Iron-catalyzed N-arylation of nitrogen nucleophiles

DOI: 10.1002/anie.200703299

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Angewandte Chemie - International Edition p. 8862 - 8865 (2007)

Update date:2022-08-03

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Correa, Arkaitz

Bolm, Carsten

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Article abstract of DOI:10.1002/anie.200703299

(Chemical Equation Presented) Easy does it! A simple procedure for the N-arylation of nitrogen-containing heterocycles and primary amides relies on a catalyst formed in situ from inexpensive and environmentally benign FeCl ₃ and a diamine ligand. The cross-coupling reaction with aryl halides provides N-arylated compounds in high yields (see scheme; R = H, Cl, Me, OMe, CO₂Et, F, CF₃).

Full text of DOI:10.1002/anie.200703299

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

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

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]

none

l-proline

l-alaninol

trans-1,2-diaminocyclohexane

dmeda

tmeda

rac-binap

Recently, Taillefer et al. reported efficient Fe/Cu cooper-

ative catalysis in the assembly of N-aryl heterocycles by C N

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

[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)₂and 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). FeCl₃was 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

under http://www.angewandte.org or from the author.

8862

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 8862 –8865

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Angewandte

Chemie

Table 2: Screening of iron sources for the N-arylation of pyrazole (2).

Table 3: FeCl₃/dmeda-catalyzed N-arylation of pyrazole (2) with aryl

iodides and bromides.

Entry

Fe source (10 mol%)

none

Method^[a]

Yield [%]^[b]

Entry ArX

Product

Yield [%]^[a]

FeCl₂·4H₂O

Fe(ClO₄)₂

[Fe(acac)₂]

Fe(oxalate)₂·2H₂O

Fe₂O₃

[Fe(acac)₃]

FeCl₃

B^[c]

B^[d]

3 f

[a] Method A: 1 (1.5 equiv), 2 (1.0 equiv), dmeda (20 mol%), K₃PO₄

(2.0 equiv), DMF, 1108C; method B: as for method A but with toluene

instead of DMF at 1358C. [b] Yield of the isolated product after flash

chromatography. [c] FeCl₃: 5 mol%; dmeda: 10 mol%. [d] FeCl₃:

20 mol%; dmeda: 30 mol%. acac=acetylacetonate.

conditions for the iron-catalyzed N-arylation involved a

combination of FeCl₃(10 mol%), dmeda (20 mol%), K₃PO₄

(2 equiv), and toluene at 1358C (Table 2, entry 9).^[13]Fur-

thermore, it is noteworthy that the cross-coupling process

proved to be tolerant to water, as evidenced by the fact that

product 3a was obtained in a remarkable 70% yield when the

reaction was carried out in a mixture of toluene and water

(1:1).

Encouraged by these results, we next investigated the

scope of the process with respect to the aryl halide substrate.

We tested a variety of substituted aryl iodides and bromides

under the optimized reaction conditions with pyrazole (2) as

the nucleophilic counterpart. In general, aryl iodides were

more reactive than aryl bromides and gave the corresponding

N-arylated products in higher yields (up to 87%). With

neither substrate type were side products observed. Further-

more, the coupling proceeded selectively at the carbon atom

with the iodo substituent when chloro or fluoro substituents

were also present (Table 3, entries 3, 5, 8, and 9). Ortho

substituents hampered the reaction and led to the formation

of the products in lower yields (Table 3, entries 2 and 3).

Other heterocycles, such as indole (Table 4, entry 1) and

7-azaindole, (Table 4, entries 2 and 3) were found to be

effective N-nucleophiles. The corresponding N-phenyl deriv-

atives 4 and 5a,b were formed in good yields (up to 84%) in

the cross-coupling of aryl iodides with indole and 7-azaindole,

respectively. Furthermore, both cyclic and acyclic amide

derivatives (Table 4, entries 4–6 and 7–9, respectively) under-

went the desired reaction to furnish the coupling products

[a] Yield of the isolated product after flash chromatography.

6a–c and 7a–c in moderate to high yields (up to 97%).

Unfortunately, aromatic and alkyl amines proved to be

unsuitable substrates and only trace amounts of the desired

products were detected when the reaction was carried out

under the standard conditions (Table 4, entries 10 and 11).

In summary, we have developed a novel and promising

ligand-assisted iron-catalyzed N-arylation of nitrogen nucle-

ophiles with differently substituted aryl iodides and bromides.

The catalyst system consists of a mixture of the inexpensive

and environmentally benign compound FeCl₃and dmeda.

This research has established a useful starting point for

investigating future applications of iron-catalyzed N-arylation

reactions, the efficiency and scope of which are the focus of

continuing studies by our research group.

