An efficient diamine·copper complex-catalyzed coupling of arylboronic acids with imidazoles

Article abstract of DOI:10.1021/ol000033j

(Equation presented) A novel diamine·copper complex-catalyzed intermolecular coupling of arylboronic acids (1) with imidazoles (3) is described. In the presence of a catalytic amount of [Cu(OH)·TMEDA]₂Cl₂ (2), arylboronic acids (1) react smoothly with imidazoles (3) in dichloromethane at room temperature to give a variety of N-arylimidazoles (4) in good to excellent yields.

Full text of DOI:10.1021/ol000033j

ORGANIC
LETTERS
2000
Vol. 2, No. 9
1233-1236
An Efficient Diamine‚Copper
Complex-Catalyzed Coupling of
Arylboronic Acids with Imidazoles
James P. Collman* and Min Zhong
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
jpc@chem.stanford.edu
Received February 15, 2000
ABSTRACT
A novel diamine‚copper complex-catalyzed intermolecular coupling of arylboronic acids (1) with imidazoles (3) is described. In the presence
of a catalytic amount of [Cu(OH)‚TMEDA]2Cl2 (2), arylboronic acids (1) react smoothly with imidazoles (3) in dichloromethane at room temperature
to give a variety of N-arylimidazoles (4) in good to excellent yields.
The N-arylimidazole subunit is a commonly found motif in
pharmaceutical molecules. A huge number of drugs bearing
N-arylimidazolyl moieties have been reported to have a broad
range of significant biological activities, which include cyclic
AMP phosphodiesterase inhibitors,1a,b thromboxane synthase
inhibitors,1b-d cardiotonic agents,1e-g topical antiglaucoma
agents,1h and AMPA receptors antagonists.1i Accordingly,
the development of efficient methods for constructing
N-arylimidazole units remains an important area of organic
synthesis.
electron-deficient aryl halides have been well-documented
by Hartwig,2 Buchwald,3 and others,4 mild and efficient
methods for the arylation of N-H-containing heterocycles
are still not satisfactory. The nucleophilic aromatic sub-
stitution1d,f,g,i,5 of imidazoles with aryl halides is one of the
most commonly used methods for constructing N-arylimi-
(2) (a) Hartwig, J. F. Synlett 1997, 329-340. (b) Hartwig, J. F. Angew.
Chem., Int. Ed. Engl. 1998, 37, 2047-2067. (c) Hartwig, J. F. Acc. Chem.
Res. 1998, 31, 852-860. (d) Hamann, B. C.; Hartwig, J. F. J. Am. Chem.
Soc. 1998, 120, 7369-7370. (e) Hartwig, J. F.; Kawatsura, M.; Hauck, S.
I.; Shaughnessy, K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64,
5575-5580.
(3) (a) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
7901-7902. (b) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1348-1350. (c) Wolfe, J. P.; Buchwald, S.
L. J. Org. Chem. 1997, 62, 6066-6068. (d) Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (e)
Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
9722-9723. (f) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576, 125-146. (g) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed.
Engl. 1999, 38, 2413-2416. (h) Wolfe, J. P.; Buchwald, S. L. J. Org. Chem.
2000, 65, 1144-1157. (i) Wolfe, J. P.; Tomori, H.; Sadighi, J. P.; Yin, J.;
Buchwald, S. L. J. Org. Chem. 2000, 65, 1158-1174.
(4) For representative examples dealing with the amination of aryl halides,
see: (a) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4087-
4810. (b) Yamamoto, T.; Nishiyama, M.; Koie, Y. Tetrahedron Lett. 1998,
39, 2367-2370. (c) Nishiyama, M.; Yamamoto, T.; Koie, Y. Tetrahedron
Lett. 1998, 39, 617-620. (d) Bei, X.; Guram, A. S.; Turner, H. W.;
Weinberg, W. H. Tetrahedron Lett. 1999, 40, 1237-1240. (e) Brenner E.;
Schneider, R.; Fort, Y. Tetrahedron 1999, 55, 12829-12842. (f) Huang,
J.; Grasa, G.; Nolan, S. P. Org. Lett. 1999, 1, 1307-1309. (g) Song, J. J.;
Yee, N. K. Org. Lett. 2000, 2, 519-521.
