Sulfonated N-heterocyclic carbenes for Pd-catalyzed sonogashira and suzuki-miyaura coupling in aqueous solvents

Article abstract of DOI:10.1002/adsc.200900886

The reactions of the N, N-diarylimidazolium and N, N-diarylimidazolinium salts with chlorosulfonic acid result in the formation of the respective disulfonated N-heterocyclic carbene (NHC) precursors in reasonable yields (46-77%). Water-soluble palladium catalyst complexes, in situ obtained from the respective sulfonated imidazolinium salt, sodium tetrachloropalladate (Na ₂PdCl₄) and potassium hydroxide (KOH) in water, were successfully applied in the copper-free Sonogashira coupling reaction in isopropyl alcohol/water mixtures using 0.2 mol% catalyst loading. The preformed (disulfonatedNHC)PdCl(cinnamyl) complex was used in aqueous Suzuki-Miyaura reactions at 0.1 mol% catalyst loading. The coupling protocol reported here is very useful for Sonogashira reactions of N- and 5-heterocyclic aryl bromides and chlorides with aryl- and alkylacetylenes.

Full text of DOI:10.1002/adsc.200900886

FULL PAPERS
DOI: 10.1002/adsc.200900886
Sulfonated N-Heterocyclic Carbenes for Pd-Catalyzed Sonoga-
shira and Suzuki–Miyaura Coupling in Aqueous Solvents
a
a,
Sutapa Roy and Herbert Plenio *
a
Organometallic Chemistry, Petersenstr. 18, 64287 Darmstadt, Germany
Fax : (+49)-6151-166-040; e-mail: plenio@tu-darmstadt.de
Received: December 21, 2009; Revised: March 5, 2010; Published online: April 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900886.
Abstract: The reactions of the N,N’-diarylimidazoli- 0.2 mol%
um and N,N’-diarylimidazolinium salts with chloro- (disulfonatedNHC)PdClAHCNUTGTRENNUNG
catalyst
loading.
(cinnamyl) complex was
The
preformed
sulfonic acid result in the formation of the respective used in aqueous Suzuki–Miyaura reactions at
disulfonated N-heterocyclic carbene (NHC) precur- 0.1 mol% catalyst loading. The coupling protocol re-
sors in reasonable yields (46–77%). Water-soluble ported here is very useful for Sonogashira reactions
palladium catalyst complexes, in situ obtained of N- and S-heterocyclic aryl bromides and chlorides
from the respective sulfonated imidazolinium salt, with aryl- and alkylacetylenes.
sodium tetrachloropalladate (Na PdCl ) and potassi-
2
4
um hydroxide (KOH) in water, were successfully ap- Keywords: cross-coupling; palladium; Sonogashira
plied in the copper-free Sonogashira coupling reac- reaction; sulfonation; Suzuki–Miyaura reaction;
tion in isopropyl alcohol/water mixtures using water
Introduction
We have therefore initiated a program aimed at es-
tablishing efficient cross-coupling reactions in water
The Sonogashira coupling is the most powerful ap- or in aqueous organic solvent mixtures, with benign
2
proach for sp-sp carbon-carbon bond formation be- co-solvents, such as short chain alcohols, to enhance
tween a terminal acetylene and an aryl-X species the solubility of organic reactants. For various
+
2
[1]
[15]
[16]
(
X=Cl, Br, I, N , SO Cl, OSO CF , OSO CH ).
