Copper-catalyzed N-arylation of imidazoles and benzimidazoles

Article abstract of DOI:10.1021/jo070807a

(Chemical Equation Presented) 4,7-Dimethoxy-1,10-phenanthroline (L1c) was found to be an efficient ligand for the copper-catalyzed N-arylation of imidazoles and benzimidazoles with both aryl iodides and bromides under mild conditions. Further optimization of the system has revealed that the addition of poly(ethylene glycol) accelerates this reaction. A variety of hindered and functionalized imidazoles, benzimidazoles, and aryl halides were transformed in good to excellent yields. Heteroaryl halides were also coupled in moderate to good yields. We also present the results obtained from a series of coupling reactions, which directly compare the use of L1c with other recently reported ligands.

Full text of DOI:10.1021/jo070807a

Copper-Catalyzed N-Arylation of Imidazoles and Benzimidazoles
Ryan A. Altman, Erica D. Koval, and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
sbuchwal@mit.edu
ReceiVed April 17, 2007
4,7-Dimethoxy-1,10-phenanthroline (L1c) was found to be an efficient ligand for the copper-catalyzed
N-arylation of imidazoles and benzimidazoles with both aryl iodides and bromides under mild conditions.
Further optimization of the system has revealed that the addition of poly(ethylene glycol) accelerates
this reaction. A variety of hindered and functionalized imidazoles, benzimidazoles, and aryl halides were
transformed in good to excellent yields. Heteroaryl halides were also coupled in moderate to good yields.
We also present the results obtained from a series of coupling reactions, which directly compare the use
of L1c with other recently reported ligands.
Introduction
variety of N-arylated products, these methods suffer from
significant limitations. In the former case, the scope of the
reaction is confined to the use of aryl halides possessing strongly
electron-withdrawing substituents. In the latter case, the range
of functional groups tolerated by the long-established Ullmann
reaction is severely restricted by the harsh conditions often
required (exposure of substrates to high temperatures, typically
150-200 °C, for extended periods of time using stoichiometric
quantities of a copper compound).2
In recent years, mild transition metal-catalyzed cross-coupling
of aryl halides with N-H heterocycles3-4 has complemented
the traditional preparations of these structures. Despite the
continued development of hindered biaryl monophosphines5 and
other ligands3 for improved Pd-catalyzed C-N bond-forming
reactions, no Pd-based catalysts display a good generality for
the N-arylation of imidazoles. Thus, Cu-based catalysts have
continued to provide the most effective systems for the
N-arylation of imidazoles.4 Although the Cu-mediated N-
arylation of imidazoles and benzimidazoles has been ac-
N-Aryl imidazoles and benzimidazoles are found in many
biologically active compounds.1 Although traditional prepara-
tions of these moieties, including nucleophilic aromatic substitu-
tion of an activated aryl halide and copper-mediated coupling
of the heterocycle with an aryl iodide, can give access to a wide
* Corresponding author. Tel.: (617) 253-1885; fax: (617) 253-3297.
(1) (a) Quan, M. L.; Lam, P. Y. S.; Han, Q.; Pinto, D. J. P.; He, M. Y.;
Li, R.; Ellis, C. D.; Clark, C. G.; Teleha, C. A.; Sun, J. H.; Alexander, R.
S.; Bai, S.; Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler, R. R. J.
Med. Chem. 2005, 48, 1729. (b) Dyck, B.; Goodfellow, V. S.; Phillips, T.;
Grey, J.; Haddach, M.; Rowbottom, M.; Naeve, G. S.; Brown, B.; Saunders,
J. Bioorg. Med. Chem. Lett. 2004, 14, 1151. (c) Smallheer, J. M.; Alexader,
R. S.; Wang, J.; Wang, S.; Nakajima, S.; Rossi, K. A.; Smallwood, A.;
Barbera, F.; Burdick, D.; Luettgen, J. M.; Knabb, R. M.; Wexler, R. R.;
Jadhav, P. K. Bioorg. Med. Chem. Lett. 2004, 14, 5263. (d) Venkatesan,
A. M.; Gu, Y.; Santos, O. D.; Abe, T.; Agarwal, A.; Yang, Y.; Petersen, P.
J.; Weiss, W. J.; Mansour, T. S.; Nukaga, M.; Hujer, A. M.; Bonomo, R.
A.; Knox, J. R. J. Med. Chem. 2004, 47, 6556. (e) Lange, J. H. M.; van
Stuivenberg, H. H.; Coolen, H. K. A. C.; Adolfs, T. J. P.; McCreary, A.
C.; Keizer, H. G.; Wals, H. C.; Veerman, W.; Borst, A. J. M.; de Looff,
W.; Verveer, P. C.; Kruse, C. G. J. Med. Chem. 2005, 48, 1823. (f)
Barchechath, S. D.; Tawatao, R. I.; Corr, M.; Carson, D. A.; Cottam, H. B.
J. Med. Chem. 2005, 48, 6409. (g) Mano, T.; Stevens, R. W.; Kazuo, A.;
Nakao, Y. O.; Sakakibara, M.; Okumura, T. T.; Miyamoto, K. Bioorg. Med.
Chem. 2003, 11, 3879. (h) Mano, T.; Okumura, Y.; Sakakibara, M.;
Okumura, T.; Tamura, T.; Miyamoto, K.; Stevens, R. W. J. Med Chem.
