NiCl2-catalyzed radical cross decarboxylative coupling between arylpropiolic acids and cyclic ethers

Article abstract of DOI:10.1016/j.tetlet.2019.01.039

A direct alkenylation of cyclic ethers via radical cross decarboxylative coupling process catalyzed by NiCl₂ and using DTBP as radical initiator and oxidant was developed. A variety of arylpropiolic acids and cyclic ethers were transformed into the corresponding 2-arylvinyl cyclic ethers in moderate to excellent yields. Mechanistic experiments were conducted to determine the nature of the reaction intermediates, and a plausible reaction mechanism involving NiCl₂-promoted radical process was proposed.

Full text of DOI:10.1016/j.tetlet.2019.01.039

Accepted Manuscript
NiCl -Catalyzed Radical Cross Decarboxylative Coupling between Arylpro-
2
piolic Acids and Cyclic Ethers
Zi-juan Wan, Jin-yuan Wang, Jun Luo
PII:
S0040-4039(19)30068-1
https://doi.org/10.1016/j.tetlet.2019.01.039
TETL 50572
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
19 December 2018
16 January 2019
21 January 2019
Please cite this article as: Wan, Z-j., Wang, J-y., Luo, J., NiCl -Catalyzed Radical Cross Decarboxylative Coupling
2
between Arylpropiolic Acids and Cyclic Ethers, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2
019.01.039
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NiCl
2
-Catalyzed Radical Cross
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Decarboxylative Coupling between
Arylpropiolic Acids and Cyclic Ethers
Zi-juan Wan, Jin-yuan Wang and Jun Luo

1
Tetrahedron Letters
NiCl
2
-Catalyzed Radical Cross Decarboxylative Coupling between Arylpropiolic
Acids and Cyclic Ethers
a
a,
Zi-juan Wan , Jin-yuan Wang and Jun Luo 
a
Affiliation 1, Address, City and Postal Code, Country School of Chemical Engineering, Nanjing University of Science and Technology, Nanjing, 210094, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A direct alkenylation of cyclic ethers via radical cross decarboxylative coupling process
catalyzed by NiCl and using DTBP as radical initiator and oxidant was developed. A variety of
2
Received in revised form
Accepted
arylpropiolic acids and cyclic ethers were transformed into the corresponding 2-arylvinyl cyclic
ethers in moderate to excellent yields. Mechanistic experiments were conducted to determine the
Available online
2
nature of the reaction intermediates, and a plausible reaction mechanism involving NiCl -
promoted radical process was proposed.
Keywords:
2
009 Elsevier Ltd. All rights reserved.
C-H functionalization
radical reaction
cross-coupling
arylpropiolic acids
alkenylation
Catalytic transformation of numerous chemicals to valuable
compounds via C-H functionalization is of great importance in
[
1]
3
organic synthesis . Direct functionalization of C(sp )−H bonds
in expectable and efficient manner has become a central
challenge in modern organic chemistry for their relatively
[
2]
stronger bond dissociation energy (BDE) and lower polarity
than C(sp )−H functionalization . Therefore, direct C(sp )−H
functionalization of cyclic ethers attracts plenty of attention
2
[3]
3
[
4]
since a large number of natural products, bearing 2-subsituted
[
5]
3
cyclic ether motif, exhibit a wide range of biological activities
.
Furthermore, direct alkenylation of cyclic ethers through C(sp )
−
H functionalization is also significant because the products,
Figure 1. Selected biologically active 2-arylvinyl cyclic ethers.
arylvinyl cyclic ethers, are very important biologically active
compounds (Figure 1) . Recently, radical activation has proven
to be an efficient pathway for converting C(sp )−H bonds to the
corresponding radicals . Using the strategy of organometallic
C-H activation and oxidative radical cross-coupling, the direct
[
6]
3
Our study started with the coupling of tetrahydrofuran (THF)
with phenylpropiolic acid to prepare 2-styryltetrahydrofuran.
Optimization of reaction conditions was inspected first and the
results are listed in Table 1.
[
7]
3
C(sp )−H functionalization methods have grown exponentially
[
8]
.
In the presence of di-tert-butyl peroxide (DTBP, 1.2 equiv.),
the desired product 2-styryltetrahydrofuran (3a) was obtained in
In recent years, the transition metal-catalyzed cross
decarboxylative coupling has become a powerful tool to prepare
organic molecules . Arylpropiolic acids were found to be a
universal coupling partner for this kind of reaction .
4
2% yield (Table 1, entry 1). A variety of catalysts including
[
9]
NiCl
NiCl
2
, Ni(acac)
afforded 3a in higher yield than Ni(acac)
gave 1,4-diphenylbutadiyne (4)
2
, CuCl and CuCl
2
were tested. It was found that
2
2
(Table 1, entries
2
and 3), while CuCl and CuCl
2
Here we report a new protocol for direct alkenylation of cyclic
ethers to prepare 2-arylvinyl cyclic ethers with high yield via
radical initiated cross decarboxylative coupling catalyzed by
as the major product (Table 1, entries 4 and 5). The category of
base affects the reaction significantly. Among the based used,
potassium carbonate gave the highest yield of 79% and by-
product 4 was not detected (Table 1, entry 6). Sodium carbonate
shows negative effect on the reaction (Table 1, entry 7). Bases
with stronger basicity than potassium carbonate lower the yield
2
NiCl .
—
——

