Site-Selective Alkoxylation of Benzylic C?H Bonds by Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201910602

Methods that enable the direct C?H alkoxylation of complex organic molecules are significantly underdeveloped, particularly in comparison to analogous strategies for C?N and C?C bond formation. In particular, almost all methods for the incorporation of alcohols by C?H oxidation require the use of the alcohol component as a solvent or co-solvent. This condition limits the practical scope of these reactions to simple, inexpensive alcohols. Reported here is a photocatalytic protocol for the functionalization of benzylic C?H bonds with a wide range of oxygen nucleophiles. This strategy merges the photoredox activation of arenes with copper(II)-mediated oxidation of the resulting benzylic radicals, which enables the introduction of benzylic C?O bonds with high site selectivity, chemoselectivity, and functional-group tolerance using only two equivalents of the alcohol coupling partner. This method enables the late-stage introduction of complex alkoxy groups into bioactive molecules, providing a practical new tool with potential applications in synthesis and medicinal chemistry.

Full text of DOI:10.1002/anie.201910602

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Site-Selective Alkoxylation of Benzylic C–H Bonds via
Photoredox Catalysis
Authors: Byung Joo Lee, Kimberly S DeGlopper, and Tehshik Peter
Yoon
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201910602
Angew. Chem. 10.1002/ange.201910602
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10.1002/anie.201910602
Angewandte Chemie International Edition
COMMUNICATION
Site-Selective Alkoxylation of Benzylic C–H Bonds via
Photoredox Catalysis
Byung Joo Lee, Kimberly S. DeGlopper, and Tehshik P. Yoon*
Abstract: Methods that enable the direct C–H alkoxylation of complex
organic molecules are significantly underdeveloped, particularly in
comparison to analogous strategies for C–N and C–C bond formation.
In particular, almost all methods for the incorporation of alcohols via
C–H oxidation require the use of the alcohol component as solvent.
This limits the practical scope of these reactions to simple,
inexpensive alcohols. We report a photocatalytic protocol for the
functionalization of benzylic C–H bonds with a wide range of oxygen
nucleophiles. Our strategy merges the photoredox activation of
arenes with copper(II)-mediated oxidation of the resulting benzylic
radicals, which enables the introduction of benzylic C–O bonds with
high site selectivity, chemoselectivity, and functional group tolerance
using only two equivalents of the alcohol coupling partners. This
method enables the late-stage introduction of complex alkoxy groups
into bioactive molecules, providing a practical new tool with potential
applications in synthesis and medicinal chemistry.
Recently, our laboratory has become interested in the
design of photocatalytic oxidative functionalization reactions. We
were inspired by the facility with which photoredox catalysis
generates organoradical intermediates from readily available
feedstocks.9 We proposed that Cu(II) salts could be ideal terminal
oxidants for net-oxidative transformations whose use has been
underexplored in photoredox reactions.10,11 Seminal studies by
Kochi demonstrated that a variety of organic radicals undergo
oxidation by Cu(II) at diffusion-controlled rates.12 Moreover, the
use of Cu(II) oxidants avoids the intermediacy of reactive oxygen
intermediates (e.g., oxygen-centered radicals, superoxide, singlet
oxygen) that can be incompatible with organoradical
intermediates or with highly functionalized complex organic
molecules.
