Regioselective Arene C?H Alkylation Enabled by Organic Photoredox Catalysis

Article abstract of DOI:10.1002/anie.202000684

Expanding the toolbox of C?H functionalization reactions applicable to the late-stage modification of complex molecules is of interest in medicinal chemistry, wherein the preparation of structural variants of known pharmacophores is a key strategy for drug development. One manifold for the functionalization of aromatic molecules utilizes diazo compounds and a transition-metal catalyst to generate a metallocarbene species, which is capable of direct insertion into an aromatic C?H bond. However, these high-energy intermediates can often require directing groups or a large excess of substrate to achieve efficient and selective reactivity. Herein, we report that arene cation radicals generated by organic photoredox catalysis engage in formal C?H functionalization reactions with diazoacetate derivatives, furnishing sp²–sp³ coupled products with moderate-to-good regioselectivity. In contrast to previous methods utilizing metallocarbene intermediates, this transformation does not proceed via a carbene intermediate, nor does it require the presence of a transition-metal catalyst.

Full text of DOI:10.1002/anie.202000684

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Regioselective Arene C–H Alkylation Enabled by Organic
Photoredox Catalysis
Authors: Natalie Holmberg-Douglas, Nicholas P. R. Onuska, and David
Nicewicz
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202000684
Angew. Chem. 10.1002/ange.202000684
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10.1002/anie.202000684
Angewandte Chemie International Edition
RESEARCH ARTICLE
Regioselective Arene C–H Alkylation Enabled by Organic
Photoredox Catalysis
Natalie Holmberg-Douglas‡, Nicholas P. R. Onuska‡ and David A. Nicewicz*
‡These authors contributed equally to this work
[a]
N. Holmberg-Douglas, N. P. R. Onuska, Prof. D. A. Nicewicz
Department of Chemistry
University of North Carolina at Chapel Hill
Chapel Hill, NC 27599-3290 (USA)
E-mail: nicewicz@unc.edu
Homepage: http://nicewicz.chem.unc.edu/
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
1
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10.1002/anie.202000684
Angewandte Chemie International Edition
RESEARCH ARTICLE
Prior Art:
excess arene and
directing groups often required
Abstract: Expanding the toolbox of C–H functionalization reactions
applicable to the late stage modification of complex molecules is of
interest in medicinal chemistry, wherein the preparation of structural
variants of known pharmacophores is a key strategy for drug
development. One manifold for the functionalization of aromatic
molecules utilizes diazo-compounds and a transition metal catalyst
to generate a metallocarbene species, which is capable of direct
insertion into an aromatic C–H bond. However, these high energy
intermediates can often requiring directing groups or large excess
of substrate to achieve efficient and selective reactivity. Herein, we
report that arene cation radicals generated via organic photoredox
catalysis engage in formal C–H functionalization reactions with
diazoacetate derivatives, furnishing sp2–sp3 coupled products with
moderate to good regioselectivity. In contrast to previous methods
utilizing metallocarbene intermediates, this transformation does not
proceed via a carbene intermediate, nor requires the presence of a
transition metal catalyst.
R
R
[M]
H
R
CO2R
CO2R
R
+
N2
CO2R
via metallocarbene
formation
This Work:
arene as limiting reagent
mild and metal-free conditions
H
R
H
R
CO2R
+
R
via cation radical
Mes-Acr-BF4
N2
CO2R
Scheme 1. C-H alkylation via metallocarbenes or
photoredox catalysis
In recent years, photoredox catalysis has served as the
conceptual basis for a number of powerful aromatic C–H
functionalization reactions.12–14 Our group has previously
reported
arene
C–H
amination
and
cyanation
Metallocarbenes are reactive organometallic species
which may be generated using a transition metal precursor
and diazoacetate derivatives.1–3 The resulting carbene
intermediate may then undergo C-H insertion with reactive
C-H bonds (often aryl or alkyl), affording the corresponding
alkylated adducts. However, due to the high reactivity of
metallocarbenes, aromatic substrates are often required to
be present in excess for efficient reactivity.
methodologies which utilize acridinium salts as organic
photoredox catalysts.15,16 These methods rely on the
catalytic generation of aromatic cation radicals via
photoinduced electron transfer (PET) between the aromatic
substrate and the excited acridinium catalyst. We sought to
probe the reactivity of nucleophilic diazoacetates in
combination with electrophilic aromatic cation radicals, as
reactions of this type have not been investigated to date.
