Copper-catalyzed aromatic C-H bond halogenation with lithium halides under aerobic conditions

Article abstract of DOI:10.1039/c3ob40185e

A concise and practical Cu-catalyzed protocol for the preparation of chloro- and bromoarenes via C-H bond activation has been developed. The advantages of this strategy are the employment of cheap Cu(NO₃) ₂·3H₂O, LiX and O₂, and its compatibility with both electron-donating and electron-withdrawing substituents on aryl rings.

Full text of DOI:10.1039/c3ob40185e

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Copper-catalyzed aromatic C–H bond halogenation
with lithium halides under aerobic conditions†
Cite this: DOI: 10.1039/c3ob40185e
Received 28th January 2013,
Accepted 15th February 2013
Song Mo,b Yamin Zhua and Zengming Shen*a
DOI: 10.1039/c3ob40185e
www.rsc.org/obc
A concise and practical Cu-catalyzed protocol for the preparation envisioned that halogenation of aryl C–H bonds could be
of chloro- and bromoarenes via C–H bond activation has been achieved in the presence of a copper catalyst combined with
developed. The advantages of this strategy are the employment cheap and nontoxic lithium halide. Copper is one of the most
of cheap Cu(NO3)2·3H2O, LiX and O2, and its compatibility with inexpensive metals; however, less attention has been paid to
both electron-donating and electron-withdrawing substituents on copper-catalyzed C–H bond halogenation.8 To the best of our
aryl rings.
knowledge, several pioneering and elegant examples of
copper-catalyzed ortho-selective halogenation have been
reported by Yu,9 Gusevskaya,10,17a Stahl11 and others.12 Unfor-
tunately, these methods are limited by the scope of electron-
rich substrates10,11,17a or by employing toxic halogen sources
such as Cl2CHCHCl2 (which is also used as a solvent in Yu’s
system).9 As part of our ongoing research, we continue to
investigate Cu-catalyzed C–H bond functionalization. In 2011,
we reported that Cu-catalyzed sp2 C–H halogenation by using
CrO3 as an oxidant and Ac2O as an additive.13 Low reactivity
and poor regioselectivity of these reactions in this oxidative
system were observed. Therefore, a general and simple copper
catalytic system with cheap LiX (X = Cl, Br) as the halogen source
and oxygen as a green oxidant is highly desired for the construc-
tion of valuable and versatile C–Cl and C–Br bonds via C–H
bond activation. Herein, we wish to demonstrate our recent
results on the aromatic C–H bond halogenation catalyzed by
cheap Cu(NO3)2·3H2O in the presence of LiX and O2.
Due to the advantage of the Cu–O2 system, initially, we en-
visioned a reaction of 2-phenylpyridine 1a with LiCl by using
20 mol% Cu(NO3)2·3H2O in an O2 atmosphere and acetic acid
as the solvent; to our delight, a 70% yield of the desired chlori-
nated product 3a was obtained (along with a trace amount of
product 2a) (Table 1, entry 1). After screening a series of
copper catalysts, we found that most copper salts, such as
Cu(OAc)2, CuSO4, Cu(OH)2, Cu(ClO4)2·H2O, Cu(acac)2,
CuS·H2O, CuO(nano), Cu2O, CuOAc, CuCN and CuSCN, gave
slightly decreased yields relative to Cu(NO3)2·3H2O (Table 1,
entries 5–11 and 13–16). In contrast, CuCl2 and Cu(OTf)2
showed very poor activity for this transformation (Table 1,
entries 12 and 17). Notably, running reactions in the absence
of a copper catalyst or under a nitrogen atmosphere showed
that no chlorinated products were observed, indicating that
both oxygen and copper catalysts are critical for chlorination
Aryl halides are a valuable class of synthetic materials that
have broad synthetic applications, for example, as coupling
partners in transition-metal-catalyzed cross-coupling reac-
tions,1 as well as important structural motifs in many natural
products and manufactured drugs.2 The majority of the syn-
thetic efforts for making halogenated arenes have focused on
electrophilic aromatic substitution using different types of
halogenating reagents (wherein dangerous Cl2 or Br2 is often
utilized)3 and ortho-lithiation followed by a halogen quench.4
Designing alternative and atom-economical methods for pre-
paring aryl halides remains a challenge in organic synthesis.
