Copper-Mediated Radical-Polar Crossover Enables Photocatalytic Oxidative Functionalization of Sterically Bulky Alkenes

Article abstract of DOI:10.1021/jacs.1c02747

Oxidative heterofunctionalization reactions are among the most attractive methods for the conversion of alkenes and heteroatomic nucleophiles into complex saturated heterocycles. However, the state-of-the-art transition-metal-catalyzed methods to effect oxidative heterofunctionalizations are typically limited to unhindered olefins, and different nucleophilic partners generally require quite different reaction conditions. Herein, we show that Cu(II)-mediated radical-polar crossover allows for highly efficient and exceptionally mild photocatalytic oxidative heterofunctionalization reactions between bulky tri- A nd tetrasubstituted alkenes and a wide variety of nucleophilic partners. Moreover, we demonstrate that the broad scope of this transformation arises from photocatalytic alkene activation and thus complements existing transition-metal-catalyzed methods for oxidative heterofunctionalization. More broadly, these results further demonstrate that Cu(II) salts are ideal terminal oxidants for photoredox applications and that the combination of photocatalytic substrate activation and Cu(II)-mediated radical oxidation can address long-standing challenges in catalytic oxidation chemistry.

Full text of DOI:10.1021/jacs.1c02747

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Copper-Mediated Radical−Polar Crossover Enables Photocatalytic
Oxidative Functionalization of Sterically Bulky Alkenes
Nicholas L. Reed, Grace A. Lutovsky, and Tehshik P. Yoon*
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ABSTRACT: Oxidative heterofunctionalization reactions are among the most attractive methods for the conversion of alkenes and
heteroatomic nucleophiles into complex saturated heterocycles. However, the state-of-the-art transition-metal-catalyzed methods to
effect oxidative heterofunctionalizations are typically limited to unhindered olefins, and different nucleophilic partners generally
require quite different reaction conditions. Herein, we show that Cu(II)-mediated radical−polar crossover allows for highly efficient
and exceptionally mild photocatalytic oxidative heterofunctionalization reactions between bulky tri- and tetrasubstituted alkenes and
a wide variety of nucleophilic partners. Moreover, we demonstrate that the broad scope of this transformation arises from
photocatalytic alkene activation and thus complements existing transition-metal-catalyzed methods for oxidative heterofunction-
alization. More broadly, these results further demonstrate that Cu(II) salts are ideal terminal oxidants for photoredox applications
and that the combination of photocatalytic substrate activation and Cu(II)-mediated radical oxidation can address long-standing
challenges in catalytic oxidation chemistry.
xidative alkene functionalizations1 are powerful methods
for the rapid synthesis of saturated heterocycles
Scheme 1. Oxidative Heterofunctionalization of Alkenes
O
commonly found in many important natural products,
pharmaceuticals, and agrochemicals.2 These reactions are
synthetically attractive for a number of reasons. First, they
enable the direct oxidative coupling of alkenes with
heteronucleophiles without the need to prepare preoxidized
and often unstable heteroatom donors as internal oxidants.3−6
Moreover, and in contrast to redox-neutral alkene hydro-
functionalization reactions,7−9 oxidative alkene heterofunction-
alizations conserve an olefin functionality that can be valuable
for further synthetic elaborations. The state-of-the-art methods
are Pd(II)-catalyzed processes that can proceed via either of
two mechanistically distinct pathways (Scheme 1):10,11 syn-
nucleopalladation involves migratory insertion of an alkene
across a Pd−heteroatom bond,12 while anti-nucleopalladation
involves attack of a heteroatomic nucleophile on a Pd(II)-
coordinated alkene. The details of these mechanisms, however,
engender several notable limitations. First, both mechanistic
manifolds rely upon the coordination of the alkene to the
Pd(II) center. Highly substituted alkenes that coordinate
weakly, therefore, are poor reaction partners in all but a
handful of highly specialized cases.13,14 Second, relatively
subtle changes to the substrate structures and reaction
conditions can switch the operative mechanistic pathway,15
requiring reoptimization of reaction conditions for heteroatom
nucleophiles with different metal-binding propensities. Thus,
the identification of conditions for the oxidative functionaliza-
tion of sterically hindered alkenes with diverse heteronucleo-
philes remains an unsolved challenge that Pd(II) catalysis
seems poorly positioned to address.
