Palladium-Catalyzed C?H Alkenylation of Arenes with Alkynes: Stereoselective Synthesis of Vinyl Chlorides via a 1,4-Chlorine Migration

Article abstract of DOI:10.1002/anie.201808866

A directing group-free, ligand-promoted palladium-catalyzed C?H arylation of internal alkynes with simple arenes was developed. Alkenyl chlorides resulting from a 1,4-chlorine migration or trisubstituted alkenes were produced in moderate to good yields depending on the type of alkyne.

Full text of DOI:10.1002/anie.201808866

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Accepted Article
Title: Palladium-Catalysed C-H Alkenylation of Arenes with Alkynes:
Stereoselective Synthesis of Vinyl Chlorides via a 1,4-Chlorine
Migration
Authors: Zhen Li and Wei-Liang Duan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201808866
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10.1002/anie.201808866
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
C–H activation
Palladium-Catalysed C–H Alkenylation of Arenes with Alkynes:
Stereoselective Synthesis of Vinyl Chlorides via a 1,4-Chlorine Migration
Zhen Li and Wei-Liang Duan*
Dedicated to Professor Tamio Hayashi on the occasion of his 70th birthday
Substituted alkenes are important intermediates for the
preparation of valuable chemicals through a wide range of organic
transformations, and their synthetic methods have received a
substantial amount of attention over the past decades.
Carbometallation of internal alkynes catalysed by various metal
catalysts is a direct and efficient approach for the synthesis of
multisubstituted alkenes (Scheme 1a).[1,2] However, these reactions
require prefunctionalized organometallic reagents. Recently, C–H
bond activation has been extensively developed for building
complex molecules from simple starting materials via C–H bond
cleavage.[3] Directing group (DG)-assisted C–H functionalization
strategies have been widely explored, and various arenes have been
reacted with alkynes and alkenes to form functionalized alkenes
(Scheme 1b).[4] Meanwhile, compounds without DGs have been
investigated less frequently and have shown limited success in C–H
activation reactions due to their inherent low reactivity and site
selectivity.[5,6] With respect to the reactions of arenes without DGs
with alkynes, the successful examples are mostly limited to electron-
rich arenes or pyridine derivatives (Scheme 1c).[7] For example,
Fujiwara and co-workers described the first example of a Pd-
catalysed hydroarylation of an activated alkyne with a simple arene
or anisole derivative under acid conditions.[8] Nakao and Hiyama et
al. reported the highly efficient hydroarylation of a series of
heteroarenes and fluoroarenes enabled by a Ni/Lewis acid catalyst
system.[9] However, electron-neutral arenes, such as benzene and
chloroarenes, have rarely been found to provide good yields and
wide functional group tolerance.[10] Herein, we report a DG-free
palladium-catalysed hydroarylation reaction of internal alkynes with
simple arenes that furnishes the corresponding alkenes or vinyl
chlorides via a 1,4-chlorine migration in good yields.
reaction of 1,4-dichlorobenzene with 4-octyne in the presence of
palladium acetate and various ligands. The use of 2-OH-1,10-
phenanthroline (L1) afforded a mixture of hydroarylation product 3a
and alkenyl chloride 4a in a ratio of 18:60 (Table 1, entry 1). In
contrast, the use of 1,10-phenanthroline (L2) did not generate any
arylation product, and the reaction did not proceed at all (Entry 2).
The more flexible 2-OH-1,1´-bipyridine (L3) afforded products 3a
and 4a in relatively low yields (Entry 3). A monoprotected amino
acid[12] was also examined, and no desired arylation product was
generated (Entry 4). Further screening of the oxidant revealed that
1.0 equiv. of silver carbonate is the optimal choice (Entries 5–11).
Control experiments indicated that ligand L1 and the palladium
catalyst are both essential for the progress of the reaction (Entries 12
and 13). The use of different solvents and reaction temperatures did
not improve the yield of product (Entries 14–20). Finally, increasing
the amount of chloroarene 1a led to an 81% yield of the product
(Entries 21 and 22).
In our previous study,
a bidentate ligand (2-OH-1,10-
phenanthroline) was developed for the palladium-catalysed
oxidative C–H alkenylation of arenes.[11] The use of this ligand
enabled the generation of the active palladium catalyst for the C–H
bond cleavage of aryl groups. The present study began with the
Scheme 1: Representative procedures for the hydroarylation of
alkynes.
