Copper fluorapatite catalyzed N-arylation of heterocycles with bromo and iodoarenes

Article abstract of DOI:10.1016/j.tetlet.2006.03.173

Copper exchanged fluorapatite (CuFAP) is an effective heterogeneous catalyst for N-arylation of heterocycles with bromo- or iodoarenes using K₂CO₃ as base. N-Arylated products were isolated in good to excellent yields, demonstrating the versatility of the reaction.

Full text of DOI:10.1016/j.tetlet.2006.03.173

Tetrahedron Letters 47 (2006) 3897–3899
Copper fluorapatite catalyzed N-arylation of heterocycles
with bromo and iodoarenes
*
M. Lakshmi Kantam, G. T. Venkanna, Ch. Sridhar and K. B. Shiva Kumar
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Tarnaka, Hyderabad 500 007, India
Received 22 December 2005; revised 18 March 2006; accepted 28 March 2006
Available online 27 April 2006
Abstract—Copper exchanged fluorapatite (CuFAP) is an effective heterogeneous catalyst for N-arylation of heterocycles with
bromo- or iodoarenes using K
tility of the reaction.
2 3
CO as base. N-Arylated products were isolated in good to excellent yields, demonstrating the versa-
Ó 2006 Elsevier Ltd. All rights reserved.
N-Arylheterocycles are common motifs in pharmaceuti-
cal research. Arylation of heterocyclic nitrogen is a
Kaneda and co-workers demonstrated the utility of
CaHAP as a solid support for Ru and Pd to perform
several organic transformations: oxidation of alcohols,
1
long-standing problem and traditionally N-arylated
heterocycles have been prepared by Ullmann-type
coupling of N–H containing heterocycles with readily
available and cheap aryl halides. The discovery and
development of the catalytic path for N-arylation of het-
erocycles with bromo- and iodoarenes by Buchwald and
6
Heck and Diels–Alder reactions.
Recently we reported the preparation of recyclable
heterogeneous Cu-exchanged fluoroapatite and copper
exchanged tert-butoxyapatite catalysts, by incorporating
2
3
À
À
co-workers and Lam et al. and exhaustive arylation with
basic species F /t-BuO in apatite in situ by co-precip-
itation and subsequent exchange with Cu(II) for N-aryl-
ation of imidazoles and other heterocycles with
chloroarenes and fluoroarenes (EW), with good to excel-
4
several nucleophiles by Taillefer using copper catalysts in
the presence of basic ligands generated great interest in
industry.
7
lent yields for the first time. In continuation of our
Heterogeneous catalysis is particularly attractive as it
allows the production and ready separation of large
quantities of products with the use of a small amount
of catalyst.
work on apatites, we herein report N-arylation of het-
erocycles with bromo- and iodoarenes catalyzed by
using the recyclable heterogeneous copper exchanged
fluorapatite (Scheme 1).
Apatites are metal basic phosphates for which the chem-
ical formula is M (PO ) (OH) [M = divalent metal];
Copper-exchanged fluorapatite (CuFAP) was character-
ized by XPS, SEM-EDAX and IR. XPS analysis of the
CuFAP catalyst indicated the same binding energy
values for Ca, P and O as in CaFAP. A narrow scan
of Cu 2p3/2 for CuFAP showed the binding energy peak
at 934.9 eV (The binding energy of Cu in Cu(II)
1
0
4 6
2
the most typical apatite is calcium hydroxyapatite
Ca (PO ) (OH) (CaHAP). CaHAP has attracted wide
1
0
4 6
2
attention due to its versatile applications in the field of
bioceramics, as a chromatographic adsorbent, and in
acid–base catalysis. It has been well established that the
8
is around 935 eV.), which indicates copper in the +2
2
+
Ca sites of CaHAP can be replaced by divalent cations,
oxidation state in CuHAP. The copper content was
2
+
2+
2+
2+ 5
À1
such as Sr , Ba , Pb and Cd . Fluorapatites are
metal basic phosphates for which the chemical formula
is M (PO ) (F) (CaFAP) [M = divalent metal].
estimated to be 1.25 mmol g using SEM-EDAX.
1
0
4 6
2
CuFAP
N-Het
DMSO, 110 ºC
X
+
Het-NH
Keywords: CuFAP; N-Arylation; Heterocycles; Heterogeneous cata-
R
lyst.
K2CO3
X = Br, I
*
Corresponding author. Tel./fax: +91 40 27160921; e-mail:
mlakshmi@iict.res.in
Scheme 1. N-Arylation of N-heterocycles with bromo- or iodoarenes.
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.03.173

