Communications
DOI: 10.1002/anie.200703299
Cross-Coupling
Iron-Catalyzed N-Arylation of Nitrogen Nucleophiles**
Arkaitz Correa and Carsten Bolm*
Transition-metal-catalyzed cross-coupling reactions for the
formation of carbon–carbon and carbon–heteroatom bonds
form the basis of essential and powerful strategies for the
preparation of important compounds in biological, pharma-
For initial optimization of the reaction conditions and the
identification of the best iron source, ligand, base, and solvent,
iodobenzene (1) and 1H-pyrazole (2) were chosen as model
substrates. We tested amino acids, amino alcohols, 1,2-
diamines, and phosphines as ligands in the presence of
Fe2O3 (10 mol%) in DMF at 1108C and found, to our delight,
that the cross-coupling reaction was possible and provided the
desired product 3a in low but promising yields, when either l-
proline (Table 1, entry 2) or diamine ligands (Table 1,
entries 4 and 5) were employed. Control experiments con-
firmed that in the absence of either the ligand or the iron
oxide no product was obtained.[10] As dmeda proved to be the
most effective ligand, further experiments were focused on its
use as an iron chelator.
ceutical, and materials sciences.[1] Among C Nbond-forming
À
processes, the N-arylation of nitrogen-containing heterocycles
is of particular interest, as the resulting products contain
important structural motifs of numerous natural products and
biologically active compounds. Despite the significant prog-
ress made in the development of palladium- and copper-
catalyzed coupling reactions of this type,[2] there is still a need
for new methods that involve cheap and environmentally
friendly catalysts.
Since the pioneering work of Tamura and Kochi,[3] iron
salts have emerged as alternative and promising catalysts for
À
many organic transformations, in particular for C C bond-
Table 1: Screening of ligands for the N-arylation of pyrazole (2).
forming reactions.[4–6] These methods are distinguished by the
low cost, readily availability, and environmentally benign
character of the iron salts used, in combination with the
exceptionally high reaction rates observed and mild reaction
conditions. Encouraged by these results, we envisaged the
application of iron catalysts in the N-arylation of nitrogen
nucleophiles with aryl halides.
Entry
Ligand[a]
Yield [%][b]
1
2
3
4
5
6
7
none
l-proline
l-alaninol
trans-1,2-diaminocyclohexane
dmeda
tmeda
rac-binap
0
35
0
31
52
Recently, Taillefer et al. reported efficient Fe/Cu cooper-
ative catalysis in the assembly of N-aryl heterocycles by C N
À
bond formation,[7] and Wakharkar and co-workers described
the N-arylation of various amines with aryl halides in the
presence of Cu–Fe hydrotalcite.[8] Although these results are
encouraging, a major drawback is the required presence of
copper salts. Furthermore, a very high catalyst loading
(30 mol% of [Fe(acac)3] and 10 mol% of CuO) proved
essential in the former procedure. Herein, we report the first
genuinely iron-catalyzed N-arylation of N-nucleophiles in
which simple aryl halides are used as electrophilic coupling
partners. The catalyst system, which is obtained by combining
readily available iron salts with chelating diamine deriva-
tives,[9] is widely applicable and promotes the N-arylation of
both primary amides and a variety of N-heterocycles, such as
pyrazole, pyrrolidin-2-one, indole, and 7-azaindole.
trace
0
[a] dmeda=N,N’-dimethylethylenediamine, tmeda=N,N,N’,N’-tetra-
methylethylenediamine, binap=2,2’-bis(diphenylphosphanyl)-1,1’-
binaphthyl. [b] Yield of the isolated product after flash chromatography.
DMF=N,N-dimethylformamide.
By screening a wide range of iron sources, we found that
the N-arylated product 3a could be obtained in yields ranging
from 14 to 85% with dmeda and a catalytic amount of an iron
salt (10 mol%) in any oxidation state (0, II, or III; Table 2).[11]
The outcome of the reaction was dependent on the nature of
the solvent and on the temperature. Thus, much better results
were obtained when the reaction was carried out in toluene at
1358C (Table 2, method B) than with DMF at 1108C (Table 2,
method A).[12] Among the iron sources, Fe(ClO4)2 and FeCl3
led to the best catalysts and afforded in both cases coupling
product 3a in 80% yield (Table 2, entries 4 and 9, respec-
tively). FeCl3 was chosen for further investigations as it is less
expensive and easier to handle than Fe(ClO4)2. With respect
to the catalyst loading, 10 mol% of the iron salt was found to
be optimal. When only 5 mol% of the iron salt were used, 3a
was formed in lower yield (56%, Table 2, entry 10), and no
significant improvement was observed with 20 mol% of the
iron salt (85%, Table 2, entry 11). In summary, the optimal
[*] Dr. A. Correa, Prof. Dr. C. Bolm
Institut für Organische Chemie
Rheinisch-Westfälische Technische Hochschule Aachen
Landoltweg 1, 52056 Aachen (Germany)
Fax: (+49)241-809-2391
E-mail: carsten.bolm@oc.rwth-aachen.de
[**] We are grateful for financial support from the Fonds der Chem-
ischen Industrie. A.C. thanks the Basque Government for support
through the “Programa de Perfeccionamiento de Doctores en el
extranjero del Departamento de Educación, Universidades e
Investigación”.
Supporting information for this article is available on the WWW
8862
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8862 –8865
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Correa, Arkaitz
