Catalytic activities of Cu(II) complexes with nitrogen-chelating bidentate ligands in the coupling of imidazoles with arylboronic Acids

Full text of DOI:10.1021/jo010615u

7892
J . Org. Chem. 2001, 66, 7892-7897
we became interested in studying direct C-N coupling
Ca ta lytic Activities of Cu (II) Com p lexes
reactions for preparing N-arylimidazoles as building
blocks10 of new model compounds incorporating N-(2′-
hydroxyphenyl)imidazole moieties as CuB site mimics.
Numerous reports describe copper-promoted N-aryla-
tion of imidazoles with arylmetalloids to furnish N-
arylimidazoles. Traditional Ullman-type coupling of im-
idazole with aryl halides,1-5,11 one of the most usually
used methods, requires high temperatures. A few ap-
proaches have also been developed using aryllead, arylb-
orane, or arylsilane reagents in the presence of Cu(OAc)2
under milder conditions. For example, Lo´pez-Alvarado12
described the coupling of imidazoles with p-tolyllead
triacetate in the presence of a stoichiometric amount of
Cu(OAc)2 at 90 °C. Interestingly, Konopelski13 found that
imidazoles react with o- or p-methoxyphenyllead triac-
etate to give the corresponding C-N coupling products
in good yields in the presence of 10% mol of Cu(OAc)2 at
room temperature. However, it should be noted that both
procedures produce toxic organolead byproducts. More-
over, Chan and Lam14 established an efficient approach
to N-arylimidazoles via Cu(OAc)2-mediated coupling of
imidazoles with readily available arylboronic acids at
room temperature,15 and Lam16 extended this methodol-
ogy to phenyl trimethoxysilane. Although both methods
are quite mild, they suffer from two main drawbacks:
more than an equimolar amount of Cu(OAc)2 and either
Et3N or pyridine are employed to promote the coupling;
moreover, the synthesis of phenyl trimethoxysilane in-
volves the use of highly toxic trimethoxysilane.17 Very
recently, both Lam18 and Buchwald19 reported the syn-
thesis of N-arylimidazoles through the coupling of imi-
dazoles with p-tolylboronic acid using 10% mol of Cu-
w ith Nitr ogen -Ch ela tin g Bid en ta te Liga n d s
in th e Cou p lin g of Im id a zoles w ith
Ar ylbor on ic Acid s
J ames P. Collman,* Min Zhong, Chi Zhang, and
Simona Costanzo
Department of Chemistry, Stanford University,
Stanford, California 94305-5080
jpc@stanford.edu
Received J une 15, 2001
In tr od u ction
N-Arylimidazoles are common motifs in pharmaceuti-
cal research because of their biomedical use as throm-
boxane synthase inhibitors,1 AMP phosphodiesterase
inhibitors,2 AMPA receptor antagonists,3 cardiotonic4 and
topical antiglaucoma agents,5 etc. Moreover, recent high-
resolution X-ray diffraction analyses have revealed in the
CuB site of cytochrome c oxidase (CcO), the terminal
respiratory enzyme of mitochondria and aerobic bacteria,6
a tyrosine-histidine (Tyr244-His240) cross-linked through
a C-N bond.7 This functionalized phenol has been
postulated to serve as a hydrogen atom donor during the
4H+, 4e- reduction of O2 to H2O.8 Thus, in the course of
our efforts in developing new active-site models of CcO,9
* To whom correspondence should be addressed. Tel: (650) 725-
0283. Fax: (650) 725-0259.
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1981, 24, 1139-1148. (b) Cozzi, P.; Carganico, G.; Fusar, D.; Grossoni,
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10.1021/jo010615u CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/19/2001

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7893
Ta ble 1. Effect of th e Bid en ta te Liga n d on th e Rea ctivity of Com p lex 3 in th e N-Ar yla tion of Im id a zole (1a ) w ith
P h en ylbor on ic Acid (2a )
a
A typical procedure: a mixture of 1 mmol of imidazole (1a ), 2 mmol of phenylboronic acid (2a ), and 0.1 mmol of Cu(II) complex (3)
b
in 4 mL of dry CH2Cl2 was stirred at room temperature overnight under an atmosphere of dioxygen. Isolated yield.
