C-H Amination via Electrophotocatalytic Ritter-Type Reaction

Article abstract of DOI:10.1021/jacs.1c03718

A method for C-H bond amination via an electrophotocatalytic Ritter-Type reaction is described. The reaction is catalyzed by a trisaminocyclopropenium (TAC) ion in an electrochemical cell under irradiation. These conditions convert benzylic C-H bonds to acetamides without the use of a stoichiometric chemical oxidant. A range of functionality is shown to be compatible with this transformation, and several complex substrates are demonstrated.

Full text of DOI:10.1021/jacs.1c03718

pubs.acs.org/JACS
Communication
C−H Amination via Electrophotocatalytic Ritter-type Reaction
Tao Shen and Tristan H. Lambert*
Cite This: J. Am. Chem. Soc. 2021, 143, 8597−8602
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A method for C−H bond amination via an electrophotocatalytic Ritter-type reaction is described. The reaction is
catalyzed by a trisaminocyclopropenium (TAC) ion in an electrochemical cell under irradiation. These conditions convert benzylic
C−H bonds to acetamides without the use of a stoichiometric chemical oxidant. A range of functionality is shown to be compatible
with this transformation, and several complex substrates are demonstrated.
he invention of methods to convert unactivated C−H
α-branched, to 3,4-dihydroimidazole products (Figure 1c).
Tbonds to C−N bonds has long been established as a Although these products represent a valuable increase in
desirable goal.1−5 In this regard, the classic Hoffmann−Lofler−
molecular complexity, it would also be desirable to access the
classic Ritter-type monoamination products as well. In this
Communication, we report that unbranched substrates under-
go efficient single site C−H amination under modified
electrophotocatalytic conditions.
̈
Freitag reaction has been a mainstay for complex molecule
synthesis,6−9 while modern incarnations of this strategy have
recently been described using photoredox catalysis.10−12
Alternatively, a variety of reactions involving nitrene
intermediates that can undergo C−H insertion or H atom
abstraction have proven exceptionally useful.13−18 Moreover,
the use of designer transition metal complexes that can effect
C−N couplings of C−H and N−H bonds have become
increasingly popular, and a wide range of impressive
applications of this strategy have been disclosed.1−22 An
orthogonal strategy entails the oxidation of a C−H bond to the
corresponding carbocation, which can then be trapped by a
nitrile, usually as solvent, leading to amide products (Figure
1a). This process is in essence a Ritter reaction,23−26 with the
difference being the means by which the carbocation is
generated. Several catalytic methods for Ritter-type C−H
amination have been reported, including work by Ishii, Baran,
Kiyokawa and Minakata, and Liu and Chen (Figure 1b).27−30
While these are important advances, the oxidants employed are
incompatible with many functional groups and in the case of
Selectfluor are quite expensive. A potentially attractive
alternative would be to use electrochemistry,31−43 which
would obviate the need for the chemical oxidant altogether.
While there have been examples of electrochemical Ritter-type
C−H aminations,44−47 these processes tend to be low-yielding
and incompatible with much native functionality due to the
high anodic potentials required. However, very recently an
electrochemical method for benzylic C−H amination with
sulfonamides was recently reported that proceeded with good
efficiency,48 although it required the use of HFIP solvent and
the range of demonstrated functional group compatibility was
narrow. Thus, there remains the need for an electrochemically
coupled version of this chemistry that has the generality
needed to operate in the context of greater molecular
complexity.
With the goal of developing a method that would be
applicable to a wide variety of substrates, we chose the complex
substrate 2, which is an analogue of the pharmaceutical agent
celecoxib, for our optimization studies (Table 1). Under the
optimal conditions we identified, TAC 1 catalyzed the
conversion of this substrate to acetamide 3 by reaction in a
divided cell (Ecell = 2.2 V, Eanode = 1.6 V vs SCE) under
irradiation from a compact fluorescent light (CFL), in the
presence of TFA, H2O, and n-Bu4NPF6 in acetonitrile solvent
(entry 1). A small amount (4%) of aldehyde 4 was also
observed. Table 1 illustrates the impact of variation from these
conditions. We found that the identity of the electrolyte was
important. Thus, the use of LiClO4 (entry 2) or n-
Bu4NBF4(entry 3) resulted in a significant decrease in yield
of 3 and a small increase in the formation of the side product 4.
