TBAF-assisted copper-catalyzed N-arylation and benzylation of benzazoles with aryl and benzyl halides under the ligand/base/ solvent-free conditions

Article abstract of DOI:10.1021/jo900752z

(Equation Presented) 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-arylation 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.

Full text of DOI:10.1021/jo900752z

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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
yjyoon@gnu.ac.kr
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
(1) For selected recent examples, see: (a) Katritzky, A. R., Ress, C. W.,
Eds. Comprehensive Heterocyclic Chemistry II; Elsevier: Oxford, 1996.
(b) Craig, P. N. In Comprehensive Medicinal Chemistry; Drayton, C. J., Ed.;
Pergamon Press: New York, 1991; Vol. 8. (c) Lopes-Alvarado, P.; Avendano, C.;
Menendex, J. C. J. Org. Chem. 1995, 60, 5678. (d) Zhong, C.; He, J.; Xue, C.; Li,
Y. Bioorg. Med. Chem. 2004, 12, 4009. (e) 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. (f) 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. (g) Mano, T.; Okumura, Y.; Sakakibara, M.;
Okumura, T.; Tamura, T.; Miyamoto, K.; Stevens, R. W. J. Med. Chem. 2004, 47,
720. (h) 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. (i) Barchechath, S. D.; Tawatao,
R. I.; Corr, M.; Carsort, D. A.; Cottam, H. B. J. Med. Chem. 2005, 48, 6409.
(j) Jiang, W.; Guan, J.; Maccielag, M. J.; Zhang, S.; Qiu, Y.; Kraft, P.; Bhattacharjee,
S.; John, T. M.; Haynes-Johnson, D.; Lundeen, S.; Sui, Z. J. Med. Chem. 2005, 48,
2126. (k) Xie, Y. X.; Pi, S. F.; Wang, J.; Yin, D. L.; Li, J. H. J. Org. Chem. 2006,
71, 8324. (l) Verma, A. K.; Singh, J.; Sankar, V. K.; Chaudhary, R.; Chandra, R.
Tetrahedron Lett. 2007, 48, 4207. (m) Klapars, A.; Antilla, J. C.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (n) Antilla, J. C.; Klapars,
A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (o) Antilla, J. C.;
Baskin, J. M.; Barder, T. E.; Buchwa;d, S. L. J. Org. Chem. 2004, 69, 5578.
(p) Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72, 6190.
(2) (a) Periasamy, M.; Vairaprakash, P.; Dalai, M. Organometallics 2008,
27, 1963. (b) Zhou, T.; Chen, Z. C. Syn. Commun. 2002, 32, 903.
(3) (a) Katritzky, A. R.; Lan, X.; Yang, J. Z.; Densko, O. V. Chem. Rev.
1998, 98, 409. (b) Beletskaya, I. P.; Davydov, D. V.; Gorovoi, M. S.;
Kardashov, S. V. Russ. Chem. Bull. 1999, 48 (8), 1533. (c) Beletskaya, I. P.;
Davydov; Moreno-Manas, M. Tetrahedron Lett. 1998, 39, 5617.
(4) (a) Fanta, P. E. Chem. Rev. 1964, 64, 613. (b) Weston, P. E.; Adkins,
H. J. Am. Chem. Soc. 1928, 50, 859. (c) Yamamoto, T.; Kurata, Y. Can. J.
Chem. 1983, 61, 86. (d) Khan, M. A.; Polya, J. B. J. Chem. Soc. C 1970, 85.
(e) Lindley, J. Tetrahedron 1984, 40, 1433.
ꢀ
(5) Molina, A.; Vaquero, J. J.; Garcia Navio, J. L.; Alvarez-Builla, J.
Tetrahedron Lett. 1993, 34, 2673.
(6) Cerrada, M. L.; Elguero, J.; de la Fuente, J.; Pardo, C.; Ramos, M.
Synth. Commun. 1993, 23, 1947.
(7) Cox, D. P.; Terpinski, J.; Lawrynowicz, W. J. Org. Chem. 1984, 49,
3216.
DOI: 10.1021/jo900752z
r
Published on Web 06/17/2009
J. Org. Chem. 2009, 74, 5675–5678 5675
2009 American Chemical Society

