Metal-Free C(sp3)-H Allylation via Aryl Carboxyl Radicals Enabled by Donor-Acceptor Complex

Article abstract of DOI:10.1021/acs.orglett.8b01172

The first aryl carboxyl radical generation by the donor-acceptor complex with N-acyloxyphthalimides and Hantzsch esters is reported. Regio- and chemoselective C(sp³)-H bond allylation is enabled by aryl carboxyl radicals with visible light irradiation under mild and metal-free conditions.

Full text of DOI:10.1021/acs.orglett.8b01172

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Metal-Free C(sp3)−H Allylation via Aryl Carboxyl Radicals Enabled by
Donor−Acceptor Complex
Yang Li,†,§ Jing Zhang,†,§ Defang Li,†,‡ and Yiyun Chen*,†,‡
†State Key Laboratory of Bioorganic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai
Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
‡School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China
S
* Supporting Information
ABSTRACT: The first aryl carboxyl radical generation by the
donor−acceptor complex with N-acyloxyphthalimides and
Hantzsch esters is reported. Regio- and chemoselective
C(sp3)−H bond allylation is enabled by aryl carboxyl radicals
with visible light irradiation under mild and metal-free
conditions.
heengagementofunactivatedC(sp3)−HbondsfornewC−
Scheme1. GenerationandReactivityofArylCarboxylRadicals
TC bond formation is fundamental in organic synthesis, in
which excellent regio- and chemoselectivity are challenging to
achieve.1 Theoxygen-centeredradicalprovidesavaluableentryto
activate C(sp3)−H bonds via the 1,5-hydrogen atom transfer
(1,5-HAT) reaction; however, such reactivity is only demon-
stratedbythealkoxylradicals,2 andtheuseofarylcarboxylradicals
for 1,5-HAT reaction is less studied.3 Currently, the use of aryl
carboxyl radicals for C(sp3)−H bond functionalization is limited
to lactone formation under oxidative conditions via the
carbocation intermediate (Scheme 1a).3a,4 The use of aryl
carboxyl radicals for C(sp3)−H bond functionalization with
new C−C bond formation is unknown.3a,5,6
Traditionally, the generation of aryl carboxyl radicals requires
harsh reaction conditions such as strong oxidants, heating, or UV
light irradiation (Scheme 1b).7 Recently, the resurgence of
photoredox catalysis has enabled aryl carboxyl radical generation
under mild and visible-light-induced radical initiation conditions.
However, heavy metal photocatalysts are typically required.5 We
expect that a new metal-free aryl carboxyl radical generation
method will be very valuable, especially for material and biological
applications.8 We and others recently discovered that the donor−
acceptor complex demonstrated unique visible-light-induced
reactivity, and we envision the donor−acceptor complex
approach may enable the aryl carboxyl radical generation.9 In
this letter, we report the first visible-light-induced aryl carboxyl
radical generation via the donor−acceptor complex, with which
the regio- and chemoselective C(sp3)−H bond allylation is
achieved (Scheme 1c).
N-acyloxyl derivatives 1−4, which could be prepared in one step
from 4-toluic acids (Scheme 2a). When N-acyloxyphthalimide 1,
tetrachloro-substituted N-acyloxyphthalimide 2, or N-acyloxy-
naphthalimide 3 was mixed with Hantzsch ester (HE) 5, the UV/
vis absorption spectrometry of HE 5 showed clear red shifts. In
particular, a strong red shift together with a charge-transfer
N-Acyloxyphthalimides are readily accessible and stable aryl
Received: April 12, 2018
carboxyl radical precursors.5e,10 We started our investigation with
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Interaction between N-Acyloxy Derivatives and
Hantzsch Esters
Table 1. Reaction between N-Acyloxy Derivatives and
Hantzsch Ester for Selective C(sp3)−H Allylation
a
b
b
entry
conditions
conversion (%)
yield (%)
1
2
7 + HE, dioxane
7 + HE, DCM
7 + HE, DMF
8 + HE, DMF
9 + HE, DMF
10 + HE, DMF
entry 3, iPr2NEt
entry 3, HCO2H
>95
38
95
95
95
0
74
12
3
80(70)
79
4
5
83
6
0
7
95
95
93
82
70
8
84(67)
82
9
entry 3, band-pass 450 nm
entry 3, band-pass 475 nm
10
65
a
Reaction conditions: N-acyloxy derivatives (0.10 mmol, 1.0 equiv),
11 (0.30 mmol, 3.0 equiv), and Hantzsch ester 5 (0.15 mmol, 1.5
equiv) in 1.0 mL of solvent under nitrogen with 8 W blue LED
irradiation at ambient temperature for 15 h, unless otherwise noted.
