pubs.acs.org/joc
play an important role as structural and functional units in
TBAF-Assisted Copper-Catalyzed N-Arylation and
Benzylation of Benzazoles with Aryl and Benzyl Halides
under the Ligand/Base/ Solvent-Free Conditions
many biological active compounds, natural products, and
useful synthons. In spite of these interests, the preparation of
N-arylazoles is severely restricted because nitrogen hetero-
cycles are not good substrates for the traditional arylation
reagents. Thus, the Ullmann reaction4 can only be per-
formed using activated aryl halides, which require a ligand
and harsh reaction conditions and very often give low yields.
Although recent developments like efficient conditions,3b,5,6
novel ligands,1k,1l,2a and additives2b,3c have been reported,
the Ullmann and related reactions suffer still from economy
and efficacy of the ligand. Therefore, we attempted the
development of a convenient and efficient method for
N-arylation of benzazoles.
Hyung-Geun Lee, Ju-Eun Won, Min-Jung Kim,
Song-Eun Park, Kwang-Ju Jung, Bo Ram Kim,
Sang-Gyeong Lee,* and Yong-Jin Yoon*
Department of Chemistry & Environmental Biotechnology
National Core Research Center, Research Institute of Natural
Sciences, Graduate School for Molecular Materials and
Nanochemistry, Gyeongsang National University,
Jinju 660-701, Korea
According to the literature,7 the tetrabutylammonium
fluoride (TBAF) decomposes to tetetrabutylammonium bi-
fluoride, tributylamine, and 1-butene at 77 °C. Therefore,
TBAF may play concurrently two roles as the ligand and the
base under the Ullmann reaction conditions.
Received April 9, 2009
As a continued interest in developing efficient and greener
processes, we expected to apply TBAF as the ligand and
the base in the N-arylation of azoles. As expected, N-aryla-
tion of 1H-benzimidazole (1) with 2-bromopyridine and
TBAF without the ligand and the solvent at 145 °C gave
N-(pyridin-2-yl)-1H-benzimidazole in the preliminary reac-
tion.
In this paper, we report the TBAF-assisted Cu-catalyzed
N-arylation and benzylation of azoles under ligand, base,
and solvent-free conditions (Scheme 1).
Using a model reaction based on 1H-benzimidazole (1)
and 2-bromopyridine (4a), five tetrabutylammonium salts
(TBAX) and five Cu catalysts have been screened. When
tetrabutylammonium fluoride (TBAF) and Cu calaysts ex-
cept for CuI were used, 1-(pyridin-2-yl)-1H-benzimidazole
(5a) was obtained in 61-85% yields (entries 1, 6, 11, and 16
in Table 1), whereas compound 5a was obtained in low yields
when four other salts such as tetrabutylammonium bromide
(TBAB), tetrabutylammonium iodide (TBAI), tetrabuty-
lammonium nitrate (TBAN), and tetrabutylammonium hy-
drosulfate (TBAS) were used (Table 1). Among the five Cu
catalysts, CuBr2 also showed the best results. Reaction of
1H-benzimidazole, however, with 2-bromopyridine without
Cu catalyst give only 5a in very low yield (entry 12 in Table 2).
We next optimized the amount of Cu catalyst and TBAF
required for the N-arylation of 1H-benzimidazole. The
following system proved to be the best: azole (1 equiv), aryl
TBAF-assisted N-arylation and benzylation of benzazoles
such as 1H-benzimidazole, 1H-indole, and 1H-benzotriazole
with aryl and benzyl halides have been demonstrated under
the ligand/base/solvent-free conditions. In the presence of
CuBr2 and TBAF (n-Bu4NF), the azoles underwent N-aryla-
tion and benzylation with aryl and benzyl halides smoothly in
moderate to good yields. It is noteworthy that the reaction is
conducted under the ligand/base/solvent-free conditions.
N-Arylazoles such as N-aryl-1H-benzimidazoles,1 N-aryl-
1H-indoles,1a-1c,1m,1n,2 and N-aryl-1H-benzotriazoles1a-1c,1o,3
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DOI: 10.1021/jo900752z
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Published on Web 06/17/2009
J. Org. Chem. 2009, 74, 5675–5678 5675
2009 American Chemical Society