(OAc)2. However, Lam’s method requires more than a
stoichiometric amount of oxidant, such as pyridine N-
oxide, TEMPO, or NMO etc., as well as Et3N or pyridine,
and elevated temperature (65 °C), whereas the system
described by Buchwald requires the addition of a sto-
ichiometric amount of 2,6-lutidine as well as myristic acid
and gives a low yield (32%). Accordingly, it is important
to develop more efficient catalytic systems to prepare
N-arylimidazoles under mild reaction conditionssat room
temperature, with a small amount of the catalyst, and
in the absence of base.
Recently, we carried out the coupling of imidazoles
with arylboronic acids at room temperature using only
10% mol of [Cu(OH)‚TMEDA]2Cl2, without the addition
of base in CH2Cl2.20a We also demonstrated that this
coupling could be performed in water to give N-arylimi-
dazoles in moderate yields.20b To the best of our knowl-
edge, this catalytic system is one of the most efficient

7894 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Ta ble 2. Effect of th e Cou n ter ion on th e Rea ctivity of
Com p lex 3 in th e N-Ar yla tion of Im id a zole (1a ) w ith
P h en ylbor on ic Acid (2a )
As shown in Table 1, several bisimidazole-type ligands
L1-4 were initially investigated. The coupling yield of
N-phenylimidazole (4a ) is not significantly affected by
either replacing the methylene with a carbonyl group or
changing the N-methyl to N-octyl groups of ligand L1.
However, the increase of the substituents’ bulk on the
carbons adjacent to the imidazole sp2-N atoms, serving
as chelating centers, results in a significantly decreased
yield of compound 4a (entries 1-4, Table 1). Other types
of sp2-N bidentate ligands have also been tested. The Cu-
(II) complexes with 2,2′-pyridyl (L5) or 1,10-phenatholine
(L6) also catalyze the coupling to give compound 4a in
moderate yields (entries 5 and 6, Table 1). However, no
coupling product is formed when employing 2, 2′-dipy-
ridylmethane or 2, 2′-dipyridyl ketone as the ligand.
A series of sp3-N bidentate ligands were also investi-
gated. A 61% yield of N-phenylimidazole (4a ) is obtained
when Proton Sponge (L7) is used (entry 7, Table 1). Both
increasing the distance between the two dimethylamino
groups and replacing one or both dimethylamino groups
with bulkier dialkylamino groups on the TMEDA (L8)
backbone result in decreased coupling yields (entries
8-13, Table 1). The Cu(II) complexes prepared from
readily available ring-containing alkyldiamines, such as
tetramethylcyclohexanediamine (L14), N,N-dimethylpip-
erazine (L15), Dabco (L16), and (-)-sparteine (L17) give
moderate coupling yields (entries 14-17, Table 1). A
relatively low yield of compound 4a is obtained when
DBU (L18) is used as a ligand (entry 18, Table 1).
The activity of Cu(II) complexes with different coun-
terions were also tested (Table 2). Only small variations
of the coupling yield are observed using TMEDA (L8) as
a ligand with different counterions, such as Cl-, Br-, I-,
and TfO-. However, in the case of Proton Sponge (L7),
the coupling yield significantly drops when CuCl is
replaced with CuBr. It should be noted that the complex
derived from 1,10-phenatholene (L6) with CuBr or CuI
does not give compound 4a . Some studies have shown
that strongly coordinating counterions, such as halides,
can affect the rate of reoxidation by acting as bridging
ligands and thus favoring the formation of the active
dinuclear bis-µ-hydroxo Cu(II) system.25 This could ex-
plain the variation in activity of the Cu(II) complexes in
the presence of different counterions.
