A Palladium-Free Sonogashira Coupling Protocol Employing an in Situ Prepared Copper/Chelating 1,2,3-Triazolylidene System

Article abstract of DOI:10.1055/a-1290-8469

A new, palladium-free Sonogashira coupling reaction protocol using a catalytic system that comprises a simple, cheap, widely available copper salt and a chelating 1,2,3-triazolylidene ligand precursor is reported. This protocol provides the desired coupling products in moderate to very good yields.

Full text of DOI:10.1055/a-1290-8469

Submission Date:
Accepted Date:
Publication Date:
2020-09-20
2020-10-15
2020-10-15
Accepted Manuscript
Synlett
A Pd-Free Sonogashira Coupling Protocol Employing an In-situ-Prepared Cop-
per/Chelating 1,2,3-Triazolylidene System
Efstathios Tonis, Felix Stein, Ioannis K Stamatopoulos, Jessica Stubbe, Athanasios Zarkadoulas, Biprajit Sarkar, Georgios C Vougiou-
kalakis.
Affiliations below.
DOI: 10.1055/a-1290-8469
Please cite this article as: Tonis E, Stein F, Stamatopoulos I K et al. A Pd-Free Sonogashira Coupling Protocol Employing an In-situ-Pre-
pared Copper/Chelating 1,2,3-Triazolylidene System. Synlett 2020. doi: 10.1055/a-1290-8469
Conflict of Interest: The authors declare that they have no conflict of interest.
This study was supported by European Cooperation in Science and Technology (http://dx.doi.org/10.13039/501100000921),
CA15106, Hellenic Foundation for Research and Innovation (http://dx.doi.org/10.13039/501100013209), Project Number: 16 – Acro-
nym: SUSTAIN
Abstract:
A new, palladium-free Sonogashira coupling reaction protocol using a catalytic system that comprises a simple, cheap, widely
available copper salt and a chelating 1,2,3-triazolylidene ligand precursor is reported. This protocol provides the desired cou-
pling products in moderate to very good yields.
Corresponding Author:
Georgios C Vougioukalakis, National and Kapodistrian University of Athens, Department of Chemistry, Panepistimiopolis Zografou,
15771 Athens, Greece, vougiouk@chem.uoa.gr
Affiliations:
Efstathios Tonis, National and Kapodistrian University of Athens, Department of Chemistry, Athens, Greece
Felix Stein, Freie Universität Berlin, Institut für Chemie und Biochemie Anorganische Chemie, Berlin, Germany
Ioannis K Stamatopoulos, National and Kapodistrian University of Athens, Department of Chemistry, Athens, Greece
[
…]
Georgios C Vougioukalakis, National and Kapodistrian University of Athens, Department of Chemistry, Athens, Greece
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Synlett
Letter
A Pd-Free Sonogashira Coupling Protocol Employing an In-situ-Prepared
Copper/Chelating 1,2,3-Triazolylidene System
a
Efstathios Tonis
Felix Stein
b
a
Ioannis K. Stamatopoulos
b
Jessica Stubbe
Athanasios Zarkadoulas
a
b,c
Biprajit Sarkar*
a
Georgios C. Vougioukalakis*
a
Laboratory of Organic Chemistry, Department of Chemistry,
National and Kapodistrian University of Athens, 15771 Athens,
Greece
b
Institut für Chemie und Biochemie Anorganische Chemie,
Freie Universität Berlin, Fabeckstraße 34/36, 14195 Berlin,
Germany
c
Chair of Inorganic Coordination Chemistry, Institute of
Inorganic Chemistry, University of Stuttgart, Pfaffenwaldring
55, D-70569 Stuttgart, Germany
*
To whom correspondence should be addressed:
Prof. Dr. B. Sarkar: biprajit.sarkar@iac.uni-stuttgart.de
Prof. Dr. G. C. Vougioukalakis: vougiouk@chem.uoa.gr
Received:
Accepted:
Published online:
DOI:
activity,6 non-linear optical materials and molecular
7
8
electronics,
polymeric and dendrimeric materials,
macrocycles
9
10
with acetylene links, as well as polyalkynylated molecules.
Abstract A new, palladium-free Sonogashira coupling reaction protocol using
a catalytic system that comprises a simple, cheap, widely available copper
salt and a chelating 1,2,3-triazolylidene ligand precursor is reported. This
protocol provides the desired coupling products in moderate to very good
yields.
Sonogashira coupling protocols initially used palladium
phosphine complexes as catalysts for the oxidative addition-
transmetalation-reductive elimination steps, copper salts as co-
catalysts (towards efficient acetylide formation), and organic
amines as bases.3,4 Later on, phosphine ligands were replaced by
N-heterocyclic carbenes (NHCs), among others, given that the
properties of NHCs can be easily adjusted on-demand, both
sterically and electronically, and, also, because the bond
Key words Sonogashira coupling, palladium-free, copper, sustainability, 1,2,3-
triazolylidenes
The Sonogashira coupling reaction is a metal-catalyzed cross-
coupling transformation widely used in organic synthesis to
between the metal and the NHC is in general stronger than the
metal-phosphorus bond.11 Nowadays, well-defined, palladium-
based tailor-designed complexes, bearing either phosphine or
NHC ligands, are attracting the interest of the organic and the
organometallic community in this regard.12
2
form Csp -Csp bonds, through the coupling of aryl- or vinyl-
halides with terminal alkynes, affording conjugated acetylenic
compounds.1 In 1975, two protocols were independently
2
3
reported by Cassar, and Dieck and Heck, who used palladium
catalysis for the conversion of monosubstituted acetylenes into
aryl- or vinyl-substituted acetylene derivatives, through their
reaction with the corresponding organohalides. In the same
year, Sonogashira, Tohda and Hagihara reported an analogous,
but more efficient protocol, in which the reaction was
materialized in the presence of copper(I) iodide as co-catalyst
under mild conditions.4
Alternative, Pd-free protocols for the Sonogashira reaction have
been also developed, mostly due to the fact that Pd catalysts
have low sustainability and are expensive.13 These protocols
include non-conventional Pd-free couplings employing Cu-, Fe-,
or Ni-based complexes as catalysts,14a-c transition-metal-free
microwave-assisted Sonogashira reactions, using water as the
solvent together with a phase-transfer agent,15 photo-induced
Sonogashira approaches,16 or even catalytic protocols involving
metal nanoparticles.17 Recently, in the framework of our interest
in sustainable catalysis,18-23 some of us reported the
The Sonogashira reaction has many applications in diverse
areas of organic chemistry and materials synthesis. For
example, in the synthesis of natural products it is used for the
preparation of compounds containing conjugated enynes or
enediynes.5 Sonogashira coupling protocols combined with
reduction transformations lead to alkaloids, polyketides, or
polycyclic xanthones, whereas couplings affording substituted
alkynes followed by regioselective hetero-annulations are
employed to synthesize indoles, oxyindoles, furans,
development of a Pd-free Sonogashira protocol using a catalytic
system comprising the widely available CuSO •5H Ο and a
4
2
cheap, commercially-available NHC precursor salt.24 This system
can successfully employ a wide variety of terminal alkynes
(electron-poor aryl, electron-rich aryl, or alkyl) with either
electron-poor or electron-rich aryl iodides.
With the same mindset, we decided to explore the potential of
another sustainable Sonogashira reaction protocol, employing
an in-situ generated, chelating 1,2,3-triazolylidene, instead of an
5
benzofurans, or isoquinolinones. Moreover, it is widely used in
the synthesis of pharmaceuticals and compounds with biological
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*
Yields calculated by GC/MS analysis. Experimental conditions: Cu salt 20 mol%,
NHC. Along these lines, herein we report the development of a
new, user-friendly protocol for the Pd-free Sonogashira coupling
reaction. This protocol requires a simple experimental setup
and can be easily followed in any synthetic laboratory. After
