Ligand-free copper-catalyzed amination of heteroaryl halides with alkyl- and arylamines

Article abstract of DOI:10.1002/adsc.201000708

N-Heteroarylations of alkyl- and arylamines with various heteroaryl halides have been achieved by ligand-free copper-catalyzed cross-couplings affording aminopyridines and aminopyrimidines in moderate to high yields (up to 99% yield). Copyright

Full text of DOI:10.1002/adsc.201000708

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DOI: 10.1002/adsc.201000708
Ligand-Free Copper-Catalyzed Amination of Heteroaryl Halides
with Alkyl- and Arylamines
Zhen-Jiang Liu,a Jean-Pierre Vors,b Ernst R. F. Gesing,c,* and Carsten Bolma,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52056 Aachen, Germany
Fax : (+49)-241-809-2391; phone: (+49)-241-809-4675; e-mail: Carsten.Bolm@oc.rwth-aachen.de
Bayer CropScience SAS, Centre de Recherche de La Dagoire, 14 Impasse Pierre Baizet, BP99163, 69009 Lyon, France
Bayer CropScience AG, BCS-R-I-CI, Building 6550, Alfred-Nobel-Strasse 50, 40789 Monheim am Rhein, Germany
b
c
Fax : (+49)-2173-38-3671; phone: (+49)-2173-38-3987; e-mail: ernst-rudolf.gesing@bayer.com
Received: September 15, 2010; Published online: December 1, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000708.
Abstract: N-Heteroarylations of alkyl- and aryl-
amines with various heteroaryl halides have been
and general copper catalyst systems for efficiently
promoting N-heteroarylations of alkyl- and aryl-
N
achieved by ligand-free copper-catalyzed cross-cou-
plings affording aminopyridines and aminopyrimi-
dines in moderate to high yields (up to 99% yield).
ACHTUNGTRENaNGNU mines is highly desirable. Recently, we described mi-
crowave-accelerated copper-catalyzed aminations of
halopyridines with various nitrogen nucleophiles
under solvent- and ligand-free conditions.[7] To our
disappointment, however, alkyl- and arylamines did
not react. In continuation of those studies and in the
Keywords: aminopyridines; aminopyrimidines;
copper; N-heteroarylation; ligand-free conditions
context of our general search for simple and environ-
[8]
À
mentally friendly catalysts for C X couplings, we
have now discovered a reaction variant that overcame
this problem. Hence, the previously unreactive alkyl-
Heteroaromatic compounds are ubiquitous in natural and arylamines can now be applied,[9] and the use of
products and biologically active molecules.[1] Among ligand-free copper catalysts allows N-heteroarylations
them, aminopyridines and aminopyrimidines are of providing coupling products in moderate to high
great interest in the fine chemical industry owing to yields.
their importance as intermediates for pharmaceuti-
ACHTUNGTRENNUNG
While searching for an efficient ligand for the pro-
cals,[2a–e] agrochemicals[2f,g] and materials.[2h–j] Tradi- motion of the copper-catalyzed coupling between 3-
tional preparations of such compounds involve nucle- iodopyridine (1a) with benzylamine (2a), we were sur-
ophilic aromatic substitutions of pyridine or pyrimi- prised to find that the reaction proceeded well in the
dine halides, but those methods suffer from a limited absence of a ligand affording the corresponding cou-
substrate scope due to the requirement of activated pling product 3a in 74% yield (Scheme 1).[10]
À
substrates or harsh reaction conditions.[3] C N cross-
Hence, we turned our attention to the coupling of
coupling reactions catalyzed by palladium and copper less reactive and economically more attractive hetero-
complexes offer an alternative approach to such com- aryl bromides. Unfortunately, the coupling of 3-bro-
pounds. Significant progress has been achieved in pal- mopyridine (1b) with benzylamine (2a) gave only
ladium-catalyzed N-heteroarylations of alkyl- and trace amounts of 3a when the reaction was carried
arylamines,[4] but their industrial applications are out under the same reaction conditions as before
often problematic due to the high costs of the palladi- (10 mol% of CuI and 2 equiv. of Cs2CO3, 1008C,
um catalysts and the requirement of air- and mois-
ture-sensitive phosphine ligands. In recent years,
copper-catalyzed Ullmann-type reactions have
emerged as alternatives.[5] Many efficient copper/
ligand combinations have been developed that allow
one to perform these reactions under comparatively
mild conditions. However, cross-couplings between
heteroaryl halides and alkyl- or arylamines have re-
Scheme 1. Ligand-free copper-catalyzed amination of 3-io-
mained challenging,[6] and the development of simple dopyridine (1a) with benzylamine (2a).
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Adv. Synth. Catal. 2010, 352, 3158 – 3162

