An efficient N-arylation of heterocycles with aryl-, heteroaryl-, and vinylboronic acids catalyzed by copper fluorapatite

Article abstract of DOI:10.1002/hlca.200900326

N-Arylation of N-containing heterocycles, such as pyrazoles, imidazoles, and benzimidazoles with aryl-, heteroaryl-, and vinylboronic acids was efficiently carried out by copper fluorapatite (CuFAP) catalyst in MeOH at room temperature under base-free conditions. The N-arylated heterocycles were isolated in good-to-excellent yields.

Full text of DOI:10.1002/hlca.200900326

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An Efficient N-Arylation of Heterocycles with Aryl-, Heteroaryl-, and
Vinylboronic Acids Catalyzed by Copper Fluorapatite
by Mannepalli Lakshmi Kantam*, Gopaladasu Tirupati Venkanna, Kota Balaji Shiva Kumar, and
Vura Bala Subrahmanyam
Inorganic & Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007,
India (fax: þ 91-40-27160921; e-mail: mlakshmi@iict.res.in)
N-Arylation of N-containing heterocycles, such as pyrazoles, imidazoles, and benzimidazoles with
aryl-, heteroaryl-, and vinylboronic acids was efficiently carried out by copper fluorapatite (CuFAP)
catalyst in MeOH at room temperature under base-free conditions. The N-arylated heterocycles were
isolated in good-to-excellent yields.
Introduction. – N-Arylated heterocycles are found in many biologically active
compounds [1 – 5]. The traditional synthesis of these compounds involves nucleophilic
aromatic substitution [6], Ullmann reaction [7], and coupling of imidazoles with
metalloarenes like aryllead, arylbismuth, arylborane, and arylsilane reagents [8 – 11].
Previously, an efficient method for N-arylation of azoles with arylboronic acids using
stoichiometric amounts of Cu(OAc)2 and pyridine as base was reported by the Chan
and Lam groups [12][13]. Later, Collman and co-workers demonstrated the use of a
diamine-copper complex for the coupling of arylboronic acids with imidazole in CH2Cl2
and H2O at room temperature [14][15]. Very recently, the same coupling reaction was
also performed by Xie and co-workers using a copper salt in protic solvents under reflux
conditions without using any base [16]. Thus, the development of mild and cost-
effective catalytic procedures for N-arylation of imidazoles and amines still remains an
active research area [17].
Heterogeneous catalysis is particularly attractive as it allows production and ready
separation of large quantities of products with the use of a small amount of catalyst.
Recently, we reported the preparation of recyclable heterogeneous Cu-exchanged
fluorapatite (CuFAP) and Cu-exchanged (tert-butoxy)apatite catalysts, by incorporat-
ing basic species Fꢀ/t-BuOꢀ in apatite in situ by co-precipitation and subsequent
exchange with CuII for N-arylation of imidazoles and other heterocycles with chloro-,
fluoro- (EW), bromo-, and iodoarenes in good-to-excellent yields for the first time
[18][19]. Later, we reported N-arylation of imidazole, benzimidazole, and amines with
arylboronic acids at room temperature under base-free conditions using CuFAP
catalyst [20].
Continuing our work on N-arylation, herein we report an efficient N-arylation of N-
containing heterocycles 1 such as pyrazoles, imidazoles, and benzimidazoles with aryl-,
heteroaryl-, and vinylboronic acids, 2 – 4, respectively, using heterogeneous CuFAP
catalyst (Scheme 1) at room temperature under base-free conditions. To the best of our
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Scheme 1. N-Arylation of N-Containing Heterocycles Using the CuFAP Catalyst
knowledge, N-arylation of substituted imidazoles or pyrazoles and the use of
heterocyclic boronic acids for such coupling at room temperature has not been
explored previously.
To identify the best catalytic system for N-arylation of 1H-pyrazole (1a) with
phenylboronic acid (2a) to form compound 5a, a variety of solvents were screened and
MeOH was found to be the best solvent. CuFAP was recovered quantitatively by
simple centrifugation and reused for four cycles with consistent activity (Table 1,
Entry 1). A control reaction conducted under identical conditions devoid of CuFAP
gave no coupled product despite prolonged reaction time.
We chose a variety of arylboronic acids, 2a – 2k, possessing a wide range of
substituents to evaluate the scope and the generality of the CuFAP-promoted N-
arylation of N-containing heterocycles to afford the corresponding N-arylated hetero-
cycles 5a – 5v, and the results are summarized in Table 1. Arylboronic acids with
electron-donating groups afforded better yields (Table 1, Entries 2, 3, 6, and 7) than the
substrates containing electron-withdrawing groups (Table 1, Entries 4 and 5). Arylbor-
onic acids with sterically demanding ortho-substituents on the phenyl ring (Table 1,
Entries 8 and 9) gave lower yields compared to their para-counterparts, which may be
attributed to an ortho steric effect.
Among the different N-containing heterocycles tested, 3,5-dimethyl-1H-pyrazole
(1b) afforded poor yields compared to 1H-pyrazole (1a), which may be due to the
sterically hindering Me groups on the pyrazole ring (Table 1, Entries 11 – 13). 2-Methyl-

