Copper-catalyzed N-arylation of amines with part-per-million catalyst loadings under air at room temperature

Article abstract of DOI:10.1039/c1cc13516c

An efficient copper-catalyzed method for N-arylation of amines has been developed with part-per-million catalyst loadings at room temperature under air. Reactions of substituted (E)-1-(2-halophenyl)alkanone oximes with aliphatic amines or aromatic amines

Full text of DOI:10.1039/c1cc13516c

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COMMUNICATION
Copper-catalyzed N-arylation of amines with part-per-million catalyst
loadings under air at room temperaturew
Ruilong Xie,ab Hua Fu*a and Yun Ling*b
Received 14th June 2011, Accepted 21st June 2011
DOI: 10.1039/c1cc13516c
An efficient copper-catalyzed method for N-arylation of amines
has been developed with part-per-million catalyst loadings at room
temperature under air. Reactions of substituted (E)-1-(2-halophenyl)-
alkanone oximes with aliphatic amines or aromatic amines provided
the N-arylation products in good to excellent yields.
developed, in which N,N0-dimethylenediamine (DMEDA)
acted as an efficient ligand. Herein, we report an efficient
copper-catalyzed N-arylation of amines with part-per-million
catalyst loadings under air at room temperature.
Coupling of (E)-1-(2-bromophenyl)ethanone oxime (1a) with
aniline wasused as the model reactiontoscreen reaction conditions
including optimization of the catalysts, ligands, solvents, and bases
under air (without extrusion of air). As shown in Table 1, several
solvents (entries 1–7) were tested using 0.008 mol% CuCl2 as the
catalyst, 20 mol% DMEDA as the ligand, 2 equiv. of K2CO3
(relative to the amount of 3a) as the base (here, we used highly pure
K2CO3 (99.997% purity) from Alfa Aesar company9 in order to
avoid the involvement of other metals in the reaction) at room
temperature (ca. 25 1C) under air (without extrusion of air), and
cyclohexane providedthe highestyield (entry 4). Further, we found
that the mixed solvent, cyclohexane/ethanol (9 : 1), was suitable for
the N-arylation (entry 8). Other copper salts were determined
(entries 9–13), and CuCl2 showed the highest efficiency (entry 8).
We investigated other bases (entries 14–17), and K2CO3 provided
the highest yield (compare entries 8 and 14–17). Some common
ligands were screened (entries 18–23), and DMEDA gave the best
result (compare entries 8 and 18–23). In the absence of a copper
catalyst (entry 24) or ligand (entry 25), only a small amount of the
product was observed. When the amount of DMEDA was
changed (entries 26 and 27), 10 mol% DMEDA (entry 26)
provided the same yield as entry 8. We attempted the N-arylation
under a nitrogen atmosphere, and an 88% yield was obtained
(entry 28). The result indicated that oxygen in air did not affect this
coupling reaction.
For over a century, N-arylation of amines has attracted wide
attention because arylamines are ubiquitous in various fields,
such as pharmaceuticals,1a agrochemicals,1b photography,1c
xeroxography,1d pigments1e and electronic materials.1f The
copper-catalyzed Ullmann and Goldberg-type N-arylations2
are traditional methods to assemble these compounds. For a
long time, harsh reaction conditions (such as high reaction
temperatures), stoichiometric amounts of copper reagents and low
toleration of functional groups prevented further development
of these methods. Since 1990s, the mild and highly efficient
palladium-catalyzed N-arylations of amines have made signifi-
cant achievements.3 Recently, there has been great progress on
the modified copper-catalyzed Ullmann-type N-arylation of
amines,4 and some methods under mild conditions, even at
room temperature,5 have been developed under the catalysis of
a specific copper-ligand catalyst system. However, high catalyst
loadings (5 to 20 mol% copper salts) were often required
because of both limited TONs (turnover numbers) as well as
TOFs (turnover frequencies) of the copper-catalysts, and the
scope of substrates was limited for copper-catalyzed N-arylation
at room temperature, only aryl iodides and aliphatic amines
were effective in most cases.5 In addition, extrusion of air
was necessary in order to prevent oxidation of the catalysts in
the previous copper or palladium-catalyzed N-arylations.3,4
Recently, Buchwald and Bolm reported iron/copper-co-catalyzed
N-arylation with minute quantities of copper salts,6 and several
copper-catalyzed cross-coupling reactions with sub-mol%7 or
part-per-million (ppm)-leveled8 copper catalysts have been
We investigated the dependence of the yield of 3a on the
amount of CuCl2 using 10 mol% N,N0-dimethylenediamine
(DMEDA) as the ligand, 99.997% K2CO3 as the base, cyclo-
hexane/ethanol (9 : 1) as the solvent at room temperature.