2004, 47, 720. (k) Roppe, J.; Smith, N. D.; Huang, D.; Tehrani, L.; Wang,
B.; Anderson, J.; Brodkin, J.; Chung, J.; Jiang, X.; King, C.; Munoz, B.;
Varney, M. A.; Prasit, P.; Cosford, N. D. P. J. Med. Chem. 2004, 47, 4645.
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(2) Lindley, J. Tetrahedron 1984, 40, 1433.
(3) (a) Jiang, L.; Buchwald, S. L. Palladium-Catalyzed Aromatic
Carbon-Nitrogen Bond Formation. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH:
Weinheim, Germany, 2004; pp 699-760. (b) Hartwig, J. F. Synlett 2006,
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S. L. Angew. Chem., Int. Ed. 2006, 45, 6523.
10.1021/jo070807a CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/11/2007
6190
J. Org. Chem. 2007, 72, 6190-6199

Cu-Catalyzed N-Arylation of Imidazoles and Benzimidazoles
complished using aryllead triacetate,6 arylboronic acid,7 triaryl-
bismuth,8 hypervalent aryl siloxane,9 diaryl iodonium salt,10 and
arylstannane11 reagents, these methods generally require the use
of toxic and/or unstable reagents that can be difficult to prepare.
Furthermore, in many cases, only one of the multiple aryl groups
is transferred to the heterocycle. In contrast, the use of more
stable and readily available aryl halides as the electrophilic
coupling partner resolves these issues.
SCHEME 1. Possible Catalytic Cycle
In our previous report, 5 mol% bis-[copper (I) triflate]benzene
[(CuOTf)2‚PhH] was shown to facilitate the coupling of
imidazole with aryl iodides under moderate conditions (100%
1,10-phenanthroline, L1a/10% dba/Cs2CO3/xylenes/110-125
°C/24-48 h).12 However, the scope of the catalyst system was
limited to the coupling of unhindered imidazoles with unhin-
dered aryl iodides. The use of air-sensitive (CuOTf)2‚PhH as
the precatalyst required the use of inconvenient glove box
techniques for reaction setup. The need for stoichiometric
quantities of the 1,10-phenanthroline ligand and long reaction
times were also undesirable.
Subsequently, we have developed effective ligands and
catalyst systems for the Cu-catalyzed coupling of aryl iodides
and bromides with a variety of N-H containing azoles;
however, little progress was made with respect to the N-arylation
of imidazoles.13 While reports by other groups have disclosed
the use of salicylaldoxime derivatives,14a amino acid deriva-
tives,14b-c N,N′-dimethylethylenediamine derivatives (DMEDA),14d
ligands first reported for C-N couplings by us,13c-e 4,7-
dichloro-1,10-phenanthroline,14e 8-hydroxyquinoline,14f amino-
arenethiol,14g oxime-phosphine oxides,14h phosphoamidites,14i
1,10-phenanthroline,14j fluoroapetite,14k and 2-aminopyrimidine-
diols14l as supporting ligands in the Cu-catalyzed N-arylation
of imidazoles with aryl iodides, very few examples of the
coupling of imidazoles with aryl bromides or of even moderately
hindered substrates (e.g., a 2-substituted imidazole or a 2-sub-
stituted aryl halide) were disclosed until our recent paper.15
Furthermore, the use of heteroaryl halides and 4(5)-substituted
imidazoles has not been reported. Herein, we describe a full
account of our recent work, which significantly expands the
substrate scope for the coupling of imidazoles and benzimida-
zoles with aryl halides. We also present results of a study in
which we compare our results with other recently reported
catalyst systems.
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M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674.
Results and Discussion
Method Development and Mechanistic Considerations.
Our initial investigations of the coupling of 2-iodotoluene with
imidazole demonstrated that 4,7-dimethoxy-1,10-phenanthroline
(L1c)16 in combination with (CuOTf)2‚PhH and Cs2CO3 in
CH3CN provided an improved catalyst system for this trans-
formation relative to those previously reported. As compared
to that derived from L1a, the enhanced reactivity of the catalyst
system based on Cu(I)-L1c can be attributed to the increased
σ-donating ability of the ligand, as evidenced by the difference
in acidities of the corresponding conjugate acids of the free
(12) Kiyomori, A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett.
1999, 40, 2657.
(13) (a) Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4,
581. (b) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (c) Klapars,
A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (d)
Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727. (e) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 11684. (f) Klapars, A.; Parris, S.; Anderson, K. W.;
Buchwald, S. L. J. Am. Chem. Soc. 2004, 126, 3529. (g) Antilla, J. C.;
Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578. (h) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(14) (a) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Chem.s
Eur. J. 2004, 10, 5607. (b) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005,
70, 5164. (c) Ma, D.; Cai, Q. Synlett 2004, 128. (d) Alcalde, E.; Dinare`s,
I.; Rodr´ıguez, S.; Garcia de Miguel, C. Eur. J. Org. Chem. 2005, 1637. (e)
Kull, M.; Bekedam, L.; Visser, G. M.; van den Hoogenband, A.; Terpstra,
J. W.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; van Strijdonck, G. P.
F. Tetrahedron Lett. 2005, 46, 2405. (f) Liu, L.; Frohn, M.; Xi, N.;
Donminguez, C.; Hungate, R.; Reider, P. J. J. Org. Chem. 2005, 70, 10135.
(g) Jerphagnon, T.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G.