The direct coupling of imidazoles with functionalized
arenes is the most efficient approach to N-arylimidazole units.
Although palladium- or nickel-catalyzed N-arylations of a
variety of amines and anilines with both electron-rich and
(1) (a) Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.;
Strosberg, A. M. J. Med. Chem. 1988, 31, 2136-2145. (b) Martinez, G.
R.; Walker, K. A. M.; Hirschfeld, D. R.; Bruno, J. J.; Yang, D. S.; Maloney,
P. J. J. Med. Chem. 1992, 35, 620-628. (c) Iizuka, K.; Akahane, K.;
Momose, D.; Nakazawa, M. J. Med. Chem. 1981, 24, 1139-1148. (d) Cozzi,
P.; Carganico, G.; Fusar, D.; Grossoni, M.; Menichincheri, M.; Pinciroli,
V.; Tonani, R.; Vaghi, F.; Salvati, P. J. Med. Chem. 1993, 36, 2964-2972.
(e) Sircar, I.; Duell, B. L.; Bobowski, G.; Bristol, J. A.; Evans, D. B. J.
Med. Chem. 1985, 28, 1405-1413. (f) Sircar, I.; Weishaar, R. E.; Kobylarz,
D.; Moos, W. H.; Bristol, J. A. J. Med. Chem. 1987, 30, 1955-1962. (g)
Gu¨ngo¨r, T.; Fouquet, A.; Teulon, J.-M.; Provost, D.; Cazes, M.; Cloarec,
A. J. Med. Chem. 1992, 35, 4455-4463. (h) Lo, Y. S.; Nolan, J. C.; Maren,
T. H.; Welstead, W. J., Jr.; Gripshover, D. F.; Shamblee, D. A. J. Med.
Chem. 1992, 35, 4790-4794. (i) Ohmori, J.; Shimizu-Sasamata, M.; Okada,
M.; Sakamoto, S. J. Med. Chem. 1996, 39, 3971-3979.
10.1021/ol000033j CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/13/2000

dazolyl moieties; however, this approach requires aryl halides
containing electron-withdrawing substituents, which limits
its scope. Another popular method for constructing N-
arylimidazoles is the traditional Ullmann-type coupling1a-c,e,g,h,j
of imidazoles with aryl halides. This coupling is successful
for a broader range of aryl halides, but it is usually performed
at high temperatures and gives varying yields. Recently,
Buchwald6 reported that this type of condensation can be
accomplished in a (CuOTf)2‚benzene/1,10-phenanthroline/
trans,trans-dibenzylideneacetone/Cs2CO3 system at relatively
low temperatures (110-125 °C). In addition to these
examples employing aryl halides, several couplings of other
activated aryls under mild conditions have also been
established. Lo´pez-Alvarado,7 for example, has described
N-arylation of imidazoles with p-tolyllead triacetate using a
catalytic amount of Cu(OAc)2 at 90 °C. However, this
method is limited to p-tolyllead, and also it produces toxic
organolead byproducts. Chan and Lam8 have reported a Cu-
(II) salt-promoted coupling to various N-arylimidazoles at
room temperature. This process is usually carried out by
treatment of commercially available arylboronic acids and
imidazoles with more than equimolar amounts of Cu(OAc)2
and either triethylamine or pyridine under ambient condi-
tions.9 The use of arylboronic acids is a significant improve-
ment over previous methods, although no catalytic process
of this coupling for preparing N-arylimidazoles has been
reported to date to our knowledge. We present here an
efficient diamine‚copper complex-catalyzed N-arylation of
imidazoles.
