Highly efficient copper-catalyzed N-arylation of nitrogen-containing heterocycles with aryl and heteroaryl halides

Article abstract of DOI:10.1021/jo062059f

(Chemical Equation Presented) New (S)-pyrrolidinylmethylimidazole ligands (4a-c) have been readily synthesized in a straightforward fashion from least expensive starting materials in short steps in high yields. Relatively mild and highly efficient Cul-catalyzed N-arylation procedures for imidazoles with aryl and heteroaryl bromides or chlorides have been developed in the presence of 4a and Cs₂CO₃. It is important to note that the protocol could tolerate functional groups such as ester, nitrile, nitro, ketone, free hydroxyl, and free primary amine on the aryl halide. The protocol could also be applicable to other π-electron-rich nitrogen heterocycles (pyrrole, pyrazole, indole, benzimidazole, and triazole), affording the N-arylazoles in good to excellent yields.

Full text of DOI:10.1021/jo062059f

Highly Efficient Copper-Catalyzed N-Arylation of
Nitrogen-Containing Heterocycles with Aryl and Heteroaryl Halides
Liangbo Zhu, Liang Cheng, Yuxi Zhang, Rugang Xie, and Jingsong You*
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, People’s Republic of China
jsyou@scu.edu.cn
ReceiVed October 5, 2006
New (S)-pyrrolidinylmethylimidazole ligands (4a-c) have been readily synthesized in a straightforward
fashion from least expensive starting materials in short steps in high yields. Relatively mild and highly
efficient CuI-catalyzed N-arylation procedures for imidazoles with aryl and heteroaryl bromides or chlorides
have been developed in the presence of 4a and Cs2CO3. It is important to note that the protocol could
tolerate functional groups such as ester, nitrile, nitro, ketone, free hydroxyl, and free primary amine on
the aryl halide. The protocol could also be applicable to other π-electron-rich nitrogen heterocycles (pyrrole,
pyrazole, indole, benzimidazole, and triazole), affording the N-arylazoles in good to excellent yields.
Introduction
directed toward the development of a mild as well as highly
efficient method for constructing N-arylazole units.4 For ex-
ample, mild conditions have been reached by using other types
of cross-coupling reagents instead of aryl halides as substrates,
such as aryllead triacetates,5 aryl siloxanes,6 triphenylbismuths,7
arylstannanes,8 diaryliodonium salts,9 or recently arylboronic
acids.10 However, these methodologies normally need additional
N-Arylazoles (e.g., N-arylpyrroles, N-arylpyrazoles, N-arylin-
doles, N-arylimidazoles, N-aryltriazoles, etc.) are ubiquitous in
biochemical, biological, and medicinal structure and function.1
Traditionally, these compounds have been synthesized via SNAr
(nucleophilic aromatic substitution) of N-H containing π-electron-
rich nitrogen heterocycles with electron-deficient aryl halides,
which limits its scope,2 or via the classical Ullmann-type
coupling with aryl halides, which generally suffers from
important limitations such as high reaction temperatures (often
150 °C or as high as 200 °C), the use of stoichiometric amounts
of copper reagents, moderate yields, and poor substrate general-
ity, sometimes preferentially with aryl iodides or aryl halides
activated by electron-withdrawing or o-carboxylic acid groups.3
It is therefore not surprising that great efforts have recently been
(3) (a) Jacobs, C.; Frotscher, M.; Dannhardt, G.; Hartmann, R. W. J.
Med. Chem. 2000, 43, 1841-1851. (b) Fan, J.; Sun, W.; Okamura, T.; Tang,
W.; Ueyama, N. Inorg. Chem. 2003, 42, 3168-3175. (c) Choudary, B. M.;
Sridhar, C.; Kantam, M. L.; Venkanna, G. T.; Sreedhar, B. J. Am. Chem.
Soc. 2005, 127, 9948-9949. Also, see refs 28a, 28b, and 37.
(4) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400-
5449.
(5) Aryllead triacetates: (a) Lo´pez-Alvarado, P.; Avendano, C.; Mene´n-
dez, J. C. Tetrahedron Lett. 1992, 33, 659-662. (b) Lo´pez-Alvarado, P.;
Avendano, C.; Menke´ndez, J. C. 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.
(6) Aryl siloxanes: 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.
(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, 2964-2972. (c)
Negwer, M. In Organic-Chemical Drugs and their Synonyms: An Interna-
tional SurVey, 7th ed.; Akademie Verlag GmbH: Berlin, Germany, 1994.
(2) Bambal, R.; Haznlik, R. P. J. Org. Chem. 1994, 59, 729-732. Also,
see refs 28a, 29c, 31b, and 37.
(7) Triphenylbismuth derivatives: Fedorov, A. Y.; Finet, J.-P. Tetrahe-
dron Lett. 1999, 40, 2747-2748.
(8) Arylstannanes: Lam, P. Y. S.; Clark, C. G.; Saunern, S.; Adams, J.;
Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000, 674-676.
