A mild and efficient method for N-arylation of nitrogen heterocycles with aryl halides catalyzed by Cu(II)-NaY zeolite

Article abstract of DOI:10.1055/s-2006-949615

A mild and efficient method for N-arylation of nitrogen-containing heterocycles with aryl halides to afford N-arylheterocycles in excellent yields using a Cu(II)-NaY catalyst in the presence of K₂CO₃ base is reported. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-949615

LETTER
2195
A Mild and Efficient Method for N-Arylation of Nitrogen Heterocycles with
Aryl Halides Catalyzed by Cu(II)-NaY Zeolite
N-Arylation of
N
itroge
.
n
H
eterocyc
L
w
ith
A
ryl
H
a
alides kshmi Kantam,*a B. Purna Chandra Rao,a B. M. Choudary,*b R. Sudarshan Reddya
a
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad – 500 007, India
Fax +91(40)27160921; E-mail: mlakshmi@iict.res.in
b
Ogene Systems (I) Pvt. Ltd., # 11-6-56, GSR Estates, Moosapet, Hyderabad –500 037, India
E-mail: bmchoudary@gmail.com
Received 28 December 2005
Table 1 Cu(II)-NaY Catalyzed Coupling of 4-Bromotoluene and
Abstract: A mild and efficient method for N-arylation of nitrogen-
containing heterocycles with aryl halides to afford N-arylheterocy-
cles in excellent yields using a Cu(II)-NaY catalyst in the presence
of K2CO3 base is reported.
Imidazolea
Cu(II)-NaY
HN
Me
Br
Me
N
+
N
N
Key words: N-arylation, nitrogen heterocycles, aryl halides,
Cu(II)-NaY zeolite
Entry
Base
Solvent
DMF
DMF
DMF
DMF
DMF
DMSO
NMP
Time (h)
20 (36)
20
Yieldb (%)
1
2
3
4
5
6
7
8
K2CO3
K3PO4
62 (95)
65
N-Arylheterocycles are common motifs in pharmaceutical
research and can be prepared either by nucleophilic aro-
matic substitution1 or by Ullmann-type coupling.2 The
former method requires substrates bearing electron-with-
drawing substituents and the latter coupling reaction re-
quires the use of stoichiometric amounts of copper and
gives low to moderate yields. Milder methods involving
various arylating agents are also reported3 but only a few
use aryl halides as the arylating agent.4 Buchwald et al.
employed copper(I) iodide and racemic trans-N,N-di-
methyl-1,2-cyclohexanediamine in the N-arylation of ni-
trogen heterocycles4f and Cristau et al. reported N-
arylation of azoles by using cuprous oxide and oxime
ligands under mild conditions.4g,4h Dawei Ma et al. report-
ed amino acid promoted, CuI-catalyzed C–N bond forma-
tion of aryl halides and amines or nitrogen heterocycles.4i
All these reactions require additives or ligands. Recently
we reported that copper basic apatites are potential cata-
lysts for N-arylation of heterocycles using fluoro- and
chloroarenes in the absence of any additive.5 Zeolites are
very useful catalysts in a large variety of reactions, includ-
ing acid, base and redox catalysis.6 Hutchings et al. report-
ed that bis(oxazoline)-modified Cu(II)-HY catalysts are
effective for asymmetric carbonyl- and imino-ene reac-
tions and aziridination of styrene.7 Recently Djakovitch
and Kohler8 found that Pd(II)-NaY zeolite activates aryl
halides towards Heck olefination, a-arylation of malonate
and amination reactions. It is well known that alkali-ex-
changed faujasite zeolites are solid base catalysts.9 We
conceived the use of a basic support, NaY zeolite to make
an electron-rich copper catalyst that activates C–Cl, C–Br
and C–I bonds. We herein report the N-arylation of nitro-
gen heterocycles with aryl halides to afford N-arylhetero-
cycles in excellent yields under mild conditions using
Cs2CO3
Et3N
20
68
20
trace
14
NaOtBu
K2CO3
K2CO3
K2CO3
20
20
60
20
52
1,4-Dioxane 20
10
a Reaction conditions: 4-bromotoluene (1 mmol), imidazole (1.2
mmol), base (2 mmol), Cu(II)-NaY (100 mg) in 3 mL of solvent.
b GC yields.
Cu(II)-modified alkali exchanged zeolite Y without the
use of any additive.
We first conducted the coupling reactions with 4-bromo-
toluene and imidazole using the Cu(II)-NaY catalyst.10
The reaction proceeded well at 120 °C in DMF in the
presence of K2CO3 to afford 1-(4-methylphenyl)-1H-imi-
dazole in 62% yield in 20 hours and 95% yield in 36 hours
(Table 1, entry 1). To our knowledge, there is no report of
the N-arylation of nitrogen heterocycles with aryl halides
using zeolite catalysts in the literature. Other bases includ-
ing K3PO4 and Cs2CO3 afforded 65% and 68% yields re-
spectively in 20 hours (Table 1, entries 2 and 3). We have
screened different solvents and the results are summarized
in Table 1 (entries 6–8). These results indicate that N-aryl-
heterocycles can be prepared using a cheap and mild base
(K2CO3) in DMF.11
After the reaction conditions were optimized, the reaction
scope was extended to different aryl halides and imida-
zole. As summarized in Table 2, N-arylation of imidazole
with chloroarenes containing electron-withdrawing
groups such as nitro-, cyano-, and trifluoromethyl gave
high yields (92%, 99% and 97%, respectively, Table 2,
SYNLETT 2006, No. 14, pp 2195–2198
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1
.0
9
.2
0
0
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Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-949615; Art ID: D38605ST
© Georg Thieme Verlag Stuttgart · New York