Suzuki and Sonogashira cross-coupling reactions,
2
2
3
2
3
Compounds bearing carbon-carbon triple bonds are especially for N-, O- and S-heterocyclic substrates the
[
2]
ubiquitous in pharmaceuticals and fine chemicals;
use of water as the reaction solvent offers significant
[
3]
5]
[4]
examples are tazarotene, terbinafin or the oncolo- advantages. This is all the more important since het-
gy candidate CP-724,714. Numerous protocols utiliz- erocycles constitute an essential class of compounds,
ing various metal complexes are useful for this trans- ubiquitous in biologically and pharmaceutically active
formation. The most popular one remains the clas- compounds. The reason for the decreased activity
sic protocol using a palladium/copper catalyst. None- of cross-coupling catalysts for such substrates is not
theless for large-scale reactions the use of copper salts known with certainty, but it is likely that the coordi-
is considered to be less favorable due to the potential nation of heteroatoms to the palladium leads to the
formation of insoluble copper acetylides. Conse- displacement of a phosphine ligand from the metal
quently, more recently a significant number of center. In order to avoid this, Hartwig utilized with
Another great success bidentate phosphines such as Josiphos
aspect to be considered in such reactions is the use of to obtain stable palladium chelates. However, while
organic solvents like DMF/DMAc, DMSO, tolu- chelating phosphines appear to be a very good choice
ene, dioxane or amine-bases. According to var- for Buchwald–Hartwig amination and Suzuki reac-
ious classifications, which take economic and ecologi- tions, they tend to be less ideal for Sonogashira reac-
cal criteria into account, these solvents are not tions. Water seems to be able to relieve the inhibi-
ideal. A less well studied, but highly attractive sol- tion of the catalyst. It is likely that this highly polar
[
[1c]
[17]
[
6]
[
18]
[
7]
copper-free protocols were developed.
[19]
[
8]
[9]
[10]
[11]
[12]
[
20]
[13]
[
14]
vent for such transformations is water.
solvent preferentially associates with the heterocyclic
1014
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Adv. Synth. Catal. 2010, 352, 1014 – 1022

Sulfonated N-Heterocyclic Carbenes for Pd-Catalyzed Sonogashira and Suzuki–Miyaura Coupling
[
21]
substrates (via hydrogen bonding) rather than coor- neutralization with NaOH and heating to 508C under
[
22]
dinating to the catalytically active Pd center.
vacuum, the desired sulfonated imidazolinium and
Obviously, the use of water as the reaction solvent imidazolium salts were obtained in reasonable yields
requires water-soluble ligands and catalyst com- (46–77%). This approach is more useful than the in-
[23]
plexes. We recently reported a reaction protocol for troduction of the sulfonato group at the beginning of
the aqueous copper-free Sonogashira coupling using a the reaction sequence, which requires some care in
sulfonated and water-soluble fluorenylphosphine (cat- the purification of the sulfonated intermediates. Fur-
[
22]
aCXium F sulf),
which was primarily geared to- thermore, the new approach is only a one-step synthe-
wards the efficient reaction of various heterocyclic sis from commercially available azolium salts.
[24]
halides. We want to demonstrate here that the ap-
However, the direct sulfonation appears less con-
plication of palladium complexes with sulfonated and venient for the synthesis of the respective sulfonated
[
25]
water-soluble N-heterocyclic carbenes leads to sig- tetraisopropyl-substituted
imidazolium
salts
nificant improvements for Sonogashira reactions.
(Scheme 2), since the steric bulk of the isopropyl
groups partially overrides the meta-directing effect of
the positively charged nitrogen atoms. The sulfona-
tion leads to a mixture of meta- and para-sulfonated
products in a 3:1 ratio, which could not be separat-
ed. The use of the 2,4,6-triisopropylphenyl-substituted
imidazolium salt (blocking of the para-position) in the
Results and Discussion
[
28]
Synthesis of Sulfonated N-Heterocyclic Carbenes
We previously reported the synthesis of disulfonated attempted sulfonation of the 2,4,6-trisisopropylphen-
N,N’-diarylimidazolium and imidazolinium salts in- yl-substituted imidazolium salt failed, probably due to
voking the normal route starting from 2,4,6-trimethyl- the difficult accessibility of the aromatic ring between
3
-sulfonato-aniline via the respective diimine or di- two isopropyl groups.
