Homobenzylic Oxygenation Enabled by Dual Organic Photoredox and Cobalt Catalysis

Article abstract of DOI:10.1021/jacs.0c04422

Activation of aliphatic C(sp3)-H bonds in the presence of more activated benzylic C(sp3)-H bonds is often a nontrivial, if not impossible task. Herein we show that leveraging the reactivity of benzylic C(sp3)-H bonds to achieve reactivity at the homobenzylic position can be accomplished using dual organic photoredox/cobalt catalysis. Through a two-part catalytic system, alkyl arenes undergo dehydrogenation followed by an anti-Markovnikov Wacker-type oxidation to grant benzyl ketone products. This formal homobenzylic oxidation is accomplished with high atom economy without the use of directing groups, achieving valuable reactivity that traditionally would require multiple chemical transformations.

Full text of DOI:10.1021/jacs.0c04422

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Communication
Homobenzylic Oxygenation Enabled by Dual
Organic Photoredox and Cobalt Catalysis
Joshua B. McManus, Jeremy D Griffin, Alexander R. White, and David A Nicewicz
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 27 May 2020
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Homobenzylic Oxygenation Enabled by Dual Organic
Photoredox and Cobalt Catalysis
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Joshua B. McManus, ‡ Jeremy D. Griffin, ‡† Alexander R. White, § David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, 27599-3290, United
States
ABSTRACT: Activation of aliphatic C(sp3)−H bonds in the presence of more activated benzylic C(sp3)−H bonds is often a
nontrivial, if not impossible task. Herein we show that leveraging the reactivity of benzylic C(sp3)−H bonds to achieve reactivity at
the homobenzylic position can be accomplished using dual organic photoredox/cobalt catalysis. Through a two-part catalytic
system, alkyl arenes undergo dehydrogenation followed by an anti-Markovnikov Wacker-type oxidation to grant benzyl ketone
products. This formal homobenzylic oxidation is accomplished with high atom economy without the use of directing groups;
achieving valuable reactivity that traditionally would require multiple chemical transformations.
Selective chemical modification of unactivated aliphatic C−H
bonds represents tremendous challenge in organic
methylene oxygenation at the homobenzylic position of
saturated alkyl arenes. This strategy would rely on a formal
dehydrogenation via the intermediacy of a photoredox-
generated benzylic radical (1•) to produce a styrene (3)
A. Nicolaou et al. Stoichiometric oxidation of benzylic C–H bonds
a
chemistry.1 Nature routinely utilizes biosynthetic enzymes to
selectively oxygenate specific C–H bonds with high substrate
fidelity.2 While such selectivity is highly coveted, chemists
have struggled to mimic nature’s adept ability for site-
selective oxidation of hydrocarbon scaffolds.
3.0 equiv. IBX
Me
Common
strategies
for
effecting
selective
C−H
Me
DMSO, 80˚C, 8 h
O
functionalization target benzylic or allylic C–H bonds, which
have low bond-dissociation energies.3,4 These methods rely on
stoichiometric specialty oxidants like IBX (Figure 1A).5,6
More recently, catalytic methods utilizing transition-metals,
electrochemistry, and photoredox chemistry have been
developed.3,7–10 While there are well established methods for
functionalizing activated positions, manipulation of remote
C−H bonds remains a challenge.
72% yield
B. Baran et al. electrochemical benzylic oxygenation
1.0 equiv. quinuclidine
1.0 equiv. Me4N•BF4
10 equiv. HFIP
O
O
O
O
O
RVC anode / Ni cathode
MeCN, 5 mA, 12 h
45% yield
Conversion of unactivated aliphatic methylenes to ketone-
Cl
Cl
bearing
carbons
represents
a
valuable
synthetic
C. this work: site-selective homobenzylic oxidation
transformation. This reactivity paradigm not only grants
access to diverse oxygenated derivatives, but the versatility of
ketones allows for streamlined diversification of the resulting
products. Curci and coworkers have demonstrated methylene
to ketone oxidation using super-stoichiometric amounts of
highly-reactive dioxirane oxidants;11 however, selectivity is
problematic.12
Acr+ [Co]
O
R
R
dehydrogenation;
R
R
2
1
Wacker-type oxidation
−H•
−H+
−H•
−e−
+H2O
Recent work has shown that remote electronics can promote
selective C–H functionalization at 2˚ positions, but only in the
absence of reactive benzylic, allylic, or 3˚ C–H bonds.13–18
While these methods represent the state-of-the-art for
achieving oxidation of unactivated C(sp3)−H bonds, they
largely give modest site-selectivity when multiple similar C–H
bonds are present. Differentiation of C–H bonds that are in
similar electronic and steric environments requires the use of
directing groups that coordinate to transition metals,
facilitating reactions with adjacent C–H bonds.19,20
−H•
OH2
R
R
R
R
R
R
2•+
1•
3
Figure 1. (A, B) Traditional and state-of-the-art methods selective
for benzylic oxidation (C) Selective homobenzylic oxidation.