With the optimized conditions in hand, we began to examine the
substrate scope of the reaction using a range of chloroarenes (Table
2). With respect to the reaction with a dialkylalkyne, various
moieties on the aryl ring para to the chlorine atom, such as nitro,
trifluoromethyl, methyl ester, and methoxyl, were tolerated and
afforded the corresponding alkenyl chlorides (4b–4f) in moderate to
good yields (43%–86%). The use of an unsymmetrical 2-octyne
afforded two isomers with a ratio of 3 to 1 in 60% yield. In the
reaction with a diaryl alkyne, alkene 3 without chlorine migration
was formed as the major product.[13] Alkynes bearing electron-
donating or electron-withdrawing substituents on the aryl ring, such
as methyl, chloro, fluoro, trifluoromethyl, and methoxyl groups,
were all smoothly converted to corresponding products (3h–3o) in
moderate to good yields. Electron-rich and electron-deficient arenes,
[]
Z. Li, Prof. Dr. W.-L. Duan
College of Chemistry and Chemical Engineering, Yangzhou
University, 180 Siwangting Road, Yangzhou 225002, China
E-mail: duanwl@yzu.edu.cn
Prof. Dr. W.-L. Duan
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences 200032, China
[] This work was financially supported by the NSFC
(21472218 and 21672183), the Priority Academic Program
Development of Jiangsu Higher Education Institutions, and
Top-notch Academic Programs Project of Jiangsu Higher
Education Institutions. We thank Mr. Cheng-Hao Ying for
preliminary experimental investigation.
Supporting information for this article is available on the
WWW under http://www.angewandte.org or from the
author.
1
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10.1002/anie.201808866
Angewandte Chemie International Edition
such as 1,4-dimethoxybenzene, 1,4-difluorobenzene, 1-chloro-4-
trifluoromethylbenzene, 1-fluoro-4-trifluoromethylbenzene, and 1,3-
bis(trifluoromethyl)benzene were also reactive under the current
conditions, affording arylation products 3p to 3t with up to 94%
yield. Table 3 summarizes the results of the reaction of benzene with
various internal alkynes under the optimized conditions. Dialkyl
alkynes and diaryl alkynes bearing various substituents at the para,
meta, and even ortho-positions were all tolerated and generated a
variety of trisubstituted alkenes (5a–5k) in 40% to 91% yield. The
use of 1-ethyl-2-phenylacetylene generated the product as a mixture
of two isomers (5la and 5lb) in 75% yield. The obtained alkenyl
chloride 4c can be utilized for the preparation of tetrasubstituted
alkene through a Pd-catalysed Suzuki coupling reaction (Scheme 2).
Table 1. Palladium-catalysed reaction of 1,4-dichlorobenzene with 4-
octyne.
Yield 3a/4a
Entry
L
Base (equiv.)
Solvent
T [°C ]
[%][a]
18/60
n.r.
1
2
L1
L2
L3
L4
L1
L1
L1
L1
L1
L1
L1
-
Ag2CO3(1)
Ag2CO3(1)
Ag2CO3(1)
Ag2CO3(1)
AgOAc(1)
AgNO3(1)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
130
140
120
130
130
3
6/6
4
n.r.
5
46/18
trace
8/14
[a] All the reactions were conducted with 0.20 mmol of alkynes and 1
g of arenes in 1.0 mL of 1,4-dioxane unless specifically noted. [b]
Isolated yield. [c] The reaction was conducted at 140 °C.
6
7
Cu(OAc)2(1) 1,4-dioxane
Cs2CO3(1) 1,4-dioxane
8
n.r.
9
Ag2CO3(0.5) 1,4-dioxane
Ag2CO3(1.5) 1,4-dioxane
Ag2CO3(2.0) 1,4-dioxane
26/49
24/56
10/57
n.r.
Table 3. Palladium-catalysed reaction of benzene with internal
alkynes.[a,b]
10
11
12
13[b]
14
15
16
17
18
19
20
21[c]
22[d]
Ag2CO3(1)
Ag2CO3(1)
1,4-dioxane
1,4-dioxane
DME
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
n.r.