screening a number of low-cost, widely-available copper
sources, in combination with the in-situ-prepared chelating
ligand L 10 mol%, 1-iodo-4-nitrobenzene 0.167 mmol, phenylacetylene 0.2 mmol,
K
o
2
CO
3
2eq, solvent DMF (1 mL), temperature = 130 C, reaction time 8h.
Satisfactory catalytic activity is provided by both copper (I) and
copper (II) sources, but we decided that the use of Cu(OAc)
2
provided the best catalytic system, taking into account the
stability, cost, toxicity, and availability of this copper source,
besides, of course, its catalytic efficiency. The copper and ligand
loading utilized are relatively low, in comparison with our
developed NHC-based catalytic system, as well as, with other
published protocols.24,26
1
,2,3-triazolylidene (Trz*Ph,Ph
efficient catalytic system was found to be the one employing
Cu(OAc) . A number of electron-poor or electron-rich aryl
)
2
CH
2
(L, Figure 1),25 the most
2
iodides, along with a variety of terminal alkynes were coupled
with satisfactory results.
After also testing some inorganic and organic bases (Table 2),
potassium carbonate was found to give the highest yield.
Solvent optimization experiments were performed as well
(
Table 3). DMF and PEG 350 are the solvents providing the best
results. Despite the more sustainable nature of PEG 350, we
decided that DMF is superior, due to difficulties and the bad
reproducibility in the isolation of the product when using PEG
Figure 1 The chelating 1,2,3-triazolylidene ligand precursor (Trz*Ph,Ph
utilized in the present work.
2 2
) CH (L)
o
3
50. Finally, we concluded that 130 C was the best temperature
Optimization experiments towards probing efficient and
straightforward catalytic conditions not requiring the formation
and isolation of well-defined copper-based complex(es) were
initially performed. Our studies also aimed at increasing the
sustainability and selectivity of the protocol in favor of the
Sonogashira product, in comparison to the simultaneously
formed Glaser coupling product, as well as at the decrease of our
protocol’s cost. The coupling of p-iodonitrobenzene with
phenylacetylene was chosen as the model reaction and all
experiments were conducted under an inert atmosphere
employing the chelating 1,2,3-triazolylidene ligand precursor
for the reaction (Table 4) and that 8 hours is the optimum
reaction time (Table 5), as prolonged reaction times did not
improve the results, at least in the specific transformation.
Table 2 Base optimization.
(
Trz*Ph,Ph
)
2
CH (L, Figure 1). Initially, we tested the catalytic
2
Entry
1
Base
Product (%)*
86%
activity of a wide variety of copper sources (Table 1).
K2CO3
2
3
4
5
Cs
KOH
COONa
NEt
2
CO
3
56%
20%
40%
0
Table 1 Copper source optimization.
CH
3
3
2
*Yields calculated by GC/MS analysis. Experimental conditions: Cu(OAc) 10 mol%,
ligand L 5 mol%, 1-iodo-4-nitrobenzene 0.167 mmol, phenylacetylene 0.2 mmol,
o
base 2eq, solvent DMF (1 mL), temperature = 130 C, reaction time 8h.
Entry
1
Copper Source
Product (%)*
14%
Table 3 Solvent optimization.
CuSO
4
anhydrous
CuCl
2
anhydrous
90%
86%
81%
74%
-
2
3
4
5
6
7
8
9
Cu(OAc)
2
.xH
2
O
CuCl .2H
2
2
O
CuCO
3
.Cu(OH)
2
2
Cu O
Entry
Solvent
Product (%)*
CuCl
CuBr
84%
80%
87%
80%
91%
89%
92%
91%
72%
1
2
3
4
5
6
7
toluene
p-cymene
NMP
9%
17%
4%
86 (80)
56%
0
CuBr
CuI(NO .3H
Cu(CH CN)
2
DMF
)
3 2
2
O
diglyme
1,4-dioxane
PEG 350
10
11
12
13
14
15
[
3
4
]PF
6
82%
Cu(acac)
2
*Yields calculated by GC/MS analysis (Isoleated yields). Experimental conditions:
Cu(OAc) 10 mol%, ligand L 5 mol%, 1-iodo-4-nitrobenzene 0.167 mmol,
Cu(OAc)
2
o
phenylacetylene 0.2 mmol, K
reaction time 8h
2 3
CO 2 eq, solvent (1 mL), temperature = 130 C,
Cu(OAc)
2
CuI
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iodonitrobenzene, aryl iodides bearing electron withdrawing
groups afford the desired cross-coupling product in very good
isolated yields (3a, 3c, and 3e, Table 6). Aryl iodides having no
substituents (3f), heterocyclic rings (3d), or electron donating
substituents (3b) provide moderate to good isolated yields
Table 4 Temperature optimization.
(
Table
6).
Aryl
bromides
(bromobenzene,
4-
bromobenzotrifluoride) and aryl chlorides (chlorobenzene) are
not amenable to this protocol, as concerns their attempted
coupling with phenylacetylene, providing very low yields of the
desired cross-coupled products, or no product at all.
Entry
Temperature
Product (%)*
1
2
3
4
RT
No product
10%
57%
70 oC
100 oC
130 oC
86%
Table 6 Aryl halide Sonogashira reaction scope.
2
*Yields calculated by GC/MS analysis. Experimental conditions: Cu(OAc) 10 mol%,
ligand L 5 mol%, 1-iodo-4-nitrobenzene 0.167 mmol, phenylacetylene 0.2 mmol,
o
2
K CO
3
2eq, solvent DMF (1 mL), temperature ( C), reaction time 8h.
Table 5 Reaction time optimization.
Entry
Time
Product (%)*
1
2
3
4
5
6
2 hrs
4 hrs
6 hrs
8 hrs
10 hrs
14 hrs
21
48
77 (69)
86
85
86
Experimental conditions: Cu(OAc)
2
10 mol%, ligand L 5 mol%, aryl halide 0.167
CO 2eq, solvent DMF 1 mL, temperature
20 mol%, ligand 10 mol%
10 mol%, ligand 5 mol%: 61% isolated yield).
mmol, phenylacetylene 0.2 mmol, K
2
3
o
=
130 C, reaction time 8h. *2x catalyst loading: Cu(OAc)
2
*
Yields calculated by GC/MS analysis (Isoleated yields). Experimental conditions:
(with Cu(OAc)
2
Cu(OAc) 10 mol%, ligand L 5 mol%, 1-iodo-4-nitrobenzene 0.167 mmol,
2
o
2 3
phenylacetylene 0.2 mmol, K CO 2eq, solvent DMF (1 mL), temperature 130 C,
reaction time (h).
Table 7 Terminal alkyne Sonogashira reaction scope.
As mentioned above, one of the known byproducts of the
Sonogashira reaction is the Glaser coupling product (coupling of
two terminal alkynes / homocoupling).24,27 In our protocol
discussed herein, the Glaser product is formed as well, however,
in very low yields. Specifically, in all of the reactions conducted,
the ratio of the Sonogashira coupling product versus the Glaser
coupling product is below 5.3/1. Moreover, although p-
iodonitrobenzene and phenylacetylene are known to provide
both the corresponding Sonogashira and Glaser products,
simply in the presence of some copper sources (albeit in low
yields and in non-favorable Sonogashira/Glaser ratios),24 and
this was confirmed in our present study, when we ran some
blank tests only with Cu(OAc)
2
, the Sonogashira product yield
obtained in this way is inferior to that of our optimized system
(
(
including L), even concerning this exceptional substrate case
Sonogashira/homocoupling product yield was 38 %/14 %
under otherwise identical to the substrate scope reaction
conditions). Along these lines, only traces of the Sonogashira
product were observed in the absence of ligand L in the coupling
of p-iodoanisole with phenylacetylene. Finally,
a blank
experiment carried out in the coupling of phenylacetylene with
p-iodonitrobenzene in the absence of a copper source did not
provide any product.
Experimental conditions: Cu(OAc)
2
10 mol%, ligand L 5 mol%, aryl halide 0.167
CO 2eq, solvent DMF 1 mL, temperature =130
mmol, terminal alkyne 0.2 mmol, K
2
3
o
C, reaction time 8h.
After the optimum catalytic system and reaction conditions
were determined, we studied our protocol’s substrate scope. As
already shown in the optimization studies above, concerning p-
We then investigated the substrate scope of our protocol with
regards to the terminal alkynes. Given that the aryl halide scope
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study showed that electron donating groups result in moderate
to good yields, we only studied the coupling of aryl halides
bearing electron withdrawing groups (Table 7). More
specifically, both alkyl- and aryl-substituted terminal alkynes,
bearing either electron-donating or electron-withdrawing
groups on the phenyl ring, afforded good to very good isolated