a
A typical procedure: a mixture of 1 mmol of imidazole (1a ), 2
mmol of phenylboronic acid (2a ), and 0.1 mmol of Cu(II) complex
(3) in 4 mL of dry CH2Cl2 was stirred at room temperature
b
overnight under an atmosphere of dioxygen. Isolated yield.
approaches to N-arylimidazoles to date. To design and
synthesize more efficient catalysts for this important
C-N coupling, it is necessary to understand the effects
of bidentate ligands as well as counterions on the
activities of the µ-hydroxo Cu(II) complexes. Thus, a
series of µ-hydroxo Cu(II) complexes with nitrogen chelat-
ing bidentate ligands were prepared and applied to the
coupling of imidazoles with arylboronic acids.
Resu lts a n d Discu ssion
[Cu(OH)‚TMEDA]2Cl2 is a binuclear bis-µ-hydroxo
copper(II) complex.21 It has been demonstrated to be an
efficient catalyst for oxidative coupling reactions of
naphthols22 or terminal alkynes.23 In our studies, all Cu-
(II) complexes (3) were prepared24 by stirring 1 equiv of
the bidentate ligand (L) with 1 equiv of CuX (X ) Cl-,
Br-, I-, or TfO-) in 95% aqueous ethanol at room
temperature overnight under an atmosphere of dioxygen.
These Cu(II) complexes (3) were used in the C-N
coupling reaction following our previously published
procedure:20a a mixture of 1 mmol of imidazole (1a ), 2
equiv of phenylboronic acid (2a ), and 0.1 equiv of Cu(II)
complex (3) in 4 mL of dry CH2Cl2 was stirred at
room temperature overnight under an atmosphere of
dioxygen.
Since regioselectivity is one of the major issues in
various coupling reactions, Cu(II) complexes (3) with
different ligands were applied to the coupling of equimo-
lar amounts of 4(5)-substituted imidazole (1b or 1c) with
o-tolylboronic acid (2b) (Table 3). The increase of either
the number of carbons or the bulk of the substituents on
the nitrogen atoms of TMEDA (L8) results in small
variations of the selectivity. No obvious linear correlation
is observed between steric hindrance in the bidentate
ligands and the regio-selectivity of the coupling products.
In general, better coupling yields and selectivities are
obtained by employing 4(5)-phenylimidazole (1c) instead
of 4(5)-methylimidazole (1b) as a substrate.
(20) (a) Collman, J . P.; Zhong, M. Org. Lett. 2000, 2, 1233-1236.
(b) Collman, J . P.; Zhong, M.; Zeng, L.; Costanzo, S. J . Org. Chem.
2001, 66, 1528-1531.
(21) Banci, L.; Bencini, A.; Gatteschi, D. J . Am. Chem. Soc. 1983,
105, 761-764 and references therein.
(22) (a) Noji, M.; Nakajima, M.; Koga, K. Tetrahedron Lett. 1994,
35, 7983-7984. (b) Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hash-
imoto, S.; Noji, M.; Koga, K. J . Org. Chem. 1999, 64, 2264-2271.
(23) Hay, A. S. J . Org. Chem. 1962, 27, 3320-3321.
(24) (a) McWhinnie, W. R. J . Chem. Soc. 1964, 2959. (b) Ferraro, J .
R.; Walker, W. R. Inorg. Chem. 1965, 4, 1385. (c) Harris, C. M.; Sinn,
E.; Walker, W. R.; Wolliams, P. R. Aust. J . Chem. 1968, 21, 631.
In our proposed mechanism for the C-N coupling of
imidazoles, phenylboronic acid (2) initially undergoes
transmetalation with complex 3 to generate boric acid
(5) and intermediate 6, which then coordinates the
imidazole substrate (1) forming complex 7. In the pres-
(25) (a) Viersen, F. J .; Challa, G.; Reedijk, J . Recl. Trav. Chim. Pays-
Bas, 1989, 108, 247-255. (b) Garozzo, M. S.; Marsich, N.; Camus, A.