Ligand-Free Copper-Catalyzed Amination of Heteroaryl Halides
Table 1. Optimization of the copper-catalyzed coupling reaction of 3-bromopyridine (1b) with benzylamine (2a).
Entry
[Cu]
Base
Temperature [oC]
Yield [%][a]
1
2
3
4
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuBr
CuCl
CuOAc
Cu2O
Cs2CO3
Cs2CO3
K3PO4
100
120
100
100
100
100
90
80
100
90
90
90
90
90
90
90
90
90
traces
11
4
12
>95
97
>95
85
67
35
33
47
92
90
> 95
93
95
95
90
70
K2CO3
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
LiOAc
NaOAc
KOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
5
6[b]
7
8
9[c]
10
11
12
13
14[d]
15
16
17
18
19
20
21
22
Cu
N
CuCl2
CuSO4·5H2O
CuO
Cu
–
90
90
90
90
98
traces
[a]
Referring to the amount of product isolated by chromatography.
Under air.
Use of DMF as the solvent instead of DMSO.
Use of 99.995% of CuCl.
[b]
[c]
[d]
Table 1, entry 1). At an elevated temperature an 11% (Table 1, entries 7 and 13–21). Copper powder was
yield of 3a was obtained (Table 1, entry 2). The choice chosen for further investigations as it is economically
of base has often been found to be critical in arylami- most attractive. A blank experiment confirmed that in
nation reactions. Subsequently, the commonly used the absence of the copper catalyst no coupling prod-
À
bases for C N couplings, such as K3PO4 and K2CO3, uct was formed (Table 1, entry 22). Hence, the opti-
were examined, but lower yields were observed in all mal reaction conditions for the ligand-free N-hetero-
cases (Table 1, entries 3 and 4). Surprisingly, when arylation of benzylamine (2a) with 3-bromopyridine
CsOAc[11] was used as the base to promote this trans- (1b) involved the use of 10 mol% of copper powder
formation, a quantitative yield was obtained (Table 1, and 2 equivalents of CsOAc in DMSO at 908C
entry 5). It is noteworthy that the cross-coupling pro- (Table 1, entry 21).
cess proved to be insensitive to oxygen, as evidenced
Encouraged by the efficiency of the new cross-cou-
by the fact that the coupling product was also ob- pling protocol, the substrate scope was investigated
tained in nearly quantitative yield when the reaction next. As shown in Table 2, all couplings proceeded
was carried out in air (Table 1, entry 6). Even when smoothly and moderate to high yields were obtained.
the reaction temperature was lowered to 908C, a high Unbranched aliphatic primary amines proved to be
yield of 3a was obtained (Table 1, entry 7). DMSO excellent substrates for the coupling with 3-bromopyr-
proved to be superior to alternative solvents (Table 1, idine (1b), providing the corresponding amination
entries 5, 6 and 9). Other acetate salts, such as products in high yields (Table 2, entries 1–3). The cou-
LiOAc, NaOAc and KOAc, furnished the coupling pling reactions of sterically hindered a-branched pri-
product in lower yields ranging from 33–47% mary amines, such as cyclohexylamine, isopropyl-
(Table 1, entries 10–12). All the copper sources tested,
ACHTUNGTRENaNUNG mine and 1-phenylethylamine, occurred in good
including Cu(I), Cu(II) and Cu(0), catalyzed the cou- yields as well (entries 4, 6 and 7), although a higher
pling reaction, affording 3a in good to excellent yields temperature was required for 1-phenylethylamine
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Zhen-Jiang Liu et al.
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Table 2. Ligand-free Cu-catalyzed amination of 3-bromo-
ACHTUNGTRENNUNGpyridine (1b).
benzylamine as model substrate. The results are sum-
marized in Table 3. Both pyridine iodides and bro-
mides, as well as pyrimidine bromides, irrespective of
the leaving group in the position of the heteroaromat-
ic ring, afforded the corresponding coupling product
in excellent yields (92–99%, Table 3, entries 1 and 2, 5
and 6, 9 and 10, 13 and 15). 3-Chloropyridine and 3-
