Benzotriazole: an excellent ligand for Cu-catalyzed N-arylation of imidazoles with aryl and heteroaryl halides

Article abstract of DOI:10.1016/j.tetlet.2007.04.061

Benzotriazole (BtH) is an efficient ligand for the Cu-catalyzed N-arylation of imidazoles with aryl and heteroaryl halides. A combination of CuI/BtH was found to be an efficient and inexpensive catalyst system to carry out the N-arylation of imidazoles affording the corresponding products in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.04.061

Tetrahedron Letters 48 (2007) 4207–4210
Benzotriazole: an excellent ligand for Cu-catalyzed N-arylation
of imidazoles with aryl and heteroaryl halides
*
Akhilesh Kumar Verma, Jaspal Singh, V. Kasi Sankar,
Ritu Chaudhary and Ramesh Chandra
Synthetic Organic Chemistry Research Laboratory, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi,
Delhi 110007, India
Received 18 January 2007; revised 12 April 2007; accepted 16 April 2007
Available online 20 April 2007
Abstract—Benzotriazole (BtH) is an efficient ligand for the Cu-catalyzed N-arylation of imidazoles with aryl and heteroaryl halides.
A combination of CuI/BtH was found to be an efficient and inexpensive catalyst system to carry out the N-arylation of imidazoles
affording the corresponding products in good to excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
N-Arylimidazoles are structural motifs found in many
biologically active compounds and natural products.
Our group has been utilizing benzotriazole as a catalyst
for various transformations due to its some interesting
properties. As a part of our research, we noticed that
this air and moisture stable compound has excellent
coordination capability, which would be favourable
for stabilizing catalytic species and assisting catalytic
cycles. Herein we report our preliminary investigations
on the use of BtH as a ligand for the Cu-catalyzed N-
arylation of imidazoles.
1
7
The development of mild and highly efficient methods
for their synthesis has recently gained considerable
attention in synthetic chemistry, and accordingly, many
2
–6
procedures have been reported for their synthesis.
Traditionally, this moiety is prepared by nucleophilic
aromatic substitution of an activated aryl halide and
by copper mediated coupling of heterocycles with aryl
halides. In both cases, the reactions were limited to those
of aryl halides bearing strong electron withdrawing
substituents and required harsh conditions (Ullmann
reaction requiring high temperature, extended periods
Table 1. Screening the reaction conditions for the copper-catalyzed N-
a
arylation of imidazole 1a with 1-iodo-4-methoxybenzene 2a
N
OMe
2
NH + MeO
I
N
N
of time using stoichiometric copper). Despite the recent
development of Pd catalyzed C–N bond forming
reactions, copper catalyzed N-arylation of imidazoles
and other nitrogen heterocycles with aryl halides pro-
moted by ligands has attracted much attention due to
1
a
2a
3a
3
Entry [Cu]/mol % BtH
Base
solvent
Yield (%)
(
mol %)
2
,4,5
its economy and efficiency.
These highly efficient
1
2
3
4
5
6
7
8
9
0
1
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/10
CuI/5
—
20
10
20
20
20
20
20
10
20
20
2
Cs CO
DMF
DMF
DMF
Trace
90
80
68
90
65
<30
96
96
<40
<30
3
3
3
3
3
3
4
a
ligands include diazabutadiene, 2-aminopyrimidine-
Cs
Cs
2
2
CO
CO
4
b
4c–f
4
ines,
,6-diol,
1,10-phenanthroline derivatives,
aminoarenethiols, amino acid derivatives,
pyrrolidine-2-phosphates,
oxime–phosphine oxides and phosphoramidite.
diam-
4
g–i
4j
4k–m
Cs CO
CH CN
DMSO
Toluene
DMSO
2
2
3
4
n
4o
Cs CO
8
-hydroxyquinoline,
4
p
4q
Cs
Et
2
CO
N
A
3
more practical ligand promoted Cu-catalyzed chemistry
is being developed and these new methods are yet to
become general for the N-arylation of imidazoles.
KOt-Bu DMSO
KOt-Bu DMSO
KOt-Bu DMSO
KOt-Bu DMSO
1
1
Cu
2
O/10
CuCl/10
a
Keywords: Benzotriazole; CuI; N-arylation; Imidazoles.
Reaction conditions: all reactions were performed with 1 mmol of
imidazole, 1 mmol of ArX, 1.4 mmol of base, in 1 ml of solvent at
110 °C.