Such transformations would be reminiscent of known
metallocarbenoid insertion reactions, while taking place in
the absence of metals or superstoichiometric quantities of
substrate. Furthermore, previous work from our group has
shown moderate to excellent regioselectivity in nucleophilic
additions to aromatic cation radicals. The observation of
comparable levels of regioselectivity in the addition of
Among methodologies based on metallocarbene C-H
insertion that do not use several-fold excess of arene,
directing groups are often required. Fox4 and Wang5 have
reported
ortho-selective
C–H
functionalization
of
heterocycles using diazoacetates. In addition, other
directing groups such as purines,6 azacycles,7 disubstituted
anilines,8 and phenols,9 have been utilized in
metallocarbene C–H alkylation reactions. Collectively, these
directing groups limit the synthetic applicability of
metallocarbene C-H alkylation reactions.
diazoacetate derivatives would represent
improvement over current aromatic C–H functionalization
methodologies utilizing metallocarbene/carbene
a
major
Recently, Suero and coworkers reported the synthesis of
aryl diazoacetate derivatives under photoredox conditions.10
During the course of this work, it was noted that photolysis
of aryldiazoacetates with blue LEDs yields free carbene
species that undergo cyclopropanation reactions in the
presence of styrene. Subsequently, Davies and coworkers
investigated the reactivity of similar photogenerated free
carbenes in combination with electron-rich aromatic
substrates and alkenes.11 In these cases, either
cyclopropanation or formal C–H insertion was observed.
However, the scope of this transformation is specific to aryl
diazoacetates and a small number of arene coupling
partners (which must be present in excess). This is largely
due to the highly reactive nature of free carbenes, which
readily undergo C-H insertion reactions with acidic C-H, O-
H, and N-H bonds. The products of reaction with solvent are
also typically observed in these cases. Due to the reactive
nature of carbenes, methodologies that rely on their
intermediacy can be incompatible with certain functional
groups and low levels of regiocontrol are often observed.
intermediates (Scheme 1). Such a reaction would also be
mechanistically distinct from recent work published by
Gryko which relies on the generation and alkylation of
alpha-keto radicals from diazoacetate derivatives using
photoredox catalysis.17
Here we report a method for C–H functionalization
reactions of arene cation radicals with diazoacetate
derivatives generated via organic photoredox catalysis.
Computational and experimental studies support a unique
mechanism involving cation radical-meditated aromatic
cyclopropanation followed by oxidative ring opening. These
results demonstrate the utility of arene cation radicals as
versatile intermediates for the construction of carbon-carbon
bonds via organic photoredox catalysis.
Reaction development began using mesitylene as a
substrate and ethyl diazoacetate as a nucleophile in the
presence of 5 mol% Mes-Acr-BF4 under irradiation from
blue LEDs. Following a screen of common solvents, a 1:1
mixture of trifluoroethanol (TFE) and acetonitrile was
identified as a suitable medium for the reaction. With one
equivalent of ethyl diazoacetate in a 1:1 TFE/acetonitrile
solvent mixture, the desired C–H functionalized product 1a
was isolated in 76% yield. In some cases, secondary
alkylation of the desired product was observed as a minor
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202000684
Angewandte Chemie International Edition
RESEARCH ARTICLE
byproduct at increased ethyl diazoacetate loadings (>2.0
eq.). Increasing diazoacetate loadings between 1.0 - 2.0 eq.
did not result in a significant increase in yield, presumably
due to competitive oxidation of the product of the reaction.
