Simple copper salt-catalyzed N-arylation of nitrogen-containing heterocycles with aryl and heteroaryl halides

Article abstract of DOI:10.1021/jo0712289

(Chemical Equation Presented) Relatively mild and highly efficient CuI-catalyzed N-arylation procedures for nitrogen-containing heterocycles (e.g., imidazoles, benzimidazoles, pyrroles, pyrazoles, indoles, triazoles, etc.) with aryl and heteroaryl halides have been developed. The protocols can be performed easily and tolerate a number of functional groups, such as ester, nitrile, nitro, ketone, free hydroxyl, and free primary amine on the aryl halide.

Full text of DOI:10.1021/jo0712289

TABLE 1. Some Representative Results from the Screening of
Reaction Conditions for the N-Arylation of Imidazole with
4-Bromoanisolea
Simple Copper Salt-Catalyzed N-Arylation of
Nitrogen-Containing Heterocycles with Aryl and
Heteroaryl Halides
Liangbo Zhu, Peng Guo, Gaocan Li, Jingbo Lan,
Rugang Xie, and Jingsong You*
imidazole
(mmol)
yieldb
(%)
entry
solvent
base
Key Laboratory of Green Chemistry and Technology of Ministry
of Education, College of Chemistry, and State Key Laboratory
of Biotherapy, West China Hospital, West China Medical
School, Sichuan UniVersity, 29 Wangjiang Road,
Chengdu 610064, PR China
1
2
3
4
5
6
7
8
9
1.6
1.4
1.2
1.0
1.4
1.4
1.4
1.4
1.4
1.4
1.4
1.4
DMF
DMF
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
KOH
86
89
78
45
72
71
c
74
48
44
63
44
none
DMSO
toluene
n-butanol
DMF
DMF
DMF
jsyou@scu.edu.cn
ReceiVed June 12, 2007
10
11
12
NaOH
K2CO3
K3PO4
DMF
a Reaction conditions: 1a (1.0 mmol), base (2.0 mmol) in the presence
of CuI (0.2 mmol) in 2.0 mL of solvent at 120 °C under N2 atmosphere.
b Isolated yields (average of two runs). c Little coupling product was
determined.
These well-known reactions, however, generally suffer from
several limitations: (i) high reaction temperatures (often 150 °C
or as high as 200 °C), (ii) the use of stoichiometric amounts of
copper reagents, (iii) moderate yields, and (iv) poor substrate
generality. It is therefore not surprising that great efforts have
been directed toward the development of a mild as well as highly
efficient method for constructing N-arylazole units.4,5 Recently,
Buchwald6 and Taillefer7 have discovered and developed the
copper catalytic path for N-arylation of nitrogen-containing
heterocycles with aryl halides in the presence of N- and O-based
ligands under relatively mild conditions, which has led to a
resurgence of interest in Ullmann-type coupling reactions due
to the economic attractiveness of copper.8 Quite recently, our
laboratory has also presented highly efficient CuI-catalyzed
N-arylation procedures for N-containing heterocycles with aryl
and heteroaryl bromides or chlorides through the use of (S)-
pyrrolidinylmethylimidazole ligands.9
Relatively mild and highly efficient CuI-catalyzed N-
arylation procedures for nitrogen-containing heterocycles
(e.g., imidazoles, benzimidazoles, pyrroles, pyrazoles, in-
doles, triazoles, etc.) with aryl and heteroaryl halides have
been developed. The protocols can be performed easily and
tolerate a number of functional groups, such as ester, nitrile,
nitro, ketone, free hydroxyl, and free primary amine on the
aryl halide.
N-Arylimidazoles, N-arylpyrroles, N-arylpyrazoles, N-arylin-
doles, and N-aryltriazoles have received great attention in a
variety of fields throughout the chemical, pharmaceutical, and
material sciences.1 Traditionally, these N-arylazoles have been
synthesized via SNAr (nucleophilic aromatic substitution) of
N-containing heterocycles with electron-deficient aryl halides2
or via the classical Ullmann-type coupling with aryl halides.3
Recently, we have developed the CuCl-catalyzed N-arylation
of imidazole with arylboronic acids in protic solvents in the
(4) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400.
