A guide to sonogashira cross-coupling reactions: The influence of substituents in aryl bromides, acetylenes, and phosphines

Article abstract of DOI:10.1021/jo202644g

The conversion-time data for 168 different Pd/Cu-catalyzed Sonogashira cross-coupling reactions of five arylacetylenes (phenylacetylene; 1-ethynyl-2-ethylbenzene; 1-ethynyl-2,4,6-R₃-benzene (R = Me, Et, i-Pr)) and Me₃SiCCH with seven

Full text of DOI:10.1021/jo202644g

Article
pubs.acs.org/joc
A Guide to Sonogashira Cross-Coupling Reactions: The Influence of
Substituents in Aryl Bromides, Acetylenes, and Phosphines
Marc Schilz and Herbert Plenio*
Organometallic Chemistry, Fachbereich Chemie, Petersenstrasse 18, Technische Universitat Darmstadt, 64287 Darmstadt, Germany
̈
S
* Supporting Information
ABSTRACT: The conversion−time data for 168 different Pd/Cu-
catalyzed Sonogashira cross-coupling reactions of five arylacetylenes
(phenylacetylene; 1-ethynyl-2-ethylbenzene; 1-ethynyl-2,4,6-R3-benzene
(R = Me, Et, i-Pr)) and Me3SiCCH with seven aryl bromides (three 2-R-
bromobenzenes (R = Me, Et, i-Pr); 2,6-Me2-bromobenzene and three
2,4,6-R3-bromobenzenes (R = Me, Et, i-Pr)) with four different phos-
phines (P-t-Bu3, t-Bu2PCy, t-BuPCy2, PCy3) were determined using
quantitative gas chromatography. The stereoelectronic properties of the
substituents in the aryl bromides, acetylenes, and phosphines were
correlated with the performance in Sonogashira reactions. It was found
that the nature of the most active Pd/PR3 complex for a Sonogashira transformation is primarily determined by the steric bulk of
the acetylene; ideal catalysts are: Pd/P-t-Bu3 or Pd/t-Bu2PCy for sterically undemanding phenylacetylene, Pd/t-BuPCy2 for 2-
and 2,6-substituted arylacetylenes or Me3SiCCH and Pd/PCy3 for extremely bulky acetylenes and aryl bromides. Electron-rich
and sterically demanding aryl bromides with substituents in the 2- or the 2,6-position require larger amounts of catalyst than 4-
substituted aryl bromides. The synthesis of tolanes with bulky groups at one of the two aryl rings is best done by placing the
steric bulk at the arylacetylene, which is also the best place for electron-withdrawing substituents.
steric bulk of phosphines or NHC ligands coordinated to Pd
promote the formation of a formally monoligated complex PdL1,
which turns out to be highly active for oxidative addition; (iii)
there is a pronounced steric effect in the transmetalation, while the
ligand bite angle and the electronic effect are less important; and
(iv) reductive elimination tends to be favored by less electron-
donating ligands and steric bulk.11
INTRODUCTION
■
The Sonogashira coupling of aryl halides and terminal
acetylenes remains the most important method for the
formation of C(sp2)−C(sp) bonds.1 Traditionally palladium
complexes, very often in combination with copper(I) salts, are
the preferred catalyst for such reactions, despite the fact that in
recent years numerous other metals were also claimed to be
effective.1c,2 Closely related approaches leading to the same
products involve the reactions of alkynyl halides and arenes
(“inverse Sonogashira reaction”)3 or of acetylenes and
heterocycles (“direct alkynylation”)4 or the reactions of aryl
boronic acids with acetylenes.5
The mechanism of the Sonogashira reaction is not understood
in detail, also since there can be additional complications due to
CuI and the metal coordination of acetylenes.6 Nonetheless,
primarily empirical studies led to a large number of powerful
catalyst recipes, which allow the efficient conversion of aryl iodides
and bromides using small catalyst loading7 or aryl chlorides.8 With
an ever larger number of catalysts and reaction conditions
published in the literature, it is not easy for the nonspecialist to
choose the best reaction conditions for certain substrates. In this
respect, answers are needed concerning the factors determining
the reactivity of individual substrates in Sonogashira reactions.
Several studies focusing on the influence of steric and electronic
variables on the individual steps in the catalytic cycles, such as the
oxidative addition,9 transmetalation and reductive elimination,
were done, and a few general rules concerning cross-coupling
reactions were derived:10 (i) the oxidative addition in Ar-X is
promoted by electron-withdrawing groups at the aryl halide; (ii)
These are useful rules. However, for certain substrate−
catalyst combinations, it is not always clear which of the various
elementary reactions actually control the outcome of a cross-
coupling reaction. Substrate−activity relationships or descriptor-
based approaches, for which stereoelectronic properties of sub-
strates or ligands are modified in a systematic manner, appear to
be useful,12 to better understand product formation as well as
more global approaches.13 In this respect, Hartwig et al. screened
a large number of phosphine ligands to find that the sterically
most demanding ligands provide the highest activities in
palladium-catalyzed Heck coupling.14 We have studied in detail
substrate−activity relationships for Sonogashira coupling reac-
tions using parallel screening.15 For sterically undemanding sub-
strates there turns out to be a good correlation between the
Sonogashira activity of various palladium−phosphine complexes
and the Tolman cone angle of the respective phosphine ligand.15
Several publications by Organ et al. center around the question
of how the steric and electronic environment of NHC ligands
influence the performance of the respective (NHC)Pd complex
Received: January 4, 2012
Published: March 6, 2012
© 2012 American Chemical Society
2798
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
Scheme 1. Representation of 140 Different Sonogashira Cross-Coupling Reactions (7 Aryl Bromides × 5 Acetylenes × 4
Phosphines)
in cross-coupling reactions.16 Concerning the role of phosphines,
Guram et al. showed that within a small series of electronically
variable phosphines, the most electron-rich ligand provides the
best results in Suzuki−Miyaura reactions.17 The effect of solvent
composition on cross-coupling efficiency was investigated in a
systematic manner for the same coupling reaction.18 Martensson
et al. studied the effect of solvent and base in copper-free
Sonogashira coupling in a systematic manner.19
It is the aim of the present study to elucidate in which manner
electronic and steric modifications at aryl bromides, acetylenes, and
the ligands influence the outcome of Sonogashira reactions.20 On
the basis of these results, it will be attempted to provide a few
general rules for the selection of suitable palladium−phosphine
catalyst complexes as well as catalytic procedures for the efficient
conversion of various substrate combinations.
in a highly systematic manner. Furthermore, we wanted to use
simple and easily available phosphines so that others can easily
use such ligands for their own experiments. For each of the 168
different Sonogashira coupling reactions, the respective time−
conversion data were independently determined twice; each
time−conversion plot consists of 10 or 11 individual GC mea-
surements. All data given are the average of two independent
determinations. For all of the tolanes studied the individual gas
chromatographic response factors were determined to enable the
precise quantification of product formation. In order to facilitate
reaction screening, a previously established parallel multisubstrate
procedure was employed.15,22 According to this procedure, all
seven aryl bromides employed were simultaneously reacted with a
single one of the six acetylenes in one reaction vessel.23 This
procedure enables the screening of a large number of reactions in
a relatively short time. Furthermore, it ensures identical reaction
conditions for each series of aryl bromide coupling and thus
allows us to obtain precise and comparable reaction data.