*
Corresponding author. Tel.: +91 11 27666272x231; fax: +91 11
7666248; e-mail: akhilesh682000@yahoo.com
2
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.04.061

4208
A. K. Verma et al. / Tetrahedron Letters 48 (2007) 4207–4210
With BtH as ligand, a set of experiments was carried out
to optimize the reaction conditions. The N-arylation of
imidazole 1a with 1-iodo-4-methoxybenzene 2a was
studied to identify a suitable catalyst/ligand/base system
in different solvents. As shown in Table 1, without the
aid of a ligand, treatment of substrate 1a with 2a, CuI
and Cs CO in DMF afforded only a trace amount of
1). Further, the study showed that almost the same yield
of product was obtained with 10 mol % of BtH. Other
solvents and bases were also investigated and we
observed a maximum yield of 96% using KOt-Bu in
8
DMSO (entry 8). Other copper compounds (CuCl
and Cu O) were also evaluated but proved inferior to
2
CuI (entries 10 and 11, Table 1).
2
3
the corresponding product 3a after 24 h (entry 1),
whereas the yield of 3a was enhanced sharply to 90%
in 12 h when 20 mol % of BtH was added (entry 2, Table
The efficacy of the CuI/BtH/KOt-Bu system for general
N-arylation of imidazoles with aryl halides and hetero-
a
Table 2. Cul catalyzed N-arylation of imidazole and benzimidazole with various aryl halides
b
Entry
1
Imidazole
1a
Arx
Product
Yield (%)
N
N
OMe 3a
95 (97)
96 (98)
N
NH
MeO
I
2a
2b
2
3
4
5
6
7
8
9
Me
I
N
N
Me
3b
3c
Me
N
N
92 (96)
98 (100)
93 (95)
96 (98)
97 (100)
98 (98)
100
2
c
I
Me
I
N
N
2
d
3d
Me
Br
Me
OMe
I
N
N
3e
2e
MeO
I
2f
N
N
Br
3f
I
N
N
3g
2
g
N
N
Br 2h
N
N
3h
3i
N
N
NO2
2
i
F
O N
2
CN
N
N
3
j
100
1
1
0
1
F
2j
NC
N
N
N
1b
94 (97)
MeO
Me
I
2
a
N
H
3k
OMe
Me
N
N
N
N
N
N
1
1
1
2
3
4
I
2b
95 (96)
98 (98)
98 (98)
3
l
I
2g
3
m
Br
2h
N
N
3n
3o
N
Me
Me
1
5
N
95 (98)
2c
I
a
Reaction conditions: all reactions were performed with 1 mmol of imidazole, 1 mmol of ArX, 1.4 mmol of KOt-Bu, 5 mol % of CuI and 10 mol % of
BtH in 1 ml of DMSO at 110 °C.
b
Isolated yields, values in parentheses are the yields determined by the GC analysis.

A. K. Verma et al. / Tetrahedron Letters 48 (2007) 4207–4210
4209
aryl bromide 2h was evaluated and the results are sum-
Acknowledgements
marized in Table 2. In the presence of CuI (5 mol %),
BtH (10 mol %) and KOt-Bu (1.4 equiv), the N-aryl-
ation of 1a with 2a and 2h occurred smoothly to afford
the corresponding products in 95% and 98% yields,
respectively. Encouraged by these results, a variety of
aryl halides 2b–j were treated with 1a or 1b under the
standard reaction conditions. The results obtained indi-
cated that all the aryl iodides with electron releasing
substituents underwent N-arylation smoothly in 3–8 h.
These N-arylations of deactivated haloarenes using
KOt-Bu as base were quite impressive over unreactive
systems using other bases (Table 1). The catalyst system
developed was also successfully amenable to the N-aryl-
ation of imidazoles with fluoroarenes (Table 2, entries 9
and 10). As illustrated in Table 2, 1-fluoro-2-nitro-
benzene 2i and 2-fluorobenzonitrile 2j gave the desired
products in short reaction times (30 min), in 100%
yields.
We thank the Department of Science and Technology,
New Delhi, for financial support. J.S. is thankful to
the CSIR for SRF.
References and notes
1
. For selected recent examples, see: (a) Zhong, C.; He, J.;
Xue, C.; Li, Y. Bioorg. Med. Chem. 2004, 12, 4009; (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.; Alexander, R. S.; Wang, J.; Wang, S.;
Nakajima, S.; Rossi, K. A.; Smallwod, 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)
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; (e) Mano, T.; Okumura, Y.;
Sakakibara, M.; Okumura, T.; Tamura, T.; Miyamoto, K.;
Stevens, R. W. J. Med. Chem. 2004, 47, 720; (f) 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; (g) 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; (h) 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; (i) 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;
As described in Scheme 1 we have formulated a possible
mechanism for the copper catalyzed N-arylation of
imidazoles based on the previously reported mecha-
2
,4,9
nism.