Over the past decades, transition-metal-catalyzed C–H bond
functionalization has attracted considerable attention and has
gradually become a modern and benign tool in organic syn-
thesis.5 Compared to the fast development of carbon–carbon
bond forming reactions via C–H bond activation, employment
of this strategy to construct carbon–halogen bonds is not well
explored.6 Recently, palladium-catalyzed C–H bond halogena-
tion was achieved under the assistance of directing groups.6 A
significant advance in this area was reported by Kakiuchi and
coworkers who demonstrated a Pd-catalyzed chlorination and
bromination of chelation-assisted aromatic C–H bonds with
simple halogenating reagents, aqueous HCl and HBr, by means
of electrochemical oxidation.7 Inspired by this work, we
aSchool of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,
800 Dongchuan Road, Shanghai, 200240, China.
E-mail: shenzengming@sjtu.edu.cn; Fax: +86-21-54741297
bDepartment of Chemistry, College of Life and Environment Sciences,
Shanghai Normal University, 100 Guilin Road, Shanghai, 200234, China
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob40185e
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Table 1 Optimization of reaction conditionsa
Table 2 Copper-catalyzed chlorination of aromatic C–H bonds with oxygen as
the terminal oxidanta,b
Yieldb (%)
Entry
[Cu] (20 mol%)
Time
2a
3a
1
Cu(NO3)2·3H2O
—
Cu(NO3)2·3H2O
Cu(NO3)2·3H2O
Cu(OAc)2
CuSO4
Cu(OH)2
Cu(ClO4)2·H2O
Cu(acac)2
CuS·H2O
CuO (nano)
CuCl2
14 h
12 h
72 h
72 h
2.5 d
2 d
32 h
2 d
3 d
2.5 d
3 d
2.5 d
30 h
4 d
4 d
2 d
3
—
11
—
4
0
9
70
—
39
—
58
48
66
52
61
39
46
27
57
49
62
45
0
2c
3d
4e
5
6
7
8
9
10
11
12
13
14
15
16
17
2
15
35
0
7
7
2
2
4
26
Cu2O
CuOAc
CuCN
CuSCN
Cu(OTf)2
3 d
a Reaction conditions: 2-phenylpyridine (0.3 mmol), Cu catalyst
(20 mol%, 0.06 mmol), LiCl (3 equiv., 0.9 mmol), HOAc (2 mL), O2
(1 atm), 150 °C. b Isolated yield: both monochlorinated product 2a and
dichlorinated product 3a can be isolated separately. c Without any
copper salts. d Under air. e Under a N2 atmosphere.
(Table 1, entries 2 and 4). Next, we tried to perform the reac-
tion under air, and found that the corresponding chlorinated
products with low yields were obtained (Table 1, entry 3). In
addition, solvent screening (AcOH, CH3CN, toluene, Ac2O)
revealed AcOH to be the most effective. Hence, the optimal
conditions involve Cu(NO3)2·3H2O (20 mol%) and LiCl
(3 equiv.) in O2 and HOAc at 150 °C.
To evaluate the generality of the Cu(NO3)2·3H2O–O2 system,
we next applied this procedure to a variety of commercially
available or readily synthesized14 arenes bearing nitrogen
atoms as directing groups (Table 2). A series of functional
groups at the para-position on the aryl rings, including fluoro
(1b), chloro (1c), trifluoromethyl (1d), methyl (1e), tert-butyl
(1f) and methoxyl (1g), proceeded very well in this system and
provided the corresponding dichlorinated products in good to
acceptable yields with trace amounts of monochlorinated pro-
ducts. It is noteworthy that exclusive ortho-regioselectivity was
observed as compared to our previous report with CrO3 as an
oxidant,13 indicating that environment-friendly molecular
oxygen as an oxidant greatly improved the efficient methodo-
logies for the synthesis of aryl halides and made this trans-
formation more practical. Gratifyingly, monochlorination of
this reaction was achieved by a steric effect. As expected, sub-
strates bearing ortho- and meta-methyl groups on the phenyl
ring produced monochlorinated products 2j (55% yield) and
2h (58% yield). When the pyridine ring contains the 3-methyl
substituent, monoselectivity becomes a single pathway to give
a Conditions: substrate
1 (0.3 mmol), Cu(NO3)2·3H2O (20 mol%,
0.06 mmol), LiCl (3 equiv., 0.9 mmol), HOAc (2 mL), O2 (1 atm),
150 °C. b Isolated yield.
the corresponding product 2k in 57% yield. In addition to this
substrate, both electron-donating and electron-withdrawing groups
on the phenyl side, such as p-methyl, p-tert-butyl, p-methoxy,
m-methoxy, p-F and p-CF3, were well-tolerated, affording mono-
chlorinated products 2l–2q in 52–72% yields. Although these reac-
tion conditions were optimized for the pyridine-directed C–H bond
chlorination, substrates bearing a pyrimidine-directing group
efficiently underwent chlorination to produce the corresponding
products in good yield. Benzo[h]quinoline under the standard
conditions resulted in the 10-chlorobenzo[h]quinoline 2w as a
single product in 78% yield. By using quinoline as the
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directing group, substrate 1x afforded monochlorinated regenerate the Cu(II) species. Nevertheless, we cannot comple-
product 2x with diminished efficiency (27% yield).