(5) Several Pd-catalyzed C-N formation methods have been discovered,
which, upon using some relatively expensive and air-sensitive sterically
hindered phosphine ligands, allowed cross-couplings of aryl halides with
N-H heterocycles to proceed under mild conditions. (a) Anderson, K. W.;
Tundel, R. E.; Ikawa, T.; Altman, R. A.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2006, 45, 6523. (b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131. (c) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem.
1999, 576, 125. (d) Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046.
(e) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (f) Wolfe, J. P.; Wagan,
S.; Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805. (g)
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; p 699.
(6) (a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 11684. (b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S.
L. J. Am. Chem. Soc. 2001, 123, 7727. (c) Antilla, J. C.; Baskin, J. M.;
Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578.
(7) (a) Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M. Eur. J.
Org. Chem. 2004, 695. (b) Taillefer, M.; Cristau, H. J.; Cellier, P. P.;
Spindler, J. F. FR 0116547, 2001. (c) Cristau, H. J.; Cellier, P. P.; Spindler,
J. F.; Taillefer, M. Chem.sEur. J. 2004, 10, 5607.
(1) (a) Craig, P. N. In ComprehensiVe Medicinal Chemistry; Drayton,
C. J., Ed.; Pergamon Press: New York, 1991; Vol. 8. (b) Cozzi, P.;
Carganico, G.; Fusar, D.; Grossoni, M.; Menichincheri, M.; Pinciroli, V.;
Tonani, R.; Vaghi, F.; Salvati, P. J. Med. Chem. 1993, 36, 2964. (c) Negwer,
M. In Organic-Chemical Drugs and their Synonyms: An International
SurVey, 7th ed.; Akademie Verlag GmbH: Berlin, Germany, 1994. (d)
Kundu, N. G.; Mahanty, J. S.; Chowdhurry, C.; Dasgupta, S. K.; Das, B.;
Spears, C. P.; Balzarini, J.; De Clercq, E. Eur. J. Med. Chem. 1999, 34,
389. (e) Kunz, K.; Scholtz, U.; Ganzer, D. Synlett 2003, 15, 2428. (f)
Herrmann, W. A. Angew. Chem., Int. Ed. 2002, 41, 1290.
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Venuti, M. C.; Stephenson, R. A.; Alvarez, R.; Bruno, J. J.; Strosberg, A.
M. J. Med. Chem. 1988, 31, 2136. (c) Qiao, J. X.; Cheng, X.; Modi, D. P.;
Rossi, K. A.; Luettgen, J. M.; Knabb, R. M.; Jadhav, P. K.; Wexler, R. R.
Bioorg. Med. Chem. Lett. 2005, 15, 29. (d) Gu¨ngo¨r, T.; Fouquet, A.; Teulon,
J.-M.; Provost, D.; Cazes, M.; Cloarec, A. J. Med. Chem. 1992, 35, 4455.
Also see ref 4.
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Med. Chem. 2000, 43, 1841. (b) Fan, J.; Sun, W.; Okamura, T.; Tang, W.;
Ueyama, N. Inorg. Chem. 2003, 42, 3168. (c) 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. Also see refs 2b and 4.
10.1021/jo0712289 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/29/2007
J. Org. Chem. 2007, 72, 8535-8538
8535

TABLE 2. Catalytic N-Arylation of Imidazole with Aryl and Heteroaryl Halides by CuIa,b
a Reaction conditions: 1 (1.0 mmol), 2a (1.4 mmol), 2.0 mmol of Cs2CO3 in the presence of 20 mol % of CuI in 2.0 mL of DMF at 120 ( 5 °C under
N2 atmosphere. b Isolated yields (average of two runs) based on 1. c 100 mg activated 4 Å molecular sieves.
absence of an additional chelating ligand.10 Thus, it was a natural
extension for us to explore new simple copper salt catalytic
systems for preparing N-arylimidazoles through the coupling
reactions of aryl halides, which are more easily available and
less expensive than the corresponding organometal reagents.11
In this study, we surprisingly found that a catalytic amount of
air-stable CuI could promote the cross-couplings of a number
of nitrogen-containing heterocycles with various aryl and
heteroaryl halides under relatively mild conditions when the
heterocycle is in excess in relation to the aryl halide, which
constitutes very practical, general, and highly efficient processes
for the synthesis of N-arylazoles.
