Suzuki cross-coupling mediated by tetradentate N-heterocyclic carbene (NHC)-palladium complexes in an environmentally benign solvent

Article abstract of DOI:10.1039/b302646a

A highly effective, easy to handle and environmentally benign process for palladium mediated Suzuki cross-coupling was developed. By utilizing a solid support based NHC-palladium catalyst, cross couplings of aryl bromides with phenylboronic acid were achieved in neat water under air. A high ratio of substrate to catalyst was also realized.

Full text of DOI:10.1039/b302646a

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Suzuki cross-coupling mediated by tetradentate N-heterocyclic
carbene (NHC)–palladium complexes in an environmentally benign
solvent†
Yuanhong Zhao,a Yongyun Zhou,a Dandan Ma,a Jingping Liu,a Liang Li,a Tony Y. Zhangb and
Hongbin Zhang*a
a School of Pharmacy, Yunnan University, Kunming, Yunnan 650091, P. R. China.
E-mail: zhang_hongbin@hotmail.com; Tel: 86 871 5031119
b Chemical Process Research and Development, Lilly Research Laboratories,
Lilly Corporate Center, Indianapolis, IN 46285-4813, USA
Received 10th March 2003, Accepted 22nd April 2003
First published as an Advance Article on the web 25th April 2003
Table 1 Room temperature Suzuki cross-coupling of aryl bromidesa
A highly effective, easy to handle and environmentally
benign process for palladium mediated Suzuki cross-
coupling was developed. By utilizing a solid support based
NHC–palladium catalyst, cross couplings of aryl bromides
with phenylboronic acid were achieved in neat water under
air. A high ratio of substrate to catalyst was also realized.
Since the discovery made by Suzuki and Miyaura in 1981,1
palladium catalyzed cross-coupling of arylboronic acids with
aryl halides, the Suzuki reaction, has been intensively studied
for its important applications in biaryl synthesis.2 In the last five
years, much attention had been paid towards the activation of
aryl chlorides which are generally less expensive and more
accessible substrates.3 Recent advances in this field have led to
the discovery of several effective ligated palladium systems that
can effect the cross-coupling between aryl chlorides and aryl-
boronic acids under mild conditions.4 Although activation of
aryl chlorides has been realized by employing these catalytic
systems, the usefulness of this process in industry was com-
promised by the requirement of a relatively high loading of
palladium (with 1–3% mol equiv.) and ligand. From the indus-
trial point of view, however, the cost of the aryl halide is only
one of the factors contributing to the total cost; as a matter of
fact, cheaper ligands that can be used in an environmentally
benign solvent while in low concentration for the activation of
aryl bromides are also highly desired. In this article, we wish to
report an air and water stable, highly effective tetradentate
N-heterocyclic carbene (NHC) ligated palladium catalyst that
can be used in high substrate to catalyst ratio (103–106) towards
the activation of aryl bromides.‡
ArBr
Time/h
mol% Pd
Yield (%)
4-Bromoanisole
4-Bromoanisole
4
48
10
2
22
22
15
15
24
0.1
0.01
0.1
0.1
0.1
0.1
0.1
0.1
0.1
98
98
65
98
84
97
98
71
98
4-Bromoveratrole
2-Bromobenzaldehyde
3-Bromoquinoline
9-Bromophenanthrene
3-Bromotoluene
3-Bromopyridine
5-Bromopyrimidine
a For reaction conditions see Notes and references. Reaction conditions
and time are not optimized. Yields represent isolated yield based on
aryl halides.
solvent (see Table 1). Although numerous non-phosphine
ligands have been developed for Suzuki cross-coupling,6 to
the best of our knowledge, synthesis of hindered biaryls has
never been reported by utilizing non-phosphine ligands. It is
noteworthy that ligand 1 can be used to effect the coupling
of sterically hindered aryl bromides. For the synthesis of
hindered biaryls, n-butanol was the solvent of choice. Other
solvents such as 1,4-dioxane or toluene tended to promote
self-coupling of arylboronic acids as well as debromination
of aryl bromides. Activation of aryl chlorides was also achieved
by employing ligand 1 in refluxing n-butanol under air (see
Table 2).
