Sulfonated N-heterocyclic carbenes for Suzuki coupling in water

Article abstract of DOI:10.1039/b703658b

Sulfonated, water-soluble imidazolium and imidazolinium salts were synthesized and the respective Pd-complexes with N,N′-bis(2,6-dialkyl-4- SO₃^--phenyl)imidazol-2-ylidene and N,N′-bis(2,6- dialkyl-4-SO₃^--phenyl)-4,5-dihydroimidazol-2-ylidene ligands were applied in aqueous Suzuki coupling reactions of aryl chlorides. The Royal Society of Chemistry.

Full text of DOI:10.1039/b703658b

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Sulfonated N-heterocyclic carbenes for Suzuki coupling in water{
Christoph Fleckenstein, Sutapa Roy, Steffen Leutha¨ußer and Herbert Plenio*
Received (in Cambridge, UK) 12th March 2007, Accepted 13th April 2007
First published as an Advance Article on the web 2nd May 2007
DOI: 10.1039/b703658b
NHC-ligands, as exemplified by the work of Grubbs23 and
Sulfonated, water-soluble imidazolium and imidazolinium
Nolan et al.17,24
salts were synthesized and the respective Pd-complexes
with
N,N9-bis(2,6-dialkyl-4-SO32-phenyl)imidazol-2-ylidene
It is therefore surprising that to the best of our knowledge
and N,N9-bis(2,6-dialkyl-4-SO32-phenyl)-4,5-dihydroimidazol-
2-ylidene ligands were applied in aqueous Suzuki coupling
reactions of aryl chlorides.
NHC-based relatives of TPPTS have not been described in the
literature. A few hydrophilic NHC compounds are known25,26 and
have been used for cross-coupling reactions.27,28 Recently, Grubbs
utilized a PEG-decorated NHC for aqueous olefin metathesis.29,30
We wish to present here the synthesis of disulfonated
N-heterocyclic imidazolium and imidazolinium salts (Schemes 2
and 3).{ Starting from 2,6-dimethyl-3-(sulfonato-Na+)aniline,
which was prepared according to a procedure by Courtin et al.,31
the condensation with glyoxal under carefully controlled reaction
conditions generates the diimine 3a in 72% yield. It should be
noted here that in our hands the synthesis of 2a is not reliable;
since often a mixture of mono- and disulfonated aniline is formed.
Fortunately, these problems can be avoided by applying the same
sulfonation reaction conditions to 2,4,6-trimethylaniline, resulting
in the monosulfonated aniline 2b. Diimines 3 can be reduced under
hydrogen pressure to generate the diamines 4, which were cyclized
to give the respective disulfonated imidazolinium salts 5?H+.
For the synthesis of the 4-sulfonato-substituted NHC-ligands a
related approach was chosen. However, the formation of the
respective diimines 6 and 7 is difficult when using a 40% aq.
solution of glyoxal. The diimines are formed in good yields
(.75%), but invariably contain a significant amount (.15%) of
From an environmental as well as from an economic point of
view, the use of volatile organic compounds as solvents for
chemical transformations is under critical discussion and alter-
natives such as scCO2,1,2 ionic liquids3 or water4 are actively
studied.5
Water especially as a cheap and non-toxic solvent has been
receiving special attention6 since the Ruhrchemie/Rhone-Poulenc
hydroformylation process is carried out in an aqueous–organic
solvent mixture,7 facilitating the recovery of the valuable rhodium
catalyst. The need to replace organic solvents by water is more
important in the fine chemicals industry since a much larger
amount of waste per mass unit of product is generated8—of which
the majority are solvents.9
Obviously catalytic reactions in water require water-soluble
catalysts and it is a typical strategy to modify transition metal
complexes by attaching phase tags which infer the desired
solubility properties.10,11 The most prominent solubilizing group
in this respect is the sulfonato group; consequently, TPPTS
[tri(m-sulfonyl)triphenylphosphine; triphenylphosphine, trisulfo-
nated] is the most important ligand among numerous other
water-soluble phosphines.12–16
Primarily due to their unique electron-donating abilities and the
stability of the resulting metal complexes, N-heterocyclic carbenes
are beginning to replace phosphines in a number of catalytic
processes.17–22 The most important class of NHC-ligands for
catalytic applications is depicted in Scheme 1.
Two of the most important transition-metal catalyzed reactions,
the Ru-mediated olefin metathesis and the large group of
Pd-mediated cross-coupling reactions, rely on this class of
Scheme 1 R = Me or iPr, saturated or unsaturated ring.
Anorganische Chemie im Zintl-Institut, Petersenstr. 18,
64287 Darmstadt, Germany. E-mail: plenio@tu-darmstadt.de
{ Electronic supplementary information (ESI) available: Full experimental
details and characterization of new compounds. See DOI: 10.1039/
b703658b
Scheme 2 Reagents and methods: (a) 20% oleum; (b) ethanol, glyoxal,
HCOOH; (c) MeOH, H2, Pd/C; (d) EtOH, HC(OEt)3, NH4Cl, HCOOH.
