Facile access to fluoroalkylated 2-aminopyridines by Cu-catalyzed [3 + 3] couplings of oxime esters with β-CF3 acrylonitrile

Article abstract of DOI:10.1016/j.tetlet.2020.151858

Copper catalyzed the [3 + 3] coupling of the oxime esters with β-CF₃-acrylonitrile toward divergent fluoroalkyl-substituted 2-aminopyridines was described. This redox-neutral coupling conditions with the acrylonitrile affording the trifluoromet

Full text of DOI:10.1016/j.tetlet.2020.151858

Journal Pre-proofs
Facile Access to Fluoroalkylated 2-Aminopyridines by Cu-catalyzed [3+3]
Couplings of Oxime Esters with β-CF3 Acrylonitrile
Xueyan Li, Yanjiang Yu, Ruobing Qi, Dachang Bai
PII:
S0040-4039(20)30298-7
DOI:
Reference:
https://doi.org/10.1016/j.tetlet.2020.151858
TETL 151858
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
8 February 2020
10 March 2020
17 March 2020
Please cite this article as: Li, X., Yu, Y., Qi, R., Bai, D., Facile Access to Fluoroalkylated 2-Aminopyridines by
Cu-catalyzed [3+3] Couplings of Oxime Esters with β-CF3 Acrylonitrile, Tetrahedron Letters (2020), doi: https://
doi.org/10.1016/j.tetlet.2020.151858
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover
page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version
will undergo additional copyediting, typesetting and review before it is published in its final form, but we are
providing this version to give early visibility of the article. Please note that, during the production process, errors
may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
© 2020 Published by Elsevier Ltd.

Graphical Abstract
A new and convenient method for the synthesis of trifluoromethylated 2-aminopyridines or difluoromethylated 2-
aminopyridines through Cu-catalyzed [3+3] couplings of oxime esters with β-CF3 acrylonitrile.
Facile Access to Fluoroalkylated 2-
Aminopyridines by Cu-catalyzed [3+3]
Couplings of Oxime Esters with β-CF3
Acrylonitrile
Leave this area blank for abstract info.
Xueyan Li, Yanjiang Yu, Ruobing Qi, Dachang Bai *
CF2H
CF3
NOAc
R2
Cu(I)/DBU
Cu(I)
CN
+
F3C
R1
Ca(OAc)2
R1
N
NH2
R1
N
NH2
R2

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Facile Access to Fluoroalkylated 2-Aminopyridines by Cu-catalyzed [3+3] Couplings
of Oxime Esters with β-CF3 Acrylonitrile
Xueyan Li a, Yanjiang Yu a, Ruobing Qi b, Dachang Bai * a
aHenan Key Laboratory of Organic Functional Molecule and Drug Innovation, Collaborative Innovation Center of Henan Province for Green Manufacturing of
Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan
Normal University, Xinxiang 453007, China. E-mail: baidachang@htu.edu.cn.
b School of Chemical Engineering, Henan Technical Institute, Zhengzhou 450042,China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Copper catalyzed the [3+3] coupling of the oxime esters with β-CF3-acrylonitrile toward
divergent fluoroalkyl-substituted 2-aminopyridines was described. This redox-neutral coupling
conditions with the acrylonitrile affording the trifluoromethylated 2-aminopyridines,
respectively, under the reductive conditions, difluoromethylated 2-aminopyridines were
obtained. The reactions occurred under mild conditions with high functional-group compatibility
and excellent regioselectivity.
