Free-Radical-Promoted Alkenylation of C(sp3)?H Bond in Chloroalkane with Cinnamic Acid and β-Nitrostyrene

Article abstract of DOI:10.1002/adsc.202000215

We demonstrated herein a free-radical alkenylation of the C(sp³)?H bond in 1,2-dichloroethane with cinnamic acid and β-nitrostyrene. This method not only provides a facile approach to chloroalkylated styrenes, but also would be instructive for halogen-atom directing selective functionalization of inert C(sp³)?H bond. (Figure presented.).

Full text of DOI:10.1002/adsc.202000215

Title: Free-Radical-Promoted Alkenylation of C(sp3)-H Bond in
Chloroalkane with Cinnamic Acid and β-Nitrostyrene
Authors: Minzhi Sun, Zhengbao Xu, Wenjie Li, Le Yang, Huichao You,
Dan Yu, Fang Fang, Yaxin Wang, and Zhong-Quan Liu
This manuscript has been accepted after peer review and appears as an
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000215
Link to VoR: http://dx.doi.org/10.1002/adsc.202000215

Advanced Synthesis & Catalysis
10.1002/adsc.202000215
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
3
Free-Radical-Promoted Alkenylation of C(sp )-H Bond in
Chloroalkane with Cinnamic Acid and β-Nitrostyrene
a†
b†
a
a
a
a
Minzhi Sun , Zhengbao Xu , Wenjie Li , Le Yang , Huichao You, Dan Yu, Fang
a
a
a
Fang, Yaxin Wang and Zhong-Quan Liu*
a
College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, P. R. China.
E-mail: liuzhq@lzu.edu.cn
Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Zibo Key Laboratory of New
Drug Development of Neurodegenerative diseases, School of Life Sciences, Shandong University of Technology, Zibo,
b
2
55000, Shandong, P. R. China.
†
These two authors contribute equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: We demonstrated herein a free-radical
alkenylation of the C(sp )-H bond in 1,2-dichloroethane
It might be due to the p-SOMO-p delocalization in
Cl CH radical (Scheme 1B). Of particular interests
are free-radical initiated highly selective
3
2
with cinnamic acid and β-nitrostyrene. This method not
only provides a facile approach to chloroalkylated
styrenes, but also would be instructive for halogen-atom
3
functionalization of C(sp )-H bond. We began to
investigate this conversion with general haloalkanes.
Herein we wish to report a free-radical alkenylation
of 1,2-dichloroethane (DCE) and 1,3-dichloropropane
3
directing selective functionalization of inert C(sp )-H
bond.
3
via selective activation of the inert C(sp )-H bond
Keywords:
Free-radical;
C-H
activation;
(
Scheme 1C). To the best of our knowledge, it is the
Decarboxylation; Haloalkane; Cinnamic acid
first example of oxidative coupling of DCE with
[6]
cinnamic acids and/or β-nitrostyrenes.
One of the most atom-economic and valuable
transformations in synthetic organic chemistry is the
free-radical promoted selective functionalization of
3
[1]
C(sp )-H bond.
As depicted in Scheme 1A,
considerable advances in site-selective conversion of
the C-H bond in amine, ether and alcohol have been
[2]
achieved in the past decades. In these cases, it is
believed that the unique selectivity is dominantly due
to bond dissociation energy (BDE) of the C-H bond,
[3]
polar effect and stability of the radical intermediate.
However, the heteroatom-directing effect seems only
limited in N and O atoms. Although halogen-atom
might play the similar role, selective activation of the
3
C(sp )-H bond in general haloalkane has not been
realized so far. Two major factors probably make it
challenging. One is the relatively weaker BDE of the
carbon-halogen bond than that of C-H bond. And the
other is the three full p-orbitals (three lone-pairs) of
halogen atom that would weaken the p-SOMO
delocalization. Nevertheless, several examples of this
Scheme
1.