2196
M. L. Kantam et al.
LETTER
Table 2 Cu(II)-NaY-Catalyzed Coupling Reactions of Aryl Halides with Imidazolea
Entry
1
Aryl halide
Product
Time (h)
20
Yieldb (%)
92c
99
97
95
N
O2N
O2N
Cl
N
2
3
4
24
30
48
N
N
C
Cl
C
N
N
F3C
Cl
Cl
N
N
F3C
O
N
N
O
5
6
30
20
99
99
N
Br
N
N
O
Br
N
O
7
8
36
48
24
24
36
40
90c (84)d
N
Br
N
85
99
99
99
99
N
MeO
Br
MeO
N
9
N
I
N
10
11
12
I
N
N
N
MeO
Cl
MeO
Cl
I
N
N
I
N
a Reaction conditions: aryl halide (1 mmol), imidazole (1.2 mmol), K2CO3 (2 mmol), Cu(II)-NaY (100 mg) in DMF (3 mL).
b GC yields; products were characterized by 1H NMR and MS.
c Isolated yields.
d Isolated yield after the third recycling.
entries 1–3) in shorter reaction times when compared with conducted with the filtrate obtained at the end of the N-
4-chloroacetophenone (Table 2, entry 4). Bromoarenes arylation reaction, no product formation was observed.
containing electron-donating groups afforded the corre-
The application of this catalytic system for the coupling of
sponding N-arylated products in high yields after 36 h
nitrogen-containing heterocycles with 4-bromo- and 4-io-
(entries 5–8). The reaction with iodoarenes resulted in
dotoluene was also explored and the desired N-arylated
complete conversion in shorter reaction times (Table 2,
products were obtained in excellent yields (Table 3).
entries 9–11). Treatment of 1-chloro-4-iodobenzene with
However, the reaction of 4-chlorotoluene with nitrogen
imidazole gave selectively N-(4-chlorophenyl)imidazole
heterocycles provided the products in only trace amounts
even after 48 hours.
(Table 2, entry 12). The catalyst was used for four cycles
successfully with minimal loss of activity (Table 2, entry
In conclusion, we have demonstrated that Cu(II)-NaY cat-
7). After completion of the reaction, the catalyst was sep-
alyzes the N-arylation of nitrogen-containing heterocy-
arated by filtration and washed with DMF and acetone
cles with chloro-, bromo-, and iodoarenes in excellent
and then dried in an oven. Atomic absorption spectrosco-
yields. The present reaction is applicable to bromo- and
py (AAS) results of the used Cu(II)-NaY catalyst indicate
iodoarenes containing electron-donating and electron-
leaching of 1.8% of copper in the N-arylation reaction of
withdrawing groups and chloroarenes containing elec-
imidazole with 4-bromotoluene after the first cycle and
tron-withdrawing groups under mild conditions without
6.2% after the fourth cycle. When a fresh reaction was
the use of any additive.
Synlett 2006, No. 14, 2195–2198 © Thieme Stuttgart · New York