Evaluation of the Individual Sonogashira Screens. As
outlined in Schemes 1 and 2 all permutations of the seven aryl
bromides and acetylenes (five arylacetylenes and Me3Si-CCH)
with four different Pd/PR3 complexes were investigated. One
multisubstrate screen including the seven aryl bromides was set
up for each of the acetylenes. The results for each of those five
screens are displayed in Figures 1 and 2 (phenylacetylene),
Figures 3 and 4 (1-ethynyl-2-ethylbenzene), Figures 5 and 6
(1-ethynyl-2,4,6-trimethylbenzene), Figures 7 and 8 (1-ethynyl-
2,4,6-triethylbenzene), and Figures 9 and 10 (1-ethynyl-2,4,
6-triisopropylbenzene). The time−conversion curves for phenyl-
acetylene, 1-ethynyl-2-ethylbenzene, 1-ethynyl-2,4,6-trimethyl-
benzene, and 1-ethynyl-2,4,6-triethylbenzene were fitted to an
exponential function to obtain rate constants.24 Because of long
inhibition periods in the 1-ethynyl-2,4,6-triisopropylbenzene
reactions, the data could not be treated in the same manner;
instead, the conversion after 210 min is given and used for the
evaluation of the reaction efficiency.
RESULTS AND DISCUSSION
■
Setting up the Sonogashira Screens. In order to probe
the influence of steric effects on Sonogashira couplings
reactions, a large number of such were carried under the
conditions reported previously,7d using HN-i-Pr2 as solvent and
base, Na2PdCl4 as the palladium source, CuI as the cocatalyst,
and a phosphine.21 This reaction procedure is highly efficient
and is characterized by an excellent selectivity for the formation
of the desired tolanes. The steric properties of aryl bromide and
arylacetylene substrates and of the catalytically active Pd/
phosphine complexes were systematically varied (Scheme 1).
All permutations of seven aryl bromides and five arylacetylenes
were tested, resulting in the synthesis of 35 different tolanes
using four different phosphine−palladium catalysts. The same
set of experiments using the seven aryl bromides were also
conducted employing trimethylsilylacetylene. The steric prop-
erties of the phosphines used (t-Bu3P, t-Bu2PCy, t-BuPCy2,
PCy3) were systematically varied by stepwise replacing tert-
butyl groups by cyclohexyl groups. We decided to use a small
set of phosphines, which are closely related and can be changed
2799
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
2-Et, 2-i-Pr) is nearly the same (Figures 1 and 2), while the
reactivity of 2,6-substituted aryl bromides is significantly lower.
This appears to be due to a combination of steric and electronic
effects.
Scheme 2. Representation of 28 Different Sonogashira
Cross-Coupling Reactions (7 Aryl Bromides × 4
Phosphines) with Trimethylsilylacetylene
1-Ethynyl-2-ethylbenzene. With this acetylene, Pd/t-
BuPCy2 is performing better than Pd/t-Bu2PCy for all aryl
bromides tested. Obviously the influence of acetylene bulk on
the Sonogashira coupling (in the choice of the “best” phosphine
ligand) is more important than that of aryl bromide bulk. The
increased bulk of 1-ethynyl-2-ethylbenzene relative to phenyl-
acetylene leads to a change in the choice of the “best”
phosphine ligand. For larger acetylenes, a smaller phosphine is
the better choice. An interesting change in the Sonogashira
reactivity is observed when 1-ethynyl-2-ethylbenzene is used
(Figures 3 and 4). Coupling reactions employing this large
Phenylacetylene. In the reactions with ortho-substituted
aryl bromides, Pd/t-Bu2PCy is slightly more efficient than Pd/t-
Bu3P (Figures 1 and 2). The latter complex performs better in
the coupling of aryl bromides and arylacetylenes with ortho-
hydrogen atoms, as reported previously.15,20 Interestingly, the
reactivity of the three 2-alkyl-substituted aryl bromides (2-Me,
Figure 3. Parallel multisubstrate screen for the reactions of 1-ethynyl-
2-ethylbenzene with seven aryl bromides catalyzed either by 0.1 mol %
Pd/t-Bu3P, Pd/t-Bu2PCy, Pd/t-BuPCy2, or Pd/PCy3.
Figure 1. Parallel multisubstrate screen for the reactions of
phenylacetylene with seven aryl bromides catalyzed either by 0.1
mol % Pd/t-Bu3P, Pd/t-Bu2PCy, Pd/t-BuPCy2 or Pd/PCy3.
Figure 4. Time conversion curves for the reactions of seven aryl
bromides with 1-ethynyl-2-ethylbenzene catalyzed by 0.1 mol % Pd/t-
BuPCy2.
substrate occur faster than analogous reactions using the
smaller phenylacetylene. This unexpected steric effect25 might
result from a hindered side-on coordination of the acetylene to
the active palladium species, which is known to be detrimental
to the activity of the catalyst in the Sonogashira coupling.6b
1-Ethynyl-2,4,6-trimethylbenzene. The reactivity trends
observed for 1-ethynyl-2-ethylbenzene are more pronounced
for reactions of 1-ethynyl-2,4,6-trimethylbenzene (Figures 5
and 6). The reaction rate is even faster than for conversions of
Figure 2. Time conversion curves for the reactions of seven aryl
bromides with phenylacetylene catalyzed by 0.1 mol % Pd/t-Bu2PCy.
2800
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
Figure 5. Parallel multisubstrate screen for the reactions of 1-ethynyl-
2,4,6-trimethylbenzene with seven aryl bromides catalyzed either by
0.1 mol % of Pd/t-Bu3P, Pd/t-Bu2PCy, Pd/t-BuPCy2, or Pd/PCy3.
Figure 7. Parallel multisubstrate screen for the reactions of 1-ethynyl-
2,4,6-triethylbenzene with seven aryl bromides catalyzed either by 0.1
mol % of Pd/t-Bu3P, Pd/t-Bu2PCy, Pd/t-BuPCy2, or Pd/PCy3.
Figure 6. Time−conversion curves for the reactions of seven aryl
bromides with 1-ethynyl-2,4,6-trimethylbenzene acetylene catalyzed by
0.1 mol % Pd/t-BuPCy2.
Figure 8. Time−conversion curves for the reactions of seven aryl
bromides with 1-ethynyl-2,4,6-triethylbenzene catalyzed by 0.1 mol %
of Pd/t-BuPCy2.
the two less bulky arylacetylenes. The Pd complex of the less
bulky phosphine t-BuPCy2 performs much better than Pd/t-
Bu2PCy.
1-Ethynyl-2,4,6-triethylbenzene. The Sonogashira reac-
tions of 1-ethynyl-2,4,6-triethylbenzene are still faster than
those of phenylacetylene but slower than those of 1-ethynyl-
2,4,6-trimethylbenzene (Figures 7 and 8). The diminished
inhibition of the active center enhances the Sonogashira rates,
while the increasing bulk begins to slow down the reaction. For
this substrate, Pd/t-BuPCy2 turns out to be the most efficient
catalyst for the Sonogashira transformations.
1-Ethynyl-2,4,6-triisopropylbenzene. The reactions of
very bulky 1-ethynyl-2,4,6-triisopropylbenzene with aryl
bromides (Figures 9 and 10) are characterized by a significant
inhibition period; no substrate conversion was observed during
the first ca. 20 min of the reaction. The solution of Na2PdCl4 in
HN-i-Pr2 is characterized by a pale yellow color, which persists
after addition of the respective aryl bromide. Upon addition of
the acetylene, a slow change to a dark yellow or orange color is
observed. This color persists throughout the coupling reaction.
