The Suzuki coupling of aryl chlorides in aqueous media catalyzed by in situ generated calix[4]arene-based N-heterocyclic carbene ligands

Article abstract of DOI:10.1002/ejoc.200500943

We report on the use of an in situ system for the catalytic Suzuki cross-coupling reaction of chlorobenzenes and benzeneboronic acid to yield biphenyls. Calix[4]arene-based imidazolium salts were used as precursors of N-heterocyclic carbene ligands and Pd(OAc)₂ as the palladium source. In dioxane as the organic medium, the steric demands of the substituents on the calixarene skeleton and on the imidazolium moiety parallel the catalytic activity; the best catalytic results were obtained by using dimesityl- or 2,6-diisopropylphenyl-substituted calixarene-imidazolium salts. Among the bases tested Cs₂CO₃ and CsF were the most effective. The catalytic protocol established for organic solvents could also be used for the Suzuki cross-coupling reaction in aqueous solution. In dioxane/water (50:50) the activity is nearly the same as in pure dioxane and in pure water, an environmentally friendly and cheap solvent, a 60 % level of reactivity was maintained; here the calixarene ligand precursor 3a showed the highest activity. Nonmacrocyclic compounds used for comparison showed considerably lower catalytic ability proving that calix[4]arene-based imidazolium salts are attractive supramolecular skeletons for the N-heterocyclic carbene ligands used in selective Suzuki cross-coupling reactions of aryl chlorides in aqueous solution. Wiley-VCH Verlag GmbH & Co. KGaA, 2006.

Full text of DOI:10.1002/ejoc.200500943

FULL PAPER
DOI: 10.1002/ejoc.200500943
The Suzuki Coupling of Aryl Chlorides in Aqueous Media Catalyzed by in situ
Generated Calix[4]arene-Based N-Heterocyclic Carbene Ligands
Thomas Brendgen,[a] Markus Frank,[a] and Jürgen Schatz*[a]
Keywords: Calixarenes / Carbene ligands / Cross-coupling / Palladium / Water chemistry
We report on the use of an in situ system for the catalytic
Suzuki cross-coupling reaction of chlorobenzenes and ben-
zeneboronic acid to yield biphenyls. Calix[4]arene-based
imidazolium salts were used as precursors of N-heterocyclic
carbene ligands and Pd(OAc)2 as the palladium source. In
dioxane as the organic medium, the steric demands of the
substituents on the calixarene skeleton and on the imid-
azolium moiety parallel the catalytic activity; the best cata-
lytic results were obtained by using dimesityl- or 2,6-di-
isopropylphenyl-substituted calixarene-imidazolium salts.
Among the bases tested Cs2CO3 and CsF were the most ef-
fective. The catalytic protocol established for organic sol-
vents could also be used for the Suzuki cross-coupling reac-
tion in aqueous solution. In dioxane/water (50:50) the activity
is nearly the same as in pure dioxane and in pure water, an
environmentally friendly and cheap solvent, a 60% level of
reactivity was maintained; here the calixarene ligand precur-
sor 3a showed the highest activity. Nonmacrocyclic com-
pounds used for comparison showed considerably lower
catalytic ability proving that calix[4]arene-based imid-
azolium salts are attractive supramolecular skeletons for the
N-heterocyclic carbene ligands used in selective Suzuki
cross-coupling reactions of aryl chlorides in aqueous solution.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2006)
lides in aqueous solution using surfactants,[25] tetrabutylam-
monium bromide (TBAB),[26] Pd/C,[27] tetradentate
NHCs[28] as ligands, or the use of microwaves[29,30] has been
reported.
Introduction
The formation of C–C bonds is an important task for
the synthetic organic chemist. In particular, the palladium-
catalyzed Suzuki–Miyaura reaction[1,2] has attracted much
attention because the synthetic protocol tolerates many
functional groups and also because the coupling reaction
occurs under mild conditions. In recent years the Suzuki
reaction of aryl chlorides has been extensively investi-
gated.[3–5] N-Heterocyclic carbenes (NHCs)[6–10] have
emerged as an effective class of ligands for palladium-cata-
lyzed cross-coupling reactions of aryl chlorides.[11,12] This
important finding has led to the vigorous development of
the Suzuki coupling of aryl chlorides. Besides the applica-
tion of well-defined Pd–NHC metal complexes,[13,14] a sim-
ple in situ system[15–18] in which the catalytically active spe-
cies was formed prior to cross-coupling by the reaction of
an imidazolium salt, a source of palladium and a base
could be used to avoid preparative problems such as the
instability[19,20] of the catalyst.