yields. This result suggests that the electronic characteristics of
the aromatic terminal alkynes employed do not play a
significant role in the outcome of the reaction, at least at the
extent of the analogous influence shown by the electronic
characteristics of the aryl halide.
Figure 2 Well-defined dicopper(I)-dimesoionic carbene complex 4 tested for
its catalytic activity under the optimized conditions.
Summing up, herein we have reported the development of a
user-friendly, sustainable protocol for the Pd-free Sonogashira
coupling reaction. Reaction conditions were optimized with
regards to the copper source, the base, the solvent, the
temperature, and the reaction time utilized. The final catalytic
system was chosen on the basis of its efficiency, components
stability, cost, toxicity, and availability. It is formed in-situ and
the necessary catalyst loading is relatively low, when compared
to analogous systems. The reaction scope of the organohalides
and the terminal alkynes amenable to this system was
investigated by employing a variety of substrates. Aryl bromides
and aryl chlorides are, in general, innocent bystanders. On the
other hand, aryl iodides bearing electron-withdrawing groups
provide very good isolated yields, while aryl iodides bearing
electron-donating groups provide moderate to good yields. With
regards to the various terminal alkynes studied, the results are
very good with aryl substituted terminal alkynes bearing either
electron withdrawing or electron donating substituents. Alkyl
substituted terminal alkynes afford the desired product in
moderate yields.
To probe the possible intervention of radical species in our
catalytic protocol, we performed a reaction in the presence of a
radical scavenger and another in the presence of a radical
initiator. More specifically, utilization of one of the most widely-
used radical scavengers, 2,2,6,6-tetramethylpiperidine 1-oxyl
(
TEMPO), afforded almost identical results with our typical
protocol, revealing that the absence of radical species does not
negatively affect the reaction’s yield. As radical initiator we used
azobisisobutyronitrile (AIBN). Again, we did not observe any
change in the reaction’s yield, thus excluding the presence of
free radical species in the reaction. The mechanism we propose
for this transformation is similar to those of analogous, copper-
based catalytic systems, including copper acetylide formation,
oxidative addition to the organohalide, and, eventually,
reductive elimination of the cross-coupled product.24,28,29 This
Cu(I)/Cu(III) catalytic cycle30 requires, in the present case, the
in-situ reduction of Cu(II) to Cu(I), which can take place by the
solvent or the ligand.24
Funding Information
Finally, we decided to study the catalytic efficiency of a pre-
formed, well-defined copper complex that could possibly form
and function under the catalytic reaction conditions employed,
in order to compare it with the in-situ generated catalytic
system. Several attempts were made to prepare such a complex:
reactions of anhydrous copper(II) acetate or copper(II) triflate
as the copper source, in the presence of the 1,2,3-triazolylidene
This work was supported by the Hellenic Foundation for Research and
Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to
support Faculty members and Researchers and the procurement of high-
cost research equipment grant” (Project Number: 16 – Acronym:
SUSTAIN). The contribution of COST Action CA15106 (C-H Activation in
Organic Synthesis - CHAOS) is also gratefully acknowledged.
Supporting Information
(
Trz*Ph,Ph
)
2
CH
2
(L, Figure 1) in various solvents of different
Cl , CH OH, CH CN, DMF,
YES (this text will be updated with links prior to publication)
polarity and coordinating ability (CH
2
2
3
3
or THF), with different bases (anhydrous sodium acetate,
sodium acetate trihydrate, anhydrous potassium carbonate, or
potassium tert-butoxide) were all unsuccessful. Performing the
complexation reactions at room temperature or under heating
also did not yield a well-defined compound. Transmetalation of
the 1,2,3-triazolylidene using silver(I) salts was unsuccessful as
well. In all cases, the products of the reactions were inorganic
salts of copper with carbonate, acetate, or triflate counter-
anions. To this end, dicopper(I)-dimesoionic carbene complex 4
References and Notes
(
(
(
(
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(
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(
Figure 2), that is, a binuclear complex with one bridging
(
(
(
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mesoionic dicarbene ligand and one bridging acetate, previously
reported by some of us,31 was alternatively used, as a well-
defined catalyst possibly resembling our in-situ prepared
system. Although the Sonogashira coupling was successful
2
1
(
GC/MS yield using the well-defined complex 46% vs GC/MS
yield using our protocol 91%), the results were significantly
inferior compared to that of the in-situ prepared system, as both
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products ratio (3/2) were lower in the case of complex 4.
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4
5
A dry Schlenk tube equipped with a magnetic stirrer is loaded
18) Neofotistos, S. P.; Tzouras, N. V.; Pauze, M.; Gomez-Bengoa, E.;
under argon with Cu(OAc) (10 mol%, 0.0167 mmol), ligand L (5
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mol%, 0.0084 mmol), K CO (0,33 mmol), the aryl halide (0.167
2
3
1
0.1002/adsc.202000566.
mmol) and DMF (1 mL). The above mixture is degassed with a slow
bubbling flow of argon for 20 minutes. The terminal alkyne (0.2
mmol) is then added and the reaction mixture is sealed under an
argon atmosphere. The Schlenk tube is transferred in a preheated
(
19) Adejumo, T. T.; Tzouras, N. V.; Zorba, L. P.; Radanović, D.; Pevec, A.;
Grubišić, S.; Mitić, D.; Anđelković, K. K.; Vougioukalakis, G. C.;
Čobeljić, B.; Turel, I. Molecules 2020, 25(18), 4043.
o
(
(
(
20) Tzouras, N. V.; Neofotistos, S. P.; Vougioukalakis, G. C. ACS Omega
oil bath (130 C) and the reaction mixture is stirred for 8h. Then, the
2
019, 4(6), 10279-10292.
reaction is cooled to room temperature and transferred in a 100 mL
21) Papastavrou, A. T.; Pauze, M.; Gomez-Bengoa, E.; Vougioukalakis, G.
C. ChemCatChem 2019, 11(21), 5379-5386.
22) Voutyritsa, E.; Triandafillidi, I.; Tzouras, N. V.; Nikitas, N. F.;
Pefkianakis, E. K.; Vougioukalakis, G. C.; Kokotos, C. G. Molecules
separating funnel with 20 mL of H
ethyl acetate (3X10mL). The organic layers are combined, washed
with brine (15 mL), and dried over MgSO . The dry organic layer is
2
O. The mixture is extracted with
4
filtered and the solvent is removed in a rotary evaporator. Products
are separated with gradient column chromatography using
2019, 24(9), 1644.
(
(
23) Pinaka, A.; Vougioukalakis, G. C. Coord. Chem. Rev. 2015, 288, 69-97.
24) Liori, A. A.; Stamatopoulos, I. K.; Papastavrou, A. T.; Pinaka, A.;
Vougioukalakis, G. C. Eur. J. Org. Chem. 2018, 44, 6134-6139.
2 2
CH Cl /petroleum ether.
1-Nitro-4-(phenylethynyl)benzene (3a). Prepared according to
the general procedure and obtained as a yellow solid in 80% yield
1
(
(
25) Suntrup, L.; Hohloch, S.; Sarkar, B. Chem. Eur. J. 2016, 22(50),
(30 mg, 0.134 mmol). H NMR (200 MHz, CDCl
3
) δ 8.23 (d, J = 9.0
1
8009–18018.
Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.61 – 7.52 (m, 2H), 7.44 – 7.34 (m,
3H). 13C NMR (101 MHz, CDCl
) δ 147.14, 132.43, 132.00, 130.43,
129.43, 128.69, 123.80, 122.26, 94.86, 87.70.
26) Chen, H.-J.; Lin, Z.-Y.; Li, M.-Y.; Lian, R.-J.; Xue, Q.-W.; Chung, J.-L.;
3
Chen, S.-C.; Chen, Y.-J. Tetrahedron 2010, 66(39), 7755–7761.
Template for SYNLETT © Thieme Stuttgart · New York
2020-10-14
page 5 of 5

