Photo-induced anti-Markovnikov hydroalkylation of unactivated alkenes employing a dual-component initiator

Article abstract of DOI:10.1016/j.cclet.2020.06.026

Metal-free anti-Markovnikov hydroalkylation of unactivated alkenes with cyanoacetate has been developed, featuring the use of a dual-component initiator containing an organic photocatalyst and a radical precursor. When combined, the two components can und

Full text of DOI:10.1016/j.cclet.2020.06.026

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Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Photo-induced anti-Markovnikov hydroalkylation of unactivated
alkenes employing a dual-component initiator
b,c,
a,**
*
Yachao Zhanga, Liang-Liang Maob, Sifan Hua, Yi Luan , Huan Cong
a
School of Materials Science and Engineering, University of Science and Technology Beijing, Beijing 100083, China
b
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
c
School of Future Technology, University of Chinese Academy of Sciences, Beijing 100190, China
A R T I C L E I N F O
A B S T R A C T
Article history:
Metal-free anti-Markovnikov hydroalkylation of unactivated alkenes with cyanoacetate has been
developed, featuring the use of a dual-component initiator containing an organic photocatalyst and a
radical precursor. When combined, the two components can undergo visible light-induced single-
electron transfer, and serve as a versatile and effective alkyl radical generator.
© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Received 4 May 2020
Received in revised form 10 June 2020
Accepted 19 June 2020
Available online xxx
Keywords:
Photocatalysis
Anti-Markovnikov
Alkene hydroalkylation
Single-electron transfer
Radical
Hydrofunctionalization of unactivated alkenes represents a
productive strategy to rapidly access diverse molecular struc-
tures from abundant and low-cost synthetic feedstocks [1].
Dictated by the empirical Markovnikov’s rule, classic olefin
electrophilic addition involving proton as the electrophile
can afford regioselective hydrofunctionalization products
(Scheme 1a) [2]. Complementary approaches have been
investigated showing anti-Markovnikov regioselectivity: (1)
transition-metal hydride-mediated olefin insertion [3] and (2)
radical addition to alkenes followed by hydrogen atom transfer
(HAT) [4].
The facile generation of radical species under mild conditions is
essential to the success of visible light photoredox catalysis
through photo-induced single-electron transfer (SET) processes
[5]. In order to achieve efficient SET, the excited states of the
photocatalysts (PC) are usually required to match the redox
properties of the starting materials [6], which may limit the scope
of applicable reaction substrates. We envisioned that a dual-
component initiator system wherein visible light-induced SET
between a photocatalyst and a radical precursor could provide a
versatile radical source [7]. The resulting radicals would further
interact with starting materials to initiate the desired reactions.
Therefore, the formation of radical intermediates would be less
dependent on the redox properties of the starting materials, which
may offer opportunity for new reaction development (Scheme 1b).
Here we report the photo-induced anti-Markovnikov hydro-
alkylation of unactivated alkenes with cyanoacetate, featuring
metal-free conditions (Scheme 1c). Specifically, an organic dye (i.e.,
eosin Y-Na2) [8] and N-hydroxyphthalimide (NHP) ester [9] prove
to be effective as the photocatalyst and the radical precursor,
respectively. As a proof of concept, such dual-component initiator
can indeed serve as an economical and environmentally friendly
alkyl radical generator under visible light irradiation.
On the basis of the aforementioned initiator design, our
investigation commenced with the model reaction between 1-
octene (1a) and ethyl cyanoacetate (2). As an abundant industrial
feedstock ($2.7 USD per mole, based on the list price from Energy
Chemical Co., one of the leading lab chemical suppliers in China, as
of April 2020), ethyl cyanoacetate exhibits versatile utility for fine
chemical synthesis because of its multiple orthogonal reactive
sites, but alkene hydroalkylation involving cyanoacetate has thus
far been reported with limited success [10]. After screening the
reaction parameters, we have determined that the desired
hydroalkylation reaction can proceed under the irradiation of
blue LED light at ambient temperature, showing exclusive anti-
Markovnikov regioselectivity and almost quantitative yield
(Table 1, entry 1). Notably, best reaction performance was obtained
* Corresponding author at: Key Laboratory of Photochemical Conversion and
Optoelectronic Materials, Technical Institute of Physics and Chemistry, Chinese
Academy of Sciences, Beijing 100190, China.
** Corresponding author.
E-mail addresses: yiluan@ustb.edu.cn (Y. Luan), hcong@mail.ipc.ac.cn (H. Cong).
https://doi.org/10.1016/j.cclet.2020.06.026
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Y. Zhang, et al., Photo-induced anti-Markovnikov hydroalkylation of unactivated alkenes employing a dual-
component initiator, Chin. Chem. Lett. (2020), https://doi.org/10.1016/j.cclet.2020.06.026