[
26]
Aa mine followed by ring closing reaction. However,
C
H
T
U
N
G
T
R
E
N
N
U
N
G
Therefore the 2,6-dimethyl-substituted sulfonated
N,N’-diarylimidazoli(ni)um salts are stable enough to NHC ligands are more easily accessible via direct sul-
allow the high-yielding, direct nitration of the N-aryl fonation, while the 2,6-diisopropyl-substituted NHC
units with HNO /H SO leading to the respective tet- ligands are better prepared utilizing the route via 4-
3
2
4
[
27]
ranitrated salts. Consequently, the synthesis of vari- sulfonated 2,6-diisopropylaniline reported previous-
[
25]
ous sulfonated and water-soluble imidazolium and ly. The reaction of the sulfonated NHC precursor 3
imidazolinium salts and the respective NHC ligands with [PdCl(cinnamyl)] in THF in the presence of
was tried via direct sulfonation (Scheme 1). The reac- base, results in the formation of the respective
tion of 1,3-bis(2,4,6-trimethylphenyl)imidazolinium (NHC)PdCl(cinnamyl) complex 4 similar to the relat-
AHCTUNGTRENNUNG
2
AHCTUNGTRENNUNG
[
29]
chloride in neat chlorosulfonic acid at 1008C initially ed literature procedure.
resulted in the formation of 1,3-bis(2,4,6-trimethyl-3-
chlorosulfonylphenyl)imidazolinium chloride, which
was carefully hydrolyzed on ice at À208C, followed
by filtration and washing with ice-cold water. After
Scheme 1. Synthesis of m-sulfonated imidazolinium and imidazolium salts.
Adv. Synth. Catal. 2010, 352, 1014 – 1022
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Sutapa Roy and Herbert Plenio
FULL PAPERS
Scheme 2. Synthesis of sulfonated imidazolinium salts.
Sonogashira Coupling
to be sufficient to obtain good cross-coupling yields in
excess of 80%. The use of isopropyl alcohol as a co-
Several reaction protocols for aqueous Sonogashira solvent leads to a slight improvement in reactivity
reactions of aryl bromides are known, but most of with respect to the performance in water as the only
these reactions require at least 1 mol% of palladium solvent. This effect is more pronounced for poorly
precursor and/or elevated temperatures above
[15b,30]
1008C.
We previously reported an aqueous cou-
pling protocol for the reaction of various aryl- and al-
kylacetylenes with aryl bromides, which requires
Table 1. Sonogashira coupling reaction of electron-rich aryl
bromides with phenylacetylene.
1
mol% of [Pd] coordinated by a sulfonated fluorenyl-
[24]
phosphine. In the present study, the activity of in-
situ generated palladium complexes in aqueous sol-
vents was improved further. For this purpose bulky
sulfonated, diisopropyl-substituted N-heterocyclic car-
bene in-situ generated from 3 in the presence of
Na PdCl in water/isopropyl alcohol 1:1 environment
2
4
was used. Isopropyl alcohol is not essential for the re-
actions reported here; it mainly serves as a solubilizer
for the organic substrates. In organic solvents the
nature of the base normally is a very important pa-
rameter determining cross-coupling efficiency. How-
ever, use of different bases (Na CO , K CO , Cs CO ,
NaOH, KOH) in the aqueous reaction mixtures used
here, does not have a significant influence on the cat-
alytic activity. This is not surprising as the addition of
these salts primarily leads to an increase in the pH of
the reaction mixture. The amount of base relative to
the reactants turned out to be more important and
the use of three equivalents of base per aryl halides
gives the best results. Initially a few standard transfor-
mations of phenylacetylene with various less reactive
aryl bromides were tested (electron-rich, entries 1, 2
and sterically demanding, entries 3, 4 in Table 1). A
relatively low catalyst loading of 0.5 mol% turned out
Entry Aryl halide
Product
Con-
version
[a]
[%]
2
3
2
3
2
3
1
2
83
82
3
4
83
86
[a]
Average of two runs, conversion determined via GC
using internal heptadecane standard.
