Optimization of the conditions for copper-mediated N-arylation of heteroarylamines

Article abstract of DOI:10.1002/ejoc.200700577

Simple and inexpensive copper-mediated N-arylation of heteroarylamines was achieved by using N,N′-dimethylethylenediamine as a ligand and K ₂CO₃ as a base in dioxane heated at 100°C. In this coupling reaction, the influence of the copper species, ligand, base and solvent was investigated in detail. N-Arylated derivatives of several heteroarylamines were synthesized under optimized reaction conditions, and all the products were isolated in good yields. By controlling the amount of CuI/DMEDA added, heteroarylamines with weak nucleophilic activity were coupled with aryl iodides or aryl bromides. The activity of the copper catalyst for this C-N bond-forming reaction follows the order Cu^I > Cu⁰ > Cu ^II. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700577

FULL PAPER
DOI: 10.1002/ejoc.200700577
Optimization of the Conditions for Copper-Mediated N-Arylation of
Heteroarylamines
Yifeng Liu,*[a] Yajun Bai,[a] Juan Zhang,[a] Yangyang Li,[b] Junping Jiao,[a] and Xiaoli Qi[a]
Keywords: Amines / Aryl halides / Arylation / Copper
Simple and inexpensive copper-mediated N-arylation of
heteroarylamines was achieved by using N,NЈ-dimethyl-
ethylenediamine as a ligand and K2CO3 as a base in dioxane
heated at 100 °C. In this coupling reaction, the influence of
the copper species, ligand, base and solvent was investigated
in detail. N-Arylated derivatives of several heteroarylamines
were synthesized under optimized reaction conditions, and
all the products were isolated in good yields. By controlling
the amount of CuI/DMEDA added, heteroarylamines with
weak nucleophilic activity were coupled with aryl iodides or
aryl bromides. The activity of the copper catalyst for this C–
N bond-forming reaction follows the order CuI ϾCu0 ϾCuII.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
As well as being important synthetic intermediates, N-
arylheteroarylamines serve as the pharmacophore in many
natural and synthetic biologically active compounds, such
as STI571 (Imatinib or Gleevec),[1] BMS354825 (Dasati-
nib),[2] RO438596,[3] GW3733,[4] CGP60474,[5] CL387626
and its analogue RFI641[6] and some interferons (IFN).[7]
However, such structures are difficult to prepare directly
from heteroarylamines and aryl halides by using traditional
Ullmann–Goldberg couplings, possibly due to the weak nu-
cleophilicity of the amine nitrogen atom as a result of the
neighbouring heteroatom.
Traditionally, N-aryl-2-aminopyrimidines have been pre-
pared by reaction of the enamine derivatives of β-aldehydes
or ketones with guanidine derivatives[8] or by reaction of 2-
arylsulfonylpyrimidine or 2-alkylsulfonylpyrimidine deriva-
tives with amines.[8c,9] Both of these approaches often re-
quire either well-defined starting materials or multistep syn-
theses, which restrict their use in the synthesis of N-arylpyr-
imidine analogues. In the last decade, palladium-catalyzed
C–N bond formation (Buchwald–Hartwig reaction) has
been extensively developed.[10] Because of the simplicity of
such a palladium-catalyzed coupling reaction, this ap-
proach was immediately used in the synthesis of N-aryl-
heteroarylamines,[11] and a number of heteroarylamines,
including 2-aminopyridines, 2-aminothiazoles and their an-
alogues, have been arylated by using this method with the
use of organophosphorus reagents as the ligands.[12] How-
ever, problems, such as the high cost of palladium and the
use of toxic organophosphorus reagents, still remain for this
method.