Available online
Keywords:
Copper
Oxime Esters
2-aminopyridines
fluoroalkyl
Naturally, fluorinated compounds synthesis are of great
interest in the fields of biomedicine, agriculture, and material
sciences.1-7 The incorporation of the fluoroalkyl substituents into
molecules is a powerful and widely employed strategy to
improve the lipophilicity and metabolic stability of important
leading compounds.8-15 While the trifluoromethyl group(-CF3)
has been widely employed in medicinal chemistry,16-21 the
relatively underexplored difluoromethyl group (-CF2H) has
recently been realized as a lipophilic hydrogen bond donor and
could act as a bioisostere of thiol or alcohol functional groups.16-
aminopyridines via the copper-catalyzed cyclization using oxime
esters and the in situ generated 2-benzylidenemalonitrile (Scheme
1B).63
A
. Examples of Bioactive Compounds
CF3
N
CF3
CF3
N
O
F
F
N
H
N
N
N
N
H
H
N
O
MeO2S
CDK9
COX-2
Nervous system agents
CF3
CF3
N
CF2H
24
HOOC
Traditional methods for the synthesis of difluoromethylated
CF3
N
CyHN
arenes include deoxyfluorination of arylaldehyde, transformation
of CF2H-containing building block or CF2R- group. Recenetly,
transition-metal catalyzed difluoromethylation of heteroarene
was developed, and provided an efficient access to
difluoromethylated heteroaromatic arenes and its derivatives.25-40
On the other side, the 2-aminopyridines are widely used in
heterocyclic synthesis, primarily because of their wide
application in medicinally relevant structures, dyes, and
luminescent materials.41-45 While, traditional approaches need
harsh reaction conditions, or pre-functional substrates.41-46
Therefore, the development of a highly efficient method for the
synthesis of fluoroalkylated 2-aminopyridine derivatives has
significance value. As shown in Scheme 1A, the fluoroalkyl-
substituted 2-aminopyridines are core structures in a large
number of pharmacologically molecules.47-49
N
NH2
N
N
N
N
NH
TRPM8
NURR-1
Anti Cancer
B.
C.
Cui's work
NOPiv
Ar
CN
Cu(I)
R2
R1
CN
Ar
NC
CN
+
+
ArCHO
R1
CN
via
R2
N
NH2
This work:
CF2H
N
CF3
N
NOAc
R2
R1
R2
R1
Cu(I)/DBU
Ca(OAc)2
Cu(I)
CN
+
F3C
R1
R2
NH2
NH2
Scheme 1. Examples of Bioactive Compounds Containing 4-
fluoroalkylated 2-Aminopyridine Skeleton and Previous
Approaches for the Synthesis of 2-Aminopyridines through
Copper-catalyzed Cyclization of Oxime Esters.
In recent decades, the oxime derivatives have emerged as
readily available reagents to construct pyridine derivatives by
transition-metal catalysis.50-54 Notably, the Cu(I) catalyzed [3+3]
annulations of oxime esters with α, β-unsaturated compounds
have provided practical and simpler accesses to pyridines.54-64
Recently, Cui and co-workers reported the synthesis of 2-
However, the methods for the synthesis of fluoroalkylated 2-
aminopyridines have been rather limited. In 2018, we developed
a
facile protocol for the synthesis of fluoroalkylated
pyridines/pyridones with β-CF3 enones.65 The β-CF3
acrylonitrilewas applied in this system, while only one example

2
Tetrahedron
of 4-CF3-2-aminopyridine was provided, the synthesis of
moderate to good yields (3a-3l), regardless of the presence of
halogens, EWGs and EDGs in the benzene ring, such as methyl,
methoxyl, cyano, bromo, SO2Me. The electron-rich arenes
afforded the desired products with higher reactivity. Notably, this
strategy was available for the construction of 3j in reasonable
yield, which could be used as therapeutic TRPM8 receptor
modulators. Heteroaryl-substituted oxime ester also performed
well in this transformation (3l, 47% yield).
difluoromethylated 2-aminopyridines was not explored. To
further apply β-CF3 acrylonitrile in this useful cyclization, we
now report divergent synthesis of 4-CF3-2-aminopyridine or 4-
CF2H-2-aminopyridine via copper catalyzed annulation of oxime
esters with β-CF3 acrylonitrile under operationally simple
conditions (Scheme 1C).