1016
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Adv. Synth. Catal. 2010, 352, 1014 – 1022

Sulfonated N-Heterocyclic Carbenes for Pd-Catalyzed Sonogashira and Suzuki–Miyaura Coupling
Table 2. Sonogashira coupling of heteroaryl halides with arylacetylenes.
[a]
Entry
Aryl halide
Alkyne
Product
Conversion [%]
1
2
ꢀ99
ꢀ99
3
4
ꢀ99
ꢀ99
5
6
ꢀ99
ꢀ99
7
8
9
96
94
91
1
0
1
ꢀ99
76
1
12
ꢀ99
[
a]
Average of two runs, conversion determined via GC using internal heptadecane standard.
water-soluble substrates and is probably due to the in- combination of 2-bromopyridine and an electron-rich
creased solubility of the coupling partners in the acetylene (Table 2, entry 7) provide virtually quantita-
aqueous/organic mixture. However, since more effi- tive conversion at a catalyst loading of 0.25 mol%
cient Sonogashira protocols are available for the reac- [Pd] for the reactions studied. It is obvious that the
[
12a]
tion of normal aryl bromides,
it was decided to not inhibiting effect of the heteroatom is less important in
study such reactions in more detail. Instead the pres- the aqueous reaction mixture. Instead the activating
ent set of reaction conditions was applied to heterocy- effect in the electron-deficient heterocycles is domi-
clic substrates, whose reactivity is known to improve nating. This is why it is also possible to successfully
[
15d]
significantly under aqueous reaction conditions.
use heterocyclic aryl chlorides in such coupling reac-
In Table 2 the Sonogashira couplings of three differ- tions. In Table 2, entries 8–12 reactions of aryl chlor-
ent phenylacetylenes with various heterocyclic sub- ides are reported; again with the exception of the
strates with nitrogen- or sulfur-containing functional electron-rich phenylacetylene (Table 2, entry 11) all
groups are reported. Entries 1–7 represent the cou- reactions furnish >90% substrate conversion. In this
pling of aryl bromides; all reactions except for the and all of the other examples reported here, excellent
Adv. Synth. Catal. 2010, 352, 1014 – 1022
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Sutapa Roy and Herbert Plenio
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Table 3. Sonogashira coupling of heteroaryl halides with alkyl acetylenes.
[a]
Entry
Aryl halide
Alkyne
Product
Conversion [%]
1
2
ꢀ99
ꢀ99
3
ꢀ99
4
5
ꢀ99
90
6
7
ꢀ99
ꢀ99
[
a]
Average of two runs, conversion determined via GC using internal heptadecane standard.
reactivity is observed, when using only a small excess cient Sonogashira coupling of bromothiophene with
(
1.1 equiv.) of acetylene relative to the aryl halide. 0.1 mol% of catalyst providing 80% conversion, how-
[
35]
Homocoupling of the acetylene, decomposition or ever NMP is used as the solvent.
Entries 6 and 7
other acetylene-consuming reactions are not observed were synthesized previously from 4-chloropyridine in
[
36]
to a significant extent. The reactivity for aryl chloride CH CN, but 1 mol% of [Pd] was employed.
3
conversion reported here is significantly improved
with respect to the reports of several other groups
(
yield >90% unless otherwise noted): Novak et al. Suzuki–Miyaura Coupling
used 1 mol% [Pd] at 1108C for 2-chloropyridine cou-
[7f]
pling, Hong Liu et al. applied 2 mol% [Pd] for the Compared to the in-situ formed catalyst (from
same substrate at 1508C under microwave condi- Na PdCl , base and the sulfonated azolium salt) re-
2
4
[
31]
[25]
tions,
Pd] at 1108C for 2-chloropyridine, while with 3-
chloropyridine only a 29% conversion was ob- significantly improved. 4-tolylboronic acid was em-
Yangjie Wu et al. 1 mol% cyclopalladated ported previously, the activity of the (NHC)PdCl-
[
ACHTUNGTRENNUNG
(cinnamyl) complex in Suzuki coupling reactions is
ACHTUNGTRENNUNG
[32]
served.
