N-arylation of N-H heterocycles with aryl bromides and aryl iodides using CuI and KF/Al2O3

Article abstract of DOI:10.1002/jhet.5570450640

(Chemical Equation Presented) Copper-catalyzed system for N-arylation of N-H group in heterocycles such as indole, pyrrole and carbazole with aryl iodides and aryl bromides using potassium fluoride supported on alumina as a base is described. This is a simple and efficient method for the coupling of aryl iodides and bromides with N-H heterocycles. Different functionalized iodo and bromo arenes were coupled with N-H heterocycles using this system.

Full text of DOI:10.1002/jhet.5570450640

Nov-Dec 2008
1815
N-Arylation of N-H Heterocycles with Aryl Bromides and Aryl
Iodides Using CuI and KF/Al2O3
Rahman Hosseinzadeh,a*, Mahmood Tajbakhsha Mohammad Alikaramia,c
,
Maryam Mohadjeranib
a
Faculty of Chemistry, Department of Organic Chemistry, Mazandaran University, Babolsar, Iran,
Faculty of Basic Science, Department of Biology, Mazandaran University, Babolsar, Iran
b
c
Islamic Azad University, Ilam, Iran
r.hosseinzadeh@umz.ac.ir
Received June 12, 2007
R
R
10 mol% CuI, KF/Al2O3, 110 o
10 mol% 1,10-phenanthroline
C
X
Het-NH
+
N-Het
X= I, Br; R= CH3, OCH3, NO2
Het-NH= indole, pyrrole, carbazole
Copper-catalyzed system for N-arylation of N-H group in heterocycles such as indole, pyrrole and
carbazole with aryl iodides and aryl bromides using potassium fluoride supported on alumina as a base is
described. This is a simple and efficient method for the coupling of aryl iodides and bromides with N-H
heterocycles. Different functionalized iodo and bromo arenes were coupled with N-H heterocycles using
this system.
J. Heterocyclic Chem., 45, 1815 (2008).
Scheme1
INTRODUCTION
R
Copper-catalyzed Ullmann-type coupling of aryl
halides with N-H heterocycles is a traditional choice for
preparing N-arylpyrroles, N-arylindoles, N-arylimidazoles
and N-arylpyrazoles which are important compounds for
both pharmaceutical and material sciences [1-3]. For a
long time, these reactions had been carried out at high
temperatures, and many functional groups could not be
tolerated. Therefore, their usage was greatly limited. In
addition, these reactions often require the use of
stoichiometric amount of copper reagents, long reaction
time, which on scale leads to problems of waste disposal
[4,5]. Another limitation is that, to date, no single method
has found success with each of the major classes of N-H
heterocycles (imidazoles, pyrroles, pyrazoles, etc.).
Moreover, several palladium-catalyzed C-N formation
methods discovered so far upon using some sterically
hindered phosphine ligands, allowed many coupling
reactions of aryl halides with N-containing compounds to
proceed under relatively mild conditions and low
temperature [6,7]. Palladium catalyzed cross-coupling of
N-H heterocycles with aryl halides has been moderately
successful, but limitations in terms of generality,
sensitivity of palladium to air and moisture, as well as the
higher costs have lessened the utility of this method [8,9].
Buchwald et al. and other groups reported the copper-
based protocol for N-arylation using cesium carbonate,
potassium phosphate, potassium carbonate, etc. as a base
in this method [4b,c,6c,8,10-13]. In our procedure we
have used potassium fluoride supported on alumina as a
base for N-arylation of indole, pyrrole and carbazole with
aryl bromides and iodides (Scheme 1).
N
N
N
HN
R
10 mol% CuI, KF/Al2O3, 110 °C
10 mol% 1,10-Phenanthroline
X
R
R
+
N
H
X= I, Br
R= CH3, OMe, NO2
N
H
The application of potassium fluoride supported on
alumina to organic synthesis has provided new methods
for a wide array of organic reactions, many of which are
staples of synthetic organic chemistry [14]. Its benefits
have been achieved by taking advantages of the strongly
basic nature of potassium fluoride supported on alumina
which has allowed it to replace organic bases in a number
of reactions [15]. In many cases, the use of this base
afforded milder conditions and simpler procedures than
previously reported methods.
RESULTS AND DISCUSSION
The reaction conditions were optimized using the cross-
coupling reaction of iodobenzene and indole in the
presence of 1,10-phenanthroline, potassium fluoride
supported on alumina and copper iodide in toluene as
solvent at 110 ˚C. The yield of N-phenylindole after 7
houre was 90%.
1,10-Phenanthroline as ligand and potassium fluoride
supported on alumina as base in the presence of copper