Org. Lett. 2005, 7, 5241. (h) Xu, L.; Zhu, D.; Wang, R.; Wan, B.
Tetrahedron 2005, 61, 6553. (i) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.; Chen,
H.; Wan, B. Tetrahedron 2006, 62, 4435. (j) Hosseinzadeh, R.; Tajbakhsh,
M.; Alikarami, M. Tetrahedron Lett. 2006, 47, 5203. (k) Kantam, M. L.;
Venkanna, G. T.; Sridhar, C.; Kumar, K. B. Tetrahedron Lett. 2006, 47,
3897. (l) Xie, Y. X.; Pi, S. F.; Yin, D. L.; Li, J. H. J. Org. Chem. 2006, 71,
8324.
phenanthrolines (pKa L1a-H+ ) 4.86 and pKa L1c-H+
)
6.45).17 The more electron-rich ligand should stabilize the
presumed Cu(III) intermediate (Scheme 1, IV) and lower the
oxidation potential for the Cu(I)-Cu(III) redox pair, thus
accelerating the rate limiting aryl halide activation.18
(15) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779.
(16) L1c is available from Aldrich or can been prepared on a large scale
in a four-step procedure. For details of the synthesis, see ref 15.
(17) Schilt, A. A.; Smith, G. F. J. Phys. Chem. 1956, 60, 1546.
(18) Similarly, (L1a)3Fe(PF6)2 has a higher oxidation potential than
(L1c)3Fe(PF6)2 (0.69 and 0.38 V vs SCE, respectively). Lewis, M.; Lu¨ning,
U.; Mu¨ller, M.; Schmittel, M.; Wo¨hrle, C. Z. Naturforsch., B: Chem. Sci.
1994, 49, 675.
J. Org. Chem, Vol. 72, No. 16, 2007 6191

Altman et al.
TABLE 1. Coupling of Imidazoles with Aryl Iodidesa
a General reaction conditions: 1.2 mmol of imidazole, 1.0 mmol of ArX, 0.025 mmol of Cu2O, 0.075 mmol of L1c, 1.4 mmol of Cs2CO3, 200 mg of
PEG, and 0.25-1.0 mL of butyronitrile under Ar or N2 atmosphere at 110 °C for 24-48 h. b 12 mmol of imidazole, 10 mmol of ArI, 14 mmol of Cs2CO3,
0.0025 mmol of Cu2O, 0.0075 mmol of L1c, 2.0 g of PEG, and 2.5 mL of butyrontile. c Reaction run in NMP for 3 h. d Reaction run at 80 °C in MeCN.
e Reaction run at 90 °C. f Reaction run at 80 °C in MeCN with 3 Å molecular sieves. g 1.2 mmol of ArI, 1.0 mmol of imidazole; 6:1 ratio of iodo-/bromo-
substituted arene. h 0.05 mmol of Cu2O and 0.15 mmol of L1c, 120 °C. i Reaction run in NMP with no PEG. j Reaction run in NMP at 150 °C. k Reaction
run in DMSO at 150 °C.
Recent reports also have demonstrated that increasing the
solubility of the base can accelerate metal-catalyzed amination
reactions of aryl halides. As cetyltrimethylammonium bromide
has been used as a phase transfer catalyst (PTC) in Pd-catalyzed
amination reactions19 and as tetraethylammonium carbonate
(TEAC) has been used as a base in the Cu-catalyzed amination
reactions14f of aryl halides, we attempted to employ tetraalkyl-
ammonium salts in our own system. While the use of these
reagents did provide increased reaction rates, product yields were
low due to alkylation of the starting imidazole. Further, TEAC
decomposed under the reaction conditions to give NEt3 and CO2,
which were detected by GCMS and by bubbling the gas
produced through 1 M HCl. The problems associated with
TEAC could be alleviated while maintaining faster reaction rates
by using non-tetraalkylammonium solid-liquid phase transfer
catalysts in combination with Cs2CO3.20 The key choice of poly-
(ethylene glycol) (PEG) as an additive allowed for the use of
inexpensive and stable copper salts (e.g., Cu2O, CuI) as
precatalysts, as opposed to air- and moisture-sensitive copper
complexes, such as [CuOTf]2‚PhH.21
is in the order MeCN > EtCN > n-PrCN at 110 °Csopposite
the trend of their boiling points in the same seriesssuggesting
that the relative insolubility of Cs2CO3, or a polar Cu complex
(Scheme 1), in less polar solvents retards the reaction. With
the use of PEG, reactions carried out in these three solvents
proceed at comparable rates at 110 °C.23 However, using PEG
as a solvent was less effective, possibly due to poor mass
transport in the highly viscous solvent. While most of the
chemistry described herein generally uses either butyronitrile
or NMP, it is also important to note that reactions using the
PEG/Cs2CO3 combination also show rate enhancements in
solvents such as MeCN, EtCN, DMF, DMA, and DMSO,
although reactions using these other solvents tend to be slower
than those conducted in butyronirile or NMP. In addition, this
imidazole N-arylation process is moderately tolerant of water,
as evidenced by the fact that our typical procedure involves
weighing out a hygroscopic base (Cs2CO3) in the air with no
protection from ambient moisture. Moreover, by using 2.5-10%
Cu2O as the precatalyst, we are necessarily producing water.24
Substrate Scope. Using the catalyst system based on L1c,
we explored the scope of the reaction with unhindered aryl
iodides (Table 1). Using a catalyst loading of only 0.05% Cu,
we were able to N-arylate imidazole with iodobenzene in 48 h
at 110 °C (1a). To the best of our knowledge, no Cu-based
system for C-N bond formation has previously been reported
to achieve as many as 2000 turnovers. The reactions of aryl
iodides possessing ester and nitrile groups were inefficient under
The use of PEG as a solid-liquid phase transfer catalyst
increases the solubility of the carbonate in organic media,
increasing the rate of reaction by 10-30%.22 Without added
PEG, the observed reactivity of our system in nitrile solvents
(19) Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. J. Org. Chem. 2002,
67, 6479.
