Efficient copper-catalyzed N-arylation of amides and imidazoles with aryl iodides

Article abstract of DOI:10.1055/s-0029-1218643

The C-N cross-coupling of amides and imidazoles with aryl iodides is described using CuI in tetrabutylammonium bromide (TBAB) under ligand-free conditions. The reaction is simple, general, and efficient affording the C-N cross-coupled products in shorter time and in high yield. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0029-1218643

9
08
SHORT PAPER
Efficient Copper-Catalyzed N-Arylation of Amides and Imidazoles with Aryl
Iodides
C
M
opper-CatalyzedN-A
d
r
ylation of
A
.
mides and
I
A
midazoles shif Ali, Prasenjit Saha, Tharmalingam Punniyamurthy*
Department of Chemistry, Indian Institute of Technology, Guwahati 781039, India
Fax +91(361)2690762; E-mail: tpunni@iitg.ernet.in
Received 22 October 2009
and C–S cross-coupling reactions in the presence of tran-
sition metal salts. Since TBAB is cheap and readily avail-
able, we became further interested to investigate its
Abstract: The C–N cross-coupling of amides and imidazoles with
aryl iodides is described using CuI in tetrabutylammonium bromide
(TBAB) under ligand-free conditions. The reaction is simple, gen-
eral, and efficient affording the C–N cross-coupled products in application in organic synthesis. Herein, we report the C–
shorter time and in high yield.
N cross-coupling of amides and imidazoles with aryl ha-
lides using CuI in TBAB under air. The procedure is gen-
eral, simple, and efficient to avail the cross-coupled
products under ligand-free conditions. Substrates having
either an electron-withdrawing or an electron-donating
group are compatible with this protocol to afford the C–N
cross-coupled products in shorter time in high yield.
Key words: N-arylation, amides, imidazoles, copper iodide, TBAB
N-Arylamides and N-arylimidazoles are prevalent in nu-
merous compounds that are of biological, material, and
pharmaceutical interest (Figure 1). The common classi-
1
cal methods used for their preparation, however, require First, the reaction condition was optimized studying the
high temperature (>150 °C) and stoichiometric amount of coupling of benzamide with aryl iodide as the model sub-
copper that, on scale-up, leads to the problem of waste dis- strate. The reaction occurred to afford the C–N cross-
2
3
posal. To overcome these limitations, palladium, cop- coupled N-phenylbenzamide in 75% yield when the sub-
4
5
per, and iron based catalytic systems have been recently strates were stirred at 110 °C for five hours using 5 mol%
studied for the cross-coupling of aryl halides with amides CuI and two equivalents of KOH in TBAB under air
and imidazoles. These studies usually involve homoge- (Table 1). Bases such as Cs CO and K CO were inferior
2
3
2
3
neous processes and the ligands bound with the metals to KOH providing the cross-coupled product in 18% and
play a crucial role in the catalysis.
12% yield, respectively. The reaction using CuI was more
effective in comparison with CuCl ·2H O, CuSO ·5H O,
2
2
4
2
Cu(OAc) ·H O and CuO nanoparticle. Of the aryl halides,
N
2
2
HN
N
N
Table 1 Optimization of the Reaction Conditionsa,b
O
X
O
copper source (5 mol%)
TBAB, base, 110 °C
Ph
HN
O
N
+
N
H
Ph
Ph
NH2
Me
N
O
N
H
Entry Catalyst
X
I
Base
Time (h) Yield (%)
N
N
Imatinib
F
H
1
2
3
4
5
6
7
8
CuI
KOH
5
7
75
18
12
50
n.r.c
57
61
52
48
anticancer drug
O
N
CuI
I
Cs CO
2
3
H
Sunitinib
receptor tyrosine kinase (RTK) inhibitor
CuI
I
K CO
9
2
3
CuI
Br
Cl
I
KOH
25
12
6
Figure 1 Examples of biologically active molecules
CuI
KOH
KOH
KOH
KOH
KOH
The use of molten salt for organic reactions has been ac-
tive in recent years due to their excellent thermal stability
and low vapor pressure. In addition, the reactions in mol-
ten salts provide the advantages of high reactivity and
simplified product isolation. More recently, tetrabutylam-
monium bromide (TBAB) has been found to be an effec-
CuCl ·2H O
2
2
6
CuSO ·5H O
I
6
4
2
Cu(OAc) ·H O
I
6
2
2
9
CuO nano
I
6
7
8
tive reaction medium as well as an additive for the C–C
a
Reaction conditions: catalyst (5 mol%), benzamide (1.1 mmol), aryl
halide (1 mmol), and base (2 mmol) were stirred at 110 °C in TBAB
(2 mmol).
SYNTHESIS 2010, No. 6, pp 0908–0910
x
x
.
x
x
.2
0
1
0
b
Advanced online publication: 08.01.2010
DOI: 10.1055/s-0029-1218643; Art ID: P14609SS
Georg Thieme Verlag Stuttgart · New York
Isolated yield.
c
n.r. = no reaction.
©

