Copper(I) thiophene-2-carboxylate (CuTC): A versatile non-nitrogen ligand-based catalyst for direct N-arylation of imidazole and pyrazole using aryl iodides, aryl bromides, and aryl chlorides

Article abstract of DOI:10.1246/bcsj.81.515

A new protocol to prepare N-aryl heterocyclic adducts in excellent yields via cross-coupling of HN-heterocycles with aryl halides is reported using commercially available and easy-to-prepare copper(I) thiophene-2-carboxylate (CuTC) as catalyst.

Full text of DOI:10.1246/bcsj.81.515

Short Articles
Bull. Chem. Soc. Jpn. Vol. 81, No. 4, 515–517 (2008)
515
tive in organic synthesis, particularly, for the construction of
C–N bonds involving modified Ulmann conditions.9 This reac-
tion is industrially very important because it enables direct
formation of C–N bonds between various aryl halides and
nitrogen-containing compounds.
Copper(I) Thiophene-2-carboxylate
(CuTC): A Versatile Non-Nitrogen
Ligand-Based Catalyst for Direct
N-Arylation of Imidazole and
In particular, such cross couplings with nitrogen hetero-
cycles, such as imidazole, pyrazole, and benzimidazole have
found extensive use in the construction of a vast range of nat-
ural products, bioactive molecules, and functional materials.10
Substantial progress has been made in this area using cop-
per(I)-catalyzed C–N coupling reactions.6e,6f,11 This is evident
from the pioneering work of Buchwald, Taillefer, and others.12
The key to success in this area is the in situ utilization of spe-
cial nitrogen ligand additives along with copper(I) precursor
salts as catalysts. In this communication, we present our stud-
ies in this dynamic field using CuTC as catalyst for N-arylation
reaction of nitrogen heterocycles with aryl halides. This proto-
col does not require additional nitrogen ligand additives to the
reaction mixture to promote direct N-arylation of HN-hetero-
cycles with aryl halides.
Pyrazole Using Aryl Iodides, Aryl
Bromides, and Aryl Chlorides
ꢀ
Hariharasarma Maheswaran, Gaddamanugu
Gopi Krishna, Vandanapu Srinivas,
Kurushunkal Leon Prasanth, and
Chinamukthevi Venkata Rajasekhar
Indian Institute of Chemical Technology,
Hyderabad-500007, India
First, CuTC was screened for its activity in the coupling
reaction of 4-bromoanisole with imidazole as standard sub-
strates in a number of solvents and with metal carbonates or
phosphates as base (Table 1). For these screening studies 25
mol % of CuTC (relative to the substrate) was used as catalyst.
At 110 ꢁC, this reaction even after 48 h gave the corresponding
product in poor yield (45%, Entry 1). However, at higher tem-
Received October 15, 2007; E-mail: maheswaran dr@yahoo.
com
A new protocol to prepare N-aryl heterocyclic adducts
in excellent yields via cross-coupling of HN-heterocycles with
aryl halides is reported using commercially available and
easy-to-prepare copper(I) thiophene-2-carboxylate (CuTC)
as catalyst.