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Table 1. N-Arylation of N-Containing Heterocycles 1 with Different Arylboronic Acids 2a)
Entry Arylboronic acid
NH-Azole
Product Time [h] Yield [%]b)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
2a (Ar¼ Ph)
1H-Pyrazole (1a)
5a
5b
5c
5d
5e
5f
5g
5h
5i
10
10
10
12
13
10
15
22
22
15
24
24
24
10
10
10
5
92, 88c)
88
87
88
80
90
75
60
65
85
58
50
53
95
92
94
96
2b (Ar¼ 4-MeꢀC6H4)
2c (Ar¼ 4-MeOꢀC6H4)
2d (Ar¼ 2-BrꢀC6H4)
2e (Ar¼ 4-CHOꢀC6H4)
1a
1a
1a
1a
2f (Ar¼ 2-Me-4-MeOꢀC6H3) 1a
2g (Ar¼ 2,4-(MeO)2ꢀC6H3) 1a
2h (Ar¼ 2-MeꢀC6H4)
1a
1a
1a
2i (Ar¼ 2-MeOꢀC6H4)
2j (Ar¼ C10H9)
5j
2a
2b
2c
2a
2b
2c
2d
3,5-Dimethyl-1H-pyrazole (1b) 5k
1b
1b
5l
5m
5n
5o
5p
5q
5r
5s
5t
5u
5v
2-Methyl-1H-imidazole (1c)
1c
1c
1c
1c
1c
1c
1c
1c
2k (Ar¼ 3-NO2ꢀC6H4)
8
91
90
92
87
2j
12
10
12
12
2g
2h
2i
89
a) Reaction conditions: N-containing heterocycle (1.2 mmol), arylboronic acid (1 mmol), CuFAP (0.1 g,
0.073 mmol, 7.3 mol-%), MeOH (4 ml), r.t., under air. All products showed correct spectral data and
elemental analyses. b) Yield of isolated product. c) Yield after fourth cycle.
1H-imidazole (1c) reacted with arylboronic acids to give similar yields as imidazole
[10], which confirms that a substituent on the heterocyclic ring has no effect on the
reaction rate (Table 1, Entries 14 – 22).
To extend the scope of the methodology, vinylboronic acid 3 was successfully
coupled with various N-containing heterocycles, such as pyrazoles 1a and 1b,
imidazoles 1c and 1d, 1H-benzimidazole (1e), and 2-methyl-1H-benzimidazole (1f),
to give the corresponding N-arylated heterocycles 6a – 6f in moderate-to-good yields
(Table 2). It is noteworthy that when the reaction was conducted in the absence of air,
no coupled product was obtained.
Later, we explored the utility of heteroarylboronic acids 4a – 4c as arylating agents
in the CuFAP catalyzed N-arylation of imidazoles 1c and 1d and 1H-benzimidazole
(1e) to give the corresponding N-arylated products 7a – 7i in good yields. The results are
shown in Table 3. We observed that a 2-substituted heteroarylboronic acid such as
thiophen-2-ylboronic acid (4b; Table 3, Entry 2) afforded lower yields compared to the
3-substituted heteroarylboronic acids 4a and 4c (Table 3, Entries 1 and 3).