SHORT PAPER
Copper-Catalyzed N-Arylation of Amides and Imidazoles
909
aryl iodide exhibited greater reactivity. The reaction with could be cross-coupled with aryl iodide having 2-OMe, 4-
aryl bromide required longer time to give the cross-cou- OMe, 4-Me, and 2,4-(Me) substituents in 55–95% yields.
2
pled product in 50% yield. In contrast, chlorobenzene Similarly, 2-methylimidazole and benzimidazole under-
showed no reaction. Similarly, the control experiment went reactions with aryl iodide in 78% and 72% yield, re-
without either CuI or KOH exhibited no reaction.
spectively. The reactions required shorter time (4–8 h)
and the cross-coupled products were obtained in high
yield. Substituted aryl iodides as well as substituted
amides and imidazoles were compatible with the proce-
dure. These results clearly suggest that the reaction is gen-
eral and can be used for the cross-coupling of amides and
imidazoles with aryl iodides.
Next, the scope of the procedure with respect to other sub-
strates was studied (Table 2). Benzamide could be cross-
coupled with aryl iodide having 2-OMe, 4-Br, 4-OMe, 4-
Me, and 2,4-(Me) substituents in 72–91% yields. Simi-
2
larly, the reactions of benzamide having 3-Br, 3-NO , 4-
2
OMe, 4-Me, and 4-NO substituents were investigated
2
with aryl iodide. As above, the reactions occurred effi-
ciently to give the corresponding cross-coupled products
in 58–79% yields. Aliphatic amides, acetamide, hexan-
amide, and 2-oxazolidinone could be cross-coupled with
aryl iodide in 75–87% yields. A similar result was ob-
tained with (E)-cinnamamide and aryl iodide.
Table 3 Reaction of Imidazoles with Aryl Iodidesa,b
I
CuI (5 mol%)
N
N
NH
+
N
R1
R1
TBAB, KOH
110 °C, 4–8 h
R2
R2
Entry
Imidazole (R1) Iodobenzene (R2) Time (h) Yield (%)
Table 2 Reaction of Amides with Aryl Iodidesa,b
1
2
3
4
5
6
7
H
H
6
8
6
8
4
7
7
85
55
93
70
95
65
78
I
O
CuI (5 mol%)
O
H
2-MeO
4-MeO
4-Me
R2
+
TBAB, KOH
110 °C, 4–8 h
R1
R1
NH2
N
H
R2
H
H
Entry Amide
Iodobenzene Time
Yield
2
(
R )
(h)
5
8
5
6
5
6
6
7
5
4
6
4
4
5
(%)
75
72
76
82
75
91
69
63
76
79
58
87
75
52
H
4-O N
2
1
2
3
4
5
6
7
8
9
0
1
2
3
4
PhCONH2
H
H
2,4-(Me)2
H
PhCONH2
PhCONH2
PhCONH2
PhCONH2
2-MeO
4-Br
2-Me
4-MeO
4-Me
8
H
6
72
N
NH
PhCONH2
2,4-(Me)2
a
Reaction conditions: CuI (5 mol%), imidazole (1.1 mmol), aryl ha-
lide (1 mmol), and KOH (2 mmol) were stirred at 110 °C in TBAB (2
mmol).
3-BrC H CONH
2
H
6
4
b
Isolated yield.
3-O NC H CONH
2
H
H
H
H
H
H
H
2
6
4
4-MeC H CONH
2
6
4
In summary, we have developed a simple and facile meth-
od for the C–N cross-coupling of amides and imidazoles
with aryl iodides using CuI in TBAB under ligand-free
conditions. The reactions are efficient affording the cross-
coupled products in shorter time with high yield.
1
1
1
1
1
4-MeOC H CONH
6 4 2
4-O NC H CONH
2
2
6
4
MeCONH2
n-C H CONH
2
5
11
(E)-PhCH=CHCONH2
C–N Cross-Coupling Reactions; General Procedure
An oven-dried round-bottomed flask was charged with the amide or
imidazole (1.1 mmol), CuI (5 mol%), KOH (2.0 mmol), aryl halide
O
1
5
H
4
85
(1.0 mmol), and TBAB (2.0 mmol) and the contents were stirred at
O
NH
1
10 °C for the appropriate time (Tables 2, 3). The reaction progress
was monitored by TLC using EtOAc and hexane (30:70 for amides;
80:20 for imidazoles) as eluent. The reaction mixture was then
cooled to r.t. and diluted with EtOAc (10 mL). The resulting solu-
a
Reaction conditions: CuI (5 mol%), amide (1.1 mmol), aryl iodide
1 mmol), and KOH (2 mmol) were stirred at 110 °C in TBAB (2
(
mmol).
Isolated yield.
tion was washed with brine (2 mL) and H O (2 × 2 mL). Drying
2
b
(Na SO ) and evaporation of the solvent gave a residue, which was
2
4
purified by column chromatography on silica gel (230–400 mesh)
using EtOAc and hexane (30:70 for amides; 80:20 for imidazoles)
These reaction conditions are also suitable for cross-cou- as eluent to yield the C–N cross-coupled products (Tables 2, 3).
1
13
pling of imidazoles with aryl iodides (Table 3). Imidazole Their identity and purity were confirmed by H and C NMR spec-
troscopic analyses.
Synthesis 2010, No. 6, 908–910 © Thieme Stuttgart · New York

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Md. A. Ali et al.
SHORT PAPER
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
This work was supported by Department of Science and Technolo-
gy, New Delhi and Council of Scientific and Industrial Research,
New Delhi.
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Synthesis 2010, No. 6, 908–910 © Thieme Stuttgart · New York