Owing to our ongoing interest in organic transforma-
tions in aqueous solution and our observations that water-
soluble calixarenes can act as inverse phase-transfer cata-
lysts[31,32] in Suzuki reactions we decided to develop cata-
lytic systems based on calixarenes for Suzuki cross-coupling
reactions in aqueous media. For this purpose, the macro-
cyclic backbone should provide a hydrophobic cavity or
niche as well as a molecular platform to attach catalytic
groups covalently to the wide rim of the macrocycle. Be-
cause calixarenes bearing imidazolium groups are water sol-
uble, for example, calixarene 2c has a solubility of 2.9 gL–1
in pure water, such heterocycles seem to be ideal candidates
to render the supramolecular catalysts water-soluble and
can act furthermore as a precursor for the formation of
NHCs used in the catalytic process.
In addition to the search for new starting materials and
catalytic systems, there is considerable interest in transition-
metal-catalyzed reactions in aqueous media.[21] Water is not
only an environmentally friendly and cheap reaction me-
Results and Discussion
Following the general reaction procedure, the calix[4]-
dium,[22,23] but also interesting from a mechanistic point of arene-imidazolium salts 2–4 (Scheme 1) were prepared by
view.[24] For example, efficient Suzuki coupling of aryl ha- simple alkylation of the appropriate N-substituted imid-
azoles with chloromethylated calix[4]arene building
blocks.[33] The noncyclic analogs 1 were chosen as reference
compounds to check the possible electronic and steric ef-
fects of the substituents on the imidazolium moiety.
[a] Division of Organic Chemistry I, University of Ulm,
Albert-Einstein-Allee 11, 89081 Ulm, Germany
Fax: +49-731-50-22803
E-mail: juergen.schatz@uni-ulm.de
2378
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2378–2383

The Suzuki Coupling of Aryl Chlorides in Aqueous Media
FULL PAPER
Furthermore, by comparing the calixarene derivatives 2–4 Table 1. Suzuki cross-coupling reaction of 4-chlorotoluene (6a)
(2: the substituent on the calixarene backbone R2 = H; 3:
with benzeneboronic acid in dioxane to yield 4-methylbiphenyl
(7a): Ligand screening and variation of base.[a]
R2 = tBu; 4: R2 = CH2OMe) with the open-chain deriva-
Li-
gand
t [h] Base
Yield
[%]
tives 1 possible participation of the macrocyclic cavity in
the reaction can be detected.
Entry
R1
R2
1
2
3
4
5
6
7
8
–
2
2
2
2
2
2
2
2
2
2
2
2
Cs2CO3
–
–
–
–
H
H
H
H
tBu
0
1a
1b
2a
2b
2c
2d
3a
3b
3c
3d
4a
4d
3a
3a
3a
3a
3a
3a
3a
Cs2CO3 mesityl
Cs2CO3 2,6-di-iPrPh
Cs2CO3 mesityl
Cs2CO3 2,6-di-iPrPh
Cs2CO3 CH3
Cs2CO3 iPr
Cs2CO3 mesityl
Cs2CO3 2,6-di-iPrPh tBu
Cs2CO3 CH3
Cs2CO3 iPr
Cs2CO3 mesityl
Cs2CO3 iPr
Cs2CO3 mesityl
NaOAc mesityl
K3PO4 mesityl
KOtBu mesityl
51[b]
38[b]
50
40
1
16
60
38
19
24
9
10
11
12
13
14
15
16
17
18
19
20
tBu
tBu
CH2OCH32
CH2OCH324
tBu
tBu
tBu
tBu
tBu
tBu
tBu
2
24
24
24
24
24
24
24
95
3
12
10
13
80
27
KF
CsF
mesityl
mesityl
K2CO3 mesityl
[a] Reagents and conditions: 1.5 mmol 6a, 1.0 mmol benzene-
boronic acid, 2 mmol base, 3 mol-% Pd(OAc)2, 3 mol-% 1–3, di-
oxane, 80 °C. [b] 6 mol-% ligand were used; entries 4–10, see ref.[32]
.
Table 2. Suzuki cross-coupling reaction of 4-aryl halides 6a–g with
benzeneboronic acid in dioxane: Variation of starting material.[a]
Entry
X
Y
Yield of 7 [%]
1
2
3
4
5
6
7
6a
6b
6c
6d
6e
6f
Cl
Br
I
Cl
Cl
Cl
Cl
4-CH3
4-CH3
4-CH3
3-OCH3
4-CF3
3-CH3
2-CH3
60
91
99
64
69
6
6g
8
[a] Reagents and conditions: 1.5 mmol 6a–g, 1.0 mmol benzene-
boronic acid, 2 mmol Cs2CO3, 3 mol-% Pd(OAc)2, 3 mol-% 2a, di-
oxane, 80 °C, reaction time 48 h.
the imidazolium moiety. The best results were obtained by
using ligands bearing mesityl substituents on the imid-
azolium salt (1a, 2a, 3a).
Scheme 1.
