Regioselective Sulfonylvinylation of the Unactivated C(sp3)-H Bond via a C-Centered Radical-Mediated Hydrogen Atom Transfer (HAT) Process

Article abstract of DOI:10.1021/acs.orglett.9b01734

Given the similarity of multiple sp³ C-H bonds in electronic properties and bond dissociation energy (BDE), regioselective sp³ C-H bond functionalization remains a paramount challenge. Here, we report a C-centered radical-mediated approach for site-specific sulfonylvinylation of the C(sp³)-H bond via the hydrogen atom transfer (HAT) process. The reaction features mild conditions, broad substrate scope, and high regioselectivity and stereoselectivity, manifesting the nontrivial synthetic potential.

Full text of DOI:10.1021/acs.orglett.9b01734

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Regioselective Sulfonylvinylation of the Unactivated C(sp3)−H Bond
via a C‑Centered Radical-Mediated Hydrogen Atom Transfer (HAT)
Process
Shan Yang,† Xinxin Wu,† Shuo Wu,† and Chen Zhu*,†,‡
†Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science,
Soochow University, 199 Ren-Ai Road, Suzhou, Jiangsu 215123, People’s Republic of China
‡Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, People’s Republic of China
S
* Supporting Information
ABSTRACT: Given the similarity of multiple sp3 C−H bonds
in electronic properties and bond dissociation energy (BDE),
regioselective sp3 C−H bond functionalization remains a
paramount challenge. Here, we report a C-centered radical-
mediated approach for site-specific sulfonylvinylation of the
C(sp3)−H bond via the hydrogen atom transfer (HAT)
process. The reaction features mild conditions, broad substrate
scope, and high regioselectivity and stereoselectivity, manifesting the nontrivial synthetic potential.
Inspired by our recent findings in the radical olefination of
n the perspective of atom economy and step economy, the
5b
Idirect transformation of ubiquitous C(sp )−H bonds into remote C(sp3)−H bonds, it is assumed that the similar
3
strategy might be suitable for the preparation of structurally
complex α,β-unsaturated sulfones that are otherwise difficult to
make. Mechanistically, addition of the sulfonyl radical, which is
obtained from sulfonyl chloride, to the readily available
propargyl alcohol generates a vinyl radical that triggers the
subsequent HAT process and functional group migration
(FGM),8 leading to α,β-unsaturated sulfones (Scheme 1, top).
Herein, we provide the concrete support for the hypothesis.
The site-specific sulfonylvinylation of C(sp3)−H bonds is
enabled by the vinyl-radical-mediated 1,5-HAT process.9
Notably, consecutive scission of an inert C−C and C−H
bond readily proceeds in the reaction. A variety of sulfone-
substituted E-olefins are furnished in good yields, which could
be further converted to valuable di/tetrahydropyrans (Scheme
1, bottom). The reaction features mild conditions, broad
substrate scope, and high regioselectivity and stereoselectivity.
The initial investigation of reaction conditions was
performed with propargyl alcohol 1a and tosyl chloride in
the presence of photocatalyst and visible-light irradiation
(Table 1). Base was added to remove byproduct HCl that
suppressed the reaction outcome. Among the screened organic
solvents, acetonitrile afforded the desired product 2a in a
higher yield (Table 1, entries 1−5).The reaction proceeded
efficiently in biphasic solution, in which H2O helped dissolve
inorganic bases, whereas, in a solely organic solvent, the
reaction yield was sharply decreased (Table 1, entry 6). The
alkene in 2a was formed with exclusive E-configuration. A
other valuable chemical bonds largely enhances the synthetic
efficiency.1 Because of the identical bond strength and
electronic property of multiple C(sp3)−H bonds, regioselective
functionalization of C(sp3)−H bonds still remains challenging,
which has prompted numerous organic chemists to devote
attention to C(sp3)−H activation over the past few decades.