Not surprisingly, without the application of the cell potential
(entry 4) or in the absence of the catalyst (entry 5), no
reaction occurred. When only the light was omitted, a small
amount (9%) of background reaction was observed (entry 6).
Changing the acid additive from TFA to AcOH was
detrimental, with the yield dropping to only 10% (entry 7).
Although product was observed without the addition of water
(entry 8), the yield was significantly diminished. Notably, the
use of a divided cell was critical to the success of this process,
as the yield of product in an undivided cell was very low (entry
9). Finally, we also attempted to conduct this reaction via
direct electrolysis, with potentials up to 3.5 V (entries 10 and
Received: April 8, 2021
Published: June 2, 2021
In this regard, we recently reported49 an electrophotocata-
lytic50−62 vicinal C−H diamination reaction that achieved the
conversion of alkylarene substrates, particularly those that were
https://doi.org/10.1021/jacs.1c03718
J. Am. Chem. Soc. 2021, 143, 8597−8602
© 2021 American Chemical Society
8597

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Table 1. Optimization Study for Electrophotocatalytic
a,b
Ritter-type C−H Amination
entry
change from standard
yield 3 (%)
yield 4 (%)
1
2
3
4
none
77
50
27
0
4
8
5
0
LiClO4 instead of n-Bu4NPF6
n-Bu4NBF4 instead of n-Bu4NPF6
no cell potential
5
6
7
8
no catalyst
no light
AcOH instead of TFA
no H2O
undivided cell
direct electrolysis (3.0 V)
direct electrolysis (3.5 V)
Pb as cathode
0
9
trace
trace
trace
trace
4
32
20
trace
10
66
14
36
33
28
9
10
11
12
a
Reaction conditions: 2 (0.5 mmol), H2O (1.0 equiv), 1 (8 mol %),
nBu4NPF6 (1.0 equiv), TFA (0.2 mL), MeCN (6.0 mL) [anode], and
nBu4NPF6 (1.0 equiv), TFA (0.2 mL), MeCN (6.0 mL) [cathode] in
H-type divided cell with carbon felt anode, Pt cathode. Reactions
performed under constant cell potential conditions with irradiation
b
for 48 h at rt under N2. Yields are of isolated and purified products 3
and 4.
formed less efficiently, and the 3-bromo isomer 11 was only
produced in 31% yield. Also, in the latter two cases, a change of
the electrolyte to LiClO4 proved necessary for maximal yield.63
On the other hand, 1-bromo-3,5-dimethylbenzene reacted with
good efficiency to furnish acetamide 12 in 61% yield.
Products resulting from functionalization of alkyl substitu-
ents other than methyl could also be obtained (e.g., 13 and
14), as long as the benzylic position was not branched. In the
case of a branched substrate like cumene, the reaction gave rise
to no acetamide product, but rather the dihydroimidazole
product 15 as we previously described.49 In examining a
substrate designed to probe the competition between methyl
and methylene sites, we found that 16 was formed with a 6.2:1
preference over the alternative methyl-functionalized site.
Meanwhile, diphenylmethane was functionalized in good
yield to furnish the α-diarylamine 17. Cyclic substrates such
as tetralin, indane, and dibenzosuberone participated in the
Ritter-type reaction as well, giving rise to acetamides 18−20,
respectively.
Figure 1. (a) Ritter reaction of carbocation intermediates. (b)
Selected examples of Ritter-type chemistry. (c) Electrophotocatalytic
Ritter-type C−H amination.
In terms of functional group compatibility, we found that an
alcohol (21), carboxylic acid (22), ester (23 and 24), alkyl
chloride (25), and tosylate groups (26) survived the amination
procedure. While a terminal alkyne containing substrate
furnished no product 27, the internal alkyne product 28 was
obtained in 70% yield. Notably, products possessing nitrogen
functionality of various types could be accessed, including
carbazole (29) trifluoroacetamide (30 and 31), pyridine (32),
and even free amine-containing structures (33 and 34).