Chelation of Cu(I) with BtH occurs to form
the Cu(I) species L1, which is more reactive towards oxi-
9
dative addition than stabilized intermediate L2 gener-
ated by the oxidative addition of L1 to the aryl halide.
In the presence of base, imidazole reacted with interme-
diate L2 readily to afford intermediate L3, which under-
goes reductive elimination to provide the desired
product and regenerate the active Cu(I) species. Further
study on the mechanism is in progress.
In conclusion, we have reported that BtH is an excellent,
inexpensive and simple ligand for the N-arylation of imi-
dazoles with a diverse range of aryl halides providing
excellent yields of products. Efforts are being made to
extend the application of the CuI/BtH/base system to
the formation of other C–N bonds.
(
j) Barch e´ chath, S. D.; Tawatao, R. I.; Corr, M.; Carson,
D. A.; Cottam, H. B. J. Med. Chem. 2005, 48, 6409; (k)
Voets, M.; Antes, I.; Scherer, C.; M u¨ ller-Vieira, U.; Biemel,
K.; Barassin, C.; Marchais-Oberwinkler, S.; Hartmann, R.
W. J. Med. Chem. 2005, 48, 6632; (l) Wiglenda, T.; Ott, I.;
Kircher, B.; Schumacher, P.; Schuster, D.; Langer, T.;
Gust, R. J. Med. Chem. 2005, 48, 6516; (m) Jiang, W.;
Guan, J.; Macielag, 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.
N
N
N
H
Cu
ArX
ArNu
3
2
. (a) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
L1
2
2
004, 248, 2337; (b) Ley, S. V.; Thomas, A. W. Angew.
Chem., Int. Ed. 2003, 42, 5400; (c) Lindley, J. Tetrahedron
984, 40, 1433.
reductive
elimination
oxidative
addition
1
3
. Jiang, L.; Buchwald, S. L. Palladium-Catalyzed Aromatic
Carbon–Nitrogen bond Formation. In Metal-catalyzed
Cross-Coupling Reactions; 2nd ed., de Meijere, A., Diede-
rich, F., Eds.; Wiley-VCH: Weinheim, 2004; pp 699–760.
N
N
N
N
H
N
4. For papers on copper-catalyzed N-arylations of imidazoles
with aryl halides, see: (a) Liu, Y.-H.; Chen, C.; Yang, L.-M.
Tetrahedron Lett. 2006, 47, 9275–9278; (b) Xie, Y.-X.; Pi,
S.-F.; Wang, J.; Yin, D.-L.; Li, J.-H. J. Org. Chem. 2006,
Ar
N
H
Ar
Nu
Cu
Cu
X
L2
L3
7
1, 8324–8327; (c) Kiyomori, A.; Marcoux, J. F.; Buch-
wald, S. L. Tetrahedron Lett. 1999, 40, 2657; (d) 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,
NuH + base
Nu = imidazole or benzimidazole
X
2
2
405; (e) Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8,
779; (f) Kuil, M.; Bekedam, E. K.; Visser, G. M.; van den
Scheme 1.
Hoogenband, A.; Terpstra, J. W.; Kamer, P. C.; van

4210
A. K. Verma et al. / Tetrahedron Letters 48 (2007) 4207–4210
Leeuwen, P. W. N. M.; van Strijdonck, G. P. F. Tetrahe-
dron Lett. 2005, 46, 2405; (g) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
6. For selected recent papers on the synthesis of N-aryl
imidazoles via other transformations, see (a) Lee, S.-H.;
Yoshida, K.; Matsushita, H.; Clapham, B.; Koch, G.;
Zimmermann, J.; Janda, K. D. J. Org. Chem. 2004, 69,
8829; (b) Li, W.; Lam, Y. J. Comb. Chem. 2005, 7, 644; (c)
Gracias, V.; Gasiecki, A. F.; Djuric, S. W. Org. Lett. 2005,
7, 3183; (d) Szczepankiewicz, B. G.; Rohde, J. J.;
Kurukulasuriya, R. Org. Lett. 2005, 7, 1833; (e) Siamaki,
A. R.; Arndtsen, B. A. J. Am. Chem. Soc. 2006, 128, 6050.
7. (a) Katritzky, A. R.; Verma, A. K.; He, H.; Chandra, R. J.