in situ (Figure 1C). Hydration followed by a second
dehydrogenation would invoke
a net anti-Markovnikov
Wacker-type oxidation to produce a ketone. The feasibility of
this sequence has been demonstrated by Lei and coworkers,23
and is dependent on the photoredox-catalyzed anti-
Markovnikov addition of nucleophiles to alkene radical
Inspired by the dual transition metal/photoredox catalyzed
dehydrogenation protocol developed by Kanai and
coworkers,21,22 we envisioned a selective reaction manifold for
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cations, a topic that has been rigorously studied by our
Page 2 of 9
concentration = 95 mM 1a) a brief induction period (~20
minutes) was observed; the reaction then proceeds at a
relatively high rate reaching ~15% conversion after 3 hours
(red trace, Figure 2). However, the reaction quickly tails off
and only reaches ~40% after 20 hours. These results suggest
that conversion may be thwarted by either product inhibition
or catalyst decomposition. To probe these possibilities, a
same-excess experiment was performed by initiating the
reaction at a lower concentration of 1a while maintaining all
other stoichiometric reagents at the same relative
concentrations (Figure 2).26 Though LiNO3 is used in
stoichiometric quantities, it was treated as a catalyst as its
effective concentration should remain constant. Because this
experiment was designed to simulate the reaction at
approximately 30% conversion, product 2a was added in an
attempt to rule out product inhibition.
group.24,25 By the virtue of this mechanism, we were able to
achieve an entirely selective oxidation at the homobenzylic
position of alkyl arenes. While many C–H functionalization
reactions exploit the inherent reactivity of labile benzylic
hydrogen atoms, this unique transformation leverages this
property to achieve a selective remote oxidation.
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Reaction development focused on the transformation of
propylbenzene (1a) to phenyl-2-propanone (2a) (Table 1).26
To invoke the desired transformation, we devised intial
9
reaction conditions consisting of
cobaloxime catalyst and an acridinium
5 mol% Mes-Acr+
a hydrogen evolving
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5-10 mol% [Co], 2.0 equiv. LiNO3
O
Me
Me
5 mol% Brønsted acid additive
9:1 MeCN/H2O, N2, 20-44 h
456 nm LEDs
1a
2a
The same-excess experiment revealed a similar reaction
profile to that of the standard conditions (Table 1 entry 5);
however, when the time axis is offset such that t0 of the same-
excess trial is aligned with the standard experiment where
concentrations of 1a are equal (65 mM), the curves are
mismatched (time offset, Figure 2B). Ideally, catalyst
concentrations should remain constant throughout; a mismatch
indicates that catalyst degradation is probable. The
concentration of 2a should also be equivalent in both reactions
at that time point, therefore product inhibition can be ruled out
as a cause for diminished consumption of 1a under standard
conditions.
Cl
H
Me
Me
Me
Me
F
O
O
B
F
N
N
Me
Me
O
O
N
N
O
Co N
O
F
Co N
F
Mes-Acr+
Me
Me
Me
Me
N
N
H
B
O
O
Me
N
[CoII]
[CoIII]A; R=H
[CoIII]B; R=Ac
[CoIII]C; R=CN
t-Bu
N
Ph
t-Bu
BF4
R
entry
[Co] source (mol%)
[CoIII]A (5)
[CoIII]B (5)
[CoIII]C (5)
[CoII] (5)
[CoII] (5)
[CoII] (5)
[CoII] (10)
[CoII] (10)
[CoII] (10)
acid
-
yield
22%
11%
4%
Further optimization included a more extensive survey of acid
additives.26 Dichloroacetic acid (DCA) was identified as a
superior additive, giving a significant boost in reproducibiliy,
though only delivering modest improvements in yield relative
to HNO3 (Table 1, entry 6). However, increasing the
cobaloxime catalyst loading from 5% to 10% furnished
1a
2 a
3 a
4 a
5 b
6 b
7 b
8 b
9b,c
-
-
-
24%
55%
57%
HNO3
DCA
HNO3
DCA
DCA
55-74%
70%
5 mol% Mes-Acr+
5 mol% [CoII], 2.0 equiv. LiNO3
O
trace
Me
5 mol% Brønsted acid additive
9:1 MeCN/H2O, N2, 456 nm LEDs
Me
1a
2a
a
b
Table 1. Optimization of homobenzylic oxidation. 20 h or 44 h
reaction time. c0 equiv. LiNO3. DCA = dichloroacetic acid. Yields
determined by NMR against HMDSO as an internal standard.