Received: March 12, 2021
Published: April 15, 2021
We imagined that photoredox catalysis might offer a
complementary strategy toward oxidative alkene heterofunc-
tionalization that would be free of these long-standing
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limitations. Electron-rich tri- and tetrasubstituted alkenes that
are generally poor substrates for Pd(II)-catalyzed oxidative
heterofunctionalizations are easily activated by photoredox
catalysts. Moreover, Nicewicz and others have shown that the
resulting alkene radical cations are susceptible to highly
regioselective nucleophilic attack, and because this step does
not involve a discrete nucleophile−catalyst interaction, they
are relatively agnostic toward the identity of the nucleophilic
reaction partner.16−22 Thus, if an appropriate terminal oxidant
could be identified to intercept the resulting organoradical
intermediate and promote oxidative elimination, this process
could constitute a new, alternative platform for oxidative
alkene heterofunctionalization. Lei and co-workers recently
demonstrated the feasibility of a similar approach in the
oxidative coupling of olefins with alcohols or azoles using a
dual photoredox/hydrogen evolution system.23 However, these
reactions were limited to activated styrenic olefins and
structurally simple nucleophiles, and thus the construction of
complex saturated heterocyclic motifs has yet to be realized.
Inexpensive Cu(II) salts are ideal terminal oxidants for
photoredox applications.24 Many electron-rich radical species
are efficiently oxidized by Cu(II), which offers a means to
divert the prototypical organoradical chemistry enabled by
photoredox catalysis toward formally cationic reactivity via
radical−polar crossover.25−27 We have leveraged this combi-
nation to design a photocatalytic protocol for the alkoxylation
of benzylic C−H bonds28 and the photocatalytic oxyamination
of electron-rich olefins.29 In both instances, oxidation of a
photogenerated organoradical was followed by substitution
with a heteroatomic nucleophile. To achieve oxidative
heterofunctionalization, however, the radical mechanism
would have to be terminated by an alternative oxidative
elimination process. Seminal investigations by Kochi showed
that thermally generated organoradicals could be diverted
either toward oxidative substitution or oxidative elimination by
tuning of reaction conditions,30−33 and more recent studies by
Glorius and Tunge have demonstrated that the Cu(II)-
mediated oxidative elimination pathway is operative for
radicals produced by photochemical decarboxylation.34,35
We therefore propose a new mechanism for copper-enabled
photoredox oxidative heterofunctionalization (Scheme 2).
Photoexcitation of MesAcrPh+ affords a highly oxidizing
Scheme 2. Proposed Reaction Design for Photocatalytic
Oxidative Heterofunctionalization
Table 1. Optimization of Oxidative Amination
a
b
entry
photocat.
oxidant
CuBr2
% yield
1
2
3
4
5
6
7
8
MesAcrPh+
MesAcrPh+
MesAcrPh+
MesAcrPh+
MesAcrPh+
MesAcrPh+
MesAcrMe+
TPPT
MesAcrPh+
none
MesAcrPh+
MesAcrPh+
0%
3%
Cu(OTf)2
Cu(OAc)2
Cu(TFA)2
Cu(OPiv)2
Cu(EH)2
Cu(EH)2
Cu(EH)2
Cu(EH)2
Cu(EH)2
none
48%
57%
57%
87%
52%
24%
28%
0%
c
9
10
11
12
0%
0%
excited state MesAcrPh+* (*E1/2 = +2.12 V vs SCE).21
red
d
Cu(EH)2
Rapid reductive quenching by alkene 1 would furnish radical
cation 2 and MesAcrPh•. Radical cation 2 is a potent
electrophile and should be readily trapped by a pendant
heteroatomic nucleophile to generate carbon-centered radical
3. Radical oxidative addition of 3 by an appropriate Cu(II)
oxidant would afford an organocopper(III) intermediate. Key
to the successful realization of this strategy would be the
optimization of the elimination step to favor contrathermody-
namic elimination to 4. The alternate regiochemistry of
oxidative elimination would afford an electron-rich enamine
that would not survive the highly oxidizing conditions of this
transformation. Finally, oxidation of MesAcrPh• by Cu(I)
generated over the course of the reaction would close the
photoredox catalytic cycle and regenerate ground-state
MesAcrPh+.
a
Reactions conducted using 1 (0.1 mmol), oxidant (2 equiv), TFA
(1 equiv), and photocatalyst (2.5 mol %) in degassed 1,2-DCE and
irradiated with a 15 W blue LED flood lamp for 16 h. Yields were
determined by H NMR analysis of the unpurified reaction mixtures
using phenanthrene as an internal standard. Reaction conducted in
absence of 1 equiv TFA. Reaction vessel was covered in aluminum
foil.