Table 1. Screening of Reaction Parameters for CuTC-Cata-
lyzed N-Arylation of Imidazole with p-BromoanisoleaÞ
N
Br
N
Catalyst (25-mol%)
Ligand (25-mol%)
Copper(I) carboxylates have emerged as one of the most
effective systems gaining wide applicability as antifungal
agents,1 enzyme models,2 in molecular magnetism,3 and very
notably, in molecular catalysis for the synthesis of organic
molecules.4 One of the most interesting aspects of copper(I)
carboxylates is the exhibition of rate enhancement in chemical
reactions.5 For example, such rate enhancements were ob-
served for ‘‘living’’ radical polymerization reactions.5 In cop-
per(I)-catalyzed Ulmann-type cross-coupling reactions, similar
positive rate enhancement with respect to unfunctionalized
substrates has been demonstrated using coupling partners that
contain a copper-chelating carboxylic group, such as 2-halo-
genobenzoic acids, ꢀ-amino acids, and ꢁ-amino acids in the
reactions.6 This can be attributed to the formation of copper(I)
carboxylates during reaction, which enables Ulmann-type
reactions to proceed with rate enhancement.6e,6f
Pioneering work by Liebeskind and Allred have shown,
copper(I) thiophene-2-carboxylate (CuTC) mediates cross cou-
pling of organostannanes and organic iodides at room temper-
ature.7 Since this report, the impact of CuTC in effecting
various cross-coupling reactions in organic synthesis has been
incredible.8 Among the various advantages of CuTC, the most
important one is that it can be easily prepared in multigram
scale from thiophene-2-carboxylic acid, and thus, is cost effec-
tive and readily available from commercial vendors. Further-
more, CuTC is a tan, air-stable powder, which can be stored
and handled at room temperature without any special precau-
tions. These characteristics of CuTC makes its use very attrac-
+
HN
N
Solvent, Base(4 equiv)
135 °C, 48 h
MeO
MeO
Entry
Catalyst
Ligand Solvent
Base YieldbÞ/%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CuTC
CuTC
Cu2O
CuI
ꢂ
ꢂ
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
45cÞ
89
84
45
20
15
55
45
65
35
NR
5
18
15
24
30
10dÞ
4
I
I
I
I
CuCl
Cu(OAc)2
CuTC
CuTC
CuTC
CuTC
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
CuTC
Cu2O
ꢂ
ꢂ
DMF
ꢂ
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
ꢂ
II
III
IV
V
VI
VII
VIII
VIII
a) Reactions were performed on a 1.0 mmol scale with CuX
(0.25 mmol, 25 mol %), bromoanisole (1.0 mmol), ligand
(0.25 mmol, 25 mol %), imidazole (1.5 mmol), K2CO3 (4
mmol), and 5 mL of DMSO at 135 ꢁC. b) Values are isolated
yields after chromatographic purification. c) Reaction was
performed at 110 ꢁC. d) Reaction performed at 105 ꢁC.
Published on the web April 10, 2008; doi:10.1246/bcsj.81.515

516 Bull. Chem. Soc. Jpn. Vol. 81, No. 4 (2008)
Ó 2008 The Chemical Society of Japan
O
Table 2. The Scope of CuTC-Catalyzed N-Arylation of
HN-Heterocycles with Various Aryl HalidesaÞ
O
O
O
O
O
OH
OH
OH
OH
CuTC (25-mol%)
K2CO3
N-Heterocycle
X
S
+
HN-Hetrocycle
OH
O2
N
DMSO, 135 °C
I
IV
III
II
O
R
R
Entry
R
X
HN-Het
Time/h
YieldbÞ/%
O
O
O
N
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
26
p-Me
I
I
I
Im
Im
Py
Im
BzIm
Py
Im
BzIm
Py
Im
BzIm
Im
Py
Im
Im
Im
Im
Im
Im
24
24
24
35
35
35
48
48
48
30
30
30
30
48
18
38
18
48
30
24
24
24
40
24
24
48
91
88
82
89
85
82
89
85
81
85
82
70
75
89
96
75
90
60
85
90
95
89
81
90
84
NR
S
N
H
OH
N
N
OH
p-OMe
p-OMe
H
H
H
p-OMe
p-OMe
p-OMe
p-COMe
p-COMe
p-CHO
p-CHO
p-Me
p-NO2
o-Me
o-NO2
o-Me
p-CF3
p-CN
p-NO2
p-NO2
p-COMe
o-NO2
o-CN
H
V
OH
VII
VIII
VI
Figure 1. Representative carboxylic acid ligands that are
screened for N-arylation reaction with copper precursor.
