Copper(II)-Promoted Mono-Selective ortho C-H Chlorination of Arenes by Using Trimethyl(trichloromethyl)silane

Article abstract of DOI:10.1055/s-0036-1591542

The first example of a Cu-promoted ortho -chlorination of aryl C-H bonds by using TMSCCl ₃ as chlorinating agent is reported. This reaction features a high selectivity toward monochlorination over dichlorination, compatibility with a variety of

Full text of DOI:10.1055/s-0036-1591542

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©
Georg Thieme Verlag Stuttgart · New York
2018, 29, A–C
letter
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en
Synlett
Z. Zhu et al.
Letter
Copper(II)-Promoted Mono-Selective ortho C–H Chlorination of
Arenes by Using Trimethyl(trichloromethyl)silane
Zhaobin Zhu
X
X
Changming Xu*
Yongchang Wang
Li Zhao
Cu(OAc)2
N
N
TMSCCl3
Cl
R
R
X = CH or N
R = H, Cl, Me, MeO, Ph
13 examples
27–72% yield
Lanzhou Jiaotong University, School of Chemical
and Biological Engineering, No. 88, Anning West
Road, Lanzhou 730070, P. R. of China
xucm@mail.lzjtu.cn
novel chloride source (solid, bench-stable)
inexpensive metal
high mono/di selectivity
Received: 08.12.2017
Accepted after revision: 17.01.2018
Published online: 15.02.2018
1, A). Unfortunately, the control of monochlorination/di-
chlorination selectivity was problematic in the above-men-
tioned cases. Recently, the groups of Carretero13 and Shi
independently reported Cu-catalyzed C–H chlorinations of
anilines and benzamides, respectively, bearing removable
directing groups, with N-chlorosuccinimide (NCS). The Han
group also achieved a Cu-mediated C–H mono- and dichlo-
rination of 2-arylpyridines with NCS (Scheme 1, A). Be-
cause of the important role of N-heterocyclic compounds in
the pharmacy field, we developed a Cu-promoted mono-se-
lective method for the ortho-chlorination of 2-arylpyridines
and 2-arylpyrimidines by using the Ruppert–Prakash re-
14
DOI: 10.1055/s-0036-1591542; Art ID: st-2017-w0887-l
Abstract The first example of a Cu-promoted ortho-chlorination of
aryl C–H bonds by using TMSCCl as chlorinating agent is reported. This
reaction features a high selectivity toward monochlorination over di-
chlorination, compatibility with a variety of functional groups, and
gram-scale synthesis.
3
15
Key words C–H activation, copper, chlorination, trimethyltrichloro-
methylsilane
Aromatic chlorides are ubiquitous building blocks in
chemical synthesis, as well as key structural motifs in nu-
merous natural products and manufactured drugs.1 They
are usually obtained by direct electrophilic chlorination of
agent (trichloromethyl)trimethylsilane (TMSCCl ) as chlori-
3
nating agent (Scheme 1, B). TMSCCl has previously been
3
–
used as a trichloromethylating reagent for addition of CCl
to aldehydes, ketones, imines, or Michael acceptors. The
present seminal work represents the first example of the
3
16
2
electron-rich arenes, Sandmeyer reactions of diazonium
3
salts, or directed ortho-metalation followed by chlorine
use of TMSCCl as a solid and bench-stable source of chlo-
3
4
quenching. The first of these methods suffers mainly from
rine.
poor regioselectivity and overchlorination of substrates,
whereas the other methods involve laborious and/or haz-
ardous reaction procedures, and show poor functional-
group tolerance.
(A) Previous work:
X
X
[
Cu ]
N
Transition-metal-catalyzed C–H activation has recently
emerged as a promising technique for the step-economic
preparation of functionalized molecules. In this context,
significant achievements have been made in direct C–H
chlorination catalyzed by transition metals such as Pd,6
N
DCE, PhCOCl, LiCl or NCS
Cl
X = CH or N
(B) This work:
5
7
8
X
N
X
Rh, or Ni. Although copper is one of the most abundant
and inexpensive metals, Cu-catalyzed or Cu-mediated C–H
Cu(OAc)2
TMSCCl3
N
9
chlorination has received relatively little attention. In a pi-
Cl
oneering work, Yu and co-workers reported a Cu-catalyzed
direct C–H chlorination of 2-arylpyridines by using 1,2-di-
chloroethane (DCE) as a chlorine source. Subsequently, a
Scheme 1 Directed copper-catalyzed or -mediated chlorination of
C(sp )–H bonds of N-heteroarenes
2
10
Cu-catalyzed ortho-chlorination of 2-arylpyridines with
11
12
PhCOCl or alkali-metal chlorides was reported (Scheme
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