Lee et al.
JOCNote
TABLE 1. Screening of Copper Halides and Tetrabutylammonium
TABLE 2. Optimization for TBAF-Assisted Copper-Catalyzed Aryla-
tion of 1 with 2-Bromopyridine (4a)a
Saltsa
entry
catalyst
TBAXb
5a (isolated yield, %)
entry
TBAF (equiv)
CuBr2 (mol %)
time (h)
5ab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr2
CuBr2
CuBr2
CuBr2
CuBr2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuI
TBAF
TBAB
TBAI
TBAN
TBAS
TBAF
TBAB
TBAI
TBAN
TBAS
TBAF
TBAB
TBAI
TBAN
TBAS
TBAF
TBAB
TBAI
TBAN
TBAS
TBAF
TBAB
TBAI
TBAN
TBAS
61
3
10
3
12
85
30
1
2
3
4
5
6
7
8
9
1
2
3
5
7
5
5
5
5
5
5
5
20
20
20
20
20
0.5
1
2
5
10
15
24
24
24
4
36
64
87
85
86
67
61
55
73
90
73
13
4
18
18
18
18
4
18
three spot
30
64
12
42
10
11
12
6
6
aReaction conditions: 1 (1 equiv), 4a (1 equiv), Cu-catalyst (0-20 mol %),
TBAF (1-7 equiv) 145 ( 2 °C in sealed tube. bIsolated yield.
6
trace
61
45
15
3
trace
trace
trace
trace
trace
trace
SCHEME 2. Plausible Mechanism of TBAF-Assisted N-Ary-
lation of Benzazoles
CuI
CuI
CuI
CuI
aReaction conditions: 1 (1 equiv), 4a (1 equiv), Cu-catalyst (10 mol %),
TBAX (3 equiv), 145 °C ((2 °C), 24 h in sealed tube. bTBAF=tetra-
butylammonium fluoride, TBAB = tetrabutylammonium bromide,
TBAl=tetrabutylammonium iodide, TBAN=tetrabutylammonium ni-
trate, TBAS=tetrabutylammonium hydrosulfate.
substitution of the benzotriazole, although N-1 arylation of
benzotriazole is more favorable than N-2 arylation.1o,8
Bletskaya et al.3b also reported N-arylation of 1H-benzo-
triazole (3) with activated aryl halide using copper 2-phenyl-
cyclopropane carboxylate/K2CO3/C16H33Me3NBr in toluene.
Reaction of 3 with 4f or 4g under the same conditions,
however, gave 1- and 2-n-butyl-1H-benzotriazoles 7d (38%
for 4f, 28% for 4g) and 7e (21% for 4f, 22% for 4g) instead of
the corresponding N-aryl (or benzyl) derivatives. The for-
mation of N-n-butylazoles may be due to 1-butene, which
is the decomposition product of TBAF. In the case of
less reactive halides like 4-methoxybromobenzene (4e) and
4-methoxychlorobenzene (4f), the N-alkylation of the azoles
may be more favorable then the corresponding N-arylation
under our conditions.
As described in Scheme 2, we have formulated a working
mechanism for the TBAF-assisted N-arylation and benzyla-
tion. The (n-Bu)3N may be act as the ligand. The fluoride ion of