10.1021/jo062059f CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/10/2007
J. Org. Chem. 2007, 72, 2737-2743
2737

Zhu et al.
steps to convert aryl halides into the corresponding 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.11 Therefore, the use of aryl halides as an
electrophilic coupling partner should resolve many of these
issues. Recently, several Pd-catalyzed C-N formation methods
have been discovered, which, upon using some sterically
hindered phosphine ligands, allowed cross-couplings of aryl
halides with N-H heterocycles to proceed under relatively mild
conditions.12 Notably, the economic attractiveness of copper has
led to a resurgence of interest in Ullmann-type coupling
reactions since Buchwald discovered and developed the Cu-
catalytic path for N-arylation of heterocycles with aryl halides
in the presence of diamine ligands.4,13 Indeed, some efficient
ligands have been disclosed in these coupling reactions, includ-
ing amino acids,14 diamines,15 diimines,16 aminoarenethiolate,17
phosphine ligands,18 2-aminopyrimidine-4,6-diol,19 and 8-hy-
droxyquinoline.20 Quite recently, particularly noteworthy is the
use of 4,7-dimethoxy-1,10-phenanthroline for the copper-
catalyzed N-arylation of imidazoles, which could tolerate an
array of functional groups on the aryl halides.21
While many significant results have been achieved for the
Cu-catlyzed N-arylation of a variety of nitrogen heterocycles
through the use of those ligands mentioned above, relatively
little progress has been made for the coupling of imidazoles.
The majority of aryl halides investigated to date, already limited
in examples, were aryl iodides.13b,c,14a,15a,18a Very few examples
of the coupling of imidazoles with aryl bromides or of a hindered
substrateoroffunctionalsubstrateshavebeendisclosed,14b,c,16,18b-21
and in some cases the electron-withdrawing groups and/or higher
reaction temperatures even have to be required.15a,17,19 Therefore,
the development of new ligand structures for copper-catalyzed
cross-coupling protocols constitutes an area of considerable
interest.
Recently, our laboratory reported the effective simple copper
salt catalyzed N-arylation of imidazole with arylboronic acids
in protic solvents.22 Thus it was a natural extension for us to
explore novel catalytic systems for preparing a variety of
N-arylazoles through the coupling reaction of aryl halides.
L-Proline has been shown to be a suitable auxiliary for the CuI-
catalyzed C-N bond formation between N-containing hetero-
cycles and aryl iodides or electron-deficient aryl bromides.
However, for electron-rich or neutral aryl bromides, low
conversions were observed due to the severe self-coupling of
L-proline with aryl bromides at higher reaction temperatures
(about 110 °C).14a,b It is reasonable to assume that the bidentate
L-proline ligand might be modified structurally by the N-
alkylation of the pyrrolidine ring to inhibit such a self-coupling
reaction, resulting in the improvement of catalytic performance.
In addition, such a modification of L-proline might improve the
solubility of the ligand. On the other hand, imidazoles them-
selves have proved to be an outstanding class of ligands, being
capable of forming a broad variety of metal complexes that are
able to catalyze a great number of reactions. These prompted
us to explore the synthesis of a new class of pyrrolidine-derived
diamine ligands in which the carboxyl group of L-proline was
replaced by an imidazole ring (4a-c) and to evaluate their scope
as ligands in the CuI-catalyzed N-arylation of π-electron-rich
nitrogen heterocycles.
(9) Diaryliodonium salts: Wang, F.-Y.; Chen, Z.-C.; Zheng, Q.-G. J.
Chem. Res. 2004, 206-207.
(10) Arylboronic acids: (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. Org. Lett. 2000, 2, 1233-1236.
(e) Collman, J. P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org. Chem. 2001,
66, 7892-7897. (f) Nishiura, K.; Urawa, Y.; Sodab, S. AdV. Synth. Catal.
2004, 346, 1679-1684.
(11) Murata, M.; Suzuki, K.; Watanabe, S.; Masuda, Y. J. Org. Chem.
1997, 62, 8569-8571 and references therein.
(12) (a) Anderson, K. W.; Tundel, R. E.; Ikawa, T.; Altman, R. A.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523 -6527. (b) Muci,
A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-209. (c) Yang,
B. H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146. (d)
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de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany,
2004; pp 699-760.
(13) (a) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 11684-11688. (b) trans-Cyclohexanediamine (10%) promoted
CuI-catalyzed coupling of imidazoles with aryl iodides in dioxane or
DMF: Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727-7729. (c) In a later publication, 1,10-phenanthroline
was also suggested to be sufficient for aryl iodides: Antilla, J. C.; Baskin,
J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578-5587.
(14) (a) Ma, D.; Cai, Q. Synlett 2004, 128-130. (b) Zhang, H.; Cai, Q.;
Ma, D. J. Org. Chem. 2005, 70, 5164-5173. (c) CuI-catalyzed C-N bond
forming reactions between aryl/heteroaryl bromides and imidazoles in ionic
liquid. The majority of aryl bromides investigated are electron-poor or
electron-neutral ones, and aryl halides bearing sterically hindered or
functional groups had not been disclosed yet: Lv, X.; Wang, Z.; Bao, W.