Supporting Information
for
A Pd-Free Sonogashira Coupling Protocol Employing an In-
situ-Prepared Copper/Chelating 1,2,3-Triazolylidene System
a
b
a
b
Efstathios Tonis, Felix Stein, Ioannis K. Stamatopoulos, Jessica Stubbe,
a
b,c
Athanasios Zarkadoulas, Biprajit Sarkar, * and
a
Georgios C. Vougioukalakis *
aLaboratory of Organic Chemistry, Department of Chemistry, National and
Kapodistrian University of Athens, 15771 Athens, Greece
bInstitut für Chemie und Biochemie Anorganische Chemie, Freie Universität
Berlin, Fabeckstraße 34/36, 14195 Berlin, Germany
cChair of Inorganic Coordination Chemistry, Institute of Inorganic Chemistry,
University of Stuttgart, Pfaffenwaldring 55, D-70569 Stuttgart, Germany
*
To whom correspondence should be addressed:
Prof. Dr. B. Sarkar: biprajit.sarkar@iac.uni-stuttgart.de
Prof. Dr. G. C. Vougioukalakis: vougiouk@chem.uoa.gr
Table of Contents
General Reagent Information
S1
S2
S2
S3
S4
General Analytical Information
General Catalytic Protocol Procedure
Compounds Characterization Data
1
13
H and C NMR Spectra
General Reagent Information
All chemicals were obtained from commercial sources and were used without
any further purification. All reactions were carried out under an atmosphere of
S1