Gazz. Chim. Ital. 1993, 123, 697-701.

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7895
Ta ble 3. Effect of th e Liga n d of Cu (II) Com p lex (3) on th e Regioselectivity of th e Cou p lin g Rea ction of 4(5)-Su bstitu ted
Im id a zole (1b or 1c) w ith O-Tolylbor on ic Acid (2b)
a
A typical procedure: a mixture of 1 mmol of 4(5)-substituted imidazole (1b or 1c), 1 mmol of o-tolylboronic acid (2b), and 0.1 mmol
b
of Cu(II) complex (3) in 4 mL of dry CH2Cl2 was stirred at room temperature overnight under an atmosphere of dioxygen. Isolated yield.
c The ratio of compounds 4b and 4b′, as well as 4c and 4c′, was determined by the comparison of the respective methyl group signals in
the corresponding 1H NMR spectrum using CDCl3 as the solvent; see the Supporting Information of ref 20a.
ence of dioxygen, complex 7 is proposed to be oxidized
forming a putative Cu(III) intermediate 8, which under-
goes reductive elimination yielding N-phenylimidazole 4
and complex 9. The latter can be reconverted to bis-µ-
hydroxo Cu(II) complex 3 in the presence of dioxygen and
water.26 It is most likely that less sterically hindered
bidentate ligands form intermediate 7 or 8 more easily
compared with hindered ligands, resulting in higher
yields of coupling product 4 (Scheme 1).
The regioselectivity of coupling is dependent on the
interaction between RL and RS on the bidentate ligands,
R3 on the phenyl and R4 on imidazole rings. As shown in
Scheme 2, regardless of the bulk of the substituents RL
and RS, the intermediates 7F and 7F ′ are more geo-
metrically favored than the intermediates 7U and 7U′,
resulting in a higher yield of 4b or 4c compared with 4b′
or 4c′. Moreover, in the case of ethylenediamine-based
ligands, TMEDA (L8) gives the highest selectivity com-
pared with other more hindered ligands (L11-L13). It
is possible that the increase in the bulk of RL enhances
the interactions between RL, R3, R4, and the counterion,
(26) De J ong, C. R. H. I. In Organic Syntheses by Oxidation with
Metal Compounds; Mijs, W. J ., de J ong, C. R. H. I., Eds.; Plenum Press
Inc.: New York, 1986; pp 423-443.

7896 J . Org. Chem., Vol. 66, No. 23, 2001
Notes
Sch em e 1
Sch em e 2
TMEDA (L8) appears to be the best ligand for the
coupling reaction. Detailed mechanistic studies of the
reaction and the application of these new catalysts to the
coupling of other NH- containing substrates27 with
arylboronic acids are being investigated and will be
reported in due course.
Exp er im en ta l Section
All reagents were used as supplied commercially without
further purification unless otherwise noted.Bis[2-(1-methylimi-
dazolyl)]methane (L1),28 bis[2-(1-methylimidazolyl)]ketone (L2),28
bis[2-(1-octylimidazolyl)]ketone (L3),9f bis[2-(4,5-diphenyl-1-me-
thylimidazolyl)]ketone (L4),9f N,N′-tert-butyl-N,N′-dimethyleth-
ylenediamine (L12),29 and N,N,N′,N′-tetramethyl-1,2-cyclohex-
anediamine (L14)30 were prepared following reported procedures.
1H and 13C NMR spectra were recorded on Varian XL-400
instruments. Mass spectra were measured by the Mass Spec-
trometry Facility at the University of California, San Francisco.
N,N-Diisop r op yl-N′,N′-d im eth yleth ylen ed ia m in e (L13).
This compound was prepared following the procedure for the
synthesis of N,N,N′,N′-tetramethyl-1,2-cyclohexanediamine (L14)30
using N,N-diisopropylethylenediamine as starting material.