Tetrahedron 2006, 62, 4756-4761.
Results and Discussion
While not being commercially available, (S)-pyrrolidinylm-
ethylimidazoles (4a-c) are stable and easily synthesized from
least expensive starting materials in high yields and on a
multigram scale. Following Scheme 1, the synthesis of 4 is a
straightforward process starting from (S)-pyrrolidin-2-ylmethanol
(1), which is easily prepared from L-proline.23 Treatment of 1
(15) (a) Alcalde, E.; Dinare`s, I.; Rodr´ıguez, S.; de Miguel, C. G. Eur. J.
Org. Chem. 2005, 1637-1643. (b) Copper(I)-catalyzed N-arylation of
azaheterocycles with aryl bromide. However, only one aryl halide substrate
(5-bromo-m-xylene) was tested: Kuil, M.; Bekedam, E. K.; Visser, G. M.;
van den Hoogenband, A.; Terpstra, J. W.; Kamer, P. C. J.; van Leeuwena,
P. W. N. M.; van Strijdoncka, G. P. F. Tetrahedron Lett. 2005, 46, 2405-
2409.
(16) The majority of copper-catalyzed N-arylation of azoles investigated
was aryl ioides: Cristau, H. J.; Cellier, P. P.; Spindler, J. F.; Taillefer, M.
Chem.-Eur. J. 2004, 10, 5607-5622.
(17) Jerphagnon, T.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G.
Org. Lett. 2005, 7, 5241-5244.
(19) Li, J. et al. just reported that under higher temperature (145-150°C)
2-aminopyrimidine-4,6-diol is an efficient ligand for copper-catalyzed
N-arylations of imidazoles with aryl and heteroaryl halides: Xie, Y.; Pi, S;
Wang, J.; Yin, D.; Li, J. J. Org. Chem. 2006, 71, 8324-8327.
(20) The protocols were applicable to the N-arylation of benzimidazole
and imidazole. However, the couplings of other nitrogen heterocycles had
not been disclosed yet, and the process required reaction temperatures as
high as 130 °C: Liu, L.; Frohn, M.; Xi, N.; Dominguez, C.; Hungate, R.;
Reider, P. J. J. Org. Chem. 2005, 70, 10135-10138.
(21) The commercially unavailable 4,7-dimethoxy-1,10-phenanthroline
was described as an efficient ligand for the copper-catalyzed N-arylation
of imidazole, but the couplings of other nitrogen heterocycles had not been
disclosed yet: Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779-
2782.
(18) (a) Xu, L.; Zhu, D.; Wu, F.; Wang, R.; Wan, B. Tetrahedron 2005,
61, 6553-6568. (b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.-
Eur. J. 2006, 12, 3636-3646. (c) Zhang, Z.; Mao, J.; Zhu, D.; Wu, F.;
Chen, H.; Wan, B. Tetrahedron 2006, 62, 4435-4443.
(22) Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.; Xie, R. G. Chem.
Commun. 2004, 188-189.
2738 J. Org. Chem., Vol. 72, No. 8, 2007

N-Arylation of Nitrogen-Containing Heterocycles
SCHEME 1. Synthesis of (S)-Pyrrolidinylmethylimidazoles
with benzyl chloride afforded 2a24 or treatment with formic acid
and aqueous formaldehyde gave 2b,25 followed by treatment
with SOCl2/HCl to yield 3.26 Thus the chloride displacement
of 3 with imidazole provided the desired ligands (4a-c).
N-Arylimidazoles have not only been recurrent templates in
medicinal chemistry27-36 but also important building blocks for
the synthesis of imidazolium quaternary salts used as key
precursors to N-heterocyclic carbenes (NHCs) as well as ionic
liquids.37 Furthermore, the arylation of imidazoles is still a long-
standing problem, which is far from being satisfactorily solved.
We therefore chose to focus initial studies on the evaluation of
the behavior of (S)-pyrrolidinylmethylimidazole 4 in the syn-
thesis of N-arylimidazoles. This was determined during a
preliminary survey of reaction conditions with use of bromoben-
zene and imidazole as model arylating agents shown in Table
1. While 5 mol % of CuI and 10 mol % of 4a were employed
in the presence of 2 equiv of Cs2CO3, a series of reaction
solvents (e.g., toluene, dioxane, n-butanol, DMF, and DMSO)
were first investigated (entries 1-6). Thus we found that more
polar solvents are favorable for the catalytic reaction, which is
in agreement with the previously reported results.14a,b,18b,19
Among the solvents tested, DMF was clearly the best choice,
and DMSO and n-butanol provided slightly lower yields, while
less polar solvents like toluene and 1,4-dioxane delivered little
desired coupling product (compare entries 1-5). Although
recent reports demonstrate that in some cases the addition of a
trace amount of water could improve the reaction efficiency,10f,20,38
in our catalytic system a negative effect was observed in the
presence of either 4a or 4c, while the effect of water was almost
ignored in the presence of 4b (entries 5, 6,and 16-19). After
screening a variety of bases (e.g., Na2CO3, K2CO3, K3PO4, and
Cs2CO3), we found that Cs2CO3 gave the best result of 96%
yield in DMF (compare entries 5 and 11-13). The results from
the ligand survey in combination with CuI are also summarized
in Table 1, and 4a and 4c were found to be particularly effective
ligands, whereas 4b afforded 85% yield (entries 5, 16, and 18).