Catalyst loadings in the range of 0–0.02 mol% were tested,
and the presence of 0.008 mol% CuCl2 provided the highest
isolated yield (90%) as shown in Fig. 1.
a Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical
Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. China.
As shown in Table 2, the N-arylation scope from reactions of
substituted (E)-1-(2-halophenyl)alkanone oximes with amines was
investigated under the optimized conditions (using 0.008 mol%
CuCl2 as the catalyst, 10 mol% N,N0-dimethylenediamine
(DMEDA) as the ligand, 99.997% K2CO3 as the base, cyclohexane/
ethanol (9 : 1) as the solvent at room temperature under air), and
the examined substrates provided good to excellent yields. For
substituted (E)-1-(2-halophenyl)alkanone oximes, aryl bromides
E-mail: fuhua@mail.tsinghua.edu.cn
b Key Laboratory of Pesticide Chemistry and Application (Ministry of
Agriculture), Department of Applied Chemistry, College of Science,
China Agricultural University, Beijing100193, P. R. China.
E-mail: lyun@cau.edu.cn
w Electronic supplementary information (ESI) available: General
procedure for synthesis, characterization data, and 1H and 13C
NMR spectra of compounds 3a–b0. See DOI: 10.1039/c1cc13516c
c
8976 Chem. Commun., 2011, 47, 8976–8978
This journal is The Royal Society of Chemistry 2011

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Table
1
Copper-catalyzed coupling of (E)-1-(2-bromophenyl)-
Table 2 Copper-catalyzed N-arylation of aminesa
ethanone oxime (1a) with aniline (2a) leading to (E)-1-(2-(phenylamino)-
phenyl)ethanone oxime (3a): optimization of conditionsa
3 (X, Yield)b
Entry Cat.
Ligand/mol% Baseb
Solvent Yieldc/%
1
2
3
4
5
6
7
8
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
K2CO3 DMF
Trace
K2CO3 DMSO Trace
K2CO3 Hexane 74
K2CO3 CH
K2CO3 Toluene 41
K2CO3 THF
K2CO3 ET
87
48
60
K2CO3 CH/ETd 90
K2CO3 CH/ET 87
K2CO3 CH/ET 88
K2CO3 CH/ET 87
K2CO3 CH/ET 32
K2CO3 CH/ET 83
Na2CO3 CH/ET Trace
Cs2CO3 CH/ET 19
K3PO4 CH/ET 85
9
CuSO4ꢀ5H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Cu(OAc)2ꢀH2O A (20)
CuBr2
CuBr
CuI
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
A (20)
B (20)
C (20)
D (20)
E (20)
F (20)
G (20)
A (20)
—
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
CuCl2
—
KOBut CH/ET
4
K2CO3 CH/ET Trace
K2CO3 CH/ET 19
K2CO3 CH/ET Trace
K2CO3 CH/ET 21
K2CO3 CH/ET
K2CO3 CH/ET Trace
K2CO3 CH/ET
K2CO3 CH/ET 18
K2CO3 CH/ET 90
K2CO3 CH/ET 81
K2CO3 CH/ET 88e
5
4
CuCl2
CuCl2
CuCl2
CuCl2
A (10)
A (5)
A (10)
a
Reaction conditions: under air, (E)-1-(2-bromophenyl)ethanone oxime
(1a) (0.25 mmol), aniline (2a) (0.50 mmol), catalyst (2.0 ꢁ 10ꢂ5 mmol), base
b
(0.50 mmol), solvent (2.0 mL) at room temperature (ca. 25 1C). 99.997%
K2CO3 from Alfa Aesar Company. Isolated yield. CH = cyclohexane,
e
ET =ethanol, CH/ET (volumeratio 9 : 1). Under a nitrogen atmosphere.
