Photoinduced α-Alkenylation of Katritzky Salts: Synthesis of β,?-Unsaturated Esters

Article abstract of DOI:10.1021/acs.orglett.0c04287

?,?-Unsaturated esters are building blocks in biologically important compounds, pharmaceuticals, and natural products. Because the current synthetic methods often require transition-metal catalysts or lack general variants, we herein describe a simple NaI-involved photoinduced deaminative alkenylation for their synthesis in the absence of photocatalysts and additives. The density functional theory study unveils that the electrostatic interaction of NaI with Katritzky salts is the key to forming the photoactive electron donor-acceptor complex, thus leading to the alkyl radicals for the alkenylation.

Full text of DOI:10.1021/acs.orglett.0c04287

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Letter
Photoinduced α‑Alkenylation of Katritzky Salts: Synthesis of β,γ-
Unsaturated Esters
Chao-Shen Zhang,† Lei Bao,† Kun-Quan Chen, Zhi-Xiang Wang,* and Xiang-Yu Chen*
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ABSTRACT: β,γ-Unsaturated esters are building blocks in bio-
logically important compounds, pharmaceuticals, and natural
products. Because the current synthetic methods often require
transition-metal catalysts or lack general variants, we herein describe
a simple NaI-involved photoinduced deaminative alkenylation for
their synthesis in the absence of photocatalysts and additives. The
density functional theory study unveils that the electrostatic
interaction of NaI with Katritzky salts is the key to forming the photoactive electron donor−acceptor complex, thus leading to
the alkyl radicals for the alkenylation.
Scheme 1. Motivation and Synthetic Strategy
he search for efficient strategies to synthesize carbonyl
compounds starting from cheap and readily available
T
materials has always been a central goal in modern organic
synthesis. In particular, β,γ-unsaturated carbonyl compounds
display privileged activity features and find wide applications as
valuable synthetic building blocks.1 Several elegant strategies
exist for the synthesis of β,γ-unsaturated esters,2 including the
nickel- or palladium-catalyzed cross-coupling of enolates and
alkenyl halides, triflates, and tosylates,3 the nickel-catalyzed
cross-coupling of α-bromo esters with alkenyl bromides,4
silanes, and Grignard reagents5 and the one-pot C−H
zincation and copper-catalyzed cross-coupling of alkenyliodo-
nium salts,6 but most require transition-metal catalysis or lack
general variants (Scheme 1A). The development of new
synthetic routes allowing greater practicality and scope from
readily available starting materials is thus highly desirable.
Recently, primary amines, which are abundant natural
feedstocks, have emerged as powerful reagents for the
generation of alkyl radicals.7 In 2017, Watson and coworkers
first reported the Suzuki−Miyaura cross-coupling of aryl
boronic acids, employing Katritzky salts as C-centered radical
precursors.8 The visible-light-induced generation of alkyl
radicals has been successfully realized by Glorius and
coworkers.9 In 2019, Lu and Xiao reported an elegant
deaminative alkyl-Heck-type reaction for alkene synthesis.10
Wang and Uchiyama achieved good E/Z selectivity of this
transformation by choosing Ir- or Ru-based photocatalysts.11
Later, Shang and Fu also realized this type of reaction by using
the electron donor−acceptor (EDA) concept,12 where both
NaI and PPh3 were necessary for the generation of alkyl
radicals (Scheme 2B).13 In our previous study, we found that
the electrostatic interaction of an alkali metal cation and
oxygen enabled the creation of a photoactive EDA complex for
the iodination of N-alkenoxypyridiniums14 (Scheme 2C) and
N-hydroxyphthalimide esters.15 As such, we envisioned that if
Received: December 29, 2020
Published: February 17, 2021
https://dx.doi.org/10.1021/acs.orglett.0c04287
Org. Lett. 2021, 23, 1577−1581
© 2021 American Chemical Society
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Letter
a
Scheme 2. Optimization of the Reaction Conditions
Scheme 3. Reaction Scope
a
GC yield using n-hexadecane as an internal standard. Isolated yield
b
c
d
in parentheses. 20 mol % of NaI was used. No irradiation. No NaI.
it were possible to form the EDA complex between NaI and
Katritzky salts bearing a carbonyl group, then a much simpler
method for the generation of alkyl radicals would be unleashed
without using expensive external photocatalysts or any
additives. We therefore set out to develop a method to access
diverse β,γ-unsaturated carbonyl compounds by using only NaI
and readily available Katritzky salts.
