Organophotoredox-Catalyzed Three-Component Coupling of Heteroatom Nucleophiles, Alkenes, and Aliphatic Redox Active Esters

Article abstract of DOI:10.1021/acs.orglett.1c00211

This manuscript describes a visible-light-mediated organophotoredox catalytic process for vicinal difunctionalization of alkenes using heteroatom nucleophiles and aliphatic redox active esters. A wide range of heteroatom nucleophiles including alcohols, water, carboxylic acids, amides, and halogens can be used for this reaction. This radical relay type reaction allows forging of C(sp3)-C(sp3) with a carbon-centered radical and C(sp3)-heteroatom bonds with a benzyl cation on the vinylarenes with complete regioselectivity in a single step.

Full text of DOI:10.1021/acs.orglett.1c00211

pubs.acs.org/OrgLett
Letter
Organophotoredox-Catalyzed Three-Component Coupling of
Heteroatom Nucleophiles, Alkenes, and Aliphatic Redox Active
Esters
Shotaro Shibutani, Kazunori Nagao,* and Hirohisa Ohmiya*
Cite This: Org. Lett. 2021, 23, 1798−1803
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ABSTRACT: This manuscript describes a visible-light-mediated organo-
photoredox catalytic process for vicinal difunctionalization of alkenes
using heteroatom nucleophiles and aliphatic redox active esters. A wide
range of heteroatom nucleophiles including alcohols, water, carboxylic
acids, amides, and halogens can be used for this reaction. This radical
relay type reaction allows forging of C(sp3)−C(sp3) with a carbon-
centered radical and C(sp3)−heteroatom bonds with a benzyl cation on
the vinylarenes with complete regioselectivity in a single step.
Scheme 1. Radical Difunctionalization of Alkenes
gainst a background of interest from the medical
Acommunity and an increasing demand for bioactive natural
products with C(sp3)-rich frameworks, much attention has been
given to the rapid and efficient construction of novel bioactive
molecules.1 Vicinal difunctionalization of alkenes has been
identified as one of the preferred approaches for preparation of
such molecules from readily available materials. Due to the
ubiquity of heteroatom functional groups in drug molecules,
vicinal difunctionalization of alkenes, which simultaneously
incorporate a carbon group and a heteroatom group onto a
carbon−carbon double bond, is highly desirable. In this context,
a number of vicinal difunctionalizations of alkenes using
transition-metal catalysts have been reported.2 However, the
reported protocols could not cover an alkyl group as a carbon
source due to the instability of alkyl halides under highly basic
reaction conditions2b and the lack of appropriate alkylating
reagents.2d
As a complementary approach, radical relay-type alkylative
difunctionalization of alkenes has been introduced (Scheme
1A).3 Therein, a transition-metal catalyst facilitates the
generation of a carbon radical via a single electron transfer
(SET) to the radical precursor. The resultant alkyl radical
undergoes an addition reaction across the alkene moiety to
produce the relatively long-lived carbon radical, which is
oxidized to the carbocation by the transition-metal catalyst
which is then intercepted by heteroatom nucleophiles. However,
suitable alkyl radical precursors have been limited to specific
substrates possessing relatively low reduction potentials, such as
alkyl diacyl peroxides,4 α-halocarbonyls,5 and hypervalent
iodine reagents.6 Recently, a visible-light photoredox catalyst
enabled the radical relay difunctionalization of alkenes and
dramatically expanded the scope of radical precursors.7−9
Although significant progress has been made in this area,
Received: January 19, 2021
Published: February 11, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00211
© 2021 American Chemical Society
Org. Lett. 2021, 23, 1798−1803
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a
currently available methods still require the use of precious
transition metals including Ru- or Ir-based photoredox catalysts.
Additionally, one of the most serious problems is the lack of a
general and powerful synthetic protocol that permits the use of a
wide range of heteroatom nucleophiles.