It is generally believed that for the Sonogashira reaction, the
conversion of the inactive Pd2+ salt into the active Pd0 species
occurs via the formation of a LnPd(CCR)2 complex, followed
by the reductive elimination of the respective butadiyne. The
initial absence of reactivity and of the typical red color of the
Figure 9. Parallel multisubstrate screen for the reactions of 1-ethynyl-
2,4,6-triisopropylbenzene with seven aryl bromides catalyzed either by
0.1 mol % Pd/t-Bu3P, Pd/t-Bu2PCy, Pd/t-BuPCy2 or Pd/PCy3
(conversion after 210 min).
reaction mixture points to the absence of catalytically active
Pd(0).26 This can be explained for sterically highly demanding
acetylenes, such as 1-ethynyl-2,4,6-triisopropylbenzene, by a
more difficult formation of the respective LnPd(CCAr)2
complexes.
2801
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
Figure 10. Time conversion curves for the reactions of seven aryl
bromides with 1-ethynyl-2,4,6-triisopropylbenzene catalyzed by 0.1
mol % Pd/PCy3.
Figure 11. Parallel multisubstrate screen for the reactions of
trimethylsilylacetylene with seven aryl bromides catalyzed either by
0.1 mol % of Pd/t-Bu3P, Pd/t-Bu2PCy, Pd/t-BuPCy2, or Pd/PCy3
(conversion after 240 min).
Concerning the choice of the “best” phosphine, the
pronounced bulk in 1-ethynyl-2,4,6-triisopropylbenzene leads
to a preference for an even smaller phosphine and Pd/PCy3
constitutes the most active catalyst. Qualitatively speaking, the
sum of the steric bulk of the respective acetylene and of the
phosphine appear to be constant: small acetylenes require large
phosphines (t-Bu3P or t-Bu2PCy), medium-sized acetylenes
(1-ethynyl-2,4,6-triethylbenzene) require smaller phosphines
(t-BuPCy2), and the largest acetylenes perform best with the
small phosphines (PCy3). The most prominent byproduct of
Sonogashira reactions reported here is the respective enyne
resulting from the dimerization of two acetylenes, while the
respective butadiyne resulting from an oxidative coupling of
two acetylenes is negligible. The amount of formed dimeriza-
tion product depends on the nature of the phosphine; with Pd/
Pt-Bu3 and Pd/t-Bu2PCy it is negligible, with Pd/t-Bu2PCy up
to 5% and with Pd/PCy3 up to 10% are formed.
should be considered as approximate values. The loading given in
Table 1 is based on reactions with simple alkyl groups and may
well be higher for other substrates with problematic
substituents. The choice of the best phosphine is primarily
guided by the nature of the respective acetylene and depends
only to a smaller extent on the bulk of the aryl bromide
substituents. In short: The higher the steric bulk of the
arylacetylene, the lower is the bulk of the phosphine ligands (in
the series P-t-Bu3 to PCy3) needed for the most efficient
Sonogashira transformation. Electron-rich and sterically
demanding aryl bromides require a considerably higher catalyst
loading than for example bromobenzene.
In order to utilize the knowledge obtained in the present study
for practical Sonogashira transformations, optimized procedures
for various substituted arylacetylenes and substituted aryl bromides
are also given in the Experimental Section.
Trimethylsilylacetylene. Me3SiCCH is a very important
substrate in Sonogashira reactions, which is often used as a
monofunctional surrogate for acetylene, since following the
cross coupling reaction the −SiMe3 group can be cleaved off
easily.1d,27 The pronounced steric bulk of this protective group
prompted us study, which of the phosphine/Pd complexes
tested here, is best suited for this substrate. This was done
according to the general protocol (scheme 2).28 Initially, the
observed product formation appeared to be modest, despite
excellent substrate reactivity. This is not due to incomplete con-
version of the reactants but is an artifact of the strongly basic
post-reaction treatment, which primarily has to ensure rapid
quenching of the catalyst. In the course of sample preparation
(see the Experimental Section) for chromatographic product
analysis, the −SiMe3 group is partially cleaved off and the
respective Ar-CCSiMe3 and Ar-CCH are both observed in
the gas chromatograms. This is why in contrast to the other
arylacetylene reactions the data evaluation is based on the
decrease in the aryl bromide concentration. Nonetheless,
the difference in the reactivity of the four Pd/phosphine
complexes tested is pronounced (Figure 11). Pd/t-BuPCy2 is
the most powerful catalyst for the Sonogashira coupling of
Me3SiCCH.29
Electronic Effect in Arylacetylenes. Electron-withdraw-
ing substituents at the aryl halides accelerate cross-coupling
reactions.11b The effect of such groups in the acetylenes on the
Sonogashira coupling is less well studied. Martensson et al.
suggested for copper-free Sonogashira reactions that different
mechanisms are followed, depending on the electronic nature
of the acetylene.30 We tested the Sonogashira coupling of four
substituted phenylacetylenes with electron-withdrawing and
-donating substituents (Scheme 3).
The respective time−conversion data are plotted in Figure 12.
The arylacetylene with the least electron-donating 4-R = CF3
is rapidly converted into the respective tolane, producing
the best chemical yields. With progressively stronger donating
4-R groups the reaction is more sluggish at the beginning and
the conversion of the respective phenylacetylene is less
efficient. The deprotonation of the acetylene may be a critical
step at the beginning of the cross-coupling reaction. However,
the use of other bases (Cs2CO3, LiN-i-Pr2, KO-t-Bu, Na-amylate)
did not lead to enhanced product formation. Interestingly, a
́
combined experimental/theoretical study by Alvares, Maseras,
Espinet et al. has shown that the coordination of acceptor olefins
to Pd enhances the reductive elimination, while at the same time
the oxidative addition is slowed down. Clearly a compromise
between the two effects should be reached, but for aryl bromide
cross coupling the oxidative addition tends to be less important,
so this might well be an explanation for the observed effects with
acetylenes.31
Guidelines for Sonogashira Coupling Reactions. On
the basis of the results of the extensive screening studies described
above, it is possible to recommend certain Pd/phosphine catalyst
complexes, which display the highest catalytic activity for certain
Sonogashira substrates (Table 1). The amount of catalyst given
2802
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
Table 1. Suitable Conditions for Pd-Catalyzed Sonogashira
Coupling of Arylacetylenes or Me3SiCCH with Aryl
Bromides (R′, R′′ ≠ H)
Scheme 4. Potential Sonogashira Routes to Tolanes
a
the two leads to better yields when R or R′ are sterically
demanding or undemanding or when R or R′ possess electron-
releasing or -donating character.
We first studied which of the two pairs of reactions (Scheme 5)
leading to the same product is influenced more strongly by
Scheme 5. Electronic Modifications of Substrates for
Sonogashira Coupling
a
Ratio of Na2PdCl4/PR3/CuI = 4:8:3; solvent/base: HNi-Pr2, T =
80 °C, PR3 used as PR3·HBF4.
electronic effects. Electron-withdrawing groups are known to
increase the reactivity of both substrates. Our experiments show
that this acceleration is more pronounced for electron-
withdrawing groups located at the arylacetylene. Reactions B
(Scheme 5) reaches 85% conversion already after 240 min and
reaction A only 18%; nonetheless, after 1200 min both
reactions stall at ca. 90% conversion. For reactions C 97%
yield is observed after 1440 min and with reaction D only 73%.