Colorless liquid, 67% yield. 1H NMR (CDCl3): δ 2.99 (m, 2H),
2.52 (m, 2H), 2.30 (m, 2H), 2.24 (s, 6H), 1.00 (d, J ) 6.5 Hz,
12H) ppm. 13C NMR (CDCl3): δ 61.8, 49.3, 45.9, 43.9, 20.6 ppm.
MS (m/z): 172 (M+), 162, 143, 114 (100), 82, 72, 58. HRMS: calcd
for C10H24N2 (M+) 172.194, found 172.195.
Gen er a l P r oced u r e for th e P r ep a r a tion of Bid en ta te
Liga n d ‚Cu (II) Com p lexes (3). A mixture of 3 mmol of biden-
tate ligand (L) and 3 mmol of CuX (X = Cl-, Br-, I-, or TfO-) in
6 mL of 95% aqueous ethanol was stirred vigorously at room
temperature overnight under an atmosphere of dioxygen. The
precipitates were filtered off, washed with a small amount of
95% ethanol, and dried in vacuo over P2O5. In some cases, the
complexes are soluble in 95% aqueous ethanol and they were
obtained by concentrating to dryness and dried in vacuo over
reducing the number of stable conformations of interme-
diates 7U and 7F and therefore yielding lower ratios of
4b/4b′ or 4c/4c′ compared with TMEDA (L8).
In summary, we have demonstrated that a series of
nitrogen chelating bidentate ligands (L) can react with
Cu(I) salt and water in the presence of dioxygen to
generate Cu(II) complexes (3) that efficiently catalyze the
coupling reaction of imidazoles with arylboronic acids
under mild conditions. The activities of the Cu(II) com-
plexes (3) are dependent both on the nature of the
bidentate ligands (L) and the counterions employed and
(27) Lam recently disclosed that [Cu(OH)‚TMEDA]2Cl2 can also
catalyze the C-N coupling reactions of phenyl trimethoxysiloxane
with benzoimidazole (ref 16) and p-tolylboronic acid with various NH-
containing heterocycles (ref 18) in moderate yields.
(28) Elgafi, S.; Field, L. D.; Messerle, B. A.; Hambley, T. W.; Turner,
P. J . Chem. Soc., Dalton Trans. 1997, 2341-2345.
(29) Mahadevan, V.; Henson, M. J .; Solomon, E. I.; Stack, T. D. P.
J . Am. Chem. Soc. 2000, 122, 10249-10250.
(30) Remenar, J . F.; Lucht, B. L.; Collum, D. B. J . Am. Chem. Soc.
1997, 119, 5567-5572.

Notes
J . Org. Chem., Vol. 66, No. 23, 2001 7897
P2O5. These complexes were used for the coupling reaction
without further purification and all the molecular weights of
these complexes were calculated on the basis of the formula of
[Cu(OH)‚L]2X2.
Gen er a l P r oced u r e for th e N-Ar yla tion of Im id a zoles.
A mixture of 1 mmol of imidazole (1), 2 mmol of arylboronic acid
(2), and 0.1 mmol of µ-hydroxo Cu(II) complex 3 in 4 mL of dry
CH2Cl2 was vigorously stirred at room temperature overnight
under an atmosphere of dioxygen. The reaction mixture was
filtered, the filtrate was concentrated, and the residue was
purified by preparative thin-layer chromatography on a 1000
µm silica gel plate using a mixed solvent of CHCl3 and n-hexane
(1/1 volume ratio, saturated with NH3 gas) to give N-arylimi-
dazole (4).
Ack n ow led gm en t. We thank the National Insti-
tutes of Health (NIH) (Grant No. GM 17880) for the
financial support of this work. We also thank the Mass
Spectrometry Facility at the University of California at
San Francisco supported by the NIH (Grant Nos. RR
04112 and RR 01614).
J O010615U