One of the most useful applications of C−H amination
chemistry is the late-stage functionalization of complex
molecules. For example, White has recently demonstrated
efficient amination reactions on a number of bioactive
11). While some product was generated under these
conditions, the yields were low, the reaction mixtures were
complicated, and a large amount of aldehyde side product 4
was formed. The contrast between the direct electrolysis and
electrophotocatalytic approach underscores the ability of the
latter to effect potent yet selective oxidative chemistry.
With these optimized conditions we explored the scope of
this method (Table 2). Toluene and 4-halogenated toluenes
gave rise to the corresponding benzylacetamides 5−9 in good
yields. Notably, the position of halogenation had a significant
impact on efficiency. Thus, whereas the 4-bromo product 8
was accessed in reasonable yield, the 2-bromo isomer 10 was
8598
https://doi.org/10.1021/jacs.1c03718
J. Am. Chem. Soc. 2021, 143, 8597−8602

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
a
Table 2. Electrophotocatalytic Ritter-type Amination of Benzylic C−H Bonds
a
Reaction conditions: substrate (0.5 mmol), H2O (1.0 equiv), 1 (8 mol %), nBu4NPF6 (1.0 equiv), TFA (0.2 mL), MeCN (6.0 mL) [anode], and
nBu4NPF6 (1.0 equiv), TFA (0.2 mL), MeCN (6.0 mL) [cathode] in H-type divided cell with carbon felt anode, Pt cathode. Reactions performed
b
c
under constant voltage (CV) (2.2 V) conditions with light irradiation for 48 h at rt under N2, isolated yield. LiClO4 instead of nBu4NPF6. 24 h.
d
e
2.6 V. Worked up with 1 M NaOH (aq).
molecules using a trichloroethylsulfoniminoiodinane using
manganese catalysis.13 We decided to see whether some of
these readily available compounds could be aminated using the
electrophotocatalytic method, which has the benefits of using
acetonitrile as the nitrogen source, requires no transition metal
catalyst, and generates more desirable acetamide products
(Table 3). Hence, the sertraline analogue 35 could be
generated in 44% yield, while the retinoic acid receptor
agonist derivative 3664 was produced in 63% yield. Meanwhile,
an isatin derivative was selectively converted to compound 37
in 58% yield. Similarly, compound 38 derived from an
inhibitor of the CYP11B165 was generated in good yield and
with complete selectivity for the position shown. Other
derivatives bearing either imide (39)66 or ketone function-
alities (40 and 41) could also be accessed. Notably, products
42−4467−69 were generated with high efficiency despite the
potential for undesired oxidation of the free amine
functionality. To demonstrate the applicability of this method
to preparative scale synthesis, we found that 41 could be
generated on a 1.5 g scale in 50% yield by extending the
reaction time to 72 h.
A mechanistic rationale for this electrophotocatalytic Ritter-
type reaction is shown in Figure 2. The TAC 1 can be oxidized
to generate the stable radical dication 45 (Ep/2 = 1.12 V in 30:1
MeCN:TFA vs SCE). Irradiation of 45 then leads to the
photoexcited intermediate 46, which engages in single-electron
oxidation of the arene substrate 47 to generate radical cation
48. Deprotonation of this intermediate results in benzylic
radical 49, which then undergoes a second oxidation event,
either by the TAC radical dication 45 or directly at the anode,
leading to carbocation 50. The carbocation then proceeds
through the classic Ritter steps by reaction with acetonitrile
solvent to form nitrilium 51 followed by hydrolysis (either by
reaction with adventitious water or with trifluoroacetic acid) to
furnish the amide product 52. Meanwhile, the redox reaction is
balanced by cathodic reduction of protons to produce
dihydrogen. A key aspect of this approach is that the cell
potential is insufficient to oxidize the substrate directly, leading
8599
https://doi.org/10.1021/jacs.1c03718
J. Am. Chem. Soc. 2021, 143, 8597−8602

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
Table 3. Electrophotocatalytic Ritter-type C−H Amination
a
of Complex Molecules
Figure 2. Mechanistic rationale for electrophotocatalytic Ritter-type
reaction.