Table 1. Screening of Reaction Conditions
Previously, we reported the organophotoredox-catalyzed
decarboxylative cross-coupling of aliphatic carboxylic acid
derived redox active esters and aliphatic alcohols (Scheme
1B).10,11 The reaction involves a SET from the excited state of
the phenothiazine (PTH) catalyst to a redox active ester,12
resulting in the formation of a PTH radical cation and an alkyl
radical, which is liberated from the redox active ester. The
resultant carbon centered-radical is oxidized by the PTH radical
cation to the corresponding carbocation intermediate (Scheme
1B, top), which couples with various heteroatom nucleophiles. It
was speculated whether the addition of the carbon-centered
radical to an alkene could be performed before the oxidation
process to accomplish three-component coupling (Scheme 1B,
bottom).13
Herein, we report a visible-light-mediated organophotoredox
catalysis process for vicinal difunctionalization of alkenes
(Scheme 1C). This protocol facilitates assembly, in a single
step, of aliphatic acid derived redox active esters, alkenes, and
various heteroatom nucleophiles, such as alcohols, water,
carboxylic acids, amides, and halogens, into densely function-
alized hydrocarbons.
The alkyletherification of styrenes was commenced with
aliphatic alcohols and aliphatic redox active esters. Previous
methods for alkyletherification of alkenes require the use of
excess amounts of alcohol nucleophiles (>5.0 equiv) and
transition metal catalysts.4f,5b,14 Additionally, the use of a tertiary
alcohol as a nucleophile is not well developed.5b,14a,b To address
these issues, the reaction conditions and scope of the substrates
were carefully evaluated. Based on a previous report,9 π-
extended benzo[b]phenothiazine derivatives were used as an
organophotoredox catalyst for this three-component coupling.
After a quick screening, the combination of PTH1, featuring a
benzo[b]phenothiazine core and a p-CF3-phenyl substituent on
the nitrogen, and LiBF4 was found to be best for the reaction
(Table 1, entry 1).15 The effect of the N-substituent of the
catalyst was next investigated. Use of H and OMe groups instead
of a CF3 group resulted in a slightly diminished product yield
(entries 2 and 3). PTH4 bearing a cyano group exhibited
comparable reactivity (entry 4). The representative Ir- or Ru-
based photoredox catalysts did not improve the product yield
(entries 5−8). PTH1 exhibited higher reactivity than PTH4
when the reaction time was shortened to 12 h (entries 9 and 10).
Finally, lowering the catalyst loading to 1 mol % and decreasing
the reaction time to 2 h did not affect the product yield (entry
11).
Using the optimal reaction conditions, the scope of each
ingredient was evaluated. First, the scope of the redox-active
esters was explored (Scheme 2, top). Dimethyl-based tertiary
redox-active esters having acetoxy and benzyloxy groups
afforded the corresponding dialkyl ethers in moderate yields
(4aab and 4aac). Additionally, a tertiary alkyl group containing
diethyl and cyano groups was introduced to the alkene (4aad).
1-Methylcyclopentyl and 1-methylcyclohexyl substituents were
efficiently incorporated (4aae and 4aaf). A heteroatom-fused
aliphatic ring system was amenable to this three-component
coupling (4aag and 4aah). A sterically hindered adamantyl
redox active ester could participate in this reaction (4aai).
Secondary carboxylic acids were also found to be suitable alkyl
a
The reaction was carried out with 1a (0.6 mmol), 2a (0.4 mmol), 3a
(0.2 mmol), PTH (0.02 mmol), and LiBF4 (0.02 mmol) in MeCN
b
(0.6 mL) under blue LED irradiation for 24 h. 1H NMR yield based
on 3a. Yield of the isolated product is in parentheses. Reaction was
carried out with 1a (0.6 mmol), 2a (0.2 mmol), 3a (0.2 mmol),
PTH1 (0.002 mmol), and LiBF4 (0.002 mmol) in MeCN (0.6 mL)
under blue LED irradiation for 2 h.
c
sources (4aaj−4aal). Unfortunately, the reactions with primary
aliphatic redox-active esters did not afford any product (data not
shown). This might be due to inefficient formation of the alkyl
radical and slow radical addition to the alkenes.
The effect of various alcohol nucleophiles was examined
(Scheme 2, middle). A broad range of functional group
compatibility was observed with primary aliphatic alcohols.