Next, the effect of steric bulk was tested in reactions
outlined in Scheme 6. Steric bulk next to the bromo
Scheme 3. Sonogashira Coupling Reactions with
Electronically Variable Acetylenes
Scheme 6. Synthesis of Tolanes with Bulky Substituents
substituents is more detrimental for the cross-coupling
reaction than steric bulk at the acetylene. The conversion
for reaction E is 90% after 20 h, while it is only 66% for
reaction F after the same time period, when using different,
but the “best”, phosphines for the respective trans-
formations. Again the choice of the phosphine determines
the reactivity differences and under the best possible
reaction condition (in the subset of reaction parameters
Figure 12. Sonogashira coupling of bromobenzene with arylacetylenes
with ewg and edg substituents catalyzed by 0.1 mol % of Pd/Pt-Bu3.
Alternative Tolane Synthesis: Steric and Electronic
Effects. In principle, the synthesis of unsymmetrical tolanes is
possible by employing two different approaches (Scheme 4).
From a synthetic point of view it is important to ask which of
2803
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
tested here) the effect of steric bulk on the reaction is less
pronounced in the arylacetylene.
synthesized by attaching bulky and/or electron-withdrawing
groups on the arylacetylene.
Effects on the Initiation Period. The use of increasingly
bulky acetylenes leads to significant initiation periods in the
Sonogashira reaction. The formation of catalytically active
Pd(0) complexes appears to rely primarily on the nature of the
acetylene.
Phosphines: Steric and Electronic Effects. Finally, the
effect of variable electron donation on the catalytic activity of
the respective palladium phosphine complexes was tested, using
two different phosphines t-Bu2P(C6H4-R)17a with R = 4-CF3, 4-
NMe2. As expected, the time−conversion curves (Figure 13)
Choosing the Best Phosphine Ligand. The detailed
investigation of substrate reactivity provides guidelines for
efficient Sonogashira coupling reactions (Table 1): (a)
reactions of arylacetylenes (no ortho-substituents other than
H) with aryl bromides (no ortho-substituents other than H)
are best done with a Pd/t-Bu3P catalyst; (b) reactions of
arylacetylenes (no ortho-substituents other than H) with aryl
bromides (bulky ortho-substituents) are best done with Pd/t-
Bu2PCy or with Pd/t-BuPCy2; (c) reactions of 2-substituted
arylacetylenes and aryl bromides are best done with Pd/t-
BuPCy2; (d) reactions of 2,6-disubstituted arylacetylenes and
aryl bromides are best done with Pd/t-BuPCy2; (e) reactions of
2,6-disubstituted arylacetylenes (very bulky ortho-substituents)
and aryl bromides are best done with Pd/PCy3; (f) reactions of
Me3SiCCH with aryl bromides are best done with Pd/t-
BuPCy2.
Figure 13. Electronic modification of the phosphine t-Bu2P(C6H4-R)
R = 4-CF3 or 4-NMe2 using 0.01 mol % of Pd/t-Bu2P(C6H4-R) in the
reaction of 4-tolyl bromide and mesitylacetylene.
EXPERIMENTAL SECTION
■
General Experimental Methods. All chemicals were purchased
as reagent grade and used without further purification unless otherwise
noted. All reactions were performed under an atmosphere of argon
using the standard Schlenk technique. Solvents for syntheses were
dried using a column purification system. HN-i-Pr2 was dried using
CaH2, distilled prior to use, and degassed three times using a “freeze
for two Sonogashira reactions provide clear evidence for the
higher reactivity of the more electron-rich phosphine.
CONCLUSIONS
■
Based on the screening of nearly 200 different Sonogashira
reactions with systematically varied aryl bromides, arylacety-
lenes and Me3SiCCH and phosphine ligands, a set of simple
rules aiding such cross coupling reactions and the choice of the
“ideal” substrate/catalyst combinations are reported. In general,
the steric bulk of the phenylacetylene is the most important
factor determining the choice of the “ideal” Pd/phosphine
catalyst.
1
and thaw” technique. H, 13C, and 31P NMR spectra were recorded at
300 MHz (1H), 75 MHz (13C), and 121 MHz (31P) or at 500 MHz
(1H), 126 MHz (13C), and 202 MHz (31P), respectively. Chemical
shifts are given in parts per million (ppm) on the delta scale (δ) and
are referred either to tetramethylsilane (1H-; 13C NMR = 0 ppm) or
the residual solvent peak. 31P NMR was referred to H3PO4 (65% aq. =
0 ppm). Thin layer chromatography (TLC) was performed using silica
gel 60 F 254 (0.2 mm) on alumina plates. For preparative
chromatography silica gel 60 (0.063−0.20 mesh) was used.
2-Bromotoluene, 1-bromo-2-ethylbenzene, 1-bromo-2-isopropyl-
benzene, and 2-bromo-m-xylene as well as 1-bromomesitylene were
available from commercial sources. 1-Bromo-2,4,6-triethylbenzene and
1-bromo-2,4,6-triisopropylbenzene were prepared according to liter-
ature procedures.32 The phosphines used were purchased and
converted into the respective phosphonium tetrafluoroborates with
HBF4·Et2O.
Gas Chromatography. A chromatograph with a split/splitless
injector system and FID was used. Chromatographic separation was
performed by using a 15 m × 0.25 mm Varian CP-Sil 8 CB column
(df = 1.0 μm) and nitrogen used as carrier gas at a flow rate of
0.35 mL·min−1. All injections were carried out in the split flow mode
with a split ratio of 20:1. The injector was maintained at a temperature
of 300 °C and the detector at 350 °C. Quantification was accomplished
by using dibenzofuran and mesitylene as internal standards, the
concentration of the standard was equal to each of the substrates in the
screening reactions. Details concerning chromatographic separation
(temperature programming, retention times) of the reactants as well as
the products are given below.
GC Temperature Programming for Compound Separation.
In the Me3SiCCH screen the following program was used: 100 °C for
1 min, heating to 262 °C at a rate of 15 °C min−1, hold 0 min and
finally heating to 310 °C at a rate of 35 °C min−1, hold isotherm for
0 min (total runtime is 13.17 min). In the phenylacetylene screen the
following program was used: 100 °C for 1 min, heating to 262 °C at a
rate of 15 °C min−1, hold 0 min and finally heating to 310 °C at a rate
of 35 °C min−1, hold isotherm for 3 min (total runtime is 16.17 min).
Electronic Effects of the Aryl Bromide Substituents.
Electron-withdrawing groups at the aryl bromides accelerate the
rate of the Sonogashira coupling. Such an electronic effect is
more important than moderate steric bulk at the aryl bromide.
Steric Effects of the Aryl Bromide Substituents. The
effect of steric bulk in 2-substituted aryl bromides on the rate of
Sonogashira reactions is modest. For 2,6-substituted aryl
bromides the steric effect is much more pronounced.
Electronic Effects of the Acetylene Substituents.
Electron-withdrawing groups on the acetylene lead to an
increase in the rate of the Sonogashira coupling. This rate
acceleration is more pronounced for arylacetylenes than for aryl
bromides with electron withdrawing substituents.
