Copper-mediated aryl amination: In situ generation of an active copper(I) species

Article abstract of DOI:10.1055/s-0030-1260954

We have developed novel conditions for copper-mediated aryl amination by using a combination of easy-to-handle and inexpensive Cu(OAc) ₂·H₂O and phenylhydrazine. Georg Thieme Verlag Stuttgart . New York.

Full text of DOI:10.1055/s-0030-1260954

LETTER
1859
Copper-Mediated Aryl Amination: In Situ Generation of an Active Copper(I)
Species
C
opper-Mediate
a
dAryl Am
k
ination ashi Komori, Nobuhiro Satoh, Satoshi Yokoshima, Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Fax +81(3)58028694; E-mail: fukuyama@mol.f.u-tokyo.ac.jp
Received 18 May 2011
presence of a copper reagent, which was generated in situ
Abstract: We have developed novel conditions for copper-mediat-
ed aryl amination by using a combination of easy-to-handle and in-
expensive Cu(OAc)2·H2O and phenylhydrazine.
by treatment of one equivalent of Cu(OAc)2·H2O in
DMSO with 0.5 equivalent of phenylhydrazine
(Scheme 2).10 The reaction proceeded efficiently by heat-
ing at 90 °C for nine hours to afford the corresponding
aniline in 83% yield. This result was comparable to yields
achieved by using our previous procedure.8
Key words: amine, aryl amination, copper, phenylhydrazine, re-
ductant
Aryl aminations have received considerable attention by
synthetic community in recent years because aromatic C–
N bonds are constituents of many biologically active com-
pounds.1 While the Ullmann–Goldberg reaction is a clas-
sic method of aryl amination,2 the harsh reaction
conditions tend to preclude its applications to the synthe-
sis of complex molecules. To overcome this drawback,
Buchwald,3–5 Hartwig,6 and Ma7 have independently de-
veloped palladium- or copper-mediated aryl amination re-
actions, which could be performed under mild conditions
and thus broaden the substrate scope. More recently, a
novel amination reaction catalyzed by CuI and CsOAc has
been developed in our laboratory.8 This copper-mediated
reaction is so mild that a wide range of functional groups
are shown to survive especially in the case of intramolec-
ular reactions.9 In this paper, we describe the development
of an alternative method for copper-mediated aryl amina-
tions using Cu(OAc)2·H2O.
n-BuNH2 (5.0 equiv)
Cu(OAc)2⋅H2O (1.0 equiv)
NHn-Bu
I
PhNHNH2 (0.5 equiv)
DMSO, 90 °C, 9 h
83%
Scheme 2 Aryl amination using a copper reagent generated in situ
by reduction of Cu(OAc)2 with phenylhydrazine
The effect of the amount of phenylhydrazine on this trans-
formation was evaluated (Table 1). Unexpectedly, the re-
action proceeded to afford the desired product in the
absence of phenylhydrazine.11,12 Nevertheless, the reac-
tion was clearly accelerated by addition of phenylhydra-
zine. Addition of phenylhydrazine in quantities greater
than 0.50 molar equivalent did not further accelerate the
reaction rate but instead caused the undesired formation of
azobenzene. This by-product was presumably produced
by aryl amination of iodobenzene with phenylhydrazine,
followed by oxidation of the resultant 1,2-diphenylhydra-
zine by copper(II) acetate. These results would indirectly
support the evidence that a copper(I) species was generat-
ed under these conditions.
In our previous report, we described that the active copper
species was considered to be CuOAc generated in situ by
exchange between CuI and CsOAc (Scheme 1). Because
CuOAc is expensive and too hygroscopic and air sensitive
to be handled in air, it was more practical to use the com-
bination of CuI and CsOAc. We envisioned that CuOAc
could also be generated by reduction of Cu(OAc)2, which
is much easier to handle in air.
Table 1 Effect of Phenylhydrazine
n-BuNH2 (5.0 equiv)
Cu(OAc)2⋅H2O (1.0 equiv)
NHn-Bu
I
PhNHNH2 (X equiv)
DMSO, 90 °C
time
CuI
+
Cu(OAc)2
+
Ratio (PhI/PhNHBu)a
CuOAc
X
Time (min)
CsOAc
reductant
0
40
40
40
20
20
20
1:0.25
1:5
Scheme 1 Generation of copper(I) acetate
0.25
0.50
0.50
0.75
1.00
1:49
1:23
1:70b
1:50b
Based on this hypothesis, the amination reaction using
Cu(OAc)2·H2O was attempted. In the event, iodobenzene
was treated with five equivalents of n-butylamine in the
SYNLETT 2011, No. 13, pp 1859–1862
x
x
.x
x
.2
0
1
1
Advanced online publication: 14.07.2011
DOI: 10.1055/s-0030-1260954; Art ID: U04411ST
© Georg Thieme Verlag Stuttgart · New York
a Determined by 1H NMR.
b Formation of azobenzene was observed.

