COMMUNICATION
DOI: 10.1002/chem.200800293
Iron-Catalyzed N-Arylations of Amides
[
a]
Arkaitz Correa, Simon Elmore, and Carsten Bolm*
Transition metal-catalyzed N-arylation of amides consti-
tutes a powerful CÀN bond-forming process that has been
in moderate to excellent yields (43–96%; Table 1). Screen-
ing studies revealed that the choice of the base and the sol-
vent played a determining role. Thus, in most cases the use
of K CO led to higher yields than K PO or NaOtBu, and
extensively utilized in pharmaceutical and medicinal chemis-
[
1]
[2]
try. Despite remarkable advances in both palladium- and
2
3
3
4
[3]
copper-catalyzed reactions of this type, the development
of alternative catalysts involving more cost-efficient, non-
toxic, and environmentally friendly metals to effect the
target process remains an issue of scientific interest and
the employment of toluene as solvent at 1358C proved to be
crucial for the success of the reaction. Benzamides bearing
electron-donating substituents (entries 3 and 4, Table 1) af-
forded better results than those having electron-withdrawing
groups (entry 2, Table 1). Also aliphatic amides provided
the arylated products in moderate to good yields (entries 6–
8, Table 1), with the exception of formamide (entry 5,
Table 1), which was almost unreactive. Gratifyingly, impor-
tant heterocyclic amides such as those bearing pyridinyl
(entry 9, Table 1) and thiophenyl (entry 10, Table 1) moiet-
ies underwent coupling reactions providing the products in
moderate to good yields under standard conditions. Con-
versely, secondary amides such as N-methylbenzamide and
N-benzylbenzamide gave the corresponding N-arylated
products in only trace amounts.
paramount industrial significance. In this respect, iron poses
A
C
H
T
R
E
U
N
G
as an ideal metal that offers significant advantages consider-
ing its low cost, ready availability, and environmentally
[4]
benign character.
Although iron-catalyzed CÀC cross-coupling reactions
[5]
have attracted particular attention, the application of iron
salts for the challenging carbon–heteroatom bond formation
has remained largely undeveloped. Only recently, we found
highly practical iron catalysts for the formation of CÀN, CÀ
[6]
O, and CÀS linkages by means of arylation of nitrogen,
[7]
[8]
oxygen, and sulfur nucleophiles, respectively, with aryl
halides. In connection with this work, we present herein a
versatile, convenient, and experimentally simple iron-cata-
lyzed N-arylation of primary amides (including aromatic,
heterocyclic, and aliphatic substrates) and demonstrate its
applicability to the synthesis of valuable N-heterocycles by
intramolecular ring closures.
To determine the applicability of the iron-catalyzed N-
arylation with respect to the aryl halides, the substrate scope
[a]
Table 1. Fe-catalyzed N-arylation of amides (1) with phenyl iodide (2).
The key components for the presented catalyst system
were 10 mol% of easy-to-handle FeCl and 20 mol% of in-
3
expensive N,N’-dimethylethylenediamine (DMEDA). In our
[6]
[b]
initial studies, we obtained promising results in conver-
sions of amides, which encouraged us to investigate the
scope of this synthetically valuable transformation. The cou-
plings of differently substituted primary amides with phenyl
iodide under the previously optimized conditions proceeded
Entry
R
Yield of 3 [%]
[
[
[
[
c]
1
2
3
4
5
6
7
8
9
Ph
3aa
3ba
3ca
3da
3e
3 fa
3ga
3ha
3ia
3ja
78
d]
d]
d]
4-Cl-Ph
3-Me-Ph
4-MeO-Ph
H
Me
Et
65
96
73
traces
[
[
[
[
[
d]
c]
c]
d]
d]
43
63
78
45
85
Pr
[
a] Dr. A. Correa, S. Elmore, Prof. Dr. C. Bolm
Institut für Organische Chemie der RWTH Aachen
Landoltweg 1, 52056 Aachen (Germany)
Fax : (+49)241-809-2391
3-Pyridinyl
2-Thiophenyl
1
0
[
3
a] Reaction conditions: 1 (1.0 equiv), 2 (1.5 equiv), FeCl (0.1 equiv),
DMEDA (0.2 equiv), base (2.0 equiv), toluene (1 mL per mmol of 1),
1358C, 24 h. [b] Yield of isolated product after flash chromatography.
E-mail: carsten.bolm@oc.rwth-aachen.de
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
3 4 2 3
[c] Use of K PO as base. [d] Use of K CO as base.
Chem. Eur. J. 2008, 14, 3527 – 3529
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3527