Visible-Light-Enabled Oxidative Alkylation of Unactivated Alkenes with Dimethyl Sulfoxide through Concomitant 1,2-Aryl Migration

Article abstract of DOI:10.1021/acs.orglett.8b03340

Metal-free oxidative radical 1,2-alkylarylation of unactivated alkenes with the α-C(sp³)-H bond of dimethyl sulfoxide has been developed. This study realizes a new, conceptually novel technology for convenient construction of a variety of α-ary

Full text of DOI:10.1021/acs.orglett.8b03340

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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Enabled Oxidative Alkylation of Unactivated Alkenes
with Dimethyl Sulfoxide through Concomitant 1,2-Aryl Migration
Maojian Lu,† Honggui Qin,† Zhaowei Lin,† Mingqiang Huang,† Wen Weng,† and Shunyou Cai*,†,‡
†Key Laboratory of Modern Analytical Science and Separation Technology of Fujian Province, School of Chemistry, Chemical
Engineering, and Environment, Minnan Normal University, Zhangzhou 363000, China
‡Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University, Shenzhen Graduate
School, Shenzhen 518055, China
S
* Supporting Information
ABSTRACT: Metal-free oxidative radical 1,2-alkylarylation of unactivated alkenes with the α-C(sp3)−H bond of dimethyl
sulfoxide has been developed. This study realizes a new, conceptually novel technology for convenient construction of a variety
of α-aryl-γ-methylsulfinyl ketones in good-to-excellent yields with the synergistic interactions of visible light irradiation, organic
fluorophores 4CzIPN, and hypervalent iodine(III) reagent under transition-metal free conditions. A remarkable kinetic isotope
effect was observed, which helped provide insight into the reaction’s mechanistic course.
strongly captures the synthetic pursuit of chemists because of
its extraordinary biological functions. The approach to
sulfoxide syntheses using dimethyl sulfoxide and unactivated
alkenes by strategic C−H functionalization is still an
undeveloped process and continues to attract crucial attention
from the synthetic community.
ulfoxides are some of the most versatile organic
Scompounds, which not only have found numerous
applications in a variety of biologically active molecules and
natural products but also commonly function as valuable
building blocks for the synthesis of varied significant chemicals
and therapeutic agents (Figure 1).1,2
Over the past decade, visible-light-enabled photoredox
catalysis employing photocatalysts has emerged as an
alternative method for the generation of various radical
species.5 Significant progress has been made by direct
functionalization of the inert sp3 C−H bond using a synergistic
catalyst system, which consists of a photosensitizer and an
external oxidant.6,7 Dimethyl sulfoxide (DMSO) is one of the
most frequently applied and commercially available solvents in
comprehensive organic transformations, owing to its relative
stability, rather low cost, low toxicity, and the fact that it is easy
to handle. Furthermore, it is also widely utilized to serve as a
multipurpose precursor in various chemical transformations,
such as an oxygen, methylsulfonyl, methyl, formyl, or cyano
source.8 However, according to what we have learned, there is
no precedent to the use of dimethyl sulfoxide as the precursor
to the α-sulfinyl radical species.
Our design concept, as illustrated in Scheme 1, anticipated
that the event of a hydrogen abstraction might be initiated on
dimethyl sulfoxide through synergistic actions of organic
fluorophore sensitization, visible light stimulation, and external
oxidation, thereby converting it into a relatively stable α-
sulfinyl radical species. Subsequent radical addition to the C
C double bond of an allylic alcohol, followed by 1,2-aryl
Figure 1. Sulfoxide Moiety in Pharmacologically Active Molecules.
For example, esomeprazole, which is employed to cure and
relieve symptoms of duodenal or gastric ulcers, is one of the
world’s most-sold pharmaceuticals. Some of the other best-
selling sulfoxide-based drugs, such as oxisurane, rabeprazole,
and armodafinil are exemplified in Figure 1.2f As a result,
considerable synthetic efforts have been directed toward the
development of efficient protocols to this class of structures.
Traditionally, the direct oxidation of sulfides to sulfoxides, with
the assistance of stoichiometric amounts of peracid or
inorganic oxidants, is the most frequently employed protocol.3
An alternative method for accessing sulfoxides is to take
advantage of the sulfoxidation of alkenes with thiols.4 Despite