(20) 18-Crown-6 has been used to accelerate the coupling of diarylamines
with aryl iodides using Cu (stoichiometric)/K2CO3/o-dichlorobenzene/
reflux: Gauthier, S.; Fre´chet, J. M. J. Synthesis 1987, 383.
(21) Recent examples of the use of PEG as a solvent in transition metal-
catalyzed processes include: (a) Nobre, S. M.; Wolke, S. I.; da Rosa, R.
G.; Monteiro, A. L. Tetrahedron Lett. 2004, 45, 6527. (b) Reed, N. N.;
Dickerson, T. J.; Boldt, G. E.; Janda, K. D. J. Org Chem. 2005, 70, 1728.
(c) Svennebring, A.; Garg, N.; Nilsson, P.; Hallberg, A.; Larhed, M. J.
Org. Chem. 2005, 70, 4720. (d) Liu, L.; Zhang, Y.; Wang, Y. J. Org. Chem.
2005, 70, 6122. (e) Wang, L.; Zhang, Y.; Liu, L.; Wang, Y. J. Org. Chem.
2006, 71, 1284.
(22) This phenomenon is likely similar to the recently reported use of
the more soluble carbonate base, TEAC, in which the amount of the base
in solution increases due to the enhanced “greasiness” of the cation.14f
(23) Increased rates involving acetonitrile and propionitrile may be
partially due to the elevation of the boiling points of these solvents.
(24) Addition of small quantities of water to accelerate solid/liquid phase-
transfer catalysis processes is well-documented. See: (a) Albanese, D.;
Landini, D.; Maia, A.; Penso, M. Ind. Eng. Chem. Res. 2001, 40, 2396. (b)
Yadav, G. D.; Jadhav, Y. B. Langmuir 2002, 18, 5595.
6192 J. Org. Chem., Vol. 72, No. 16, 2007

Cu-Catalyzed N-Arylation of Imidazoles and Benzimidazoles
TABLE 2. Couplings of Imidazoles with Aryl Bromidesa
a Reaction conditions: 1.2 mmol of imidazole, 1.0 mmol of ArX, 0.05 mmol of Cu2O, 0.15 mmol of L1c, 1.4 mmol of Cs2CO3, 200 mg of PEG, and
0.25-1.0 mL of butyronitrile under Ar at 110 °C for 24-48 h. b 0.10 mmol of Cu2O and 0.30 mmol of L1c at 120 °C. c Reaction run in NMP. d 1.0 equiv
of ArBr and 2.4 equiv of imidazole with 2.8 equiv of Cs2CO3.
the standard conditions, due to the partial hydrolysis of the ester
to benzoic acid and of the nitrile to benzamide. However, by
lowering the reaction temperatures to 80-90 °C, excellent yields
of the N-arylated products could be obtained (1b,d). Aryl iodides
were selectively coupled in the presence of substrates containing
aryl bromides, chlorides, and fluorides (1e,j,k). Electron-rich,
-neutral, and -deficient aryl iodides all provided products in good
to excellent yields. The coupling of hindered substrate combina-
tions could also be accomplished using this catalyst system;
2-alkyl and 2-aryl imidazoles (1j-l) and ortho-substituted aryl
iodides (1f-i) were effectively converted to product. The
coupling of more hindered substrate combinations (1l-m) could
be accomplished at higher reaction temperatures (150 °C). In
the combination of imidazole with mesityl iodide, mesitylene
from the reduction of the aryl iodide was the major side product.
At this point, we do not fully understand the mechanism of the
reduction pathway, although we speculate that it might involve
a radical pathway.
Aryl bromides were also successfully coupled under our
reaction conditions (Table 2). Higher quantities of catalyst and
longer reaction times, however, were often necessary to provide
good yields of product. The combination of 2-substituted
imidazoles with aryl bromides provided N-arylated products in
good yields (2d,e). Additionally, the coupling of imidazole and
2-bromotoluene can be accomplished in good yield (2f). Further,
imidazole can be selectively arylated in the presence of a free
-OH or -NH2 group (2b,c). This selectivity is particularly
interesting, as 1,10-phenanthroline derivatives have also been
reported as ligands in the Cu-catalyzed syntheses of aryl ethers
and aryl amines from aryl halides.25
h using butyronitrile. More difficult cases, including reactions
of hindered aryl halides and 2-substituted imidazoles, also
reacted more efficiently using NMP (1i,l, 2f,h, and 3d). The
rate enhancement using NMP can be seen in Figures 1-4.
