Full text of DOI:10.1021/acs.orglett.8b00272

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light-Mediated Synthesis of Ketones by the Oxidative
Alkylation of Styrenes
Adrian Tlahuext-Aca, R. Aleyda Garza-Sanchez, Michael Schafer, and Frank Glorius*
̈
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat Munster, Corrensstraße 40, 48149 Munster, Germany
̈
̈
̈
̈
S
* Supporting Information
ABSTRACT: The oxidative coupling of photogenerated alkyl
radicals with readily available styrenes is disclosed. This visible-
light-mediated method allows rapid access to a wide range of
α-alkyl-acetophenones in good yields and with high functional
group tolerance. In addition, the developed protocol features
room temperature conditions, low photocatalyst loadings, and
the use of dimethyl sulfoxide as nontoxic and mild terminal
oxidant.
etones are among the most fundamental functionalities in
under thermal- and light-mediated conditions.4−7 However,
Ksynthetic organic chemistry since they are reactive centers strategies for the use of C(sp3)-centered radicals have remained
for a wide range of functional group interconversions involving
C−C and C−X bond forming reactions.1 Moreover, these
carbonyl compounds are ubiquitous in important natural
products and synthetic bioactive molecules.2 Owing to their
relevance, the development of novel synthetic approaches
toward ketones from simple and readily accessible building
blocks has gained attention during recent years. In this regard,
the oxidative coupling of olefins in the presence of reactive radical
intermediates has emerged as a powerful transformation that
enables the rapid installation of a carbonyl group and a C−R
bond across an olefin (Scheme 1a).3 Using this elegant and step-
economical strategy, a variety of transformations have been
developed for the oxidative coupling of olefins with trifluor-
omethyl-, aryl-, sulfonyl-, and phosphinoyl-radical intermediates
limited, and current methods suffer from elevated reaction
temperatures and the use of strong oxidative conditions (Scheme
1b).8,9 Furthermore, due to the common use of peroxides as
terminal oxidants as well as radical initiators, the scope of alkyl
radicals has been limited to those that can be generated upon
homolytic cleavage of a weak C−H bond at one of the coupling
partners. This might limit the straightforward incorporation of
relevant molecular scaffolds such as aliphatic heterocycles or
tertiary carbon centers since they possess similarly weak C−H
bonds that can be degraded during the course of the reaction.
In light of the aforementioned limitations, herein we sought to
demonstrate that C(sp3)-centered radicals generated by the
direct photoinduced reduction of N-(acyloxy)phthalimides10 can
be effectively engaged in the functionalization of styrenes leading
to the formation of α-alkyl-acetophenones under mild light-
mediated conditions where dimethyl sulfoxide (DMSO) acts as a
nontoxic and mild oxidant (Scheme 1c).11,12
Scheme 1. Strategies of the Oxidative Coupling of Olefins with
Radical Intermediates
N-(Acyloxy)phthalimides have been widely used as electro-
philic substrates to form alkyl radicals upon decarboxylation.
Nevertheless, the large negative reduction potentials (Ered
≈
−1.3 V vs SCE in MeCN)10a generally hinder their use in direct
photoinduced electron transfer (PET) chemistry since very few
existing photocatalysts feature enough reductive power. Among
them, however, the Ir(III)-catalyst fac-Ir(ppy)3 (ppy = 2-
phenylpyridine) should, in principle, be suitable to engage in
direct PET with N-(acyloxy)phthalimides based on its estimated
excited state oxidation potential (E1/2IV/*III = −1.73 V vs SCE in
MeCN).12e On the basis of this, we began our optimization
studies by irradiating an equimolar DMSO solution of 4-tert-
butylstyrene (1a) and the N-(acyloxy)phthalimide (2a) with
visible light from 5 W blue LEDs (λmax = 455 nm) in the presence
of 0.1 mol % of fac-Ir(ppy)3. To our delight, the α-alkyl-
Received: January 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00272
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acetophenone 3aa was obtained in 55% GC-FID yield after 12 h
of irradiation. Encouraged by this result, we conducted further
optimization experiments where good yield of 3aa could be
obtained with a slight excess of 2a (1.25 equiv) in combination
with 0.2 mol % of fac-Ir(ppy)3 (Table 1, entry 3).
Scheme 3. Scope of N-(Acyloxy)pthalimides Derived from
Synthetic, Biomass, and Bioactive Carboxylic Acids
a
a
Table 1. Optimization of the Oxidative Alkylation of 1a
b
entry
photocatalyst (mol %)
2a (equiv)
yield (%)
1
2
3
fac-Ir(ppy)3 (0.1)
fac-Ir(ppy)3 (0.1)
fac-Ir(ppy)3 (0.2)
1.0
55
62
78
1.25
1.25
a
General conditions: 1a (0.1 mmol), 2a, photocatalyst, and DMSO (1
b
mL) under argon. Yields determined by GC-FID using mesitylene as
the internal standard.