In contrast to palladium, copper is an inexpensive and
moderately effective catalyst in Ullmann-type coupling re-
actions, and consequently, it has attracted much attention
in the synthesis of N-arylheteroarylamines. Copper-cata-
lyzed N-arylation of aliphatic amines,[13] arylamines,[14]
amides,[15] hydrazides[16] and nitrogen-containing heterocy-
cles[17] has been reported. Joshi[18] and coworkers also re-
ported N-arylation of 2-aminopyrimidine derivatives with
arylboronic acids in moderate yields by employing a cata-
lytic amount of Cu(OAc)2 at room temperature. Although
arylboronic acids are very active substrates, their cost is
very high. In addition, Arterburn[19] and Zhang[20] have,
respectively, reported their cross-coupling reaction between
2-aminopyrimidine and 1,3-dibenzyl-5-iodouracil in dif-
ferent copper/ligand catalytic systems. Studies on the cop-
per-catalyzed N-arylation of arylamine derivatives thus far
suggest that only heteroarylamines possessing strongly elec-
tron-donating groups or aryl halides possessing strongly
electron-withdrawing group can be coupled smoothly. For
heteroarylamines with neighbouring nitrogen or sulfur
atoms within the aryl ring, it was difficult to perform the
N-arylation reaction. Therefore, we attempted the coupling
reaction in the presence of a copper salt and N,NЈ-dimethyl-
ethylenediamine (DMEDA) as a ligand. Thus, the reaction
conditions for the copper-mediated N-arylation of heteroar-
ylamines were optimized. Here we report our investigation
and the results of these studies.
[a] Applied Chemical Institute, Northwest University,
Xi’an, 710069, P. R. China
Fax: +86-029-88303023
E-mail: abc981@163.com
[b] The Technologic Office of Criminal Detecting Bureau, The
Public security Bureau of Xi’an,
Xi’an, 710016, P. R. China
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
6084
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 6084–6088

Optimization of the Copper-Mediated N-Arylation of Heteroarylamines
the success of the reaction. For example, the reaction of
iodobenzene with 2-amino-4-phenylpyrimidine proceeded
smoothly in the presence of CuI (Ն0.25 equiv.; Table 1, En-
tries 4–7). In contrast, less than 10% of the desired product
was formed with lower quantities (Ͻ10 mol-%) even with
increased reaction time and higher temperatures. With re-
gard to the ligand, N,NЈ-dimethylethylenediamine was ini-
tially selected and employed in the reaction, because it was
previously reported to be an excellent ligand in various cop-
per-catalyzed coupling reactions.[15b,21a] Indeed, in our case,
it was more effective than other agents, such as -proline or
1,10-phenanthroline (Table 1, Entries 12–14). Another vari-
able is the base; although K2CO3, NaOH and Cs2CO3 all
proved effective (Table 1, Entries 4, 20 and 21), the yields
were higher when K2CO3 or Cs2CO3were used. Therefore
K2CO3 was selected as the base of choice due to its cost
effectiveness. Other bases tested, including K3PO4·3H2O,
Na2CO3, Et3N and pyridine, were ineffective (Table 1, En-
tries 22–25). Of the solvents investigated, dioxane was
found to be effective, whereas toluene, DMF and DMSO
were less effective (Table 1, Entries 28–30). Moreover, the
reaction in THF required long reaction times, presumably
Results and Discussion
Optimization of Reaction Conditions
In a preliminary study, we used iodobenzene and 2-
amino-4-phenylpyrimidine as substrates and varied the cop-
per source, ligand, base and solvent in order to find the
most effective conditions (Table 1). As anticipated, no de-
sired coupling product was obtained in the absence of cop-
per or ligand (Table 1, Entries 1 and 8). The absence of
product was a result of the poor solubility of CuI combined
with the low nucleophilicity of the substrates. Upon ad-
dition of a strongly electron-donating agent such as
DMEDA, however, the reaction mixture quickly turned
deep green in colour and the product was obtained in good
yield after 22 h. We also found that the catalytic activity
of copper source decreased in the order CuI ϾCu0 ϾCuII
(Table 1, Entries 4, 14–18). This observation is consistent
with previous reports.[21] Cuprous salts such as CuI and
CuCl were the most efficient. Unexpectedly, Cu2O (Table 1,
Entry 19) was almost ineffective under our conditions,
whereas Cu powder displayed better efficacy. It is also no-
table that the stoichiometry of the copper is a key factor in
Table 1. Optimization of reaction conditions.