The reactions of 4(5)-substituted imidazoles with aryl halides
showed varying degrees of regioselectivity, with the preferential
formation of 4-substituted imidazoles (Table 3).26 With 4-phenyl
imidazole, the 1,4-diarylimidazole was the exclusive product
observed (3a). Reactions of 4-methyl imidazoles with aryl
bromides lacking an ortho-substituent showed similar selectivity
for the formation of 1-aryl-4-alkyl imidazoles similar to that
previously observed (3b,c).12 As in the study conducted by
Collman et al. on the coupling of 4-substituted imidazoles with
aryl boronic acids,26 the preferential selectivity for the 4-re-
gioisomer over the 5-regioisomer is likely due to the greater
steric interactions when the substituent R1 resides at the
5-position as compared to the 4-position either prior to aryl
halide activation (Scheme 2, V to VI) or upon activation of the
aryl halide (VII to VIII). In contrast, reactions of 4(5)-
methylimidazole with ortho-substituted aryl halides provided
the 4-regioisomer with significantly better selectivity (3d-f).
This increase in regioselectivity when using a hindered aryl
halide likely arises due to the additional unfavorable steric
interaction between the group ortho to the halide (R2) and R1
when R1 is situated in the 5-position (IX) as opposed to the
4-position (X). The reaction of 4-bromo-2-methylimidazole with
4-iodoanisole provided 4-bromo-1-(4-methoxyphenyl)-2-methyl-
1H-imidazole as the major product (3g). Formation of the
5-bromo-1-(4-methoxyphenyl)-2-methyl isomer was not detected
1
by GC or H NMR techniques. In this case, the selectivity is
Butyronitrile was employed as a solvent for many of the
reactions described because it is relatively volatile, nonpolar,
and easy to remove from products as compared to the higher
boiling point solvents such as DMF, DMSO, and NMP.
However, in some cases, the use of NMP as the solvent provided
faster reactions. For example, we found that we were able to
arylate imidazole with iodobenzene in excellent yields in 3 h
with 5% Cu in NMP (1a), while the same reaction required 4
likely dictated by the increased steric effects that exist in the
Cu (III) intermediate when the large bromide-substituent resides
at the 5-position (XI) relative to the 4-position (XII).
As N-heteroaryl imidazoles are interesting targets in drug
discovery and medicinal chemistry,27 the coupling of imidazoles
with unactivated heteroaryl bromides and iodides was examined
(Table 4). Generally, isolated yields for reactions of imidazoles
(26) Increased selectivity for the preferential formation of the 4-substi-
tuted N-aryl imidazole over the 5-regioisomer, due to increased steric effects,
has also been observed in the Cu-catalyzed coupling of 4(5)-substituted
imidazoles with aryl boronic acids. See: Collman, J. P.; Zhong, M.; Zhang,
C.; Costanzo, S. J. Org. Chem. 2001, 66, 7892.
(25) (a) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001,
3, 4315. (b) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org.
Lett. 2002, 4, 973. (c) Nordmann, G.; Buchwald, S. L. J. Am. Chem. Soc.
2003, 125, 4978.
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Altman et al.
TABLE 3. Coupling of 4(5)-Substituted Imidazolesa,b
a 4-R1: 5-R1 selectivity is reported in parentheses and was determined by GC analyses of the crude reaction mixtures and/or 1H NMR spectra of the pure
products. b Reaction conditions for ArBr: 1.2 mmol of imidazole, 1.0 mmol of ArBr, 0.05 mmol of Cu2O, 0.15 mmol of L1c, 1.4 mmol of Cs2CO3, 200 mg
of PEG, and 0.25-1.0 mL of butyronitrile under Ar atmosphere at 110 °C for 24-30 h. Isolated yields reported. c Reaction conditions for ArI: 1.2 mmol
of imidazole, 1.0 mmol of ArI, 0.025 mmol of Cu2O, and 0.075 mmol of L1c, with ArI. d NMP used as solvent. GC yield reported. e 1.2 mmol of ArI, 1.0
mmol of imidazole, no PEG, 0.05 mmol of CuI, and 0.075 mmol of L1c in 0.5 mL of MeCN. Only one regioisomeric bromide was detected by GC and 1H
NMR.
SCHEME 2. Consideration of Steric Effects in Reactions of 4(5)-Substituted Imidazoles
with heteroaryl iodides and bromides were slightly lower than
those with simple aryl halides due to the formation of the
reduced heteroarene as a byproduct.28 In some cases, the use
of DMSO as a solvent caused an increase in the yield of the
desired product and decreased the quantity of the dehalogenated
byproduct.
tion for uncatalyzed SnAr. In this case, the Cu-catalyzed
substitution occurred predominantly at the iodide to provide 4a
in good yield. In the coupling of 5-iodoindole with imidaozle
(4b), the N-heteroaryl imidazole was isolated in good yield, with
trace amounts of N-aryl indole formed as a side product.29 This
selectivity likely arises from the more rapid transmetallation of
imidazole with Cu(I) through the sp2-hybridized lone pair
electrons as compared to the case of indole, where coordination
Useful selectivity was observed in the reaction of imidazole
with 2-chloro-5-iodopyridine, a substrate activated at the 2-posi-
6194 J. Org. Chem., Vol. 72, No. 16, 2007

Cu-Catalyzed N-Arylation of Imidazoles and Benzimidazoles
TABLE 4. Couplings of Heteroaryl Halides
a Reaction conditions for ArI: 1.0 mmol of imidazole, 1.2 mmol of ArI, 0.025 mmol of Cu2O, 0.075 mmol of L1c, 1.4 mmol of Cs2CO3, 200 mg of PEG,
and 0.5 mL of DMSO under Ar at 110 °C for 12-24 h. b Reaction conditions for ArBr: 1.0 mmol of imidazole, 1.2 mmol of ArBr, 0.05 mmol of Cu2O,
0.15 mmol of L1c, 1.4 mmol of Cs2CO3, 200 mg of PEG, and 0.5 mL of DMSO under Ar at 110 °C for 24-48 h. c 1.2 mmol of imidazole, 1.0 mmol of
ArI, 0.025 mmol of Cu2O, 0.075 mmol of L1c, 1.4 mmol of Cs2CO3, and 0.5 mL of butyronitrile under Ar at 110 °C for 16 h.