Initially, the reaction of the Katritzky salt 1a and 1,1-
diphenylethylene 2a was investigated (Scheme 2A). We were
pleased to find that the reaction with a catalytic amount of NaI
under the irradiation of blue light furnished the desired
alkenylation product 3a in 67% yield (entry 1). After
optimization (entries 2−10), the yield was increased to 95%
when the reaction was carried out in DMA with 20 mol % of
NaI (entry 10). Control experiments showed that no reaction
was observed without irradiation or NaI (entries 11 and 12).
To confirm our above conjecture (Scheme 1D), we
investigated the involvement of the EDA complex. Whereas
the Katritzky salt 1a, 2a, and NaI individually showed no
significant UV−vis absorption in the visible region of the
spectra, an obvious red shift of absorption could be observed in
the spectrum of the reaction mixture and the mixture of 1a and
NaI. These experiments indicate the formation of a visible-
light-active EDA complex (Scheme 2B). Furthermore, using
density functional theory (DFT) calculations (see the SI for
computational details), we were able to locate the EDA
complex with a complexation free energy of 9.6 kcal/mol
(Scheme 2C). The optimized structure of the complex with
a
Yield of isolated products 3 after chromatography.
Na···OC (2.30 Å) and I−···pyridine ring (3.80 Å) distances
indicates that the EDA complex is stabilized by the Naσ+···Oσ−
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Figure 1. Free-energy profiles (in kcal/mol) for the reaction of 1a with 2a in dimethylacetamide.
electrostatic interaction and the Iσ−···π anion−π interaction.
The complex was predicted to feature an absorption peak at
430 nm, which is in agreement with the UV−vis spectrum of
NaI and 1a. The absorption originates from excitation from the
iodine lone pair to the π* orbital of the pyridine ring.
With the optimized conditions in hand, we then investigated
the generality of this protocol (Scheme 3). A series of
phenylalanine-derived Katritzky salts bearing electron-donating
or electron-withdrawing substituents (4-NO2C6H4, 4-FC6H4,
4-tBuOC6H4, and 4-HOC6H4) reacted smoothly and gave the
corresponding products 3a−e in 43−81% yields. This was also
true for the homophenylalanine- and phenylethylamine-
derived Katritzky salts, giving rise to products 3f and 3g.
Moreover, the method tolerated a variety of functional groups,
such as thioether, esters, ketone, and nitrile (3h−n). The effect
of alkenes was examined as well. Both electron-donating (4-Me
and 4-MeO) and electron-withdrawing (4-F, 4-Cl, and 4-Br)
groups on the phenyl ring of 1,1-diphenylethylenes were
tolerable and afforded the desired products 3o−s in good
yields. Notably, the reaction of the styrene gave the
corresponding β,γ-unsaturated product 3t with excellent
diastereomeric ratios, albeit in somewhat decreased yield. In
addition, substituted styrenes were also suitable reaction
partners, whereas a decrease in E/Z selectivity was observed
(3u−x).
photoinduced NaI-catalyzed reaction of 1a+ and 1,1-diphenyl-
ethylene (2a). According to the computational results, we
propose a plausible mechanism, as illustrated in Figure 1.
Starting with the electron donor−acceptor complex
1
(namely, EDA), the blue light first excites the singlet ground
state 1EDA to the first singlet excited state 1EDA*.
Subsequently, 1EDA* undergoes homolytic C−N bond
cleavage to generate the alkyl radical through two possible
mechanisms. It may take place on the first singlet excited state,
2
directly giving the IM1 radical. Previously, we have shown
that the first singlet excited state of an EDA complex could
undergo homolytic bond cleavage without an apparent
barrier.14 Alternatively, 1EDA* may convert to the triplet
3
3EDA via intersystem crossing; then EDA, breaks the C−N
3
bond via TS1+ to give the 2IM1 radical with a barrier of 18.0
kcal/mol. It is not certain which pathway is preferred, but it is
certain that the 2IM1 radical can be generated. After the radical
2
generation, the resultant radical IM1 attacks the terminal
2
carbon of 2a via TS2 to form the C−C bond with a low
2
barrier of 12.6 kcal/mol, leading to IM2. We considered two
2
mechanisms to convert IM2 to the final product 3a. On the
one hand, the radical Py−Na+I• released from radical
2
3
generation abstracts a hydrogen atom from IM2 via TS3+
with a barrier of 23.1 kcal/mol to afford 3a. The regeneration
of the NaI catalyst is achieved via intramolecular electron
transfer from the PyH fragment and Na+I•, with the byproduct
The reaction scope of this protocol was further demon-
strated by using widely available carboxylic acids as starting
materials. Various substituted cinnamic acids were readily
reacted under the standard reaction conditions, and the
corresponding products (3t and 3y−b′) were obtained with
high E/Z ratios.