in the catalytic cycle,11 and used a 2/1 ratio of phenylboronic
acid (1a)/imidazole (3a) for the coupling according to Chan
and Lam’s studies.8 A general procedure for optimizing the
reaction condition is described as follows: 2 equiv of
phenylboronic acid (1a) are stirred overnight with 1 equiv
of imidazole (3a) and a catalytic amount of [Cu(OH)‚
TMEDA]2Cl2 (2) in dry dichloromethane under an atmo-
sphere of O2. As shown in Table 1, reaction yields were
Table 1. Effect of the Amount of [Cu(OH)‚TMEDA]2Cl2 (2)
on the Coupling
catalyst 2
yield
(%)b
entrya
(mol %)
1
2
3
4
5
6
2
5
7.5
10
15
20
5
54
62
71
73
72
a A typical procedure: A mixture of 2 mmol of phenylboronic acid (1a),
1 mmol of imidazole (3a), and a catalytic amount of [Cu(OH)‚TMEDA]2Cl2
(2) in 4 mL of dry dichloromethane is stirred at room temperature overnight
under an atmosphere of O2. b Isolated yields of N-phenylimidazole (4a)
represent the average of two runs.
Readily available Cu(OH)Cl‚TMEDA10 has been success-
fully employed in aerobic oxidative coupling of 2-naph-
thols,11 where dioxygen plays a critical role to regenerate
the active catalyst in the catalytic cycle. We believe that this
catalyst could be an excellent replacement for the Cu(II) salts
and tertiary amines that are used in Chan and Lam’s system.8
We have successfully employed and optimized this catalytic
system for the cross-coupling reaction of arylboronic acids
with imidazoles.
found to be dependent on the amount of 2. When 0.1 equiv
of 2 was used, the anticipated N-phenylimidazole (4a) was
obtained in 71% yield (entry 4, Table 1). However, only a
trace amount of 4a was formed using 0.02 equiv of 2 (entry
1, Table 1). Moreover, no significant improvement of the
yield of 4a was observed even employing more than 0.1
equiv of 2 (entries 5 and 6, Table 1).
In a preliminary study, we selected pure dioxygen gas as
a dioxygen source rather than ambient air because of the
importance of dioxygen for regenerating Cu(OH)Cl‚TMEDA
We have also investigated effects of varying the concen-
tration and ratio of reactants, the reaction atmosphere and
the addition of molecular sieves on the coupling reaction.
Varying concentrations of the reaction mixture over a given
range (0.1-0.5 M of 3a, 0.2-1.0 M of 1a) has no notable
effect on the reaction yield (entries 1-4, Table 2). On the
other hand, the ratio of phenylboronic acid (1a)/imidazole
(3a) is an important factor for this intermolecular reaction.
The optimal ratio of 1a/3a is 2/1 (entry 4, Table 1), which
gives the product in a higher yield compared to a 1/1 ratio
(entry 5, Table 2). However, none of the desired product
was obtained when a 1/2 ratio of 1a/3a was employed (entry
6, Table 2). Another variable is the reaction atmosphere. We
found that the reaction also succeeds under ambient condi-
tions, although a lower yield was found compared with that
using pure O2 (entries 2 and 7, Table 2). Not surprisingly,
none of the desired coupling product was generated under
N2 (entry 8, Table 2). Attempts to increase the reaction yield
by prolonging the reaction time were not effective. Overnight
stirring is optimal. The addition of 4 Å molecular sieves
(5) Antonini, I.; Cristalli, G.; Franchetti, P.; Grifantini, M.; Martelli, S.
Synthesis 1983, 47-49,
(6) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657-1660.
(7) (a) Lo´pez-Alvarado, P.; Avendan˜o, C.; Mene´ndez, J. C. Tetrahedron
Lett. 1992, 33, 659-662. (b) Lo´pez-Alvarado, P.; Avendan˜o, C.; Mene´ndez,
J. C. J. Org. Chem. 1995, 60, 5678-5682.
(8) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.;
Chan, D. M. T.; Combs, A. Tetrahedron Lett. 1998, 39, 2941-2944.
(9) This system has also been successfully applied to the N-arylation of
other types of N-H-containing heterocycles, see: (a) Chan, D. M. T.;
Monaca, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39,
2933-2936. (b) Cundy, D. J.; Forsyth, S. A. Tetrahedron Lett. 1998, 39,
7979-7982. (c) Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux,
D. Tetrahedron 1999, 55, 12757-12770.
(10) (a) Hay, A. S. J. Org. Chem. 1962, 27, 3320-3321. (b) de Jong, C.