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
I
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
perature (135 ꢁC), the reaction proceeded smoothly, and gave
yields up to 89% for the N-arylated product (Entry 2). Cop-
per(I) oxide in the presence of thiophene-2-carboxylic acid
(TCA) ligand also promoted cross-coupling of 4-bromoanisole
with imidazole in DMSO, and the yields are comparable to
those obtained using CuTC (Entry 3). In contrast, copper salts
such as CuI, CuCl, and Cu(OAc)2 in the presence of TCA,
gave comparably lower yields than those obtained using CuTC
(Entries 4–6). Among various solvents and bases screened,
DMSO and K2CO3 were found to be the best under our exper-
imental conditions (Entries 2 and 7–10).
To investigate whether this reaction is unique to CuTC or
rather to copper carboxylates in general, more relevant control
experiments using additional carboxylic acid ligands (II–VII,
Figure 1) were carried out under our experimental conditions.
As can be seen in Entries 11–16, the reactions of imidazole
with p-bromoanisole, in the presence of carboxylic acid li-
gands such as benzoic acid, p-nitrobenzoic acid, (+)-2,3-O-
isopropylidinetartaric acid, pyrrolidine-2-carboxylic acid, pyr-
idine-2-carboxylic acid, and thiazolidine-2-carboxylic acid
proceed rather sluggishly, and gave low yields (0–29%) for the
desired product. Thus, there does not appear to be any direct
correlation between carboxylic acid groups in the structural
motif of ligand and good catalytic activity for C–N coupling
reactions. The observed efficacy with CuTC in our study is
most likely due to the unique ability of CuTC to stabilize
the oxidative addition product during the course of the reaction
as was originally proposed by Liebeskind et al. for direct C–C
cross-coupling reactions. Further, to see whether lower reac-
tion temperatures could be achieved with the addition of a
nitrogen ligand as an additive, 1,10-phenanthroline was added
to CuTC-catalyzed reaction of 4-bromoanisole and imidazole
at 105 ꢁC. However, interestingly, the desired cross-coupled
product was obtained in low yield (Entry 17). It is to be noted
that we have obtained best results with CuTC in DMSO and
K2CO3 at 135 ꢁC (Entry 2).
BzIm
Im
BzIm
Im
Im
Im
Im
a) Reactions were performed on a 1.0 mmol scale with CuTC
(0.25 mmol, 25 mol %), bromoanisole (1.0 mmol), HN-hetero-
cycle (1.5 mmol), K2CO3 (4 mmol), and 5 mL of DMSO at
135 ꢁC. b) Values are isolated yields after chromatographic
purification.
4–14). For example, bromobenzene reacts with imidazole, pyr-
azole, and benzimidazole providing the corresponding cou-
pling products in excellent yields (Entries 4–6). Aryl bromides
with strong electron-donating groups such as p-OMe and p-Me
substituents also reacted with various HN-heterocycles yield-
ing the corresponding N-arylated adducts in good yields
(Entries 7–9 and 14). Interestingly, reactions of aryl bromides
containing electron-withdrawing groups like p-COMe, p-CHO,
and p-NO2 proceeded much faster than those containing elec-
tron-donating groups (Entries 10–14). Finally, to our delight,
we observe that the present methodology also enables direct
cross-coupling reaction between various HN-heterocycles with
difficult aryl chloride substrates, particularly when they con-
tain electron-withdrawing groups. To date, only a few exam-
ples involving aryl chloride activation for copper-catalyzed
C–N bond formation with azaheterocycles have been report-
ed.13 To verify whether unactivated aryl chlorides could also
be used, the reaction of chlorobenzene with imidazole was
first attempted. However, this reaction, even after 48 h, gave
insignificant amounts of cross-coupled product (Entry 26).
Extension of CuTC based methodology to ortho-substituted
In an attempt to probe the generality of the CuTC method, a
variety of structurally divergent aryl halide substrates were
subjected to the cross-coupling reaction with HN-heterocycles
such as benzimidazole, pyrazole, and imidazole, and the re-
sults are summarized in Table 2. Aryl iodides with strongly
electron-donating groups like p-Me and p-OMe groups react
smoothly with imidazole and pyrazole giving excellent yields
of the coupling adducts within 24 h at 135 ꢁC (Entries 1–3).