With the optimized reaction conditions in hand, we turned our
attention to investigate the substrate scope of the oxidative
alkylation with a diverse range of commercially available styrenes
using 2a as the alkyl radical source (Scheme 2). Interestingly, a
a
Scheme 2. Scope of Styrenes
a
b
Reaction performed on a 0.40 mmol scale of 1a. Reaction performed
on a 7 mmol scale of 1a.
ketone, fluorine, and Boc-protected piperidine units were
efficiently engage in oxidative alkylation processes with 1a
yielding ketones 3ab−3aj in good yields.
Due to the fact that aliphatic acids are readily encountered
functionalities in biomass and bioactive compounds, we
investigated a selection of N-(acyloxy)phthalimides derived
from such sources as radical precursors. As shown in Scheme 3,
different α-alkyl-acetophenones (3ak−3ao) were prepared using
radical sources derived from naturally occurring caproic and
linoleic acids (both found in animal fats), Boc-protected γ-
aminobutyric acid (a neurotransmitter), and deoxycholic acid (a
synthetic bile acid). In addition, Gemfibrozil, which is a drug used
to lower lipid levels, could be employed as a tertiary alkyl radical
source to access 3ao in good yield. Finally, the scalability of our
method was demonstrated by preparing ketone 3ak in good yield
on a 7 mmol scale of 1a.
a
Reaction performed on a 0.40 mmol scale of 1a−1k.
To gain insight into the reaction mechanism for the developed
oxidative alkylation protocol, several experiments were per-
formed. Control experiments in the strict absence of either visible
light irradiation or fac-Ir(ppy)3 showed no reactivity toward 3aa.
Moreover, the presence of TEMPO as a radical scavenger
completely inhibited the formation of 3aa. Altogether, these
experiments support the visible-light-mediated nature as well as
the intermediacy of radical species in our developed method.
Next, a Stern−Volmer quenching study was conducted to
monitor the kinetic behavior of the excited iridium-catalyst in the
presence of the N-(acyloxy)phthalimide 2a. Interestingly, the
photoexcited state of fac-Ir(ppy)3 was readily quenched by 2a in
degassed DMSO at room temperature.13 From this analysis, a
Stern−Volmer quenching constant of 3342 M−1 was obtained.
These observations in combination with thermodynamic data
variety of electron-donating and -withdrawing functional groups
at the para-position of the arene moiety were well tolerated,
giving access to the α-alkyl-acetophenones 3aa−3ha in good
yields. Moreover, 3- and 2-substituted styrenes (1i and 1j) as well
as the naphthalene derivative 1k could be reacted to give their
corresponding ketones in moderate to good yield.
N-(Acyloxy)phthalimides are attractive sources of C(sp3)-
centered radicals due to their low synthetic cost and
straightforward synthesis from abundant aliphatic acid feed-
stocks. Thus, we prepared a variety of functionalized radical
sources from commercially available carboxylic acids and tested
them for our visible-light-mediated protocol. As shown in
Scheme 3, a wide array of primary, secondary, and tertiary N-
(acyloxy)phthalimides bearing thioanisole, anisole, veratrol,
B
DOI: 10.1021/acs.orglett.8b00272
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(vide infra) suggest that electron transfer between *[fac-
Ir(ppy)3] and 2a is both exergonic and kinetically favorable.
Finally, the quantum yield (Φ) of the reaction was estimated by
chemical actinometry and a very low value was observed (Φ =
0.03) (see SI for details).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: glorius@uni-muenster.de.
ORCID
Based on our assays as well as literature reports, a mechanistic
proposal for the visible-light mediated oxidative alkylation of
styrenes is depicted in Scheme 4. After photoexcitation with
Frank Glorius: 0000-0002-0648-956X
Notes
The authors declare no competing financial interest.
Scheme 4. Mechanistic Proposal
ACKNOWLEDGMENTS
■
Financial support by the NRW Graduate School of Chemistry
(to A.T.A.) and the Deutsche Forschungsgemeinschaft (Leibniz
Award) is gratefully acknowledged. We thank Dr. Sara
Cembellin-Santos, Santanu Singa (WWU Munster), and
̈
Hyung Yoon (University of Toronto) for helpful discussions.
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IV/ III
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*
= −1.73 V vs SCE in
MeCN)12e engages in single electron transfer (SET) with the N-
(acyloxy)phthalimide 2 (Ered ≈ −1.30 V vs SCE in MeCN)10a
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=
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nontoxic oxidant. Overall, our method demonstrates the
powerful application of visible-light photocatalysis for the
conversion of simple organic substrates into carbonyl com-
pounds.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b00272.
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D
DOI: 10.1021/acs.orglett.8b00272
Org. Lett. XXXX, XXX, XXX−XXX