these recent advances, the sulfoxide functional group still
Received: October 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03340
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
reaction (entry 3). Thus, a number of similar additives,
involving 1,3-dimethoxybenzene (B), 1,3,5-trimethoxybenzene
(C), and 1,3,5-trimethylbenzene (D) were explored next, from
which the more electron-rich 1,3,5-trimethoxybenzene explic-
itly turned out for its prominent capacity to provide the
product in high yield (65%, entry 5). Remarkably, a respectable
89% yield of desired product 2a was observed by increasing the
loading of PIFA and 1,3,5-trimethylbenzene up to 2.0 equiv
(entry 8). The choice of an oxidant was also revealed to be
significant, because the use of hydroxybenziodoxole (BI-OH)
and acetoxybenziodoxole (BI-OAc) both resulted in significant
reductions in reactivities (entries 9 and 10). Furthermore,
solvent screening suggested that DMSO should be the best
solvent, and addition of other solvents gave lower yields of the
desired products (entries 11 and 12). By contrast, other
attempts employing eosin Y, Ru(bpy)3Cl2, or even Ir[dF-
(CF3)ppy]2(dtbpy)PF6 as an alternative photocatalyst were
manifested to be disadvantageous for the product yield (entries
13−15). Finally, control experiments performed without a
photocatalyst, an oxidant, or visible light (entries 16−18)
unambiguously led to complete inhibition of the reactivity.
We next examined the substrate scope of the visible-light-
promoted oxidative coupling reaction of symmetrical α,α-
diaryl allylic alcohols with dimethyl sulfoxide under the
optimized conditions (Scheme 2). Allylic alcohols with a
para- or meta-methyl substituent on the aromatic ring could
react smoothly to allow access to the corresponding products
2b and 2c in 74% and 70% yields, respectively. Interestingly,
the reaction of electron-rich 1,1-bis(4-methoxyphenyl)prop-2-
Scheme 1. Visible-Light-Promoted C−H Functionalization
Strategy to α-Aryl-γ-Methylsulfinyl Ketones
migration, would accomplish formal C−H to C−C bond
conversion and lead to α-aryl-γ-methylsulfinyl ketones. Under
the designed scenario, the choice of an external oxidant is
considerably crucial because it should not only ideally serve as
a hydrogen acceptor but also must be able to avoid the over
oxidation of sulfoxide to sulfone. The hypervalent iodine(III)
compounds9 appear to be feasible candidates fitting this
purpose. Gratifyingly, through careful optimizations of the
reaction conditions, an unusually simple, robust, and versatile
method was eventually built up for furnishing a range of α-aryl-
γ-methylsulfinyl ketones at room temperature.
A preliminary investigation of the potential reaction
conditions was carried out utilizing α,α-diphenyl allylic alcohol
1a as the substrate and 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-
dicyanobenzene (4CzIPN)10 as the photocatalyst (Table 1).
An initial survey of external oxidants showed that commercially
available hypervalent iodine(III) compounds such as PhI-
(OAc)2 (PIDA) and PhI(OCOCF3)2 (PIFA) only resulted in
decomposition (entries 1 and 2). Fortunately, a subsequent
vital observation was recorded that the desired α-aryl-γ-
methylsulfinyl ketone 2a was, indeed, produced in 21% yield
when 1.5 equiv of anisole (A) were purposefully added into the
Table 1. Condition Survey for the γ-Methylsulfinyl Ketone Formation
d
e
f
entry
PC (2 mol %)
oxidant (equiv)
additive (equiv)
solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
yield (%)
1
2
3
4
5
6
7
8
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
4CzIPN
eosin Y
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.5)
PIDA (1.8)
PIDA (2.0)
BI−OH (2.0)
BI-OAc (2.0)
PIFA (2.0)
PIFA (2.0)
PIFA (2.0)
PIFA (2.0)
PIFA (2.0)
PIFA (2.0)
decomp
decomp
21
58
65
trace
78
89
63
32
61
55
trace
23
47
trace
NR
NR
A (1.5)
B (1.5)
C (1.5)
D (1.5)
C (1.8)
C (2.0)
C (2.0)
C (2.0)
C (2.0)
C (2.0)
C (2.0)
C (2.0)
C (2.0)
C (2.0)
C (2.0)
C (2.0)
9
10
11
12
13
14
DMSO
DMSO/DMF
DMSO/DCE
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
[Ru(bpy)3Cl2]
[Ir-cat.]
b
15
16
17
18
4CzIPN
4CzIPN
c
PIFA (2.0)
a
Structures of A−D:
b
c
d
e
[Ir-cat.] = Ir[dF(CF3)ppy]2(dtbpy)PF6. No light. 4CzIPN = 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene. PIDA = PhI(OAc)2; PIFA =
f
PhI(OCOCF3)2; BI-OH = hydroxybenziodoxole; BI-OAc = acetoxy-benziodoxole. Yield of isolated product.
B
DOI: 10.1021/acs.orglett.8b03340
Org. Lett. XXXX, XXX, XXX−XXX