LETTER
N-Arylation of Nitrogen Heterocycles with Aryl Halides
2197
Table 3 N-Arylation of Various Nitrogen Hetrocyclesa
Cu(II)-NaY
Me
X
+
Het-NH
Me
N-Het
K2CO3, DMF
Entry
Nitrogen hetrocycle
Product
X = Br
X = I
Time (h)
Yieldb (%)
99
Time (h)
Yieldb (%)
99
1
2
48
36
N
N
N
N
H
36
99
22
99
H
H
N
N
N
N
N
3
4
24
20
99
99
20
22
99
99
N
N
N
H
a Conditions as in Table 2.
b GC yields; products were characterized by 1H NMR and MS.
Taillefer, M. Eur. J. Org. Chem. 2004, 695. (h) Cristau, H.
J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J.
2004, 10, 5607. (i) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem.
2005, 70, 5164.
Acknowledgment
We wish to thank the CSIR for financial support under the Task For-
ce Project CMM-0005. B.P.C.R. and R.S.R. thank the Council of
Scientific and Industrial Research (CSIR), India, for the award of
Research Fellowships.
(5) Choudary, B. M.; Sridhar, Ch.; Kantam, M. L.; Venkanna,
G. T.; Sreedhar, B. J. Am. Chem. Soc. 2005, 127, 9948.
(6) Corma, A. J. Catal. 2003, 216, 298.
(7) (a) Caplan, N. A.; Hancock, F. E.; Bulman Page, P. C.;
Hutchings, G. J. Angew. Chem. Int. Ed. 2004, 43, 1685.
(b) Gullick, J.; Taylor, S.; Ryan, D.; McMorn, P.; Coogan,
M.; Bethell, D.; Bulman Page, P. C.; Hancock, F. E.; King,
F.; Hutchings, G. J. Chem. Commun. 2003, 2808.
(8) (a) Djakovitch, L.; Heise, H.; Köhler, K. J. Organomet.
Chem. 1999, 584, 16. (b) Djakovitch, L.; Köhler, K. J. Mol.
Catal. A: Chem. 1999, 142, 275. (c) Djakovitch, L.; Köhler,
K. J. Am. Chem. Soc. 2001, 123, 5990. (d) Djakovitch, L.;
Köhler, K. J. Organomet. Chem. 2000, 606, 101.
(e) Djakovitch, L.; Wagner, M.; Köhler, K. J. Organomet.
Chem. 1999, 592, 225.
References and Notes
(1) (a) Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.;
Sakamoto, S. J. Med. Chem. 1996, 39, 3971. (b) Antonini,
I.; Cristalli, G.; Franchetti, P.; Grifantini, M.; Martelli, S.
Synthesis 1983, 47.
(2) (a) Lindley, J. Tetrahedron 1984, 40, 1433. (b) Kiyomori,
A.; Marcoux, J. F.; Buchwald, S. L. Tetrahedron Lett. 1999,
40, 2657. (c) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz,
E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
(3) (a) Elliott, G. I.; Konopelski, J. P. Org. Lett. 2000, 2, 3055.
(b) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941. (c) Mederski, W. W. K. R.; Lefort, M.;
Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757.
(d) Collman, J. P.; Zhong, M. Org. Lett. 2000, 2, 1233.
(e) Lam, P. Y. S.; Deudon, S.; Averill, K. M.; Li, R. H.; He,
M. Y.; Deshong, P.; Clark, C. G. J. Am. Chem. Soc. 2000,
122, 7600.
(4) (a) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett 2001, 3, 4315. (b) Klapars, A.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 7421. (c) Klapars, A.;
Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727. (d) Antilla, J. C.; Klapars, A.; Buchwald,
S. L. J. Am. Chem. Soc. 2002, 124, 11684. (e) Klapars, A.;
Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am. Chem.
Soc. 2004, 126, 3529. (f) Antilla, J. C.; Baskin, J. M.;
Baarder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5579. (g) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.;
(9) Davis, R. J. J. Catal. 2003, 216, 396.
(10) Catalyst preparation: Cu(II)-NaY zeolite was prepared by
ion-exchange of zeolite NaY (10 g) with a solution of
copper(II) acetate (2.86 g, 15.75 mmol in deionized water
(150 mL) at r.t. for 24 h. The material was recovered by
filtration, dried (110 °C) and calcined (550 °C) in a flow of
air. AAS analysis showed that the zeolite contained 6.84
wt% of Cu.
(11) Typical Experimental Procedure: A mixture of 4-bromo-
toluene (1 mmol), imidazole (1.2 mmol), K2CO3 (2 mmol)
and Cu(II)-NaY (100 mg) in DMF (3 mL) was heated to
120 °C for the specified time (Table 2). The progress of the
reaction was monitored by GC or TLC. The reaction mixture
was filtered to separate the catalyst and the filtrate was
quenched with aq NaHCO3 and the product extracted with
EtOAc. The combined organic layers were washed with
brine, dried over Na2SO4 and concentrated. The residue was
purified by column chromatography to afford pure 1-(4-
methylphenyl)-1H-imidazole.
Synlett 2006, No. 14, 2195–2198 © Thieme Stuttgart · New York

2198
M. L. Kantam et al.
LETTER
1-(4-Methylphenyl)-1H-imidazole (Table 2, entry 7). 1H
NMR (CDCl3): d = 7.76 (br s, 1 H), 7.24 (br s, 4 H), 7.19 (br
s, 1 H), 7.13 (br s, 1 H), 2.39 (s, 3 H); MS (EI): m/z (%) =
158, 131, 104, 91 (100) 50; Anal. Calcd for C10N2H10: C,
75.95; N, 17.72; H, 6.33. Found: C, 76.09; N, 17.75; H, 6.16.
1-(4-Nitrophenyl)-1H-imidazole (Table 2, entry 1): mp
203 °C; 1H NMR (CDCl3): d = 8.37 (d, J = 9.0 Hz, 2 H),
7.93 (br s, 1 H), 7.58 (d, J = 9.0 Hz, 2 H), 7.32 (br s, 1 H),
7.24 (br s, 1 H); MS (EI): m/z (%) = 189 (100), 159, 141, 116,
89, 50; Anal. Calcd for C9N3O2H7: C, 57.14; N, 22.2; H, 3.7;
Found C, 57.42; N, 22.59; H, 3.19.
All products are reported compounds and have been
identified by 1H NMR and mass spectrometric data.5
Synlett 2006, No. 14, 2195–2198 © Thieme Stuttgart · New York