Nishihara et al. used 10 mol% [Pd] at ployed as a normal substrate, while naphthylboronic
1
208C for 2-chloropyridine conversion with a 60% acid was chosen as the example for a sterically more
[33]
yield,
2
Buchwald et al. for 3-chloropyridine demanding substrate. When comparing the activity of
[
30h]
.5 mol% [Pd] at 1008C
and Doucet, Santelli et al. normal aryl chlorides with that of heteroaryl chlor-
used 0.1 mol% for 2-chlorpyridine conversion, but ides, the reactivity of the former compounds in
[
34]
1
mol% for 3-chlorpyridine conversion at 1108C.
Suzuki reactions is good, but not outstanding, when
Alternatively, the preformed complex 4 was tested in comparing the reactivity data reported in Table 4 with
[
29,37]
[38]
such reactions, but the coupling yields were not im- conversions reported by Nolan,
or Cazin
for
proved. those substrates using a related preformed catalyst
The newly established set of reaction conditions complex. A Pd catalyst loading of 0.1 mol% is suffi-
were also tested in Sonogashira reactions employing cient for a number of transformations, only sterically
alkylacetylenes. These substrates tend to be less reac- demanding combinations of substrates (Table 4,
[
10]
tive than arylacetylenes,
yields are observed (Table 3) at a [Pd] loading of
.25 mol%. For the substrates mentioned here, there cyclic chlorides with tolylboronic acid and naphthyl-
is only a protocol by Najera et al. reporting on effi- boronic acid are summarized. The results for the
nonetheless excellent entry 7) require slightly higher loading (0.2 mol%).
In Table 5 the results from the screening of hetero-
0
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Adv. Synth. Catal. 2010, 352, 1014 – 1022

Sulfonated N-Heterocyclic Carbenes for Pd-Catalyzed Sonogashira and Suzuki–Miyaura Coupling
Table 4. Suzuki–Miyaura coupling of aryl chlorides with
tolyl- and naphthylboronic acid.
Table 5. Suzuki–Miyaura coupling of 2-chloropyridines with
tolyl- and naphthylboronic acid.
[a]
Entry Aryl chloride
1
Product
Conversion [%]
Entry Aryl chloride
Product
Conversion
[a]
[
%]
[b]
[c]
ꢀ99, ꢀ99
[
b]
[c]
[c]
1
2
3
4
5
89, 98
[
b]
[c]
2
3
4
ꢀ99, 99
[
b]
85, 99
[
[
[
b]
b]
b]
ꢀ99
ꢀ99
ꢀ99
[b]
[c]
99, 94
[b]
[c]
ꢀ99, 97
[
c]
6
7
87
[b]
[c]
5
87, 87
[c]
ꢀ99
[b]
[c]
6
ꢀ99, ꢀ99
[
[
[
c]
c]
c]
[a]
8
9
84
97
80
Average of two runs, conversion determined via GC
using internal heptadecane standard.
Ar=4-tolyl.
[
[
b]
c]
Ar=1-naphthyl.
complexes obtained in situ from Na PdCl , sulfonated
azolium salt and KOH in isopropyl alcohol/water mix-
ture for Sonogashira coupling and of the preformed
2
4
1
0
sulfonated complex (NHC)PdCl AHCUTNGRNENUG( cinnamyl) in Suzkui–
Miyaura reactions were studied. The conversion data
for the Sonogashira reactions involving heterocyclic
substrates are remarkable both for aryl- and alkylace-
tylenes. The Suzuki–Miyaura reactivities based on the
[
a]
Average of two runs, conversion determined via GC
using internal heptadecane standard.
Ar=4-tolyl.