stronger acid like triflic acid. Thus, under the current
conditions using TFA, the unbranched substrates furnish
only the monoamination products 52.
a
Reaction conditions: substrate (0.3−0.5 mmol, 1.0 equiv), H2O (1.0
equiv), 1 (8 mol %), nBu4NPF6 (1.0 equiv), TFA (0.2 mL), MeCN
(6.0 mL) [anode], and nBu4NPF6 (1.0 equiv), TFA (0.2 mL), MeCN
(6.0 mL) [cathode] in H-type divided cell with carbon felt anode, Pt
cathode. Reactions performed under constant voltage (CV)
conditions with light irradiation for 48 h at rt under N2, isolated
yield. LiClO4 instead of nBu4NPF6. 72 h reaction time. Run at 2.6
V.
It might be stressed that the risk of overoxidation presents a
significant challenge for C−H amination chemistry, particularly
if the installed nitrogen is not sufficiently deactivated (e.g., by a
tosyl protecting group). We measured the redox potentials of
several of the products shown in Table 2 using cyclic
voltammetry and have found that they are very close to
those of the corresponding starting materials (see Supporting
Information for details). It seems that the introduction of an
acetamide moiety slows the kinetics of single-electron
oxidation by TAC 1, which may be why the electro-
photocatalytic process is more efficient than the direct
electrochemical one. However, we found that prolonged
exposure to the standard reaction conditions (48 h) does
result in some acetamide decomposition (7−30% in the
compounds tested).
The direct amination of C−H bonds via Ritter-type
reactions offers a potentially simple and scalable approach to
molecular upgrading. The current work demonstrates that
electrophotocatalysis can help achieve these transformations
without the need for stoichiometric chemical oxidants and with
enough selectivity to operate with a reasonable range of native
b
c
d
to selective single electron oxidations by the electrophotoca-
talyst, which minimizes the risk of side reactions.
An important distinction should be made between the
monoaminations described in this work and the diaminations
we recently reported under similar conditions.49 Our
hypothesis for the diamination reaction is that initially formed
benzylic acetamides 52 undergo an acid-catalyzed E1
elimination reaction to furnish styrenes 53, which then
undergo further oxidation and Ritter-type trapping reactions
to eventually form one or both of the regiosiomeric
dihydroimidazoles 54a, b. In the case of benzylic-branched
substrates, the elimination reaction is facile with TFA, and thus
monoamination products 52 are not observed. With
unbranched substrates, the elimination reaction requires a
8600
https://doi.org/10.1021/jacs.1c03718
J. Am. Chem. Soc. 2021, 143, 8597−8602

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(13) Clark, J. R.; Feng, K.; Sookezian, A.; White, M. C. Manganese-
catalysed benzylic C(sp3)-H amination for late-stage functionalization.
Nat. Chem. 2018, 10, 583−591.
functionality. As such, this method should be a useful addition
to the C−H functionalization toolbox.
(14) Huang, M.; Yang, T.; Paretsky, J. D.; Berry, J. F.; Schomaker, J.
M. Inverting steric effects: Using “attractive” noncovalent interactions
to direct silver-catalyzed nitrene transfer. J. Am. Chem. Soc. 2017, 139,
17376−17386.
(15) Nasrallah, A.; Boquet, V.; Hecker, A.; Retailleau, P.; Darses, B.;
Dauban, P. Catalytic enantioselective intermolecular benzylic C(sp3)-
H amination. Angew. Chem., Int. Ed. 2019, 58, 8192−8196.
(16) Bess, E. N.; DeLuca, R. J.; Tindall, D. J.; Oderinde, M. S.;
Roizen, J. L.; Du Bois, J.; Sigman, M. S. Analyzing site selectivity in
Rh2(esp)2-catalyzed intermolecular C-H amination reactions. J. Am.