Corresponding author. Tel.: +86-25-84315514; fax: +86-25-84315030; e-mail: luojun@njust.edu.cn.

2
Tetrahedron
dramatically (Table 1, entries 8-10). The reason might be
substrates, the ortho-isomers afforded a little lower yields but
much higher Z/E ratios. To our surprise, when 2-
thiophenepropiolic acid was used, the corresponding product 3q
was obtained in an amazing high yield of 86%. But 2-
naphthalenepropiolic acid gave 3p in an unsatisfactory yield of
40%. Considering the importance of direct functionalization of
different ethers, other simple cyclic ethers including 1,4-dioxane
(3r) and 1,3-dioxolane (3s) were also tested to couple with
phenylpropiolic acid under optimized conditions, unfortunately,
the yields were relative low (Table 2, 3r and 3s).
assigned to the fact that phenylpropiolic acid was partially even
completely neutralized to potassium phenylpropiolate, which is
completely insoluble in the reaction mixture, by strong bases.
Organic tertiary amines such as triethylamine and DBU afford
low and moderate yield and slight 4 was detected (Table 1,
entries 11 and 12). Having the above results in hand, the effect of
radical initiators such as tert-butyl hydroperoxide (TBHP), 3-
chloroperoxybenzoic acid (mCPBA), 2,3-dichloro-5,6-dicyano-
1
,4-benzoquinone (DDQ), 2,2'-azobis(2-methylpropionitrile)
(
AIBN) and benzoyl peroxide (BPO) on the reaction was
Table 2. Substrate scope a b
investigated. The results indicated that all the initiators were
inferior to DTBP (Table 1, entries 13-17). When a classical
ligand 2,2’-bipyridine was added, 1,4-diphenylbutadiyne (4) was
obtained as major product (Table 1, entry 18).
Table 1. Optimization of Reaction Conditions a
b
Entry
Catalyst
-
Base
radical
initiator
Yield(3a/4)(%)
1
2
3
4
5
6
7
8
9
-
-
-
-
-
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
42/<5
65/21
51/23
32/65
31/58
NiCl
2
Ni(acac)
2
CuCl
CuCl
2
c
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
2
K
2
CO
3
79/ND
2
Na
Cs
2
CO
3
43/ND
21/ND
ND/ND
47/ND
28/<5
2
2
2
2
2
2
2
2
2
2
2
2
CO
3
t-BuOK
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
NaOAc
NEt
3
DBU
56/<5
d
K
2
CO
CO
CO
CO
CO
CO
3
3
3
3
3
3
TBHP
59/ND
ND/ND
ND/ND
68/ND
54/ND
33/48
K
2
mCPBA
DDQ
K
2
K
2
AIBN
BPO
K
2
e
1
8
K
2
DTBP
a
General reaction conditions : 1a (0.5 mmol), catalyst (10 mol%), radical
initiator (1.2 equiv.), base (1.1 equiv.), THF (3 mL), 120 °C, 24 h, N
atmosphere.
2
a
Reaction conditions: 1 (0.5 mmol), NiCl
2
(10 mol %), DTBP(1.2 equiv.),
atmosphere.
K
2
CO (1.1 equiv.), 2 (3 mL), 120 °C, 24 h, N
3
2
b
Isolated yield.
b
Isolated yield.
c
ND=Not detected.
c
1
Z/E ratios were determined by H NMR based on Ref. 10b.
d
TBHP (5–6 M in decane).
e
Then, control experiments were performed to probe the
2
,2’-bipy (20 mol%) was used as ligand.
reaction mechanism (Scheme 1). Adding the typical radical
scavenger 2,2,6,6-tetramethylpiperidine N-oxide (TEMPO)
completely inhibited the reaction. Almost no desired product was
detected at all, however, along with the formation of a radical-
trapping product (5) in 52% yield. The results indicate that this
With the optimized reaction conditions in hand, a variety of
arylpropiolic acids were selected to couple with cyclic ethers and
the results are listed in Table 2. It was observed that the reaction
of THF with phenylpropiolic acid containing electron-donating
groups such as methoxy and methyl underwent smoothly and
generated the corresponding products 3b-g in good yields (57–
reaction must proceed via a radical procedure. When NiCl
2
and
K
2
CO were not added, a by-product of cinnamic acid 6 was
3
7
3%). Meanwhile, the reaction of THF with phenylpropiolic acid
isolated in 44% yield while 42% of 3a was detected. The by-
product 6 could not be decarboxylated smoothly under the three
conditions.
bearing electron-withdrawing groups also proceeded well and
afforded the desired products 3h-3o in 35-68% yields. The steric
hindrance did not interfere with this transformation too much
(3b-i). However, in comparison with meta- and para-substituted