To test the catalytic ability of he calixarene derivatives a
Assuming[14] that the precursor of the catalytic species
standardized and parallel test reaction was used to avoid formed by the in situ system is similar to the cis-Pd(L–L)
any source of error stemming from reactions carried out Cl2 complex 5 characterized by single-crystal structure
individually under slightly varying conditions. The results analysis[33] it is likely that the steric bulk induced additional
obtained by this approach are compiled in Table 1, Table 2 strain into the palladium chelate. This favors the dissoci-
and Table 3.
ation of one NHC ligand to form a catalytically active com-
Because of the possibility of ligand- or “metal-free” Su- plex.[15,35] This would explain the higher activity of the li-
zuki coupling reactions[34] such a reaction pathway had to gands 2a,b and 3a,b and why the activity of calixarene 3a
be ruled out first for the test reaction under investigation exceeds its nonmacrocyclic analog 1a. In the case of 2,6-
(Table 1, entry 1).
diisopropylphenyl-substituted ligand precursors (Table 1,
In pure dioxane as the reaction medium the catalyst de- entries 3, 5, and 9) identical efficiencies were revealed. Here,
rived from calixarene 2a exhibited basically the same ac- the steric stress induced by the 2,6-diisopropylphenyl
tivity as the open-chain analog 1a (cf. entries 2 and 4, groups seems to prevail.
Table 1). By using the macrocyclic imidazolium salts as li-
Calixarenes 4 were included in the study to test the effect
gand precursors (Table 1, entries 4–13) the yield of biphenyl of possible dangling donor ligands in the proximity of the
increased with increasing steric bulk of the substituents on catalytic center. However, the introduction of a CH2OMe
Eur. J. Org. Chem. 2006, 2378–2383
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2379

T. Brendgen, M. Frank, J. Schatz
Table 3. Suzuki cross-coupling reaction of 4-chlorotoluene (6a) and benzeneboronic acid in mixtures of dioxane/water.[a]
FULL PAPER
Entry
Ligand
Dioxane/water
Yield of 7a [%]
Yield of 8a [%]
Yield of 9a [%]
1
2
3
4
5
6
7
8
1a
100:0
50:50
0:100
100:0
50:50
0:100
100:0
50:50
0:100
100:0
50:50
0:100
100:0
50:50
0:100
100:0
50:50
0:100
100:0
50:50
0:100
56
54
3
60
55
37
64
32
2
31
11
2
46
5
8
34
8
6
0
3
1
7
3
1
8
0
1
10
2
0
12
6
3
15
6
2
16
0
0
0
3
0
0
1
0
0
1
12
0
4
0
1
9
3
0
5
5
0
6
8
0
2
3
2a
2b
9
10
11
12
13
14
15
16
17
18
19
20
21
2d
2e
3c
None
[a] Reagents and conditions: 1.5 mmol 6a, 1.0 mmol benzeneboronic acid, 2 mmol Cs2CO3, 3 mol-% Pd(OAc)2, 3 mol-% 1–3, 80 °C,
reaction time 48 h.
group did not improve the catalytic ability; the yields of 60:40 dioxane/water were inhomogeneous and therefore are
biphenyl dropped from 60 and 50% for 3a and 2a, respec- not included in further discussions. All other solvent mix-
tively, to 2% for 4a in the case of R1 = mesityl (Table 1, tures led to homogeneous reaction mixtures.
entries 8, 4, and 12). Surprisingly, this is not the case for R1
The best results were obtained in the pure organic phase.
= isopropyl. Here, yields remained around 20% in all three In a 1:1 mixture of dioxane/water nearly similar yields as in
ligand systems (Table 1, entries 11, 7, and 13).
pure dioxane were obtained for 1a and 2a. Beyond the 1:1
As expected[15] from all the bases tested (Table 1, en- solvent mixture the efficiency of the Suzuki coupling
tries 14–20) Cs2CO3 was the base of choice. By using ligand dropped again despite the observed homogeneous reaction
3a and Cs2CO3 and by extending the reaction time to 24 h, conditions. However, the calixarene-based ligand 2a showed
quantitative conversion to 4-methylbiphenyl is possible.
somewhat exceptional behavior. Here, 37% of the coupling
By using calixarene 2a as the ligand precursor, the effect product was observed (Table 3, entry 6); all the other li-
of different substrates was tested (Table 2). As expected, gands tested gave yields well below the 10% level although
aryl iodides and bromides gave better yields of biaryls the macrocyclic ligands were usually still superior to the
(Table 2, entries 1–3). Trifluoromethyl- or methoxy-substi- nonmacrocyclic precursor 1a. Increasing the amount of
tuted chlorobenzenes gave similar yields to 4-chlorotoluene. added calixarene-based ligand precursor did not improve
However, there was a striking difference between the activi- the yields in pure water.