Free-radical
promoted
selective
3
functionalization of C(sp )-H bond via heteroatom
directing.
conversion have been achieved in dichloromethane
(
DCM).[ The homolytic cleavage of the C-H bond
4]
occurred prior to that of the C-Cl bond leading to a
more stable Cl
Initially we chose (E)-3-(4-bromophenyl)acrylic
acid and DCE as the model substrate to optimize the
reaction conditions (Table 1). We started with a series
of peroxides, and TBPA was found more effective
0
2
CH radical (formation enthalpy: H
f
=
22.3 ± 1.0 kcal/mol) than ClCH
2
radical
0
[5]
(
formation enthalpy: H
f
= 28.0 ± 0.7 kcal/mol).
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202000215
than others to afford the desired product 1 (entries
Di-tert-butyl peroxide; TBHP= tert-Butyl hydroperoxide; DCP= Dicumyl
peroxide; TBPA= tert-Butyl peroxyacetate.
1
6
-4). Then temperature was monitored (entries 5 and
). An elevated temperature cound not give a better
yield. Next an array of metal and or metal salts were
screened (entries 7-14). As a result, low yields of the
products were obtained with or not the initiators
With the information in hand, we then evaluated
the substrate scope (Table 2). It was found that
various cinnamic acids yielded the corresponding
(
entry 15). Subsequently, we examined the
products
smoothly.
A
series
of
concentration of the reactants (entries 16-18). To our
delight, the yield increased to 42% by using 5 mL of
DCE as the solvent. Interestingly, decreasing the
amounts of TBPA to 2 equivalents gave a better yield
rather than 3 equivalents (entries 19-21). Furthermore,
(
E)-(3,4-dichlorobut-1-en-1-yl)benzenes
were
isolated as the major products with electron-deficient
aryl substituted cinnamic acids (1-12). Gratifyingly,
(
E)-3-(pyridin-3-yl)acrylic acid afforded the expected
product in 61% yield (8). In addition, cinnamic acids
containing the aromatic cores with substituents in
different positions affected the yield slightly (9 and
addition of a catalytic Cu
2
O led to a similar result
(
entry 22). Finally, a mixed solvent cound not
accelerate
the
reaction
(entry
23).
The
1
0). (E)-3-(4-(trifluoromethoxy)phenyl)acrylic acid
gave 62% yield of the product while
E)-3-(4-acetoxyphenyl)acrylic acid only afforded a
decarboxylative methylation would occur in t-BuOH,
a
which
might
undergo
an
addition
and
(
decarboxylation reaction of the methyl radical with
[7]
yield of 30% (11 and 12). It indicated that the
electron density of the aromatic core in cinnamic
acids might play a critical role in this reaction. In
order to investigate the electronic effect, a set of
cinnamic acids with electron-rich arenes were
examined (13-17). To our surprise, a series of
cinnamic acid. It‘s worth noting that only E-alkenes
were observed in all cases.[8]
Table 1. Modification of the typical reaction conditions.a
(
E)-1-chloro-4-arylbut-3-en-2-yl acetates (13-16)
were isolated as the major products with these type of
cinnamic acids. Furthermore, (2E,4E)-5-phenylpenta-
2
,4-dienoic acid also yielded the corresponding
peroxide
equiv.)
solvent
(mL)
o
b
entry
catalyst (mol%)
T ( C)
1 %
-
(
product 17. In these cases, a catalytic amount of
1
2
3
4
5
6
7
8
9
DTBP (3)
TBHP (3)
DCP (3)
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
Cu
2
O (5)
O (5)
O (5)
O (5)
O (5)
O (5)
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
5
7
5
5
5
120
120
120
120
130
110
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
Cu O (2 mol%) could improve the yields. Low
2
conversion of the starting materials were often found
in the cases of 10, 12 and 17, which resulted in
relatively low yields of the corresponding products.
Finally, we had also evaluated bromo and iodo and
even fluoroalkanes. But all failed. The former two
kinds of haloalkanes gave a mass involving
dehalogenative products. And only low yield of
decarboxylative methylation products was isolated
with fluoroalkanes.
