A soluble base for the copper-catalyzed imidazole N-arylations with aryl halides

Article abstract of DOI:10.1021/jo051640t

CuI-catalyzed N-arylation of imidazoles with aryl bromides has been achieved in a near-homogeneous system that utilizes tetraethylammonium carbonate as base, 8-hydroxyquinoline as ligand, and H₂O as cosolvent. Preliminary results with aryl chlo

Full text of DOI:10.1021/jo051640t

Therefore, methods that circumvent these limitations are
highly desirable.
In 1999, Buchwald reported the first catalytic Ullmann
coupling of imidazoles with aryl halides at low temper-
atures (110 °C) with (CuOTf)2-PhH as catalyst.17 Key
features of the Buchwald protocol are (1) the use of
A Soluble Base for the Copper-Catalyzed
Imidazole N-Arylations with Aryl Halides†
Longbin Liu,* Mike Frohn, Ning Xi, Celia Dominguez,
Randy Hungate, and Paul J. Reider
Chemical Research and Discovery, Amgen Inc.,
One Amgen Center Drive, Thousand Oaks, California 91320
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Veerman, W.; Borst, A. J. M.; de Looff, W.; Verveer, P. C.; Kruse, C.
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and references therein.
lliu@amgen.com
Received August 4, 2005
CuI-catalyzed N-arylation of imidazoles with aryl bromides
has been achieved in a near-homogeneous system that
utilizes tetraethylammonium carbonate as base, 8-hydroxy-
quinoline as ligand, and H2O as cosolvent. Preliminary
results with aryl chlorides are also reported.
Copper-catalyzed C-N, C-O, and C-S bond forma-
tions between aryl halides and NH, OH, SH-containing
heterocycles have evolved as a major method for the
synthesis of novel heterocyclic compounds.1 One excep-
tion, however, has been the imidazole N-arylation with
aryl halides.
N-Arylimidazoles have been recorded in medicinal,2
biological,3 and recently, in the area of N-heterocyclic
carbene chemistry.4 Traditionally, these compounds were
synthesized via SNAr substitution of imidazoles with aryl
halides bearing electron-withdrawing substituents5 or via
the Ullmann-type coupling at high temperatures.6 The
Lam-Chan reaction (Cu-catalyzed cross-coupling be-
tween imidazoles and aryl boronic acids) has emerged
as a method of choice partly because it requires much
lower temperatures.7 However, it is often necessary to
optimize the conditions (solvent,8 base,9 additive,10 and
substrate types11) for a given reaction. In addition, one
is limited by the high cost and poor availability of
functionalized boronic acids.
(3) Tyr244-His240 cross-link was found in the active site of cyto-
chrome c oxidase: (a) Yoshikawa, S.; Shinzawa-Itoh, K.; Nakashima,
R.; Yaono, R.; Yamashita, E.; Inoue, N.; Yao, M.; Fei, M. J.; Libeu, C.
P.; Mizushima, T.; Yamaguchi, H.; Tomizaki, T.; Tsukihara, T. Science
1998, 280, 1723-1729. (b) Bambal, R. B.; Hanzlik, R. P. Chem. Res.
Toxicol. 1995, 8, 729-735.
(4) For a recent account, see: Herrmann, W. A. Angew. Chem., Int.
Ed. 2002, 41, 1290-1309.
(5) Bambal, R.; Haznlik, R. B. J. Org. Chem. 1994, 59, 729-732.
Also, see ref 2a,d,h,j.
(6) Jacobs, C.; Frotscher, M.; Dannhardt, G.; Hartmann, R. W. J.
Med. Chem. 2000, 43, 1841-1851. Also, see ref 2a,b,c,j.
(7) (a) 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. (b) Combs, A. P.; Saubern, S.; Rafalski, M.; Lam, P. Y. S.
Tetrahedron Lett. 1999, 40, 1623-1626. (c) Lam, P. Y. S.; Vincent, G.;
Clark, C. G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42,
3415-3418. (d) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J.
Org. Chem. 2001, 66, 7892-7897. For the use of polymer-supported
Cu catalyst, see: (e) Chiang, G. C. H.; Olsson T. Org. Lett. 2004, 6,
3079-3082.
Other types of cross-coupling reagent for the synthesis
of N-arylimidazoles include (p-Tol)Pb(OAc)3,12 (Ph)3Bi,13
ArSnR3,14 ArSi(OR)3F-,15 and Ar2IBr.16 These reagents
are generally less accessible, and some are highly toxic.