−
PyH+ being stabilized by the counteranion (BF4 ). On the
2
other hand, Py−Na+I• and IM2 first undergo intermolecular
single-electron transfer (SET) to regenerate the catalyst NaI,
1
1
1
giving IM3+ and Py. Then, Py deprotonates IM3+ via TS4+
with a barrier of 15.4 kcal/mol, giving 3a and PyH+. Overall,
the reaction has accessible kinetic barriers with gradually
To understand the reaction mechanism, we performed DFT
calculations to construct the free-energy profile for the
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2002, 8, 853−858. (c) Fordred, P. S.; Bull, S. D. Tandem
hydroboration/reduction of trisubstituted β,γ-unsaturated esters for
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downhill thermodynamics, rationalizing the occurrence of the
reaction.
In summary, we herein developed a much simpler method
for the synthesis of β,γ-unsaturated compounds by using only
the weak interactions of NaI. The DFT studies depicted that
the weak interaction of Katritzky salt and NaI hastens the
formation of the EDA complex and revealed a comprehensive
mechanistic understanding of the radical reaction process. The
method is characterized by operational simplicity, generality,
no need for the use of transition-metal catalysts or any
additives, and easily accessible starting materials. In light of the
promising properties of β,γ-unsaturated compounds as well as
the potential applications of weak interactions, we anticipate
that the presented strategy will facilitate the pharmaceutical
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c04287.
Experimental details, DFT calculations, characterization
data, and spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhi-Xiang Wang − School of Chemical Sciences, University of
Chinese Academy of Sciences, Beijing 100049, China;
orcid.org/0000-0001-5815-3032; Email: zxwang@
ucas.ac.cn
Xiang-Yu Chen − School of Chemical Sciences, University of
Chinese Academy of Sciences, Beijing 100049, China;
orcid.org/0000-0002-0383-0910;
Email: chenxiangyu20@ucas.ac.cn
Authors
Chao-Shen Zhang − School of Chemical Sciences, University
of Chinese Academy of Sciences, Beijing 100049, China
Lei Bao − School of Chemical Sciences, University of Chinese
Academy of Sciences, Beijing 100049, China
Kun-Quan Chen − School of Chemical Sciences, University of
Chinese Academy of Sciences, Beijing 100049, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c04287
(6) Liu, C.; Wang, Q. Alkenylation of C(sp3)−H Bonds by
Zincation/Copper-Catalyzed Cross-Coupling with Iodonium Salts.
Angew. Chem., Int. Ed. 2018, 57, 4727−4731.
Author Contributions
(7) (a) He, F.-S.; Ye, S.; Wu, J. Recent Advances in Pyridinium Salts
as Radical Reservoirs in Organic Synthesis. ACS Catal. 2019, 9,
8943−8960. (b) Pang, Y.; Moser, D.; Cornella, J. Pyrylium Salts:
Selective Reagents for the Activation of Primary Amino Groups in
†C.-S.Z. and L.B. contributed equally.
Notes
The authors declare no competing financial interest.
̈
Organic Synthesis. Synthesis 2020, 52, 489−503. (c) Rossler, S. L.;
Jelier, B. J.; Magnier, E.; Dagousset, G.; Carreira, E. M.; Togni, A.
Pyridinium Salts as Redox-Active Functional Group Transfer
Reagents. Angew. Chem., Int. Ed. 2020, 59, 9264−9280. (d) Correia,
J. T. M.; Fernandes, V. A.; Matsuo, B. T.; Delgado, J. A. C.; de Souza,
ACKNOWLEDGMENTS
■
Support was provided by the National Natural Science
Foundation of China (21773240 and 22001248) and the
Fundamental Research Funds for the Central Universities and
the University of the Chinese Academy of Sciences.
W. C.; Paixao, M. W. Photoinduced deaminative strategies: Katritzky
̃
salts as alkyl radical precursors. Chem. Commun. 2020, 56, 503−514.
(8) (a) Basch, C. H.; Liao, J.; Xu, J.; Piane, J. J.; Watson, M. P.
Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross
Couplings via C−N Bond Activation. J. Am. Chem. Soc. 2017, 139,
5313−5316. (b) Liao, J.; Guan, W.; Boscoe, B. P.; Tucker, J. W.;
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