With optimized conditions in hand, the scope of the
transformation with respect to both the arene and
diazoacetate partners was explored. Simple aromatic
substrates and electron-rich anisole derived substrates
smoothly
undergo
the
desired
Me
Mes-Acr-BF4
R
R
H
Mes-Acr-BF4 (5 mol %)
Me
EtO2C
CO2Et
N2
Me
+
1:1 MeCN:TFE (0.1 M)
465 nm LEDs, N2
t-Bu
N
Ph
(1.0 equiv.)
(1.0 equiv.)
t-Bu
BF4
2
Simple arenes:
Anisole derivatives:
Me
CO Et
Cl
2
1
CO2Et
CO2Et
PhO
CO2Et
CO2Et
CO2Et
OMe
CO2Et
OMe
O
Ph
Me
Me
3a
24% yield
5:1 (1:2)
2a
42% yield
4a
36% yield
4:1 para/ortho
5a
29% yield
5:1 para/ortho
1a
Cl
Br
76% yield
6a
47% yield
7a
33% yield
OMe
Br
OMe
2
OMe
1
2
5
CO2Et
MeO2C
6
OMe
CO2Et
OMe
CO2Et
CO2Et
CO2Et
OMe
CO2Et
MeO
CO2Et
TsO
Me
OMe
Cl
3
Me
Me
4
4
O
Ph
9a
10a
8a
55% yield
11a
14a
33% yield
2.3:1 (1:3)
12a
31% yield
13a
57% yield
3.5 : 1.0 : 1.8 (1:3:5)
48% yield
47% yield
2.7:2.0:1.0 (4:6:2)
63% yield
6.0 : 1.0 (2:4)
Heterocycles and pharmaceutical scaffolds:
CO2Me
CO2Et
F
O
BocHN
CO2Et
CO2Me
Me
O
OMe
Hex
O
3
1
N
N
CO2Et
OMe
N
CO2Et
CO2Et
N
N
Hex
O
MeO
Me
MeO
3
CO2Et
17a
23% yield
10:1 (3:7)
Tyrosine Derivative (19a)
16a
21% yield
18a
13% Yield
15a
50% yield
3.8:1 (1:3)
Flurbiprofen methyl ester (20a)
28% yield
37% yield
7.2:1 (p:o)
CO2Et
formal C-H methylation via photoredox sequence
CO2Et
O
1.) KOH, dioxane/H2O
BocHN
Me
CO2Et
MeO2C
Fenoprofen
methyl ester (22a)
32% yield
2.) Mes-Acr-BF4 (5 mol%),
DIPEA (0.2 eq.), Ph2S2 (0.2 eq.)
TFE (0.5 M), 465 nm LEDs
Me
Ph
Ph
53% yield
2a
42% yield from biphenyl
Tyrosine Derivative (21a)
CO2Me
17% yield
2:1 para/ortho
Me
Diazo-compound Scope
O
O
Me
Me
Me
Me
Me CO2Me
Me i-Pr
O
O
CO2Bn
CO2tBu
Me
CO2Me
Me
O
O
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
1b
61% yield
1c
44% yield
1d
39% yield
1e
57% yield
1f
19% yield
Menthol Derivative 1g
45% yield
Chart 1: Scope of photoredox-catalyzed C-H alkylation
transformation in poor to good yields, tolerating synthetically
useful cross-coupling functional handles such as aryl
chlorides (6a, 8a), bromides (7a), and tosylates (14a).
Pharmacologically-relevant heterocycles were competent
substrates for the reaction, with 2,6-dimethoxypyridine and
N-methylindazole furnishing the desired adducts, 16a and
17a with high regioselectivity, albeit in reduced yield.
Tyrosine derivatives containing protected amines, acidic C–
H bonds and benzylic hydrogens underwent the desired
transformation selectively, yielding derivatives 19a and 21a
in poor to moderate yield. This method was also applicable
to the selective functionalization of drug-like motifs. Under
the optimized conditions, flurbiprofen methyl ester and
fenoprofen methyl ester furnished the desired products, 20a
and 22a respectively with moderate to good regioselectivity,
despite relatively low chemical yield. Functionalization
ortho- to electron donating groups is observed in most
cases, with para- selectivity favored in the presence of
3
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10.1002/anie.202000684
Angewandte Chemie International Edition
RESEARCH ARTICLE
increased steric hinderance (8-14a). In biaryl systems,
functionalization is favored on the more electron-rich ring
system (4a, 8a). The mass balance for these reactions
typically consists exclusively of returned starting material
and C–H functionalized product.
resulting enolate by the solvent closes the second catalytic
cycle.