photooxidant. Upon irradiation with blue LEDs, quenching of
the acridinium excited state by LiNO3 generates a nitrate
radical capable of abstracting a benzylic hydrogen atom,27
initiating the reaction. We investigated cobaloxime complexes
judiciously, as they are known to be effective hydrogen
evolving catalysts,28–30 especially in the presence of organic
acids generated by acridinium photooxidants.21,23 Of the Co
catalysts that were explored, the difluoroborate-bridged [CoII]
species outperformed [CoIII]A-C (Table 1, entries 1-4),
although it was only marginally superior to [CoIII]A. It was
later determined that yields could be dramatically improved by
including a catalytic amount of HNO3, which is suspected to
promote turnover of the cobaloxime (Table 1, entry 5).29,30
Reaction progress kinetic analysis (RPKA) has been employed
as a tool for studying reaction kinetics. It can be used to gain
mechanistic insight and guide the optimization of reactions
without the need for multiple pseudo first order experiments.31
Under RPKA conditions (Table 1, entry 5) (initial
experiment
[1a]0
[H2O]0
excess
[2a]0
–
standard conditions
95 mM
65 mM
5 M
5 M
4.91 M
4.94 M
same-excess
+ product
30 mM
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Figure 2. Kinetic profile of 1a oxidation under the HNO3
conditions (red trace) and the same excess experiment (blue
trace).
We propose that this reaction proceeds through the mechanism
outlined in Scheme 1. Initial oxidation of the nitrate anion (
1
2
3
4
5
6
7
8
표푥
32
E
= +1.97 V
)
occurs from the excited state photooxidant,
푝/2
F
E ∗ = +2.13 V
+*
33
Xyl -Acr (
). The resulting nitrate radical is
푟푒푑
a potent H-atom abstracting agent,27 allowing it to excise the
reproducibly good yields. (Table 1, entries 7, 8). We believe
the implementation of DCA, by acting as a buffer for in situ-
generated HNO3, is benificial for mitigating acid-induced
decomposition of the cobaloxime catalyst. These findings are
congruent with the results of the same-excess experiment.
weak C(sp3)−H bond of 1 generating HNO3 and benzylic
E표푥 = ―0.54 V
•
F
•
radical 1 . Xyl -Acr (
single electron transfer (SET) with [Co ] (
) can feasibly undergo
1/2
E
푟푒푑 = ―0.51 V
) to
1/2
II
regenerate XylF-Acr+ and a reduced cobalt complex (vide
infra). [CoI]– likely undergoes protonation to form [CoIII]–H
assisted by the aforementioned acid additive. 1• is then
intercepted by [CoIII]–H, liberating H2 and 3. There are several
mechanisms by which this could occur:34–37 One possibility is
9
Similarly, we recognized that the benzylic protons present on
the mesityl group of our most commonly utilized acridinium
photocatalyst, Mes-Acr+, represented a liability for catalyst
decomposition. Unsurprisingly, replacement of the most
sterically accessible methyl group with a fluorine atom
resulted in increased robustness with a variety of other alkyl
arenes. As such, the modified catalyst, XylF-Acr+ (Chart 1),
was implemented to explore the remainder of the substrate
scope.
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the direct protonation of [CoIII]–H. This would form [CoIII]+ (
E푟1푒/푑2~ + 0.2 V
E표푥
28
)
which could potentially oxidize 1•
(
1/2
38
~ + 0.37 V
). While this SET is endergonic by about +0.2 V
(4.6 kcal/mol), rapid deprotonation of the resulting benzylic
cation intermediate would render SET irreversible, ultimately
generating styrene 3. Alternatively, two molecules of [CoIII]–H
could undergo a bimolecular reductive elimination of H2
generating two equivalents of [CoII].29 3 would then be formed
via the addition of 1• to [CoII], forming a putative [CoIII] alkyl
Simple linear alkyl-substituted arenes, such as propyl and
heptyl benzene, were competent substrates in this reaction
giving smooth conversion to the desired ketone products 2a
and 2b, respectively. Modest yields were observed for 2c,
demonstrating that the homobenzylic position can be oxidized
selectively in the presence of 3˚ benzylic C–H bonds.