Chem. Soc. 2014, 136, 5783−5789.
(17) Prier, C. K.; Zhang, R. K.; Buller, A. R.; Brinkmann-Chen, S.;
Arnold, F. H. Enantioselective, intermolecular benzylic C-H
amination catalysed by an engineered iron-haem enzyme. Nat.
Chem. 2017, 9, 629−634.
(18) Bakhoda, A.; Jiang, Q.; Bertke, J. A.; Cundari, T. R.; Warren, T.
H. Elusive terminal copper arylnitrene intermediates. Angew. Chem.,
Int. Ed. 2017, 56, 6426−6430.
(19) Collet, F.; Lescot, C.; Dauban, P. Catalytic C-H amination: the
stereoselectivity issue. Chem. Soc. Rev. 2011, 40, 1926−1936.
(20) Ramirez, T. A.; Zhao, B.; Shi, Y. Recent advances in transition
metal-catalyzed sp3 C-H amination adjacent to double bonds and
carbonyl groups. Chem. Soc. Rev. 2012, 41, 931−942.
(21) Collet, F.; Dodd, R. H.; Dauban, P. Catalytic C-H amination:
recent progress and future directions. Chem. Commun. 2009, 5061−
5074.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c03718.
■
sı
Experimental procedures and product characterization
data (PDF)
AUTHOR INFORMATION
Corresponding Author
Tristan H. Lambert − Department of Chemistry and
Chemical Biology, Cornell University, Ithaca, New York
14853, United States; orcid.org/0000-0002-7720-3290;
Email: Tristan.Lambert@Cornell.edu
■
Author
Tao Shen − Department of Chemistry and Chemical Biology,
Cornell University, Ithaca, New York 14853, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c03718
Notes
The authors declare no competing financial interest.
(22) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Recent advances in
the transition metal-catalyzed twofold oxidative C-H bond activation
strategy for C-C and C-N bond formation. Chem. Soc. Rev. 2011, 40,
5068−5083.
(23) Ritter, J. J.; Minieri, P. P. A new reaction of nitriles; amides
from alkenes and mononitriles. J. Am. Chem. Soc. 1948, 70, 4045−
4048.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by NIGMS (R35
GM127135). We would like to thank Prof. Ke-Yin Ye (Fuzhou
University) for the use of instrumentation during the revision
stage of this mansucript.
REFERENCES
(24) Ritter, J. J.; Kalish, J. A new reaction of nitriles; synthesis of t-
carbinamines. J. Am. Chem. Soc. 1948, 70, 4048−4050.
(25) Jiang, D.; He, T.; Ma, L.; Wang, Z. Recent developments in
Ritter reaction. RSC Adv. 2014, 4, 64936−64946.
■
(1) Davies, H. M. L.; Manning, J. R. Catalytic C-H functionalization
by metal carbenoid and nitrenoid insertion. Nature 2008, 451, 417−
424.
(26) Guérinot, A.; Reymond, S.; Cossy, J. Ritter reaction: recent
catalytic developments. Eur. J. Org. Chem. 2012, 2012, 19−28.
(27) Michaudel, Q.; Thevenet, D.; Baran, P. S. Intermolecular
Ritter-type C-H amination of unactivated sp3 carbons. J. Am. Chem.
Soc. 2012, 134, 2547−2550.
(28) Kiyokawa, K.; Takemoto, K.; Minakata, S. Ritter-type
amination of C-H bonds at tertiary carbon centers using iodic acid
as an oxidant. Chem. Commun. 2016, 52, 13082−13085.
(29) Sakaguchi, S.; Hirabayashi, T.; Ishii, Y. First Ritter-type reaction
of alkylbenzenes using N-hydroxyphthalimide as a key catalyst. Chem.
Commun. 2002, 5, 516−517.
(30) Li, G.-X.; Morales-Rivera, C. A.; Gao, F.; Wang, Y.; He, G.; Liu,
P.; Chen, G. A unified photoredox-catalysis strategy for C(sp3)-H
hydroxylation and amidation using hypervalent iodine. Chem. Sci.