† This article is dedicated to Prof. Gilbert Stork on the occasion of
his 84th birthday.
(8) For reactions performed in H2O or MeOH, see: (a) Collman, J.
P.; Zhong M.; Zeng, Li.; Costanzo, S. J. Org. Chem. 2001, 66, 1528-
1531. (b) Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R. G. Chem.
Commun. 2004, 2, 188-189.
(9) A “base-free anaerobic” system: Berkel, S. S.; Hoogenband, A.;
Terpstra, J. W.; Tromp, M.; Leeuwena, P. W. N. M.; Strijdoncka, G. P.
F. Tetrahedron Lett. 2004, 45, 7659-7662.
(10) Use of molecular sieves: (a) Evans, D. A.; Katz, J. L.; West, T.
R. Tetrahedron Lett. 1998, 39, 2937-2940. (b) References 7a and 11.
(11) Electron-rich substrates may result in low yield under the
oxidative condition (Collman J. P.; Zhong, M. Org. Lett. 2000, 2, 1233-
1236), except with excess ArB(OH)2 or in protic solvents (cf. ref 8b).
(1) For reviews on Cu-catalyzed coupling reactions, see: (a) Lindley,
J. Tetrahedron 1984, 40, 1433-1456. (b) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400-5449. (c) Kunz, K.; Scholz, U.;
Ganzer, D. Synlett 2003, 2428-2439. (d) Beletskaya, I. P.; Cheprakov,
A. V. Coord. Chem. Rev. 2004, 248, 2337-2364. For recent examples
of Cu-catalyzed N-arylations with aryl halides, see: (e) Klapars, A.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421-7428
and references therein. (f) Okano, K.; Tokuyama, H.; Fukuyama, T.
Org. Lett. 2003, 5, 4987-4990. (g) Kwong, F. Y.; Buchwald, S. L. Org.
Lett. 2003, 5, 793-796. (h) He, H.; Wu, Y.-J. Tetrahedron Lett. 2003,
44, 3385-3386.
10.1021/jo051640t CCC: $30.25 © 2005 American Chemical Society
Published on Web 10/12/2005
J. Org. Chem. 2005, 70, 10135-10138
10135

SCHEME 1
FIGURE 1. Ligands for Cu-catalyzed N-arylations of imid-
azoles.
stoichiometric amount (relative to halide) of 1,10-
phenanthraline (I, Figure 1) along with a secondary
ligand, dibenzylidene acetone (dba, 5%), for maintaining
reproducibility, (2) high substrate concentrations ([ArX]
≈ 2.5-5 M), and (3) the use of relatively insoluble
inorganic base (Cs2CO3) in nonpolar solvent (xylenes).
This procedure was modified by Hanzlik, who used DMF
(20%) as cosolvent to accommodate the poor solubility of
functionalized substrate (N-Ac-L-His-OMe) in the syn-
thesis of Nτ-arylhistidine derivatives (12% yield from
iodobenzene).18
Subsequently, Buchwald has shown that 1,2-diamines
(10%, such as II), in combination with catalytic amounts
of I (10-20%), promoted CuI-catalyzed coupling of imid-
azoles with aryl iodides in dioxane or DMF.19 Recently,
Cristau et al.20 reported that salicylaldehyde-derived
ligands such as III (20%) promoted Cu2O-catalyzed
N-arylations of imidazoles with aryl halides in MeCN.
These examples represented significant advances in the
synthesis of N-arylazoles in general and N-arylimidazoles
in particular. Most importantly, they demonstrated the
critical role of ligands in Cu-catalyzed cross-coupling
reactions with aryl halides. However, both Buchwald and
Cristau’s systems still rely on the use of excess Cs2CO3
at high substrate concentrations (>1.7 M). As a result,
maintaining efficient mixing of these highly heteroge-
neous, multicomponent systems presents an operational
challenge that may affect the reproducibility of these
reactions, especially on large scales. So far, most of the
aryl halides reported in the N-arylation of imidazoles,
already limited in examples, were aryl iodides,21 with
only four tested substrates being aryl bromides.22 Clearly
there is a need to develop a process that allows direct
coupling of a wide range of aryl halides with imidazoles,
by far the least reactive NH-containing azoles in cross-
coupling reactions. We wish to disclose an alternative
system that employs a soluble base (1.1 equiv) and a
readily available ligand for the CuI-catalyzed N-arylation
of imidazoles with aryl iodides, aryl bromides, and even
aryl chlorides.