-
-
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (3)
TBPA (2)
TBPA (1.5)
TBPA (1.75)
30
18
21
12
15
16
13
15
10
-
Cu (5)
CuCl (5)
CuI (5)
Table 2. Decarboxylative coupling of cinnamic acids with
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
CuF
Cu(acac)
Cu(OAc)
FeCl
2
(5)
DCE.a
2
(5)
(5)
2
2
(5)
(5)
AgNO
3
-
-
-
-
-
-
-
-
16
23
42
41
54
30
38
TBPA (2)
TBPA (2)
Cu
2
O (2)
-
5
5
120
120
53
35
c
23
a
Conditions: cinnamic acid (1 equiv., 0.2 mmol), DCE (as solvent), heat
measured temperature of oil bath), sealed tube, 5 h., unless otherwise noted. b
(
Isolated yield. c Solvent (4 mL of DCE and 1 mL of t-BuOH). DTBP=
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202000215
a
Conditions: cinnamic acid (1 equiv., 0.2 mmol), DCE (5 mL), TBPA (2
Scheme
2.
Free-radical
promoted
selective
o
equiv., 0.4 mmol), 120 C (measured temperature of oil bath), sealed tube, 5 h.,
unless otherwise noted. b Isolated yield. c Cu
3
functionalization of C(sp )-H bond in chloroalkanes.
2
O (2 mol%, 0.004 mmol).
Finally, mechanistic studies were carried out to
get insight into the details of this process (Scheme 3).
As demonstrated in Scheme 3A, a radical trapping
experiment showed that no desired product was
observed by loading a radical scavenger TEMPO.
Furthermore, radical adducts I and II were detected
by GC-MS, which indicated that the methyl radical as
well as the 1,2-dichloroethyl radical might be the
active intermediates in this process. Based upon the
Next, we also examined other chloroalkanes and
coupling partners (Scheme 2). As depicted in Scheme
2
A, reaction of (E)-3-(4-cyanophenyl)acrylic acid
with 1,3-dichloropropane afforded the expected
product 18 in 25% yield. The relatively low yield
might be due to the solvent effect, which affected the
efficiency of reaction critically. It’s noteworthy that
2
6% yield of (E)-1-phenylpent-1-en-3-yl acetate 19
can be isolated from a relatively complex system
given by radical coupling reaction of cinnamic acid
with 1-chloropropane (Scheme 2B). Although the
yield is relatively low, this example suggested that
[9]
previous literatures and the above results, we
proposed a possible mechanism for this reaction
(
Scheme 3B and 3C). Thermal homolysis of TBPA
would generate acetic and tert-butoxy radicals.
Alternatively, single-electron reduction of TBPA by
Cu(I) would afford acetic anion and t-BuO radical.
Then -fragmentation of tert-butoxy radical gave
acetone and methyl radical. Hydrogen-atom-transfer
3
highly site-specific functionalization of the C(sp )-H
bond in more general haloalkanes could be realized in
the future. Additionally, -nitrostyrenes also could be
utilized as the effective coupling partners in this
system (Scheme 2C). Furthermore, we had carefully
studied the effect of copper salts in both electron-rich
and electron-poor aryl-substituted cinnamic acids.
And we found that the copper salts affected the
electron-defficient acids little. But the electron-rich
acids and β-nitrostyrene substrates would give a more
complex system without the copper salts. And we
proposed that the copper salts might accelerate the
single-electron oxidation of the radical adduct and
therefore a nuclophilic substitution occurred with
electron-rich substrates.
(
HAT) from chloroalkane to tert-butoxy or methyl
radical occurred to form radical A, which then added
to the carbon-carbon double bond leading to radical B.
Subsequently, decarboxylation followed by HAT of
B would yield (E)-(3,4-dichlorobut-1-en-1-yl)arene if
the
substituents
on
the
arene
are
electron-withdrawing groups. While the substituents
are electron-donating groups, one electron oxidation
of B by Cu(II) leading to a benzyl cation C would be
faster than decarboxylation. And then a radical cation
D would be formed by decarboxylation and HAT of
C. Allyl nucleophilic substitution followed by single
electron reduction would yield the final product.
3
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10.1002/adsc.202000215
References
3
[
1] For selected recent reviews on C(sp )−H
functionalization, see: a) H. M. L. Davies and D.