Ag2CO3(1.0)
Ag2CO3(1.0)
Ag2CO3(1.0)
Ag2CO3(1.0)
Ag2CO3(1.0)
14/21
24/16
12/22
21/28
17/15
24/65
12/23
17/65
9/82(81[e])
DMF
MeCN
THF
t-Amyl-OH
Ag2CO3(1.0) 1,4-dioxane
Ag2CO3(1.0) 1,4-dioxane
Ag2CO3(1.0) 1,4-dioxane
Ag2CO3(1.0) 1,4-dioxane
[a] Yields were determined by 1H NMR analysis of the crude product
using CH2Br2 as the internal standard. [b] No Pd cat. [c] 10 equiv. of
1a was used. [d] 34 equiv. of 1a was used. [e] Isolated yield.
Table 2. Palladium-catalysed reaction of arenes with internal
alkynes.[a,b]
2
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10.1002/anie.201808866
Angewandte Chemie International Edition
[a] All the reactions were conducted with 0.20 mmol of alkyne in 1.0
mL of benzene unless specifically noted. [b] Isolated yield.
Scheme 2. Pd-catalysed Suzuki coupling reaction for the preparation
of tetrasubstituted alkene.
Scheme 5. The proposed catalytic cycle.
A proposed catalytic cycle is shown in Scheme 5. Ligand L1
first reacts with Pd(OAc)2, generating intermediated I11. I bears only
one acetate anion on the palladium atom and a vacant coordination
site could easily be generated for the incoming substrate. Then, C–H
bond cleavage of the 1,4-chlorobenzene occurs to afford aryl
palladium species II in the presence of silver carbonate. Next, the
insertion of alkyne 2 into the aryl palladium bond afforded alkenyl
palladium intermediate III. In the case of a dialkyl alkyne, the
generated palladium intermediate, which has greater electron density,
undergoes oxidative addition with the cleavage of the C–Cl bond to
form Pd(IV) species IV via pathway a. The reductive elimination
from Pd(IV) IV along with the construction of the alkenyl C–Cl
bond completes the 1,4-chlorine migration[16,17], affording aryl Pd(II)
species V. Protonolysis of V with acetic acid turns over the catalytic
cycle with the formation of chlorine migration product 4 and
regeneration of Pd catalyst I. With respect to the diaryl alkyne,
formed alkenyl Pd(II) intermediate III mainly directs the hydrolysis
via pathway b, affording product 3 without a 1,4-halide shift.
In summary, we have described a ligand-promoted palladium-
catalysed C–H activation of simple arenes without directing groups
with internal alkynes. The alkenyl chlorides resulting from a 1,4-
chlorine migration and trisubstituted alkenes were obtained in
moderate to good yields.
Scheme 3. Experiments with isotopically labelled compounds.
Scheme 4. C-H alkenylation of chlorobenzene with 4-octyne.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
To obtain more information to understand the reaction
mechanism, reactions of an alkyne with deuterium-labelled benzene
and benzene in separate vessels were conducted to determine the
kinetic isotope effect (KIE). A KIE of 1.6 was obtained, which
indicates that the C–H bond cleavage may be the rate-limiting step
(Scheme 3a and 3b).[14] Deuterated 1,4-dichlorobenzene was also
reacted with 4-decyne, and the corresponding alkenyl chloride was
obtained in 27% yield with 78% D atom incorporation at the
position para to the Cl atom on the aromatic ring (Scheme 3c).
Chlorobenzene was also reacted with 4-octyne under the optimal
conditions, and a mixture of alkenyl chloride P1a, meta-Cl
substituted product P1b, and para-Cl substituted product P1c, in a
ratio of 2:2:1 was formed in 45% combined yield (Scheme 4).15
Keywords: C-H activation · palladium · alkyne · ligand-accelerated
catalysis · 1,4-chlorine migration
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10.1002/anie.201808866
Angewandte Chemie International Edition
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4
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10.1002/anie.201808866
Angewandte Chemie International Edition
Table of Contents
C–H Activation
Zhen Li and Wei-Liang Duan*
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Palladium-Catalysed C–H Alkeylation of
Arenes with Alkynes: Stereoselective
Synthesis of Vinyl Chlorides via a 1,4-
Chlorine Migration
A directing group-free, ligand-promoted palladium-catalysed C-H arylation of
internal alkynes with simple arenes was developed, and alkenyl chlorides via 1,4-
chlorine migration or trisubstituted alkenes were produced in moderate to good
yields depending on the type of alkyne.
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