Convenient copper-mediated Chan-Lam coupling of 2-aminopyridine: Facile synthesis of N-arylpyridin-2-amines

Article abstract of DOI:10.1016/j.tetlet.2015.06.092

A new and practical process for the synthesis of N-arylpyridin-2-amine derivatives has been developed. Under the assistance of copper, the desired products were produced from commercially available 2-aminopyridine and aryl boronic acids in moderate to good yields with good functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2015.06.092

Accepted Manuscript
Convenient Copper-Mediated Chan-Lam Coupling of 2-Aminopyridine: Facile
Synthesis of N-arylpyridin-2-amines
Jianbin Chen, Kishore Natte, Nikki Y.T. Man, Scott G. Stewart, Xiao-Feng Wu
PII:
S0040-4039(15)01111-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.06.092
TETL 46484
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
22 May 2015
24 June 2015
29 June 2015
Please cite this article as: Chen, J., Natte, K., Man, N.Y.T., Stewart, S.G., Wu, X-F., Convenient Copper-Mediated
Chan-Lam Coupling of 2-Aminopyridine: Facile Synthesis of N-arylpyridin-2-amines, Tetrahedron Letters (2015),
doi: http://dx.doi.org/10.1016/j.tetlet.2015.06.092
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Graphical Abstract
Copper-Mediated Chan-Lam Coupling of 2-
Aminopyridine: Facile Synthesis of N-
arylpyridin-2-amines
Leave this area blank for abstract info.
Jianbin Chen,a Kishore Natte,a Nikki Y. T. Man,b Scott G. Stewart,b and Xiao-Feng Wu*a

1
Tetrahedron Letters
journal homepage: www.els evier.com
Convenient Copper-Mediated Chan-Lam Coupling of 2-Aminopyridine: Facile
Synthesis of N-arylpyridin-2-amines
Jianbin Chen,a Kishore Natte,a Nikki Y. T. Man,b Scott G. Stewart,b and Xiao-Feng Wu*a
a Leibniz-Institut für Katalyse an der Universität Rostock e.V. Albert-Einstein-Str. 29a, 18059 Rostock, Germany
b School of Chemistry and Biochemistry, The University of Western Australia, 35 Stirling Hwy, Crawley, WA, 6009, Australia
E-mail: xiao-feng.wu@catalysis.de
ARTICLE INFO
ABSTRACT
Article history:
Received
A new and practical process for the synthesis of N-arylpyridin-2-amine derivatives has been
developed. Under the assistance of copper, the desired products were produced from
commercially available 2-aminopyridine and aryl boronic acids in moderate to good yields with
good functional group tolerance.
Received in revised form
Accepted
Available online
2015 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Chan-Lam coupling
Copper catalyst
Pyridine
Aryl boronic acid
1. Introduction
Nitrogen-containing motifs are an important class of
molecules which are frequently encountered in pharmaceuticals
and biologically active compounds.1 Among them, pyridine-rings
not only hold unique biologically activities, taking nicotine as an
example,2 but also have been exploited as directing groups in
transition metal-catalyzed C-H activations because of the
excellent coordination ability of the nitrogen atom to the metal
center.3 Among them, N-arylpyridin-2-amines are interesting
molecules. The pyridyl core bearing two functions: directing
group in the C-H activation and/or reaction reagent (Scheme 1).
More recently examples included: Chu et. al. developed a
palladium-catalyzed arylation of 3a (Scheme 1, procedure a);4
it’s annulation reaction with alkyl resulting indoles was reported
by Li5 and Ackermann6 with palladium, rhodium, ruthenium or
nickel as the catalysts, independently (Scheme 1, procedure b).
Interestingly, our group investigated the carbonylative C-H
annulation with alkynes for the quinolin-2(1H)-ones core
synthesis (Scheme 1, procedure c).7 We also successfully
developed a heterogeneous palladium catalyzed cyclization of
alkynes with 3a to give indoles synthesis (Scheme 1, procedure
b).8 Additionally, the usage of the pyridyl group both as directing
group and reaction reagent with the hypervalent iodine(III)4a, 9 or
transition-metals10 as the catalysts were developed as well
(Scheme 1, procedures d and e) and some other organic
transformations of 3a were also developed.11
Scheme 1. N-phenylpyridin-2-amine as a useful building block in C-H
functionalizations.
commercially available. And very scarcely synthetic methods
were documented to access them. In 2010, Li and co-workers
demonstrated
a
palladium-catalyzed amination of 2-
bromopyridine5a and a similar process for amination of 2-
chloropyridine was reported by Maes in 2011.10b The SNAr of 2-
chloropyridine at 160 oC for the N-arylpyridin-2-amines
production was reported as well.10b In 2014, Wang established a
Although many transformations of N-arylpyridin-2-amines
have been developed, unfortunately, only very few of these
substrates are