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Scheme 2. Substrate Scope of Symmetrical Allylic Alcohols
Scheme 3. Substrate Scope of Unsymmetrical Allylic
Alcohols
en-1-ol with dimethyl sulfoxide only resulted in complicated
mixtures (2d). The halogen substituents on the aromatic
moiety of the substrates seemed to have little influence on the
reaction efficiency (2e,2f). From the results depicted in
Scheme 3, what captures one’s attention is that the desired
products 2i−2k, bearing a quaternary carbon center, could be
unambiguously produced by this method. However, the
substrates with dipentafluorophenyl (2l) were proven to be
inapplicable under our conditions.
To explore the substrate scope of this method further,
various unsymmetrical allylic alcohols 3 were next subjected to
the optimal reaction conditions. As illustrated in Scheme 3, the
allylic alcohols 3 containing aromatic substituents, both
electron-donating and electron-withdrawing groups, were well
tolerated and proceeded effectively to afford the products 4 in
diverse yields (49−92%). Unambiguously, the electronic
characteristics, as well as the steric size of the substituents
on the aromatic rings, were revealed to have a significant
influence on the migration. For example, preferential migration
of the more electron-poor aryl group was recorded in the cases
of 4a−4l, suggesting that the radical process should be
involved in this migration. For the substrates 4m−4t, the 2-
substituted aryl rings in 3 seemed to retard the migration rate
to some extent. Notably, the substrates bearing either a thienyl-
(4u or 4v) or an alkyl- (4w or 4x) substituent were also
demonstrated to be accommodated in the transformation.
Several mechanistic experiments were next conducted to
gain insight into the potential reaction pathways, and the
relevant results are shown in Scheme 4. In the model reaction,
accompanying 2a, was the generation of 2-iodo-1,3,5-
trimethoxybenzene 5, which apparently arose from iodination
of 1,3,5-trimethoxybenzene additive. Furthermore, the reaction
was almost inhibited if 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO) was added, suggesting that the reaction should
undergo a radical pathway. It merits attention that PhI-
(OCOCF3)2 was able to react efficiently with 1,3,5-
trimethoxybenzene (C) to yield a new hypervalent iodine(III)
compound 8, which was subsequently used as the oxidant
under the standard reaction conditions. The desired sulfinyl
Scheme 4. Experiments on Reaction Mechanism
ketone product 2a was produced in 83% yield. Interestingly,
the hypervalent iodine(III) compound 8 could also be
smoothly converted to 2-iodo-1,3,5-trimethoxybenzene 5
only in the presence of a photocatalyst 4CzIPN and visible
light irradiation. Finally, an obvious kinetic isotope effect (KH/
C
DOI: 10.1021/acs.orglett.8b03340
Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters
Letter
KD = 9.4) was noted in the process, affording direct evidence
that the event of C−H bond cleavage might have constituted a
rate-determining step.
Experimental procedures and spectral data for all new
compounds (PDF)
To elucidate further whether the excited photocatalyst was
quenched by hypervalent iodine(III) compound 8 or allylic
alcohol 1a in this reaction, a series of fluorescence quenching
(Stern−Volmer) experiments on 4CzIPN were therefore
performed (see the Supporting Information). The increase in
the concentration of hypervalent iodine(III) compound 8
resulted in a significant decrease of fluorescence intensity of
4CzIPN, which strongly implied that the hypervalent iodine-
(III) compound 8 should take part in single electron transfer
with the photocatalyst.11
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: caishy05@mnnu.edu.cn
ORCID
Shunyou Cai: 0000-0001-8959-245X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
On the basis of the observed reactivities, and the above
investigations, a proposed reaction pathway is shown in
Scheme 5. Initially, PhI(OCOCF3)2 reacts with 1,3,5-
■
We thank the National Natural Science Foundation of China
(21502086 and 41575118), the Natural Science Foundation of
Fujian Province (2015J05028), the Outstanding Youth Science
Foundation of Fujian Province (2015J06009), and the
Program for Excellent Talents of Fujian Province for financial
support.
Scheme 5. Proposed Mechanistic Network
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* Supporting Information
■
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03340.
D
DOI: 10.1021/acs.orglett.8b03340
Org. Lett. XXXX, XXX, XXX−XXX