b
1
c
d
We began our investigations by examining the oxidative
cyclization of trisubstituted alkene 1 upon irradiation in the
presence of 2.5 mol % N-phenylacridinium tetrafluoroborate
(MesAcrPh+), 1 equiv of trifluoroacetic acid (TFA), and a
variety of Cu(II) terminal oxidants (Table 1, entries 1−6). The
formation of cyclized product 4 is observed in most cases, but
as expected, the identity of the Cu(II) oxidant proved to be
crucial. We hypothesize that sterically bulky carboxylate ligands
improve the regioselectivity of alkene formation during Cu(II)-
mediated oxidative elimination.36−38 Other highly oxidizing
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a
Table 2. Scope of Photocatalytic Oxidative Heterofunctionalization
a
Reaction conditions: substrate (0.3 mmol, 1 equiv), MesAcrPh+ (2.5 mol %), Cu(EH)2 (2 equiv), TFA (1 equiv), and 1,2-DCE. Irradiated for 8−
b
96 h. Diastereomer and regioisomer ratios were determined by 1H NMR analysis of the unpurified reaction mixtures. p-TsOH (2 equiv) instead of
TFA. p-TsOH (1 equiv) instead of TFA. Reaction irradiated for 30 min.
c
d
photocatalysts afford 4 in moderate yields (entries 7 and 8),
but MesAcrPh+ proved optimal for this transformation.
Empirically, we also observed that the addition of 1 equiv
TFA improved the rate and reproducibility of oxidative
cyclization (entry 9). This is most readily rationalized by the
increased solubility of Cu(II) salts in organic media upon the
addition of trifluoroacetic acid.39−41 Thus, optimized con-
ditions were found to be 2.5 mol % MesAcrPh+, 2 equiv of
copper(II) 2-ethylhexanoate (Cu(EH)2), 1 equiv of 1, and 1
equiv of TFA in 1,2-DCE with irradiation by two 15 W blue
LED flood lamps (entry 6). Control reactions verified the
photocatalytic nature of this process: omitting photocatalyst,
Cu(II) oxidant, or light resulted in no formation of pyrrolidine
4 (entries 10−12).
The degree of generality exhibited by this transformation is
notable (Table 2). A wide variety of arylsulfonamides undergo
efficient oxidative cyclization. Electron-rich and electron-
deficient aryl sulfonamides react smoothly (4−8), including
sterically hindered ortho-substituted sulfonamides (8). Un-
fortunately, 2-nosylsulfonamide was not tolerated (9),
presumably due to the redox activity of the nitroarene. Alkyl
sulfonamides are excellent reaction partners (10 and 11); these
include a sterically hindered tert-butylsulfonamide, which gives
a 67% yield of 12. Sulfamoyl ureas (13), alcohols (14), and
carboxylic acids (15) give high yields of cyclized product,
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offering efficient access to a diverse array of heterocyclic
scaffolds. Importantly, no alteration of the catalyst system or
reaction conditions is necessary in these cases despite the
disparate nucleophiles examined.
Pd(II)-based catalyst systems for oxidative amination (Table
3a and 3b).50−53 These systems uniformly afforded unsat-
Table 3. Survey of Oxidative Amination Methods
Modifications to the length and identity of the tethering
group are readily accommodated, and the functional group
tolerance of this method is excellent. Common organic
functional groups including esters (16), alcohols (17), silyl
ethers (18), and acetals (19) are tolerated. These reactions
exhibit excellent chemoselectivity as only cyclization of the
sulfonamide is observed in the presence of nucleophilic free
alcohols (17). While cyclizations affording five-membered
rings are most efficient (20), six-membered rings are also
readily accessible (21). Given the oxidizing nature of these
conditions, we were pleased to find that tertiary amines (22)
and anilines (23) are well tolerated. Lewis basic heterocycles
that might coordinate to Cu(II) also do not interfere with the
desired transformation (24); however, substrates containing
Lewis basic functionalities react most efficiently with 2 equiv of
p-TsOH acid in place of TFA, presumably because the basic
nitrogen is protonated under these conditions. These
functionalities are also particularly noteworthy because they
are common poisons for transition metal catalysts, further
demonstrating the unique complementarity of this photo-
catalytic system to its Pd(II)-catalyzed counterparts. A
sterically hindered tertiary nucleophile undergoes cyclization,
delivering a densely functionalized spirocyclic tetrahydrofuran
(25) in 57% yield. Azetidine 26 was prepared in 54% yield,
showcasing the potential utility of this method in the synthesis
of medicinally desirable structures.42 Bicyclic heterocycles
could also be synthesized (27), demonstrating the application
of this method in the construction of higher-order molecular
architectures.