b
1
Conversion and yields were determined by H NMR analysis, and
isolated yields are in parentheses.
thelackofdonor−acceptorcomplexformation(entries4−6). We
also tested the addition of acids or bases to the reaction and found
the reaction was not significantly affected (entries 7−8).
The possible reaction initiation with shorter wavelength
irradiation for the direct photoexcitation of N-acyloxy-
phthalimides or HE was next tested.5e,14 Using irradiation with
aband-pass at450nm, inwhich N-acyloxyphthalimides orHEhas
minimal absorption, the reaction went uncompromised with 82%
yield(entry9). Usinga475nmband-passwithoutemissionbelow
460 nm (see Figures S9−S10), the 65% yield of 12 could be
obtained (entry 10). Taken together, the donor−acceptor
complex formation is essential for the reaction with visible light
at longer wavelengths. The light irradiation and HE are both
found to be critical for the reaction (see Table S2).
orange-yellowish color appeared when HE 5 was mixed with the
electron-deficient 2, which was consistent with the N-acyloxy-
phthalimides as electron acceptors (Scheme 2a). In contrast, no
signal change was observed between N-acyloxysuccinimide 4 and
HE 5.9j
The Job’s plot was next performed with UV/vis absorption
spectrometryandindicatedthe1:1ratioofcomplexationbetween
2and5(Scheme2b).11 ThedissociationconstantKEDA between2
and 5 was calculated to be 3.7 M−1 in dichloromethane.12 The 1H
NMR signal of HE 5 shifted with the addition of N-
acyloxyphthalimide 1 by NMR titration experiments (Scheme
2c). When the N-acyloxyphthalimide 1 and HE 5 were subjected
to blue LED light irradiation, the phthalimides and methyl 4-
tolylate 6 were yielded after (trimethylsilyl)diazomethane
treatment, which suggested the aryl carboxyl radical generation
(Scheme 2d).
We then investigated the aryl carboxyl radical reactivity and
synthesized 2-ethylbenzoic phthalimide 7 for either 1,5-HAT or
1,6-HAT reaction. Under blue LED irradiation with allyl sulfone
11 as the radical acceptor, we observed the methyl ester 12 in 74%
yield after (trimethylsilyl)diazomethane treatment, which in-
dicated the sequential reaction of aryl carboxyl radical generation,
1,5-HAT reaction, and radical allylation (entry 1 in Table 1).13
The solvent screening indicated DMF was optimal to give 12 in
80% yield (70% isolated yield in two steps, entries 1−3). The use
of tetrachloro-substituted N-acyloxyphthalimide 8 and N-
acyloxynaphthalimide 9 gave similar 79−83% yields, while the
N-acyloxysuccinimide 10 did not lead to any conversion due to
Subsequently, the substrate scope of the C(sp3)−H allylation
was tested (Scheme 3). The electron-rich methyl or electron-
deficient chloride and fluoride groups as the aryl substituents did
not affect the reaction to give methyl esters 13−15 in 58−64%
yields. For substrates 16a and 17a with secondary C(sp3)−H
bonds at both the 5- and 6-position, only 1,5-HAT adducts were
obtained exclusively in 62−65% yields. We tested benzyl,
phenolic, and silyl ether derivatives 18a−20a and observed the
allylation adducts 18−20 in 58−65% yields. For substrates 21a
with a fused ring or 22a with a tertiary C(sp3)−H bond, the
decreased 45% yields of 21 and 22 were obtained. It is worth
noting that there is no lactone product formation in the aryl
carboxyl radical HAT reactions via the carbocation intermediate.6
The 5-exo alkene addition of aryl carboxyl radicals was further
investigated. While it is a typical reactivity of oxygen-centered
radicals, such reports of aryl carboxyl radicals are limited,4b and
the new C−C bond formation following 5-exo alkene addition is
unknown.15 Under our standard reaction conditions (entry 3 in
Table 1), we observed the alkene difunctionalization adduct 24 in
B
DOI: 10.1021/acs.orglett.8b01172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 3. Substrate Scope of C(sp3)−H Allylation
Scheme 4. Substrate Scope of Alkene Difunctionalization
a
Reaction conditions are the same as those in entry 3 of Table 1, and
isolated yields are reported.