Ester, alkyne, ether, amide, and alkyl bromide groups did not
inhibit the reaction (4baa−4faa). Benzyl ethers were obtained
in good yields (4gaa and 4haa). Although iodoarene is known to
be reduced by the PTH catalyst, the compound survived in this
system. Secondary aliphatic alcohols could also participate in
this reaction (4iaa−4laa). It is noteworthy that the reaction with
sterically hindered tertiary alcohols gave the desired dialkyl ether
in high yield (4maa−4oaa).
Next, functionalized vinyl arenes were investigated (Scheme
2, bottom). A p-methoxy substituent on the aromatic ring was
found to be compatible (4aba). Halogen substituents survived
under reaction conditions without reduction (4acc and 4adc).
m-Substituents did not inhibit the reaction (4aec). Dialkyl
ethers containing naphthalene and thiophene were obtained in
moderate yields (4afa and 4agc). When α-methyl or phenyl
styrenes were subjected to the optimal reaction conditions, the
corresponding tertiary benzylic dialkyl ethers were obtained
(4ahc and 4dia). When cinnamyl ester was used, regio- and
diastereoselective C(sp3)−C(sp3) and C(sp3)−O bond for-
mation occurred to provide the synthetically valuable β-
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a
Scheme 2. Substrate Scope
a
The reaction was carried out with 1 (0.6 mmol), 2 (0.2 mmol), 3 (0.2 mmol), PTH1 (0.002 mmol), and LiBF4 (0.002 mmol) in MeCN (0.6 mL)
b
c
under blue LED irradiation for 2 h. The reaction conditions were modified. (see Supporting Information) The reaction was carried out with 1
(0.6 mmol), 2 (0.4 mmol), 3 (0.2 mmol), PTH1 (0.01 mmol), and LiBF4 (0.01 mmol) in MeCN (0.6 mL) under blue LED irradiation for 6 h.
alkoxylcarbonyl compound (4aja). Coumarin also exhibited
high regio- and stereoselectivity (4aka). Both cinnamaldehyde
and β,β-difluoroalkene were employed to provide the
corresponding functionalized molecules, respectively (4ala
and 4ama).
The scope of the nucleophiles could be expanded to include
fluoride and chloride anions (Scheme 3). Although catalytic
alkylfluorination of alkenes using the fluoride anion has been
reported,4d17 the incorporation of a tertiary alkyl group without
using transition metals is a noteworthy feature of the present
protocol. Screening of the fluoride anion revealed that
triethylamine trihydrofluoride (NEt3·3HF) was identified to
be the best source. An acyclic or cyclic tertiary alkyl group and a
fluorine atom were efficiently introduced to an alkene with
complete regioselectivity (13aab−13aah). In contrast to the
alkylfluorination, alkylchlorination with a chloride anion has
received less attention.18 Following the alkylfluorination,
triethylamine hydrochloride was used as a chloride anion
source, but the desired product was obtained in 8% yield with
formation of the E2/E1 product. To avoid the elimination
reaction induced by a conjugate base, a bulky collidine
hydrochloride salt was selected. This approach resulted in a
dramatic improvement in the product yield, providing a series of
benzyl chlorides in high yield (14aab−14aah).
To demonstrate the versatility of this oraganophotoredox
catalysis, reactions with other heteroatom nucleophiles were
examined (Scheme 3). After a quick screening, it was found that
various heteroatom nucleophiles were applicable. A water
participated in the reaction to afford the alkylhydroxylation
product (10aaa). Carboxylic acids were also applicable as
oxygen nucleophiles to provide benzyl ester derivatives.16
Aromatic, benzylic, primary, and secondary alkyl carboxylic
acids were successfully introduced (11aaa−11faa). The
trifluoroacetoxylated product was also obtained (11gaa). Next,
nitrogen nucleophiles were investigated. Both cyclic amide and
carbamate acted as good nucleophiles (12aaa and 12bac).
Acetyl-protected anilines were also found to be suitable
substrates (12caa−12faa).
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a
Scheme 3. Scope of Other Heteroatom Nucleophiles
Scheme 4. Mechanistic Studies
a
The reaction was carried out with 5−9 (0.6 mmol), 2a (0.2 mmol),
3a (0.2 mmol), PTH1 (0.002 or 0.01 mmol), and LiBF4 (0.002 or
0.01 mmol) in solvent (see Supporting Information) under blue LED
irradiation for 12−24 h.