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results compared to other organic dyes (Table S1 in Supporting
information) and the more expensive Ru-bipyridyl complex (entry
6). Evaluation of a series of NHP esters (Table S2 in Supporting
information) and bases (entry 7 and Table S3 in Supporting
information) further established the metal-free standard
condition.
We next examined the scope of the standard condition for
photo-induced anti-Markovnikov hydroalkylation with ethyl
cyanoacetate. A range of functionalized unactivated alkenes were
found to be suitable substrates, including a demonstration of
scalability with a gram-scale reaction (Scheme 2), but styrenes
were found to be unproductive substrates. Certain reactive or labile
functional groups such as hydroxy (3c), ketone (3d), imide (3g),
and acetal (3j) are compatible with the standard condition,
affording good yields. In addition to mono-substituted olefins, a
cyclic internal alkene (3l) and 1,1-disubstituted alkenes (3m and
3n) can also undergo hydroalkylation smoothly. For all substrates,
the anti-Markovnikov hydroalkylation products were exclusively
observed.
The α-cyanoester products are highly useful compounds which
can be converted into important synthetic building blocks. For
example, the N-Boc amino ester 4 can be rapidly prepared through
reduction [12] of cyanoester 3c followed by Boc-protection. The
unprotected hydroxyl group remained intact under the low-
temperature reductive condition of sodium borohydride in the
presence of nickel chloride. Subsequent tosylation of 4 and SN2
with potassium phthalimide furnished the β2-amino acid deriva-
tive 6, a key intermediate of a biologically active somatostatin
analog (Scheme 3) [13].
Scheme 1. Background and design of the photo-induced anti-Markovnikov
hydroalkylation.
Table 1
Reaction optimization.
To gain insight into whether radical-based mechanism is
operating, we conducted a radical clock experiment using the 1,6-
diene 1o as the substrate [14]. As shown in Scheme 4, our
observation that the 5-exo cyclized product 3o’, rather than the
linear compound 3o, was isolated suggests the existence of radical
intermediates.
We proposed a plausible reaction mechanism (Scheme 5)
wherein the visible light-induced SET between the photo-excited
Entry
Variations from the standard condition
Conv. (%)
Yield (%)
1
2
3
4
5
6
7
none
no light
no eosin Y-Na2
no N-(pivaloyloxy)phthalimide
no pyridine
97
<2
<2
25
54
37
<2
92
<2
<2
20
40
15
<2
Ru(bpy)3Cl2 instead of eosin Y-Na2
Et3N instead of pyridine
The conversions and yields were determined by GC analysis using a calibrated
internal standard (n-tetradecane).
in the presence of excess ethyl cyanoacetate without external
solvent. Under the optimized condition, the dual-component
initiator is composed of eosin Y-Na2 and N-(pivaloyloxy)phthali-
mide, with control experiments confirming the necessity of light
and each component (entries 2 À 4). Following the control
experiment of Table 1, entry 4, prolonging the reaction time to
24 h in the absence of N-(pivaloyloxy)phthalimide afforded 73% of
alkene conversion and 40% yield of the product based on calibrated
GC analysis. The substantial product formation catalyzed by eosin
Y-Na2 alone indicates that parallel HAT processes may also be
possible. [11]. In addition, the use of pyridine as base is beneficial to
achieve enhanced reaction efficiency (entries 1 vs. 5). Upon
investigating an array of photocatalysts, we discovered that eosin
Y-Na2, with a relatively low loading (0.5 mol%), provided superior
Scheme 2. Substrate scope.
Please cite this article in press as: Y. Zhang, et al., Photo-induced anti-Markovnikov hydroalkylation of unactivated alkenes employing a dual-
component initiator, Chin. Chem. Lett. (2020), https://doi.org/10.1016/j.cclet.2020.06.026

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Y. Zhang et al. / Chinese Chemical Letters xxx (2019) xxx–xxx
3
initiator containing an organic photocatalyst and
a
radical
precursor as an effective alkyl radical generator, thereby avoiding
the use of conventional toxic radical initiators and metal-based
reagents. Further studies on the applications of this versatile
photoredox initiator design would inspire the development of
novel radical-based synthetic methods.
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
Acknowledgments
This work was supported by the Strategic Priority Research
Program of the Chinese Academy of Sciences (No. XDB17000000),
the National Natural Science Foundation of China (Nos. 21672227,
21922113), the National Key Research and Development Program
of China (No. 2017YFA0206903), Beijing Natural Science Founda-
tion (No. L182020), Fundamental Research Funds for the Central
Universities (No. FRF-TP-19-013B1), K.C. Wong Education Founda-
tion, and the TIPC Director’s Fund. We thank Profs. Li-Zhu Wu
(TIPC-CAS), Wenxiong Zhang (PKU), and Congyang Wang (ICCAS)
for the help with instrumental analysis.
Scheme 3. Synthetic application.
Appendix A. Supplementary data
Supplementarymaterialrelatedtothisarticlecanbefound, inthe
online version, at doi:https://doi.org/10.1016/j.cclet.2020.06.026.
Scheme 4. Radical clock experiment.
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