ties of 2-, 3-, and 4-chlorotoluene (Table 2, entries 1, 6, and
Besides the desired 4-methylbiphenyl, homocoupling to
7). Whereas, the para isomer gave the corresponding biaryl give 4,4Ј-dimethylbiphenyl and dehalogenation to yield tol-
in 60% yield, the ortho and meta isomers gave less than uene were also observed. In dioxane, the calixarene ligands
10% of the coupled product. With other catalysts, these 2a,b, 2d,e and 3c gave 8–16% toluene, but no homocoupling
three substrates usually give similar yields.[36,37] This strik- product was detected. In pure water virtually no toluene
ing difference can be rationalized in terms of the reaction (Ͻ3%) was detected for any of the calixarene-based ligand
taking place near a cavity/cleft formed by the calixarene precursors. In contrast, the amount of homocoupling prod-
backbone and the NHC center. Because organic substrates uct, 4,4Ј-dimethylbiphenyl, increased with increasing water
such as chlorotoluene are usually bound inside the cavity content. In pure dioxane the yields of the homocoupling
of cationic calixarenes [Kass
Ϸ
200 Lmol–1(∆G
Ϸ
product were Ͻ1% in all cases, but increased significantly
3 kcalmol–1) as determined by NMR titration experiments] (2a: 12%; 2d: 3%; 2e: 5%; 3c: 8%) in water. Here, the imid-
with the methyl group of the substrate pointing inside the azolium salt 2a exhibited the highest activity in both the
aromatic cavity,[31] it is likely that the geometry of the niche desired cross-coupling and the homocoupling reactions.
could not accommodate the ortho and meta isomers in a
It is somewhat difficult to compare the results obtained
productive way.
with ligand precursor 2a directly with similar coupling reac-
To test the effect of different reaction media the solvent tions in aqueous solution because in the cases reported in
was changed systematically from pure dioxane to pure the literature solvent mixtures were usually used.[25,27,38–40]
water (Table 3). Here, reactions performed in 80:20 and However, yields of Ͻ35% of aryl–aryl coupling products
2380
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2378–2383

The Suzuki Coupling of Aryl Chlorides in Aqueous Media
FULL PAPER
and the corresponding 1-arylimidazole in dichloromethane was re-
fluxed for 1 d. After removal of the solvent the remaining residue
was digerated for 3 h with hot Et2O. The product was isolated by
filtration and dried in vacuo.
seem to be quite typical. For example, the use of Pd/C in
DMA/H2O (20:1) in the coupling of 4-chlorotoluene and
PhB(OH)2 (K2CO3, 80 °C, 48 h) gave 36% of the coupling
product.[38] The use of a 1,1Ј-N-substituted ferrocenediyl-
PdII complex did not catalyze the coupling of 4-CNC6H4Cl
1-Mesityl-3-(4-methoxybenzyl)imidazolium Chloride (1a): The prod-
although this ligand was active in the coupling of aryl bro- uct was obtained from the reaction of: 4-methoxybenzyl chloride
mides.[39] In comparison, good results (62% yield) were ob-
(0.87 g, 5.60 mmol), 1-mesitylimidazole (1.09 g, 5.85 mmol), CHCl3
(30 mL), and Et2O (70 mL). Yield: 0.85 g (2.48 mmol, 42%). M.p.
tained in the reaction of 4-chlorotoluene and benzenebo-
ronic acid in pure water by using microwaves instead of
conventional heating.[40]
It is known that polar calixarenes form host–guest com-
plexes with aromatic compounds[31] and imidazolium
groups can act as recognition elements for anions.[41] From
this we could hypothesize that some kind of supramolecular
effect is playing a crucial role in this Suzuki coupling reac-
Ͼ205 °C (decomp.). IR (KBr): ν = 3109 (m), 3072 (m) (Ar-H), 2956
˜
(s) (C–H), 1612 (m), 1586 (w), 1544 (m), 1514 (s) (C=C and C=N),
1487 (w), 1459 (m), 1379 (w), 1305 (w) (C–H), 1250 (s), 1212 (m),
1196 (w), 1177 (m), 1159 (w), 1030 (m) (Ar-O–C), 850 (w), 818 (w),
754 (w) (Ar-H) cm–1. 1H NMR (CDCl3): δH = 2.02 and 2.31 (2s, 6
H and 3 H, ArCH3), 3.78 (s, 3 H, ArOCH3), 5.85 (s, 2 H, Ar-
CH2Im), 6.86–6.89 (m, 2 H, Ar-H), 6.95 (s, 2 H, Ar-H), 7.15 (t, J
= 1.8 Hz, 1 H, Im), 7.60–7.63 (m, 2 H, Ar-H), 7.87 (t, J = 1.4 Hz,
tion in pure water. Microsolubilization of hydrophobic 1 H, Im), 10.75 (s, 1 H, NCHN) ppm. 13C NMR (CDCl3): δC
=
17.5 and 20.9 (ArCH3), 52.8 (ArCH2Im), 55.2 (OCH3), 114.6,
122.6, 123.1, 125.8, 129.7, 129.8, 130.7, 134.0, 138.0, 141.0, 160.1
(Ar-C and Im-C) ppm. MS:(CI): calcd. for C20H23N2O: 307.2;
found m/z = 307.0 [M – Cl]+. C20H23N2OCl·0.4H2O (350.07):
calcd. C 68.62, H 6.85, N 8.00; found C 68.55, H 6.85, N 8.57.
starting material by a host–guest complex formed in an
inverse phase-transfer catalysis is conceivable[31] as well
as activation of the base[42] by complexation of the
counteranion.[43]
1-(2,6-Diisopropylphenyl)-3-(4-methoxybenzyl)imidazolium Chloride
(1b): The product was obtained from the reaction of: 4-meth-
oxybenzyl chloride (3.00 g, 19.2 mmol), 1-(2,6-diisopropylphenyl)
imidazole (4.57 g, 20.0 mmol), CHCl3 (30 mL), and Et2O (70 mL).