argon. The course of the reactions was followed by 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).
General Analytical Information
1
13
19
H, C and F NMR spectra were measured on a Varian Mercury 200 MHz, or
a Brucker Avance 400 MHz instrument, using CDCl as the solvent and its
3
residual solvent peak as a reference. NMR spectroscopic data are 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. The GC-MS spectra were recorded with a Shimandzu GCMS-
®
QP2010 Plus, Chromatograph Mass Spectrometer using a MEGA (MEGA-5,
o
F.T: 0.25 μm, I.D.: 0.25 mm, L: 30 m, Tmax: 350 C, Column ID# 11475)
column, using n-octane as the internal standard.
General Catalytic Protocol Procedure
A dry Schlenk tube equipped with a magnetic stirrer is loaded under argon with
Cu(OAc)
2
(10 mol%, 0.0167 mmol), ligand L (5 mol%, 0.0084 mmol), K
2
CO
3
(0,33 mmol), the aryl halide (0.167 mmol) and DMF (1 mL). The above mixture
is degassed with a slow bubbling flow of argon for 20 minutes. The terminal
alkyne (0.2 mmol) is then added and the reaction mixture is sealed under an
argon atmosphere. The Schlenk tube is transferred in a preheated oil bath
o
(
130 C) and the reaction mixture is stirred for 8h. Then, the reaction is cooled
to room temperature and transferred in a 100 mL separating funnel with 20 mL
of H O. The mixture is extracted with ethyl acetate (3X10mL). The organic
layers are combined, washed with brine (15 mL), and dried over MgSO . The
2
4
dry organic layer is filtered and the solvent is removed in a rotary evaporator.
Products are separated with gradient column chromatography using
CH
2
Cl /petroleum ether.
2
S2