TABLE 5. Coupling of Benzimidazoles with Aryl Bromidesa
a General reaction conditions: 1.2 mmol of benzimidazole, 1.0 mmol of ArBr, 0.10 mmol of Cu2O, 0.20 mmol of L1c, 1.4 mmol of Cs2CO3, 200 mg of
PEG, and 0.5 mL of DMSO under Ar or N2 atmosphere at 110 °C for 24 h. b MTBD used as base. c Reaction run at 130 °C for 24 h. d 0.05 mmol of Cu2O
and 0.15 mmol of L1c.
of the p-hybridized lone pair electrons results in a partial loss
of aromaticity. Imidazoles were also successfully combined with
a variety of heteroaryl halides including 3-halofuran (4c),
3-haloisoquinoline (4d), 2-halothiazole (4e), 2-halothiophene
(4f,h),30 and a 3-halobenzothiophene (4g).
The use of DMSO and L1c also permits the successful
coupling of benzimidazoles to unactivated aryl bromides (Table
5), which until recently14f had previously been limited to aryl
iodides and unhindered aryl bromides using Cu-catalyzed
methodology.12,13g,14 As seen previously, substrates containing
a free anilino-NH2 groups (5e) were good substrates under our
conditions. ortho-Substituted aryl bromides, as well as 2-sub-
stituted benzimidazoles, were successfully used as partners
(5a,c,e,f). In some cases, the use of 7-methyl-1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (MTBD) as a base provided better yields than
the Cs2CO3/PEG combination (5a,c).31
(27) Representative examples: (a) Maekawa, T.; Sakai, N.; Tawada, H.;
Murase, K.; Hazama, M.; Sugiyama, Y.; Momose, Y. Chem. Pharm Bull.
2003, 51, 565. (b) Hoffmann-La Roche Inc. Heteroaryl-Substituted Imida-
zole Derivatives. U.S. Patent 20,040,254,179, December 16, 2004. (c)
Smithkline Beecham Corporation. Thiophene Compounds. WO/014899 A1,
February 19, 2004. (d) Chen, P.; Doweyko, A. M.; Norris, D.; Gu, H. H.;
Spergel, S. H.; Das, J.; Moquin, R. V.; Lin, J.; Wityak, J.; Iwanowicz, E.
J.; McIntyre, K. W.; Shuster, D. J.; Behnia, K.; Chong, S.; de Fex, H.;
Pang, S.; Pitt, S.; Shen, D. R.; Thrall, S.; Stanley, P.; Kocy, O. R.; Witmer,
M. R.; Kanner, S. B.; Schieven, G. L.; Barrish, J. C. J. Med. Chem. 2004,
47, 4517.
(28) Significant reduction in the Cu-catalyzed amination of heteroaryl
halides has been observed. See: Arterburn, J. B.; Pannala, M.; Gonzalez,
A. M. Tetrahedron Lett. 2001, 42, 1475.
(30) 2-Aminothiophenes are unstable in air oxidation and decompose
readily upon exposure to air. See: Lu, Z.; Twieg, R. J. Tetrahedron 2005,
61, 903.
(29) The Cu-catalyzed N-arylation of indole under mild conditions has
been previously reported by our group.13e
J. Org. Chem, Vol. 72, No. 16, 2007 6195

Altman et al.
TABLE 6. Ligands Reported for Cu-Catalyzed N-Arylation of Imidazoles
Comparison of Ligands Commonly Employed for N-
Arylation of Imidazoles. After most of our work for this paper
was finished, several catalyst systems were reported for the
N-arylation of imidazoles and benzimidazoles (Table 6).14-15
To evaluate our new catalyst system in light of those previously
published, we decided to undertake a study to compare our
system not only with those that had been previously reported
for this coupling but also with other 1,10-phenanthroline
derivatives. While ligands L1a, L1b, L1c, L2-L6, and L10
are commercially available, L7-9 are only accessible through
multiple step sequences. Furthermore, the harsh conditions
necessary for the use of L9,10 (145-160 °C) suggest that at
the time of the report, these ligands were useful only in specific
circumstances. For this reason, we focused the following study
on L1-L6. L11 was also examined to assess the significance
of ligand rigidity for this transformation. Importantly, no reaction
was observed for control reactions in which no ligand or PEG
was added.
Case 1: Aryl Bromide, No Issues of Steric Hindrance.