OR
Cu
hν
Me
Me
HO
R
The development of methods for the site-selective
functionalization of sp3-hybridized C–H bonds has profoundly
influenced the way that organic chemists approach complex
molecule synthesis.1 Late-stage functionalization strategies that
enable one-step incorporation of new functional groups are
particularly important because they can provide an efficient
strategy to rapidly assess structural analogues of pharmaceutical
candidates for new chemical and biological properties.2 Much of
the recent activity in this field has centered on cross-coupling
reactions that enable the site-selective incorporation of complex
carbon- and nitrogen-centered fragments at aliphatic positions.3
Dialkyl ether linkages are ubiquitous in pharmaceuticals,
natural products, and other bioactive compounds.4 There are
numerous established methods for the oxidative functionalization
of aliphatic C–H bonds in complex organic molecules using
MeO
MeO
C–H alkoxylation
arene
alcohol
CF3
F
CF3
CF3
N
CF3
O
NCMe
O
O
N
F
F
O
O
IrIII
MeCN Cu
O
Cu
O
N
O
N
F3C
CF3
F
CF3
CF3
photoredox oxidation
radical oxidation
+
– H+
Ir
[O]
Me
Me
Me
Me
SET
SET
MeO
MeO
MeO
MeO
A
B
C
D
structurally
simple
alcohols,
including
electrochemical
oxidations,5 chemical oxidations,6 and transition metal catalyzed
C–H alkoxylation protocols.7 With a few notable exceptions,7ef
however, none of these strategies are appropriate for couplings
involving structurally complex alcohols. This is because in these
methods, solvent quantities of the alcohol coupling partner are
typically required for optimal reactivity, which limits the practical
scope of these alkoxylation reactions to inexpensive simple
alcohols that are produced on commodity chemical scales.8 A
more synthetically useful method for C–H alkoxylation that would
enable couplings with structurally much more complex alcohols,
therefore, requires a new approach that operates at a more
reasonable stoichiometry.
Scheme 1. Design Strategy for Photocatalytic Etherification of Benzylic C–H
Bonds.
We imagined a strategy exploiting a photoredox catalyst in
combination with a Cu(II) oxidant would enable the direct
incorporation of a wide range of simple nucleophilic alcohols into
Csp3–H bonds.
A brief outline of our design strategy is
summarized in Scheme 1. Photoinduced one-electron oxidation
of an electron-rich arene (A) would afford a radical cation (B)
whose benzylic C–H bonds are significantly acidified;13 facile
deprotonation would afford benzylic radical intermediate C.
Radicalophilic Cu(II) could transform C into the corresponding
carbocation (D), which could be trapped by a nucleophilic alcohol.
An analogous oxidation–deprotonation–oxidation sequence was
proposed in the electrochemical benzylic methoxylation of
estrone.5a This method, however, requires the use of an alcohol
solvent because proton reduction at the counterelectrode drives
this net-oxidative process. More recently, Pandey14 and Hong15
[*]
B. J. Lee, K. S. DeGlopper, Prof. T. P. Yoon
Department of Chemistry, University of Wisconsin–Madison
1101 University Avenue, Madison
E-mail: tyoon@chem.wisc.edu
Supporting information for this article is given via a link at the end of
the document.
adopted
an
analogous
oxidation-deprotonation-oxidation
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10.1002/anie.201910602
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COMMUNICATION
sequence in photoredox protocols for benzylic ether formation
none produced significant yields of 1 (entry 4), consistent with our
using oxygen as
a
terminal oxidant. These photocatalytic
guiding hypothesis. Alternate photocatalysts also afforded
methods, however, are limited to intramolecular bond formations
and thus cannot be applied to intermolecular cross-coupling
reactions.
diminished reaction efficiency.
Both less-oxidizing Ir
18
photocatalysts
(entry 5) and more-oxidizing organic
photocatalysts 19 (entry 6 and 7) afforded diminished yields.
Finally, control experiments validated the photocatalytic nature of
this reaction and the necessity of Cu(II) co-oxidant; no product
was observed in the absence of photocatalyst, Cu(II) terminal
oxidant, or light (entries 8–10).
Table 1. Optimization Studies for Methoxylation of Benzylic C–H Bonds.