In addition, lowering the amount of CuI to 2.5 mol % led to
incomplete consumption of bromobenzene after 24 h of heating
(50% yield, Cu/4a ) 1:2, entry 10). Further experiments showed
that a 24 h reaction time period was the optimal choice (entries
5, 14, and 15).
(23) McKennon, M. J.; Meyers, A. I.; Drauz, K.; Schwarm, M. J. Org.
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(24) Itsuno, S.; Ito, K.; Hirao, A.; Nakahama, S. J. Chem. Soc., Perkin
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4873-4876.
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Acad. Sci. U.S.A. 1997, 94, 10547-10553. (c) 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.
(28) Cyclic AMP phosphodiesterase inhibitors: (a) Venuti, M. C.;
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1988, 31, 2136-2145. (b) Martinez, G. R.; Walker, K. A. M.; Hirschfeld,
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(29) Thromboxane synthase inhibitor: (a) Iizuka, K.; Akahane, K.;
Momose, D.; Nakazawa, M. J. Med. Chem. 1981, 24, 1139-1148. (b) Cozzi,
P.; Carganico, G.; Fusar, D.; Grossoni, M.; Menichincheri, M.; Pinciroli,
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(c) Qiao, J. X.; Cheng, X.; Modi, D. P.; Rossi, K. A.; Luettgen, J. M.;
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15, 29-35.
(30) Angiotensin-II agonist: Wan, Y.; Wallinder, C.; Plouffe, B.;
Beaudry, H.; Mahalingam, A. K.; Wu, X.; Johansson, B.; Holm, M.;
Botoros, M.; Karlen, A.; Pettersson, A.; Nyberg, F.; Fandriks, L.; Gallo-
Payet, N.; Hallberg, A.; Alterman, M. J. Med. Chem. 2004, 47, 5995-
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Lundeen, S.; Sui, Z. J. Med. Chem. 2005, 48, 2126-2133.
(34) Bradykinin B1 antagonist: Su, D.-S.; Markowitz, M. K.; Murphy,
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In an effort to obtain an optimum CuI/ligand ratio, we found
that a 1:2 CuI/4a ratio is the best choice, while a 1:1 and a 2:1
CuI/4a ratio provided yields of 86% and 43%, respectively
(entries 5, 8, and 9). It should be noted that no significant effect
on reactivity was observed when further raising the ratio of CuI/
4a from 1:2 to 1:4 while the process still required the same
time period although the product yield was improved slightly
from 96% to 98% (entry 7).
(35) CB-1 antagonist: 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.;
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Zhu et al.
TABLE 1. Some Representative Results from the Screening of
Reaction Conditions for the N-Arylation of Imidazole with
Bromobenzenea
First, some functional groups themselves might be decomposed
at higher reaction temperatures, for example, the partial hy-
drolysis of the ester to benzoic acid and of the nitrile to
amide.20,21 We were pleased to find that our catalytic system
could tolerate a variety of functional groups such as ester,
nitrile, ketone, and nitro (entries 1-3, 20, and 21). Another
problematic situation in this area is the competition from the
formation of C(aryl)-N and C(aryl)-O bonds when there is
a free OH or NH directly bound to the aromatic ring that
contains the halide.4,40 Generally, free hydroxyl and primary
amine groups should be protected before carrying out the
N-arylation of imidazoles.41 It is important to note that this
protocol could almost exclusively carry out the selective
N-arylation of 2-bromophenol (5k), 4-bromophenol (5l), 4-bro-
moaniline (5m), 3-bromoaniline (5n), and 2-amino-5-bromopy-
ridine (5o) to provide the corresponding N-arylimidazoles in
good yields (entries 11-15), avoiding the formation of diaryl
ethers and diarylamines. In addition, we also found that the
N-arylation with p-dibromobenzene (5j) afforded exclusively
the mono N-arylimidazole product in an excellent yield and no
trace of the dicoupled product was detected when a 1.2:1
ratio of p-dibromobenzene to imidazole was employed
(entry10).