B
Synlett
Z. Zhu et al.
Letter
Initially, we envisioned a reaction of 2-phenylpyridine
the reaction did not proceed in its absence (entry 10). A
lower loading of TFA led to an increased amount of byprod-
uct 4a, whereas higher loadings of TFA led to the formation
of monochlorinated product 3a in slightly reduced yields
(entries 11–12). The use of other additives such as acetic
acid, pivalic acid (PivOH), or 3-nitrobenzoic acid gave infe-
rior results (entries 13–15).
(
1a) with two equivalents of TMSCCl in the presence of
3
Cu(OAc) and trifluoroacetic acid (TFA) under a nitrogen at-
2
mosphere. Unexpectedly, the monochlorinated product 3a
72% yield) and a trace of the dichlorinated product 4a were
obtained, whereas the trichloromethylated product 5 was
not observed after reaction in DCE at 80 °C for 96 hours (Ta-
(
ble 1, entry 1). When TMSCCl was removed from the reac-
tion system, the reaction was completely shut down (entry
By using the optimized conditions, we then examined
3
18
the substrate scope of this chlorination reaction. As
shown in Scheme 2, a variety of phenylpyridines bearing
various substituents, such as chloro (1b), phenyl (1c),
methyl (1d and 1e), or methoxy (1g and 1h) in the para- or
meta-positions of the aromatic ring provided the desired
monochlorinated products in good yields. However, with
the ortho-methyl-substituted substrate 1f and the ortho-
methoxy-substituted substrates 1i, lower yields were ob-
tained due to the steric effect, and large quantities of the
starting materials were recovered. Notably, this chlorina-
tion reaction showed a high regioselectivity toward sub-
strates containing a meta-substituent in the phenyl ring. It
also proceeded with less sterically hindered ortho-C–H
bonds, giving the monochlorinated products 3e and 3h in
good yield. When pyrimidine was employed as a directing
group, the reaction proceeded smoothly to afford the corre-
2
). This control experiment indicated that the chlorine
10
source was TMSCCl rather than the solvent DCE; this is
probably due to the decomposition of CCl into dichloro-
carbene and a chloride ion. Note also that no reaction oc-
3
–
3
17
curred in the absence of Cu(OAc) (entry 3). Lowering the
2
Cu(OAc) loading to a catalytic amount led to the formation
2
of traces of the product under a N or air atmosphere (entry
2
4). Screening of other copper salts was also conducted, but
none of them gave superior results (entries 5–9). The acid
TFA was found to be essential for this transformation, and
Table 1 Optimization of the Reaction Conditionsa
N
N
3a
Cu(OAc)2 (1 equiv)
Cl
Cl
1a
N
+
X
X
+
TFA (5 equiv)
Cl
Cu(OAc)2 (1 equiv)
CCl3
TMSCCl3 (2 equiv)
TMSCCl3
N
DCE, 80 °C, 96 h
standard conditions
5
N
N
2
not observed
TFA (5 equiv)
X = CH or N
1
Cl
R
R
DCE, 80 °C, 96 h
4
a
3
b
Entry
Variation from standard conditions
Yield (%)
3
a
4a
N
N
N
1
2
3
4c
5
6
7
8
9
none
72
0
5
0
0
0
0
Cl
Cl
Cl
Ph
Cl
no TMSCCl
no Cu(OAc)
Cu(OAc) (0.2 equiv)
3
3a, 72%
3b, 49%
3c, 50%
2
0
Me
2
trace
40
32
trace
0
Me
N
N
N
CuCl
CuCl
2
Me
Cl
Cl
3e, 69%
Cl
3f, 27%
0
0
3
d, 63%
CuBr
OMe
CuI
0
MeO
N
N
Cu(OTf)
2
0
0
N
Cl
Cl
1
0
1
2
3
4
5
no TFA
trace
53
60
6
0
MeO
Cl
g, 51%
3
3h, 69%
3i, 35%
1
1
1
1
TFA (3.0 equiv)
TFA (10.0 equiv)
AcOH
27
2
N
N
N
N
0
N
N
N
N
PivOH
23
54
0
Cl
Me
Cl
3k, 58%
MeO
Cl
3l, 47%
Cl
Cl
1
3-O
2
NC
6
H
4
CO
2
H
12
3j, 65%
3m, 48%
a
Standard conditions: 1a (0.2 mmol), 2 (0.4 mmol), Cu salt (1.0 equiv),
TFA (5.0 equiv), DCE (2.0 mL), 80 °C, 96 h, under N
2
.
Scheme 2 Copper-mediated chlorination of aromatic C–H bonds with
b
Isolated yield.
TMSCCl3
c
2
Under N or air.
©
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–C

C
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.
2006, 8, 2523. (c) Song, B.; Zheng, X.; Mo, J.; Xu, B. Adv. Synth.
Catal. 2010, 352, 329. (d) Korwar, S.; Brinkley, K.; Siamaki, A. R.;
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
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ce
1(
6
0
6
RZ
J
A
0
2
8
N) oaitn
a
l
N
a
ut ra
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Secince
F
o
u
n
d
oaitn
of
C
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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