2017, 8, 7180−7185.
(31) Milton, R. D.; Minteer, S. D. Nitrogenase bioelectrochemistry
for synthesis applications. Acc. Chem. Res. 2019, 52, 3351−3360.
(32) Shi, S.-H.; Liang, Y.; Jiao, N. Electrochemical oxidation induced
selective C-C bond cleavage. Chem. Rev. 2021, 121, 485−505.
(33) Siu, J. C.; Fu, N.; Lin, S. Catalyzing electrosynthesis: a
homogeneous electrocatalytic approach to reaction discovery. Acc.
Chem. Res. 2020, 53, 547−560.
(2) Park, Y.; Kim, Y.; Chang, S. Transition metal-catalyzed C-H
amination: scope, mechanism, and applications. Chem. Rev. 2017, 117,
9247−9301.
(3) Che, C.-M.; Lo, V. K.-Y.; Zhou, C.-Y.; Huang, J.-S. Selective
functionalization of saturated C-H bonds with metalloporphyrin
catalysts. Chem. Soc. Rev. 2011, 40, 1950−1975.
(4) Roizen, J. L.; Harvey, M. E.; Du Bois, J. Metal-catalyzed
nitrogen-atom transfer methods for the oxidation of aliphatic C-H
bonds. Acc. Chem. Res. 2012, 45, 911−922.
(5) Louillat, M.-L.; Patureau, F. W. Oxidative C-H amination
reactions. Chem. Soc. Rev. 2014, 43, 901−910.
(6) Wolff, M. E. Cyclization of N-halogenated amines (The
̈
Hofmann-Loffler reaction). Chem. Rev. 1963, 63, 55−64.
(7) Stateman, L. M.; Nakafuku, K. M.; Nagib, D. A. Remote C-H
functionalization via selective hydrogen atom transfer. Synthesis 2018,
50, 1569−1586.
(8) Hofmann, A. W. Piperidine and pyridine. Ber. Dtsch. Chem. Ges.
1879, 12, 984−990.
(9) Löffler, K.; Freytag, C. New method for the formation of N-
alkylated pyrrolidines. Ber. Dtsch. Chem. Ges. 1909, 42, 3427−3431.
(10) Wappes, E. A.; Fosu, S. C.; Chopko, T. C.; Nagib, D. A.
Triiodide-mediated delta-amination of secondary C-H bonds. Angew.
Chem., Int. Ed. 2016, 55, 9974−9978.
(34) Jiao, K. J.; Xing, Y. K.; Yang, Q. L.; Qiu, H.; Mei, T. S. Site-
selective C-H functionalization via synergistic use of electrochemistry
and transition metal catalysis. Acc. Chem. Res. 2020, 53, 300−310.
(35) Wang, F.; Stahl, S. S. Electrochemical oxidation of organic
molecules at lower overpotential: accessing broader functional group
compatibility with electron-proton transfer mediators. Acc. Chem. Res.
2020, 53, 561−574.
(11) Martinez, C.; Mun
reaction. Angew. Chem., Int. Ed. 2015, 54, 8287−8291.
(12) Becker, P.; Duhamel, T.; Stein, C. J.; Reiher, M.; Mun
Cooperative light activated iodine and photoredox catalysis for the
amination of Csp3-H bonds. Angew. Chem., Int. Ed. 2017, 56, 8004−
8008.
̃
iz, K. An iodine-catalyzed Hofmann-Loffler
̃
iz, K.
8601
https://doi.org/10.1021/jacs.1c03718
J. Am. Chem. Soc. 2021, 143, 8597−8602

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(36) Kingston, C.; Palkowitz, M. D.; Takahira, Y.; Vantourout, J. C.;
Peters, B. K.; Kawamata, Y.; Baran, P. S. A survival guide for the
“electro-curious. Acc. Chem. Res. 2020, 53, 72−83.
trisaminocyclopropenium radical dication. Angew. Chem., Int. Ed.