During a study on the Goldberg amidation under the
Buchwald protocol,23 we discovered that bis(tetraethyl-
ammonium) carbonate, (Et4N)2CO3 (TEAC),24 which un-
like K2CO3 or Cs2CO3 dissolves in the mixture, promotes
the CuI-catalyzed N-arylation of benzimidazoles with aryl
halides in DMF. For example, the reaction between
2-bromoaniline and formamide led to 2-(1H-benzo[d]-
imidazol-1-yl)benzenamine (1) as the major product
(Scheme 1).25 Presumably, the initial amidation product
was converted in situ into benzimidazole,26 the latter then
underwent rapid N-arylation with the remaining aryl
bromide to form the observed end product (1).
Support for the above hypothesis can be drawn from
the reaction between benzimidazole and 2-bromo-
aniline: the desired product (1) was formed cleanly in
high yield with TEAC (96%) in contrast to low (∼40%)
conversion with other bases such as K2CO3.27
The superiority of TEAC as base for the N-arylation
is further illustrated in Table 1. Under the conditions of
Buchwald,17,19a,b 1-iodo-3,5-bis(trifluoromethyl)benzene
was converted to 2 in >97% yield after 10 h with TEAC,
whereas twice as much time was needed to reach similar
conversion with Cs2CO3 as base. Similarly, with the less
reactive substrate 1-bromo-3,5-dimethylbenzene, the use
of TEAC resulted in higher conversion to 3 (61%) than
of Cs2CO3 (44%).27 To the best of our knowledge, this is
the first time an organic carbonate salt had been reported
in metal-catalyzed cross-coupling with aryl halides.28
Most significantly, the improved efficiency in the reaction
of 1-bromo-3,5-dimethylbenzene suggested that TEAC as
a base might be useful in expanding the scope of
(12) (a) Lo´pez, A. P.; Avendano, CÄ .; Mene´ndez, J. C. Tetrahedron
Lett. 1992, 33, 659-662. (b) J. Org. Chem. 1995, 60, 5678-5682. (c)
Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 2, 3055-3057. (d)
Fedorov, A. U.; Finet, J.-P. Eur. J. Org. Chem. 2004, 9, 2040-2045.
(13) Fedorov, A. Y.; Finet, J.-P. Tetrahedron Lett. 1999, 40, 2747-
2748.
(14) Lam, P. Y. S.; Clark, C. G.; Saunern, S.; Adams, J.; Averill, K.;
Chan, D. M. T.; Combs, A. P. Synlett 2000, 674-676.
(15) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R.; He, M. Y.;
DeShong, P.; Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600-7601.
(16) Nontransition metal catalyzed direct arylation in ionic liquid:
Wang, F.-Y.; Chen, Z.-C.; Zheng, Q.-G. J. Chem. Res. 2004, 206-207.
(17) Kiyomori, A.; Marcoux, J.-F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657-2660.
(22) A ligandless N-arylation of (S)-1-(3-bromophenyl)-ethylamine
under microwave heating (195 °C and 2-3 h): Wu, Y.-J.; He, H.;
L’Heureux, A. Tetrahedron Lett. 2003, 44, 4217-4218.
(23) See ref 1e and references therein.
(24) (a) TEAC is very soluble in most organic solvents and gives
nearly homogeneous reaction mixtures. The commercial material from
Fluka (90% or 95%) was used in this study. (b) Other soluble bases
such as pyridine and TBAF did not yield any products.
(25) Based on LC-MS analyses. Some optimizations were carried
out under microwave heating at various temperatures.
(26) This type of in situ conversion to benzimidazole had been
observed before (personal communication with Prof. Stephen L.
Buchwald at MIT, 2004).
(18) Yue, W.; Lewis, S. I.; Koen, Y. M.; Hanzlik, R. P. Bioorg. Med.
Chem. Lett. 2004, 14, 1637-1640.
(19) (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727-7729. A later publication suggested
that either trans-1,2-cyclohexanediamine or 1,10-phenanthroline was
sufficient for aryl iodides: (b) Antilla, J. C.; Baskin, J. M.; Barder, T.
E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578-5587.
(20) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M.
Chem.-Eur. J. 2004, 10, 5607-5622. This report appeared after the
completion of our own work. As a result, we have not performed direct
comparison with ligand III.