TBAF may also act as the base. The structures of compounds
5-7 were established by IR, NMR, and elemental analyses.
In summary, we have reported the TBAF-assisted Cu-
catalyzed N-arylation, and benzylation of azoles such as 1H-
benzimidazole, 1H-indole, and 1H-benzotriazole with aryl,
benzyl, and heteroaryl halides providing moderate to good
yields. It is noteworthy that the present reaction is conducted
under ligand, solvent, and base-free conditions and is of
great value to the research and development efforts in the
chemical industry. Further work including the applications
of the TBAF/Cu catalyst system in the formation of other
C-N bond transformations is currently underway in our
laboratory.
SCHEME 1
halide (1 equiv), CuBr2 (10 mol %), and TBAF (5 equiv)
(entry 10 in Table 2).
1H-Benzimidazole (1) was reacted with some aryl and
benzyl halides under the optimized conditions to give the
corresponding 1-arylated or benzlated 1H-benzimidazoles 5
except for 4-methoxyhalobenzene (4e, 4f, and 4g) in 69-90%
yields. Reaction of 1 with 4e or 4g under the same conditions
gave 1-arylated compound 5e (8% for 4e, 18% for 4g) and
1-n-butyl-1H-benzimidazole (5f, 69% for 4e, 17% for 4g).
Compound 1 was also treated with 4f under the same
conditions to afford only 1-n-butyl derivative 5f in 15%
yield. On the other hand, 1H-indole (2) was reacted with
4b, 4d, 4g, or 4h under the same conditions to give N-aryl-1H-
indoles 6a (61%), 6b (58% for 4d, 64% for 4h), or 6c (47%),
whereas reaction with 4-methoxybromobenzene (4e) under
the same conditions did not give any product. 1H-Benzo-
triazole (3) was reacted with 4b, 4c, 4d, 4g, or 4h in the
presence of CuBr2 (10 mol %)/TBAF (5 equiv) under the
ligand/base/solvent-free conditions to give 1-aryl(or benzyl)
benzotriazoles [7a (76% for 4b), 7b (72% for 4c) and 7f (38%
for 4d, 35% for 4h)], 2-aryl(or benzyl)benzotriazoles [7c
(23% for 4c) and 7g (30% for 4d, 25% for 4h)], and/or
1-(n-butyl)benzotriazole [7d (14% for 4d, 13% for 4h)] except
for 4-methoxyhalobenzenes 4f and 4g. It is interesting that
the reactions of 4b and 4c show very high selectivity for N-1
(8) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic
Chemistry, 2nd ed.; Pergamon: New York, 2000; p 134.
5676 J. Org. Chem. Vol. 74, No. 15, 2009