Entry
Catalyst [equiv.]
Ligand
Base
Solvent
Time[h]
Yield [%][a]
1
2
3
4
5
6
7
8
–
–
0.05
0.1
0.25
0.5
1.0
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
–
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NaOH
Cs2CO3
K3PO4·3H2O
Na2CO3
Et3N
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
n-butanol
THF
18
22
22
18
14
14
14
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
48
18
18
18
0[b]
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuCl
Ͻ5[b]
Ͻ10[b]
86
89
87
2.0
89
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0[b]
9
DMEDA
DMEDA
DMEDA
-proline
1,10-phenanthroline
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
DMEDA
68[c]
65[d]
71[e]
Ͻ15[b]
Ͻ10[b]
85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Cu powder 0.25
46
26
31
CuSO4
Cu(OAc)2
CuBr2
Cu2O
CuI
CuI
CuI
CuI
CuI
CuI
CuI
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
27
Ͻ5[b]
81
88
Ͻ2[b]
Ͻ3[b]
Ͻ2[b]
Ͻ4[b]
Ͻ4[b]
56[f]
61
pyridine
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
CuI
CuI
CuI
CuI
toluene
DMF
DMSO
53
34
[a] Isolated yields (average of two runs). [b] GC yields (average of two runs). [c] Performed in air. [d] Performed in the presence of H2O
(2.0 equiv.). [e] Performed with a catalyst/ligand ratio of 1:2. [f] Performed at 65 °C.
Eur. J. Org. Chem. 2007, 6084–6088
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y. F. Liu, Y. J. Bai, J. Zhang, Y. Y. Li, J. P. Jiao, X. L. Qi
FULL PAPER
because the temperature of this system is too low (Table 1, Results of the Copper-Mediated N-Arylation of
Entry 27), and n-butanol was ineffective (Table 1, Entry 26). Heteroarylamines
The impact of water and oxygen were also studied (Table 1,
Entries 9 and 10). Pleasingly, only a slightly lower yield of
Further investigation of the reaction of iodobenzene with
product was obtained in the presence of air or H2O other heteroarylamines, as well as aniline, under the opti-
(2 equiv.).This implies that this procedure has potential use mized conditions was also undertaken (Table 2). It was
in large-scale industrial applications.
found that both aniline and 2-aminopyridine can be trans-
Table 2. Copper-mediated N-arylation of heteroarylamines.
[a] Isolated yields (average of two runs). [b] Aryl halide (1.5 mmol). [c] KI (2.0 equiv.). [d] Heteroarylamine (1.0 mmol). [e] GC yields
(average of two runs).
6086
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Eur. J. Org. Chem. 2007, 6084–6088

Optimization of the Copper-Mediated N-Arylation of Heteroarylamines
formed smoothly into the desired adducts (Table 2, En-
Experimental Section
tries 1 and 3). However, 2-aminothiazole as a substrate
gives low yields (Ͻ5%) under the same conditions. When
CuI/DMEDA (1:1, 1.0 equiv.) was employed, product 2b
was generated in 78% yield (Table 2, Entry 2). It is known
that the nucleophilicity of the amine decreases in the order
anilineϾ2-aminopyridineϾ2-aminothiazole. We discov-
ered that these amines required 0.1, 0.25, and 1.0 equiv.,
respectively, of the CuI/EMEDA catalyst to accomplish the
reaction. These results imply that more nucleophilic amines
react more readily with the aryl halide. In contrast, the use
of bromobenzene instead of iodobenzene resulted in a de-
creased yield under the same reaction conditions (Table 2,
Entry 10). Nevertheless, the addition of KI (2.0 equiv.)