OMe
Me
1 mol% photocatalyst
1.2 equiv terminal oxidant
3.0 equiv K2HPO4
Me
MeOH
(2 equiv)
+
The scope of this benzylic alkoxylation protocol is
summarized in Table 2. The reaction is most efficient at
secondary benzylic positions; primary C–H bonds undergo
competitive overoxidation that diminishes the yield of
monoalkoxylation products somewhat (3), and tertiary sites
undergo functionalization at significantly slower rates (4). The
latter can be addressed by diluting the reaction to increase photon
flux and by increasing the amount of MeOH to 8 equiv. The
presence of alkoxy substituents on the arene that could stabilize
the putative quinone methide intermediate is strictly required, but
a variety of such groups along with additional substituents are well
tolerated (5–9, 17–21). The functional group compatibility of this
method is high and includes acidic heteroatoms (10 and 14), basic
heterocycles (20), base-sensitive moieties (11 and 12), and
boronate ester or azide groups that provide handles for further
synthetic manipulation (13 and 15). In general, this reaction
displayed a remarkable degree of site selectivity consistent with
the predicted stability of the quinone methide intermediate (17–
19). Thus functionalization of p-alkoxy-activated benzylic
positions is highly selective even in the presence of weaker
benzylic C–H bonds (20–22). Finally, the benzylic positions of a
variety of electron-rich heterocycles that are also readily oxidized
by the photocatalyst can also be functionalized using this protocol
(23–25).
The scope of the reaction with respect to the heteroatomic
nucleophile was also explored. Water, unfortunately, is not a
suitable nucleophile, and overoxidation to the ketone was the
major product of this reaction (26). Alcohols of increased steric
bulk react more slowly, although the yields of these reactions can
be increased using 8 equiv of alcohol (27–29). A variety of diverse
functional groups were readily tolerated (30–40), including those
containing easily oxidizable moieties (30–33, and 37) and
potentially base-sensitive groups (36, 38, and 39). An
unsymmetrical 1,3-diol reacted exclusively through the less-
sterically-bulky primary alcohol (40). Carboxylic acids were also
readily incorporated, including both simple aliphatic and more
functionalized acids (41–45). Nucleophiles that are more readily
oxidized than the anisole unit (47) or that bear strongly
coordinating heterocycles (48) were unfortunately not suitable
reaction partners. Finally, although N-Boc carbamate reacted with
reasonable efficiency (46), other nitrogen nucleophiles were
generally not effective (49), suggesting that alternate conditions
will be required for the general introduction of C–N bonds using
this photocatalytic strategy.
MeO
MeCN, rt, 6 h
MeO
427 nm blue LED
1
2
Entry[a] Photocatalyst
Terminal oxidant
Yield[b]
8%
1
2
3
4
[Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 Cu(OAc)2•H2O
[Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 Cu(TFA)2•H2O
61%
73%
[Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 Cu(TFA)2•MeCN
[Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 Air, PhI(OAc)2, TEMPO, <10%
MnO2, FeCl3, t-BuOOH,
or benzoquinone
5
6
7
8
9
[Ir(dF(CF3)ppy)2(bpy)]PF6
Fukuzumi acridinium (5.0 mol%)
Triphenylpyrylium (2.5 mol%)
none
Cu(TFA)2•MeCN
Cu(TFA)2•MeCN
Cu(TFA)2•MeCN
Cu(TFA)2•MeCN
23%
10%
5%
0%
[Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 none
0%
10[c] [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 Cu(TFA)2•MeCN
0%
[a] Unless otherwise noted, all reactions were conducted using 0.3 mmol of 1 in
degassed MeCN and irradiated with a 427 nm Kessil lamp for 6 h. [b] Yields
determined by 1H NMR analysis of the crude reaction mixtures using
phenanthrene as an internal standard. [c] Reaction was conducted in the dark.
We reasoned that a combination of photoredox catalyst and
Cu(II) oxidant might provide a highly effective method for
performing benzylic C–H alkoxylation reactions without the need
for solvent-quantity alcohol donors. To test this hypothesis, we
examined the reaction of 4-ethylanisole (1) with 2 equiv of
methanol (Table 1). [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 was
selected as a photocatlyst because its excited-state reduction
potential (+1.68 V vs SCE) 16 should be sufficiently positive to
oxidize 1 (+1.52 V). The use of Cu(OAc)2 as a terminal oxidant
indeed produced the desired product 2, but in only 8% yield (entry
1). Acetoxylation was the major oxidation pathway in this
experiment. We hypothesized that less nucleophilic ligands on
Cu(II) might decrease the formation of this undesired product.