Org. Chem. 2003, 68, 4938; (b) Tiwari, R. K.; Singh, J.;
Singh, D.; Verma, A. K.; Chandra, R. Tetrahedron 2005,
61, 9513; (c) Tiwari, R. K.; Singh, D.; Singh, J.; Chhillar,
A.; Chandra, R.; Verma, A. K. Eur. J. Med. Chem. 2006,
41, 40; (d) Tiwari, R. K.; Singh, D.; Singh, J.; Yadav, V.;
Phatak, A. K.; Dabur, R.; Chhillar, A.; Singh, R.; Sharma,
G. L.; Chandra, R.; Verma, A. K. Bioorg. Med. Chem. Lett.
2006, 16, 413–416; (e) Chaudhary, P.; Kumar, R.; Verma,
A. K.; Singh, D.; Yadav, V.; Chhillar, A.; Sharma, G. L.;
Chandra, R. Bioorg. Med. Chem. 2006, 14, 1819; For a
review on the use of benzotrizole see: (f) Katritzky, A. R.;
Lan, X.; Yang, J. Z.; Denisko, O. V. Chem. Rev. 1998, 98,
409.
7
727; (h) Alcalde, E.; Dinar e` s, I.; Rodr ´ı yguez, S.; Garcia de
Miguel, C. Eur. J. Org. Chem. 2005, 1637; (i) Antilla, J. C.;
Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem.
2004, 69, 5578; (j) Jerphagnon, T.; van Klink, G. P. M.; de
Vries, J. G.; van Koten, G. Org. Lett. 2005, 7, 5241; (k) Ma,
D.; Cai, Q. Synlett 2004; (l) Zhang, H.; Cai, Q.; Ma, D. J.
Org. Chem. 2005, 70, 5164; (m) Lv, X.; Wang, Z.; Bao, W.
Tetrahedron 2006, 62, 4756; (n) Liu, L.; Frohn, M.; Xi, N.;
Dominguez, C.; Hungate, R.; Reider, P. J. J. Org. Chem.
2005, 70, 10135; (o) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J.
Org. Chem. 2005, 70, 8107; (p) Xu, L.; Zhu, D.; Wu, F.;
Wang, R.; Wan, B. Tetrahedron 2005, 61, 6553; (q) Zhang,
Z.; Mao, J.; Zhu, D.; Wu, F.; Chen, H.; Wan, B.
Tetrahedron 2006, 62, 4435; (r) Choudary, B. M.; Sridhar,
C.; Kantam, M. L.; Venkanna, G. T.; Sreedhar, B. J. Am.
Chem. Soc. 2005, 127, 9948; (s) Son, S. U.; Park, I. K.;
Park, J.; Hyeon, T. Chem. Commun. 2004, 778.
. For selected representative papers on copper-catalyzed N-
arylations of imidazoles with other reagents, see: (a) Lopez-
Alvarado, P.; Avenda n˜ o, C.; Men e´ ndez, J. C. J. Org. Chem.
5
1
2
995, 60, 5678; (b) Collman, J. P.; Zhong, M. Org. Lett.
000, 2, 1233; (c) Collman, J. P.; Zhong, M.; Zeng, L.;
8. Typical experimental procedure: To a round-bottomed flask
containing CuI (5 mol %) and benzotriazole (10 mol %) in
1 ml of DMSO, 1 mmol of aryl halide was added followed
by 1 mmol of imidazole and 1.4 equiv KOt-Bu. The
reaction mixture was stirred vigorously for 3–8 h at
110 °C. After the reaction was complete, ethyl acetate was
added to the mixture, which was then washed with water,
Costanzo, S. J. Org. Chem. 2001, 66, 1528; (d) Collman, J.
P.; Zhong, M.; Zhang, C.; Costanzo, S. J. Org. Chem. 2001,
6
Xie, R.-G. Chem. Commun. 2004, 188; (f) 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; (g)
Fedorov, A. Y.; Finet, J.-P. Tetrahedron Lett. 1999, 40,
2
1
6, 7892; (e) Lan, J.-B.; Chen, L.; Yu, X.-Q.; You, J.-S.;
2 4
dried over Na SO and evaporated under vacuum. The
residue was purified by column chromatography (hexanes)
to afford the desired product. All the products are known
747; (h) Kang, S.-K.; Lee, S.-H.; Lee, D. Synlett 2000,
022; (i) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams,
1
2
and have been characterized by H NMR and LCMS.
J.; Averill, K. M.; Chan, D. M. T.; Combs, A. Synlett 2000,
74.
9. Zhang, S.; Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1997,
62, 2312.
6