Aryl bromides substrates, however, required longer reaction
times (35–48 h) for the completion of the reaction (Entries

H. Maheswaran et al.
Bull. Chem. Soc. Jpn. Vol. 81, No. 4 (2008)
517
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or sterically hindered bromoarene substrates has yielded prom-
ising results. As can be seen in Table 2, o-bromonitrobenzene,
o-bromotoluene, and o-iodotoluene react with imidazole yield-
ing corresponding N-arylated adducts in moderate to excellent
yields (Entries 16–18). It is important to note that o-bromo-
nitrobenzene having a supplementary chelating nitro group re-
acted much faster (18 h) with imidazole than other hindered
substrates. However, it is very unlikely this reaction proceeds
through chelation of the nitro group to copper because p-bro-
monitrobenzene also took about 18 h for the completion under
identical reaction conditions with imidazole (Entries 15 and
17). More importantly, with CuTC, we also observed sterically
hindered o-substituted chloroarenes react with imidazole
giving excellent yields in 24–40 h (Entries 19–25). Unlike Pd0
mediated protocols,14 tolerance to steric factors by copper is
well known in C–N cross-coupling chemistry. This distinct
feature could be related to mechanistic divergence in their
chemistry as well as due to the different nature of intermedi-
ates that are formed in the catalytic cycle.13c,15
In conclusion, we have shown CuTC is a versatile catalyst
for effecting direct N-arylation of aryl halides with various im-
portant nitrogen heterocycles. It is clear from the above discus-
sion that the CuTC-based catalyst system for direct N-arylation
demands slightly higher temperatures (135 ꢁC), which is some-
what on the higher side when compared to copper-catalyzed N-
arylation reaction promoted by basic nitrogen ligand additives
(110–125 ꢁC).12 Nevertheless, CuTC-based methodology re-
ported herein is a very important synthetic protocol because
we have shown diverse aryl halides including activated chloro-
arenes undergo direct N-arylation smoothly in the presence of
CuTC with no side-products being formed at the working tem-
perature range (135 ꢁC). Even though we could not find any di-
rect correlation with ligand carboxylic acid ligand structures
and C–N cross-coupling reaction (see Figure 1 and Table 1),
we are currently investigating this aspect of chemistry in our
laboratory.
6
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9
a) For CuTC-catalyzed cross-coupling reaction of vinyl-
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reaction for synthesis of bezodiazepinedinones, see: G. Cuny,
M. Bois-Choussy, J. Zhu, J. Am. Chem. Soc. 2004, 126, 14475.
10 a) M. L. Quan, P. Y. S. Lam, Q. Han, D. J. P. Pinto, M. Y.
He, R. Li, C. D. Ellis, C. G. Clark, C. A. Teleha, J. H. Sun, R. S.
Alexander, S. Bai, J. M. Luettgen, R. M. Knabb, P. C. Wong,
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11 For copper(I)-catalyzed C–N coupling reactions see:
a) I. P. Beletskaya, A. V. Cheprakov, Coord. Chem. Rev. 2004,
248, 2337. b) J.-P. Corbet, G. Mignani, Chem. Rev. 2006, 106,
2651. For palladium-catalyzed C–N coupling reactions see:
c) K. W. Anderson, R. E. Tundel, T. Ikawa, R. A. Altman, S. L.
Buchwald, Angew. Chem., Int. Ed. 2006, 45, 6523. d) J. P. Wolfe,
S. L. Buchwald, Angew. Chem., Int. Ed. 1999, 38, 2413. e) L.
Jiang, S. L. Buchwald, in Palladium-Catalyzed Aromatic Carbon-
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VCH, Weinheim, 2004, pp. 699–760.
G. G. Krishna, V. Srinivas, K. L. Prasanth, and H.
Maheswaran thank CSIR for financial support under grant
CMM-0005.
Supporting Information
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Soc. 2002, 124, 1168. b) J. C. Antilla, J. M. Baskin, T. E. Barder,
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General synthesis procedure for N-arylation and spectral data.
This material is available free of charge on the web at http://
www.csj.jp/journals/bcsj/.
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