Despite significant progress in the Cu-catalyzed N-arylation
of nitrogen heterocycles with aryl halides, only a few reports
have appeared describing the couplings of imidazoles with aryl
bromides or of functional substrates or of hindered substrates.7-9
The majority of aryl halides investigated to date, already limited
in examples, are aryl iodides.6b,c,8a,d,g In some cases with respect
to aryl bromides, the electron-withdrawing groups and/or higher
reaction temperatures even have to be required.8d,f,j We therefore
chose to focus initial studies on the cross-couplings of imidazole
through the use of CuI without the assistance of an additional
chelating ligand.
(8) (a) Ma, D.; Cai, Q. Synlett 2004, 128. (b) Zhang, H.; Cai, Q.; Ma,
D. J. Org. Chem. 2005, 70, 5164. (c) Lv, X.; Wang, Z.; Bao, W. Tetrahedron
2006, 62, 4756. (d) Alcalde, E.; Dinare`s, I.; Rodr´ıguez, S.; de Miguel, C.
G. Eur. J. Org. Chem. 2005, 1637. (e) Kuil, M.; Bekedam, E. K.; 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) Jerphagnon, T.; van Klink, G. P. M.; de Vries, J. G.; van
Koten, G. Org. Lett. 2005, 7, 5241. (g) Xu, L.; Zhu, D.; Wu, F.; Wang, R.;
Wan, B. Tetrahedron 2005, 61, 6553. (h) Rao, H.; Jin, Y.; Fu, H.; Jiang,
Y.; Zhao, Y. Chem.sEur. J. 2006, 12, 3636. (i) Zhang, Z.; Mao, J.; Zhu,
D.; Wu, F.; Chen, H.; Wan, B. Tetrahedron 2006, 62, 4435. (j) Xie, Y.; Pi,
S.; Wang, J.; Yin, D.; Li, J. J. Org. Chem. 2006, 71, 8324. (k) Liu, L.;
Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.; Reider, P. J. J. Org. Chem.
2005, 70, 10135. (l) Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. AdV.
Synth. Catal. 2006, 348, 2197. (m) Lv, X.; Bao, W. L. J. Org. Chem. 2007,
72, 3863. (n) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779. (o)
Chang, J. W. W.; Xu, X.; Chan, P. W. H. Tetrahedron Lett. 2007, 48, 245.
(p) Vargas, V. C.; Rubio, R. J.; Hollis, T. K.; Salcido, M. E. Org. Lett.
2003, 5, 4847. (q) Wu, Q.; Hook, A.; Wang, S. Angew. Chem., Int. Ed.
2000, 39, 3933. (r) Choudary, B. M.; Sridhar, C.; Kantam, M. L.; Venkanna,
G. T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948. (s) Taillefer, M.;
Xia, N.; Ouali, A. Angew. Chem., Int. Ed. 2007, 46, 934. (t) Altman, R.
A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72, 6190.
(9) Zhu, L.; Cheng, L.; Zhang, Y.; Xie, R.; You, J. J. Org. Chem. 2007,
72, 2737.
It was determined during a preliminary survey of reaction
conditions using 4-bromoanisole (1a) and imidazole (2a) as
model arylating agents shown in Table 1. We found that the
amount of imidazole was crucial to the outcome of the reaction,
and the catalytic performance proved to be improved by
increasing the quantity of nitrogen-containing heterocycle, which
(11) Relatively mild conditions have been achieved by the use of other
types of cross-coupling reagents in place of aryl halides as substrates, such
as aryllead triacetates, aryl siloxanes, triphenylbismuths, arylstannanes,
diaryliodonium salts, or, recently, arylboronic acids. However, these methods
generally require additional steps to transform aryl halides into the
corresponding organometal reagents and thus are limited by the high cost
and poor availability of functionalized substrates. In addition, the synthesis
of some reagents may involve the use of highly toxic materials and/or
unstable reagents.
(10) Lan, J.; Chen, L.; Yu, X.; You, J.; Xie, R. Chem. Commun. 2004,
188.