[17c]or CuI/DMEDA (1.0 equiv.) under the same conditions
resulted in the efficient transformation of a range of bro-
mides into the desired products in moderate-to-good yields
(Table 2, Entry 4–11). Amination of chlorobenzene was un-
successful under the same conditions, even with prolonged
reaction times and greater quantities of CuI/DMEDA
(Table 2, Entry 12). It is noteworthy that N-(2-methyl-5-ni-
trophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (Table 2, En-
try 11), an important intermediate in the synthesis of the
anticancer drug Imatinib, was first synthesized by this Cu-
catalyzed C–N bond-forming reaction. Additionally, we
also found that steric hindrance persists in this system. For
example, when the amination of 2-bromo-4-nitrotoluene
was carried out, an increased amount of 2-bromo-4-nitro-
toluene (1.5–2.0 equiv.) and a longer reaction time were re-
quired (Table 2, Entry 11). Diarylation products were de-
tected in almost all reactions, but in this case, no bis(aryl-
ated) product was detected because of the sterically hin-
dered nature of 2-bromo-4-nitrotoluene.
General: All reactions were carried out under a nitrogen atmo-
sphere in oven-dried, Schlenk-type glassware. Elemental analyses
were performed with an Elementar Vario EL III. IR spectra were
recorded with a Bruker Equinox-55. 1H NMR spectra were re-
corded with a Varian Inova 400 MHz instrument with chemical
shifts reported relative to tetramethylsilane (TMS). GC–MS spec-
tra were recorded with
a Varian 3800 spectrometer. Gas
chromatography analyses were performed with a Hewlett Packard
5890 instrument. All materials were weighed in the open atmo-
sphere. Flash column chromatography was performed with silica
gel (100–200 mesh). All reagents were purchased from commercial
suppliers and used without further purification.
General Procedure for the copper-Mediated N-Arylation of Het-
eroarylamines: The heteroarylamine (1.1 mmol), CuI (0.019–0.19 g,
0.1–1.0 mmol) and anhydrous K2CO3 (0.276 g, 2.0 mmol) were
added to a Schlenk-type, three-neck flask fitted with a thermome-
ter, magnetic stirbar and septum. The flask was evacuated and back
filled with nitrogen gas three times. Dioxane (5 mL), aryl halide
(1.0 mmol) and DMEDA (0.1–1.0 mmol) were added by syringe at
room temperature. The reaction mixture was stirred at 100 °C for
20 h and then cooled to room temperature. Concentrated ammonia
(4 mL) and a saturated solution of NaCl (20 mL) were added, and
the mixture was extracted with ethyl acetate (3ϫ15 mL). The com-
bined organic layer was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel.
N-Phenylpyridin-2-amine (2a): M.p. 108–110 °C. 1H NMR
(400 MHz, CDCl3): δ = 8.20 (d, J = 4.0 Hz, 1 H), 7.48–7.53 (m, 1
H), 7.26–7.34 (br. m, 4 H), 7.06–7.08 (br. m, 1 H), 6.89 (d, J =
8.4 Hz, 1 H), 6.73–6.76 (m, 1 H), 6.69 (s, 1 H) ppm. IR (KBr): ν
˜
= 3448, 3223, 3174, 3096, 3006, 1592, 1529, 1492, 1464, 1325, 1152,
988, 769, 747, 694, 510 cm–1. MS: m/z = 170 [M]+, 169 [M – 1]+.
C11H10N2 (170.21): calcd. 77.62, H 5.92, N 16.46; found C 77.49,
H 5.90, N 16.53.
N-Phenylthiazol-2-amine (2b): M.p. 127–128 °C. 1H NMR
(400 MHz, CDCl3): δ = 10.16 (s, 1 H), 7.64 (d, J = 7.8 Hz, 2 H),
7.28 (t, J = 7.6 Hz, 2 H), 7.24 (d, J = 3.6 Hz, 1 H), 6.92 (t, J =
7.2 Hz, 1 H), 6.89 (d, J = 3.6 Hz, 1 H) ppm. IR (KBr): ν = 3410,
˜
Conclusions
3290, 3140, 3120, 3082, 1598, 1520, 1496, 1460, 1330, 990 cm–1.