Initially, we commenced our study by investigating the
copper-catalyzed cyclization of oxime ester 1a with 2a (for
details, see Table S1 in the Supporting Information). To our
delight, the reaction delivered the desired product 3a in 58%
yield when CuCl was used at 100℃. Screening of the Cu(I)
catalysts and temperature showed that the combination of CuCl
and DMSO at 60℃ was optimal (Table 1, entries 1-5). Increasing
the equivalent of 1a, the product 3a could be obtained in 71%
yield at 80℃ (Table 1, entries 6 and 7). Interestingly, the addition
of DBU switching the trifluoromethylated product 3a to
difluoromethylated product 4a in 31% yield at 120℃. Different
copper salts and F- scavenges were examined, and further studies
showed that when DBU and Ca(OAc)2 were added, the yield of
4a improved to 57% (Table 1, entries 8-12), more catalyst
loading improved the yield to 65% (Table 1, entry 13). When
Ca(OAc)2 or LiOAc was used without DBU, only
trifluoromethylated product 3a was obtained (Table 1, entries 14
and 15). Based on our previous work, the DBU was probably
served as a base as well as a reductant.65
CF3
NOAc
R2
CuCl
CN
R1
+
F3C
DMSO, 80ºC
R2
R1
N
NH2
CF3
1
2
3
CF3
N
CF3
NH2
N
NH2
N
NH2
R
3b,
3c,
MeO
i
3a
3d,
, 71% yield
CF3
68% yield
CF3
R = Pr, 32% yield
R = Me, 49% yield
CF3
N
NH2
N
NH2
N
NH2
R
Br
R
3e
3g
3h
, R = CN, 23% yield
, 40% yield
CF3
, R = Me, 30% yield
R = MeO, 73% yield
3i
,
3f
, R = SO2Me, 41% yield
CF3
CF3
N
N
NH2
N
NH2
N
NH2
O
CF3
3j
3k
3l
, 47% yield
, 51% yield
, 72% yield
Table 1. Optimization Studiesa
Scheme 2. Scope of oxime esters affording the 4-
trifluoromethylated 2-aminopyridines. Conditions A: a Reaction
Conditions: 1a (0.3 mmol), 2a (0.2 mmol), CuCl (0.04 mmol),
DMSO (2.0 mL), 24 h, isolated yields.
CF3
CF2H
NOAc
Cu(I)
CN
+
or
F3C
DMSO
Ph
Ph
N
NH2
Ph
N
NH2
1a
2a
3a
4a
We next examined the scope of the transformation for the
synthesis of 4-difluoromethyl-2-aminopyridines (Scheme 3, 4a-
4j). The coupling systems also tolerated oxime esters bearing p-
Me, p-iPr, p-SO2Me, m-MeO, o-Me, o-CF3 substituents in the
benzene ring (4a-4g, 31-65% yield), The coupling of oxazole and
2-Np substituted oxime esters also proceed smoothly to afford
the corresponding products (4h and 4i, 41% yield and 31%
yield ). Tetra-substituted difluoromethyl 2-aminopyridine 4j was
synthesized in 43% yield with the α-substituted oxime ester.
Catalyst
(mol %)
CuCl
Yield Yield
3a(%) 4a(%)
Entry
1a：2a T(℃) Additive
1
2
1:1.5 100
--
--
58
61
--
--
CuCl
1:1.5
60
3
4
5
6
7
8
9
10
11
CuCl
CuBr
CuI
CuCl
CuCl
CuCl
CuCl
CuI
1:1.5
1:1.5
1:1.5
1.5:1
1.5:1
40
60
60
60
80
--
--
--
--
--
14
40
46
62
71
--
--
--
--
--
--
--
--
--
31
13
41
43
CF2H
NOAc
R2
CuI
CN
R1
+
F3C
DBU, Ca(OH)2,
DMSO
R2
CF2H
N
R1
N
NH2
1:1.5 120
1:1.5 80
1:1.5 120
1.5:1 120
DBU
DBU
DBU
DBU
DBU/
Ca(OAc)2
DBU/
Ca(OAc)2
1
2
4
CF2H
CF2H
CuI
N
NH2
N
NH2
NH2
MeO2S
R
12
CuI
CuI
1.5:1 120
1.5:1 120
--
--
57
4a
4d,
, 65% yield
CF2H
37% yield
CF2H
4b
, R = Me, 38% yield
i
4c
, R = Pr, 44% yield
CF2H
13b
65
--
N
NH2
N
NH2
N
NH2
14
15
CuI
CuI
1.5:1 120 Ca(OAc)2
1.5:1 120 LiOAc
61
50
CF3
OMe
4e,
4f,
4g,
32% yield
CF2H
41% yield
CF2H
36% yield
CF2H
a Reaction Conditions: 1a (0.2 mmol), 2a (0.2 mmol), CuI (0.04
mmol), DMSO (2.0 mL), 24 h, DBU (0.4 mmol), Ca(OAc)2 (0.2
mmol), LiOAc (0.2 mmol), isolated yields. bCuI (0.08 mmol)
N
O
N
NH2
N
NH2
N
NH2
On the basis of these optimized reaction conditions, we first
investigated the scope and generality of the coupling systems for
the preparation of 4-trifluoromethylated products (Scheme 2, 3a-
3l). Variation of the oxime esters with differential substitution on
the aromatic ring, exhibited good functional group tolerance to
afford the desired products with excellent chemoselectivity in
4h,
4i,
4j,
43 % yield
41% yield
31% yield
Scheme
3
Scope of oxime esters affording the 4-
a
difluoromethylated 2-aminopyridines. Conditions B: Reaction
Conditions: 1a (0.3 mmol), 2a (0.2 mmol), CuI (0.08 mmol),

3
DBU (0.4 mmol), Ca(OAc)2 (0.2 mmol), DMSO (2.0 mL), 24 h,
isolated yields.