8536 J. Org. Chem., Vol. 72, No. 22, 2007

TABLE 3. Catalytic N-Arylation of Azoles with Aryl Halides by CuIa,b
a Reaction conditions: see Table 2. b Isolated yields (average of two runs) based on 1. c The regioselectivity was determined by GC-mass analysis and
is described in parentheses.
shows a clear maximum at 1.4 equiv of imidazole (compare
entries 1-4). While 20 mol % of CuI was employed in the
presence of 2 equiv of Cs2CO3, a series of reaction solvents
(e.g., toluene, n-butanol, DMF, and DMSO) were also inves-
tigated (entries 2, 6-8). Among the solvents tested, DMF was
clearly the best choice, and DMSO and n-butanol provided
slightly low yields while the use of toluene delivered little
desired coupling product. These results suggest that imidazole
and/or the solvent itself might possibly act as the ligand(s) for
the copper. Subsequently, we surprisingly found that this
coupling reaction could give the corresponding product in good
yield (72%) without addition of any solvent, which excludes
the possibility of the solvent as a ligand (entry 5). It is also
noteworthy that imidazoles as well as other nitrogen heterocycles
themselves have proved to be outstanding classes of ligands,
being capable of forming a broad variety of metal complexes
that are able to catalyze a great number of reactions.9 It is
therefore reasonable to assume that this procedure could be
extended to other nitrogen-containing heterocycles for the
synthesis of N-arylazoles. After screening a variety of bases
(e.g., KOH, NaOH, K2CO3, K3PO4, and Cs2CO3), we found that
Cs2CO3 gave the best result of 89% yield in DMF (compare
entries 2, 9-12).
With optimized conditions now in hand, we explored the
scope of the coupling reactions of aryl and heteroaryl halides
with imidazole in the presence of 20 mol % of CuI and 2 equiv
of Cs2CO3 in DMF at 120 °C under N2, and the results are
summarized in Table 2. We were delighted to find that the
catalytic system was able to tolerate a broad range of aryl
bromides (e.g., electron-rich, electron-deficient, electron-neutral,
sterically hindered, and functionalized bromoarenes, 3a-l).
Notably, our catalyst system could facilitate the coupling
reactions with regard to electron-rich aryl halides, although
transition-metal-catalyzed reactions involving these electron-
rich arylating agents are traditionally less straightforward (3a,
3h, 3j-l). In addition, Ullmann-type condensations are generally
sensitive to steric hindrance near the halogen atom, and there
are rare examples describing the Cu-catalyzed couplings of
imidazole with sterically hindered aryl halides. Our catalytic
system could be applied to N-arylation of imidazole with ortho-
or pseudo-ortho-substituted aryl bromides (3f-h). It is note-
worthy that the N-arylation of imidazole could be performed
without problems on 10 mmol scales.
Substrates that contain certain functional groups have proven
to be persistently problematic in the N-arylation of imidazoles.
To our delight, our catalytic system could almost exclusively
undergo the selective N-arylation of 4-bromophenol, 4-bromoa-
niline, 3-bromoaniline, and 2-amino-5-bromopyridine to afford
the corresponding N-arylimidazoles (3j-m) in good yields,
avoiding the competition from the formation of diaryl ethers
and diarylamines.4,8n,s,12,13 On the other hand, our protocol could
also tolerate a number of functional groups, such as ester, nitrile,
ketone, and nitro, although these functional groups themselves
might be decomposed at higher temperatures, for example, the
partial hydrolysis of the ester to benzoic acid and of the nitrile
to amide (3b-d,r).8k,n Thus, our protocol has offered a new
addition for the synthesis of highly functionalized azoles.
Preliminary results suggest that the current system could be
applicable to aryl chlorides to a less extent (3d,q-r). Further
exploration revealed that some heteroaryl halides were compat-
ible with these reaction conditions, giving satisfactory yields
of 72-98% (3m-q).8c,j,14 Notably, we run the control reactions
of aryl chlorides bearing strong electron-withdrawing groups
(e.g., 4-chlorobenzonitrile and 4-chloronitrobenzene) and acti-
vated heteroaryl bromides and halides (2-bromopyridine, 2-bro-
mothiazole, 2-chloropyrimidine) in the absence of Cu and found
(12) (a) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J. F.; Taillefer,
M. Org. Lett. 2004, 6, 913. (b) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799.
(c) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org. Lett. 2001, 3,
4315. (d) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante, R.
