A Three-Phase Four-Component Coupling Reaction: Selective Synthesis of o-Chloro Benzoates by KCl, Arynes, CO2, and Chloroalkanes

Article abstract of DOI:10.1021/acs.orglett.8b03193

A transition-metal-free three-phase four-component coupling reaction (3P-4CR) involving KCl, arynes, chloroalkanes and CO₂ has been reported for the first time, enabling the incorporation of both chloro and CO₂ into an aryne simultaneously. The reactions for the synthesis of different types of o-chloro benzoates can be selectively modulated by the chloroalkane utilized. The corresponding products can be alternatively transformed for postsynthetic functionalizations conveniently.

Full text of DOI:10.1021/acs.orglett.8b03193

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
A Three-Phase Four-Component Coupling Reaction: Selective
Synthesis of o‑Chloro Benzoates by KCl, Arynes, CO2, and
Chloroalkanes
Huanfeng Jiang,* Yu Zhang, Wenfang Xiong, Jinghe Cen, Lu Wang, Ruixiang Cheng, Chaorong Qi,
and Wanqing Wu
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering,
South China University of Technology, Guangzhou 510640, P. R. China
S
* Supporting Information
ABSTRACT: A transition-metal-free three-phase four-component coupling reaction (3P-4CR) involving KCl, arynes,
chloroalkanes and CO2 has been reported for the first time, enabling the incorporation of both chloro and CO2 into an aryne
simultaneously. The reactions for the synthesis of different types of o-chloro benzoates can be selectively modulated by the
chloroalkane utilized. The corresponding products can be alternatively transformed for postsynthetic functionalizations
conveniently.
ulticomponent reactions (MCRs) are a class of reaction
compounds react with various gases (CO,3 CO2,7,10−12 NH3,4
Min which the starting materials (more than two) are etc.), and the other is the combination of organic components
with different inorganics such as NaNO2,13b Na2S,5a and
NaN3.5b Due to the poor transmission between two phases,
2P-MCRs become more complicated and challenging than the
former one and (c) 3P-MCRs are a heterogeneous system
containing three phases among various substrates. Although
limited attention of 3P-MCRs6,8j has been paid, the reactions
show their enormous potential by utilizing both inexpensive
and abundant gas and inorganics for organic synthesis.
Therefore, the exploration of more novel and distinctive 3P-
MCRs is highly desirable.
The utilization of carbon dioxide to construct various high
value-added products is an appealing and challenging subject,
as CO2 is a low-cost, abundant, nontoxic but inert gas.7
Despite the intrinsic inactivity of CO2, a large amount of effort
has been devoted to tackle the problem in recent years.8
Among various conceivable strategies, the combination of
highly reactive aryne intermediates9 with CO2 offers a unique
opportunity to facilitate this transformation. Generally, the
highly electrophilic aryne can be attacked by different
uncharged nucleophiles such as imines,10a amines,10b,c and
isocyanides10d to form 1,3-zwitterionic intermediates respec-
tively, which may be intercepted by CO2 to afford diverse 1,2-
difunctionolized arenes. In particular, our group has developed
a multicomponent coupling reaction of CO2, amines, cyclic
incorporated in the final product by a one pot method.1 In
contrast with multistep synthesis, MCRs are commonly
highlighted by their high step efficiency, atom economy, and
synthetic convergence. According to different reactant states in
the reaction, MCRs can be simply classified into three
categories (Scheme 1): (a) 1P-MCRs, such as the Strecker
3CR,2a Ugi 4CR2b as well as recently elegant works,2c−h are
one of the most common reactions in which all reactants are
dissolved in a homogeneous state, and (b) 2P-MCRs are
defined as reactions in which the starting materials of MCRs
consist of two states in the reaction. One is that organic
Scheme 1. Three Fundamental Categories of MCR
Received: October 7, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03193
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ethers, and 3-triflyloxybenzynes for the synthesis of various
carbamates recently.11 Apart from these elegant works, the
other multicomponent reactions involving both CO2 and
arynes are still in their infancy.12
concentration of the F source carefully (Table 1, entry 13).
Further replacing KF with CsF or TBAF did not give better
results (Table 1, entries 14−15), and prolonging the reaction
time to 24 h did not alter the reaction outcome to a large
extent either (Table 1, entry 16).
With the optimal conditions in hand, we next set out to
investigate the scope of the four-component coupling reaction
with various aryne precursors (Scheme 2). Interestingly,
o-Chloro benzoats are an important class of synthetic
intermediate,13 and their unique structure units are also found
in various pharmaceuticals and agrochemicals, such as
Chloroprocaine,14a Butafenacil and Fluazolate.14b Several
remarkable advances15 have been reported for the synthesis
of o-chloro benzoates in recent decades. However, the use of
expensive transition-metal catalysts and highly reactive
reagents has limited their applications to some extent.
