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Synlett
Z. Zhu et al.
Letter
sponding monochlorinated products 3j–m in moderate
yields. Both electron-deficient (1b and 1m) and electron-
rich arenes (1d, 1g, 1k, and 1l) showed comparable reactiv-
ities under the optimized conditions. A high selectivity to-
ward monochlorination over dichlorination was main-
tained in all cases, with only traces of dichlorinated prod-
ucts were detected by TLC analysis.
(b) Kalyani, D.; Dick, A. R.; Anani, W. Q. Sanford M. S. Org. Lett.
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Gupton, B. F.; Ellis, K. C. Org. Lett. 2015, 17, 1782. (e) Kang, K.;
Lee, S.; Kim, H. Asian J. Org. Chem. 2015, 4, 137. (f) Zhang, Q.;
Yang, F.; Wu, Y. Org. Chem. Front. 2014, 1, 694. (g) Zhao, X.;
Dimitrijević, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131, 3466.
(h) Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano,
S.; Sato, M.; Nishiyama, S.; Tanabe, T. J. Am. Chem. Soc. 2009,
To demonstrate the practicability of this method, we
131, 11310. (i) Zhang, G.; Sun, S.; Yang, F.; Zhang, Q.; Kang, J.;
conducted
a gram-scale experiment. Gratifyingly, the
Wu, Y.; Wu, Y. Adv. Synth. Catal. 2015, 357, 443.
monochlorinated product 3a was obtained in 51% isolated
yield with recovery of the 48% of the starting material 1a af-
ter 96 hours in DCE at 80 °C; the dichlorinated product 4a
was not detected (Scheme 3).
(
7) (a) Qian, G.; Hong, X.; Liu, B.; Mao, H.; Xu, B. Org. Lett. 2014, 16,
5
294. (b) Zhang, P.; Hong, L.; Li, G.; Wang, R. Adv. Synth. Catal.
2015, 357, 345. (c) Lied, F.; Lerchen, A.; Knecht, T.; Mück-Licht-
enfeld, C.; Glorius, F. ACS Catal. 2016, 6, 7839.
(8) Zhan, B.-B.; Liu, Y.-H.; Hu, F.; Shi, B.-F. Chem. Commun. 2016, 52,
4
934.
Cu(OAc)2 (1 equiv)
TMSCCl3 (2 equiv)
(
9) For a review on copper-mediated functionalization of nonacti-
vated C–H bonds, see: Rao, W.-H.; Shi, B.-F. Org. Chem. Front.
2016, 3, 1028.
N
N
1
a
TFA (5 equiv)
3a
Cl
DCE, 80 °C, 96 h
(10) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
006, 128, 6790.
(11) Wang, W.; Pan, C.; Chen, F.; Cheng, J. Chem. Commun. 2011, 47,
978.
1
.0 g
5
1%, 0.62 g
2
Scheme 3 Gram-scale experiment for chlorination of 2-phenylpyridine
3
(
(
12) Mo, S.; Zhu, Y.; Shen, Z. Org. Biomol. Chem. 2013, 11, 2756.
13) Urones, B.; Manu Martínez, Á.; Rodríguez, N.; Gómez Arrayás,
R.; Carretero, J. C. Chem. Commun. 2013, 49, 11044.
In summary, we have developed the first copper-medi-
ated ortho-chlorination of aromatic C–H bonds by using
(
(
14) Li, B.; Liu, B.; Shi, B.-F. Chem. Commun. 2015, 51, 5093.
15) Du, Z.-J.; Gao, L.-X.; Lin, Y.-J.; Han, F.-S. ChemCatChem 2014, 6,
TMSCCl as a chlorine source. This reaction showed a high
3
selectivity toward monochlorination over dichlorination in
all cases, and a high regioselectivity toward substrates bear-
ing a meta-substituent in the benzene ring. Moreover, the
reaction is compatible with a variety of functionalities and
is amenable to be scaled up to a gram scale.
1
23.
(16) (a) Fujita, M.; Hiyama, T. J. Am. Chem. Soc. 1985, 107, 4085.
(b) Wu, N.; Wahl, B.; Woodward, S.; Lewis, W. Chem. Eur. J.