Among these efforts, transition-metal-mediated C(sp3)−H
activation has been extensively studied, in which the
regiocontrol is generally achieved by harnessing the strategi-
cally placed directing groups.2 Recently, the renaissance of
radical-mediated regioselective C(sp3)−H bond functionaliza-
tion has attracted broad interest,3 complementary to the
transition-metal catalysis. Hydrogen atom transfer (HAT)
mediated by N- or O-centered radicals has proven to be among
the ingenious tactics used to address the regioselectivity issue
for C(sp3)−H activation.4 In contrast, functionalization of
remote C(sp3)−H bonds mediated by C-centered radicals has
been scarcely reported.5
Given the unique chemical and biological activities, e.g.,
Michael acceptor, 2π partner in cycloaddition, and inhibitor of
cysteine protease, α,β-unsaturated sulfones are regarded as
important intermediates in synthetic chemistry.6 The conven-
tional synthetic methods mainly focus on the alkyl sulfones-
involved Knoevenagel reaction, the oxidation of sulfides or
sulfoxides, and acetylenic sulfone mediated addition or
reduction.7 However, they sometimes suffer from the limited
substrate scope and tedious synthetic approach for starting
materials. Thus, seeking a new efficient strategy to prepare α,β-
unsaturated sulfones bearing a diversity of skeletons is still in
demand.
Received: May 16, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01734
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. C-Centered Radical-Mediated C(sp3)−H
drawing substituents were smoothly converted to the desired
products in excellent yields (2a−2q). The bromide residue in
product 2n is synthetically useful, which offered a platform for
further modification by cross-coupling reactions. The reaction
solely occurred at a terminal alkyne rather than an internal
alkyne, indicating a great chemoselectivity (2r). Cyclic
C(sp3)−H bond was also reactive, affording the vinylated
product in good yields (2s). In addition to the tertiary
C(sp3)−H bonds, the secondary ones, including benzylic and
aliphatic C(sp3)−H bonds, were also readily functionalized
(2t−2w). Remarkably, only the vinylation of δ-C(sp3)−H
bonds via 1,5-HAT was allowed (2w), manifesting an exclusive
regioselectivity. The C(sp3)−H bond adjacent to heteroatoms
such as oxygen was also apt for the remote vinylation (2x).
The supreme chemoselectivity of this protocol was further
demonstrated in the reaction with the heteroaryl-substituted
substrates. Although we have previously disclosed the
migratory aptitude of heteroaryls,8f herein, the migration of
the vinyl occurred in preference to the heteroaryls, leading the
unique vinyl-migrated products (2y−2ac). The method was
also suitable for the synthesis of trisubstituted alkenes by using
the less-reactive internal propargyl alcohols (2ad−2ae). The
configuration of 2ad and 2ae was ambiguously assigned by
NOE analysis.
Sulfonylvinylation
variety of bases were then examined (Table 1, entries 7−10),
showing that the use of 1.0 equiv of Na2CO3 gave rise to 90%
yield (Table 1, entry 9). Compared to other photosensitizers,
fac-Ir(ppy)3 offered the best catalytic efficiency under blue
LEDs irradiation (Table 1, entries 11−14). Control experi-
ments revealed that the reaction gave lower yield in the
absence of base (Table 1, entry 15), and no reaction occurred
without photocatalyst or in darkness (Table 1, entries 16 and
17).
With the optimized reaction conditions in hand, the
generality of the protocol, as well as the scope of propargyl
alcohols, were evaluated (see Scheme 2). Electronic effects did
not have much impact on the reaction outcome, as propargyl
alcohols bearing either electron-donating or electron-with-
The scope of sulfonyl chlorides were next defined (see
Scheme 3). Both aryl and alkyl sulfonyl chlorides were
compatible with the mild conditions. It seemed that electronic
and steric effects did not influence the transformation. While a
series of aryl sulfonyl chlorides bearing either electron-
donating (2ag−2ah) or electron-withdrawing (2ai−2ak)
substituents led to the corresponding products in high yields,
alkyl sulfonyl chlorides delivered lower yields (2al−2am).
Intriguingly, naturally occurring camphor skeleton could be
a
Table 1. Survey of Reaction Parameters
b
entry
photocatalyst
fac-Ir(ppy)3
base (equiv)
solvent
yield (%)
1
2
3
4
5
K2HPO4 (1.5)
K2HPO4 (1.5)
K2HPO4 (1.5)
K2HPO4 (1.5)
K2HPO4 (1.5)
K2HPO4 (1.5)
Na2HPO4 (1.5)
K2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.0)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
Na2CO3 (1.5)
−
DMSO
acetone
CH3CN
DCM
trace
85
87
84
trace
56
86
87
88
90
83
80
42
37
50
0
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
Ir(ppy)2(dtbbpy)(PF6)
Ir[dF(CF3)ppy]2(dtbbpy)(PF6)
Ru(bpy)3Cl2
Eosin Y
CH3OH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
c
6
7
8
9
10
11
12
13
14
15
16
fac-Ir(ppy)3
−
fac-Ir(ppy)3
Na2CO3 (1.0)
Na2CO3 (1.0)
d
17
0
a
Reaction conditions: propargyl alcohol 1a (0.2 mmol), TsCl (1.5 equiv), base (as shown), and photocatalyst (3 mol %) in organic solvent/H2O
b
c
d
(2.0 mL/0.2 mL), irradiated with 30 W blue LEDs at room temperature (rt). Yields of isolated products. In dry CH3CN, without H2O. In
darkness.
