A simple copper salt catalyzed N-arylation of amines, amides, imides, and sulfonamides with arylboronic acids

Article abstract of DOI:10.1055/s-2004-820059

A simple copper salt catalyzed N-arylation reaction with arylboronic acids is reported. In the presence of a catalytic amount of a simple copper salt, the coupling of arylboronic acids with imides was performed in MeOH to give N-arylimides in excellent yields; a variety of amines, amides and sulfonamides could also be successfully coupled with arylboronic acids to give corresponding N-arylated products in moderate yields.

Full text of DOI:10.1055/s-2004-820059

LETTER
1095
A Simple Copper Salt Catalyzed N-Arylation of Amines, Amides, Imides, and
Sulfonamides with Arylboronic Acids
S
imple Co
i
ppe
r
Sa
n
lt Catalyzed
g
N
-
Arylat ion-Bo Lan,a Guo-Lin Zhang,b Xiao-Qi Yu,*a Jing-Song You,a Li Chen,a Mei Yan,a Ru-Gang Xie*a
a
Department of Chemistry, Sichuan University, Chengdu 610064, P. R. China
b
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, P. R. China
Fax +86(28)85412285; E-mail: schemorg@mail.sc.cninfo.net.
Received 16 February 2004
obtaining corresponding N-arylimidazoles in almost
quantitative yields.10 The successful N-arylation reaction
of imidazole with arylboronic acids encouraged us further
to explore the generality of this procedure, and we found
Abstract: A simple copper salt catalyzed N-arylation reaction with
arylboronic acids is reported. In the presence of a catalytic amount
of a simple copper salt, the coupling of arylboronic acids with imi-
des was performed in MeOH to give N-arylimides in excellent
yields; a variety of amines, amides and sulfonamides could also be that the simple copper salt can also catalyze the N-aryla-
successfully coupled with arylboronic acids to give corresponding
N-arylated products in moderate yields.
tion reaction of a variety of amines, amides, imides and
sulfonamides in protic solvent in the absence of additional
Key words: N-arylation, copper salt, boronic acid, coupling, Ull-
mann reaction
ligands or bases to give corresponding N-arylated prod-
ucts in moderate to excellent yields (Scheme 1). N-Aryla-
tion reaction of amines, amides, imides and sulfonamides
with arylboronic acids has recently gained considerable
The copper-mediated N-arylation reaction is an important attention, because of their potential application in pharma-
transformation and has been developed to include a wide ceutical, agrochemical industries.6,7,9,11 To the best of our
range of substrates. The classical copper-mediated Ull- knowledge, N-arylation of amines, amides, imides and
mann reaction has underpinned the research community sulfonamides with arylboronic acids conducted in protic
when functionalities of these sorts are required.1 Howev- solvent with the use of simple copper salts has not been
er, the harsh reaction conditions led to severe limitations explored previously; this represents an advance over the
in the general use of this reaction, especially on a large use of complex copper salts together with a substantial
scale. In recent years, a few approaches have also been de- amount of base in non-protic solvent.
veloped by using aryllead,2 arylbismuth,3 arylstannane,4
arylsilane5 reagents as the aryl donor in the presence of
Simple Copper Salt
R1
R2
R1
CH3OH, Air, Refluxed
Cu(OAc)2 and base. The recent introduction of arylboron-
ic acids as reaction partners has been a significant im-
provement over previous methods.6 In 1997, the copper-
mediated heteroatom arylation reaction with the use of
arylboronic acids was discovered independently by Chan,
Evans and Lam.6,7 A more important discovery by Coll-
man has demonstrated that the N-arylation reaction of im-
idazoles with arylboronic acids can be rendered when a
catalytic amount of copper complex was used.8 Based on
these studies, further improvements to the catalytic varia-
tion of boronic acid cross coupling have been reported.9
However, all these reactions are carried out with either
Et3N or pyridine as base, or with the use of copper com-
plex in halogenated hydrocarbon. These reactions are nor-
mally slow, which generally need 18 hours–13 days to
proceed to complete. Moreover, the use of excess arylbo-
ronic acids is also a major limitation of the method. There-
fore, it is necessary to develop more general and efficient
catalytic systems for N-arylation of a variety of substrates.
ArB(OH)2
NH
+
N
Ar
10 min – 3h
R2
No Base or Ligand
Scheme 1 A simple copper salt catalyzed N-arylation reaction.
Treatment of 1.4–2 mmol of N-H containing substrate
with 1 mmol of arylboronic acid in the presence of cata-
lytic amount of a simple copper salt in MeOH at reflux
temperature was found to lead to coupling products. In
preliminary study, CuCl was evaluated for the desired re-
activity. Excellent yields of cross-coupled products were
obtained for imides (Table 1, entries 1 and 7), whereas
amines, amides and sulfonamides were afforded in poor
yields. When Cu(OAc)2·H2O was used as copper source,
satisfactory results were obtained with amines, amides,
imides and sulfonamides.
A series of arylboronic acids were employed for the cou-
pling reaction with imides under the conditions outlined in
Table 1. It was found that 10% mol of Cu(OAc)2·H2O was
sufficient for imides. It is worth mentioning that the cou-
pling reaction with phenylboronic acid was complete in 2
hours, and the corresponding N-arylation products were
obtained in excellent yields (Table 1, entries 1, 7), which
are superior to previous work.7d,9c A variety of substituted
phenylboronic acids and naphthylboronic acid were also
Recently, we have carried out the N-arylation reaction of
imidazole with arylboronic acids using only 5% mol of a
simple copper salt, without any additives in protic solvent,
SYNLETT 2004, No. 6, pp 1095–1097
0
6.
0
5.
2
0
0
4
Advanced online publication: 25.03.2004
DOI: 10.1055/s-2004-820059; Art ID: U04304ST
© Georg Thieme Verlag Stuttgart · New York