dihydropyridine intermediate C, and further oxidation of C by
two copper(II) species furnishes 4-CF3-2-aminopyridine 3a with
regeneration of the copper(I) catalyst. In presence of a suitable
base and reductant, C would afford intermediate E through β-F
elimination, which then isomerizes to the 4-CF2H-2-amino-
pyridine 4a. Meanwhile, the Cu(I) catalyst is regenerated by
further reduction of Cu(II). Following this mechanism, the
dihydropyridone C species is either oxidized by Cu(II), or
undergoes elimination of HF with DBU, which served as a
stronger base and reductant.
The synthetic utility of the fluoroalkylated 2-aminopyridines
was then briefly demonstrated (Scheme 4). The amino product 3a
could be easily transformed to N-acetyl derivative 5 in 72% yield.
It has been reported that the pyrido[1,2-a]pyrimidine-3-
carboxamide derivatives, which showed promising anticancer
activity, could be synthetized from the 4-CF3-2-aminopyridine
3a.66
CF2H
CF2H
F
F
Py, DMAP
CF3
CF3
O
O
O
+
-F elimination
Hexane
72% yield
Base
O
Ph
N
N
-F-
Ph
N
NH2
H
Ph
N
H
C'
NH2
Ph
N
NH2
Ph
N
NH2
4a
5
D
E
CF3
Ph
O
O
2CuII
O
O
CF3
CF3
Ref. [66]
R
N
N
aromatization
Ph
EtO
EtO
OEt
+
Ph
N
C
NH2
H
F3C
N
Ph
N
NH2
N
3a
NH2
CuI
pyrido[1,2-a]pyrimidine-3-
carboxamide derivatives
3a
CF2H
NH CF3
reducing
agent
Scheme 4. Derivatization Reactions.
To gain the mechanism of the present 2-aminopyridine
CN
CuII
Ph
+
B
Ph
N
NH2
4
51,65
synthesis, several experiments were performed.
Addition of
CuX(OAc)
TEMPO or 1,1-diphenylethylene to the coupling of 1a and 2a did
not inhibit the formation of the 3a, and the addition of TEMPO
also did not inhibit the formation of 4-CF2H-2-NH2-pyridine 4a,
these results indicated that this reaction did not proceed through a
radical pathway. When an equimolar mixture of 1a and 1c was
used to competitively couple with β-CF3 acrylonitrile, products
3a and 3c were obtained in 21% and 34% yield, indicating that
the electron-rich oxime ester reacted at a slightly higher rate
(Scheme 5b). We also performed the H/D exchange experiment,
with the tBuOD as deuterium source (modified conditions B), the
isolated product 4a-dn revealed that both 3- and 5- positions were
equally deuterated (27% D), and H/D exchanged was also
detected at the difluoromethyl position (20% D), these results
supports the tautomerization of intermediate E (see Scheme 6) in
the system, which is consist with our previous studies.65
Ph
NOAc
CN
F3C
Ph
NH
CuIIX
1a
2
A
Scheme 6. Proposed Mechanism.