By using the catalyst system based on 4a, the coupling
reactions of aryl chlorides such as 2-chloropyrimidine (5s),
4-chloronitrobenzene (5t), and 4-chlorobenzonitrile (5u) could
also deliver the corresponding N-arylated products in excellent
yields (entries 19-21). Further exploration revealed that some
heteroaryl halides were compatible with these reaction condi-
tions, giving satisfactory yields (75-97% yields) (entries 15-
19). It may be noted that only a few papers have described the
Cu-catalyzed N-arylation of imidazoles with heteroaryl halides
in the presence of ligand.14c,19,42
To date the development of chemistry that could emanate
from a single method for each of the major classes of nitrogen-
containing heterocycles (e.g., pyrroles, pyrazoles, indazoles,
imidazoles, triazoles, etc.) has been seriously inhibited. In an
endeavor to expand the scope of the methodology, the protocol
based on the use of our new catalytic system was also applied
to other π-electron-rich nitrogen heterocycles (Table 3). It is
worth noting that these optimized conditions were also suitable
for the N-arylation of other imidazole derivatives. For example,
the coupling reaction of 1H-benzimidazole (6b) with bromoben-
zene afforded the corresponding N-arylated product in 75% yield
(entry 1). Sterically hindered 2-(1H-imidazol-2-yl)-1H-imidazole
(6c) could be selectively monoarylated in 62% yield (entry 2).
We were pleased to discover that the arylation of pyrazole and
pyrrole with bromobenzene was accomplished through the
application of a general reaction procedure to afford the
N-arylated products in 87% and 72% yield, respectively (entries
3 and 4). Moreover, the yield of 1-phenyl-1H-pyrrole (7x) could
be improved from 72% to 98% while iodobenzene was used in
place of bromobenzene at relatively low temperature (90 °C)
(entries 4 and 5). While the use of 1,2,4-triazole and indole
was disappointing with bromobenzene, providing only very low
amount of amount of
ligand
entry [mol %]
CuI
reaction
yield
(%)b
[mol %] time [h]
solvent
toluene
dioxane
DMSO
n-butanol
DMF
base
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
4a (10)
4a (10)
4a (10)
4a (10)
4a (10)
4a (10)
4a (20)
4a (5)
5
5
5
5
5
5
5
5
5
2.5
5
5
5
5
5
5
5
5
5
24
24
24
24
24
24
24
24
24
24
24
24
24
40
12
24
24
24
24
Cs2CO3
Cs2CO3
c
c
Cs2CO3 71
Cs2CO3 82
Cs2CO3 96
DMF-H2O Cs2CO3 84d
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Cs2CO3 98
Cs2CO3 86
Cs2CO3 43
Cs2CO3 50
4a (2.5)
4a (5)
4a (10)
4a (10)
4a (10)
4a (10)
4a (10)
4b (10)
4b (10)
4c (10)
4c (10)
K3PO4
K2CO3 32
Na2CO3
90
c
Cs2CO3 98
Cs2CO3 48
Cs2CO3 87
DMF-H2O Cs2CO3 87d
DMF
Cs2CO3 94
DMF-H2O Cs2CO3 84d
a Reaction conditions: 5a (1.2 mmol), 6a (1.0 mmol), base (2.0 mmol)
in the presence of ligand 4 and CuI in 2.0 mL of solvent at 110 °C under
N2 atmosphere. b Isolated yields (average of two runs) based on 6a. c Little
coupling product was determined. d DMF (2.0 mL) and H2O (0.1 mL) as
solvent.
After optimized reaction conditions were obtained, the scope
of the process with respect to aryl halide structure was
investigated by using our catalyst system generated in situ from
5 mol % of CuI and 10 mol % of 4a in the presence of 2 equiv
of Cs2CO3 in DMF at 110 °C under N2, and the results are
summarized in Table 2. We were delighted to find that the
N-arylation of imidazole with a variety of aryl bromides could
be conducted smoothly to give the corresponding products in
good to excellent yields (61-99%) (entries 1-14). It should
be pointed out that the reaction of deactivated 4-bromoanisole
(5i) could afford a good product yield (88%) (entry 9).
Generally, Ullmann-type condensations were sensitive to steric
hindrance near the halogen atom, and there are rare examples
describing the Cu-catalyzed couplings of imidazole with steri-
cally hindered aryl halides. Our catalytic system could be applied
to imidazole N-arylation with ortho or pseudo-ortho substituted
aryl bromides shown in entries 6-8. It is worth noting that the
reaction of the notoriously recalcitrant hindered and deactivated
2-bromoanisole (5h) with imidazole even proceeded in 64%
yield (entry 8). Generally, the synthesis of 1-naphthalen-1-yl-
1H-imidazole (7g) requires more reactive 1-iodonaphthalene or
arylboronic acid,15a,21,22 or even in the presence of stoichiometric
amounts of ligand.39 In contrast, this study demonstrates that
1-bromonaphthalene (5g) was efficiently coupled with imidazole
to give 7g in 66% yield (entry 7). Regrettably, in this way, the
coupling of more hindered mesityl bromide could not be
accomplished smoothly under our standard conditions, affording
a very low yield.
(40) (a) Cristau, H. J.; Cellier, P. P.; Hamada, S.; Spindler, J. F.; Taillefer,
M. Org. Lett. 2004, 6, 913-916. (b) Ma, D.; Cai, Q. Org. Lett. 2003, 5,
3799-3802. (c) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315-4317. (d) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer,
P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623-1626.
(41) Collman, J. P.; Wang, Z.; Zhong, M.; Zeng, L. J. Chem. Soc., Perkin
Trans. 1 2000, 1217-1221.