3898
M. L. Kantam et al. / Tetrahedron Letters 47 (2006) 3897–3899
a
To identify the best system for N-arylation of imidazole
with bromobenzene, a variety of bases were screened
Table 2. N-Arylation of various nitrogen heterocycles
9
Br
CuFAP
and it was found that CuFAP catalyst with K CO
2
3
+
Het-NH
o
N-Het
(
1
2 equiv) afforded a good yield (90%) in DMSO at
10 °C. A control reaction conducted under identical
DMSO, 110 C
b
Entry
1
N-Het
Time (h)
15
Yield (%)
conditions devoid of CuFAP gave no coupled product.
CuFAP was recovered quantitatively by simple filtration
and reused, which gave consistent activity even after a
fourth cycle (Table 1, entry 5). Moreover, the absence
of copper in the filtrate was confirmed by AAS, which
reiterates that no leaching of copper occurred during
the reaction and provides evidence for heterogeneity
throughout the reaction.
H
N
88
N
2
3
4
12
10
10
90
92
89
N
H
N
We chose a variety of substituted bromo- and iodoarenes
possessing a wide range of functional groups for our
study, to demonstrate the scope and the generality of
the CuFAP promoted N-arylation of imidazole with
K CO as base, and the results are summarized in Table
N
H
2
3
N
H
1
. 2-Bromopyridine, 2-bromopyrimidine and bromo-
a
Reaction conditions: aryl halide (1 mmol), Het-NH (1.2 mmol),
a
Table 1. N-Arylation of imidazole with bromo- or iodoarenes
CuFAP (0.1 g), DMSO (5 mL), K
Isolated yields.
2 3
CO (2 equiv), reaction, 110 °C.
b
H
N
CuFAP
N
X +
N
R
DMSO, 110 ºC
benzenes with electron-withdrawing groups, such as
-nitro bromobenzene and 4-bromobenzaldehyde, pro-
N
4
X = Br , I
vided excellent yields in short reaction times (Table 1,
entries 8–11) compared with bromobenzene. Bromobenz-
enes with electron-donating groups such as 4-bromotolu-
ene and 4-bromoanisole, took longer reaction times with
moderate yields (Table 1, entries 6 and 7). Among the
iodoarenes tested, iodobenzenes with electron-withdraw-
ing groups underwent smooth reaction with excellent
yields compared to iodobenzene with electron-donating
groups (Table 1, entries 2–4). As expected iodobenzene
provided good yields in a shorter time than bromobenz-
ene (Table 1, entry 1).
b
Entry
1
Aryl halide
Time (h)
Yield (%)
I
I
6
14
14
3
92
2
3
4
90
91
95
H C
3
I
H CO
3
I
O N
2
In order to expand the scope of the methodology, a vari-
ety of other nitrogen containing heterocycles, such as
benzimidazole, pyrrole, pyrazole and piperidine, were
successfully coupled with bromobenzene to give the cor-
responding N-arylated products in good yields. Among
these heterocycles, piperidine and pyrrole gave the cor-
responding N-arylated products in good yields in short
periods (Table 2, entries 3 and 4).
Br
c
5
10
90, 89
Br
6
7
8
9
15
15
4
88
85
95
90
H C
3
Br
Br
H CO
3
In conclusion, we have developed a simple and efficient
method for N-arylation of heterocycles using CuFAP as
a heterogeneous catalyst. Various bromo- and iodo-
arenes were coupled with N-heterocycles to yield the cor-
responding N-arylated products with good to excellent
yields (85–98%). The catalyst can be readily recovered
and reused. This methodology may find widespread use
for the preparation of N-arylated products.
O N
2
Br
8
OHC
N
Br
1
1
0
1
2
6
98
92
N
Br
Acknowledgements
N
a
We wish to thank the CSIR for financial support under
the Task Force Project CMM-0006. G.T.V. and
K.B.S.K. thank the CSIR and UGC for their respective
fellowships.
Reaction conditions: aryl halide (1 mmol), imidazole (1.2 mmol),
CuFAP (0.1 g), DMSO (5 mL), 110 °C.
Isolated yields.
b
c
Yield after fourth cycle.

M. L. Kantam et al. / Tetrahedron Letters 47 (2006) 3897–3899
3899
References and notes
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. A typical procedure for N-arylation of imidazole with
bromobenzene: Bromobenzene (157 mg, 1 mmol), imid-
azole (81 mg, 1.2 mmol), potassium carbonate (276 mg,
1
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2
mmol) and the catalyst (CuFAP, 100 mg) were stirred in
3
4
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was filtered and the filtrate was quenched with aq sodium
hydrogen carbonate and the product was extracted with
ethyl acetate. The combined organic extracts were dried
over anhydrous sodium sulfate and filtered. The solvent
was evaporated under reduced pressure and concentrated
in vacuo to give the crude product. The crude product was
purified by column chromatography on silica gel (hexane/
ethyl acetate, 70/30) to afford N-phenylimidazole (130 mg,
7
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5
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1
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9
0%, Table 1, entry 5). The spectroscopic data for the
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known products compared well with the reported data and
melting points.
1
1
-Phenyl-1H-imidazole (Table 1, entry 5). H NMR
(
300 MHz, CDCl
3
): d 7.83 (br s, 1H), 7.50–7.30 (m, 5H),
7
7
.25 (br s, 1H), 7.18 (br s, 1H); EI-MS: 144 (100%), 117,
7, 51 GC/MS: t = 16.20 min; m/z: 144.20; IR: (thin
R
À1
film/neat): cm : 3424, 3117, 1600, 1509, 1304, 1253, 1110,
1
058, 908, 760, 690, 659, 520.