Compounds Characterization Data
1
(
(
(
Trz*Ph,Ph
)
2
CH
s, 2H, N-CH
m, 2H, aryl-H), 7.60 – 7.54 (m, 4H, aryl-H), 7.50 – 7.46 (m, 4H, aryl-H). C NMR (100
2
(L). H NMR (400 MHz, acetone-d6): δ 9.69 (s, 2H, triazole-5H), 8.09
2
-N), 7.82 – 7.79 (m, 2H, aryl-H), 7.77 – 7.73 (m 8H, aryl-H), 7.68 – 7.63
13
MHz, acetone-d6): δ 145.6 (triazole-5C), 135.1, 133.3, 132.6, 132.1, 130.9, 129.9,
1
2
27.4, 123.3 (all aryl-C), 65.8 (N-CH
2
-N). MS (ESI): m/z found 228.1044 calcd
2+
28.1026 for [C29
H
24
N ] .
6
1
Well-defined dicopper(I)-dimesoionic carbene complex (4). H NMR (400 MHz,
13
CD
2
Cl
2
) δ 7.75–7.28 (m, 22H, aryl-H + methylene-H), 2.09 (s, 3H, acetate-H). C NMR
Cl ) δ 83.38 (Carbene), 149.79, 135.15,132.07, 130.93, 130.49, 130.10,
29.69, 127.22, 125.85, 70.50, 68.31 (THF), 31.17, 26.14 (THF), 22.63. Anal. Calcd
Cu S·0.60 C O] C 49.6, H 3.61, N 10.09; Found C 49.21, H
(101 MHz, CD
2
2
1
(%) for [C32
H
25
N
6
O
2 5
F
3
H
4 8
3
.627, N 9.747. ESI-MS: m/z: [M–OTf] + Calcd 639.063, Found 639.062.
1
-Nitro-4-(phenylethynyl)benzene (3a). Prepared according to the general
1
procedure and obtained as a yellow solid in 80% yield (30 mg, 0.134 mmol). H NMR
(
2
1
200 MHz, CDCl ) δ 8.23 (d, J = 9.0 Hz, 2H), 7.67 (d, J = 9.0 Hz, 2H), 7.61 – 7.52 (m,
3
13
H), 7.44 – 7.34 (m, 3H). C NMR (101 MHz, CDCl
30.43, 129.43, 128.69, 123.80, 122.26, 94.86, 87.70.
3
) δ 147.14, 132.43, 132.00,
1
-Methoxy-4-(phenylethynyl)benzene (3b). Prepared according to the general
1
procedure and obtained as a white solid in 34% yield (12 mg, 0.057 mmol). H NMR
(
3
200 MHz, CDCl ) δ 7.60 – 7.41 (m, 4H), 7.38 – 7.30 (m, 3H), 6.90 (d, J = 8.8 Hz, 2H),
3
13
.82 (s, 3H). C NMR (50 MHz, CDCl ) δ 159.66, 133.12, 131.51, 128.39, 128.01,
3
1
23.64, 115.37, 114.05, 89.51, 88.17, 55.29.
1
-(Phenylethynyl)-4-(trifluoromethyl)benzene (3c). Prepared according to the
general procedure and obtained as a yellow solid in 61% yield (25 mg, 0.102 mmol).
1
H NMR (200 MHz, CDCl
H). C NMR (101 MHz, CDCl ): δ 131.96, 131.90, 130.07 (q, J = 32.6 Hz), 128.98,
28.60, 127.29, 125.48 (q, J = 3.8 Hz), 124.21 (q, J = 270.2 Hz), 122.72, 91.91, 88.12.
3
) δ 7.66 – 7.59 (m, 4H), 7.58 – 7.51 (m, 2H), 7.42 – 7.34 (m,
13
3
1
3
3
-(Phenylethynyl)pyridine (3d). Prepared according to the general procedure and
1
obtained as a yellow solid in 51% yield (15 mg, 0.085 mmol). H NMR (200 MHz,
CDCl ) δ 8.82 – 8.73 (m, 1H), 8.60 – 8.51 (m, 1H), 7.88 – 7.75 (m, 1H), 7.59 – 7.48
3
13
(
m, 2H), 7.44 – 7.27 (m, 4H). C NMR (101 MHz, CDCl
3
) δ 152.43, 148.71, 138.56,
1
31.85, 128.96, 128.60, 123.19, 122.70, 120.67, 92.79, 86.09.
Methyl 2-(phenylethynyl)benzoate (3e). Prepared according to the general
1
procedure and obtained as a yellow oil in 64% yield (25 mg, 0.107 mmol). H NMR
(
2
200 MHz, CDCl
H), 7.52 – 7.41 (m, 1H), 7.40 – 7.29 (m, 4H), 3.97 (s, 3H). C NMR (101 MHz, CDCl
δ 166.86, 134.11, 132.00, 131.87, 131.82, 130.60, 128.65, 128.49, 128.02, 123.84,
3
) δ 7.98 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.61 – 7.53 (m,
13
3
)
1
23.45, 94.46, 88.35, 52.32.
1
,2-Diphenylethyne (3f). Prepared according to the general procedure and obtained
1
as a white solid in 16% yield (5 mg, 0.027 mmol). H NMR (200 MHz, CDCl
3
) δ 7.73 –
1
3
7.61 (m, 4H), 7.48 – 7.36 (m, 6H). C NMR (50 MHz, CDCl
3
) δ 131.71, 128.45, 128.36,
1
23.39, 89.53.
S3