2019, 58, 13318−13322.
(60) Huang, H.; Strater, Z. M.; Lambert, T. H. Electrophotocatalytic
C-H functionalization of ethers with high regioselectivity. J. Am.
Chem. Soc. 2020, 142, 1698−1703.
(37) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic organic
electrochemical methods since 2000: On the verge of a renaissance.
Chem. Rev. 2017, 117, 13230−13319.
(61) Kim, H.; Kim, H.; Lambert, T. H.; Lin, S. Reductive
Electrophotocatalysis: Merging Electricity and Light To Achieve
Extreme Reduction Potentials. J. Am. Chem. Soc. 2020, 142, 2087−
2092.
(38) Ackermann, L. Metalla-electrocatalyzed C-H activation by
earth-abundant 3d metals and beyond. Acc. Chem. Res. 2020, 53, 84−
104.
(62) Cowper, N. G. W.; Chernowsky, C. P.; Williams, O. P.;
Wickens, Z. K. Potent Reductants via Electron-Primed Photoredox
Catalysis: Unlocking Aryl Chlorides for Radical Coupling. J. Am.
Chem. Soc. 2020, 142, 2093−2099.
(63) We found that changing the electrolyte to LiClO4 often
increased conversion and reaction rate. In addition, using LiClO4 in
many cases reduced the difficulty of isolating the pure products
because TBAPF6 often has very similar polarity as some of the
products, making them difficult to purify by chromatography.
(64) Lund, B. W.; Piu, F.; Gauthier, N. K.; Eeg, A.; Currier, E.;
Sherbukhin, V.; Brann, M. R.; Hacksell, U.; Olsson, R. Discovery of a
potent, orally available, and isoform-selective retinoic acid β2 receptor
agonist. J. Med. Chem. 2005, 48, 7517−7519.
(65) Hille, U. E.; Zimmer, C.; Vock, C. A.; Hartmann, R. W. First
selective CYP11B1 inhibitors for the treatment of cortisol-dependent
diseases. ACS Med. Chem. Lett. 2011, 2, 2−6.
(66) Alibert, S.; Santelli-Rouvier, C.; Castaing, M.; Berthelot, M.;
Spengler, G.; Molnar, J.; Barbe, J. Effects of a series of
dihydroanthracene derivatives on drug efflux in multidrug resistant
cancer cells. Eur. J. Med. Chem. 2003, 38, 253−263.
(67) Chambers, M. S.; Baker, R.; Billington, D. C.; Knight, A. K.;
Middlemiss, D. N.; Wong, E. H. F. Spiropiperidines as high-affinity,
selective σ ligands. J. Med. Chem. 1992, 35, 2033−2039.
(68) Taylor, C. P.; Traynelis, S. F.; Siffert, J.; Pope, L. E.;
Matsumoto, R. R. Pharmacology of dextromethorphan: relevance to
dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol.
Ther. 2016, 164, 170−182.
(69) Merarchi, M.; Jung, Y. Y.; Fan, L.; Sethi, G.; Ahn, K. S. A brief
overview of the antitumoral actions of leelamine. Biomedicines 2019, 7,
53−65.
(39) Tang, S.; Liu, Y.; Lei, A. Electrochemical oxidative cross-
coupling with hydrogen evolution: a green and sustainable way for
bond formation. Chem. 2018, 4, 27−45.
(40) Sperry, J. B.; Wright, D. L. The application of cathodic
reductions and anodic oxidations in the synthesis of complex
molecules. Chem. Soc. Rev. 2006, 35, 605−621.
(41) Xiong, P.; Xu, H.-C. Chemistry with electrochemically
generated N-centered radicals. Acc. Chem. Res. 2019, 52, 3339−3350.
(42) Jing, Q.; Moeller, K. D. From molecules to molecular surfaces.
exploiting the interplay between organic synthesis and electro-
chemistry. Acc. Chem. Res. 2020, 53, 135−143.
(43) Yoshida, J.; Shimizu, A.; Hayashi, R. Electrogenerated cationic
reactive intermediates: The pool method and further advances. Chem.