Angew. Chem. Int. Ed. 2007, 46, 8862 –8865

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

8863

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Communications

¹³C NMR spectroscopic analysis. See the

Supporting Information for full details.

Table 4: FeCl₃/dmeda-catalyzed N-arylation of (aza)indole, pyrrolidin-2-one, and benzamide with aryl

iodides.

Received: July 23, 2007

Published online: October 17, 2007

Keywords: arylation ·cross-coupling·

diamine ligands · iron catalysis ·

nitrogen heterocycles

Entry

NuH

ArI

Product

Yield [%]^[a]

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[2] For reviews, see: a) K. Kunz, U.

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trace

BnNH₂

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[a] Yield of the isolated product after flash chromatography.

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Angew. Chem. 2005 , 117 , 1682; Angew. Chem. Int. Ed. 2005 , 44 ,

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Egami, T. Katsuki, J. Am. Chem. Soc. 2007 , 129 , 8940.

Experimental Section

Typical procedure: 1H-Pyrazole (2; 300 mg, 4.32 mmol), FeCl₃

(70 mg, 0.432 mmol), and K₃PO₄(1.83 g, 8.64 mmol) were placed in

an oven-dried tube, and phenyl iodide (1; 0.73 mL, 6.48 mmol) and

dmeda (84 mL, 0.864 mmol) were added under an argon atmosphere,

followed by dry toluene (4 mL). The tube was sealed under argon, and

the mixture was heated to 1358C and stirred at this temperature for

24 h. The heterogeneous mixture was then cooled to room temper-

ature and diluted with dichloromethane. The resulting solution was

filtered directly through a pad of silica gel and concentrated to yield

the product, which was purified by chromatography on silica gel

(pentane/ethyl acetate 1:1) to yield 3a (500 mg, 80%) as a yellowish

[6] For selected iron-catalyzed reactions reported by our research

group, see: a) J. Legros, C. Bolm, Angew. Chem. 2003 , 115 , 5645;

oil. The identity and purity of the product was confirmed by H and

8864 www.angewandte.org

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Angew. Chem. Int. Ed. 2007, 46, 8862 –8865

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&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Take advantage of blue reference links

&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&

Angewandte

Chemie

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Angew. Chem. 2004 , 116 , 4321; Angew. Chem. Int. Ed. 2004 , 43 ,

4225; c) J. Legros, C. Bolm, Chem. Eur. J. 2005 , 11 , 1086; d) O. G.

Mancheæo, C. Bolm, Org. Lett. 2006, 8, 2349; e) M. Nakanishi, C.

Bolm, Adv. Synth. Catal. 2007 , 349 , 861.

M. K. Tse, M. Beller, Angew. Chem. 2007 , 119 , 7431; Angew.

Chem. Int. Ed. 2007 , 46 , 7293.

[10] Product 3a was not detected in the absence of a ligand even

when a stoichiometric amount of Fe₂O₃was used.

[11] The use of other iron sources, such as Fe(ClO₄)₃, Fe(OTf)₂, or

FeCl₂, led to only trace amounts of N-phenyl pyrazole (3a).

[12] An increase in the temperature from 110 to 1358C in method A

resulted in lower yields of 3a than those observed with

method B.

[7] M. Taillefer, N. Xia, A. Oualli, Angew. Chem. 2007 , 119 , 952;

Angew. Chem. Int. Ed. 2007 , 46 , 934.

[8] V. H. Jadhav, D. K. Dumbre, V. B. Phapale, H. B. Borate, R. D.

Wakharkar, Catal. Commun. 2007 , 8 , 65.

[9] For an Fe-catalyzed asymmetric epoxidation of aromatic alkenes

[13] When other bases (NaOtBu, Cs₂CO₃, K₂CO₃) were used, or

when dioxane was used as the solvent, the N-phenyl derivative

was obtained in lower yields. All the experiments were carried

out with anhydrous FeCl₃(purity > 98%) provided by Merck.

in which

a related catalyst system formed by combining

FeCl₃·6H₂O, a chiral diamine, and pyridine-2,6-dicarboxylic

acid was used, see: F. G. Gelalcha, B. Bitterlich, G. Anilkumar,

Angew. Chem. Int. Ed. 2007, 46, 8862 –8865

ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

www.angewandte.org

8865

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Article Doi

Iron-catalyzed N-arylation of nitrogen nucleophiles

DOI: 10.1002/anie.200703299

Source and publish data:

Authors:

Article abstract of DOI:10.1002/anie.200703299

Full text of DOI:10.1002/anie.200703299

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