1860
T. Komori et al.
LETTER
Table 3 Aryl Amination of Various Substrates
After extensive investigation, we found that catalyst load-
ing could be reduced to 40 mol% without affecting the
yields of the desired product. The optimal conditions were
found to include use of 4.0 equivalents of amine, 0.4
equivalent of Cu(OAc)2·H2O, and 0.2 equivalent of phe-
nylhydrazine.13
R1R2NH (4.0 equiv)
Cu(OAc)2⋅H2O (0.40 equiv)
PhNHNH2 (0.20 equiv)
ArNR1R2
ArI
DMSO, 90 °C, 23 h
ArI
R1R2NH
Yield
(%)a
Reported
We next investigated the scope of the reaction by examin-
ing a variety of iodobenzenes (Table 2). It was found that
m- or p-substituted iodobenzenes bearing either electron-
withdrawing or electron-donating substituent groups were
suitable substrates to give the corresponding disubstituted
anilines in moderate to good yields. On the other hand, o-
substituted iodobenzenes gave the corresponding anilines
in low yield. Selective monoamination reactions were
possible when m- or p-diiodobenzene was used. These
tendencies were similar to those described in our previous
report.8a–c
yield (%)b
n-BuNH2
n-BuNH2
88
84
71
34
70
96
68
73
N
I
I
N
I
I
HN
Table 2 Substitution Effects on the Aryl Amination
HN
O
n-BuNH2 (4.0 equiv)
Cu(OAc)2⋅H2O (0.40 equiv)
I
I
I
I
I
I
NHn-Bu
PhNHNH2 (0.20 equiv)
28
24
68
24
X
X
N
H
DMSO, 90 °C, 23 h
H2N
Entry
1
X
Yield (%)a
Reported yield (%)b
o-NO2
m-NO2
p-NO2
o-Me
m-Me
p-Me
o-OMe
m-OMe
p-OMe
m-I
20
66
94
30
93
74
26
87
50
52
64
17
78
95
99
21
99
86
49
89
84
50
76
37
H2N
R = OMe; 26
R = NO2; 20
44
63
2
3
R
H2N
R
R
R = OMe; 27
R = NO2; 13
4
12
4
5
H2N
R = OMe; 31
R = NO2; 16
38
64
6
7
a Isolated yield.
b See ref. 8.
8
9
In summary, we have developed novel conditions for the
copper-mediated aryl amination by combining easy-to-
handle and inexpensive Cu(OAc)2·H2O and phenylhydra-
zine. Although the yields are generally lower than the pre-
vious conditions, this work provides an alternative
method for aryl aminations.
10
11
12
p-I
o-F
a Isolated yields unless otherwise noted.
b See ref. 8.
Acknowledgment
We next examined the generality of the amination reac-
tion by evaluating a variety of aryl iodides and amines
(Table 3). It was found that 2- and 3-iodopyridine were
suitable substrates for the amination. While acyclic sec-
ondary amines such as diethylamine afforded the corre-
sponding products in trace amounts, cyclic secondary
amines gave the corresponding anilines in moderate
yields. In the case of aniline or indole, these conditions ap-
peared to be less effective, providing low yields of the
products.
This work was financially supported in part by a Grant-in-Aids
(20002004) from the Ministry of Education, Culture, Sports, Sci-
ence and Technology of Japan. T.K. was a visiting researcher from
Sumitomo Chemical Co., Ltd. N.S. was a research fellow of the Ja-
pan Society for the Promotion of Science (JSPS).
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T. Komori et al.
LETTER
(13) Typical Procedure: A solution of copper(II) acetate
(10) Reductions of Cu(II) salts with phenylhydrazine have been
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Tetrahedron Lett. 1990, 31, 6005. (c) Glos, M.; Reiser, O.
Org. Lett. 2000, 2, 2045. The reductions have also been
used to generate aryl radicals: (d) Varea, T.; González-
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(11) We reported that the aryl amination reaction with Cu(OAc)2
did not proceed in DMF (ref. 8). DMSO might work as a
reductant under these conditions.
(12) A possibility that amines might work as a reductant has been
reported: Qin, W.; Kakusawa, N.; Wu, Y.; Yasuike, S.;
Kurita, J. Chem. Pharm. Bull. 2009, 57, 436.
monohydrate (0.40 mmol) and amine (4.0 mmol) in DMSO
(1 mL) was stirred for 30 min at r.t., whereupon
phenylhydrazine (0.20 mmol) was added. After stirring for
30 min, aryl iodide (1.0 mmol) was added to the solution.
The reaction mixture was stirred for 30 min, and the solution
was warmed to 90 °C. After stirring for 23 h at the same
temperature, the solution was cooled to r.t. and diluted with
EtOAc. The solution was washed with aq ammoniacal
sodium chloride (3 ×). The combined aqueous layer was
extracted with EtOAc (3 ×). The combined organic layer was
washed with brine, dried over Na2SO4, and concentrated
under reduced pressure. The residue was purified by column
chromatography to give the corresponding aniline.
Synlett 2011, No. 13, 1859–1862 © Thieme Stuttgart · New York