(27) (a) Conversion based on LC-MS analyses. The isolated yield
of 1 was 63% from TEAC. (b) These reactions were run in a sealed
tube without using any inert gases. (c) Examples of other inorganic
bases screened include Cs2CO3, K3PO4, CaCO3, and MgO. These
experiments were conducted under microwave heating (Smith Syn-
thesizer, from Personal Chemistry, 180 oC, 20 min total) under identical
conditions (CuI, IV, DMF).
(21) Proline-promoted Ullmann coupling: (a) Cai, Q.; Zhu, W.;
Zhang, H.; Zhang, Y.; Ma, D. Synthesis 2005, 496-499. (b) Ma, D.;
Cai, Q. Synlett 2004, 128-130.
10136 J. Org. Chem., Vol. 70, No. 24, 2005

TABLE 1. Effect of Bases on Reaction Ratea,e
TABLE 2. N-Arylation of Benzimidazole with ArBra
a 110 °C, ArX (1.0), BzImd (1.15), CuI (10%), ligand (20%), DMF
(1.0 mL). b 10 h. c 22 h. d 60 h. e I was used with Cs2CO3, whereas
II (cf. ref 19a) was used for TEAC.
imidazolyl N-arylations from traditional aryl iodides as
substrates to include aryl bromides in general.
Indeed, further optimization of the reaction conditions
led to the following observations: (1) 8-hydroxyquinoline
(IV)29 is more effective as a ligand than either 1,10-
phenanthroline (I)17 or the 1,2-diamine ligands (II);19 (2)
the ratio of IV to CuI (10% mol) can be reduced from the
conventional 2:1 to 1:1 without noticeable reduction in
the reaction yield; (3) addition of a small amount of H2O
as cosolvent significantly accelerates the N-arylation
reaction.30 These findings have made it possible, for the
first time, to effectively convert nonactivated31 aryl
bromides to N-aryl benzimidazoles at reasonable temper-
atures (130 °C). Table 2 summarizes the reaction of
benzimidazole with a wide range of aryl bromides under
the current protocol.32,33 The reaction worked well with
aryl bromides bearing both nonpolar and polar (OH, NH2,
OMe, SMe) groups except for the nitrile group that was
hydrolyzed to the carboxyamide (6, entry 5).
Cu-catalyzed N-arylations are known to be very sensi-
tive to steric hindrance. In Table 3, substrates with
varying degrees of substitution proximal to the reaction
centers (excluding chelating groups31) were examined.
When either o-alkyl-substituted aryl bromides or 2-alkyl
imidazoles were reacted with their nonhindered coun-
terparts, modest yields were still achieved (entries 2-5).33
a Conditions: 130 °C for 16 h, ArBr (1.0), BzImd (1.15), TEAC
(1.0), CuI (10%), IV (10%), DMF (1.0 mL), H2O (0.1 mL). b 24 h.
c 70 h at 120 °C. d 64 h, (∼10% 5 was formed).
However, only a trace of the product was observed when
2-phenyl imidazole and 2-bromotoluene (entry 6) were
coupled, suggesting that concurrent steric hindrance from
both substrates is incompatible in the current system.
Preliminary results also suggest that the current
system can be applied to aryl chlorides. For example
p-CF3-PhCl and m-Me-PhCl34 were converted to 17 and
18 in 50 and 40% isolated yields, respectively (Figure 2).
To date, this constitutes the first soluble copper-ligand
system that at relatively low temperatures catalyzes the
N-arylation of an imidazole by ArCl.35
In summary, a near homogeneous system for the
synthesis of N-arylimidazoles has been established that
features the use of a readily available, crystalline ligand
(IV), H2O as cosolvent, and a soluble carbonate (TEAC)
as base. The system is effective for aryl iodide, aryl
bromides, and, to a less extent, for simple aryl chlorides.
It is anticipated that, because it is homogeneous, this
(28) (a) (NH4)2CO3 and polymer-supported carbonate were ineffec-
tive. (b) TEAC as carboxylating reagents: Arcadi, A.; Inesi, A.;
Marinelli, F.; Rossi, L.; Verdecchia, M. Synlett 2005, 67-70 and
references therein. (c) TEAC as base for sulfide synthesis: Feroci, M.;
Inesi, A.; Rossi, L. Synth. Commun. 1999, 29, 2611-2615.
(29) For use of quinolinol ligands in biaryl ether synthesis, see:
Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem.
Soc. 2000, 122, 5043-5051.
(30) (a) We found the optimal ratio to be 10-26% H2O in DMF (v/
v). H2O also accelerates reactions with Cs2CO3 to a smaller extent.