2870 | Chem. Commun., 2007, 2870–2872
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Table 1 Aqueous Suzuki coupling reaction of aryl chlorides utilizing
azolium salts 5b, 11 and 13
Boronic
acid
Entry Aryl chloride
Catalyst NHC Conv.a
1
2
3
4
5
6
7
8
9
4-Chlorotoluene
4-Chloroanisole
4-Chloroacetophenone 4-Tolyl
4-Tolyl
4-Tolyl
1 mol% 5b
1 mol% 5b
1 mol% 5b
1 mol% 5b
0.5 mol% 5b
1 mol% 11
1 mol% 11
1 mol% 13
0.1 mol% 13
0.1 mol% 13
0.1 mol% 13
.99%
.99%
.99%
.99%
84%
63%
56%
.99%
91%
4-Chlorobenzonitrile
4-Chlorotoluene
4-Chloroacetophenone 4-Tolyl
4-Tolyl
4-Tolyl
4-Chlorotoluene
4-Chlorotoluene
4-Chlorotoluene
4-Tolyl
4-Tolyl
4-Tolyl
10
11
4-Chloroacetophenone 4-Tolyl
4-Chlorobenzene-
sulfonamide
.99%
.99%
4-Tolyl
12
13
14
15
16
4-Chloroanisole
4-Chloroaniline
2-Chloropyridine
2-Chloropyridine
4-Amino-2-chloro-
pyridine
4-Tolyl
4-Tolyl
4-Tolyl
1-Naphthyl 0.5 mol% 13
1-Naphthyl 1 mol% 13
0.1 mol% 13
0.5 mol% 13
0.1 mol% 13
74%
80%
.99%
.99%
85%
17
2-Chloro-4-methyl-
quinoline
1-Naphthyl 0.5 mol% 13
.99%
a
Average of two runs.
of the NHC–Pd complex followed by addition of the substrates. A
set of four aryl chlorides (Table 1, entries 1–4) was reacted with
tolylboronic acid at 100 uC using 1 mol% of the Pd catalyst during
12 h to result in the near quantitative formation of the respective
coupling products. However, when the Pd-catalyst concentration is
lowered to 0.5 mol%, the limits of catalysts based on 5b become
apparent as only 84% of product is formed (entry 5).
Scheme 3 Reagents and methods: (a) Ethanol, 1,4-dioxane-2,3-diol,
HCOOH; (b) MeOH, H2, Pd/C; (c) EtOH, HC(OEt)3, HCOOH; (d)
chloromethyl pivalate, dmso.
iPr-substituted NHC-ligands tend to be more active in cross-
coupling reactions than their Me-substituted relatives.
Consequently, we studied the imidazolinium salt 11?H+ and the
imidazolium salt 13?H+ in Pd-catalyzed cross-coupling reactions.
To our surprise, the saturated NHC-ligand 11 is less efficient than
5b; even at 1 mol% catalyst loading the respective Pd complexes
gave only 63% and 56% conversion with 4-chloroacetophenone
and 4-chlorotoluene, respectively (entries 6 and 7). With ligand 11
the formation of a black Pd precipitate was observed during the
first few minutes of the catalytic reaction, which is normally
indicative of catalyst decomposition. Therefore we stopped
screening this ligand. Fortunately, the Pd complex of 13 turned
out to be a much more active catalyst. At 1 mol%, 4-chlorotoluene
is converted in .99% yield and even at 0.1 mol% catalyst loading
91% of this coupling product is formed (entries 8 and 9). Activated
aryl chlorides give full conversion at 0.1 mol% (entries 10 and 11),
while the deactivated chloroaniline (entry 13) requires 0.5 mol%
catalyst for an 80% conversion.
unreacted aniline. Obviously, the equilibrium for the formation of
the diimine and water is unfavourable. However, the diimine can
be obtained in excellent yields when using 1,4-dioxane-2,3-diol, the
anhydrous adduct of ethylene glycol and glyoxal. The Pd/C-
catalyzed reduction of the pure diimines 6 and 7 in methanol with
H2 resulted in the formation of the desired diamines 8 and 9. Again
diamine 8 is contaminated with the respective aniline due to the
facile hydrolysis of diimine 6. This reduction proceeds cleanly only
with strict exclusion of water. The cyclization of the diamines 8
and 9 to the respective imidazolinium salts, 10?H+ and 11?H+,
utilizes HC(OEt)3 according to standard procedures. The synthesis
of the two imidazolium salts 12?H+ and 13?H+ was effected using
chloromethyl pivalate as a C1-building block.