Conclusion
In summary, catalytic species derived from calixarene-
based imidazolium salts as ligand precursors show high ac- Yield: 7.00 g (18.2 mmol, 95%). M.p. 173–175 °C. IR (KBr): ν =
˜
3153 (w), 3124 (m), 3073 (m) (Ar-H), 2964 (s), 2931 (s), 2870 (m),
2837 (m) (C–H), 1611 (m), 1585 (w), 1561 (m), 1537 (m), 1514 (s)
(C=C and C=N), 1459 (s) (C–H), 1382 (m), [C(CH3)2], 1305 (m),
(C–H), 1253 (s), 1176 (s), 1118 (m), 1032 (m) (Ar-O–C), 890 (w),
tivity in the Suzuki cross-coupling of aryl chlorides. Bulky
substituents on both the heterocyclic and macrocyclic skel-
eton enhanced the catalytic efficiency. This is probably due
to the strain induced into the catalytically active metal–
organic species. The catalytic protocol tested in dioxane as
the organic solvent could be used without further adapta-
tion for the coupling of aryl chlorides in aqueous solution.
Although the catalytic activity decreased it was still possible
to form biaryls even in pure water indicating that calix-
850 (w), 817 (m), 760 (m) (Ar-H) cm–1. 1H NMR (CDCl3): δH
=
1.10 and 1.17 [d, 2× J = 6.8 Hz, 2×6 H, CH(CH3)2], 2.22 [sept, J
= 6.8 Hz, 2 H, CH(CH3)2], 3.78 (s, 3 H, ArOCH3), 5.91 (s, 2 H,
ArCH2Im), 6.84–6.88 (m, 2 H, Ar-H), 7.15 (t, J = 1.8 Hz, 1 H,
Im), 7.26 (d, J = 7.8 Hz, 2 H, Ar-H), 7.50 (t, J = 7.8 Hz, 1 H, Ar-
H), 7.65–7.69 (m, 2 H, Ar-H), 8.16 (t, J = 1.7 Hz, 1 H, Im), 10.81
arene-based imidazolium salts are promising as ligand pre- (s, 1 H, NCHN) ppm. 13C NMR (CDCl3): δC = 23.8 and 24.2
[CH(CH3)2], 28.5 [CH(CH3)2], 52.7 (ArCH2Im), 55.1 (OCH3),
114.4, 123.0, 123.9, 124.4, 126.1, 130.3, 130.6, 131.5, 138.3, 145.2,
160.1 (Ar-C and Im-C) ppm. MS (CI): calcd. for C23H29N2O:
349.2; found m/z = 349 [M – Cl]+. C23H29N2OCl (384.95): calcd.
C 71.76, H 7.59, N 7.27; found C 71.35, H 7.61, N 7.41.
cursors for selective organometallic catalysis in aqueous
solution, an environmentally benign reaction media.