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Table 2. N-Arylation of N-Containing Heterocycles 1 with Vinyl Boronic Acids 3a)
Entry
NH-Azole
Time [h]
Product
Yield [%]b)
1
2
3
4
5
6
1H-Imidazole (1d)
1c
1H-Benzimidazole (1e)
1a
10
10
10
13
20
24
6d
6c
6e
6a
6b
6f
95
92
90
88
70
30
1b
2-Methyl-1H-benzimidazole (1f)
a) Reaction conditions: N-containing heterocycle (1.2 mmol), arylboronic acid (1 mmol), CuFAP
(100 mg), MeOH (4 ml), r.t., under air. All products showed correct spectral data and elemental
analyses. b) Yield of isolated products.
Table 3. N-Arylation of N-Containing Heterocycles 1 with Heteroarylboronic Acids 4a)
Entry
Boronic acid
NH-Azole
Time [h]
Product
Yield [%]b)
1
2
3
4
5
6
7
8
9
4a (X ¼ S, R ¼ 3-(OH)2B)
1d
1d
1d
1c
1c
1c
1e
1e
1e
13
16
13
13
15
13
18
20
18
7a
7b
7c
7d
7e
7f
7g
7h
7i
90
60
90
92
65
92
88
69
89
4b (X ¼ S, R ¼ 2-(OH)2B)
4c (X ¼ O, R ¼ 3-(OH)2B)
4a
4b
4c
4a
4b
4c
a) Reaction conditions: N-containing heterocycle (1.2 mmol), heteroarylboronic acid (1 mmol), CuFAP
(100 mg), MeOH (4 ml), r.t., under air. All products showed correct spectral data and elemental
analyses. b) Yield of isolated products.
A possible mechanism for the N-arylation of heterocycles is depicted in Scheme 2.
The Cu(II) in the CuFAP catalyst (shown as A) forms a complex with pyrazole via
deprotonation of the NH-azoles to form the CuII intermediate shown as B in Scheme 2
[18]. An FT-IR spectrum of B indicates PꢀOH stretching frequency, which is in
consonance to the analogous Ru-enolate intermediate of a ruthenium(II) apatite
complex reported earlier [21]. Reductive elimination of 1-phenyl-1H-pyrazole (as an
example for NH-Het) takes place by the addition of phenylboronic acid via transition
stage C to give a CuI species, depicted as D. Oxidation of CuI to CuII takes place in
presence of O2, thereby continuing the catalytic cycle. The reaction devoid of O2 or air

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Scheme 2. Possible Mechanism for the N-Arylation of Heterocycles
does not proceed, which confirms that CuI species are formed during the reaction, but
they are not active for the progress of the reaction.
Conclusions. – In conclusion, we have developed a simple and efficient method for
the N-arylation of N-containing heterocycles using the CuFAP catalyst. Various aryl,
heteroaryl, and vinylboronic acids were coupled with different N-containing hetero-
cycles to yield the corresponding N-arylated heterocycles in good to excellent yields.
The catalyst can be readily recovered and reused. This methodology may find
widespread use for the preparation of N-arylated heterocycles.
Experimental Part
All chemicals were purchased from Aldrich and were used as received. All solvents were of
analytical grade from Merck India Pvt. Ltd. and used as such. 1H-NMR Spectra: Varian-Gemini-200 MHz
and Bruker-Avance-300 MHz spectrometer, with TMS as an internal standard in CDCl3.
Typical Procedure for N-Arylation of Azoles with Arylboronic Acids at Ambient Temperature. In a
typical experiment, CuFAP (100 mg) [20] was added to a mixture of N-containing heterocycle (1.2 mmol)
and arylboronic acid (1 mmol) in MeOH (4 ml) at r.t., and the mixture was stirred for 5 – 24 h under an
atmosphere of air. The progress of the reaction was monitored by TLC, and on completion of the
reaction, the mixture was centrifuged to remove the catalyst, and the centrifugate was concentrated
under reduced pressure to give the crude product. The crude product was purified by column
chromatography using silica gel to afford the N-arylated heterocycles.
Spectral data of the N-arylated heterocycles are available on demand.
G. T. V. wishes to thank CSIR, India for SRF fellowship.
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Received September 11, 2009