Interestingly, introducing additional benzylic C–H bonds on
the aryl ring did not have a significant effect on reactivity, as
2d was still formed in good yield. Arenes with useful
functional handles – such as bromide – and biphenyl moieties
were also competent substrates as demonstrated by 2e and 2f,
respectively. One potentially synthetically valuable application
of this methodology is exemplified by the direct conversion of
1g to the corresponding β-ketoester 2g.
intermediate capable of undergoing
a
net -hydride
elimination. 3 can then engage in a second catalytic cycle to
form the olefin radical cation (3•+) whereupon trapping with
water would afford a distonic radical cation (2•+). Subsequent
deprotonation and a second dehydrogenation would furnish
the desired product 2 via a sequence akin to the mechanisms
proposed by Lei and Nicewicz.23,24
The role of the cobaloxime in this reaction is two-fold: it is
responsible for (1) hydrogen evolution and (2) turnover of the
photoredox cycle via oxidation of XylF-Acr•. The latter was
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Page 4 of 9
5 mol% XylF-Acr+
1
2
3
4
5
6
10 mol% [CoII]
F
Me
Me
F
O
XylF-Acr+
B
F
2.0 equiv. LiNO3
N
O
O
N
R
R
Me
O
F
Co N
F
Me
Me
Me
5 mol% dichloroacetic acid
9:1 MeCN/H2O, N2, 20-44 h
456 nm LEDs
R
R
N
B
O
1
2
t-Bu
N
[CoII]
t-Bu
Ph
BF4
7
8
substrate scope
O
Me
O
O
O
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Me
2a 70% yielda,c,d
Me
Me
2c 43% yieldb
Me
2d 64% yielda,c
2b 73% yieldb
Br
Ph
O
O
O
O
Me
Me
OMe
2g 46% yieldb
2e 78% yielda,c
2f 52% yielda,b
Chart 1. Homobenzylic oxidation scope. aYields determined by NMR vs an internal standard, b20 h, c44 h. dMes-Acr+ in place of
XylF-Acr+.
H2O
OH2
R
O
R
R
R
R
R
H
H
3•+
2•+
2
R
R
H−NO3
−e−, −H2
+e−
1
H
H
−e−
+e−
XylF-Acr•
[CoII]
H
H
•
NO3
R
R
R
R
1•
3
[CoIII]−H
−e−, −H2
+e−
−e− +e−
XylF-Acr•
E1/2 = −0.54 V
XylF-Acr+*
−e−
+e−
[CoII]
−
E1/2 = −0.51V
NO3
+H+
XylF-Acr+
[CoIII]−H
[CoI]
hν
−e− +e−
XylF-Acr+*
E*red = +2.13 V
F
Me
Me
F
O
XylF-Acr+
Me
B
N
F
O
N
+H+
XylF-Acr+
O
F
Co
N
F
Me
[CoI]
Me
Me
N
B
hν
O
t-Bu
N
Ph
[CoII]
t-Bu
BF4
Scheme 1. Mechanistic proposal for LiNO3-mediated homobenzylic oxidation
probed using stopped-flow kinetic analysis.26 Surprisingly,
given only a modest driving force for electron-transfer, the
bimolecular electron-transfer between acridine radical and the
Co(II) complex was found to occur during the mixing time of
the experiment; thus only a lower limit estimate of >107 M-1s-1
could be determined for the rate of electron-transfer.26
present in the reaction mixture, with the styrenyl intermediate
only existing transiently before rapidly oxidizing to the olefin
radical cation. Furthermore, subjecting 3a to the reaction
conditions produced near-quantitative conversion to 2a,
indicating that styrenes are plausible intermediates.
Having established a working mechanism for the disclosed
transformation, we were curious about the performance of
more electron rich substrates such as tetralin (1h), as these
compounds may compete with LiNO3 by reductively
quenching XylF-Acr+* (Chart 2A). Owing to the extremely
high acidity of the benzylic protons of arene radical cations,39
one could envision an alternate mechanistic pathway where
radical 1• is formed through oxidation and deprotonation of 1,
Stern-Volmer analysis revealed that both the nitrate anion and
β-methylstyrene quench the excited state acridinium on the
order of 109 M-1s-1, unlike 1a, which was a poor quencher
(Chart 2A). These observations lend credence to the proposed
photoinduced electron transfer events outlined in Scheme 1.