Substrates that contain certain functional groups have proven
to be persistently problematic in the N-arylation of imidazoles.
(39) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.-R.; Reibenspies, J.
H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113-123.
(42) Son, S. U.; Park, I. K.; Park, J.; Hyeon, T. Chem. Commun. 2004,
778-779.
2740 J. Org. Chem., Vol. 72, No. 8, 2007

N-Arylation of Nitrogen-Containing Heterocycles
TABLE 2. Catalytic N-Arylation of Imidazole with Aryl or Heteroaryl Halides by CuI/4a
a Reaction conditions: 5 (1.2 mmol), 6a (1.0 mmol), 2.0 mmol of Cs2CO3 in the presence of 10 mol % of ligand 4a and 5 mol % of CuI in 2.0 mL of
DMF at 110 °C under N2 atmosphere for 24 h. b Isolated yields (average of two runs) based on 6a. c 48 h at 110 °C.
product yields, these reactions could smoothly proceed with
iodobenzene to give 7y and 7z in 96% and 98% yields,
respectively (entries 6 and 7).
chlorides. Particularly noteworthy are our protocols could
tolerate an array of functional groups such as ester, nitrile, nitro,
ketone, free hydroxyl, and free primary amine on the aryl halide.
To the best of our knowledge, our catalytic process is among
the most efficient approaches to the N-arylation of imidazoles
with aryl halides so far reported. The protocol could also be
applicable to the N-arylation of other π-electron-rich nitrogen
heterocycles (pyrrole, pyrazole, indole, benzimidazole, and
triazole). We believe that this catalyst system could provide an
excellent complement to the Pd- or Cu-catalyzed methods that
have already been utilized in a number of applications. This
Conclusion
We have disclosed that (S)-pyrrolidinylmethylimidazole 4a,
which has been readily synthesized in a straightforward fashion
from inexpensive L-proline and imidazoles in short steps, acted
as a highly efficient ligand for the Cu-catalyzed N-arylation of
imidazoles with aryl or heteroaryl halides. The system is
effective for aryl bromides, and to a less extent, for aryl
J. Org. Chem, Vol. 72, No. 8, 2007 2741

Zhu et al.
TABLE 3. Catalytic N-Arylation of Azoles with Aryl Halides by
2.92-2.97 (m, 1H), 3.10 (br s, 1H), 3.32 (d, J ) 13.2 Hz, 1H),
3.41 (dd, J ) 2.0, 4.0 Hz, 1H), 3.44 (dd, J ) 2.0, 4.0 Hz, 1H),
3.94 (d, J ) 13.2 Hz, 1H), 7.20-7.32 (m, 5H) ppm. 13C NMR
CuI/4aa
(100 MHz, CDCl3): δ 23.2, 27.6, 54.3, 58.5, 61.9, 64.3, 126.8,
128.1, 128.6, 139.1 ppm. MS (ESI+) m/z 192.4 [M + 1]
.
+
(S)-1-Benzyl-2-(chloromethyl)pyrrolidine Hydrochloride ((S)-
3a). A solution of (S)-(1-benzylpyrrolidin-2-yl)methanol ((S)-2a)
(3.82 g, 20 mmol) in 20 mL of CHCl3 at -4 °C was saturated with
HCl gas and dried by bubbling through a H2SO4 trap. Then thionyl
chloride (8 mL, 110 mmol) was added dropwise at the same
temperature. The temperature was slowly raised to 20 °C, and the
reaction mixture was then refluxed for 2 h. Chloroform and an
excess of thionyl chloride were removed under reduced pressure.
Active charcoal and 25 mL of methanol were then added to the
residue, and the mixture was refluxed for 1 h and filtered through
celite; the operation was repeated three times. After removal of
methanol, the orange oil was crystallized by addition of THF to
afford (S)-1-benzyl-2-(chloromethyl)pyrrolidine hydrochloride as
1
a white solid (3.94 g, 80%). H NMR (400 MHz, D2O): δ 2.00-
2.15 (m, 2H), 2.18-2.24 (m, 1H), 2.41-2.45 (m, 1H), 3.37-3.43
(m, 1H), 3.51-3.57 (m, 1H), 3.85-3.94 (m, 2H), 4.07-4.13 (m,
1H), 4.37 (d, J ) 12.8 Hz, 1H), 4.64 (d, J ) 12.8 Hz, 1H), 7.60
(s, 5H) ppm. 13C NMR (100 MHz, D2O): δ 24.4, 30.2, 45.2, 57.6,
61.2, 70.2, 132.1, 132.3, 132.9, 133.5 ppm. MS (ESI+) m/z 210.3
+
[M - Cl]
.
(S)-(1-Methylpyrrolidin-2-yl)methanol ((S)-2b). (S)-Pyrrolidin-
2-yl-methanol (1) (2.02 g, 20 mmol) was added to 4 mL of formic
acid at 5 °C, followed by 3 mL of 40% aqueous formaldehyde.