[
[
b]
c]
Ar=1-naphthyl.
sulfonated (NHC)PdCl AHCTUNGTRENNUN(G cinamyl)-type complex re-
ported here are significantly improved with respect to
our previous report, but are less efficient than the
Suzuki–Miyaura coupling reported here are good, but best systems known in the literature under non-aque-
nonetheless the catalysts reported here are less effi- ous conditions.
cient than the best systems reported in the literature
[29,37]
for aqueous
ACHTUNGTRENNUNGt ions.
and non-aqueous coupling reac-
[
15a,39]
Experimental Section
All chemical reagents were purchased as reagent grade from
commercial sources and used as received unless otherwise
noted. Solvents like water, n-butanol, isopropyl alcohol
Summary and Conclusions
We report on the facile synthesis of sulfonated and
water-soluble N-heterocyclic carbenes via the direct
(
technical grade) were degassed by the freeze and thaw
technique. Potassium hydroxide used in the coupling reac-
sulfonation of the respective N,N’-diarylazolium salts tions was technical grade. All experimental conditions were
utilizing ClSO H. The activities of the respective Pd conducted under Schlenk conditions using inert (argon) at-
3
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Sutapa Roy and Herbert Plenio
FULL PAPERS
1
À
mospheres unless otherwise mentioned. H NMR and
MS: m/z=511.3 [calcd. for C H N Na O S (MÀCl ):
2
1
25
2
2
6 2
13
À
+
C NMR spectra were recorded on a Bruker DRX 500 in-
511.1], 465.1 [calcd. for (MÀCl À2Na ): 465.1].
strument at 500 and 125.75 MHz, respectively at 293 K. The
chemical shifts are given in parts per million (ppm) on the
delta scale (d) scale and are referenced to tetramethylsilane
N,N’-Bis(2,6-dimethyl-3-sodium-sulfonatophenyl)imidazo-
lium chloride (2a): From N,N’-bis(2,6-dimethylphenyl)imida-
zolinium chloride (2.4 g, 7.6 mmol) and ClSO H (15 mL);
3
1
13
1
(
d=0 ppm, H and C). Abbreviations for NMR data: s=
yield: 2.32 g (59%); H NMR (300 MHz, DMSO-d ): d=
6
singlet, d=doublet, t=triplet, q=quartet, dd=doublet of
doublets, m=multiplet, br=broad signal etc. Thin layer
chromatography (TLC) was performed on Fluka silica gel
9.72 (d, 1H, CH, J=6 Hz), 8.32 (d, 2H, CH, J=6 Hz), 7.93
(d, 2H, ArH, J=9 Hz), 7.32 (d, 2H, ArH, J=9 Hz), 2.33 (s,
1
3
6H, CH ), 2.11 (s, 6H, CH ); C NMR (75.5 MHz, DMSO-
3
3
6
0 F 254 (0.2 mm) on alumina plates. Silica gel column chro-
d ): d=161.0, 140.2, 139.9, 138.5, 133.5, 132.5, 17.1, 14.3;
6
À
matography were prepared with E. Merck silica gel 60 (63–
ESI-MS: m/z=481.07 [calcd. for C H N Na O S (MÀCl )
1
9
19
2
2
6 2
À
+
200 mm. Gas chromatography was performed on a Clarus
481.05], 463.08 [calcd. for (MÀCl À2 Na ): 438.07].
N,N’-Bis(2,4,6-trimethyl-3-sodium-sulfonatophenyl)imida-
zolium chloride (2b): From N,N’-bis(2,4,6-trimethylphenyl)-
5
00 GC with an autosampler and FID detector; column:
Varian CP-Sil 8 CB (l=15 m, d=0.25 mm, dF=1.0 mm), N
2
À1
(
flow: 17 cms ; split 1:50); injection temperature: 2708C,
A
H
U
G
R
N
U
G
3
1
detector temperature: 3508C, temperature program: iso-
therm 1508C for 5 min, heating to 3008C at 258Cmin , iso-
therm for 15 min.