P.; Reider, P. J. Org. Lett. 2002, 4, 1623. Also see ref 4.
(13) Collman, J. P.; Wang, Z.; Zhong, M.; Zeng, L. J. Chem. Soc., Perkin
Trans. 1 2000, 1217.
(14) Son, S. U.; Park, I. K.; Park, J.; Hyeon, T. Chem. Commun. 2004,
778.
J. Org. Chem, Vol. 72, No. 22, 2007 8537

that the desired coupling reactions did not occur under our
standard conditions.
containing heterocycles with aryl and heteroaryl halides. The
system is effective for aryl bromides and, to a less extent, for
aryl chlorides. Particularly noteworthy is the fact that our
protocols could tolerate a number of functional groups, such as
ester, nitrile, nitro, ketone, free hydroxyl, and free primary
amine, on the aryl halide. In addition, the procedures could be
performed easily. This work should find wide application among
synthetic and medicinal chemists in industry and academics.
The development of chemistry that could emanate from a
single method for each of the major classes of nitrogen-
containing heterocycles has been seriously inhibited so far. In
an endeavor to expand the scope of the methodology, we found
that our new catalytic system was also suitable for other
π-electron-rich nitrogen heterocycles (e.g., pyrroles, pyrazoles,
indazoles, imidazoles, triazoles, etc.; Table 3). It is worth noting
that these optimized conditions could be applied to the N-
arylation of other imidazole derivatives. For example, the
coupling reaction of 1H-benzimidazole with iodobenzene af-
forded the corresponding N-arylated product in 91% yield (4e,
Table 3). The hindered 2-(1H-imidazol-2-yl)-1H-imidazole
could be selectively monoarylated with bromobenzene in 53%
yield (4f, Table 3). The coupling of 4-methyl-1H-imidazole with
bromobenzene gave a mixture of regioisomers of 1-aryl-4-
methyl imidazole and 1-aryl-5-methyl imidazole, which stems
from the two possible imidazole tautomers on the NH position
(4g, Table 3). As demonstrated by Collman15 and Buchwald,8t
the major product is the 4-regioisomer because the substituent
at the 4-position of imidazole is more geometrically favored
than that situated in the 5-position during the formation of the
intermediate. Similarly, the coupling of 3-methyl-1H-pyrazole
with iodobenzene afforded a mixture of regioisomers with the
preferential selectivity for the 3-regioisomer (4h, Table 3).7a
To our delight, the sterically hindered heterocycles such as
2-methyl-1H-indole and 3,5-dimethyl-1H-pyrazole could also
work with iodobenzene using our new method (4i-j, Table 3).
In summary, we have developed relatively mild and highly
efficient CuI-catalyzed N-arylation procedures for nitrogen-
Experimental Section
General Procedure for the Catalytic N-Arylation of Nitrogen-
Containing Heterocycles with Aryl Halides. To a flame-dried
Schlenk test tube with a magnetic stirring bar was charged CuI
(38.2 mg, 0.2 mmol), Cs2CO3 (0.65 g, 2.0 mmol), nitrogen-
containing heterocycle (1.4 mmol), aryl or heteroaryl halide (1.0
mmol), and DMF (2 mL) under N2. A rubber septum was replaced
with a glass stopper, and the system was then evacuated twice and
back filled with N2. The reaction mixture was stirred for 30 min at
room temperature, and then heated at 120 °C for 40 h. The reaction
mixture was then cooled to ambient temperature, diluted with 2-3
mL of ethyl acetate, filtered through a plug of silica gel, and washed
with 10-20 mL of ethyl acetate. The combined organic extracts
were concentrated, and the resulting residue was purified by column
chromatography on silica gel to provide the desired product.
Acknowledgment. This work was supported by grants from
the National Natural Science Foundation of China (Grant Nos.
20572074, 20602027, and 20472057).
Supporting Information Available: Detailed experimental
procedures for the synthesis of N-arylazoles, characterizational
NMR spectral data (1H and 13C) of N-arylazoles, and copies of 1H
and 13C NMR spectra for compounds 3a-r and 4a-j. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org. Chem.
2001, 66, 7892.
JO0712289
8538 J. Org. Chem., Vol. 72, No. 22, 2007