We developed a mild, convenient and inexpensive cop- MS: m/z = 176 [M]+. C9H8N2S (176.24): calcd. C 61.34, H 4.58, N
15.90; found C 61.15, H 4.24, N 16.03.
per-catalyzed system for the N-arylation of heteroaryl-
amines. By using this protocol, heteroarylamines were cou-
pled with aryl iodides and aryl bromides in good yields.
The right combination of copper source, ligand, base and
solvent, and the amount of CuI/DMEDA was the key in
the amination reaction of aryl iodides and aryl bromides.
The activity of the copper catalyst decreases in the order
CuI ϾCu0 ϾCuII. Aryl iodides react more readily with het-
eroarylamines than aryl bromides. Phenyl chloride showed
very low reactivity towards heteroarylamines. For most het-
eroarylamines, the high nucleophilicity of the amino group
resulted in facile coupling with aryl halides. The important
compound, N-(2-methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyr-
imidin-2-amine, an intermediate in the synthesis of Imati-
nib, was first prepared by copper-mediated N-arylation of
heteroarylamines in 82% yield, under these optimized con-
ditions. In comparison to the conventional, Pd-catalyzed
protocol, we anticipate that such a copper-catalyzed ap-
proach could be see wider application in the fields of medic-
inal chemistry and pesticide synthesis.
N,4-Diphenylpyrimidin-2-amine (2h): M.p. 122–124 °C. 1H NMR
(400 MHz, CDCl3): δ = 7.08 (t, J = 7.2 Hz, 1 H), 7.19 (d, J =
4.8 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 2 H), 7.52 (t, J = 3.0 Hz, 4 H),
7.72 (d, J = 10.8 Hz, 2 H), 8.09–8.08 (m, 2 H), 8.49 (s, 1 H) ppm.
IR (KBr): ν = 3432, 3254, 3113, 1609, 1580, 1557, 1494, 1438, 1403,
˜
1333, 752, 690 cm–1. MS: m/z = 247 [M]+, 246 [M – 1]+. C16H13N3
(247.30): calcd. C 77.71, H 5.30, N 16.99; found C 77.68, H 5.36,
N 16.86.
N-(2-Methyl-5-nitrophenyl)-4-(pyridin-3-yl)pyrimidin-2-amine (2i):
1
M.p. 194–195 °C. H NMR (400 MHz, [D6]DMSO): δ = 9.34 (s, 1
H), 9.28 (s, 1 H), 8.81 (dd, J = 7.2, 2.4 Hz, 1 H), 8.72 (d, J =
4.4 Hz, 1 H), 8.64 (d, J = 4.8 Hz, 1 H), 8.50 (d, J = 8.0 Hz, 1 H),
7.91 (dd, J = 8.4, 2.0 Hz, 1 H), 7.52–7.61 (m, 3 H), 2.44 (s, 3 H)
ppm. IR (KBr): ν = 3441, 3253, 3097, 1584, 1557, 1534, 1407, 1346,
˜
792, 735, 698, 651 cm–1. MS: m/z = 307 [M]+, 292, 260, 246.
C16H13N5O2 (307.31): calcd. C 62.53, H 4.26, N 22.79; found C
62.72, H 4.31, N 22.66.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data for aryl-
ation products 2c–g.
Eur. J. Org. Chem. 2007, 6084–6088
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Y. F. Liu, Y. J. Bai, J. Zhang, Y. Y. Li, J. P. Jiao, X. L. Qi
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Acknowledgments
Financial support was provided by the Nature Science Foundation
of ShaanXi Province, China (03JC01), and Scientific Technology
Foundation of Educational Committee of ShaanXi Province, China
(2003k08-G5).
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Received: June 22, 2007
Published Online: October 16, 2007
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