(25 mL); yield: 5.52 g (77%); H NMR (300 MHz, D O):
À1
d=9.22 (d, 1H, CH), 7.86 (s, 2H, CH), 7.27 (s, 2H, ArH),
2.58 (s, 6H, CH ), 2.33 (d, 6H, CH , J=6 Hz), 2.11 (d, 6H,
3
3
1
3
CH , J=3 Hz); C NMR (75.5 MHz, D O): d=140.4, 139.9,
3
2
1
37.1, 134.0, 132.9, 132.4, 125.2, 22.5, 16.8, 15.8; ESI-MS:
À
m/z=509.2 [calcd. for C H N Na O S (MÀCl ): 509.1],
2
1
23
+
2
2
6 2
À
General Procedure for the Synthesis of Sulfonated
Imidazolinium or Imidazolium Salts
463.1 [calcd. for (MÀCl À2Na ): 463.1].
The azolium chloride was added to a two-necked round-bot-
tomed flask, equipped with reflux condenser, chlorosulfonic imidazolylidene]PdCl
acid (ca. 5 mL acid per gram of azolium salt) was added
ACHTUNGTRENNU[GN N,N’-Bis(2,6-diisopropyl-4-sulfonatophenyl)-
ACHTUNGTRENNGNU( cinnamyl) (4)
N,N’-Bis(2,6-diisopropyl-4-sulfonatophenyl)imidazolium
chloride (0.150 g, 0.238 mmol) and sodium amylate (1.7M in
toluene, 0.15 mL, 0.24 mmol) were added to dry THF and
stirred for 30 min. at room tempertaure. After cooling to
dropwise into the flask at 08C. After warming to room tem-
perature, the mixture was slowly heated to 1008C for 3 h.
Then the cold (208C) and viscous reaction mixture was
poured directly onto ice (externally cooled to À208C) and
the partially liquid mixture stirred rapidly to avoid lump for-
mation. The product was finally filtered off and most of the
water removed under vacuum at 508C. The filtrate still con-
tains a lot of sulfuric acid, which was removed by extracting
the crude product with ethyl acetate. After repeating this
procedure five times, the acid was removed completely. The
remaining sulfonic acid was dissolved in a minimum amount
of water, reacted with two equivalents of NaOH to obtain
the disodium salt of the sulfonated imidazolium salt. The
water was completely removed by heating (24 h, 508C)
under vacuum to afford the pure sodium salt. The respective
products are designated as chlorides, but actually contain a
mixture of counter ions such as chloride, nitrate and hydro-
gen sulfate.
À708C [PdCl
ACHTUNGTNERNUNG( cinnamyl)] (0.058 g, 0.114 mmol) was added
2
and stirring continued for 30 min, the reaction mixture was
then slowly allowed to warm to room temperature and stir-
ring continued for an additional 4 h. The volatiles were
evaporated under vacuum to leave a grey solid powder. The
residual solid was extracted with 5 mL of dry and degassed
methanol, filtered and the filtrate evaporated to afford 4;
1
yield: 0.180 g (89%); H NMR (500 MHz, DMSO-d ): d=
6
7
.78 (s, 2H, CH), 7.60 (s, br, 4H, ArH), 7.14 (s, br, 5H,
3 3
ArH), 5.26 (m, 1H, CH, J=9 Hz, J=4 Hz), 4.29 (d, 2H,
CH , J=12.5 Hz), 4.06 (s, br, 1H, CH), 3.58 (s, br, 1H,
2
CH ), 2.91 (m, br, 4H, CH), 1.28 (m, 12H, CH J=6.5 Hz),
2
3
1
3
1
.10 (m, 12H, CH3 J=6.5 Hz); C NMR (125.8 MHz,
DMSO-d ): d=184.6, 150.6, 146.8, 139.6, 137.6, 130.2, 129.6,
6
1
7
29.5, 129.0, 128.9, 127.9, 127.4, 127.3, 122.5, 110.2, 91.3,
N,N’-Bis(2,6-dimethyl-3-sodium-sulfonatophenyl)imidazo-
linium chloride (1a): From N,N’-bis(2,6-dimethylphenyl)imi-
0.5, 47.2, 30.4, 29.7, 27.4, 24.3, 24.2; ESI-MS: m/z=833.4,
+
calcd. for C H N Na O PdS (M ÀCl): 833.14.