1816
R. Hosseinzadeh,, M. Tajbakhsh, M. Alikarami and, M. Mohadjerani
Vol 45
iodide were chosen as we have recently used this system
for C-N and C-O bond formation in arylation of amides,
alcohols, phenols and diazoles [16].
Using the above protocol, we subjected a series of aryl
bromides and aryl iodides to these reaction conditions
(Table 1).
Table 1
The copper-catalyzed N-arylation of N-H heterocyles in the presence of potassium fluoride supported on alumina
Entry
Aryl halide
Heterocycle
Product [a]
Time (h)
Mp(ºC)
Yield (%) [b]
Found (Reported)
N
I
Br
I
1
2
3
8
9
58-60(62)[4b]
58-60(62)[4b]
85
81
N
H
N
N
H
N
7
8
Liquid[4b]
Liquid[4b]
90
86
N
H
Br
N
4
5
N
H
I
N
H
N
7
8
87-89(89-90)[19a]
86-89(89-90)[19a]
90
84
Br
6
N
H
N
N
OMe
MeO
MeO
MeO
I
7
8
9
9
10
8
108-110(112-113) [19b]
85
80
89
N
H
Br
N
OMe
108-110(112-113)
[19b]
N
H
I
151-153(155-156)
[ 8]
N
H
N
OMe
MeO
Br
10
11
10
151-153(155-156)
[8]
83
87
N
H
N
OMe
57-59(59.5-60.5)
[18]
MeO
I
N
OMe
8
N
H

Nov-Dec 2008
N-Arylation of N-H Heterocycles with Aryl Bromides and Aryl Iodides
1817
Table 1 (continued)
Entry
Aryl halide
Heterocycle
Product [a]
Time (h)
Mp(ºC)
Yield (%) [b]
Found (Reported)
MeO
Br
N
OMe
12
9
57-59(59.5-60.5)
[18]
84
78
N
H
OMe
I
MeO
N
13
14
11
12
Liquid[19c]
N
H
OMe
Br
MeO
N
Liquid[19c]
73
N
H
H3C
I
N
CH3
N
H
15
8
7
81-83(81.5-83)[18]
Liquid[18]
84
89
H3C
I
N
CH3
16
N
H
CH3
I
H3C
N
17
18
9
Liquid[19c]
Liquid[19c]
81
N
H
CH3
Br
H3C
N
N
H
10
8
76
94
O2N
I
N
NO2
19
129-131(131-132)
[19d]
N
H
O2N
Br
N
NO2
20
9
7
129-131(131-132)
[19d]
89
91
N
H
Br
N
21
Liquid[7d]
N
N
N
H
a] Reaction was performed using 10 mol% of 1,10-phenanthroline as ligand, 1.0 equivalent of aryl halides, 2 equivalent of heterocycle and 5 equivalent
1
of potassium fluoride supported on alumina as base in toluene as solvent at 110 ˚C .[b] Isolated yields; products were characterized by H NMR and
from mps.
As can be seen in Table 1, indole, pyrrole and carbazole
were successfully transformed to the corresponding N-aryl
compounds. The reactions between pyrrole and iodo- and
bromobenzenes under optimum reaction conditions gave
excellent yields of the corresponding N-aryl compounds
(entries 1, 2). Under similar reaction conditions indole and
carbazole reacted with iodo- and bromobenzenes to give
high yields of the N-phenylindole and N-phenylcarbazole,
respectively (entries 3-6). Aryl halides possessing electron-
releasing groups such as methoxy (entries 7-14), and methyl
(entries 15-18) in the ortho- and para-positions of the
aromatic ring also gave good to excellent yields of the
corresponding N-aryl compounds. Aryl halides with
electron-withdrawing groups such as NO2 in para-position
on the reaction with indole also gave a satisfactory yields of
the corresponding N-aryl compound (entries 19, 20). 3-
Bromopyridine reacted with indole to give a high yield of
the N-(pyridin-3-yl) compound (entry 21).