When the initial vigorous evolution of carbon dioxide had subsided,
the whole was refluxed for 20 h. The mixture was acidified with 5
N hydrochloric acid (5 mL), and evaporated in vaccuo to afford a
dark gum. The residue was dissolved in a minimum quantity of
water, saturated with sodium hydroxide, and extracted with
chloroform. The combined extracts were dried over K2CO3, and
chloroform was then removed under reduced pressure. The fraction,
bp 49-50 °C/2 mm, on redistillation gave (S)-(1-methylpyrrolidin-
2-yl)methanol as colorless oil (1.50 g, 65%). 1H NMR (400 MHz,
CDCl3): δ 1.63-1.88 (m, 4H), 2.19-2.25 (m, 1H), 2.28-2.34 (m,
1H), 2.31 (s, 3H), 3.00-3.05 (m, 1H), 3.39 (dd, J ) 4.0, 2.8 Hz,
1H), 3.41 (dd, J ) 4.0, 2.8 Hz, 1H), 3.47 (br s, 1H) ppm. 13C NMR
(100 MHz, CDCl3): δ 23.1, 27.5, 40.8, 57.5, 61.9, 66.4 ppm. MS
+
(ESI+) m/z 116.2 [M + 1]
.
(S)-1-Methyl-2-(chloromethyl)pyrrolidine Hydrochloride ((S)-
3b). This compound was prepared following the same procedure
as described above for (S)-3a. Starting material is from (S)-(1-
methylpyrrolidin-2-yl)methanol ((S)-2b). (S)-3b was obtained in
a Reaction conditions: 5 (1.2 mmol), 6 (1.0 mmol), 2.0 mmol of Cs2CO3
in the presence of 10 mol % of ligand 4a and 5 mol % of CuI in 2.0 mL
of DMF at 110 °C under N2 atmosphere for 24 h. b Isolated yields (average
of two runs) based on 6. c 24 h at 90 °C.
1
85% yield as a white solid. H NMR (400 MHz, D2O): δ 2.08-
2.18 (m, 2H), 2.21-2.30 (m, 1H), 2.41-2.48 (m, 1H), 3.09 (s,
3H), 3.29-3.36 (m, 1H), 3.78-3.84 (m, 1H), 3.92-3.98 (m, 1H),
4.02 (dd, J ) 5.2, 3.6 Hz, 1H), 4.13 (dd, J ) 5.2, 3.6 Hz, 1H)
work should find wide application among synthetic and
medicinal chemists in industry and academics.
ppm. 13C NMR (100 MHz, D2O): δ 24.4, 29.9, 43.1, 44.6, 59.9,
71.8 ppm. MS (ESI+) m/z 134.3 [M - Cl]
.
+
(S)-1-((1-Benzylpyrrolidin-2-yl)methyl)-2-methyl-1H-imida-
zole ((S)-4a). To a solution of 2-methyl-1H-imidazole (2.46 g,
30 mmol) in 100 mL of THF was added NaH (2.4 g, 60 mmol) at
0 °C. After the mixture was stirred for 0.5 h, (S)-1-benzyl-2-
(chloromethyl)pyrrolidine hydrochloride ((S)-3a) (6.15 g, 25 mmol)
was added. The temperature was slowly raised to 25 °C, and the
reaction mixture was stirred at 40 °C for 10 h and was allowed to
warm to room temperature. The mixture was then filtered through
celite and washed well with 20 mL of THF. The filtrate was
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel eluting with ethyl acetate/
methanol (15/1) to afford (S)-4a as a pale yellow oil (5.10 g, 80%).
1H NMR (600 MHz, CDCl3): δ 1.52-1.57 (m, 1H), 1.69-1.72
(m, 2H), 1.84-1.89 (m, 1H), 2.28-2.32 (m, 1H), 2.35 (s, 3H),
2.88-2.90 (m, 1H), 2.98-3.01 (m, 1H), 3.44 (d, J ) 12.6 Hz,
1H), 3.69 (dd, J ) 7.2, 5.4 Hz, 1H), 3.72 (dd, J ) 7.2, 5.4 Hz,
1H), 3.75 (d, J ) 12.6 Hz, 1H), 6.89 (s, 2H), 7.26-7.34 (m, 5H)
Experimental Section
Procedure for the Preparation of Ligands 4a-c: (S)-(1-
Benzylpyrrolidin-2-yl)methanol ((S)-2a). A mixture of (S)-
pyrrolidin-2-yl-methanol (1) (2.02 g, 20 mmol), benzyl chloride
(3.80 g, 30 mmol), and anhydrous potassium carbonate (2.76 g,
20 mmol) in 15 mL of toluene was refluxed with stirring under
nitrogen for 16 h. Dilute hydrochloric acid was then added until
the aqueous layer was strongly acidic. The aqueous layer was
separated, shaken with ether, basified with ammonium hydroxide,
and extracted with methylene chloride. The organic layer was dried
over MgSO4, and the solvent was then removed under reduced
press. The residue was purified by column chromatography on silica
gel eluting with ethyl acetate/methanol (10/1) to afford (S)-(1-
benzylpyrrolidin-2-yl)methanol as a viscous oil (3.52 g, 92%). 1H
NMR (400 MHz, CDCl3): δ 1.63-1.71 (m, 2H), 1.77-1.86 (m,
1H), 1.88-1.96 (m, 1H), 2.23-2.30 (m, 1H), 2.67-2.73 (m, 1H),
2742 J. Org. Chem., Vol. 72, No. 8, 2007

N-Arylation of Nitrogen-Containing Heterocycles
ppm. 13C NMR (150 MHz, CDCl3): δ 13.2, 22.9, 28.9, 50.3, 54.7,
59.9, 63.6, 119.8, 126.8, 127.0, 128.3, 128.7, 139.2, 144.6 ppm.