Lee et al.
JOCNote
TABLE 3. TBAF-Assisted Copper-Catalyzed N-Arylation and Benzylation of Benzazoles with Aryl Halides Using the CuBr2/TBAF Systema
a Reaction conditions: 1 (1 equiv), 4 (1 equiv), CuBr2 (10 mol %), TBAF (5 equiv), 145 ( 2 °C in sealed tube. bIsolated yield. cUnreacted reagents were
isolated.
Experimental Section
progressing. After the mixture was cooled and then ethyl acetate
(10 mL) was added, the mixed solvent (ethyl acetate/water =
150 mL/80 mL) was added. The organic layer was separated and
dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure. The resulting residue was
Typical Experimental Procedure for TBAF-Assisted N-Aryla-
tion and Benzylation of Azoles. A mixture of azole (1-3,
1.7 mmol), halide (4, 1.7 mmol), CuBr2 (10 mol %), and TBAF
(5 equiv) was stirred at 145 °C until the reaction stopped
J. Org. Chem. Vol. 74, No. 15, 2009 5677

Lee et al.
JOCNote
applied to an open-bed silica gel column (10Â3 cm). The colu-
mn was eluted with ethyl acetate/n-hexane (1/10, v/v). Frac-
tions containing the product were combined, and the solvent
was evaporated under reduced pressure to give the products
5-7.
(d, 1H, J=7.7 Hz), 8.15-8.16 (d, 1H, J=3.6 Hz), 8.42-8.46
(m, 1H), 8.51-8.52 (d, 1H, J=2.6 Hz), 8.60-8.61 (m, 1H), 9.18
(s, 1H); 13C NMR (75 MHz, DMSO-d6) δ 107.0, 114.8, 121.4,
122.3, 123.9, 126.4, 130.6, 135.1, 136.9, 140.6, 141.7, 142.8.
Anal. Calcd for C13H10N2:C,80.39; H, 5.19; N, 14.42. Found:
C, 80.41; H, 5.23; N, 14.45.
1-(Pyridin-2-yl)-1H-benzimidazole (5a): mp oil (lit.1 mp 59-
60 °C); IR (KBr) 3081, 3057, 3016, 1589, 1495, 1474, 1454, 1438,
1295, 1236, 1203 cm-1; 1H NMR (300 MHz, DMSO-d6) δ 7.32-
7.44(m, 3H), 7.76-7.79 (m, 1H), 7.91-7.94 (m, 1H), 8.03-8.08
1-Benzyl-1H-benzotriazole (7b): mp 114-115 °C (lit.8 mp
114-115 °C); IR (KBr) 3085, 3065, 3029, 2975, 2943, 1497,
1
1456, 1365, 1325, 1262, 1225, 1162, 1095, 1070, 947 cm-1; H
(m, 1H), 8.26-8.29 (m, 1H), 8.61-8.64 (m, 1H), 8.95 (s, 1H); 13
C
NMR (300 MHz, DMSO-d6): δ 5.99 (s, 2H), 7.27-7.38 (m, 5H),
7.39-7.43 (m, 1H), 7.50-7.56 (m, 1H), 7.83-7.86 (m, 1H),
8.04-8.08 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 51.4,
111.1, 119.7, 124.5, 127.9, 128.2, 128.5, 129.3, 133.1, 136.3,
145.8. Anal. Calcd for C13H11N3: C, 74.62; H, 5.30; N, 20.08.
Found: C, 74.65; H, 5.33; N, 20.10.
NMR (75 MHz, DMSO-d6) δ 114.4, 115.1, 120.3, 122.5, 123.5,
124.4, 132.3, 140.1, 142.1, 144.6, 149.4, 150.2. Anal. Calcd for
C12H9N3: C, 73.83; H, 4.65; N, 21.52. Found: C, 73.85; H, 4.70;
N, 21.56.
1-(4-Nitrophenyl)-1H-benzimidazole (5d): mp 181 °C (lit.4 mp
175-178 °C); IR(KBr) 3088, 1595, 1453, 1347, 1199, 852 cm-1;1H
NMR (300 MHz, DMSO-d6) δ 7.34-7.43 (m, 2H), 7.76-7.83
Acknowledgment. This work was supported by a grant
from the Korea Science and Engineering Foundation (KO-
SEF) to the Environmental Biotechnology National Core
Research Center (Grant No. R15-2003-012-02001-0).
(m, 2H), 8.01-8.06 (m, 2H), 8.44-8.49 (m, 2H), 8.75 (s, 1H); 13
C
NMR (75 MHz, DMSO-d6) δ 111.5, 120.7, 123.7, 124.3, 124.5,
126.0, 132.8, 141.8, 143.8, 144.6, 146.2. Anal. Calcd for
C13H9N3O2: C, 65.27; H, 3.79; N, 17.56. Found: C, 65.30; H,
3.81; N, 17.58.
Supporting Information Available: Experimental proce-
dures, 1H and 13C NMR spectral data, CHN analyses and
melting points for compounds 5-7. This material is available
free of charge via the Internet at http://pubs.acs.org.
1-(Pyridin-2-yl)-1H-indole (6a): mp 73-74 °C; IR (KBr) 3106,
3070, 3052, 3017, 1584, 1522, 1488, 1450, 1419, 1363, 1251,
1
1212, 1135, 1018, 839 cm-1; H NMR (300 MHz, DMSO-d6)
δ 6.83 (d, 1H, J = 3.6 Hz), 7.17-7.32 (m, 2H), 7.66-7.68
5678 J. Org. Chem. Vol. 74, No. 15, 2009