2
014, 20, 7718. (c) Fustero, S.; Herrera, L.; Lázaro, R.; Rodríguez,
E.; Maestro, M. A.; Mateu, N.; Barrio, P. Chem. Eur. J. 2013, 19,
1776. (d) Li, Y.; Cao, Y.; Gu, J.; Wang, W.; Wang, H.; Zheng, T.;
1
Sun, Z. Eur. J. Org. Chem. 2011, 676. (e) Wahl, B.; Lee, D. S.;
Woodward, S. Eur. J. Org. Chem. 2015, 6033. (f) Kister, J.;
Mioskowski, C. J. Org. Chem. 2007, 72, 3925. (g) Wahl, B.; Cabré,
A.; Woodward, S.; Lewis, W. Tetrahedron Lett. 2014, 55, 5829.
17) Fedoryński, M. Chem. Rev. 2003, 103, 1099.
Funding Information
National Natural Science Foundation of China (21662024). Natural
Science Foundation of Gansu Province (1606RJZA028). Young Scholars
Science Foundation of Lanzhou Jiaotong University (2016008).
(
(
18) Copper-Promoted Monochlorination of 2-Arylpyridines or 2-
N
a
ut ra
l
Secince
F
o
u
n
d
oaitn
of
G
a
nsu
P
orvn
i
ce
1(
6
0
6
RZ
J
A
0
2
8
N) oaitn
a
l
N
a
ut ra
l
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
Arylpyrimidines 1 with TMSCCl ; General Procedure
3
A solution of 1 (0.2 mmol), Cu(OAc)2 (0.2 mmol), TMSCCl3 (0.4
Supporting Information
mmol), and TFA (1.0 mmol) in DCE (2.0 mL) was stirred in a
reaction tube under N (1 atm) at 80 °C for 96 h, then cooled to
2
Supporting information for this article is available online at
r.t. A 2 M aq solution of NaOH (8.0 mL) was added, and the
mixture was extracted with CH Cl (3 × 10.0 mL). The organic
https://doi.org/10.1055/s-0036-1591542.
S
u
p
p
ortioIgnfrm oaitn
S
u
p
p
ortioIgnfrm oaitn
2
2
layers were combined, dried (MgSO ), and concentrated under
4
vacuum. The crude product was purified by chromatography
References and Notes
[
silica gel, PE–EtOAc (20:1)].
2
-(2-Chlorophenyl)pyridine (3a)
(
1) Petrone, D. A.; Ye, J.; Lautens, M. Chem. Rev. 2016, 116, 8003.
1
Yellow oil; yield: 27.2 mg (72%). H NMR (400 MHz, CDCl ): δ =
3
(
2) De La Mare, P. B. D. Electrophilic Halogenation: Reaction Path-
ways Involving Attack by Electrophilic Halogens on Unsaturated
Compounds; Cambridge University Press: Cambridge, 1976.
3) Hodgson, H. H. Chem. Rev. 1947, 40, 251.
7.29–7.32 (m, 1 H), 7.32–7.39 (m, 2 H), 7.48 (dd, J = 1.6, 7.2 Hz, 1
H), 7.60 (dd, J = 2.0, 7.6 Hz, 1 H), 7.65 (d, J = 8.0 Hz, 1 H), 7.77 (td,
J = 1.6, 7.6 Hz, 1 H), 8.73 (d, J = 4.8 Hz, 1 H).
(
(
(
2-(2,6-Dichlorophenyl) pyridine (4a)
4) Snieckus, V. Chem. Rev. 1990, 90, 879.
5) For a review, see: Liao, G.; Shi, B.-F. Acta Chim. Sinica 2015, 73,
1
Yellow oil; yield: 2.2 mg (5%). H NMR (400 MHz, CDCl ): δ =
3
7
7
.26–7.28 (m, 1 H), 7.34–7.37 (m, 2 H), 7.41 (d, J = 8.8 Hz, 2 H),
.82 (td, J = 2.0, 8.0 Hz, 1 H), 8.76–8.75 (m, 1 H).
1283.
(6) For selected examples of N-heteroarenes directed, palladium-
2
catalyzed, direct chlorination of C(sp )–H bonds, see: (a) Dick,
A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C