To investigate the energetic feasibility of the proposed
mechanism, the reaction between mesitylene and ethyl
diazoacetate was modeled using DFT (B3LYP, 6-31+g(d))
calculations (see SI for complete computational details).
Following oxidation of mesitylene, ethyl diazoacetate
undergoes nucleophilic addition to the arene cation radical
with a transition state energy of +11.7 kcal/mol and an
overall free energy change of +5.9 kcal/mol. The calculated
endergonicity of this process is in agreement with the
Next, the scope of this transformation with respect to the
diazo compound coupling partner was explored. This
reaction proceeded efficiently with simple diazoesters
possessing tert-butyl, benzyl and cyclopentyl diazoacetates,
affording the desired adducts 1e, 1c, and 1d in good to
moderate yields. Cyclic diazodihydrofuranone furnished
product 1b in 61% yield. Less nucleophilic methyl
diazomalonate formed product 1f, albeit with reduced yield.
Following C-H alkylation, the resulting ester products can be
converted into formal C-H methylation adducts via a simple
hydrolysis/decarboxylation sequence, utilizing a photoredox
hydrodecarboxylation method previously developed by our
group.18 The installation of tert-butyl, benzyl-, and malonate
esters are also valuable due to the number of possible
further transformations, which can be used to elaborate
these products. For example, benzyl esters can be cleaved
to the corresponding acid19, tert-butyl esters can be
converted to an acid chloride20 and malonate derivatives
can be used in the malonic ester synthesis to give
substituted acids.21
To probe the mechanism of this transformation, we
conducted a series of experimental and computational
investigations. Based on previous studies on the reaction of
diazoacetate derivatives with alkene cation radicals, we
initially hypothesized that following nucleophilic addition to
the aromatic cation radical, electron transfer from the
reduced form of the catalyst to the generated
cyclohexadienyl radical could trigger a 1,2-hydride shift and
expulsion of N2, leading to the formation of the observed C–
known equilibrium between arene cation radical/nucleophile
23,24
pairs and the corresponding σ-adducts.
Following
single electron transfer from the reduced form of the
catalyst to the σ-adduct, a barrierless loss of N2 and
cyclization forms norcaradiene 9 with an overall free energy
change of -6.5 kcal/mol relative to the starting materials. A
second single electron transfer event generates cation
radical intermediate 8 which then undergoes ring opening to
form a distonic cation radical. This process has a calculated
transition state energy of +5.0 kcal/mol and an overall free
energy change of -0.6 kcal/mol. Following electron transfer
from the reduced catalyst and proton transfer, the desired
C–H alkylation product is formed. The free energy change
for this overall process was calculated to be -50.9 kcal/mol.
Norcaradienes are known to exist as equilibrium
mixtures with the corresponding cycloheptatrienes.25,26 To
further explore the impact of this equilibrium in our system,
the free energy change for the interconversion of these
species was modeled for intermediates 6 and 7 (V, Chart 2).
In the neutral species, the cycloheptatriene form (6) is
favored by 1.8 kcal/mol. However, upon oxidation of this
species, the equilibrium was calculated to favor
norcaradiene cation radical 8 by 4.1 kcal/mol. This suggests
that, under the reaction conditions, the equilibrium between
norcaradiene and cycloheptriene may be driven towards
products via electron transfer.
To support this proposal, we subjected cycloheptatriene
6 to our optimized conditions (VI, Chart 2). Following
irradiation for 18 h, full conversion of 6 to the desired
product 1a was observed. Control experiments indicated
that the presence of Mes-Acr-BF4 is required for conversion.