3
On the basis of the above results and the literature reports [10]
,
reactions between a wide range of arylpropiolic acid and cyclic
a plausible mechanism containing a radical oxidative coupling
process is illustrated in Scheme 2. Using the reaction of
phenylpropiolic acid (1a) and THF as an example, the reaction
should be initiated by the cleavage of DTBP to gives a tert-
butoxy radical, which abstracts a hydrogen atom from THF to
afford radical I. The radical I may engage on two competing
pathways, i.e., addition to the 2-position carbon in intermediate
II, generated from the reaction of phenylpropiolic acid (1a) with
potassium carbonate and nickel chloride, to produce intermediate
III. The other pathway is addition to the 3-position carbon in
phenylpropiolic acid (1a) to generate the intermediate VI, which
produces the stable cinnamic acid 6 through hydrogen abstraction
of THF. The intermediate III then proceeds via an abstraction of
THF to generate intermediate IV, which undergoes an
elimination through a single electron transfer process to release
carbon dioxide, alkenyl radical V and Ni(I). Alkenyl radical V
abstracts a hydrogen atom from THF to generate the product 3a.
Ni(II) would be regenerated by oxidation of Ni(I) with a tert-
butoxy radical and converted to intermediate II to complete the
catalytic cycle. Ni(II) might have two roles in this reaction: one is
the formation of salt with phenylpropiolic acid to facilitate the 2-
position attack by I; the other is to facilitate the radical
decarboxylatioin of intermediate III.
ethers. Based on the control experiments, a radical mechanism
was proposed.
Acknowledgments
We acknowledge Dr. Xiaofeng Yuan and Dr. Rongbin Cai for
detailed NMR structure determination for compounds 3a–s.
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6
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4
Tetrahedron
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5
Highlights



Ligand-free NiCl2-
catalyzed direct alkenylation of cyclic ethers.
A radical cross decarboxylative coupling strategy was
applied.
Mechanistic experiments were conducted to establish
a plausible reaction mechanis.