R. H. I. In Organic Syntheses by Oxidation with Metal Compounds; Mijs,
W. J., de Jong, C. R. H. I., Eds.; Plenum Press Inc.: New York, 1986; pp
423-443. (c) Cu(OH)Cl‚TMEDA dimer ([Cu(OH)‚TMEDA]2Cl2) is com-
mercially available now from TCI (D2542).
(11) (a) Noji, M.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1994, 35,
7983-7984. (b) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto, S.;
Noji, M.; Koga, K. J. Org. Chem. 1999, 64, 2264-2271.
1234
Org. Lett., Vol. 2, No. 9, 2000

Table 2. Effects of the Ratio of Phenylboronic Acid (1a)/
Imidazole (3a), the Concentration of Reactants, the Reaction
Atmosphere, and Molecular Sieves (MS) on the Coupling
Table 3. Synthesis of a Variety of N-Arylimidazoles (4) by
[Cu(OH)‚TMEDA]2Cl2 (2) Catalyzed N-Arylation of
Arylboronic Acids (1) with Imidazoles (3)
entrya C (M)b 1a /3a
atmosphere MS (mg)c yield (%)d
1
2
3
4
5
6
7
8
9
0.5
2/1
2/1
2/1
2/1
1/1
1/2
2/1
2/1
2/1
2/1
O2
O2
O2
O2
O2
O2
air
N2
O2
O2
none
none
none
none
none
none
none
none
100
70
71
69
71
52
0
62
0
81
4
0.25
0.125
0.1
0.25
0.25
0.25
0.25
0.25
0.25
10
200
a A typical procedure: A mixture of phenylboronic acid (1a), 1 mmol
of imidazole (3a), and 0.1 mmol of [Cu(OH)‚TMEDA]2Cl2 (2) in dry
dichloromethane is stirred at room temperature overnight. b The concentra-
tion of reaction mixture is based on imidazole (3a) (1 mmol of 3a/mL of
dichloromethane). c The amount of 4 Å molecular sieves is based on
imidazole (3a) (mg of 4 Å MS/1 mmol of 3a). d Isolated yields of
N-phenylimidazole (4a) represent the average of two runs.
powder (100 mg of 4 Å MS/1 mmol of 3a) to the reaction
mixture results in a moderate improvement of the reaction
yield (entry 9, Table 2), which is consistent with Evans’
observation.12 However, molecular sieves inhibit the reaction
when greater quantities are used (200 mg of 4 Å MS/1 mmol
of 3a) (entry 10, Table 2).
Subsequently, a number of structurally and electronically
diverse substrates have been employed for this catalytic
coupling (Table 3). When either o- or p-tolylboronic acid
(1c or 1b) was used, the corresponding N-arylation products
were obtained in good yields (entries 1, 2, 6, and 9, Table
3). Upon treatment of p-fluorophenylboronic acid (1d) with
imidazole (3a), a fluoronated N-phenylimidazole (4d) was
formed in 58% yield (entry 3, Table 3). However, the cross-
coupling yields are depressed for methoxyphenylboronic
acids (entries 4, 5, and 10, Table 3). When o-methoxyphen-
ylboronic acid (1f) was applied to this coupling, only a trace
amount of the coupling product was obtained. However, the
yield of this coupling was improved dramatically by adding
a third equivalent of 1f (entry 4, Table 3). In fact, o-
methoxyphenylboronic acid (1f) shows a propensity to
decompose under the reaction conditions, which may account
for the low conversion.13 2-Methylimidazole (3b) also reacts
with 1b to yield a single coupling product in good yield
(entry 6, Table 3).
a A typical procedure: A mixture of 2 mmol of arylboronic acid (1), 1
mmol of imidazole (3), and 0.1 mmol of [Cu(OH)‚TMEDA]2Cl2 (2) in 4
mL of dry dichloromethane is stirred at room temperature overnight under
an atmosphere of O2. b Isolated yields of N-arylimidazoles (4) represent
the average of two runs. c A total of 1 mmol of 4-fluorophenylboronic acid
(1d) was used. d A total of 3 mmol of 2-methoxyphenylboronic acid (1f)
was used. e A total of 1 mmol of 2-tolylboronic acid (1c) was used. f A
total of 100 mg of 4 Å MS was added, and the reaction mixture was stirred
under ambient conditions.