c
d
Fig. 1 Yield of compound 3a versus catalyst loading (expressed in
mol% of CuCl2).
almost showed similar reactivity to aryl iodides. In general, no
significant difference in reactivity was observed for the examined
substituted (E)-1-(2-halophenyl)alkanone oximes with varied
electronic properties, including electron-rich, electron-poor and
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 8976–8978 8977

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Table 2 (continued )
3 (X, Yield)b
catalyzed N-arylation of amines with part-per-million catalyst
loadings at room temperature thus far.
This research was supported by the National Natural Science
Foundation of China (Grant No. 20972083), the Ministry of
Science and Technology of China (2009ZX09501-004) (financial
support), the National Key Project for Basic Research
(2010CB126104), and the National Scientific and Technology
Supporting Program of China (2011BAE06B05).
Notes and references
a
Reaction conditions: under air (1 amt.), CuCl2 (2.0 ꢁ 10ꢂ5 mmol),
N,N0-methylenediamine (0.025 mmol), 1 (0.25 mmol), 2 (0. 50 mmol),
99.997% K2CO3 from Alfa Aesar Company (0.50 mmol for free amines;
1.0 mmol for amine hydrochlorides), cyclohexane (1.8 mL), ethanol
(0.2 mL), reaction time (24 h) at room temperature (ca. 25 1C).
1 (a) M. Negwer, Organic-Chemical Drugs and Their Synonyms: An
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C. K. Hsiao and P. M. Kazmaier, Photogr. Sci. Eng., 1983, 27, 5;
(d) L. B. Schein, Electrophotography and Development Physics, Springer-
Verlag, Berlin, 2nd edn, 1992; (e) Pigment Handbook, ed. P. A. Lewis,
John Wiley & Sons, New York, 1988, vol. I; (f) G. D’Aprano,
M. Leclerc, G. Zotti and G. Schiavon, Chem. Mater., 1995, 7, 33.
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40, 1433; (d) I. Goldberg, Ber. Dtsch. Chem. Ges., 1906, 39, 1691.
3 For reviews on Pd-catalyzed N-arylations, see: (a) J. F. Hartwig,
Angew. Chem., Int. Ed., 1998, 37, 2046; (b) J. P. Wolfe, S. Wagaw,
J.-F. Marcoux and S. L. Buchwald, Acc. Chem. Res., 1998, 31, 805;
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(d) B. H. Yang and S. L. Buchwald, J. Organomet. Chem., 1999,
576, 125; (e) J. F. Hartwig, Acc. Chem. Res., 1998, 31, 852.
4 For recent reviews on Cu-catalyzed N-arylations, see: (a) J. S. Sawyer,
Tetrahedron, 2000, 56, 5045; (b) K. Kunz, U. Scholz and D. Ganzer,
Synlett, 2003, 2428; (c) S. V. Ley and A. W. Thomas, Angew. Chem.,
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Chem. Res., 2008, 41, 1450; (g) F. Monnier and M. Taillefer, Angew.
Chem., Int. Ed., 2009, 48, 6954; (h) H. Rao and H. Fu, Synlett, 2011,
745 and references cited therein; for selected papers, see:
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Chem. Soc., 2001, 123, 7727; (j) A. Klapars, X. H. Huang and
S. L. Buchwald, J. Am. Chem. Soc., 2002, 124, 7421;
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b
c
d
Isolated yield. Using ethanol as the solvent. Reaction time (48 h).
neutral groups. Among amines, aromatic amines displayed higher
reactivity than aliphatic amines, and aromatic amines containing
electron-donating groups afforded higher yields than ones containing
withdrawing groups. The reactions could tolerate various func-
tional groups including oxime, ether group (3e, 3z, 3a0 and 3b0),
carbon-halo bonds (3f–g, 3p–u and 3b0), and hydroxyl (3o) in the
substrates. Inspiringly, the N-arylations above were smoothly
performed at room temperature, including both aliphatic and
aromatic amines. The room temperature copper-catalyzed N-
arylation of arylamines still is rare thus far. In addition, the
coupling reactions did not need extrusion of air.
