Decarboxylative C-H alkylation of heteroarene N-oxides by visible light/copper catalysis

Article abstract of DOI:10.1021/acs.orglett.0c03382

This paper reports a highly site-selective alkylation of heteroarene N-oxides using hypervalent iodine(III) carboxylates to serve as an alkylating agent in the presence of a cheap copper catalyst under visible light conditions. This mild method proceeds at room temperature in an air atmosphere and can withstand various heteroarene N-oxides as well as various primary, secondary, and tertiary alkyl carboxylic acids. It also provides a practical method for enabling the rapid conversion of commercially available raw materials into medically relevant “drug-like” molecules.

Full text of DOI:10.1021/acs.orglett.0c03382

pubs.acs.org/OrgLett
Letter
Decarboxylative C−H Alkylation of Heteroarene N‑Oxides by Visible
Light/Copper Catalysis
Duan-Yang Liu, Xu Liu, Yan Gao, Chao-Qun Wang, Jie-Sheng Tian,* and Teck-Peng Loh*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03382
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: This paper reports a highly site-selective alkylation of
heteroarene N-oxides using hypervalent iodine(III) carboxylates to serve
as an alkylating agent in the presence of a cheap copper catalyst under
visible light conditions. This mild method proceeds at room temperature
in an air atmosphere and can withstand various heteroarene N-oxides as
well as various primary, secondary, and tertiary alkyl carboxylic acids. It
also provides a practical method for enabling the rapid conversion of
commercially available raw materials into medically relevant “drug-like”
molecules.
eteroarene N-oxides has become privileged pharmaco-
H
phores in medicinal chemistry,1 important substrates
and intermediates in synthetic chemistry,2 and useful oxidants
in some reactions3 due to their unique electronic arrangement.
In addition, reduction of heteroarene N-oxides can afford N-
heterocycles, both of which are important frameworks in drugs
(Figure 1), especially those with heteroaryl aliphatic
Figure 1. Heteroaryl aliphatic functionality in commercial medicinal
agents.
functionality. As a result, for the alkylation of N-heterocycles4
among these reported methods, the use of cheap, abundant
carboxylic acids as the starting materials was very attractive for
the C−H bond alkylation reaction. Decarboxylative coupling
of heterocycles using classical Minisci reactions has been
reported by the Minisci group5 and others6 (Figure 2a).
However, the reaction with unoxidized N-heterocycles is
difficult to control site-selectively, giving byproducts with
multiple-site couplings. Wherefore, seeking a new alternative so
that such a reaction produces only a single product has been
especially important, and heteroarene N-oxides have been
demonstrated to be efficient substrates (Figure 2b). In the past
reports, several methods for the synthesis of single-site
alkylated pyridine N-oxide included metal catalysis or photo-
catalysis.7 However, harsh catalytic conditions and the use of
highly toxic, unstable, difficult-to-obtain alkylating reagents
limit the applications of these reactions. Wishing to develop a
more attractive synthesis to realize highly site-selective C−H
Figure 2. Strategy for the alkylation of heteroaromatics.
alkylation of N-heterocycles and their N-oxides using abundant
and inexpensive alkylating agents for the acquisition of high-
value drugs, we were very interested in using hypervalent
iodine(III) carboxylates as alkylating agents. This hypervalent
iodine(III) carboxylate was easily prepared from carboxylic
acid and had been developed into effective reagents for
decarboxylative coupling under visible light photocatalysis or
transition metal catalysis due to its strong electrophilicity, low
Received: October 9, 2020
https://dx.doi.org/10.1021/acs.orglett.0c03382
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
toxicity, and oxidizing activity.8 Furthermore, the byproducts
of carboxylic acid and iodobenzene can be recycled after the
decarboxylation coupling.9 Here, we achieved the ortho
alkylation of heteroarene N-oxides by employing hypervalent
iodine(III) carboxylates under copper photocatalysis (Figure
2c). Although the system using a copper complex as a
photocatalyst under visible light is still in its infancy, the
copper complex has great potential in photocatalysis because it
is cheap and abundant on the Earth. Compared to ruthenium
or iridium photocatalysts, copper photocatalysts not only have
economic advantages but also play a unique role in promoting
the transfer of electrons to organic substrates.10 In this work,