Steric Effects of the Acetylene Substituents. Moderate
steric bulk at the arylacetylene is beneficial and leads to a
significant increase in the rate of the Sonogashira reaction
compared to phenylacetylene. However, this is only true, when
the increase in the steric bulk of the acetylene is compensated
by using progressively smaller phosphine ligands. There exists
an ideal combination of steric bulk at the acetylene and the
phosphine. Consequently, the nature of the acetylene
determines the choice of the ideal phosphine for a Sonogashira
coupling reaction. Bulky acetylenes require small phosphines,
smaller acetylenes require larger phosphines. An unsymmetrical
tolane with sterically demanding groups on one aryl ring is best
2804
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
In the mesitylacetylene screen the final isotherm was extended to 6
min (total runtime is 19.17 min), in the 1-ethynyl-2,4,6-triethylben-
zene screen to 9 min (total runtime is 22.17 min) and in the 1-ethynyl-
2,4,6-triisopropylbenzene screen to 12 min (total runtime is 25.17
min). In the 1-ethynyl-2-ethylbenzene screen the following program
was used: 150 °C for 0 min, heating to 200 °C at a rate of 10 °C
min−1, hold 5 min, heating to 262 °C at a rate of 10 °C min−1, hold 5
min and finally heating to 310 °C at a rate of 35 °C min−1, hold
isotherm for 4 min (total runtime is 21.90 min).
Sonogashira Coupling Reactions. Catalyst Stock Solution.
Na2PdCl4 (17.7 mg; 60 μmol), CuI (8.6 mg; 45 μmol) and the
respective trialkylphosphonium tetrafluoroborate salt (120
μmol) were placed in an oven-dried Schlenk tube, evacuated,
and backfilled with argon three times. Subsequently, HN-i-Pr2
(15 mL) was added and the resulting mixture stirred at 40 °C
for 60 min. After the mixture was cooled to room temperature,
the formed salt was filtered off. The resulting solution had a
concentration of 4 μmol Pd/mL. Two hundred and fifty
microliters of this solution correspond to a catalyst loading
(Pd/phosphine/CuI = 4:8:3) of 0.1 mol % in the screening
reactions with a total aryl bromide loading of 1 mmol.
Aryl Bromide Stock Solution. Aryl bromides were weighed with the
appropriate amount of the internal GC-standard and subsequently
filled up with HN-i-Pr2 to reach the desired concentration. The
concentration for the aryl bromide stock solution was 1 mmol/mL for
the sum of all components and (n(components) M)−1 for
dibenzofuran as internal GC standard.
Sonogashira Screening Reactions. A mixture of the aryl bromide
stock solution (1000 μL, 1 mmol) and the respective catalyst stock
solution (250 μL, 1 μmol, 0.1 mol %) in HN-i-Pr2 (5000 μL) was
degassed using a “freeze and thaw” technique and then heated to
80 °C under vigorous stirring for 10 min. Initiation of the reaction is
done by the addition of 1.05 mmol (1.05 equivs) of the respective alkyne.
The precipitation of H2N-i-Pr2Br indicates the start of the reaction,
and GC samples were taken at given times.
Sonogashira Reactions of Substituted Acetylenes with Aryl
Bromides (General Procedure). Na2PdCl4 (7.1 mg, 0.025 mmol),
0.05 mmol of the respective phosphonium salt, and CuI (3.6 mg, 0.019
mmol) were weighed in an oven-dried two-necked Schlenk-flask
equipped with a reflux condenser. HN-i-Pr2 (50 mL) was transferred
to the flask via cannula. The respective ortho-alkylated aryl bromide
(10 mmol) was transferred to the flask with a syringe and the mixture
carefully degassed via “freeze and thaw” technique. After being warmed
to rt, the mixture was warmed and stirred at 80 °C for 10 min and 1.05
equiv of the respective acetylene added via syringe. The precipitation
of H2N-i-Pr2Br and a darkening of the reaction mixture indicated the
onset of the reaction, and stirring was continued for the appropriate
time (see Table 1). After the mixture was cooled to room temperature,
the precipitate was separated via suction filtration (glass frit G4) and
washed twice with HNi-Pr2. The volatiles are evaporated in vacuo. The
residue is purified by column chromatography using cyclohexane/ethyl
acetate mixtures as the eluent.
procedure as a white solid (yield: 93%, 651 mg): 1H NMR (CDCl3) δ
7.55 (d/d, J = 6.8/1.5 Hz, 1H), 7.29 − 7.18 (m, 3H), 6.94 (d, J = 0.6
Hz, 2H), 2.57 (s, 3H), 2.53 (s, 6H), 2.33 (s, 3H); 13C NMR (CDCl3)
δ 140.2, 139.8, 137.8, 131.9, 129.6, 128.1, 127.8, 125.7, 124.0, 120.5,
96.3, 91.5, 21.5, 21.3, 21.2; HRMS (EI) for C18H18 (M+) calcd
234.1408, found 234.13989; mp 38−39 °C.
1,3,5-Trimethyl-2-[(2-ethylphenyl)ethynyl]benzene. This com-
pound was isolated from the reaction of 1-bromo-2-ethylbenzene
with mesitylacetylene (0.5 mol % Pd/t-BuPCy2) according to the
1
general procedure as a colorless oil (yield 85%, 422 mg): H NMR
(CDCl3) δ 7.52−7.49 (d/t, J = 7.5/1.0 Hz, 1H), 7.27−7.13 (m, 3H),
6.89 (d, J = 0.6 Hz, 2H), 2.90 (q, J = 7.6 Hz, 2H), 2.48 (s, 6H), 2.28
(s, 3H), 1.29 (t, J = 7.6 Hz, 1H); 13C NMR (CDCl3) δ 145.8, 140.2,
137.8, 132.3, 128.3, 128.2, 127.8, 125.8, 123.3, 120.5, 96.0, 91.0, 28.1,
21.5, 21.2, 15.2; HRMS (EI) for C19H20 (M+) calcd 248.1565, found
248.15365.
1,3,5-Trimethyl-2-[(2-isopropylphenyl)ethynyl]benzene. This
compound was isolated from the reaction of 1-bromo-2-isopropyl-
benzene with mesitylacetylene (0.5 mol % Pd/t-BuPCy2) according to
the general procedure as a colorless oil (yield 94%, 491 mg): 1H NMR
(CDCl3) δ 7.58−7.54 (m, 1H), 7.36−7.29 (m, 2H), 7.23−7.17 (m,
1H), 6.94 (d, J = 0.6 Hz, 2H), 3.66 (sept, J = 6.9 Hz, 1H), 2.53 (s,
6H), 2.33 (s, 3H), 1.35 (d, J = 6.9 Hz, 6H); 13C NMR (CDCl3) δ
150.1, 140.2, 137.8, 132.5, 128.5, 127.8, 125.7, 125.0, 123.0, 120.5,
96.1, 91.3, 31.8, 23.3, 21.5, 21.2; HRMS (EI) for C20H22 (M+) calcd
262.1721, found 262.16913.
2-((2,6-Dimethylphenyl)ethynyl)-1,3,5-trimethylbenzene. This
compound was isolated from the reaction of 2-bromo-m-xylene with
mesitylacetylene (0.5 mol % Pd/t-BuPCy2) according to the general
procedure as a white solid (yield 81%, 402 mg): 1H NMR (CDCl3) δ
7.18−7.10 (m, 3H), 6.95 (d, J = 0.6 Hz, 2H), 2.58 (s, 6H), 2.55(s,
6H), 2.34 (s, 3H); 13C NMR (CDCl3) δ 140.1, 137.8, 127.8, 127.6,
126.9, 124.0, 120.8, 96.2, 95.2, 21.8, 21.6, 21.5; HRMS (EI) for C19H20
(M+) calcd 248.1565, found 248.15380; mp 89−90 °C.