Aiming to find novel ligands for palladium catalyzed
transformations, we synthesized a number of tetradentate
imidazoliums as depicted in Scheme 1.5 By coupling with
palladium() acetate, ligands 1 and 2 are highly effective for
the Suzuki reaction. Room temperature cross couplings of aryl
bromides with phenylboronic acid were realized in aqueous
ethanol (70–95%), a cheaper and environmentally benign
There has recently been considerable interest in the appli-
cation of water as a solvent for the Suzuki reaction.6e,7 Due to a
solubility problem, however, the catalyst generated by directly
mixing NHC ligand 1 with palladium() acetate under the
above reaction conditions failed to afford good Suzuki cross-
coupling in neat water with palladium black formation being
observed. We reckoned that a preformed solid support based
catalyst might be suitable for reactions in water. Thus NHC
ligand 1 (0.055 mmol, 75 mg) and palladium() acetate
Scheme 1 Ligands for Suzuki cross-coupling.
† Electronic supplementary information (ESI) available: general
experimental procedures and characterization data. See http://
www.rsc.org/suppdata/ob/b3/b302646a/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 3
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 4 3 – 1 6 4 6
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Table 2 Suzuki reaction of aryl halides in n-butanola
ArBr
Time/h
mol% Pd
0.5
Product
Yield
98%
4
8
0.5
0.5
83%
55%
3
20
20
10
5
0.5
0.5
0.5
0.5
50%
77%
85%
74%
3
0.5
78%
2
0.1
98%
98%
24
0.0001
3
0.1
98%
a Reactions were carried out in n-butanol at reflux under air. Yields represent isolated yield based on aryl halides.
(0.1 mmol, 22.49 mg) were stirred in 1,2-dichlorethane (20 mL)
for 24 hours then silica gel or alumina (200–300 mesh, 2.505 g)
was added. After 2 hours, the solvent was removed under
vacuum to yield the solid support based catalyst. By variation
of the amount of silica gel or alumina added, the NHC–
palladium catalyst absorbed on an inorganic solid surface in
different concentrations can be obtained very conveniently.
To our delight, the catalytic system prepared in this way was
also effective towards the activation of aryl bromides. It is of
industrial importance that the cross-coupling reaction mediated
by solid support based NHC–carbene palladium could be
carried out in neat water with no presence of a phase transfer
catalyst such as n-Bu4NBr (see Table 3, Method A).8 The results
summarized in Table 3 are the only examples of a Suzuki cross-
coupling mediated solely by an NHC ligated palladium catalyst
in water. The solid support based NHC–palladium complex can
be stored for more than two months without significant loss of
activity and can be reused (2–3 times) in refluxing water under
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 4 3 – 1 6 4 6
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Table 3 Suzuki cross-coupling mediated by solid support based catalysts in neat watera
ArBr
Time (h)
4
mol% Pd
0.1
Product
Yieldmethod
98%A
48
8
0.0001
0.1
70%A
90%A
48
0.0001
76%A
48
24
0.0001
0.1
55%A
80%A
8
8
0.1
0.1
70%A
61%A
48
28
0.1
0.5
52%A
87%A
8
8
8
0.1
0.1
0.1
92%B
75%B
78%B
a For general procedure see reference 8. Reaction conditions and time are not optimized. Yields represent isolated yield based on aryl halides.
air. A high ratio of substrate to catalyst (106) was realized in
aqueous solvent (Entries 2,4,5 in Table 3).
handle and environmentally benign process for palladium
mediated Suzuki cross-coupling. By utilizing a solid support
based NHC–palladium catalyst, cross coupling of aryl brom-
ides, including highly electron rich substrates, were realized
in neat water. The ligands are comparatively inexpensive and
very easily synthesized. The process described herein has the
potential for large-scale industrial application. Further utiliz-
ation of these NHC–palladium complexes is currently under
investigation.