88% isolated yield, which indicated the sequential reaction of aryl
carboxyl radical generation, 5-exo cyclization, and radical
allylation (Scheme 4).13 As substrate 23 has both possible 1,5-
HAT and 5-exo reaction pathways, the exclusive formation of the
lactone 24 suggested the preferred 5-exo cyclization.16 The aryl
substitution of electron-rich or -deficient methoxyl, methyl,
fluoro, chloro, and trifluoromethyl groups did not significantly
affect the reaction to give 25−34 in 59−85% yields. The pyridine
heterocycle was well tolerated to give 35 in 64% yield, and the
alkyl or aryl substituents at the alkene were both tolerated to give
36−38 in 68−80% yields. The di-, tri-, and tetra-substituted
alkenes all reacted uneventfully to give 39−41 in 69−73% yields.
The ethyl acrylate and acrylonitrile were also used as radical
acceptors to give 42−43 in 72−83% yields.
a
Reaction conditions are the same as those in entry 3 of Table 1, and
isolated yields are reported.
Scheme 5. Mechanistic Investigations and Proposals
To gain mechanistic insight, we prepared vinylcyclopropane-
substituted N-acyloxyphthalimide 44 and subjected it to the
standard reaction conditions. The ring-opening adduct 45 was
obtained in 41% yield and suggested the radical reaction pathway
(Scheme 5a). We also performed the crossover experiment with
N-acyloxyphthalimide 13a and 2-ethylbenzoic acid 46 (Scheme
5b). The exclusive formation of product 13 suggested the
intermolecular hydrogen abstraction reaction was unlikely. Based
on the mechanistic investigations above, we propose that the
reaction is initiated by the donor−acceptor complex formation
between N-acyloxyphthalimides and Hantzsch esters (Scheme
5c). After the visible-light-induced electron transfer, the N-
acyloxyphthalimide radical anion is formed and eliminates
phthalimides to generate the aryl carboxyl radical. Afterward,
the aryl carboxyl radical engages in either 1,5-HAT reaction or 5-
exo alkene addition to yield the alkyl radical for C(sp3)−H
allylation or alkene difunctionalization, while the eliminated
sulfone radical is reduced by the Hantzsch ester radical.
In conclusion, we have developed the first donor−acceptor
complex approach to generate aryl carboxyl radicals under metal-
free conditions with visible light irradiation. C(sp3)−H allylation
and alkene difunctionalization of N-acyloxyphthalimides were
realized via aryl carboxyl radicals. We envision this metal-free
C
DOI: 10.1021/acs.orglett.8b01172
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.8b01172.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yiyunchen@sioc.ac.cn.
ORCID
́
F.; Lalevee, J.; Gaumont, A. C.; Lakhdar, S. J. Am. Chem. Soc. 2016, 138,
7436. (g) Spell, M. L.; Deveaux, K.; Bresnahan, C. G.; Bernard, B. L.;
Sheffield, W.; Kumar, R.; Ragains, J. R. Angew. Chem., Int. Ed. 2016, 55,
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Pradeilles, J.; Wang, Y.; Mutsuga, T.; Myers, E. L.; Aggarwal, V. K. Science
2017, 357, 283. (j) Zhang, J.; Li, Y.; Xu, R. Y.; Chen, Y. Y. Angew. Chem.,
Int. Ed. 2017, 56, 12619.
Yiyun Chen: 0000-0003-0916-0994
Author Contributions
§Y.L. and J.Z. contributed equally to this work.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by the National Natural Science
Foundation of China 21472230, 21622207, 91753126; the
National Basic Research Program of China 2014CB910304;
and the Strategic Priority Research Program of the Chinese
Academy of Sciences XDB20020200.
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DOI: 10.1021/acs.orglett.8b01172
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