In an attempt to clarify the reaction mechanism, the following
experiments were conducted. First, the SET from the PTH1
catalyst to a redox active ester was investigated. It is well-known
that redox active esters tend to form electron-donor−acceptor
(EDA) complexes with electron-rich organic molecules, hence
facilitating SET.19 To confirm the intermediacy of the EDA
complex, the UV/vis absorption spectra for various combina-
tions of reaction components were measured under identical
concentrations to that for the optimal reaction conditions
(Scheme 4A). As a result, a significant red shift of the absorption
band was observed when PTH1 and the redox active ester 3a
coexisted. This finding indicated the involvement of an EDA
complex in the initial photoactivation step.20
Next, possible mechanisms for the nucleophile substitution
step were considered. There are two plausible reaction
pathways, an SN2 type reaction with a benzylsulfonium
intermediate or an SN1 type reaction with a benzyl cation.20 In
an attempt to monitor the benzylsulfonium intermediate, the
reaction was carried out under stoichiometric conditions
without a heteroatom nucleophile. Then, the corresponding
benzylsulfonium (15aa) was detected by direct analysis using
real time-high resolution mass spectrometry (HRMS-DART).
Density-functional theory (DFT) calculations indicated that the
Gibbs free energy of the benzylsulfonium intermediate was
lower than that of the benzyl cation (see Supporting
Information). These results suggested that the benzylsulfonium
was the dominant species in the nucleophilic substitution step.
Based on the mechanistic studies depicted above, the
proposed mechanism for the organophotoredox-catalyzed
difunctionalization of alkenes is outlined in Scheme 4C. The
catalytic cycle begins with a photoinduced SET within the EDA
complex (B) composed of the PTH catalyst (A) and redox
active ester 3 which results in the production of the PTH radical
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cation (C) and the radical anion form (D) of the redox active
ester. The radical anion D then collapses to afford the
corresponding alkyl radical (E) and the phthalimide anion
with release of CO2. The addition of the alkyl radical E to
vinylarene 2 produces the relatively long-lived benzyl radical (F)
(E1/2 = 0.23 V vs SCE),21 which couples with the PTH radical
cation C (E1/2 = 0.87 V vs SCE)9 through single-electron
oxidation followed by complexation to produce the benzylsulfo-
nium intermediate (G). Finally, G is intercepted by a
heteroatom nucleophile to give the dialkyl ether and regenerate
A. The role of LiBF4 as an additive would be to facilitate
acceleration of the SET from PTH to the redox active esters.
In summary, visible-light-mediated organophotoredox catal-
ysis afforded a versatile protocol for vicinal difunctionalization of
alkenes. This protocol permitted the assembly of readily
available, various heteroatom nucleophiles, vinylarenes, and
aliphatic acid derived redox active esters into highly function-
alized C(sp3)-rich motifs. Nitrogen, oxygen, and halogen
nucleophiles functioned as nucleophiles without the require-
ment to be in excess. Transition-metal-free and mild reaction
conditions are attractive features of this protocol. Extending this
approach to other multicomponent couplings is ongoing in our
laboratory.
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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.1c00211.
Experimental details and characterization data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Kazunori Nagao − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan; orcid.org/0000-0003-3141-
5279; Email: nkazunori@p.kanazawa-u.ac.jp
Hirohisa Ohmiya − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan; JST, PRESTO, Saitama 332-
0012, Japan; orcid.org/0000-0002-1374-1137;
Email: ohmiya@p.kanazawa-u.ac.jp
Author
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Chem. Soc. Jpn. 2019, 92, 1419−1429.
Shotaro Shibutani − Division of Pharmaceutical Sciences,
Graduate School of Medical Sciences, Kanazawa University,
Kanazawa 920-1192, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00211
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant No.
JP18H01971 to Scientific Research (B), JSPS KAKENHI Grant
No. JP17H06449 (Hybrid Catalysis), Kanazawa University
SAKIGAKE project 2018, Kanazawa University SAKIGAKE
project 2020, Takeda Pharmaceutical Company Limited, and
JST, PRESTO Grant No. JPMJPR19T2 (to H.O.).
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1803
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