In order to determine the effect of adding silica gel or alu-
mina, Suzuki cross-couplings of 4-bromoanisole with phenyl-
boronic acid in ethanol (95%) were carried out both at room
temperature and at reflux in the presence of NHC ligand 1,
palladium() acetate and silica gel (or alumina). No reaction
rate enhancement or yield improvement was observed in either
case. For the NHC–palladium mediated Suzuki reaction in neat
water, however, putting silica gel or alumina in the reaction
system8 (Method B) did have a good effect towards the stabiliz-
ation of the catalyst and afforded similar results to those reac-
tions which were conducted by using a preformed solid support
based catalyst. It was observed that without NHC ligand 1,
palladium() acetate alone on silica gel or alumina was less
effective towards the same cross-coupling reaction. In the
absence of palladium() acetate and NHC ligand, silica gel or
alumina alone were unable to promote Suzuki cross-coupling in
neat water as well as in ethanol (95%).
Acknowledgements
This work was supported by a grant from the foundation
of the China Ministry of Education for the promotion of
Excellent Young Scholar and a grant for scientific research on
fundamental areas from Yunnan Provincial Natural Science
Foundation (2000B0022R).
Notes and references
It is noteworthy that all cross-couplings listed in Table 1,
Table 2 and Table 3 were carried out under air and no visible
palladium black formation was observed during the catalytic
process.
‡ Reaction conditions: palladium() acetate (0.1 mmol%), NHC ligand
1 (0.05 mmol%), K2CO3 (2 mmol), aryl bromide (1 mmol) and phenyl-
boronic acid (1.5 mmol) in ethanol (70–95%, 5 mL) were stirred at
room temperature under air. The reaction was monitored by thin-layer
chromatography. After removal of the solvent, the residue was diluted
In summary, we have developed a highly effective, easy to
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 4 3 – 1 6 4 6
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with water (50 mL) and extracted with diethyl acetate (3 × 15 mL). The
organic phases were combined, washed with brine and dried over
anhydrous Na2SO4. The solvent was removed and the residue was
chromatographed on silica gel to afford the pure products. All new
s, Himidazole-5), 8.14 (4H, t, J = 1.6 Hz, Himidazole-3), 8.04 (4H, t,
J = 1.6 Hz, Himidazole-2), 7.81 (2H, s, Hbenzene), 7.14 (8H, s, Hmesitylene
-
3,5), 5.88 (8H, s, Hbenzyl), 2.33 (12H, s, CH3), 2.02 (24H, s, CH3).
13C-NMR (75 MHz, DMSO): δ 140.60, 138.26, 134.92, 134.69,
133.49, 131.46, 129.62, 124.41, 123.74, 49.27, 21.01, 17.76. MS
(FABϩ) m/z: 1116 (2%), 1034 (0.5), 848 (1), 661 (1), 583 (1.5), 499 (3),
314 (16), 279 (4), 187 (100), 146 (10). HRMS (ESIϩ) m/z
Found: 1115.3267 [M ϩ 4H Ϫ Br]5ϩ, C58H70Br3N8 requires 1115.3273.
Compound 3: IR: νmax (KBr)/cmϪ1: 3497 (m), 3425 (m), 3288 (m),
3129 (m), 3039 (s), 2980 (m), 1630 (w), 1563 (m), 1478 (w), 1446 (w),
1376 (w), 1349 (w), 1319 (w), 1292 (w), 1234 (w), 1209 (s), 1137 (m),
1
compounds were characterized by H-NMR, 13C-NMR and GC-MS.
Yield represents isolated yield based on aryl bromide.
1 N. Miyaura, T. Yanagi and A. Suzuki, Synth. Commun., 1981, 11,
513.