Morton, Chem. Soc. Rev. 2011, 40, 1857; b) T.
Newhouse and P. S. Baran, Angew. Chem., Int. Ed.
2
011, 50, 3362; c) J. L. Roizen, M. E. Harvey and J. Du
Bois, Acc. Chem. Res. 2012, 45, 911; d) G. Rouquet
and N. Chatani, Angew. Chem., Int. Ed. 2013, 52,
1
1726; e) S. A. Girard, T. Knauber and C.-J. Li, Angew.
Chem., Int. Ed. 2014, 53, 74; f) J. He, M. Wasa, K. S. L.
Chan, Q. Shao and J.-Q. Yu, Chem. Rev. 2017, 117,
8
754; g) H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang,
A. K. Singh and A. Lei, Chem. Rev. 2017, 117, 9016.
For selected recent reviews on general C-H
functionalization, see: h) J. Le Bras and J. Muzart,
Chem. Rev. 2011, 111, 1170; i) C.-L. Sun, B.-J. Li and
Z.-J. Shi, Chem. Rev. 2011, 111, 1293; j) S. H. Cho, J.
Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev. 2011,
4
2
2
0, 5068; k) X. Shang and Z.-Q. Liu, Chem. Soc. Rev.
013, 42, 3253; l) L. Yang and H. Huang, Chem. Rev.
015, 115, 3468; m) X.-X. Guo, D.-W. Gu, Z. Wu and
W. Zhang, Chem. Rev. 2015, 115, 1622; n) R. Narayan,
K. Matcha, A. P. Antonchick, Chem. Eur. J. 2015, 21,
1
2
4678; o) Q.-Z. Zheng and N. Jiao, Chem. Soc. Rev.
016, 45, 4590; p) K. Murakami, S. Yamada, T.
Kaneda and K. Itami, Chem. Rev. 2017, 117, 9302; q) J.
He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q. Yu, Chem.
Rev. 2017, 117, 8754; r) D. J. Abrams, P. A.
Provencher, E. J. Sorensen, Chem. Soc. Rev. 2018, 47,
8
925; s) H. Sterckx, B. Morel, B. U. W. Maes, Angew.
Scheme 3. Mechanistic studies.
Chem. Int. Ed. 2019, 58, 7946.
[
[
[
2] For selected reviews, see: a) S. Zhang, F. Zhang, Y.-Q.
Tu, Chem. Soc. Rev. 2011, 40, 1937-1949; b) X. Shang,
Z.-Q. Liu, Acta. Chim. Sin. 2015, 73, 1275-1282; c) M.
K. Lakshman, P. K. Vuram, Chem. Sci. 2017, 8, 5845; d)
S.-R. Guo, P. S. Kumar, M. Yang, Adv. Synth. Catal.
2017, 359, 2-25.
In summary, a free-radical alkenylation of the
C(sp )-H bond in DCE with cinnamic acids and/or
-nitrostyrenes was developed. It allows a convenient
access to a variety of chloroalkylated styrenes, which
are valuable building blocks by diverse late-stage
3

transformations.
Besides,
the
results
of
3] a) Tedder, J. M. Angew. Chem. Int. Ed. Engl. 1982, 21,
401; b) Giese, B. Angew. Chem. Int. Ed. Engl. 1985, 24,
1
-chloropropane and 1,3-dichloropropane indicated
3
that site-specific HAT of the C(sp )-H bond in
haloalkane via halogen-atom direction would be
possible. Continuous investigations in this field are
ongoing in this lab.
5
9
53; c) Giese, B. Angew. Chem. Int. Ed. Engl. 1989, 28,
69; d) X.-S. Xue, P. Ji, B. Zhou, J.-P. Cheng, Chem.
Rev. 2017, 117, 8622; e) D. Šakić, H. Zipse, Adv. Synth.
Catal. 2016, 358, 3983.
4] a) Y. Tian, Z.-Q. Liu, RSC Adv. 2014, 4, 64855; b) M.-Z.
Lu, T.-P. Loh, Org. Lett. 2014, 16, 4698; c) Y. Liu, J.-L.