We investigated intramolecular cyclization of the synthesized
compound 3a as shown in Scheme 1 according to the previous
procedure,10 and the corresponding N-aryl-1H-indazole (4) and
benzimidazole (5) were selectively prepared through change of
the bases in the presence of methanesulfonyl chloride (MsCl). The
result showed that our approach to compounds 3 was very useful.
In summary, we have developed copper-catalyzed N-arylation
of amines with part-per-million catalyst loadings at room
temperature. The protocol uses CuCl2 as the catalyst, N,N0-
dimethylenediamine as the ligand, K2CO3 as the base, and
cyclohexane/ethanol mixed solvent as the medium, and the
corresponding N-arylation products were obtained in good to
excellent yields. The method did not need extrusion of air, and
the coupling reaction could tolerate various functional groups.
The synthesized target products as the materials could trans-
form into the corresponding phenyl-1H-indazoles and
benzo[d]imidazoles. This is the first example for copper-
5 (a) A. Shafir and S. L. Buchwald, J. Am. Chem. Soc., 2006,
128, 8742; (b) D. Wang and K. Ding, Chem. Commun., 2009,
1891; (c) C.-T. Yang, Y. Fu, Y.-B. Huang, J. Yi, Q.-X. Guo and
L. Liu, Angew. Chem., Int. Ed., 2009, 48, 7398; (d) C.-Z. Tao,
W.-W. Liu, J.-Y. Sun, Z.-L. Cao, H. Li and Y.-F. Zhang, Synth-
esis, 2010, 1280; (e) D. Wand and K. Ding, Chem. Commun., 2009,
1891; (f) D. Jiang, H. Fu, Y. Jiang and Y. Zhao, J. Org. Chem.,
2007, 72, 672; (g) Q. Jiang, D. Jiang, Y. Jiang, H. Fu and Y. Zhao,
Synlett, 2007, 1836; (h) L. Zeng, H. Fu, R. Qiao, Y. Jiang and
Y. Zhao, Adv. Synth. Catal., 2009, 351, 1671; (i) X. Liu, H. Fu,
Y. Jiang and Y. Zhao, Angew. Chem., Int. Ed., 2009, 48, 348.
6 S. L. Buchwald and C. Bolm, Angew. Chem., Int. Ed., 2009, 48, 5586.
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(b) P.-F. Larsson, C. Bolm and P.-O. Norrby, Chem.–Eur. J.,
2010, 16, 13613.
8 P.-F. Larsson, A. Correa, M. Carril, P.-O. Norrby and C. Bolm,
Angew. Chem., Int. Ed., 2009, 48, 5691.
9 K2CO3 (99.997%), Mg (2 ppm), Na (8 ppm), other elements
including Al, Sb, As, Ba, Bi, B, Cd, Ca, Cr, Co, Cu, In, Fe, Pb,
Li, Mn, Mo, Ni, P, Si, Te, Sn, Ti, V, Zn, Zr (sought but not
detected; the data were provided by Alfa Aesar company).
10 B. C. Wray and J. P. Stambuli, Org. Lett., 2010, 12, 4576.
Scheme 1 Intramolecular cyclization of the synthesized compound
3a to form 3-methyl-1-phenyl-1H-indazole (4) (a) and 2-methyl-1-
phenyl-1H-benzo[d]imidazole (5) (b) in the presence of methanesulfonyl
chloride (MsCl) and 2-aminopyridine or triethylamine.
c
8978 Chem. Commun., 2011, 47, 8976–8978
This journal is The Royal Society of Chemistry 2011