2 For reviews see (a) N. Miyaura and A. Suzuki, Chem. Rev., 1995, 95,
2457; (b) S. P. Stanforth, Tetrahedron, 1998, 54, 263; (c) A. Suzuki,
J. Organomet. Chem., 1999, 576, 147.
1
1017 (w). H-NMR (300 MHz, DMSO): δ 9.68 (4H, s, Himidazole-5),
3 See the following for leading references: (a) W. A. Herrmann,
C.-P. Reisinger and M. J. Spiegler, J. Organomet. Chem., 1998, 557,
93; (b) A. F. Littke and G. C. Fu, Angew. Chem., Int. Ed., 1998, 38,
3387; (c) X. Bei, H. W. Turner, H. Weinberg and A. S. Guram, J. Org.
Chem., 1999, 64, 6797; (d ) C. Zhang, J. Huang, M. L. Trudell and
S. P. Nolan, J. Org. Chem., 1999, 64, 3804; (e) J. P. Wolfe, R. A. Singer,
B. H. Yang and S. L. Buchwald, J. Am. Chem. Soc., 1999, 121, 9550;
( f ) C. Zhang and M. L. Trudell, Tetrahedron Lett., 2000, 41, 595;
(g) A. Zapf, A. Ehrentraut and M. Beller, Angew. Chem., 2000, 112,
4317; A. Zapf, A. Ehrentraut and M. Beller, Angew. Chem., Int. Ed.,
2000, 39, 4153; (h) V. P. W. Böhm, C. W. K. Gstöttmayr, T. Weskamp
and W. A. Herrmann, J. Organomet. Chem., 2000, 595, 186; (i) G. Y.
Li, J. Org. Chem., 2002, 67, 3643.
8.07 (4H, t, J = 1.8 Hz, Himidazole-3), 7.88 (4H, t, J = 1.8 Hz,
Himidazole-2), 7.62 (2H, s, Hbenzene), 5.72 (8H, s, Hbenzyl), 1.62 (36H, s,
CH3). 13C-NMR (75 MHz, DMSO): δ 135.47, 134.53, 132.16, 123.10,
120.89, 60.27, 48.75, 29.39. MS (FABϩ) m/z: 867 (4%), 785 (1), 662
(4), 537 (2), 458 (3), 309 (3), 252 (11), 217 (14), 195 (7), 125 (100), 69
(35). HRMS (ESIϩ) m/z Found: 867.2659 [M ϩ 4H Ϫ Br]5ϩ
,
C38H62Br3N8 requires 867.2647.
6 (a) H. Weissman and D. Milstein, Chem. Commun., 1999, 1901;
(b) D. A. Alonso, C. Najera and M. C. Pacheco, Org. Lett., 2000, 2,
1823; (c) R. B. Bedford and C. S. J. Cazin, Chem. Commun., 2001,
1540; (d ) G. A. Grasa, A. C. Hiller and S. P. Nolan, Org. Lett., 2001,
3, 1077; (e) L. Botella and C. Najera, Angew. Chem., Int. Ed., 2002,
41, 179; ( f ) W. A. Herrmann, Angew. Chem., Int. Ed., 2002, 41,
1290.
7 (a) K. H. Shaughnessy and R. S. Booth, Org. Lett., 2001, 3, 2757;
(b) H. Sakurai, T. Tsukuda and T. Hirao, J. Org. Chem., 2002, 67,
2721; (c) Y. M. A. Yamada, K. Takeda, H. Takahashi and S. Ikegami,
Org. Lett., 2002, 4, 3371.