Zhang, R.-J. Song, J.-H. Li, Org. Chem. Front. 2014, 1,
1289; d) Y. Liu, J.-L. Zhang, R.-J. Song, J.-H. Li, Eur. J.
Org. Chem. 2014, 1177; e) X. Li, J. Xu, Y. Gao, H.
Fang, G. Tang, Y. Zhao, J. Org. Chem. 2015, 80, 2621;
f) Y. Liu, R.-J. Song, S. Luo, J.-H. Li, Org. Lett. 2018,
20, 212.
Experimental Section
General procedure: A mixture of cinnamic acids (1
equiv., 0.2 mmol) and TBPA (2 equiv., 0.4 mmol) was
o
heated in DCE (5 mL) under reflux at 120 C (measured
temperature of oil bath) for about 5 h in a sealed tube.
After the reaction finished, the mixture was evaporated
under vacuum and purified by column chromatography to
afford the desired product.
[
[
5] Y.-R. Luo, Handbook of Bond Dissociation Energies in
Organic Compounds, CRC Press, Boca Raton, 2002.
6] For a review on decarboxylation of C-H with cinnamic
Acknowledgements
acid, see: a) A. J. Borah, G. Yan, Org. Biomol. Chem.
2
015, 13, 8094; For selected examples of alkenylation
We thank the National Natural Science Foundation of China (No.
of C-H with cinnamic acid and -nitrostyrene, see: b)
Z. Cui, X. Shang, X.-F. Shao, Z.-Q. Liu, Chem. Sci.
2
1672089, 21971116) for financial support.
2
012, 3, 2853-2858; c) Y.-J, Jang, Y.-K. Shih, J.-Y. Liu,
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202000215
W.-Y. Kuo, C.-F. Yao, Chem. Eur. J. 2003, 9, 2123; d)
[9] For reviews on decarboxylative C-C/C-X bond
formation, see: a) L. J. Gooßen, N. Rodríguez and K.
Gooßen, Angew. Chem. Int. Ed. 2008, 47, 3100-3120;
b) N. Rodríguez, L. J. Gooßen, Chem. Soc. Rev. 2011,
40, 5030-5048; c) R. Shang, L. Liu, Sci. China Chem.
2011, 54, 1670-1687; d) W. I. Dzik, P. P. Lange, L. J.
Gooßen, Chem. Sci. 2012, 3, 2671-2678; e) C. Shen, P.
Zhang, Q. Sun, S. Bai, T. S. Andy Hor, X. Liu, Chem.
Soc. Rev. 2015, 44, 291-314; f) J. Xuan, Z.-G. Zhang,
W.-J. Xiao, Angew. Chem. Int. Ed., 2015, 54,
15632-15641; g) Y. Wei, P. Hu, M. Zhang, W. Su,
Chem. Rev. 2017, 117, 8864-8907.
J.-F. Xue, S.-F. Zhou, Y.-Y. Liu, X. Pan, J.-P. Zou, O. T.
Asekun, Org. Biomol. Chem. 2015, 13, 4896; For a
recent example of C-C bond formation with DCE, see:
e) Z. Wang, J. Yin, F. Zhou, Y. Liu, J. You, Angew.
Chem., Int. Ed. 2019, 58, 254; f) J. Gong, P. L. Fuchs, J.
Am. Chem. Soc. 1996, 118, 4486.
[
[
7] Z. Xu, C. Yan, Z.-Q. Liu Org. Lett. 2014, 16, 5670.
8] For a discussion of the E/Z selectivity, see: L. Zhang, Z.
Hang, Z.-Q. Liu Angew. Chem. Int. Ed. 2016, 55,
2
36-239.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.202000215
COMMUNICATION
Free-Radical-Promoted Alkenylation of
3
C(sp )-H Bond in Chloroalkane with Cinnamic
Acid and β-Nitrostyrene
Adv. Synth. Catal. Year, Volume, Page – Page
a†
b†
a
Minzhi Sun , Zhengbao Xu , Wenjie Li , Le
a
a
a
a
Yang , Huichao You, Dan Yu, Fang Fang, Yaxin
Wang and Zhong-Quan Liu*
a
a
6
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