1,3,5-Triethyl-2-[(2,4,6-trimethylphenyl)ethynyl]benzene. This
compound was isolated from the reaction of 1-bromo-2,4,6-triethylbenzene
with mesitylacetylene (0.5 mol % Pd/t-BuPCy2) according to the
1
general procedure as a white solid (yield 82%, 749 mg): H NMR
(CDCl3) δ 6.99 (s, 2H), 6.95 (d, J = 0.6 Hz, 2H), 2.96 (q, J = 7.6
Hz, 4H), 2.67 (q, J = 7.6 Hz, 2H), 2.54 (s, 6H), 2.34 (s, 3H), 1.34
(t, J = 7.6 Hz, 6H), 1.29 (t, J = 7.6 Hz, 3H); 13C NMR (CDCl3) δ
146.4, 144.4, 140.1, 137.6, 127.8, 125.2, 121.1, 119.7, 94.7, 94.27,
29.1, 28.5, 21.4, 15.6, 15.4; HRMS (EI) for C23H28 (M+) calcd 304.2191,
found 304.21780; mp 76−77 °C.
1,3,5-Triisopropyl-2-[(2,4,6-trimethylphenyl)ethynyl]benzene.
This compound was isolated from the reaction of 1-bromo-2,4,6-
triisopropylbenzene with mesitylacetylene (0.5 mol % Pd/t-BuPCy2)
according to the general procedure as a white solid (yield: 75%, 778
mg). The isolated yield is significantly lower than in the multisubstrate
screen, since the enyne byproduct is difficult to separate by
1
chromatography: H NMR (CDCl3) δ 7.06 (s, 2H), 6.94 (d, J = 0.5
Hz, 2H), 3.74 (sept, J = 6.9 Hz, 2H), 2.95 (sept, J = 6.9 Hz, 1H), 2.53
(s, 6H), 2.33 (s, 3H), 1.34 (d, J = 6.9 Hz, 12H), 1.30 (d, J = 6.9 Hz,
6H); 13C NMR (CDCl3) δ 150.5, 149.1, 140.1, 137.6, 127.9, 121.1,
120.4, 119.4, 94.8, 94.5, 34.7, 32.0, 24.1, 23.6, 21.4; HRMS (EI) for
C26H34 (M+) calcd 346.266, found 346.26818; mp 84−85 °C.
2-[(2-Ethylphenyl)ethynyl]-1,3-dimethylbenzene. This compound
was isolated from the reaction of 2-bromo-m-xylene with 1-ethyl-2-
ethynylbenzene (0.25 mol % Pd/t-BuPCy2) according to the general
procedure as a slight yellow oil (yield: 90%, 420 mg): 1H NMR
(CDCl3) δ 7.56−7.53 (m, 1H), 7.28−7.06 (m, 6H), 2.93 (q, J = 7.6
Hz, 2H), 2.54 (s, 6H), 1.31 (d, J = 7.6 Hz, 3H), 1.26 (d, J = 6.9 Hz,
6H); 13C NMR (CDCl3) δ 145.9, 140.3, 132.4, 128.5, 128.2, 127.8,
126.9, 125.8, 123.5, 123.1, 96.8, 90.7, 28.1, 21.4, 15.3; HRMS (EI) for
C18H18 (M+) calcd 234.1408, found 234.14032.
Following this general procedure, the respective coupling products
were obtained in yields of 70−98% yield (Supporting Information).
Table 1 shows the recommended acetylene/phosphine combinations
and catalyst loadings for certain substrate combinations, which were
applied for the products reported here.
Data for previously unknown Sonogashira products are listed below:
1,3,5-Triethyl-2-(phenylethynyl)benzene. This compound was
isolated from the reaction of 1-bromo-2,4,6-triethylbenzene with
phenylacetylene (0.25 mol % Pd/t-BuPCy2) according to the general
procedure as a colorless oil (yield 69%, 362 mg): 1H NMR (CDCl3) δ
7.57−7.54 (m, 2H), 7.40−7.31 (m, 3H), 6.96 (s, 2H), 2.91 (q, J = 7.6
Hz, 4H), 2.66 (q, J = 7.6 Hz, 2H), 1.34 (t, J = 7.6 Hz, 6H), 1.28 (t, J =
7.6 Hz, 3H); 13C NMR (CDCl3) δ 146.7, 144.7, 131.4, 128.5, 128.0,
125.2, 124.3, 118.9, 96.3, 87.1, 29.1, 28.3, 15.6, 15.1; HRMS (EI) for
C20H22 (M+) calcd 262.1721, found 262.17034.
2-((2,6-Dimethylphenyl)ethynyl)-1,3,5-triisopropylbenzene. This
compound was isolated from the reaction of 2-bromo-m-xylene with
1-ethynyl-2,4,6-triisopropylbenzene (0.5 mol % Pd/PCy3) according
to the general procedure as a slight yellow oil (yield: 70%, 491 mg).
The isolated yield is significantly lower than in the multisubstrate
1,3,5-Trimethyl-2-[(2-methylphenyl)ethynyl]benzene. This com-
pound was isolated from the reaction of 2-bromotoluene with
mesitylacetylene (0.5 mol % Pd/t-BuPCy2) according to the general
2805
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
screen, since the enyne byproduct is difficult to separate by
chromatography: H NMR (CDCl3) δ 7.18−7.09 (m, 3H), 7.07 (s,
2H), 3.75 (sept, J = 6.8 Hz, 2H), 2.95 (sept, J = 6.9 Hz, 1H), 2.57 (s,
6H), 1.35 (d, J = 6.8 Hz, 12H), 1.31 (d, J = 6.9 Hz, 6H); 13C NMR
(CDCl3) δ 150.6, 149.3, 140.2, 127.6, 127.0, 124.1, 120.4, 119.2, 95.3,
94.6, 34.7, 32.0, 24.1, 23.7, 21.5; HRMS (EI) for C25H32 (M+) calcd
332.2504, found 332.25207.
Trimethyl[(2,4,6-triisopropylphenyl)ethynyl]silane. This com-
pound was isolated from the reaction of 1-Bromo-2,4,6-triisopropyl-
benzene with trimethylsilylacetylene (0.5 mol % Pd/t-BuPCy2)
according to the general procedure as pale yellow crystals (yield:
72%, 4.47 g): 1H NMR (CDCl3) δ 6.97 (s, 2H), 3.52 (sept, J = 6.8 Hz,
2H), 2.89 (sept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.8 Hz, 12H), 1.26 (d, J =
6.9 Hz, 6H); 13C NMR (CDCl3) δ 151.2, 149.4, 120.3, 118.7, 102.9,
101.9, 34.7, 31.9, 24.1, 23.3, 0.2; HRMS (EI) for C20H32Si (M+) calcd
300.2273, found 300.22474; mp 58−59 °C.