Experimental Section
5,17-Bis[(3-mesitylimidazolium-1-yl)methyl]-11,23-bis(methoxy-
methyl)-25,26,27,28-tetrapropoxycalix[4]arene Dichloride (4a): The
product was obtained by refluxing 5,17-bis(chloromethyl)-11,23-
bis(methoxymethyl)-25,26,27,28-tetrapropoxycalix[4]arene
(800 mg, 1.03 mmol), 1mesitylimidazole (402 mg, 2.16 mmol),
CHCl3(abs.) (10.0 mL), and Et2O (70 mL) for 2 d. Yield: 490 mg
General Remarks: Melting points were determined with a Büchi
B-540 apparatus and are uncorrected. Infrared (IR) spectra were
obtained with a Bruker Vector 22 instrument using KBr pellets
unless otherwise stated. Absorptions (ν) are given in wavenumbers
˜
(cm–1). NMR spectra were recorded with a Bruker DRX 400 in-
strument (400.13 MHz for 1H and 100.62 MHz for 13C). Tet-
ramethylsilane was used as the internal standard (δ = 0.00 ppm)
for 1H NMR spectroscopy and the solvent signals for 13C NMR
spectroscopy [δ (CDCl3) = 77.0, δ ([D6]DMSO) = 39.5, δ ([D4]meth-
anol) = 49.3 ppm]. Chemical shifts (δ) are given in ppm and coup-
ling constants (J) in Hz. Assignments of 13C chemical shifts are
based on proton-coupled 13C, (C,H) correlation, and DEPT-135
spectra. Mass spectra were obtained with a Finnigan MAT
TSQ7000 (FAB) or Bruker Daltonics Reflex III (MALDI-TOF)
spectrometer. All reaction mixtures were stirred magnetically. The
synthesis of calixarenes 2 and 3 has been reported previously.[32]
(0.48 mmol, 47%). M.p. Ͼ200 °C (decomp.). IR (KBr): ν = 2962
˜
(s), 2926 (s), 2874 (s) (C–H), 1607 (w), 1546 (m) (C=C and C=N),
1465 (s), 1379 (m), 1292 (w) (C–H), 1216 (m), 1145 (m), 1092 (m),
1067 (m), 1039 (m), (Ar-O–C and C–O), 861 (w), 751 (w) (Ar-
H) cm–1. 1H NMR (CDCl3): δH = 0.88 and 1.10 (t, J = 7.5, 7.3 Hz,
2×6 H, CH2CH3), 1.85–1.96 (m, 8 H, CH2CH3), 2.04 and 2.31 (s,
12 H and 6 H, ArCH3), 3.16 (d, J = 13.1 Hz, 4 H, ArCH2Ar), 3.45
(s, 6 H, OCH3), 3.70 and 4.01 (t, J = 6.8, 8.2 Hz, 2×4 H, ArOCH2),
4.46 (d, J = 13.4 Hz, 4 H, ArCH2Ar), 4.49 (s, 4 H, ArCH2O), 5.25
(s, 4 H, ArCH2Im), 6.33 (s, 4 H, Ar-H), 6.95 (s, 4 H, Ar-H), 7.12
(s, 4 H, Ar-H), 7.28 (s, 2 H, Im), 7.35 (s, 4 H, Im), 10.09 (s, 2 H,
NCHN) ppm. 13C NMR (CDCl3): δC = 9.7 and 10.6 (CH2CH3),
17.5 and 20.9 (Ar-CH3), 22.8 and 23.4 (CH2CH3), 30.9 (ArCH2Ar),
General Procedure for the Synthesis of 1-Aryl-3-(4-methoxybenzyl)-
imidazolium Chlorides (1):: A solution of p-methoxybenzyl chloride
Eur. J. Org. Chem. 2006, 2378–2383
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2381

T. Brendgen, M. Frank, J. Schatz
FULL PAPER
53.1 (ArCH2Im), 58.3 (OCH3), 74.8 (ArCH2O), 76.4 and 77.1 (Ar-
OCH2), 122.2 and 123.3 (Im-C), 125.9, 128.6, 128.9, 129.6, 130.8,
132.0, 134.2, 134.8, 136.1 (Ar-C), 137.2 (Im-C), 140.8, 156.5, 157.1
(Ar-C) ppm. MS (MALDI-TOF): calcd. for C60H71N4O5: 927.5;
BMBF for a Ph. D. grant. Generous support from Prof. G. Maas,
University of Ulm, is gratefully acknowledged.
found m/z = 927.0 [M – 2HCl – OCH3]+. C60H76N4O6Cl2 [1] N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457–2483.
[2] S. Kotha, K. Lahiri, D. Kashinath, Tetrahedron 2002, 58, 9633–
(1020.18): calcd. C 70.64, H 7.51, N 5.49; found C 71.17, H 7.69,
N 4.79.
9695.
[3] A. F. Littke, G. C. Fu, Angew. Chem. 2002, 114, 4350–4386;
Angew. Chem. Int. Ed. 2002, 41, 4176–4211.
[4] A. C. Hillier, G. A. Grasa, M. S. Viciu, H. M. Lee, C. Yang,
S. P. Nolan, J. Organomet. Chem. 2002, 653, 69–82.
[5] M. Miura, Angew. Chem. 2004, 116, 2251–2253; Angew. Chem.
Int. Ed. 2004, 43, 2201–2203.
[6] H.-W. Wanzlick, E. Schikora, Angew. Chem. 1960, 72, 494.
[7] D. Bourissou, O. Guerret, F. Gabbai, G. Bertrand, Chem. Rev.
2000, 100, 39–92.
[8] M. Regitz, Angew. Chem. 1996, 108, 791–794; Angew. Chem.
Int. Ed. Engl. 1996, 35, 725–728.
5,17-Bis[(3-isopropylimidazolium-1-yl)methyl]-11,23-bis(methoxy-
methyl)-25,26,27,28-tetrapropoxycalix[4]arene Dichloride (4d): The
product was obtained by refluxing: 5,17-bis(chloromethyl)-11,23-
bis(methoxymethyl)-25,26,27,28-tetrapropoxycalix[4]arene (1.00 g,
1.29 mmol), 1isopropylimidazole (299 mg, 2.71 mmol), CHCl3(abs.)