fluoropyridine showed very low reactivity, and the
coupling reactions gave less than 10% yield even at
higher temperature (entries 3 and 4). The couplings of
benzylamine with 4-fluoropyridine hydrochloride and
2-fluoropyridine furnished the products in moderate
yields (entries 8 and 12), and probably those reactions
involved an SNAr mechanism. Although low yields
were obtained in couplings of 4-chloropyridine hydro-
chloride (entry 7) and 2-chloropyridine (entry 11), an
almost quantitative yield was observed in the coupling
with 2-chloropyrimidine (entry 14). Furthermore, 3-
bromothiophene also coupled well with 2a affording
the coupling product in a moderate yield (entry 16).
Use of 2-bromothiophene as the coupling partner was
unsuccessful (entry 17).
In summary, we have developed a simple and versa-
tile, ligand-free copper-catalyzed coupling protocol
Table 3. Ligand-free Cu-catalyzed N-heteroarylations of
benzylamine (2a) with various heteroaryl halides.
[a]
Referring to the amount of product isolated by chroma-
tography.
Use of 3.0 equiv. of amine and CuI instead of Cu.
Use of 5.0 equiv. of amine.
[b]
[c]
[d]
Reaction performed at 1108C.
(entry 7). When cyclopropylamine was used as the
coupling partner, only a moderate yield was obtained,
presumably due to the lability of both cyclopropyl-
amine and the coupling product (entry 5).[12] Further-
more, cyclic and acyclic aliphatic secondary amines,
aniline and pyrazole could be coupled with 3-bromo-
pyridine, affording the corresponding products in
moderate yields (entries 8–11).
To further evaluate the scope of the process with
respect to the heteroaryl halides, a variety of hetero-
aryl iodides, bromides, chlorides and fluorides were
tested under the optimized reaction conditions using
[a]
Referring to the amount of product isolated by chroma-
tography.
Reaction performed at 1208C.
Starting from the hydrochloride of the halopyridine.
[b]
[c]
[d]
Reaction performed at 1108C.
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Ligand-Free Copper-Catalyzed Amination of Heteroaryl Halides
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ides. The procedure is insensitive to air and moisture,
which makes it more attractive for an industrial appli-
cation than the related Pd-catalyzed reactions. The
method described here also complements our previ-
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scope. Further studies to find more efficient catalyst
systems and to continue expanding the substrate
scope are currently in progress in our laboratories.
Experimental Section
General Procedure for N-Heteroarylations of Nitro-
gen Nucleophiles [Example: Synthesis of N-Benzyl-
pyridin-3-amine (3a)]
After cooling of an oven-dried tube to room temperature
under argon, it was charged with copper powder (3.3 mg,
0.05 mmol) and CsOAc (196 mg, 1.0 mmol). 3-Bromopyri-
dine (1b, 50 mL, 0.5 mmol) and benzylamine (2a, 84 mL,
0.75 mmol) were added followed by dry DMSO (0.5 mL).
The tube was sealed and the mixture was heated to 908C.
After stirring at this temperature for 24 h, the heterogene-
ous mixture was cooled to room temperature and diluted
with ethyl acetate (10 mL). The resulting solution was fil-
tered through a pad of silica gel and concentrated to give
the crude product. Purification by silica gel chromatography
(1:1 pentane/ethyl acetate) gave N-benzylpyridin-3-amine
(3a) as a white solid; yield: 91 mg (98%). The identity and
purity of the product was confirmed by 1H and 13C NMR
spectroscopic analysis. See the Supporting Information for
full details.
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Acknowledgements
ZJL thanks Bayer CropScience for postdoctoral funding.
Furthermore, we are grateful to the Fonds der Chemischen
Industrie for financial support.
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