1096
J.-B. Lan et al.
LETTER
subjected to coupling with phthalimide and succinimide that o-substituted phenylboronic acids afforded the de-
respectively. Good results were obtained with p- and sired compounds in very poor yields (Table 1, entries 5, 6,
m-substituted phenylboronic acids and naphthylboronic 12, 13). These low yields appear to be a result of steric
acid (Table 1, entries 2–4 and 8–11). It should be noted hindrance.
The application of this reaction to the coupling of amines,
Table 1 Cu(OAc)2·H2O-Catalyzed N-Arylation Reaction of Imides
amides and sulfonamides with phenylboronic acid was
also briefly explored. Such coupling was found to give the
desired N-arylation products in moderate yields, as shown
in Table 2. The amount of Cu(OAc)2·H2O can be quite de-
pendent on the nature of the substrate. 10% mol of
Cu(OAc)2·H2O was sufficient for amines (Table 2, entries
1–7). The use of 40% mol of Cu(OAc)2·H2O is suitable for
amides and p-tolylsulfonamide (Table 2, entries 8–10).
Especially for the latter, the yield increased while the
amount of Cu(OAc)2·H2O increased. The conditions used
in Table 2 were unoptimized, and it is likely that further
optimization of conditions for the coupling reaction could
result in higher yields. It is interest that bis-arylated prod-
ucts were never detected during the course of the coupling
reactions, which is consistent with Buchwald’s report.9a
with Arylboronic Acidsa
Entry Imides
ArB(OH)2
Product
Yieldb
(%)
1
96,96c
O
N
O
O
N
O
O
N
O
O
N
O
O
B(OH)2
NH
O
2
3
4
5
6
7
8
94
O
H3C
B(OH)2
B(OH)2
B(OH)2
NH
CH3
O
O
93
H3CO
NH
OCH3
O
O
90
NH
H3C
Table 2 Cu(OAc)2·H2O-Catalyzed N-Arylation Reaction of
CH3
O
O
Amines, Amides and Sulfonamides with Phenylboronic Acida
20
O
N
B(OH)2
CH3
Yieldb (%)
78
NH
Entry
1
Substrate
Product
O
O
CH3
O
O
H
N
trace
88,86c
86
B(OH)2
OCH3
NH2
NH
N
2
3
76
52
H
N
O
O
OCH3
NH2
O
O
B(OH)2
N
NH
H
N
O
O
O
Cl
NH2
NH2
Cl
O
B(OH)2
4
5
6
74
56
39
N
NH
NH
O
O
O
H
N
9
10
11
12
13
87
NH2
NH2
O
H3C
B(OH)2
B(OH)2
B(OH)2
NH
N
CH3
O
O
H
O
N
85
O
H3CO
NH
N
OCH3
7
8
43
H
N
NH2
O
O
O
11
11
72
O
51c
O
NH
N
NH
H3C
CONH2
CH3
O
O
O
O
40c
19
9
O
B(OH)2
CH3
O
CH3CNH
O
N
NH
CH3CNH2m
50,c 73d
O
O
CH3
O
O
10
O
S NH2
O
H
trace
S N
O
B(OH)2
OCH3
N
NH
a,b See Table 1, except 2 mmol of N-H containing substrate was used.
c 40% mol of Cu(OAc)2·H2O was used
O
OCH3
O
a Reaction conditions: 1.4 mmol imides, 1 mmol arylboronic acid, and
10% mol of Cu(OAc)2·H2O in 10 mL anhyd MeOH were stirred
drastically, air bubbled in and refluxed 10 min–3 h. The reaction was
judged complete by TLC. The reaction mixture was concentrated and
the residue was purified by silica gel column chromatography to give
N-arylated product.
d 100% mol of Cu(OAc)2·H2O was used.
It is essential to add base or ligand in the coupling reaction
of arylboronic acids in previous work, except for the re-
cent report by Quach and Batey12. We found that neither
base nor ligand was necessary for the catalyzed system of
b Isolated yield, purity confirmed by HPLC, MS and 1H NMR.
c 10% mol of CuCl was used.
Synlett 2004, No. 6, 1095–1097 © Thieme Stuttgart · New York

LETTER
Simple Copper Salt Catalyzed N-Arylation
1097
(3) (a) Arnauld, T.; Barton, D. H. R.; Doris, E. Tetrahedron
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simple copper salts. Moreover, the coupling reaction is
very fast. It took only 10 minutes–3 hours to complete
transformation to arylated product, which is much faster
than that reported previously. To the best of our knowl-
edge, the majority of previously reported reaction condi-
tions tend to use the N-H containing substrate as the
limiting agent and the boronic acid in excess. Our proce-
dure actually has the boronic acid as the limiting agent
with the N-H containing substrate in excess, this could ac-
count for the seemingly lower yields when compare with
the work of Buchwald9c as well as Quach and Batey.12
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In summary, we have developed a simple copper salt
catalyzed coupling of arylboronic acids with amines,
amides, imides and sulfonamides in moderate to excellent
yields. The further work including the study on mecha-
nism is being in progress.
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Acknowledgment
This work was supported by the National Natural Science Founda-
tion of China (20172038, 20132020) and Doctoral Foundation of
the Education Ministry of China.
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Synlett 2004, No. 6, 1095–1097 © Thieme Stuttgart · New York