A mass corresponding to the desired [4+2] adduct (5) was
observed by GC-MS upon the inclusion of maleic anhydride
(1 equiv.) as a Diels-Alder trap under otherwise optimized
conditions, supporting the formation of norcaradiene 9
during the reaction (VI, Chart 2). Diazoacetates bearing aryl
substituents, which are known to form free carbenes upon
irradiation with blue light, gave solely the product resulting
from O-H insertion of trifluoroethanol into the corresponding
carbene. Ethyl diazoacetate, which absorbs at 371 nm with
no overlap at 465 nm (SI 35), shows no formation of these
O-H insertion byproducts. This suggests that under these
reaction conditions a carbene is not formed and instead
ethyl diazoacetate behaves as a polar nucleophile. Control
experiments also indicated that the blue LEDs used for this
reaction are unable to trigger photolysis of ethyl
diazoacetate in a similar manner to aryl diazoacetates. This
is in accordance with other experimental and computational
data in support of the proposed mechanism given above.
In conclusion, we have developed an operationally
simple, metal-free site-selective aromatic C–H alkylation
which utilizes equimolar quantities of coupling partners,
unlike known metallocarbene chemistry which requires
H
functionalization product (IV, Chart 2). Such
a
mechanism would be reminiscent of that proposed for the
cyclopropanation of alkene cation radicals by Ferreira and
coworkers.22 When utilizing d3-Mesitylene as a substrate, no
deuterium incorporation was observed in the C–H alkylation
product, suggesting that a 1,2-hydride shift is an unlikely
step in the mechanism (II, Chart 2). When d1-TFE is used
as the reaction solvent, a mixture of non-deuterated, mono-
deuterated and di-deuterated products is observed with the
mono-deuterated formed as the major product in 72% yield.
The presence of non-deuterated and di-deuterated products
in the presence of the singly labeled product was
rationalized as the result of enolate equilibration. Treatment
of the proteo-product with d1-TFE did not lead to any
observable deuterium incorporation. This is consistent with
a mechanism invoking the protonation of an enolate by the
solvent as part of the mechanism.
Based on this evidence, we propose an alternative
mechanism as follows: following excitation by blue light,
Mes-Acr-BF4* engages in photoinduced electron transfer
(PET) with an arene, producing cation radical 1 and the
reduced form of the catalyst (Mes-Acr·). Polar nucleophilic
addition of ethyl diazoacetate forms distonic cation radical 2,
which is reduced by acridine radical (Mes-Acr·) to form the
intermediate norcaradiene 3 and regenerate ground state
Mes-Acr-BF4. Following a second PET event, intermediate
3 undergoes ring-opening to form distonic benzylic radical
cation 4. Reduction of this intermediate by Mes-Acr·,
deprotonation (presumably by conjugate base of the
solvent) to rearomitize the product, and protonation of the
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202000684
Angewandte Chemie International Edition
RESEARCH ARTICLE
excess arene substrate to achieve efficient reactivity. This
transformation is compatible with a range of aromatic
radicals and subsequent oxidative ring opening. This work
represents both a fundamental insight into the reactivity of
aromatic cation radicals and a valuable approach for the
formation of sp3–sp2 bonds through a C–H functionalization
manifold in the absence of transition metal catalysts.
substrates,
including
those
containing
known
pharmaceutical motifs and cross-coupling handles.