tely exclude a single electron transfer (SET) pathway proposed
by Yu.9
ð1Þ
For bromination, LiBr was used as a brominating reagent in
place of LiCl. It was found that the Cu(NO3)2·3H2O–O2 system
is still the best condition (Table 3). Meanwhile, it is observed
that a red-brown gas was generated upon heating, implicating
the possible formation of bromine during this process. In
order to test this hypothesis, next, we ran two control reactions
in the presence of Br2 (2 equiv.): one experiment with the
addition of 20 mol% Cu(NO3)2·3H2O afforded the desired pro-
ducts (eqn (4)); in sharp contrast to this experiment, no reac-
tion occurred in the absence of Cu(NO3)2·3H2O (eqn (5)).
These experiments reveal that a copper catalyst is necessary for
C–H halogenation of substrate 1a and the generation of mole-
cular bromine in situ is a likely step.11,17 Although the actual
mechanism of a bromination reaction is not clear at this
moment, it can be suggested that electrophilic bromination is
likely to operate in this transformation, as proposed by Stahl.11
Five substrates bearing electron-donating and electron-with-
drawing groups showed Cu-catalyzed bromination with slightly
less reactivity than a chlorination reaction (displayed in
Table 3).
ð2Þ
ð3Þ
To gain an insight into the mechanism of a chlorination
reaction, we investigated the isotope effect by using substrate
1aa bearing deuterate atom at the 2-position of the phenyl
ring. When 1aa was subjected to the standard chlorination
conditions, no obvious intramolecular isotope effect was
observed (eqn (1)). This experiment revealed that the C–H
bond activation is not the turnover limiting step. Next, we
added radical inhibitors, such as 2,6-di-tert-butyl-4-methylphe-
nol (BHT, 20 mol%) and 1,4-dinitrobenzene (20 mol%), into
reactions. The results showed that both radical inhibitors have
no evidently suppressing effect on these reactions (eqn (2) and
(3)). Thus, these two experiments ruled out the possibility of a
radical pathway.12,15
On the basis of the seminal reports on Cu(III) intermediates
in the field of the copper-mediated aromatic C–H bond acti-
vation by Stahl15 and others,16 a plausible mechanism is out-
lined in Scheme 1. Firstly, the coordination of a nitrogen atom
in substrate 1a to the copper center, followed by ortho-C–H
bond activation, would form the cyclometalated Cu(II) inter-
mediate 6. Disproportionation of Cu(II) species takes place to
afford the Cu(III) intermediate 7 and Cu(I) species. Lastly, the
reductive elimination of Cu(III) intermediate 7 can provide the
corresponding chlorinated product 2a and Cu(I) species, which
would then be oxidized by O2 under acidic conditions to
Table 3 Copper-catalyzed bromination of 2-arylpyridines with LiBr as a bromi-
nating reagenta
Entry
1
Substrate
Time (h)
5.5
Yield (%) (4/5)b
44/27
2
20
7/51
3
4
12
Trace/54
30/0
6.5
5
5
46/0
a Conditions: substrate
1 (0.3 mmol), Cu(NO3)2·3H2O (20 mol%,
0.06 mmol), LiCl (3 equiv., 0.9 mmol), HOAc (2 mL), O2 (1 atm),
150 °C. b The yields of 4 and 5 were isolated separately by column.
Scheme 1 Proposed reaction pathway.
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Particularly notably, Cu-catalyzed halogenation of an aro-
matic C–H bond is not limited to lithium halide as the halo-
genating reagents. The representative results presented here
are realized by using cheaper chlorinating sources in place of
LiCl. It is observed that the chlorination of 2-phenylpyridine
with NaCl provides the desired product in 65% yield, slightly
less than that of LiCl (eqn (6)). Other chloride salts, such as
CaCl2 and KCl, are efficient chlorinating reagents as well.
Accordingly, these results further expand the generality and
application of Cu-catalyzed halogenation transformation.
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ð6Þ
Conclusions
We have demonstrated a concise and practical Cu-catalyzed
protocol for the preparation of chloro- and bromoarenes via
C–H bond activation. The use of readily available and inexpen-
sive Cu(NO3)2·3H2O as a catalyst, LiX (X = Cl, Br) as a halogen-
ating reagent and O2 as the terminal oxidant is the significant
advantage for this transformation. Moreover, the halogenating
source can be extended to cheaper sodium halide. Further
investigation of a catalytic C–H halogenation mechanism is
currently in progress in our lab.
This work was supported by the National Natural Sciences
Foundation of China (20852004, 20902058, 21272001), Shang-
hai Pujiang Program (09PJ1408100), Shanghai Education
Committee (13ZZ014) and Shanghai Jiao Tong University
(“SMC Rising Star Project” and Present Funding).
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