B
DOI: 10.1021/acs.orglett.9b01734
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Scope of Propargyl Alcohols
Scheme 3. Scope of Sulfonyl Chlorides
a
Reaction conditions: propargyl alcohol 1a (0.2 mmol), TsCl (1.5
equiv), Na2CO3 (1.0 equiv), and fac-Ir(ppy)3 (3 mol %) in CH3CN/
H2O (2.0 mL/0.2 mL), irradiated with 30 W blue LEDs at rt. Yields
of isolated products are given.
Scheme 4. Synthetic Applications
a
Reaction conditions: propargyl alcohol 1 (0.2 mmol), TsCl (1.5
equiv), Na2CO3 (1.0 equiv), and fac-Ir(ppy)3 (3 mol %) in CH3CN/
H2O (2.0 mL/0.2 mL), irradiated with 30 W blue LEDs at rt. Yields
of isolated products are given.
easily incorporated into alkenes by using (+)-10-camphorsul-
fonyl chloride (2an).
The reaction could be performed at gram-scale, affording
product 2a in synthetically useful yield (Scheme 4a). Treating
2a with potassium methoxide at 0 °C furnished the
dihydropyran derivative 3; reduction of 2a to alcohol 4,
followed by the treatment of potassium methoxide, gave the
sole cis-diastereomer, tetrahydropyran derivative 5, in almost
quantitative yield through the intramolecular Michael addition
(Scheme 4b). Moreover, the ketone in product 2d could be
transformed to the corresponding ester 6 in 92% yield by the
Baeyer−Villiger oxidation (Scheme 4c).
The proposed mechanism is depicted in Scheme 5. Initially,
a sulfonyl radical generated from the single-electron reduction
of sulfonyl chloride by excited photocatalyst IrIII* complex
adds to propargyl alcohol 1, leading to the reactive vinyl radical
species a. Because of the high bond dissociation energy (BDE)
of the alkenyl C(sp2)−H bond (∼110 kcal/mol),10 the vinyl
radical-mediated 1,5-HAT readily proceeds to generate the
alkyl radical intermediate b. The addition of b to alkene
triggers the intramolecular vinyl migration via the five-
membered cyclic transition state.11 The subsequent oxidation
by IrIV complex provides the cation d and perpetuates the
photocatalytic cycle.12 The deprotonation of d gave the final
product 2.
In summary, we have disclosed a novel site-selective
sulfonylvinylation of unactivated C(sp3)−H bonds via the
vinyl radical-mediated HAT and intramolecular FGM process.
The inert C−H and C−C bonds are readily cleaved in
sequence under the photocatalytic conditions. A vast array of
the sulfone-substituted E-olefins are obtained in good yields.
The reaction features mild conditions, broad functional group
tolerance, and unique regioselectivity/stereoselectivity, thus
rendering a practical strategy for remote C(sp3)−H vinylation
and the synthesis of valuable α,β-unsaturated sulfones.
C
DOI: 10.1021/acs.orglett.9b01734
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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Scheme 5. Proposed Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01734.
Experimental details, compound characterization data,
and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: chzhu@suda.edu.cn.
ORCID
Chen Zhu: 0000-0002-4548-047X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
C.Z. is grateful for the financial support from Soochow
University, the National Natural Science Foundation of China
(No. 21722205), the Project of Scientific and Technologic
Infrastructure of Suzhou (No. SZS201708), and the Priority
Academic Program Development of Jiangsu Higher Education
Institutions (PAPD).
(5) For the examples of the site-selective functionalization of remote
C(sp3)−H bonds mediated by C-centered radicals, see: (a) Friese, F.
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