Mahon, S. I. Pascu, M. K. Whittlesey,
Organometallics, 2010, 29, 4097-4104.
[19] V. S. Borude, R. V. Shah, S. R. Shukla, Monatsh Chem, 2013, 144, 1663-
1669.
[6]
[7]
[20] D. Domyati, R. Latifi, L. Tahsini, J. Organomet. Chem., 2018, 860, 98-
105.
a) P. Sun, H. Yan, L. Lu, D. Liu, G. Rong, J. Mao, Tetrahedron. 2013, 69,
6969-6974, b) K. S. Sindhu, A. P. Thankachan, A. M. Thomas, G.
Anilkumar, ChemistrySelect, 2016, 3, 556-559.
[21] R. Chinchilla, C. Najera, Chem. Soc. Rev. 2011, 40, 5084-5121.
[22] Z. Gonda, G. L. Tolnai, Z. Novák, Chem.Eur.J., 2010, 16, 11822-11826.
[23] P. Y. Lee, P. Liang, W. Y. Yu Org. Lett. 2017, 19, 2082−2085.
[24] D. A. Everson, J. A. Buonomo. D. J. Weix Synlett 2014; 25,: 233-238.
[25] A. Dewanji, S. Murarka, D. P. Curran, A. Studer Org. Lett., 2013, 15,
6102–6105
[8]
a) M. Karak, L. C. A. Barbosa, G. C. Hargaden RSC Adv., 2014, 4,
53442-53466, b) C. González-Arellano, A. Abad, A. Corma, H. García,
M. Iglesias, F. Sánchez Angew. Chem. Int. Ed. 2007, 46, 1536 –1538, c)
O. Vechorkin, D. Barmaz, V. Proust, X. Hu J. Am. Chem. Soc., 2009, 131,
12078–12079, d) M. Carril, A. Correa, C. Bolm Angew. Chem. Int. Ed.
2008, 47, 4862 –4865, e) X. Qi, L.-B. Jiang, X.-F. Wua Tetrahedron Lett.,
2016, 57, 1706–1710
[26] K. Okuro, M. Furuune, M. Enna, M. Miura, M. Nomura, J. Org. Chem.
1993, 58, 4716-4721.
[27] M. B. Thathagar, J. Beckers, G. Rothenberg, Green Chem. 2004, 6, 215-
218.
[9]
A.Pinaka, G. C. Vougioukalakis, Coord. Chem. Rev. 2015, 288, 69-97.
N. V. Tzouras, I. K. Stamatopoulos, A. T. Papastavrou, A. Liori, G. C.
Vougioukalakis, Coord. Chem. Rev, 2017, 343, 25-138.
[28] F. Monnier, F. Turtaut, L. Duroure, M. Taillefer, Org.Lett., 2008, 10, 3203-
3206.
[10]
[29] C. L. Deng, Y. X. Xie, D. L. Yin, J. H. Li Synthesis, 2006, 3370-3376.
[30] Y. Liu, V. Blanchard, G, Danoun, Z. Zhang, A. Tlili, W. Zhang, F. Monnier,
A. Van Der Lee, J. Mao, M. Taillefer ChemistrySelect 2017, 2, 11599 –
11602.
[11] A. M. Thomas, A. Sujatha, G. Anilkumar, RCS Adv. 2014, 4, 21688-
21698.
[12] a) W. Xu, B. Yu, H. Sun, G. Zhang, W. Zhang, Z. Gao, Appl. Organomet.
Chem.2015, 29, 353–356, b) W. Xu, B. Yu, H. Sun, G. Zhang, W. Zhang,
Z. Gao, Appl. Organomet. Chem.2015, 29, 301-304.
[31] W. L. F. Armarego, C. Chai in Purification of Laboratory Chemicals 7th
Edition, Butterworth-Heinemann Elsevier, 2012.
[13] J. Kou, A. Saha, C. Bennett-Stamper, R. S. Varma, Chem. Commun.
2012, 48, 5862-5864.
[32] a) A. W. Waltman, R. H. Grubbs, Organometallics, 2004, 23, 3105-3107,
b) G. C. Vougioukalakis, R. H. Grubbs, Organometallics 2007, 26, 2469-
2472, c) G. C Vougioukalakis, R. H. Grubbs, Chem. Eur. J., 2008, 14,
7545-7556.
[14] a) A. Sagadevan, K. C. Hwang, Adv. Synth. Catal. 2012, 354, 3421–3427,
b) C. Maaliki, E. Thiery, J. Thibonnet, Eur. JOC. 2017, 2017, 209-228.
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10.1002/ejoc.201800827
European Journal of Organic Chemistry
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Sustainable Catalysis
Aggeliki A.Liori, Ioannis K.
Stamatopoulos, Argyro T. Papastavrou,
Afroditi Pinaka, G. C. Vougioukalakis*
Page No. – Page No.
An efficient, user-friendly protocol for the Pd-free, Cu-catalyzed Sonogashira cross-
coupling reaction was developed. The (pre)catalytic species utilized are low-cost,
stable and widely available: CuSO4•5H2O as the copper source, an NHC salt
precursor and K2CO3 as the base.
A Novel, Sustainable, User-Friendly
Protocol for the Pd-Free Sonogashira
Coupling Reaction
This article is protected by copyright. All rights reserved.