1818
R. Hosseinzadeh,, M. Tajbakhsh, M. Alikarami and, M. Mohadjerani
Vol 45
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In summary, we have developed an experimentally
simple, efficient and inexpensive catalyst system for the
N-arylation of N-H heterocycles. With this protocol both
of bromo- and iodo arenes coupled with indole, pyrrole
and carbazole successfully. We believe that potassium
fluoride supported on alumina provides an excellent
complement to other bases such as cesium carbonate, in
copper-catalyzed coupling reactions which have already
been utilized in a number of applications.
EXPERIMENTAL
General procedure. To a solution of heterocyclic compounds
(2 mmol) and aryl bromides or iodides (1 mmol) in toluene (5 mL)
under an argon atmosphere were added copper iodide (19 mg, 10
mol%) and 1,10-phenanthroline (20 mg, 10 mol%) and then by
potassium fluoride supported on alumina [17] (5 equivalents, 780
mg). The reaction mixture was stirred at 110 ˚C for the specified
time (Table 1). The progress of the reaction was monitored by thin
layer chromatography. The reaction mixture was allowed to cool to
room temperature, filtered and was then partitioned between
dichloromethane (30 mL) and saturated aqueous ammonium
chloride solution (3ꢀ10 mL). The organic fraction was washed with
water (3ꢀ10 mL), dried (sodium sulfate), filtered and concentrated.
The crude product was purified by column chromatography on
silica gel using hexane : ethyl acetate (9:1) as eluent to afford the
pure product. The spectroscopic data for the known products was
identical with the reported data and melting points.
N-phenyl indole (Table1, Entry 4). An oily liquid; [1H nmr
(deuteriochloroform), 500 MHz): ꢀ 7.66 (br d, J= 7.3 Hz, 1H),
7.53 (br d, J= 8.1 Hz, 1H), 7.43-7.40 (m, 4H), 7.27-7.24 (m,
2H), 7.20-7.12 (m, 2H), 6.63 (d, J= 3.2 Hz, 1H).
9-(4-methoxy phenyl) carbazole (Table1, Entry 9). A white
solid; mp 151–153 °C (Lit.[8] 155-156 °C); [ 1H nmr
(deuteriochloroform), 500 MHz): ꢀ 8.14 (d, J= 7.7 Hz, 2H),
7.46-7.43 (m, 2H), 7.41-7.37 (m, 2H), 7.32 (d, J= 8.1 Hz, 2H),
7.28-7.24 (m, 2H), 7.12-7.08 (m, 2H), 3.91(s, 3H).
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Tetrahedron Lett. 2006, 47, 3897. [c] Kang, S.; Lee, S.; Lee, D. Synlet,
2000, 1022.
N-(4-methyl phenyl) pyrrole (Table1, Entry 15). A solid,
1
mp 81–83 °C (Lit.[18] 81.5-83 °C); [ H nmr (deuteriochloro-
form), 90 MHz) ꢀ 7.30 (s, 4H), 7.05 (pseudo t, 2H), 6.36
(pseudo t, 2H), 2.40 (s, 3H).
N-(4-methyl phenyl) indole (Table1, Entry 16). A liquid;
[1H nmr (deuteriochloroform), 500 MHz): ꢀ 7.67 (br d, J= 7.8
Hz, 1H), 7.51 (d, J= 8.2 Hz, 1H), 7.32 (d, J= 8.2 Hz, 2H), 7.24
(d, J= 3.2 Hz, 1H), 7.23-7.14 (m, 4H), 6.64 (d, J= 3.2 Hz, 1H),
2.43 (s, 3H).
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Kabalka, G. W.; Wang, L.; Namboodiri, V.; Pagni, R. M. Tetrahedron
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[16a] Hosseinzadeh, R.; Tajbakhsh, M.; Mohadjerani, M.;
Mehdinejad, H. Synlett, 2004, 1517. [b] Hosseinzadeh, R.; Tajbakhsh,
M.; Mohadjerani, M.; Alikarami, M. Synlett, 2005, 1101. [c]
Hosseinzadeh, R.; Tajbakhsh, M.; Alikarami, M. Tetrahdron Lett. 2006,
47, 5203. (d) Hosseinzadeh, R.; Tajbakhsh, M.; Alikarami, M. Synlett,
2006, 2124.
1
N-(3-pyridyl) indole (Table1, Entry 21). yellow oil, [ H
nmr (deuteriochloroform), 90 MHz): ꢀ 8.82 (m, 1H), 8.57 (m,
1H), 7.88-7.12 (m, 7H), 6.72 (d, 1H).
Acknowledgement. Financial support of this work from the
Research Council of Mazandaran University is gratefully
acknowledged.
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