In order to probe the catalytic performance of 5b in Pd-
mediated aqueous cross-coupling reactions,32 we studied the
Suzuki coupling of several aryl chlorides with a catalyst formed
in situ from 5b?H+ and Na2PdCl4 in water with KOH as the base
(Table 1). While the deprotonation of imidazolium or imidazoli-
nium salts in protic solvents is not possible due to insufficient
acidity,33 the respective Pd–NHC complexes are directly obtained
using palladium salts in the presence of base and the sulfonated
carbene precursor 5b?H+ in pure water. The coupling procedure
consists of mixing the respective NHC-precursor, Na2PdCl4 and
KOH in water, stirring for 30 min to first allow for the formation
Remarkably, nitrogen-containing heterocycles are coupled with
high efficiencies (entries 14–17). Not only 2-chloropyridine, but
also difficult substrates such as 4-amino-2-chloropyridine or the
related quinoline derivative are reacted in excellent yields with
tolylboronic or naphthylboronic acid. These results compare
favourably with catalysts published by Buchwald et al.,32 Fu
et al.,34 and Guram et al.35
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Consequently, even the first generation of water-soluble NHC–
Pd complexes is comparable in activity to the phosphines described
in the literature for aqueous Suzuki reactions.16,36
In conclusion, the successful synthesis of sulfonated imidazolium
and imidazolinium salts opens the door to the aqueous
organometallic chemistry of NHC-ligands. In a preliminary study
we have demonstrated the utility of sulfonated NHC-ligands in the
aqueous Suzuki coupling of aryl chlorides; additional optimization
of the catalytic performance in water will be undertaken in the
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Notes and references
{ All NMR spectra were recorded in dmso-d6 at 300 MHz (1H NMR) and
75.5 MHz (13C NMR).
2,6-Dimethyl-3-(sulfonato-Na+)aniline (2a). 1H-NMR: d 2.06 (s, 3H,
CH3), 2.29 (s, 3H, CH3), 4.45 (s, 2H, NH2), 6.73 (d, 1H, ArH, J = 9 Hz),
7.01 (d, 1H, ArH, J = 9 Hz). 13C-NMR: d 14.2 (CH3), 17.9 (CH3), 115.0
(aryl-CH), 118.2 (aryl-CH), 121.9 (aryl-CMe), 125.6 (aryl-CMe), 144.1
(aryl-CSO3Na), 144.5 (aryl-CNH2).
N,N9-(Ethane-1,2-diylidene)-bis[2,6-dimethyl-3-(sulfonato-Na+)]aniline
(3a). In a round-bottom flask the sulfonated aniline 2a (10.0 g, 44.8 mmol)
was dissolved in methanol (2500 mL). Then glyoxal (4.1 mL, 22.4 mmol)
was added dropwise to the solution, followed by the addition of two drops
of formic acid. The reaction mixture was stirred overnight at room
temperature and then for 24 h at 50 uC. A yellow solid precipitated which
was filtered off and then dried in vacuo. Yield: 8.1 g (16.1 mmol, 72%). 1H-
NMR: d 2.08 (s, 6H, CH3), 2.32 (s, 6H, CH3), 7.05 (d, 2H, CH, JH–H
=
9 Hz), 7.53 (d, 2H, CH, JH–H = 9 Hz), 8.10 (s, 2H, CH). 13C-NMR: d 14.8
(CH3), 18.0 (CH3), 123.0 (HCaryl), 123.9 (HCaryl), 125.9 (Caryl-Me), 126.4
(Caryl-Me), 144.9 (C-SO3Na), 150.2 (Caryl-N), 163.9 (HCimine). HR-MS
calcd for C18H18N2NaO6S2 (M 2 NaCl) 445.0504; found: 445.0509.
N,N9-Ethane-bis[2,6-dimethyl-3-(sulfonato-Na+)]aniline (4a). 5.0 g
(10.0 mmol) of the diimine 3a was dissolved in methanol (120 mL) in an
autoclave flask. Then Pd/C 10% (1.13 g, 1.2 mmol) was added to the
solution and the mixture was stirred for 3 h under 7 bar H2 pressure. The
Pd/C was filtered off through celite and the solution was evaporated under
reduced pressure to obtain the diamine as a white solid. Yield: 4.1 g
(8.1 mmol, 84%). 1H-NMR: d 2.20 (s, 6H, CH3), 2.43 (s, 6H, CH3), 3.00 (s,
4H, CH2), 6.86 (d, 2H, CH, JH–H = 9 Hz), 7.32 (d, 2H, CH, JH–H = 9 Hz).
13C-NMR: d 14.8 (CH3), 18.5 (CH3), 48.5 (H2Camine), 120.4 (HCaryl), 126.3
(HCaryl), 127.9 (Caryl-Me), 130.8 (Caryl-Me), 144.6 (C-SO3Na), 146.8
(Caryl-N). HR-MS calcd for C18H22N2NaO6S2 (M 2 NaCl) 449.08173;
found: 449.08208.
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3.0 mmol) and a single drop of formic acid. The reaction mixture was
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=
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9 Hz), 7.83 (d, 2H, CH, JH–H = 9 Hz), 9.11, 9.15 (Im-CH). 13C-NMR: d
14.6 (CH3), 17.5 (CH3), 50.9 (CH2), 127.4 (HCaryl), 128.1 (HCaryl), 133.9
(Caryl-Me), 136.3 (Caryl-Me), 145.7 (C-SO3Na), 145.9 (Caryl-N), 160.5
(HCim-N). HR-MS calcd for C19H21N2NaO6S2 (M 2 NaCl) 483.06368;
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2872 | Chem. Commun., 2007, 2870–2872
This journal is ß The Royal Society of Chemistry 2007