For example, 3 (Table 2) reached 80 and 60% after 7 h with TEAC
and Cs2CO3 (Aldrich) as bases, respectively. Both reactions went to
completion after 24 h. (b) Effect of H2O on the amination reactions
has been controversial. For a recent example, see: Meyers, C.; Maes,
B. U. W.; Loones, K. T. J.; Bal, G.; Lemie`re, G. L. F.; Dommisse, R. A.
J. Org. Chem. 2004, 69, 6010-6017.
(31) A comparison between Scheme 1 and Table 1 offers an example
of possible chelation (substrate based) assisted Cu catalysis. We suspect
that this was the case in the N-arylation of purine (ref 19b).
(32) A small amount of ethylation products (5-10%), likely by TEAC,
of benzimidazole or IV, was observed (LC-MS), especially with long
reaction times. 8-MeO-quinoline (Tre´court, F.; Mallet, M.; Mongin, F.;
Que´guiner, G. Synthesis 1995, 1159-1162) as ligand is somewhat less,
but still, effective for the reaction.
(34) (a) No regioisomers were detected. (b) In the absence of TEAC
and ligand (IV), only a trace amount of 18 was formed.
(35) (a) Nanoparticles of Cu coated with Cu2O were reported to
catalyze N-arylation of imidazole with activated chlorides (DMSO, 150
°C): Son, S. U.; Park, I. K.; Park, J.; Hyeon, T. Chem. Commun. 2004,
778-779. (b) Cu(II) apatites were recently reported in the N-arylation
of imidazoles with chloroarenes: Choudary, B. C.; Sridhar, C.; Kantam,
M. L.; Venkanna, G. T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127,
9948-9949.
(33) Lower yields were often obtained for polar imidazoloids (see
Table 2, entries 3 and 4), partially due to loss of products during
workup and purifications.
J. Org. Chem, Vol. 70, No. 24, 2005 10137

TABLE 3. N-Arylation of Imidazoles with Aryl
Bromidesd
FIGURE 2. N-Arylimidazoles from aryl chlorides (130 °C, 60
h).
8-hydroxyquinoline (IV, 0.015 g, 0.1 mmol), bis(tetraethylam-
monium) carbonate (TEAC, 95%, 0.37 g, 1.1 mmol), and aryl
bromide (1.0 mmol). DMF (1.0 mL) and H2O (0.1 mL) were
added, and the vessel was capped with a rubber septum. The
system was stirred while degassed under vacuum and purged
with nitrogen three times. The septum was either replaced with
a pressure cap or kept if the system was allowed to remain
connected to nitrogen supply. The reaction mixture was heated
to 130 °C in an oil bath for 16 h whereby an aliquot was taken
for HPLC and LC-MS analyses. Upon cooling to room temper-
ature, the mixture was subject to one of the following procedures
for product isolation. The purified product was subject to 1H
NMR, HPLC, LC-MS, HRMS, 13C NMR, or elemental analyses.
Method A. The almost homogeneous mixture was loaded onto
a silica column (with MeOH/CH2Cl2 rinse) and eluded first with
1:1 mixture of hexanes/EtOAc, then with either MeOH in EtOAc
or MeOH (for very polar products 2 N NH3 in MeOH was used)
in CH2Cl2.
Method B. The mixture was diluted with EtOAc (20 mL) and
washed with H2O, NH4Cl (saturated), H2O, and NaHCO3
(saturated). The organic layer was dried over Na2SO4, concen-
trated, and subject to flash chromatography.
a Cs2CO3 was used as base (cf. ref 30a). b 74% when 2-methyl
iodobenzene was used. c 36 h. d Conditions: 130 °C for 16 h (unless
otherwise noted), TEAC (1.0), CuI (10%), IV (10%), DMF-H2O
(1.0-0.1 mL).
system will make it possible for copper-catalyzed N-
arylations to be studied spectroscopically. It also promises
to lead to the discovery of even better catalyst systems.
Acknowledgment. We thank Prof. Stephen L.
Buchwald for providing helpful suggestions and encour-
agement.
Supporting Information Available: Detailed experi-
mental procedures and compound characterization data. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Experimental Section
Typical Experimental Procedure for Table 2. In a
pressure reaction vessel (a 10-mL microwave tube was used in
this case) equipped with a magnetic stirring bar was added
benzimidazole (0.17 g, 1.43 mmol), CuI (0.019 g, 0.1 mmol),
JO051640T
10138 J. Org. Chem., Vol. 70, No. 24, 2005