To test the regioselectivity of the N-arylation reaction,
4(5)-substituted imidazoles were treated with o-tolylboronic
acid (1c). When 4(5)-methylimidazole (3c) was used, a
mixture of coupling compounds 4h and 4h′ was obtained in
66% yield with a 2.5/1 ratio. Furthermore, the 4h/4h′ ratio
increased to 3.8/1 with a decreased reaction yield (37%) by
employing a 1/1 ratio of 1c/3c (entry 7, Table 3). Changing
the methyl substituent on imidazole to a phenyl group further
increases the regioselectivity. When a 1/1 ratio of o-
tolylboronic acid (1c)/4(5)-phenylimidazole (3d) was em-
ployed, coupling products 4i and 4i′ were generated in 77%
yield with a ratio of 8.7/1. An additional equivalent of 1c
resulted in a lower ratio of 4i/4i′ (3.7/1), but a higher reaction
yield (94%) (entry 8, Table 3).
Moreover, benzimidazole (3e) reacts with arylboronic acids
to yield the corresponding N-arylbenzimidazoles (4j,k) in
good yields. However, when the coupling of p-tolylboronic
acid (1b) with 3e was performed under ambient conditions
(12) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998, 39,
2937-2940.
(13) (a) Kuivila, H. G.; Reuwer, J. F., Jr.; Mangravite, J. A. Can. J.
Chem. 1963, 41, 3081-3090. (b) Kuivila, H. G.; Reuwer, J. F., Jr.;
Mangravite, J. A. J. Am. Chem. Soc. 1964, 86, 2666-2670.
Org. Lett., Vol. 2, No. 9, 2000
1235

with the addition of 4 Å molecular sieves, 4k was generated
only in 19% yield (entries 9 and 10, Table 3). It should be
noted that when 4,5-dicyanoimidazole and methyl 4(5)-
imidazolyl-carboxylate were employed for the coupling, none
of the desired product was obtained.
putative Cu(III) intermediate (7) which would subsequently
undergo reductive elimination to give the N-arylimidazole
(4) along with the Cu(I) complex (8). The latter, should
readily regenerate catalyst 210a,b (Scheme 1). It was reported
that 1 can release H2O through triarylboroxine formation,15
which could result in the competitive arylation of water and
the subsequent competition of phenol with imidazole sub-
strates, thereby diminishing yields of the desired coupling
products. Presumably, during the oxidation of Cu(II) to Cu-
(III), hydrogen peroxide would also be produced, which
could decompose 1.16 These could explain the use of more
than 1 equiv of 1 in the coupling to obtain synthetically useful
yields. We have not attempted to analyze the intermediates
and byproducts produced or involved in the coupling. The
mechanism described here is speculation and the actual
pathway of the coupling may be elucidated in due course.
In summary, we have developed a novel system for
preparing a variety of N-arylimidazoles (4) in good to
excellent yields through cross coupling arylboronic acids (1)
with imidazole compounds (3) in the presence of a catalytic
amount of [Cu(OH)‚TMEDA]2Cl2 (2).
The speculated mechanism in Scheme 1 stems from Evans’
Scheme 1
Acknowledgment. This work was supported by the NIH
(grant GM17880). We thank the Mass Spectrometry Facility
at the UCSF supported by the NIH (grants RR 04112 and
RR 01614).We also thank Professor Scott E. Denmark for
helpful discussion.
postulation for coupling arylboronic acids (1) with phenols.12
The initial transmetalation of 1 with catalyst 2 would generate
5. The imidazole (3) could coordinate to the Cu(II) to
generate 6, thus reducing the reduction potential14 of the Cu-
(III)/Cu(II) couple. In the presence of O2, the Cu(II) in 6
should be readily oxidized to Cu(III), thereby forming a
Supporting Information Available: Experimental pro-
cedures and characterizations for compounds 4a-k. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(14) Bratsch, S. G. J. Phys. Chem. Ref. Data 1989, 18, 1-21
(15) Santucci, L.; Triboulet, C. J. Chem. Soc. A 1969, 392-396.
(16) Lappert, M. F. Chem. ReV. 1956, 959-1064 and references therein.
OL000033J
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