LETTER
1517
Copper-Catalyzed Amidation of Aryl Iodides Using KF/Al2O3: An Improved
Protocol
C
opper-Catalyzed
a
A
midatio
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n of
A
ryl Iodmides using KF/A 3
l
O
2 an Hosseinzadeh,* Mahmood Tajbakhsh,* Maryam Mohadjerani, Hamidreza Mehdinejad
Faculty of Basic Science, Mazandaran University, Babolsar, Iran
Fax +98(11252)42002; E-mail: r.hosseinzadeh@umz.ac.ir
Received 4 February 2004
We have explored the CuI-catalyzed N-arylation of aryl
iodides with amides using 1,10-phenanthroline (10 mol%)
as a simple ligand and KF/Al2O3 as a suitable base in the
presence of CuI (10 mol%) (Scheme 1). To find optimum
Abstract: A mild method for the copper-catalyzed amidation of
aryl iodides is reported. This simple C-N bond forming procedure
shows that the combination of air stable CuI and 1,10-phenanthro-
line in the presence of KF/Al2O3 comprises an extremely efficient
and general catalyst system for the N-amidation of aryl iodides. Dif- conditions a series of experiments has been performed
ferent functionalized aryl iodides were efficiently coupled with
amides using this method.
with iodobenzene and benzamide as model compounds,
which are summarized in Table 1.
Key words: amidation, aryl iodides, copper iodide, potassium
fluoride on alumina, coupling reaction
During the past few years significant advances have oc-
curred in the development of cross-coupling methodolo-
gy. The formation of carbon-nitrogen bonds via cross-
coupling reactions represents a powerful means for the
preparation of numerous products important in pharma-
ceutical and material science.1 Recently Buchwald,2a–c
Hartwig2d,e and others2f have developed a valuable and
new palladium-catalyzed for C-N bond-forming process,
which has supplanted the classical Ullmann coupling
reaction (copper-catalyzed N-arylation of amines)3 and
the related Goldberg coupling reaction (copper-catalyzed
N-arylation of amides).4 However, despite significant
improvements in these methods, some limitations still re-
main. For example, the amidation of electron-rich ortho-
substituted electronically neutral aryl halides is difficult.5
Additionally, Pd-based methods can often be relatively
sensitive to moisture.6 Moreover, the high cost of palladi-
um and removal of palladium residues from polar reaction
products, particularly in the late stage of the synthesis of
a pharmaceutical substance, can be challenging.7 Recent-
ly, Buchwald, et al.8 reported a copper catalyst system for
the amidation of aryl halides. Their method requires a di-
amine, such as N,N¢-dimethylethylenediamine as a ligand,
and Cs2CO3 as a base in a sealed tube.
Scheme 1
Of the ligands tested 1,10-phenanthroline, N,N¢-dimethyl-
ethylenediamine, and ethylenediamine, 1,10-phenanthro-
line was the best choice (Table 1, entries 1, 6 and 7).
Amidation of the aryl iodides proceeds best with KF/
Al2O3 as the base, the reaction being much slower if
K3PO4 or K2CO3 is used instead. As a solvent toluene was
better than other solvents.
The N-arylation of aryl iodides with amides was very sen-
sitive to the substrates and the results are summarized in
Table 2. Iodobenzene reacted with benzamide using CuI
(10 mol%), 1,10-phenanthroline (10 mol%) as a ligand in
toluene under reflux for 1.5 hours in the presence of KF/
Al2O3 to afford the N-arylation product in >99% yield
(Table 2, entry 1). Similarly with other amides such as
acetamide, acetanilide and d-valerolactam under the same
conditions the corresponding N-substituted amides were
obtained in 95–100% yields (Table 2, entries 2–4). p-Io-
doanisole with benzamide after 3.5 hours gave the cou-
pling product in >99% yield (Table 2, entry 5). With
acetamide and acetanilide as the amides the correspond-
ing N-arylated amides afforded in 90–95% yield after
longer reaction times (Table 2, entries 6 and 7). When o-
iodoanisole was employed as a substrate for N-arylation
the corresponding benzamide and acetamide were ob-
tained in 95% yield (Table 2, entries 8 and 9). However
with acetanilide as amide, coupling occurred in only 67%
yield, probably due to steric effects (Table 2, entry 10).
Benzamide, acetamide and acetanilide were coupled with
p-iodotoluene and afforded the N-arylation products in
90–95% yields (Table 2, entries 11–13). Similarly, o-io-
dotoluene coupled with benzamide and acetamide to give
92–100% yields (Table 2, entries 14 and 15). Under
similar reaction conditions, again probably due to steric
The application of KF/Al2O3 to organic synthesis has pro-
vided new methods for a wide array of organic reactions,
many of which are staples of synthetic organic chemistry.9
Its benefits have been achieved by taking advantage of the
strongly basic nature of KF/Al2O3 which has allowed it to
replace organic bases in a number of reactions.10 In many
cases, the use of this base provides milder conditions and
simpler procedures than previously reported methods.
SYNLETT 2004, No. 9, pp 1517–1520
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Advanced online publication: 29.06.2004
DOI: 10.1055/s-2004-829099; Art ID: D02704ST
© Georg Thieme Verlag Stuttgart · New York