Experimental and computational studies suggest a unique
mechanism involving cyclopropanation of arene cation
I
II
N2
CO2Et
No deuterium incorporation at α-carbon from d3-mesitylene
R
R
Me
Me
H
1
Mes-Acr-BF4
Me
D
D
H
CO2Et
D
(5 mol %)
CO2Et
Me
+
Me
TFE (0.1 M)
18 h, 465 nm LEDs
–e–
+e–
N2
Me
R
N2
CO2R
Me
Me
Me
D
D
CO2R
t-Bu
N
Ph
H
Deuterium is incorporated from d1-TFE
t-Bu
2
Me
R
Me
D
H
Mes-Acr-BF4
(5 mol %)
Mes-Acr
·
Mes-Acr-BF4*
E1/2red* = +2.15 V vs. SCE
Mes-Acr-BF4
H
CO2Et
CO2Et
+
–e– +e–/-N2
hν
d1-TFE (0.1 M)
18 h, 465 nm LEDs
N2
Me
Me
Me
Me
72%
Me
–e– +e–/H+
Mes-Acr-BF4*
No deuterium incorporation from d1-TFE occurs after product formation
CO2R
H
Me
H
+e–
–e–
Me
hν
Me
D
Me
H
Mes-Acr
·
no catalyst
D/H
Me
CO2R
H
D/H
Me
CO2Et
Me
CO2Et
t-Bu
N
t-Bu
Ph
R
BF4
d1-TFE (0.1 M)
18 h, 465 nm LEDs, N2
Me
not observed
4
3
4
R
Mes-Acr-BF4
D/H
D/H
O
O
EtO2C
Me
cycloheptatriene/norcaradiene equilibrium
IV
V
VI
Me
O N2
(1.0 equiv.) (1.0 equiv.)
(5 mol %)
CO2Et
Me
H
H
Gcalc
=
CO2Et
initial mechanistic proposal
H
O
CO2Et
Me
+
1a
- 4.1 kcal/mol
Me
H
5
Mes-Acr-BF4
O
H
Me
Me
Me
(+ isomers)
1:1 MeCN:TFE (0.1 M)
465 nm LEDs, N2
Me
R
R
O
(1.0 equiv.)
Me
Me
Me
Me
detected by GC-MS
7
8
9
[1,2]-shift
Gcalc
+ 1.8 kcal/mol
=
Me
CO2Et
CO2Et
Me
CO2Et
+e–
H
Me
Mes-Acr-BF4 (5 mol%)
CO2Et
–N2
H
RO2C
N2
RO2C
H
1:1 MeCN:TFE (0.1 M)
465 nm LEDs, N2
Me
1a
Me
Me
Me
Me
Me
Me
Me
6
6
93% yield (100% conversion)
Chart 2: Investigation of the mechanism of an organic photoredox C-H alkylation. I: Current mechanistic proposal. II:
Deuterium labeling studies with d3-mesitylene and d1-TFE. III: Reaction energy diagram for an arene cation radical
cyclopropanation. IV: Initial mechanistic proposal involving a 1,2-hydride shift. V: Thermodynamics of the
norcaradiene and cycloheptatriene equilibrium. VI: Evidence for a norcaradiene intermediate.
5
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10.1002/anie.202000684
Angewandte Chemie International Edition
RESEARCH ARTICLE
(16)
(17)
(18)
McManus, J. B.; Nicewicz, D. A. Direct C–H Cyanation of
Arenes via Organic Photoredox Catalysis. J. Am. Chem. Soc.
Acknowledgements
2017,
https://doi.org/10.1021/jacs.6b12708.
139
(8),
2880–2883.
This work was supported by the National Institutes of Health
(NIGMS) Award No. R01 GM120186. 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. The
authors would additionally like to thank the Johnson
laboratory at UNC-Chapel Hill for their generous donation of
several diazo-compounds.
Ciszewski, Ł. W.; Durka, J.; Gryko, D. Photocatalytic
Alkylation of Pyrroles and Indoles with α-Diazo Esters. Org.
Lett.
https://doi.org/10.1021/acs.orglett.9b02612.
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Griffin, J. D.; Zeller, M. A.; Nicewicz, D. A.
Hydrodecarboxylation of Carboxylic and Malonic Acid
Derivatives via Organic Photoredox Catalysis: Substrate Scope
and Mechanistic Insight. J. Am. Chem. Soc. 2015.
https://doi.org/10.1021/jacs.5b07770.
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10.1002/anie.202000684
Angewandte Chemie International Edition
RESEARCH ARTICLE
Me
(5 mol %)
Me
Me
R
t-Bu
N
H
t-Bu
R
Ph
CO2R
BF4
+
R
N2
CO2R
465 nm LEDs
via:
Me
CO2Et
H
CO2Et
■ metal-free
■ arene limiting reagent
■ 28 examples
7
This article is protected by copyright. All rights reserved.