8 General method for Suzuki cross-coupling in neat water: Method A:
Aryl bromide (1 mmol), phenylboronic acid (1.5 mmol), K2CO3
(2 mmol) and the solid support based catalyst (0.1 mmol%, 25 mg),
which was preformed by mixing palladium() acetate (22.5 mg) with
ligand 1 (75 mg) in 1,2-dichloroethane (20 mL) overnight and then
absorbed on alumina or silica gel (2.505 g), were stirred in neat water
(5 mL) at reflux. The reaction mixture was extracted with ethyl acet-
ate (3 × 10 mL). The organic phases were combined and washed with
brine and dried over anhydrous Na2SO4. The solvent was removed
and the residue was chromatographed on silica gel to afford the prod-
ucts. Method B: Palladium() acetate (0.1 mmol%), NHC ligand 1
(0.05 mmol%), K2CO3 (2 mmol), silica gel or alumina (25 mg), aryl
bromide (1 mmol) and phenylboronic acid (1.5 mmol) in neat water
(5 mL) were stirred at reflux under air for 8 hours. The reaction
mixture was extracted with ethyl acetate (3 × 10 mL). The organic
phases were combined and washed with brine and dried over
anhydrous Na2SO4. The solvent was removed and the residue was
chromatographed on silica gel to afford the products. All compounds
were characterized by 1H-NMR, 13C-NMR and GC-MS.
4 (a) A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000, 122,
4020; (b) C. W. K. Gstöttmayr, V. P. W. Böhm, E. Herdtweck,
M. Grosche and W. A. Herrmann, Angew. Chem., Int. Ed., 2002, 41,
1363.
5 The ligands were prepared by refluxing 1,2,4,5-tetrabromomethyl-
benzene with the corresponding 1-substituted imidazole in toluene
for 24 hours. Compound 1: IR: νmax (KBr)/cmϪ1: 3436 (s), 3119 (m),
3071 (m), 2966 (s), 2931 (m), 2871 (m), 1619 (w), 1546 (m), 1467 (m),
1460 (m), 1404 (w), 1388 (w), 1368 (m), 1313 (w), 1183 (m), 1145 (w),
1104 (w), 1069 (w), 1002 (w), 1018 (w), 958 (w), 936 (w).
1H-NMR (300 MHz, DMSO): δ 10.15 (4H, s, Himidazole-5), 8.29 (4H, t,
J = 1.3 Hz, Himidazole-3), 8.23 (4H, t, J = 1.3 Hz, Himidazole-2), 7.99 (2H,
s, Hbenzene), 7.63 (4H, t, J = 7.8 Hz, H2,6-diisopropylbenzene-4), 7.45 (8H, d,
J = 7.8 Hz, H2,6-diisopropylbenzene-3,5), 5.99 (8H, s, Hbenzyl), 2.29 (8H,
septet, J = 6.6 Hz, Me2CH), 1.14 (24H, d, J = 6.6 Hz, CH3), 1.12 (24H,
d, J = 6.6 Hz, CH3). 13C-NMR (75 MHz, DMSO): δ 145.44, 138.42,
135.02, 134.30, 131.91, 130.81, 125.70, 124.80, 123.84, 49.35, 28.47,
24.21, 24.18. MS (FABϩ) m/z: 1280 (1.5%), 1202 (0.5), 1066 (0.3),
667 (1), 583 (1), 517 (1), 437 (3), 357 (6), 321 (12), 229 (100). HRMS
(ESIϩ) m/z Found: 1281.4978 [M ϩ 2H Ϫ Br]3ϩ, C70H92Br3N8
requires 1281.4995. Compound 2: IR: νmax (KBr)/cmϪ1: 3414 (s), 3123
(s), 2979 (m), 1659 (m), 1609 (m), 1548 (s), 1484 (m), 1447 (m), 1402
(m), 1330 (w), 1290 (w), 1199 (m), 1156 (m), 1108 (s), 1069 (w), 1036
(w), 987 (w), 935 (w). 1H-NMR (300 MHz, DMSO): δ 9.77 (4H,
O r g . B i o m o l . C h e m . , 2 0 0 3 , 1, 1 6 4 3 – 1 6 4 6
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