Rev. 2018, 118, 4702−4730.
(44) Becker, J. Y.; Byrd, L. R.; Miller, L. L.; So, Y.-H. Remote anodic
substitution of ketones. J. Am. Chem. Soc. 1975, 97, 853−856.
(45) Becker, J. Y.; Byrd, L. R.; Miller, L. L. Remote, anodic
rearrangement-substitution reaction of aliphatic-ketones. J. Am. Chem.
Soc. 1974, 96, 4718−4719.
(46) Becker, J. Y.; Miller, L. L.; Siegel, T. M. Anodic α-cleavage of
ketones. J. Am. Chem. Soc. 1975, 97, 849−853.
(47) Tajima, T.; Ishii, H.; Fuchigami, T. Anodic benzylic
fluorination of toluene, ethylbenzene, and cumene derivatives.
Electrochem. Commun. 2002, 4, 589−592.
(48) Hou, Z.-W.; Liu, D.-J.; Xiong, P.; Lai, X.-L.; Song, J.; Xu, H.-C.
Site-selective electrochemical benzylic C-H amination. Angew. Chem.,
Int. Ed. 2021, 60, 2943−2947.
(49) Shen, T.; Lambert, T. H. Electrophotocatalytic diamination of
vicinal C-H bonds. Science 2021, 371, 620−626.
(50) Moutet, J.-C.; Reverdy, G. Phototochemistry of cation radicals
in solution; photoinduced electron-transfer reactions between
alcohols and the N, N, N’, N’,-tetraphenyl-p-phenylenediamine cation
radical. J. Chem. Soc., Chem. Commun. 1982, 0, 654−655.
(51) Scheffold, R.; Orlinski, R. Carbon-carbon bond formation by
light-assisted B12 catalysis. nucleophilic acylation of Michael olefins. J.
Am. Chem. Soc. 1983, 105, 7200−7202.
(52) Yan, H.; Hou, Z.-W.; Xu, H.-C. Photoelectrochemical C-H
alkylation of heteroarenes with organotrifluoroborates. Angew. Chem.,
Int. Ed. 2019, 58, 4592−4595.
(53) Wang, F.; Stahl, S. S. Merging photochemistry with
electrochemistry: functional-group tolerant electrochemical amination
of C(sp3)-H bonds. Angew. Chem., Int. Ed. 2019, 58, 6385−6390.
(54) Zhang, L.; Liardet, L.; Luo, J.; Ren, D.; Grätzel, M.; Hu, X.
Photoelectrocatalytic arene C-H amination. Nat. Catal. 2019, 2, 366−
373.
(55) Zhang, W.; Carpenter, K.; Lin, S. Electrochemistry broadens
the scope of flavin photocatalysis: photoelectrocatalytic oxidation of
unactivated alcohols. Angew. Chem., Int. Ed. 2020, 59, 409−417.
(56) Niu, L.; Jiang, C.; Liang, Y.; Liu, D.; Bu, F.; Shi, R.; Chen, H.;
Chowdhury, A. D.; Lei, A. Manganese-catalyzed oxidative azidation of
C(sp3)-H bonds under electrophotocatalytic conditions. J. Am. Chem.
Soc. 2020, 142, 17693−17702.
(57) Liu, J.; Lu, L.; Wood, D.; Lin, S. New redox strategies in
organic synthesis by means of electrochemistry and photochemistry.
ACS Cent. Sci. 2020, 6, 1317−1340.
(58) Yu, Y.; Guo, P.; Zhong, J.-S.; Yuan, Y.; Ye, K.-Y. Merging
photochemistry with electrochemistry in organic synthesis. Org. Chem.
Front. 2020, 7, 131−135.
(59) Huang, H.; Strater, Z. M.; Rauch, M.; Shee, J.; Sisto, T. J.;
Nuckolls, C.; Lambert, T. H. Electrophotocatalysis with a
8602
https://doi.org/10.1021/jacs.1c03718
J. Am. Chem. Soc. 2021, 143, 8597−8602