Indeed, Cu(TFA)2 provided a higher yield and no observable ester
product (entry 2); however, benzylic alcohol was a significant
byproduct, which we attributed to the presence of water in the
hydrate form of the commercial salt. We thus prepared the
anhydrous acetonitrile complex Cu(TFA)2(MeCN),17 the use of
which prevented formation of the hydroxylated product and
afforded the desired methanol adduct in 73% yield (entry 3). Cu(II)
salts were unique in their ability to promote this alkoxylation: we
screened a wide range of other common terminal oxidants, and
The combination of high site selectivity and significant
functional group compatibility suggested to us that this method
might be applicable to the diversification of highly complex
bioactive organic compounds. Table
3
outlines the
functionalization of a range of commercially available natural
product scaffolds, all of which are selectively functionalized at the
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Table 2. Scope of C–H Oxygenation via Photoredox Catalysisa
Arene Scope
Alcohol Scope
Me
OMe
Me
OMe
OMe
Me
OH
O
Me
O
Me
Me
Me
Me
MeO
2, 70% yield
MeO
MeO
MeO
26, 23% yieldb
MeO
MeO
3, 21% yieldb
4, 28% yield
27, 55% yield
28, 52% yield
81% yieldc
68% yieldd
66% yieldd
Me
Me
Me
Me
OMe
Me
OMe
Me
OMe OMe
O
O
O
Me
Me
Me
Me
Me
Me
O
Me
TIPSO
MeO
MeO
MeO
5, 78% yield
6, 53% yieldc
7, 38% yieldb,c
29, 23% yield
45% yieldd
30, 56% yield
31, 53% yield
O
OMe
Me
OMe
Me
OMe
O
O
O
MeO
MeO
Br
OH
Me
Me
Me
O
MeO
MeO
MeO
MeO
MeO
8, 70% yieldc
9, 39% yieldc
10, 68% yieldc
32, 58% yield
33, 43% yield
34, 30% yield
NBoc
Me
Me
Si
OMe
OMe
OMe
O
O
Cl
O
Me
OBz
Cl
Bpin
Me
Me
Me
MeO
MeO
MeO
MeO
MeO
MeO
Me
35, 35% yield
36, 52% yield
37, 48% yield
11, 64% yield
12, 79% yieldc
13, 60% yield
O
S
O
Me Me
N
OMe
OMe
OMe
O
O
O
OH
NHTs
MeO
N3
MeO
Me
Me
Me
MeO
OMe
MeO
MeO
MeO
14, 67% yield
15, 51% yield
16, 59% yieldc
38, 49% yield
40, 62% yield
39, 43% yield
Site Selectivity
Other Nucleophiles
O
O
O
Me
OMe
Me
OMe
Me
Me
OMe OMe
O
O
O
Me
Me
OMe
OMe
Me
Me
Me
N
O
MeO
MeO
MeO
MeO
Me
17, 54% yieldc
18, 60% yield
19, 60% yieldc
20, 51% yieldc
41, 51% yield
42, 54% yield
43, 58% yield
O
O
O
HN
Me
OMe
Me
Me
Me
NHTs
O
O
O
O
OMe
Me
Me
Me
O
O
MeO
MeO
MeO
MeO
21, 75% yield
22, 67% yieldb
44, 50% yield
45, 56% yield
46, 38% yieldd
Heteroarene Scope
Incompatible Nucleophiles
O
O
O
Me
OMe
OMe
O
S
OMe
O
HN
O
O
N
S
Me
Me
N
Me
Me
MeO
MeO
MeO
23, 41% yieldc
24, 44% yieldc
25, 47% yieldc
47, 0% yield
48, 6% yieldb,d
49, 0% yield
[a] Reaction condition: substrate (0.6 mmol, 1 equiv.), [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 (1 mol%), K2HPO4 (3 equiv), Cu(TFA)2(MeCN) (1.2 equiv), methanol
(2 equiv), MeCN (0.2 M) unless otherwise noted. Yields represent the averaged isolated yields from two experiments. [b] Yield determined by 1H NMR analysis
of the crude reaction mixtures using phenanthrene as an internal standard. [c] Reaction conducted at 0.1 M using 8 equiv methanol. [d] Reaction conducted
using 8 equiv alcohol.