In summary, we have developed Cu-catalyzed [3+3]
cycloaddition of oxime acetates with β-CF3 acrylonitrile for the
synthesis of 4-CF3-2-NH2-pyridines and 4-CF2H-2-NH2-
pyridines with high regioselectivity and redoxselectivity. Under
redox-neutral conditions, the coupling afforded 4-CF3-2-NH2-
pyridines smoothly. When DBU was used, 4-CF2H-2-NH2-
pyridines were formed. The systems cover a particularly broad
range of oxime acetates. The elegant control of reaction
selectivity may provide insight for future studies of other Cu-
catalyzed annulation reactions. Further studies and the
application of this protocol are in progress.
(a) radical inhibitor
CF3
Additive Yield
Acknowledgments
NOAc
2.0 equiv TEMPO 70%
Conditions A
CN
CN
F3C
+
+
2.0 equiv
50%
Ph
Ph
Ph
Ph
N
NH2
Ph
Ph
Project supported by the NSFC (No. 21801067), the
Education Department of Henan Province Natural Science
Research Program (No.18A150010), and fund from Henan
Normal University (qd17108 and 2019QK01)
1a
2a
2a
3a
Conditions B
TEMPO (2 equiv)
CF2H
NOAc
F3C
26%
N
NH2
1a
4a
Conflicts of interest
(b) Competition experiment
NOAc
CN
There are no conflicts to declare
NOAc
+
F3C
2a
3a
yield 21%
3c
yield 34%
+
Ph
MeO
Conditions A
References and notes
1a
1c
1.
2.
3.
Uneyama, K. Organofluorine Chemistry; Blackwell: Oxford,
2006; (b) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis,
Reactivity, Applications; Wiley-VCH: Weinheim, 2004.
Hiyama, T.; Kanie, K.; Kusumoto, T.; Morizawa, Y.; Shimizu, M.;
Organofluorine Compounds: Chemistry and Application;
Springer: Berlin, 2000.
Zhuo, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; AceÇa, J. L.;
Soloshonok, V. A.; Izawa, K.; Liu, H. Chem. Rev.
2016, 116, 422-518;
20% D
CF2H/D
H/D
(c) H/D exchange
28% D
27% D
Conditions B
NOAc
D/H
Ph
CN
+
F3C
(CH3)3OD (15 equiv)
25% yield
Ph
N
NH2 20% D
1a
4a-
2a
dn
Scheme 5. Mechanistic studies.
4.
5.
Campbell, M. G.; Ritter, T. Chem. Rev. 2015, 115, 612-633.
Vitale, A.; Bongiovanni, R.; Ameduri, B. Chem. Rev. 2015, 115,
8835-8866.
Tomashenko, O. A.; Grushin, V. V. Chem. Rev. 2011, 111, 4475-
4521.
Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc.
Rev. 2008, 37, 320-330.
Meanwell, N. A. J. Med. Chem. 2018, 61, 5822-5880.
Ni, C.-F.; Hu, J.-B. Chem. Soc. Rev. 2016, 45, 5441-5454.
On the basis of the above results and previous studies on the
copper-catalyzed annulation of oxime derivatives, a plausible
mechanism is given for the formation of fluoroalkylated 2-
aminopyridines (Scheme 6). Oxidation of Cu(I) by oxime ester
1a gives an intermediate A together with another Cu(II) species.
Conjugate addition of A to β-CF3 acrylonitrile and subsequent
protolonysis leads to intermediate B. cyclization would produce a
6.
7.
8.
9.

4
Tetrahedron
10. Alonso, C.; Marigorta, E. M.de.; Rubiales, G.; Palacios, F.
Chem. Rev. 2015, 115, 1847-1935.
41. Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem.
Rev. 2012, 112, 2642-2713.
11. Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. J. Med. Chem. 2015, 58, 8315 - 8359.
12. Meanwell, N. A. J. Med. Chem. 2011, 54, 2529 - 2591.
42. Chernyark, N.; Gevorgyan, V. Angew. Chem., Int. Ed., 2010, 49,
2743–2746.
43. Chinchilla, R.; Nájera, C.; Yus, M. Chem. Rev. 2004, 104, 2667-
2722.
13. Lundgren, R. J.; Stradiotto, M. Angew. Chem. Int. Ed. 2010, 49,
44. Liao, J.-Y.; Wu, Q.-Y.; Lu, X.; Zou, N.; Pan, C.-X.; Liang, C.; Su,
G.-F.; Mo, D.-L. Green Chem. 2019, 21, 6567-6573.