1
Interestingly, styrenes were seldom detected in the H NMR
spectra of crude reaction mixtures. This is likely a result of
styrene being the most efficient quencher of XylF-Acr+*
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Chart 2. (A) Stern-Volmer analysis of potential quenching molecules. (B) proposal for direct substrate oxidation mechanism (C)
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Scope for homobenzylic oxidation Yields determined by NMR vs internal standard, b20 h, c44 h.
a
1
2
3
4
5
6
7
8
obviating the need for LiNO3 (Chart 2B). As expected, tetralin
ACKNOWLEDGMENTS
(1h) can be efficiently converted to 2-tetralone (2h), a
challenging motif to access directly by traditional synthetic
methods, without the use of LiNO3 (Chart 2C). These
conditions also allowed for lower [CoII] loadings and shorter
reaction times, further supporting our hypothesis that
prolonged exposure of the cobaloxime to in situ generated
HNO3 likely leads to catalyst decomposition. These conditions
also proved to be more functional group tolerant than those
presented in Chart 1.
Financial support was provided in part by the National Institutes
of Health (NIGMS) Award No. R01 GM098340. Photophysical
measurements were performed in the AMPED EFRC
Instrumentation Facility established by the Alliance for Molecular
PhotoElectrode Design for Solar Fuels (AMPED), an Energy
Frontier Research Center (EFRC) funded by the U.S. Department
of Energy, Office of Science, Office of Basic Energy Sciences
under Award DE-SC0001011. We thank the University of North
Carolina’s Department of Chemistry Mass Spectrometry Core
Laboratory, especially, Dr. Brandie Ehrmann, for their assistance
with mass spectrometry analysis. We acknowledge Professor
Thomas Meyer (UNC) for assistance in stopped-flow
experimentation.
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When selecting the appropriate conditions for this
transformation, the redox properties of both the photocatalyst
and substrate should be considered. As a general rule of
thumb, if electron transfer is energetically favorable, the
conditions without LiNO3 should be employed. For example,
E표푥
1a was found by cyclic voltammetry to have a 푝/2of +2.27 V
and is therefore not likely to undergo facile SET with XylF-
REFERENCES
E ∗ = +2.13 V)
Acr+* (
and will require the use of LiNO3 as
푟푒푑
(1)
(2)
(3)
White, M. C.; Zhao, J. Aliphatic C–H Oxidations for
Late-Stage Functionalization. J. Am. Chem. Soc. 2018,
140
E표푥
a mediator. However, 1h ( 푝/2= +2.03 V) is poised to undergo
thermodynamically favorable SET. Stern-Volmer analysis
should be used to determine actual ability of a particular
substrate to quench XylF-Acr+*; however, CV analysis will
allow for a reasonable approximation.
(43),
13988–14009.
https://doi.org/10.1021/jacs.8b05195.
Meunier, B.; de Visser, S. P.; Shaik, S. Mechanism of
Oxidation Reactions Catalyzed by Cytochrome P450
Enzymes. Chem. Rev. 2004, 104 (9), 3947–3980.
https://doi.org/10.1021/cr020443g.
Fernandes, R. A.; Nallasivam, J. L. Catalytic Allylic
Functionalization via π-Allyl Palladium Chemistry.
Org. Biomol. Chem. 2019, 17 (38), 8647–8672.
https://doi.org/10.1039/C9OB01725A.
In conclusion, we have developed a protocol for the selective
oxidation of traditionally unreactive C−H bonds. Experiments
were performed to probe the mechanism of this dual-catalytic,
two-part transformation, which guided efforts to devise
separate sets of conditions to address differences associated
with the electronic properties of individual substrates. An
initial look into the substrate scope has revealed the potential
utility of this reaction, which allows for the direct access of
dissonant motifs from inexpensive and simple starting
materials. Ongoing work is focused on refining this protocol
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AUTHOR INFORMATION
Corresponding Author
* nicewicz@unc.edu
The authors declare not competing financial interest.
Present Addresses
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† Department of Chemistry, University of Utah, 315 South 1400
East, Salt Lake City, Utah 84112, United States
§ FMC Stine Research Center, 1090 Elkton Rd. Newark, DE
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Author Contributions
‡J.B.M. and J.D.G. contributed equally.
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