Synthesis of Known Arylacetylenes Synthesized Accord-
ing to the General Procedure. 1-Methyl-2-(phenylethynyl)-
benzene.7d This compound was isolated from the reaction of
2-bromotoluene with phenylacetylene (0.25 mol % Pd/t-
Bu2PCy) according to the general procedure as yellow oil,
which solidified on standing (yield 97%). 1-Ethyl-2-
(phenylethynyl)benzene.33 This compound was isolated
from the reaction of 1-bromo-2-ethylbenzene with phenyl-
acetylene (0.25 mol % Pd/t-Bu2PCy) according to the general
procedure as colorless oil (yield 87%). 1-Isopropyl-2-
(phenylethynyl)benzene.34 This compound was isolated
from the reaction of 1-bromo-2-isopropylbenzene with phenyl-
acetylene (0.25 mol % Pd/t-Bu2PCy) according to the general
procedure as colorless oil (yield 91%).7d This compound was
isolated from the reaction of 2-bromo-m-xylene with phenyl-
acetylene (0.25 mol % Pd/t-BuPCy2) according to the general
procedure as colorless oil (yield 86%). 1,3,5-Trimethyl-2-
(phenylethynyl)benzene.35 This compound was isolated from
the reaction of 2-bromomesitylene with phenylacetylene (0.25
mol % Pd/t-BuPCy2) according to the general procedure as a
white solid (yield 74%). 1,3,5-Triisopropyl-2-(phenylethynyl)-
benzene.36 This compound was isolated from the reaction
of 1-bromo-2,4,6-triisopropylbenzene with phenylacetylene
(0.25 mol % Pd/t-BuPCy2) according to the general proce-
dure as a colorless oil (yield 69%). The isolated yield is
lower than GC conversion, since the enyne byproduct is
difficult to separate by chromatography. 1,1′-Ethyne-1,2-
diylbis(2,4,6-trimethylbenzene).37 This compound was isolated
from the reaction of 2-bromomesitylene with mesitylacetylene
(0.5 mol % Pd/t-BuPCy2) according to the general procedure
as a white solid (yield 83%). Trimethyl(o-tolylethynyl)silane.38
This compound was isolated from the reaction of 2-bromo-
toluene with trimethylsilylacetylene (0.5 mol % Pd/t-
BuPCy2) according to the general procedure as yellow oil
(yield 91%). (2-Ethylphenyl)ethynyltrimethylsilane.39 This
compound was isolated from the reaction of 1-bromo-2-
ethylbenzene with trimethylsilylacetylene (0.5 mol % Pd/t-
BuPCy2) according to the general procedure as yellow oil
(yield 88%).
ACKNOWLEDGMENTS
■
1
This work was supported by the DFG through Grant No. Pl
178/12-1. We are grateful to Dipl.-Ing. Christiane Wolff for
help with the electronic screening experiments.
REFERENCES
■
(1) (a) Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874−922.
(b) Doucet, H.; Hierso, J.-C. Angew. Chem., Int. Ed. 2007, 46, 834−
871. (c) Plenio, H. Angew. Chem., Int. Ed. 2008, 47, 6954−6956.
(d) Chinchilla, R.; Najera, C. Chem. Soc. Rev. 2011, 40, 5084−5121.
(e) Jenny, N. M.; Mayor, M.; Eaton, T. R. Eur. J. Org. Chem. 2011,
2011, 4965−4983.
(2) (a) Lauterbach, T.; Livendahl, M.; Rosellon
Echavarren, A. M. Org. Lett. 2010, 12, 3006−3009. (b) Gonda, Z.;
Tolnai, G. L.; Novak
́
, A.; Espinet, P.;
́
, Z. Chem.Eur. J. 2010, 16, 11822−11826.
(c) Leadbeater, N. E. Nature Chem. 2010, 2, 1007−1009.
(3) Dudnik, A. S.; Gevorgyan, V. Angew. Chem., Int. Ed. 2010, 49,
2096−2098.
(4) (a) Matsuyama, N.; Kitahara, M.; Hirano, K.; Satoh, T.; Miura,
M. Org. Lett. 2010, 12, 2358−2361. (b) Kim, S. H.; Chang, S. Org.
Lett. 2010, 12, 1868−1871. (c) Brand, J. P.; Charpentier, J.; Waser, J.
Angew. Chem., Int. Ed. 2009, 48, 9346−9349.
(5) Nie, X.; Liu, S.; Zong, Y.; Sun, P.; Bao, J. J. Organomet. Chem.
2011, 696, 1570−1573.
(6) (a) Tougerti, A.; Negri, S.; Jutand, A. Chem.Eur. J. 2007, 13,
666−676. (b) Amatore, C.; Bensalem, S.; Ghalem, S.; Jutand, A.;
Medjour, Y. Eur. J. Org. Chem. 2004, 366−371. (c) Vikse, K. L.;
Henderson, M. A.; Oliver, A. G.; McIndoe, J. S. Chem. Commun. 2010,
46, 7412−7414.
(7) (a) Brenstrum, T.; Gerristma, D. A.; Adjabeng, G. M.; Frampton,
C. S.; Britten, J.; Robertson, A. J.; McNulty, J.; Capretta, A. J. Org.
Chem. 2004, 69, 7635−7639. (b) Lipshutz, B. H.; Chung, D. W.; Rich,
B. Org. Lett. 2008, 10, 3793−3796. (c) Hundertmark, T.; Littke, A. F.;
Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729−1731.
(d) Kollhofer, A.; Plenio, H. Adv. Synth. Catal. 2005, 347, 1295−
̈
1300. (e) Hierso, J.-C.; Beauperin, M.; Meunier, P. Eur. J. Inorg. Chem.
2007, 24, 3767−3780. (f) Hierso, J.-C.; Fihri, A.; Amardeil, R.;
Meunier, P.; Doucet, H.; Santelli, M.; Ivanov, V. V. Org. Lett. 2004, 6,
3473−3476. (g) Torborg, C.; Zapf, A.; Beller, M. Chem. Sus. Chem.
2008, 1, 91−96. (h) Lee, D.-H.; Qiu, H.; Cho, M.-H.; Lee, I.-M.; Jin,
M.-J. Synlett 2008, 1657−1660. (i) Bolliger, J. L.; Frech, C. M. Adv.
Synth. Catal. 2009, 351, 891−902. (j) Roy, S.; Plenio, H. Adv. Synth.
Catal. 2010, 352, 1014−1022. (k) Fleckenstein, C. A.; Plenio, H.
Organometallics 2007, 26, 2758−2767. (l) Fleckenstein, C. A.; Plenio,
H. Organometallics 2008, 27, 3924−3932. (m) Feuerstein, M.; Doucet,
H.; Santelli, M. J. Mol. Catal. A: Chem. 2006, 256, 75−84.
(n) Nishihara, Y.; Inoue, E.; Okada, Y.; Takagi, K. Synlett 2008, 19,
3041−3045. (o) Moon, J.; Jeong, M.; Nam, H.; Ju, J.; Moon, J. H.;
Jung, H. M.; Lee, S. Org. Lett. 2008, 10, 945−948. (p) Fleckenstein,
C. A.; Plenio, H. Green Chem. 2008, 10, 563−570. (q) Severin, R.;
Reimer, J.; Doye, S. J. Org. Chem. 2010, 75, 3518−3521. (r) Hillerich,
J.; Plenio, H. Chem. Commun. 2003, 3024−3025.
(8) (a) Kollhofer, A.; Pullmann, T.; Plenio, H. Angew. Chem., Int. Ed.
̈
ASSOCIATED CONTENT
* Supporting Information
■
2003, 42, 1056−1058. (b) Fleckenstein, C. A.; Plenio, H. Chem.Eur.