(10.0 mL), and Et2O (70 mL) for 2 d. Yield: 0.81 g (0.81 mmol,
63%). M.p. 133–135 °C. IR (KBr): ν = 2966 (s), 2933 (s), 2875 (s)
˜
(C–H), 1606 (w), 1554 (m) (C=C and C=N), 1464 (s), 1379 (m),
1309 (m) (C–H), 1274 (m), 1222 (m), 1179 (m), 1147 (s), 1087 (m),
1040 (w) (Ar–O–C and C–O), 888 (w), 865 (w), 753 (w) (Ar- [9] W. A. Herrmann, C. Köcher, Angew. Chem. 1997, 109, 2256–
H) cm–1. 1H NMR (CDCl3): δH = 0.88 and 1.10 (t, J = 7.6, 7.5 Hz,
2×6 H, CH2CH3), 1.59 [d, J = 6.8 Hz, 12 H, CH(CH3)2] 1.84–1.98
(m, 8 H, CH2CH3), 3.16 (d, J = 13.4 Hz, 4 H, ArCH2Ar), 3.47 (s,
6 H, OCH3), 3.68 and 4.01 (t, J = 6.8, 8.2 Hz, 2×4 H, ArOCH2),
4.44 (d, J = 13.4 Hz, 4 H, ArCH2Ar), 4.47 (s, 4 H, ArCH2O), 4.74
[sept, J = 6.7 Hz, 2 H, NCH(CH3)2], 4.93 (s, 4 H, ArCH2Im), 6.26
(s, 4 H, Ar-H), 6.80 (t, J = 1.6 Hz, 2 H, Im), 7.12 (s, 4 H, Ar-H),
7.65 (t, J = 1.6 Hz, 2 H, Im), 10.24 (s, 2 H, NCHN) ppm. 13C
NMR (CDCl3): δC = 9.6 and 10.6 (CH2CH3), 22.7 (CH2CH3), 22.9
[CH(CH3)2], 23.3 (CH2CH3), 30.8 (ArCH2Ar), 52.7 (ArCH2Im),
53.0 [NCH(CH3)2], 58.3 (OCH3), 74.7 (ArCH2O), 76.4 and 77.1
(ArOCH2), 120.1 and 121.0 (Im-C), 125.5, 128.7, 128.9, 131.8,
134.6 (Ar-C), 135.2 (Im-C), 136.1, 156.4, 157.0 (Ar-C) ppm. MS
(MALDI-TOF): calcd. for C58H78N4O6Cl: 961.6; found m/z =
961.4 [M – Cl]+. C58H78N4O6Cl2·2H2O (1034.21): calcd. C 67.36,
H 7.99, N 5.42; found C 67.21, H 8.16, N 5.57.
2282; Angew. Chem. Int. Ed. Engl. 1997, 36, 2162–2187.
[10] N. M. Scott, S. P. Nolan, Eur. J. Inorg. Chem. 2005, 1815–1828.
[11] A. C. Hillier, S. P. Nolan, Platinum Met. Rev. 2002, 46, 50–64.
[12] M. C. Perry, K. Burgess, Tetrahedron: Asymmetry 2003, 14,
951–961.
[13] C. W. K. Gstöttmayr, V. P. Böhm, E. Herdtweck, M. Grosche,
W. A. Herrmann, Angew. Chem. 2002, 114, 1421–1423; Angew.
Chem. Int. Ed. 2002, 41, 1363–1365.
[14] H. Lebel, M. K. Janes, A. B. Charette, S. P. Nolan, J. Am.
Chem. Soc. 2004, 126, 5046–5047.
[15] G. A. Grasa, M. S. Viciu, J. Huang, C. Zhang, M. L. Trudell,
S. P. Nolan, Organometallics 2002, 21, 2866–2873.
[16] A. Fürstner, A. Leitner, Synlett 2001, 290–292.
[17] C. Zhang, J. Huang, M. L. Trudell, S. P. Nolan, J. Org. Chem.
1999, 64, 3804–3805.
[18] N. Hadei, E. A. B. Kantchev, C. J. O’Brien, M. G. Organ, Org.
Lett. 2005, 7, 1991–1994.
[19] P. E. Garrou, Chem. Rev. 1985, 85, 171–185.
[20] W. A. Herrmann, M. Elison, J. Fischer, C. Köcher, G. R. J.
Artus, Angew. Chem. 1995, 107, 2602–2605; Angew. Chem. Int.
Ed. Engl. 1995, 34, 2371–2374.
[21] B. Cornis, W. A. Herrmann (Eds.), Aqueous-Phase Organome-
tallic Catalysis in Aqueous-Phase Organometallic Catalysis,
Wiley-VCH, Weinheim, 2004.
[22] C.-J. Li, Chem. Rev. 2005, 105, 3095–3166.
[23] P. A. Grieco (Ed.), Organic Synthesis in Water, Blackie Aca-
demic & Professional, London, Weinheim, New York, Tokyo,
Melbourne, Madras, 1998.