45. Elmkaddem, M. K.; Fischmeister, C.; Thomas, C. M.; Renaud, J.-
L. Chem. Commun. 2010, 46, 925–927.
9322-9324.
14. Manfred, S. Angew. Chem. Int. Ed. 2006, 45, 5432-5446.
15. Shimizu, M.; Hiyami, T. Angew. Chem. Int. Ed. 2005, 44, 214-
231.
16. Chu, L.-L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298-1304.
17. Liu, T.-F.; Shao, X.-X.; Wu, Y.-M.; Shen, Q.-L. Angew. Chem.
Int. Ed. 2012, 51, 540-543.
18. Furuya, T.; Kamlet ,A. S.; Ritter, T. Nature 2011, 473, 470-477.
19. Zhang, C.-P.; Wang, Z.-L.; Chen, Q.-Y.; Zhang, C.-T.; Gu Y.-C.;
Xiao, J.-C. Angew. Chem. Int. Ed. 2011, 50, 1896-1900.
20. Mu, X.; Chen, S.-J.; Zhen, X.-L.; Liu, G.-S. Chem. Eur. J. 2011,
17, 6039-6042.
46. Pasumansky, L.; Hernandez, A. R.; Gamsey, S.; Goralski, C. T.;
Singaram, B. Tetrahedron Lett. 2004, 45, 6417–6420.
47. Rageot, D.; Bohnacker, T.; Keles, E.; McPhail, J. A.; Hoffmann,
R. M.; Melone, A.; Borsari, C.; Sriramaratnam, R.; Sele, A. M.;
Beaufils, F.; Hebeisen, P.; Fabbro, D.; Hillmann, P.; Burke, J.E.;
Wymann, M.P. J. Med. Chem. 2019, 62, 6241−6261.
48. Rageot, D.; Bohnacker, T.; Melone, A.; Langlois, J. B.; Borsari,
C.; Hillmann, P.; Sele, A. M.; Beaufils, F.; Zvelebil, M.;
Hebeisen, P.; Löscher, W.; Burke, J.; Fabbro, D.; Wymann, M. P.
J. Med. Chem. 2018, 61, 10084−10105.
21. Oishi, M.; Kondo, H.; Amii, H. Chem. Commun. 2009, 1909-
1911.
49. Stark, D G.; Morrill, L. C.; Yeh, P P.; Slawin, A. M.; O'Riordan,
T. J.; Smith, A. D. Angew. Chem. Int. Ed. 2013 , 52, 11642-11646.
50. Zhao, B.; Liang, H.-W.; Yang, J.; Yang, Z.; Wei, Y. ACS Catal.
2017, 7, 5612-5617.
51. Huang, H.-W.; Ji, X.-C.; Wu, W.-Q.; Jiang, H.-F. Chem. Soc. Rev.
2015, 44, 1155-1171.
22. Sessler, C. D.; Rahm, M.; Becker, S.; Goldberg, J. M.; Wang, F.;
Lippard, S. J. J. Am. Chem. Soc. 2017, 139, 9325-9332.
23. Zafrani, Y.; Yeffet, D.; Sod-Moriah, G.; Berliner, A.; Amir, D.;
Marciano, D.; Gershonov, E.; Saphier, S. J. Med. Chem. 2017, 60,
797-804.
52. Zhao, M.-N.; Ren, Z.-H.; Yu, L.; Wang, Y.-Y.; Guan, Z.-H. Org.
Lett. 2016, 18, 1194–1197.
53. Xu, Y.; Hu, W.; Tang, X.; Zhao, J.; Wu, W.; Jiang, H. Chem.
Commun. 2015, 51, 6843-6846.
54. Too, P. C.; Noji, T.; Lim, Y. J.; Li, X.; Chiba, S. Synlett. 2011,
2789-2794.
55. Tan, W.-W.; Ong, Y. J.; Yoshikai, N. Angew. Chem. Int. Ed. 2017,
56, 8240-8244.
56. Zhu, C.; Zhu, R.; Zeng, H.; Chen, F.; Liu, C.; Wu, W.; Jiang, H.
Angew. Chem. Int. Ed. 2017, 56, 13324-13328.