a
Trisubstituted alkenes are excellent substrates in this
reaction, and in all cases, we observe exclusive anti-
Markovnikov selectivity in the initial bond-forming
event.43−45 Thus, cyclization can proceed in endo fashion,
consistent with generation of a more stable radical
intermediate upon nucleophilic trapping (28). In this experi-
ment, the oxidative elimination gives a moderate preference for
the exocylic terminal olefin (4:1), in line with the
regioselectivites observed by Glorius for decarboxylative
olefination.34 Additionally, oxidative elimination affording
endocyclic olefins can be conducted without issue (29).
Styrenic olefins afford 1,1-disubstituted styrenes (30) as the
sole products. Importantly, and in contrast to many Pd(II)-
catalyzed oxidative amination methods, no alkene isomer-
ization is observed.46−49 Short reaction times were crucial to
obtain good yields of cyclized product, however, as 30
undergoes slow oxidative decomposition under the reaction
conditions. To our delight, tetrasubstituted alkenes, typically
among the most challenging substrates for Pd(II)-catalyzed
heterofunctionalization methods, react smoothly, and consis-
tent with the absence of a discrete catalyst−nucleophile
interaction, the identity of the heteroatomic nucleophile has
little effect on the efficiency of cyclization. Sulfonamides (31),
carboxylic acids (32), and alcohols (33) all afford good to
excellent yields of the desired heterocycles.
Reaction conducted using MesAcrPh+ (2.5 mol %), Cu(EH)2 (2
equiv), TFA (1 equiv), and 1,2-DCE. Irradiated for 16−18 h.
b
Reaction conducted using Pd(OAc)2 (5 mol %), NaOAc (2 equiv),
c
O2, DMSO, rt, 72 h. Reaction conducted using Pd(OAc)2 (5 mol %),
d
pyridine (10 mol %), O2, toluene (0.1 M), 80 °C, 24 h. Reaction
conducted using Pd(TFA)2 (10 mol %), (−)-sparteine (40 mol %),
DIPEA (2 equiv), MS 3 Å, O2, toluene (0.1 M), 80 °C, 26 h.
isfactory yields of oxidative cyclization with significant
decomposition of the starting alkenes. The highest yields
were obtained with the catalyst system reported by Stahl
(Pd(OAc)2/pyridine)52 but only after extended reaction times
at elevated temperatures (13% and 22% yield of 4 and 31,
respectively). In contrast, our photocatalytic protocol effects
rapid and efficient oxidative cyclization of both 1 and 34 to
their corresponding heterocycles.
The origin of this complementary reactivity can readily be
rationalized upon examination of each reaction component by
cyclic voltammetry (Figure 1). Trisubstituted alkenes are
oxidized at significantly less positive potentials than sulfona-
mides, alcohols, or carboxylic acids in 1,2-DCE. Moreover, the
oxidation of functionalized alkene 1 occurs at significantly less
positive potentials than either alkenes or sulfonamides alone.
As detailed by Moeller in studies of the reactions of
heteronucleophiles with electrochemically generated alkene
radical cations,54,55 this observation would be consistent with a
relatively slow alkene oxidation followed by a rapid cyclization
event. Thus, the activation of the polysubsituted alkene moiety
by photochemical oxidation rather than by transition metal
Importantly, the scope of this new oxidative heterofunction-
alization reaction provides a synthetic capacity that state-of-
the-art Pd(II)-catalyzed methods do not. To demonstrate this
complementarity, we subjected trisubstituted alkene 1 and
tetrasubstituted alkene 34 to several known, highly active
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Grace A. Lutovsky − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-6040-546X
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c02747
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding for this project was provided by the NIH
(GM095666). G.L. is grateful to 3M for a 3M Science &
Technology Fellowship. NMR and MS facilities at UW−
Madison are funded by the NIH (1S10 OD020022-1) and a
generous gift from the Paul J. and Margaret M. Bender Fund.
Figure 1. Cyclic voltammetry experiments.
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In summary, we have shown that a photocatalytic system
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c02747.
■
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AUTHOR INFORMATION
Corresponding Author
Tehshik P. Yoon − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0002-3934-4973;
Email: tyoon@chem.wisc.edu
■
Authors
Nicholas L. Reed − Department of Chemistry, University of
WisconsinMadison, Madison, Wisconsin 53706, United
States; orcid.org/0000-0003-4234-5464
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