3
7
49
2
2
6
2
dazolinium chloride (1.0 g, 3.19 mmol) and ClSO H (5 mL);
3
1
yield: 0.77 g (46%); H NMR (300 MHz, DMSO-d ): d=
6
9
.12 (d, 1H, CH, J=6 Hz), 7.82 (d, 2H, ArH, J=9 Hz), 7.22
General Procedure for Sonogashira Coupling
Reactions
(
d, 2H, ArH, J=9 Hz), 4.47 (s, 4H, CH ), 2.61 (s, 6H, CH ),
2
3
1
3
2
1
.37 (s, 6H, CH ); C NMR (75.5 MHz, DMSO-d ): d=
3 6
60.5, 145.9, 145.7, 136.3, 133.9, 128.1, 127.4, 50.9, 17.5, 14.6;
Preparation of catalyst stock solution: In a Schlenk tube,
Na PdCl (8.82 mg, 0.03 mmol), N,N’-bis(2,6-diisopropyl-4-
HR-MS: m/z=483.0627, calcd. for C H N S O Na
1
9
21
2
2
6
2
2
4
À
(
MÀCl ): 483.0636.
sulfonatophenyl)imidazolium chloride (37.7 mg, 0.06 mmol)
and KOH (13.5 mg, 0.24 mmol) were dissolved in 6 mL de-
gassed water under argon. The mixture was stirred at 50 to
558C for 2 h during which time the solution became a dark
orange, clear solution.
N,N’-Bis(2,4,6-trimethyl-3-sodium-sulfonatophenyl)imida-
zolinium chloride (1b): From N,N’-bis(2,4,6-trimethylphen-
ACHTUNGTRENNUNGy l)imidazolinium chloride (4.94 g, 14.5 mmol) and ClSO H
3
1
(
25 mL); yield: 5.5 g (69%); H NMR (500 MHz, D O): d=
2
8
4
.55 (d, 1H, CH, J=2.4 Hz), 7.19 (s, 2H, ArH, J=9 Hz),
Coupling reaction in water/isopropyl alcohol (1:1): In a
Schlenk tube, KOH (1.5 mmol) was added to water and iso-
propyl alcohol (1:1) and degassed by freeze and thaw. Then
aryl halide (0.5 mmol) and catalyst (0.25 mL from the above
.46 (s, 4H, CH ), 2.59 (s, 6H, CH ), 2.54 (s, 6H, CH ), 2.34
2
3
3
13
(s, 6H, CH ); C NMR (125.8 MHz, D O): d=160.5, 145.9,
3
2
145.7, 136.3, 133.9, 128.1, 127.4, 51.6, 22.7, 17.5, 16.4; ESI-
1020
asc.wiley-vch.de
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2010, 352, 1014 – 1022

Sulfonated N-Heterocyclic Carbenes for Pd-Catalyzed Sonogashira and Suzuki–Miyaura Coupling
stock solution) were added and heated. When the reaction
Rutherford, B. Sitter, A. M. Stewart, M. G. Vetelino, L.
temperature reached 60–708C, the respective acetylenes
Wei, Org. Process Res. Dev. 2005, 9, 440.
(
0.55 mmol) was added and heated at 90–958C for 12 h. Fi-
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diethyl ether was added, followed by washing with water
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either by column chromatography (cyclohexane/ethyl ace-
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glycol di-n-butyl ether as internal standard.
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4
2
The product was either purified by silica gel column chro-
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[
2
[
[
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NMR spectroscopic data of all coupling products reported
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[15a,b,d]
shira and Suzuki coupling reactions.
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