unique activated benzylic C–H position. No diastereoselectivity is
observed when the substrate lacks significant stereochemical
bias (50), but six-membered rings with a strong preference for a
single
chair
conformation
undergo
highly
selective
functionalization of the axial C–H bond (51 and 52).
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COMMUNICATION
Table 3. Late-Stage Functionalization via Oxidative Photoredox Catalysis[a]
OMe
OMe
OMe
Me
Me
O
H
Me
Me
MeO
O
Me
MeO
CO2Me
Me
Me
Me
Me
OMe
OH
OMe Me
OMe OMe
50, 31% yield (d.r 1:1) (41%)b
51, 50% yieldc
52, 74% yieldc
tocopherol
methyl podocarpate
catechin
Me
OMeOMe
OMe
MeO
Me
MeO
MeO
O
O
H
O
O
OMe
O
O
O
O
OMe
i-Pr
NHBoc
H
H
H
H
Me
CO2Me
Me
CO2Me MeO
Me
Me
CO2Me
H
Me
CO2Me
MeO
MeO
CO2Me MeO
MeO
Me
Me
Me
Me
Me
53, 68% yield
54, 71% yield
55, 66% yield
56, 68% yield
57, 46% yield
carbohydrates
terpenes
amino acids
[a] Reaction condition: substrate (0.3 mmol, 1 equiv), Ir[dF(CF3)ppy]2(5,5’-dCF3bpy)]PF6 (1 mol%), K2HPO4 (3 equiv.), Cu(TFA)2(MeCN) (1.2 equiv.), alcohol
(2 equiv.), MeCN (0.2 M), 9.5 h–10 h unless otherwise noted. Yields represent the averaged isolated yields from two experiments. [b] Reaction conducted at
0.05 M MeCN:CH2Cl2 using 8 equiv methanol. RSM yield is provided in parentheses. [c] Reaction conducted at 0.05 M using 8 equiv methanol.
The observation that synthetically useful yields can be
obtained using only two equivalents of the alcohol nucleophile
A
Stern-Volmer Quenching Studies
also suggests that this intermolecular C–H functionalization might
operate as a method to couple two high-value reaction partners.
Thus, the ability to conjugate O-methylpodocarpate with a variety
of structurally complex nucleophilic partners was explored. The
alcohol moiety of a protected serine can readily be installed in
good yield (53) without competitive attack of the Boc carbamate.
The reaction also incorporates protected hexose and pentose
moieties (54 and 55) as well as primary and secondary terpene
alcohols (56 and 57) in synthetically useful yields.
To better understand the mechanism of this transformation,
we first examined the nature of the initial photoinduced electron-
transfer step.
The excited-state reduction and oxidation
potentials of the optimal photocatalyst (+1.68 V and –0.43 V vs
SCE, respectively) are sufficient to either oxidize arene substrate
1 (Ep/2 = +1.52 V) or reduce Cu(II) (E1/2 = +0.38 V). Indeed, a
Stern–Volmer analysis indicates that both can quench the
photocatalyst excited state at similar rates (Scheme 2A). Thus the
arene radical cation might be generated either by the excited
Ir*(III) photocatalyst or the Ir(IV) complex (E1/2 = +1.94 V vs SCE)
resulting from oxidative quenching by Cu(II). Both mechanisms
might be operative. Consistent with this hypothesis, a less
strongly oxidizing photocatalyst ([Ir(dF(CF3)ppy)2(bpy)]PF6, *E1/2
= +1.31 V) that is not capable of directly oxidizing 1 nevertheless
provides the methoxylation product, albeit in diminished yield
(Table 1, entry 4). We also examined the photocatalytic reaction
of 1 with CD3OD, which resulted in the formation of d-2 in 83%
yield with no incorporation of deuterium at the benzylic position.
