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Green Chemistry
DOI: 10.1039/C9GC02407G
Journal Name
ARTICLE
Transition-Metal-Free Decarboxylative Halogenation of 2-Picolinic
Acids with Dihalomethane under Oxygen Conditions
Xitao Zhang,a Xiujuan Feng,*a Haixia Zhang,a Yoshinori Yamamoto,ab and Ming Bao*a
Received 00th January 20xx,
Accepted 00th January 20xx
A convenient and efficient method for the synthesis of 2-halogen-substituted pyridines is described. The decarboxylative
halogenation of 2-picolinic acids with dihalomethane proceeded smoothly via N-chlorocarbene intermediates to afford 2-
halogen-substituted pyridines in satisfactory to excellent yields under transition-metal-free conditions. This new type of
decarboxylative halogenation is operationally simple and exhibits high functional-group tolerance.
DOI: 10.1039/x0xx00000x
a) Transition-metal-catalyzed decarboxylative halogenation of aromatic acids
CuX2 or NaX
cat. M
Introduction
R
R
R
130 °C-160 °C
X
The 2-halogen-substituted pyridine motif is present in many
important bioactive molecules and pharmaceuticals,1 and 2-
halogen-substituted pyridine derivatives can serve as useful
intermediates in the synthesis of drug molecules and function
materials through transition metal-catalyzed cross-coupling
reactions2 or a nucleophilic aromatic substitution reaction (SNAr
reaction)3. The importance of 2-halogen-substituted pyridines
provides the continuous impetus for the synthetic chemists to seek
simple and valid methods to construct them. Three main methods
for preparing 2-halogen-substituted pyridines have been developed
over the past decades. One method involves the direct chlorination
of pyridine ring with chlorine gas at high temperatures.4 This
method generally results in overhalogenation and poor
regioselectivity. Another method involves the substitution reaction
of 2-hydroxy group with halogen atoms, with POCl3, PCl5, POBr3,
and PBr3 as halogen sources.5 The last method involves the
halogenation of pyridine-N-oxides with almost the same halogen
sources mentioned above.6,7 However, these halogen sources are
harmful, moisture sensitive, and difficult to handle. Moreover,
these methods also suffer from harsh reaction conditions, limited
substrate scope, and poor regioselectivity. Therefore, developing a
M
CO2H
X = Cl, Br, I
M = Pd, Ag, Cu
b) Transition-metal-free decarboxylative halogenation of aromatic acids
O
N(nBu4)Br3 or I2, K3PO4
R
R
O
X
X
MeCN, 100 °C
CO2H
X
X = Br, I
c) Transition-metal-free decarboxylative halogenation of 2-picolinic acids
(This work)
CH2X2
R
t-BuOCl, NaHCO3
R
R
N
O2, 60 °C-70 °C
N
N
CO2H
X = Cl, Br
Cl
.
.
transition-metal-free
mild conditions
.
oxygen as an oxidant
cheap and readily available halogen source
.
Scheme 1. Decarboxylative Halogenation of aromatic acids.
2-metallapyridine intermediates generated in situ are unstable
and easily undergo protodemetalation.10 Recently, Larrosa and
co-workers disclosed a study on the transition-metal-free
convenient and efficient method for synthesizing 2-halogen- decarboxylative halogenation of benzoic acids with N(nBu4)Br3
or I2 (Scheme 1b).11 Nevertheless, we failed to synthesize 2-
halogen-substituted pyridines by this protocol. In the course of
our research on the development of efficient methods for
synthesizing aromatic halides,12 we found that 2-halogen-
substituted pyridines can be synthesized also through
transition-metal-free decarboxylative halogenation; the
decarboxylative halogenation of 2-picolinic acids proceeded
smoothly via N-chlorocarbene intermediates (Scheme 1c). The
results are reported in this paper.
substituted pyridines is highly desired.
A rapidly growing number of decarboxylative coupling reactions
in the formation of C‒C and C‒heteroatom bonds have attracted
increasing attention because aromatic carboxylic acids show good
stability and high commercial availability and are low cost.8 The
transition metal-catalyzed decarboxylative halogenation has been
demonstrated to be a powerful method for constructing C‒X bond
(Scheme 1a).9 However, this method cannot be utilized to
synthesize 2-halogen-substituted pyridines because
In our initial study, we selected the reaction of quinoline-2-
carboxylic acid (1a) with dichloromethane as a model reaction
for optimizing reaction conditions. The results are shown in
Table 1. The 2-chloroquinoline (2a) product was obtained in
32% yield without a base (entry 1). Several bases, including
potassium carbonate (K2CO3), sodium acetate (NaOAc), sodium
aState Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian
116023, China. Fax: +86-0411-84986181; Tel: +86-0411-84986180; E-mail:
fengxiujuan@dlut.edu.cn; mingbao@dlut.edu.cn
b WPI-AIMR (WPI-Advanced Institute for Materials Research), Tohoku University,
Sendai 980-8577, Japan.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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