1
,2-bis(4-nitrophenyl)ethyne (3g). Prepared according to the general procedure and
1
obtained as a white solid in 16% yield (5 mg, 0.027 mmol). H NMR (200 MHz, CDCl
3
)
δ 8.26 (d, J = 8.8 Hz, 4H), 7.71 (d, J = 8.8 Hz, 4H). 13C NMR (101 MHz, CDCl
3
) δ
1
47.81, 132.77, 129.02, 123.94, 92.14.
1
-Methoxy-4-((4-nitrophenyl)ethynyl)benzene (3h). Prepared according to the
1
general procedure and obtained as a yellow solid in 59% yield (25 mg, 0.1 mmol). H
NMR (200 MHz, CDCl ) δ 8.20 (d, J = 8.9 Hz, 2H), 7.63 (d, J = 8.9 Hz, 2H), 7.50 (d, J
8.8 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 3.85 (s, 3H). 13C NMR (50 MHz, CDCl
) δ
3
=
1
3
60.53, 146.79, 133.58, 132.12, 130.83, 123.77, 114.34, 114.23, 95.28, 86.77, 55.51.
1
-Nitro-4-((4-(trifluoromethyl)phenyl)ethynyl)benzene (3i). Prepared according to
the general procedure and obtained as a yellow solid in 61% yield / 66% yield (26 mg,
1
0
–
3
9
.09 mmol / 32 mg, 0,11 mmol). H NMR (200 MHz, CDCl ) δ 8.29 – 8.14 (m, 2H), 7.74
3
13
7.57 (m, 6H). C NMR (101 MHz, CDCl3): δ 147.55, 132.65, 132.24, 131.06 (q, J =
2.8 Hz), 129.56, 126.05, 125.64 (q, J = 3.7 Hz), 123.91 (q, J = 271.2 Hz), 123.87,
2.94, 89.67.
1
-methyl-4-((4-nitrophenyl)ethynyl)benzene (3j). Prepared according to the general
1
procedure and obtained as a yellow solid in 74% yield (29 mg, 0.12 mmol). H NMR
(
200 MHz, CDCl
3
) δ 8.21 (d, J = 8.9 Hz, 2H), 7.64 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 8.1
1
3
Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 2.39 (s, 3H). C NMR (101 MHz, CDCl
1
3
) δ 146.97,
39.80, 132.29, 131.90, 130.66, 129.45, 123.75, 119.16, 95.24, 87.22, 21.32
1
-Methyl-3-(2-(4-nitrophenyl)ethynyl)benzene (3k). Prepared according to the
1
general procedure and obtained as a yellow solid in 68% yield (27 mg, 0.11 mmol). H
NMR (200 MHz, CDCl ) δ 8.21 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.9 Hz, 2H), 7.42 – 7.32
m, 2H), 7.28 – 7.24 (m, 1H), 7.23 – 7.17 (m, 1H), 2.37 (s, 3H). 13C NMR (101 MHz,
3
(
CDCl ) δ 147.08, 138.45, 132.54, 132.39, 130.54, 130.35, 129.09, 128.59, 123.79,
3
1
22.05, 95.14, 87.39, 21.38.
1
-(tert-butyl)-4-((4-nitrophenyl)ethynyl)benzene (3l). Prepared according to the
general procedure and obtained as a pale-yellow solid in 69% yield (32 mg, 0.115
1
mmol). H NMR (200 MHz, CDCl ) δ 8.25 – 8.12 (m, 2H), 7.71 – 7.60 (m, 2H), 7.54 –
3
13
7
.45 (m, 2H), 7.44 – 7.37 (m, 2H), 1.34 (s, 9H). C NMR (101 MHz, CDCl ) δ 152.92,
3
1
46.98, 132.33, 131.76, 130.70, 125.71, 123.76, 119.20, 95.23, 87.21, 35.07, 31.27.
1
-(oct-1-yn-1-yl)-4-(trifluoromethyl)benzene (3m). Prepared according to the
1
general procedure and obtained as a yellow oil in 30% yield (12.5 mg, 0.05 mmol). H
NMR (200 MHz CDCl
3
) δ 7.54 (d, J = 8.7 Hz, 2H), 7.48 (d, J = 8.7 Hz, 2H), 2.43 (t, J =
7
6
=
.0 Hz, 2H), 1.71 – 1.55 (m, 2H), 1.52 – 1.41 (m, 2H), 1.39 – 1.29 (m, 4H), 0.92 (t, J =
13
.7 Hz, 3H). C NMR (CDCl
3
): δ 131.92, 129.43 (q, J = 32.6 Hz), 128.27, 125.29 (q, J
3.7 Hz), 124.2 (q, J = 280 Hz), 93.53, 79.68, 31.51, 28.77, 28.70, 22.71, 19.59, 14.17.
Methyl 2-((4-nitrophenyl)ethynyl)benzoate (3n). Prepared according to the general
1
procedure and obtained as a yellow solid in 36% yield (17 mg, 0.06 mmol). H NMR
(
7
1
200 MHz, CDCl ) δ 8.27 – 8.19 (m, 2H), 8.07 – 8.00 (m, 1H), 7.76 – 7.65 (m, 3H),
3
13
.59 – 7.41 (m, 2H), 3.97 (s, 3H). C NMR (101 MHz, CDCl ) δ 166.34, 147.33, 134.36,
3
32.58, 132.20, 132.08, 130.84, 130.45, 129.05, 123.79, 122.85, 93.55, 92.29, 52.46.
S4