Therefore, based on the above observations and our previous
reports about CO2,17 we envisioned that the reaction might
proceed by employing KCl as anionic nucleophiles16 and using
CO2 as the source of ester to access o-chloro benzoate
derivatives.
a
Scheme 2. Substrate Scope of the Aryne Precursors
We commenced our study by employing Kobayashi aryne
precursor 1a18 in the presence of KF/18-crown-6 in DCE (1,2-
dichloroethane) at room temperature (rt) for 12 h under an
atmosphere of CO2 (Table 1, entry 1). Unfortunately, only a
a
Table 1. Reaction Optimization
b
entry
F− system
additive (equiv)
t (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
KF+18-crown-6
KF+18-crown-6
KF+18-crown-6
KF+18-crown-6
KF
KF+18-crown-6
KF+18-crown-6
KF+18-crown-6
KF+18-crown-6
KF+18-crown-6
KF+18-crown-6
KF+18-crown-6
KF+18-crown-6
CsF+18-crown-6
TBAF
−
rt
rt
rt
rt
rt
rt
0
46
55
46
46
46
46
46
46
46
trace
37%
trace
n.d.
n.d.
n.d.
KCl (2)
NaCl (2)
LiCl (2)
KCl (2)
KCl (2)
KCl (2)
KCl (2)
KCl (2)
KCl (0.2)
KCl (3)
KCl (4)
KCl (4)
KCl (4)
KCl (4)
KCl (4)
c
n.r.
49%
47%
27%
54%
58%
66%
34%
n.d.
d
e
f
a
15
16
Reaction conditions: 1 (0.2 mmol), 2a (0.5 mL), CO2 (1 atm), KCl
b
g
(4 equiv), KF (4 equiv), 18-crown-6 (4 equiv), 46 °C for 12 h. The
regioisomer ratio was determined by H NMR analysis.
KF+18-crown-6
67%
1
a
Reaction conditions: 1a (0.2 mmol), 2a (0.5 mL), CO2 (1 atm), KF
(3 equiv), 18-crown-6 (3 equiv) at various temperatures for 12 h.
b
Yield based on 1a and determined by 1H NMR analysis using
monosubstituted substrates, such as 3-methoxybenzyne (from
1b) and 3-fluoro benzyne (from 1c), could be transformed
with complete regioselectivity, while the reactions of different
4-substituted aryne precursors 1d−1f only gave moderate to
good yields with poor regioselectivity. Similarly, in the case of
triflate 1g, an inseparable mixture of regioisomers (1:1.9) was
isolated in 48% yield. The above results might be attributed to
different degrees of aryne distortions, which influenced the
regioselectivity signal.20 Additionally, electronically dissimilar
disubstituted symmetrical arynes (from 1h−1j) proceeded
with good chemical efficiency and provided the expected
products 3ha−3ja in 47%−55% yields. In the case of
unsymmetrical disubstituted aryne 3,5-dimethoxybenzyne
(from 1k), the carboxylated product 3ka could also be isolated
in 54% yield with excellent regioselectivity. Furthermore, the
fused ring systems 1l−1o reacted smoothly under the standard
reaction conditions, furnishing the desired products in
c
d
CH3NO2 as an internal standard. Under a N2 atmosphere. KF (4
e
equiv), 18-crown-6 (4 equiv). CsF (4 equiv), 18-crown-6 (4 equiv).
f
g
TBAF (4 equiv). Reaction time: 24 h.
trace amount of the desired product 3aa was detected by GC-
MS. We wondered if the yield could be improved by
introducing a more nucleophilic Cl source. To our delight,
after a screen of different salts, KCl was found to be the best
one (Table 1, entries 2−4). Subsequently, a series of control
experiments confirmed that both crown ether and CO2 played
essential roles in this transformation (Table 1, entries 5−6).
Further study revealed that 46 °C was the optimal temperature
(Table 1, entries 7−9). Decreasing the loading of KCl was less
effective,19 and the yield could be enhanced to 58% by
increasing the amount of KCl to 4 equiv (Table 1, entries 10−
12). Finally, the best results were obtained by adjusting the
B
DOI: 10.1021/acs.orglett.8b03193
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Organic Letters
Letter
moderate yields. Specifically, the trisubstituted aryne precursor
1p was also a suitable substrate in this reaction and converted
to the corresponding benzoate 3pa in 34% yield.
The scope of the reaction was further expanded to a range of
dichlorides. As shown in Scheme 3, replacement of DCE with
nitrile, methoxy, fluoro, bromo, and even nitro, were well
tolerated at different positions on the aromatic ring of benzyl
chlorides, leading to the desired products (3ag−3al) in good
to excellent yields. In addition, a scale-up experiment was
performed; carrying out the reaction on a 1 mmol scale of 2g
provided 3ag in 74% isolated yield. Notably, several
polysubstituted benzyl chlorides 2m and 2n were also suitable
substrates for this transformation, providing the corresponding
products in 85% and 78% yields, respectively. Moreover, the
cinnamyl chloride 2o performed well under our reaction
conditions and afforded the o-chloro benzoate 3ao in 75%
yield, implying the versatility of this reaction.
a
Scheme 3. Scope of Dichloroalkanes
A series of transformations were investigated to further
demonstrate the synthetic utility of this method. As shown in
Scheme 5, product 3aa could be converted to 4 in 79% yield
a
Scheme 5. Transformations of Product 3aa
a
Reaction conditions: 1a (0.2 mmol), 2 (0.5 mL), CO2 (1 atm), KCl
(4 equiv), KF (4 equiv), 18-crown-6 (4 equiv), 46 °C for 12 h.