S
J. 2007, 13, 2701−2716. (c) Torborg, C.; Huang, J.; Schulz, T.;
Documentation of synthetic work, gas chromatographic
measurements, and selected chromatograms; copies of NMR
spectra and high-resolution mass spectrometry. This material is
available free of charge via the Internet at http://pubs.acs.org.
Schaffner, B.; Zapf, A.; Spannenberg, A.; Borner, A.; Beller, M.
̈
̈
Chem.Eur. J. 2009, 15, 1329−13363. (d) Komar
́ ́
omi, A.; Novak, Z.
Chem. Commun. 2008, 4968−4970. (e) Gelman, D.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2003, 42, 5993−5996. (f) Jin, M.-J.; Lee, D.-H.
Angew. Chem., Int. Ed. 2010, 49, 1119−1122. (g) Lee, D.-H.; Kwon,
Y.-J.; Jin, M.-J. Adv. Synth. Catal. 2011, 353, 3090−3094.
AUTHOR INFORMATION
Corresponding Author
*E-mail: plenio@tu-darmstadt.de.
■
(9) (a) Christmann, U.; Vilar, R. Angew. Chem., Int. Ed. 2005, 44,
366−374. (b) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am.
Chem. Soc. 2009, 131, 8141−8154. (c) Li, Z.; Fu, Y.; Guo, Q.-X.; Liu,
L. Organometallics 2008, 27, 4043−4049.
Notes
The authors declare no competing financial interest.
(10) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936−1947.
2806
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807

The Journal of Organic Chemistry
Article
(11) (a) Clarke, M. L.; Frew, J. J. R. Organomet. Chem. 2009, 35, 19−
46. (b) Fleckenstein, C. A.; Plenio, H. Chem. Soc. Rev. 2010, 39, 694−
711.
(35) Adjabeng, G.; Brenstrum, T.; Frampton, C. S.; Robertson, A. J.;
Hillhouse, J.; McNulty, J.; Capretta, A. J. Org. Chem. 2004, 69, 5082−
5086.
(36) Feuerstein, M.; Berthiol, F.; Doucet, H.; Santelli, M. Synthesis
2004, 8, 1281−1289.
(12) Fey, N.; Orpen, A. G.; Harvey, J. N. Coord. Chem. Rev. 2009,
253, 704−722.
(37) Park, K.; Bae, G.; Moon, J.; Choe, J.; Song, K. H.; Lee, S. J. Org.
Chem. 2010, 75, 6244−6251.
(13) Harper, K. C.; Sigman, M. S. Science 2011, 333, 1875−1878.
(14) Shaughnessy, K. H.; Kim, P.; Hartwig, J. F. J. Am. Chem. Soc.
1999, 121, 2123−2132.
(38) Panda, J.; Virkler, P. R.; Detty, M. R. J. Org. Chem. 2003, 68,
1804−1809.
(15) an der Heiden, M. R.; Plenio, H.; Immel, S.; Burello, E.;
Rothenberg, G.; Hoefsloot, H. C. J. Chem.Eur. J. 2008, 14, 2857−
2866.
(39) Koumbis, A.; Kyzas, C.; Savva, A.; Varvoglis, A. Molecules 2005,
10, 1340−1350.
(16) (a) O’Brien, C. J.; Kantchev, E. A. B.; Chass, G. A.; Hadei, N.;
Hopkinson, A. C.; Organ, M. G.; Setiadi, D. H.; Tang, T.-H.; Fang,
D.-C. Tetrahedron 2005, 61, 9723−9735. (b) Hadei, N.; Kantchev, E.
A. B.; O’Brien, C. J.; Organ, M. G. Org. Lett. 2005, 7, 1991−1994.
(c) Nasielski, J.; Hadei, N.; Achonduh, G.; Kantchev, E. A. B.; O’Brien,
C. J.; Lough, A.; Organ, M. G. Chem.Eur. J. 2010, 16, 10844−10853.
(d) Organ, M. G.; Abdel-Hadi, M.; Avola, S.; Dubovyk, I.; Hadei, N.;
Kantchev, E. A. B.; O’Brien, C. J.; Sayah, M.; Valente, C. Chem.Eur.
J. 2008, 14, 2443−2452.
(17) (a) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel,
L. B.; Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M.
J.; Reider, P. J. Org. Lett. 2006, 8, 1787−1789. (b) Guram, A. S.; Wang,
X.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J. J. Org.
Chem. 2007, 72, 5104−5112.
(18) Fleckenstein, C. A.; Plenio, H. Chem.Eur. J. 2008, 14, 4267−
4279.
(19) Ljungdahl, T.; Pettersson, K.; Albinsson, B.; Martensson, J.
J. Org. Chem. 2006, 71, 1677−1687.
(20) an der Heiden, M.; Plenio, H. Chem. Commun. 2007, 972−974.
(21) There is an important difference with respect to the previous
study: Earlier we focussed on low catalyst loading, this time we took a
more practical approach and optimized for faster substrate conversion.
(22) Satyanarayana, T.; Kagan, H. B. Adv. Synth. Catal. 2005, 347,
737−748.
(23) The 0.1 mol % [Pd] of catalyst used is relative to the acetylene
and to the sum of the seven aryl bromides.
(24) For 1-ethynyl-2,4,6-trimethylbenzene and 1-ethynyl-2,4,6-
triethylbenzene a short inhibition period was not taken into account
for the exponential fit. The time was set to zero after the initiation
period at the onset of the Sonogashira conversion.
(25) Hansch, C.; Leo, A. In Exploring QSAR: Fundamentals and
Applications in Chemistry and Biology; Heller, S. R., Ed.; American
Chemical Society: Washington, DC, 1995; pp 69−96.
(26) Li, H.; Grasa, G. A.; Colacot, T. J. Org. Lett. 2010, 12, 3332−
3335.
(27) Greene’s Protective Groups in Organic Synthesis, 4th ed.; Wuts,
P. G. M., Green, T. W., Eds.; Wiley-VCH: Weinheim, 2006.
(28) The reaction temperature was lowered to 50 °C because of the
low bp of trimethylsilylacetylene; otherwise, a significant loss of this
substrate during the probe sampling might have taken place.
(29) The prounced steric bulk of Me3SiCCH also results in a
significant inhibition period (ca. 30 min) during which no substrate
conversion is observed.
(30) Ljungdahl, T.; Bennur, T.; Dallas, A.; Emtenas, H.; Martensson,
̈
J. Organometallics 2008, 27, 2490−2498.
(31) Per
́
ez-Rodríguez, M.; Braga, A. A. C.; Garcia-Melchor, M.;
ez-Temprano, M. H.; Casares, J. A.; Ujaque, G.; de Lera, A. R.;
Alvarez, R.; Maseras, F.; Espinet, P. J. Am. Chem. Soc. 2009, 131,
3650−3657.
Per
́
́
(32) (a) Fuson, R. C.; Corse, J. J. Am. Chem. Soc. 1938, 60, 2063−
2066. (b) Whitesides, G. M.; Eisenhut, M.; Bunting, W. M. J. Am.
Chem. Soc. 1974, 96, 5398−5407.
(33) Maji, M. S.; Murarka, S.; Studer, A. Org. Lett. 2010, 12, 3878−
3881.
(34) Komar
49, 7294−7298.
́ ́
omi, A.; Tolnai, G. L.; Novak, Z. Tetrahedron Lett. 2008,
2807
dx.doi.org/10.1021/jo202644g | J. Org. Chem. 2012, 77, 2798−2807