This result indicates that the deprotonation step is essentially
irreversible under the optimized conditions, as might be expected
from Kochi’s observation that the oxidation of electron-rich
organoradicals by Cu(II) occurs at diffusion-controlled rates.12
B
Hydrogen–Deuterium Exchange
1 mol%
OCD3
Me
[Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6
1.2 equiv Cu(TFA)2•MeCN]
3.0 equiv K2HPO4
Me
CD3OD
(8 equiv)
+
MeO
MeO
MeCN, rt, 6 h
427 nm blue LED
d-2, 83% yield
no benzylic deuteration
1
C
Proposed Mechanism
OMe
– H+
+ HOMe
Me
Me
2CuI
CuII
Cu0
MeO
MeO
IrIII
*
CuI
CuI
SET
hν
SET
CuII
IrIII
IrIV
– H+
Me
Me
Me
SET
MeO
MeO
MeO
Scheme 2. Development of a Mechanistic Hypothesis.
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10.1002/anie.201910602
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COMMUNICATION
A mechanistic proposal consistent with these data is
outlined in Scheme 2C. Photoexcitation of the Ir(III) catalyst
affords a triplet excited state that is oxidatively quenched by Cu(II)
to afford a strongly oxidizing Ir(IV) complex. Subsequent oxidation
of the arene affords an arene radical cation that undergoes
benzylic deprotonation and rapid oxidation by Cu(II). The resulting
quinone methide undergoes nucleophilic attack by the alcohol
coupling partner to afford the observed benzylic ether products.
The reaction proceeds to completion with only 1.2 equiv of Cu(II).
Thus both oxidizing equivalents of Cu(II) are consumed in this
reaction, which could be attributed to the disproportionation of the
Cu(I) byproduct of either oxidation step to Cu(II) and Cu(0), the
latter of which we observe precipitating from solution during the
reaction.
excess of the alcohol reaction partner, which enables the
formation of new benzylic ether compounds from the coupling of
two structurally complex units. From a broader perspective, these
results are intriguing because they demonstrate that the
organoradical intermediates that are readily generated by
photoredox activation can be diverted towards cationic reactivity
via in situ oxidation by Cu(II). This combination thus provides a
promising new platform to design new bond-forming oxidative
functionalization reactions with broad utility in synthetic and
medicinal chemistry.
Acknowledgements
In summary, we have developed a new photocatalytic
strategy to introduce diverse alkoxide functionalities into complex
organic molecules by functionalization of benzylic C–H bonds.
The site selectivity and broad functional group compatibility of this
method renders it amenable to the late-stage functionalization of
complex bioactive compounds. Importantly, the efficiency of the
reaction provides synthetically useful yields using only a two-fold
We gratefully acknowledge the NIH (GM095666) for funding this
work. We thank Prof. Shannon Stahl and Sijie Chen (UW–
Madison) for sharing unpublished data.
Keywords: C–H alkoxylation • copper • oxidation •
photocatalysis • radicals
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This article is protected by copyright. All rights reserved.

10.1002/anie.201910602
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
OMe
MeO
OMe
B. J. Lee, K. S. DeGlopper, T. P. Yoon*
MeO
O
MeO
MeO
MeO
MeO
site-selective alkoxylation
high chemoselectivity
O
1 mol% [Ir]
1.2 equiv [CuII]
HO
O
+
Page No. – Page No.
Me
visible light
Me
Me
Me
CO2Me
high functional group tolerance
Site-Selective Alkoxylation of
Benzylic C–H Bonds via Photoredox
Catalysis
MeO
CO2Me
MeO
H
H
C–H alkoxylation: Photocatalysis offers a one-step strategy to selectively
functionalize the benzylic positions of electron-rich arenes with alcohols in
structurally complex organic molecules.
This article is protected by copyright. All rights reserved.