To examine a process in which steric hindrance was not a
significant factor, the reaction of 4-t-butylbromobenzene with
imidazole was conducted (eq 1). Of the catalysts examined, only
systems derived from the 4,7-disubstituted-1,10-phenanthrolines
and L6 (with PEG/Cs2CO3 instead of TEAC) provided reason-
able results (>60% GC yield). Of these, the use of L1c provided
a nearly quantitative yield of N-aryl product, followed by L1e
and L1b (86 and 76% GC yields, respectively).
sensitivity of each catalytic system to substitution on the
nucleophile (eq 2). Only catalyst systems based on 4,7-
disubstituted-1,10-phenanthrolines (L1b-e), L6, and L11 were
effective for this transformation. Of those mentioned, L1b, L1c,
and L6b provided slightly better yields (>95% GC yield) of
product than did L1e (86-88% GC yield). All other ligands
were ineffective for this transformation within a reasonable time
period (<20% GC yield).
Case 3: Hindered Aryl Bromide with Imidazole. The very
few examples of Cu-catalyzed reactions of ortho-substituted aryl
bromides with imidazole require high temperatures and/or long
reaction times.14b,f,l We, therefore, chose to examine the reaction
of 2-bromotoluene with imidazole (eq 3). The majority of the
ligands screened provided similarly efficacious catalysts (40-
60% GC yield). The use of L1e provided a slightly higher yield
of product (66%). Only the use of dimethoxy L1c and L6 as
ligands provided synthetically useful yields (83-85% GC yield,
respectively) using PEG/Cs2CO3. However, using L6 and TEAC
as the base, 15% of the aryl bromide was lost.
Case 4: Hindered Aryl Iodide with 4(5)-Substituted
Imidazole. To explore the effect of the ligand employed on
the regioselectivity of the coupling process, 4-methylimidazole
was combined with 2-isopropyliodobenzene (eq 4). Systems
based on most ligands provided low catalytic activity (<40%
GC yield) and moderate selectivity in favor of the 4-regioisomer.
Reactions utilizing L1b and L1e provided reasonable reaction
efficiencies (51-62% GC yield) with excellent selectivity for
the 4-alkyl imidazole (30-42:1). Once again, the use of L1c
provided the best result, giving an 82% GC yield with a
selectivity of 37:1 in favor of the 4-methyl regioisomer.
Summary of Ligand Comparisons Screens. In general, L1c
outperformed other 1,10-phenanthrolines lacking heteroatoms
in the 4- and 7-positions (L1a and L1f). The catalyst derived
from anionic 4,7-dihydroxy derivative L1b showed a higher reac-
tivity than unsubstituted L1a but was generally less active than
that with L1c. This may be due to the relative insolubility of
L1b in the solvents employed. Interestingly, L1c outperformed
4,7-dibutoxy-1,10-phenanthroline (L1d),33 which we had pos-
tulated might be a better ligand due to its increased solubility.
Case 2: Aryl Iodide, 2-Substituted Imidazole. The efficient
N-arylation of 2-substituted imidazoles had not been achieved
prior to our earlier paper.15,32 The reaction of 4-n-butyliodo-
benzene with 2-methylimidazole was chosen to probe the
(31) MTBD previously has been used as a soluble base for the
Pd-catalyzed amination of aryl nonaflates using microwave irradiation.
Tundel, R. E.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2006, 71,
430.
(32) Coupling of 2-methylimidazole with 4-iodoanisole proceeds to 65%
conversion in 48 h (10% (CuOTf)2‚PhH/10% dba/100% L1a/xylenes/125
°C/48 h).12 Coupling of 2-methylimidazole with 5-bromo-m-xylene (10%
CuI, 10% L6/TEAC/10:1 DMF/H2O/130 °C, 16 h) yields 64% of N-aryl
imidazole.14f
6196 J. Org. Chem., Vol. 72, No. 16, 2007

Cu-Catalyzed N-Arylation of Imidazoles and Benzimidazoles
FIGURE 1. Reaction of imidazole with 4-t-butylbromobenzene.
FIGURE 2. Reaction of 2-methylimidazole with 4-n-butyliodobenzene.
Reactions using chlorinated L1e as a ligand demonstrated good
conversion to product, which we found surprising considering
the electron-deficient nature of the ligand as compared to the
methoxy counterpart. However, using L1e, reisolation of the
ligand at the end of the reaction showed that the chlorides had
been displaced at the 4- and 7-positions by a mixture of both
residual water and imidazole. Thus, using the Cu/L1e combina-
(33) 4,7-Diethoxy-1,10-phenanthroline was also found to be more
effective than L1d but less effective than L1c for this transformation.
J. Org. Chem, Vol. 72, No. 16, 2007 6197

Altman et al.
FIGURE 3. Reaction of imidazole with 2-bromotoluene.
FIGURE 4. Reaction of 4-methylimidazole with 2-isopropyliodobenzene.
tion, it is unclear as to the nature of the actual ligand in the ac-
tive catalyst. The increased efficiency of catalysts based on L1c
relative to L11 demonstrated the significance of the rigid phenan-
throline backbone over the 2,2′-bipyridine structure, which
6198 J. Org. Chem., Vol. 72, No. 16, 2007

Cu-Catalyzed N-Arylation of Imidazoles and Benzimidazoles
with additional dichloromethane (20 mL). The filtrate was con-
centrated, and the resulting residue was purified by flash chroma-
tography using a mixture of hexane and ethyl acetate to provide
the desired product. Representative examples are as follows.