2
Tetrahedron
Table 1. Substrate Scope for the Synthesis of N-arylpyridin-2-amines.a
copper-catalyzed
ligand
free
N-arylation
of
2-
aminopyridines.12a However, there are several drawbacks such as
utilizing noble metal catalysts and expensive ligands, running at
high temperature or very limited substrates scope. Moreover,
over amination to give tri(hetero)arylamines is not avoidable.
Thus, the development of new selective procedure under mild
conditions is still highly desirable. In the past decades, Chan-
Lam coupling have been regarded as one of the powerful tools
for the construction of C-X (X= N, O, S) bonds.13 Utilizing
copper salts as the non-expensive catalyst and milder reaction
conditions are the main advantages. Herein, we wish to report our
results on the synthesis of N-arylpyridin-2-amines via copper-
mediated N-arylation of 2-amino pyridine with aryl boronic
acids.
Entry
1
Product
Yieldb
71%
Substrate
2 mmol
B(OH)2
NHPy
2
3
4
5
6
7
83%
77%
61%
79%
82%
54%
2. Discussion
0.5 mmol
We started our optimization with phenyl boronic acid 1a and
2-aminopyridine 2a as the model substrates. After careful
reaction conditions variation, the best results can be realized in
71% isolated yield in the presence of: 1.2 equivalents of
Cu(OAc)2·H2O as the promoter, 2 equivalents of K3PO4·H2O as
NHPy
O
0.5 mmol
o
the base in DMSO, at 120 C for 24h. Unfortunately, low yields
were observed when 10-20 % amount of copper salt was applied.
With the best system in hand, we focused on the generality and
limitation testing of this method.14 As shown in Table 1, a series
of functional groups can be tolerated. For the electron effect of
the substrates, taken the methyl and methoxy as the examples of
electron-donating group, good yields were obtained under
optimized conditions (Table 1, entries 2 and 3). The substrates
bearing electron-withdrawing groups such as the fluoro, chloro
and trifluoromethyl provide the desired products also in good
yields (Table 1, entries 4-6). Interestingly, the methylthio group
which could be oxidized under the oxidative conditions was
untouched under our aerobic system and gives the desired
product in acceptable yield (Table 1, entry 7). The (4-
acetylphenyl)boronic acid and (4-(benzyloxy)phenyl)boronic
acid gave the targeted products in good yields as well (Table 1,
entries 8 and 9). Importantly, the vinyl group was successfully
incorporated into the final products in 84% yield which provide
the possibility for further modification via the Heck reaction
(Table 1, entry 10). Compared to the substrate-bearing
trifluoromethyl group, the trifluoromethoxy group-substituted
arylboronic acid resulted in moderate yield (Table 1, entry 11).
Substrates with meta substitutions such as methyl, bromo and
nitro worked as well although low yields for (3-
nitrophenyl)boronic acid and (3-bromophenyl)boronic acid were
given (Table 1, entries 12-14). However, the yield can be
improved by simply decreasing the reaction temperature to 60 oC.
It should be noted that 1- or 2-naphthylboronic acid run smoothly
in our systems too (Table 1, entries 15 and 16). Notably, when
using the symmetrical [1,1'-biphenyl]-4,4'-diyldiboronic acid as
the starting material, only N-([1,1'-biphenyl]-4-yl)pyridin-2-
amine was obtained because of deboronication reaction (Table 1,
entry 17). Unfortunately, low yield was observed while sterically
bulk arylboronic acid was applied in our system (Table 1, entry
18). To our delight, the heteroaryl boronic acid which is less
stable compared to the aryl boronic acid analogues can provided
the desired product in moderate yield under low temperature
(Table 1, entry 19). 2-Aminopyrimidine can also serve as the
coupling partner and resulted in moderate yield (Table 1, entry
20). Moreover, aryl boronic acid derivatives such as potassium
aryltrifluoroborate, phenylboronic acid N-butyldiethanolamine
ester and phenylboronic acid pinacol ester could deliver the
desired products without any further optimizations (Table 1,
entries 21-23).
0.5 mmol
0.8 mmol
B(OH)2
F3C
0.5 mmol
NHPy
S
2 mmol
8
75%
0.5 mmol
9
88%
84%
41%
2 mmol
B(OH)2
10
11
1 mmol
NHPy
F3CO
2 mmol
12
73%
0.5 mmol