CH2Cl2 failed to provide the product 3ab. Compared with 3aa,
the reactions delivered 3ac and 3ad in lower yields gradually
when we lengthened the carbo-chain of DCE slowly. In
addition, the reactions were found to be applicable to
dichloroalkanes (2e−2f) containing different forms of olefin
skeletons, which provided ample opportunities for the
products (3ae−3af) to construct more complicated organic
architectures.
a
Reaction Condition: (1) 3aa (0.2 mmol), NaI (5 equiv), acetone (1
mL), reflux, 48 h. (2) 3aa (0.2 mmol), NaN3 (2 equiv), DMF (1 mL),
70 °C, 12 h. (3) 3aa (0.5 mmol), NaI (6 mol %), 1-methyl piperazine
(1 mmol), NaHCO3 (2 equiv), CH3CN (3.5 mL), 90 °C, 24 h. (4)
3aa (0.2 mmol), 4-tolylboronic acid (2.6 equiv), Ni(PPh3)2Cl2 (3 mol
%), PPh3 (6 mol %), K3PO4·3H2O (2.6 equiv), toluene (0.6 mL), 120
°C for 12 h.
Encouraged by these preliminary results, we speculated that
the reaction might be modulated alternatively by introducing
another electrophile with a higher activity such as benzyl
chlorides. After careful modification of preceding optimized
reaction conditions,21 the best outcome was obtained by using
2 (0.2 mmol), 1a (3 equiv), KCl (4 equiv), KF (4 equiv), and
18-crown-6 (4 equiv), in DCE (0.2 mL) at 46 °C for 18 h. We
then explored the substrate scope of different benzyl chlorides
(Scheme 4). To our delight, a series of substituents, such as
via a halogen-exchange reaction.22 The nucleophilic sub-
stitution of 3aa with NaN3 afforded alkyl azide 5 in 95%
yield.23 Notably, treatment of 3aa with 1-methyl piperazine
gave the piperazine derivative 6 in 42% yield, which is a
potential drug analogue for the treatment of atherosclerosis.24
Furthermore, the Suzuki−Miyaura cross-coupling reactions of
3aa with 4-tolylboronic acid furnished the arylated compound
7 in 38% yield.25
To gain insight into the mechanism, several control
experiments were conducted. Deuterium labeling studies of
1l and KCl were carried out by adding 2 equiv of D2O under a
N2 atmosphere in DCE and THF, respectively (Scheme 6, eq
a
Scheme 4. Scope of Benzyl Chlorides
Scheme 6. Mechanistic Experiments
a
Reaction conditions: 1a (3 equiv), 2 (0.2 mmol), CO2 (1 atm), KCl
(4 equiv), KF (4 equiv), 18-crown-6 (4 equiv), DCE (0.2 mL), 46 °C
b
for 18 h. Reaction conditions: 1a (3 equiv), 2g (1 mmol), CO2
(balloon), KCl (4 equiv), KF (4 equiv), 18-crown-6 (4 equiv), DCE
(1 mL), 46 °C for 12 h, isolated yield.
C
DOI: 10.1021/acs.orglett.8b03193
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Organic Letters
Letter
1). The results indicated that DCE is a better solvent than
THF to generate free chloride. In addition, we also tried to
catch the possible intermediate by adding 1 N HCl to quench
the reaction (Scheme 6, eq 2.1). To our delight, we could
detect very small amounts of the carboxylic acid 9 by GC-MS.
To further identify our assumption, treatment of potassium
benzoate 10 instead of aryne in the model conditions could
afford corresponding ester 11 in 88% isolated yield (Scheme 6,
eq 2.2), indicating that the o-chloro benzoate anion might be
the possible intermediate.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jianghf@scut.edu.cn.
ORCID
Huanfeng Jiang: 0000-0002-4355-0294
Chaorong Qi: 0000-0003-4776-2443
Wanqing Wu: 0000-0001-5151-7788
Notes
Based on previous studies10,17and a series of control
experiments, a plausible mechanism for the CO2 incorporation
reaction is presented (Scheme 7). Initially, the in situ formed
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Program on the Key Research
Project (2016YFA0602900), the National Natural Science
Foundation of China (21420102003), and the Guangdong
Natural Science Foundation (2018B030308007) for financial
support.
Scheme 7. Proposed Mechanism
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
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DOI: 10.1021/acs.orglett.8b03193
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