contains conformational freedom about the biaryl bond. While
catalysts using ligands L3-L5 demonstrated sluggish reactivity
with more challenging imidazole/aryl halide substrate combina-
tions under the reported conditions,14a-d their use with the PEG/
Cs2CO3 conditions described here provided higher conversions
and yields. The effect of PEG can be further seen as the Cu2O/
PEG combination, L2 (without a N-containing ligand), which
provided similar reactivity as when unsubstituted 1,10-phenan-
tholine (L1a) was used as the ligand. The use of L6 as a ligand
for these reactions provided high reactivity; however, the use
of TEAC as a base provided low yields as previously mentioned
in this text. Using L6, the use of PEG/Cs2CO3 instead of TEAC
as the base provided higher yields of N-aryl imidazoles due to
the formation of multiple byproducts due to three processes:
(1) reduction of the aryl halide, (2) O-arylation of the ligand,
and (3) N-alkylation of imidazole by the tetraalkylammonium
cation. Because of their low cost, many of these systems might
still be attractive for the coupling of more facile substrate
combinations; however, there are significant limitations to the
scope of imidazoles and aryl halides that can be effectively
coupled by these systems as compared to L1c.
1-(3,5-Dichloro-phenyl)-2-methyl-1H-imidazole (1j). The gen-
eral procedure was followed using Cu2O (7.2 mg, 0.05 mmol), L1c
(36 mg, 0.15 mmol), PEG (200 mg), Cs2CO3 (0.45 g, 1.4 mmol),
1,3-dichloro-5-iodobenzene (273 mg, 1.00 mmol), and 2-meth-
ylimidazole (100 mg, 1.2 mmol) with butyronitrile (0.5 mL) as
solvent for 24 h at 110 °C. Chromatographic purification (hexane/
ethyl acetate 1:3) provided the title compound as white needles
1
(194 mg, 86%). H NMR (300 MHz, CDCl3) d 7.44 (t, 1H, J )
1.8 Hz), 7.23 (d, 2H, J ) 1.9 Hz), 7.05 (d, 1H, J ) 1.2 Hz), 6.99,
(d, 1H, J ) 1.2 Hz), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
139.8, 135.8, 128.5, 128.4, 124.1, 14.0. IR (KBr disc, cm-1) 1534,
1501, 1463, 1451, 1405, 1305, 1176, 1143, 1115, 1099, 985, 850,
781. Anal. Calcd for C10H8N2Cl2: C 52.89, H 3.55. Found: C 52.95,
H 3.44. mp 122-125 °C.
4-Imidazol-1-yl-isoquinoline (4d). The general procedure was
followed using Cu2O (7.2 mg, 0.05 mmol), L1c (36 mg, 0.15
mmol), PEG (200 mg), Cs2CO3 (0.45 g, 1.4 mmol), 4-bromoiso-
quinoline (250 mg, 1.2 mmol), and imidazole (68 mg, 1.00 mmol)
with DMSO (0.5 mL) as solvent for 24 h at 110 °C. Chromato-
graphic purification (ethyl acetate/hexane 3:1) provided the N-aryl
1
Conclusion
product as clear crystals (165 mg, 85%). H NMR (300 MHz,
CDCl3) δ 9.27 (d, 1H, 0.9 Hz), 8.48 (s, 1H), 8.08 (m, 1H), 7.78-
7.62, (m, 4H), 7.30 (bs, 1H), 7.25 (bs, 1H). 13C NMR (100 MHz,
CDCl3) δ 153.3, 139.6, 138.2, 132.1, 131.9, 130.2, 129.2, 128.8,
128.4, 127.9, 121.5, 121.2. IR (KBr disc, cm-1) 1589, 1508, 1491,
1406, 1307, 1107, 1078, 1038, 942, 913, 782, 660. Anal. Calcd
for C12H9N3: C 73.43 H 4.65. Found: C 73.43, H 4.63. mp 67-
71 °C.
In conclusion, we have demonstrated the utility of 4,7-
dimethoxy-1,10-phenanthroline as an excellent ligand for the
Cu-catalyzed arylation of imidazoles and benzimidazoles with
aryl and heteroaryl iodides and bromides in combination with
PEG and Cs2CO3. Not only is our system the most general
reported to date, it also allows for the cross-coupling of hindered
substrate combinations. The mild conditions employed also
manifest a high functional group tolerance.
Acknowledgment. We thank the National Institutes of
Health (GM58160) for financial support for this project. We
are grateful to Merck, Amgen, and Boehringer-Ingelheim for
additional unrestricted support. We also thank Dr. Alex Shafir
for providing L1c. The Varian NMR instruments used for this
publication were paid for by the NSF (CHE 9808061 and DBI
9729592). E.D.K. thanks MIT UROP for funding.
Experimental Section
General Procedure for Tables 1-5. An oven-dried screw-
capped test tube was charged with Cu2O, L1c, imidazole, aryl halide
(if solid), PEG, Cs2CO3, and a magnetic stir bar, and the reaction
vessel was fitted with a rubber septum. The vessel was evacuated
and back-filled with argon or nitrogen, and this sequence was
repeated an additional time. Aryl halide (if liquid) and solvent were
then added successively. The reaction tube was sealed and stirred
in a pre-heated oil bath for the designated time period. The reaction
mixture was cooled to room temperature, diluted with dichlo-
romethane (15 mL), and filtered through a plug of celite, eluting
Supporting Information Available: Experimental procedures
and characterization data for all new and known compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
JO070807A
J. Org. Chem, Vol. 72, No. 16, 2007 6199