3
copper(0). At the same time, the oxidation of complex C in the
presence of ambient oxygen from air generates the copper(III)
species D which provides the products and copper(I) via
reductive elimination is also possible. At last, the copper(0) or
copper(I) could be oxidized to the active copper(II) species if the
coupling proceeds through a catalytic manner.
17%
35%c
13
14
1 mmol
NHPy
24%
Br
0.38 mmol
NHPy
15
16
61%
1 mmol
B(OH)2
15%d
1 mmol
17
18
47%e
0.5 mmol
8%
Scheme 2. Proposed reaction mechanism.
2 mmol
1 mmol
2 mmol
2%
52%d
In conclusion, a practical procedure for the synthesis of N-
arylpyridin-2-amine analogues has been developed. The reaction
go through copper-promoted Chan-Lam coupling of 2-
aminopyridine with aryl boronic acids. The desired products
were isolated in moderate to good yields with good functional
group tolerance.
19
20
68%
6%c
Acknowledgments
21
17%
The authors thank the state of Mecklenburg-Vorpommern, the
Bundesministerium für Bildung und Forschung (BMBF) and the
Deutsche Forschungsgemeinschaft for financial support. We also
thank Dr. C. Fischer, S. Schareina and Dr. W. Baumann for their
excellent technical and analytical support. We also appreciate the
general supports from Prof. Matthias Beller in LIKAT.
2 mmol
22
45%f
References and notes
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Reaction conditions: Aryl boronic acid (1 equiv.), 2-amino-pyridine (1
a
equiv.), Cu(OAc)2·H2O (1.2 equiv.), K3PO4·H2O (2 equiv.), DMSO as
solvent, 120 oC, 24h; For 2 mmol scale, 5 mL of DMSO was used while for
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Analogues: An oven-dried 25 mL sealed tube with stirring bar was
charged with aryl boronic acid (1 equiv.), 2-amino pyridine (1
equiv.), Cu(OAc)2·H2O (1.2 equiv.), K3PO4·H2O (2 equiv.) and 3
or 5 mL of DMSO and then closed the sealed tube. The reaction
mixture was heated at 120 °C for 24 h. After the reaction finished,
the product was extracted with ethyl acetate (5 × 3 mL). The
organic layers were washed with brine, dried over Na2SO4, and
evaporated to yield the crude reaction mixture. The purification
was done by combi flash machine flash chromatography on silica
gel (eluent: heptanes:EtOAc = 3:2).
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