Suzuki Cross-Coupling Reactions: The necessary ligand 1–4 (3 mol-
%) was added to degassed solvent in vials that could be sealed with
a screw-cap. After adding base (2 mmol) and Pd(OAc)2 (3 mol-%)
as the source of palladium the reaction mixture was heated to 80 °C
for 30 min. During this period of time the solutions turned deep-
red; the aryl halide (1.0 mmol) and benzeneboronic acid (1.5 mmol)
were then added under an inert atmosphere and the sealed reaction
vessels were heated to 80 °C in a heating block that held up to 24
test tubes. After the desired time of heating (Table 1) the reaction
was stopped and the product ratio determined. For this purpose,
an aliquot was withdrawn from the reaction mixture and analyzed
by NMR spectroscopy. No volatiles were removed because such a
procedure changed the product ratio as proven by blank experi-
ments.
[24] S. Otto, J. B. F. N. Engberts, Org. Biomol. Chem. 2003, 1, 2809–
2820.
[25] A. Arcadi, G. Cerichelli, M. Chiarini, M. Correa, D. Zorzan,
Eur. J. Org. Chem. 2003, 20, 4080–4086.
[26] R. B. Bedford, M. E. Blake, C. P. Butts, D. Holder, Chem.
Commun. 2003, 466–467.
[27] H. Sakurai, T. Tsukuda, T. Hirao, J. Org. Chem. 2002, 67,
For the cross-coupling reaction in aqueous media the reaction mix-
ture was extracted with CHCl3. The combined organic extracts
were filtered through a short pad of Celite, an aliquot (0.2 mL) was
withdrawn, CDCl3 (0.4 mL) was added, and the product ratio was
determined by NMR spectroscopy as before. The product ratio
over the whole concentration range was not affected by the extrac-
tion process as indicated by blank extraction experiments per-
formed on all solvent mixtures. The yields quoted are the average
yields obtained from two to five independent runs.
2721–2722.
[28] Y. Zhao, Y. Zhou, D. Ma, J. Liu, L. Li, T. Y. Zhang, H. Zhang,
Org. Biomol. Chem. 2003, 1, 1643–1646.
[29] W. Zhang, C. Hiu-Tung Chen, Y. Lu, T. Nagashima, Org. Lett.
2004, 6, 1473–1476.
[30] D. Sauer, Y. Wang, Org. Lett. 2004, 6, 2793–2796.
[31] M. Baur, M. Frank, J. Schatz, F. Schildbach, Tetrahedron 2001,
57, 6985–6991.
[32] F. Hapiot, J. Lyskawa, H. Bricout, E. Monflier, Adv. Synth.
Catal. 2004, 346, 83–89.
[33] M. Frank, G. Maas, J. Schatz, Eur. J. Org. Chem. 2004, 607–
613.
Acknowledgments
[34] R. K. Arvela, N. E. Leadbeater, M. S. Sangi, V. A. Williams, P.
Granados, R. D. Singer, J. Org. Chem. 2005, 70, 161–168.
[35] A. F. Littke, G. C. Fu, Angew. Chem. 1998, 110, 3586–3587;
Angew. Chem. Int. Ed. 1998, 37, 3387–3388.
This work was supported by the Deutschen Forschungsgemein-
schaft. M.F. thanks the Fonds der Chemischen Industrie and the
2382
www.eurjoc.org
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2006, 2378–2383

The Suzuki Coupling of Aryl Chlorides in Aqueous Media
FULL PAPER
[36] G. Altenhoff, R. Goddard, C. W. Lehmann, F. Glorius, Angew.
Chem. 2003, 115, 3818–3821; Angew. Chem. Int. Ed. 2003, 42,
3690–3693.
[37] K. Arentsen, S. Caddick, F. G. N. Cloke, A. P. Herring, P. B.
Hitchcock, Tetrahedron Lett. 2004, 45, 3511–3515.
[38] C. R. LeBlond, A. T. Andrews, Y. Sun, J. R. Sowa Jr, Org. Lett.
2001, 3, 1555–1557.
[40] N. E. Leadbeater, M. Marco, Org. Lett. 2002, 4, 2973–2976.
[41] H. Ihm, S. Yun, H. G. Kim, J. K. Kim, K. S. Kim, Org. Lett.
2002, 4, 2897–2900.
[42] T. Fahlbusch, M. Frank, J. Schatz, D. Schühle, J. Org. Chem.
2006, 71, 1688–1691.
[43] T. Fahlbusch, M. Frank, J. Schatz, H. Schmaderer, Eur. J. Org.
Chem., DOI: 10.1002/ejoc.200500825.
[39] Z. Weng, L. L. Koh, T. S. A. Hor, J. Organomet. Chem. 2004,
689, 18–24.
Received: December 2, 2005
Published Online: March 13, 2006
Eur. J. Org. Chem. 2006, 2378–2383
© 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2383