1
13
H and C NMR Spectra
(
Trz*Ph,Ph
)
2
CH (L)
2
S5

1
-Nitro-4-(phenylethynyl)benzene (3a)
S6

1
-Methoxy-4-(phenylethynyl)benzene (3b)
S7

1
-(Phenylethynyl)-4-(trifluoromethyl)benzene (3c)
S8

3
-(Phenylethynyl)pyridine (3d)
S9

Methyl 2-(phenylethynyl)benzoate (3e)
S10

1
,2-Diphenylethyne (3f)
S11

1
,2-bis(4-nitrophenyl)ethyne (3g)
S12

1
-Methoxy-4-((4-nitrophenyl)ethynyl)benzene (3h)
S13

1
-Nitro-4-((4-(trifluoromethyl)phenyl)ethynyl)benzene (3i)
S14

1
-methyl-4-((4-nitrophenyl)ethynyl)benzene (3j)
S15

1
-Methyl-3-(2-(4-nitrophenyl)ethynyl)benzene (3k)
S16

1
-(tert-butyl)-4-((4-nitrophenyl)ethynyl)benzene (3l)
S17

1
-(oct-1-yn-1-yl)-4-(trifluoromethyl)benzene (3m)
S18

Methyl 2-((4-nitrophenyl)ethynyl)benzoate (3n)
S19