57. Jiang, H.-F.; Yang, J.-D.; Tang, X.-D.; Li, J.-X.; Wu, W.-Q. J.
Org. Chem. 2015, 80, 8763-8771.
58. Du, W.; Zhao, M.-N.; Ren, Z.-H.; Wang ,Y.-Y.; Guan, Z.-H.
Chem. Commun. 2014, 50, 7437-7439.
59. Wei, Y.; Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756-3759.
60. Tang, X.; Huang, L.; Qi, C.; Wu, W.; Jiang, H. Chem.
Commun.2013, 49, 9597-9599.
24. Caminati, W.; Melandri, S.; Moreschini, P.; Favero, P. G. Angew.
Chem. Int. Ed. 1999, 38, 2924-2925.
25. Yerien, D. E.; Barata-Vallejo, S.; Postigo, A. Chem. Eur. J. 2017,
23, 14676-14701.
26. Rong, J.; Ni, C.; Hu, J. Asian J. Org. Chem. 2017, 6, 139-152.
27. Fu, X-P.; Xue, X-S.; Zhang, X-Y.; Xiao, Y-L.; Zhang, S.; Guo, Y-
L.; Leng, X.-B.; Houk, K.N.; Zhang, X.-G. Nat. Chem. 2019. 11,
948–956.
28. Miao, W.; Zhao, Y.; Ni, C.; Gao, B.; Zhang,W.; Hu, J. J. Am.
Chem. Soc. 2018, 140, 880-883.
29. Xu, C.; Guo, W.-H.; He, X.; Guo, Y.-L.; Zhang, X.-Y.; Zhang, X.
Nat. Commun. 2018, 9, 1170.
30. Lu, C.-H.; Gu, Y.; Wu, J.; Gu, Y.-C.; Shen, Q.-L. Chem. Sci.2017,
8, 4848-4852.
61. Ren, Z.-H.; Zhang, Z.-Y.; Yang, B.-Q.; Wang,Y.-Y.; Guan, Z.-H.
Org. Lett.2011, 13, 5394-5397.
31. Xu, L.; Vicic, D. J. Am. Chem. Soc. 2016, 138, 2536-2539.
32. Gu, Y.; Leng, X.; Shen, Q. Nat. Commun. 2014, 5, 5405.
33. Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524-5527.
34. Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baran, P. S. J. Am.
Chem. Soc. 2012, 134, 1494-1497.
35. Ling, Y.; An, D.; Zhou, Y.-Y.; Rao, W. Org. Lett. 2019, 21, 3396-
3401.
36. Feng, Z.; Xiao, Y.-L.; Zhang, X. Acc. Chem. Res. 2018, 51,
2264−2278.
62. Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc.2008, 130, 6918-6919.
63. Wu, Q.; Zhang, Y.; Cui, S. Org. Lett. 2014, 16, 1350-1353
64. Cai, Z-J.; Lu, X-M.; Wang, S-Y. Ji, S-J. Acta Chim. Sinica. 2014,
72, 914-919.
65. Bai, D.-C.; Wang, X.-L.; Zheng, G.-F.; Li, X.-W. Angew. Chem.
Int. Ed. 2018, 57, 6633-6637.
66. Kumar, G. S.; Dev, G. J.; Kumar, N. R.; Swaroop, D. K.; Chandra,
Y. P.; Kumar, C. G.; Narsaiah, B. Chem. Pharm. Bull. 2015, 63,
584–590.
37. Feng, Z.; Min, Q.-Q.; Fu, X.-P.; An, L.; Zhang, X. Nat. Chem.
2017, 9, 918−923.
38. Feng, Z.; Min, Q.-Q.; Zhang, X. Org. Lett. 2016, 18, 44−47.
39. Feng, Z.; Min, Q.-Q.; Zhao, H.-Y.; Gu, J.-W.; Zhang, X. Angew.
Chem., Int. Ed. 2015, 54, 1270−1274.
Click here to remove instruction text...
40. Feng, Z.; Min, Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X. Angew.
Chem., Int. Ed. 2014, 53, 1669−1673.
1. Excellent regioselectivity
2. Broad substrate scope with good
functional group tolerance
3. Trifluoromethylated or
difluoromethylated 2-aminopyridines
formation