HRMS (EI) calcd for [C16H21N3]+ 255.1735, found 255.1730. Anal.
Calcd: C 75.26, H 8.29, N 16.46. Found: C 74.33, H 8.45, N 15.75.
(S)-1-((1-Benzylpyrrolidin-2-yl)methyl)-1H-imidazole ((S)-4b).
This compound was prepared following the same procedure as
described above for (S)-4a. Starting material is from (S)-3a and
imidazole. (S)-4b was obtained in 85% yield as a pale yellow oil
after purification by column chromatography on silica gel eluting
with ethyl acetate/methanol (15/1). 1H NMR (600 MHz, CD3OD):
δ 1.52-1.57 (m, 2H), 1.66-1.68 (m, 1H), 1.87-1.91 (m, 1H),
2.28-2.31 (m, 1H), 2.89-2.95 (m, 2H), 3.39 (d, J ) 13.2 Hz,
1H), 3.78 (d, J ) 13.2 Hz, 1H), 3.94 (dd, J ) 6.0, 4.8 Hz, 1H),
3.96 (dd, J ) 6.0, 4.8 Hz, 1H), 6.96 (s, 1H), 7.17 (s, 1H), 7.23-
7.26 (m, 1H), 7.30-7.34 (m, 4H), 7.70 (s, 1H) ppm. 13C NMR
(150 MHz, CD3OD): δ 23.9, 29.6, 51.8, 55.7, 60.6, 65.0, 121.5,
128.2, 128.6, 129.4, 130.2, 139.1, 140.4 ppm. HRMS (EI) calcd
for [C15H19N3]+ 241.1579, found 241.1586. Anal. Calcd for
C15H19N3: C 74.65, H 7.94, N 17.41. Found: C 74.32, H 8.00, N
17.29.
(S)-1-((1-Methylpyrrolidin-2-yl)methyl)-1H-imidazole ((S)-4c).
This compound was prepared following the same procedure as
described above for (S)-4a. Starting materials are from (S)-3b and
imidazole. (S)-4c was obtained in 82% yield as a pale yellow oil
after purification by column chromatography on silica gel eluting
with ethyl acetate/methanol (1/4). 1H NMR (400 MHz, CDCl3): δ
1.44-1.50 (m, 1H), 1.60-1.67 (m, 2H), 1.78-1.88 (m, 1H), 2.19-
2.25 (m, 4H), 2.46-2.52 (m, 1H), 3.01-3.06 (m, 1H), 3.81 (dd, J
) 6.0, 4.8 Hz, 1H), 3.85 (dd, J ) 6.0, 4.8 Hz, 1H), 6.93 (s, 1H),
7.00 (s, 1H), 7.48 (s, 1H) ppm. 13C NMR (50 MHz, CDCl3): δ
22.4, 28.8, 40.8, 50.4, 57.3, 65.3, 119.4, 128.7, 137.4 ppm. HRMS
(FAB) calcd for [C9H15N3 + H] + 166.1344, found 166.1352. Anal.
Calcd: C 65.42, H 9.15, N 25.43. Found: C 64.19, H 9.76, N 24.77.
General Procedure for the Catalytic N-Arylation of Nitrogen-
Containing Heterocycles with Aryl Halides. A flame-dried
Schlenk test tube with a magnetic stirring bar was charged with
CuI (9.6 mg, 0.05 mmol), ligand (0.1 mmol), Cs2CO3 (0.652 g,
2.0 mmol), nitrogen-containing heterocycle (1.0 mmol), aryl or
heteroaryl halide (1.2 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 to 110 °C
for 24 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 filtrate was 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 No.
20572074), the Program for New Century Excellent Talents in
University (NCET-04-0881), the Outstanding Young Scientist
Award of Sichuan Province, the Setup Foundation of Sichuan
University, and the Foundation of the Education Ministry of
China for Returnees.
Supporting Information Available: Detailed experimental
procedures for the synthesis of N-arylazoles, characterizational
NMR spectral data (1H and 13C) of N-arylazoles and compounds
4a-c, 3a,b, and 2a,b; copies of 1H and 13C NMR spectra for
compounds 4a-c, 3a,b, 2a,b, and 7a-z. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO062059F
J. Org. Chem, Vol. 72, No. 8, 2007 2743