we report a highly site-selective C−H functionalization using a
copper complex in addition as a photocatalyst.
directly increased to 77% (entry 8). Finally, other 1,10-
phenanthroline ligands, such as 1,10-phenanthroline L2, 4,7-
dimethoxy-1,10-phenanthroline L3, and 2,9-dimethyl-4,7-
diphenyl-1,10-phenanthroline L4, were also explored for this
transformation, but no further increase in the yield of 3a was
achieved (entries 9−11, respectively). Control experiments in
the absence of ligand or visible light were also conducted, and
no coupling product could be obtained (entry 12 or 13,
respectively). It is noteworthy that this reaction requires only
16 W white light instead of blue light that may irritate eyes and
can also react in the air.
After optimizing the reaction conditions for our decarbox-
ylative C−H alkylation of heteroarene N-oxides, we next
expanded the scope of the hypervalent iodine(III) carbox-
ylates. As shown in Scheme 1, a variety of primary, secondary,
To optimize this reaction, we chose hypervalent iodine(III)
cyclohexanoate 1a and quinoline N-oxide 2a as the model
substrates. At the beginning of the study, we used metal-free
a
Scheme 1. Scope of Hypervalent Iodine(III) Carboxylates
photocatalyst (Acr-Mes)+ClO4 or Eosin Y (Table 1, entry 1
−
a
Table 1. Optimization of the Reaction Conditions
yield (%)
ligand
(equiv)
b
c
c
entry
catalyst (equiv)
3a
3a′
3a″
1
2
3
4
5
6
7
8
(Acr-Mes)+CIO4− (0.1)
Eosin Y (0.1)
Cu(OAc)2 (0.1)
CuBr2 (0.1)
CuBr (0.1)
CuCI (0.1)
CuI (0.1)
CuCI (0.2)
CuCI (0.2)
CuCI (0.2)
CuCI (0.2)
CuCI (0.2)
CuCI (0.2)
−
−
41
30
40
trace
45
12
6
0
0
0
0
0
0
0
0
0
0
0
5
trace
0
L1 (0.15)
L1 (0.15)
L1 (0.15)
L1 (0.15)
L1 (0.15)
L1 (0.3)
L2 (0.3)
L3 (0.3)
L4 (0.3)
−
0
0
0
0
0
0
0
0
55
0
d
77 (81)
a
9
45
40
64
trace
0
The reactions were carried out using 2a (0.2 mmol, 1.0 equiv), 1
10
11
12
(0.3 mmol, 1.5 equiv), CuCl (0.2 equiv), BPhen (0.3 equiv), and
DCM (2.0 mL) under white light-emitting diodes for 12 h at rt.
Isolated yields based on quinoline N-oxides 2a.
0
0
e
13
L1 (0.3)
a
and tertiary alkyl decarboxylative couplings with quinoline N-
oxide 2a were successful. Hypervalent iodine(III) 1a−c with
the decarboxylative centers in six- and five-membered rings can
furnish the desired products 3a−c in good yields of 77%, 75%,
and 63%, respectively. Even with more strained cyclobutyl and
cyclopropyl hypervalent iodine(III) carboxylates 1d and 1e,
the coupling products 3d and 3e, respectively, could be
obtained in good to moderate yields. Furthermore, general
secondary alkyl hypervalent iodine(III) carboxylate 1f gave
target product 3f in excellent yield. The primary alkyl
hypervalent iodine(III) carboxylates 1g−j were also found to
be suitable for the reaction, affording the corresponding
products 3g−j, respectively, in good to excellent yields, and
these mild reaction conditions displayed good compatibility
with sensitive groups, such as amino, alkenyl, and alkynyl
groups. Interestingly, this transformation can also provide an
enantiopure amino acid derivative 3k by employing aspartic
Reaction conditions: hypervalent iodine(III) cyclohexanoate 1a (0.3
mmol, 1.5 equiv), quinoline N-oxide 2a (0.2 mmol), catalyst, ligand in
DCM (2.0 mL) under white light-emitting diodes for 12 h at rt.
b
c
d
e
Isolated yields. GC yields. N2 atmosphere. No light.
or 2, respectively), and the product 2-cyclohexylquinoline 1-
oxide 3a can be obtained in a yield of 41% or 30%,
respectively. At the same time, two byproducts, 3a′ and 3a″,
were detected by GC-MS (entry 3). Then we examined copper
salts under the same conditions, and the results showed that
divalent copper CuBr2 provided only a trace of the product
(entry 4); in contrast, product 3a can be obtained in a yield of
45% by using monovalent copper CuBr (entry 5). When CuBr
was replaced by CuCl, the yield of 3a increased to 55% (entry
6). For CuI, no desired product was generated (entry 7). As
the catalytic amount of CuCl was increased to 20% and that of
the ligand BPhen was changed to 30%, the yield of 3a was
B
https://dx.doi.org/10.1021/acs.orglett.0c03382
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
acid-derived hypervalent iodine(III) 1k as the starting material.
Finally, the sterically hindered tertiary alkyl hypervalent
iodine(III) carboxylate 1l can be transformed into the
decarboxylative coupling product 3l in a yield of 38%.
Scheme 3. Diversification of N-Heteroarene Drugs
Next, the scope of heteroarene N-oxides was explored by
using the hypervalent iodine(III) carboxylate 1a as the model
substrate under the standard conditions (Scheme 2). A
a
Scheme 2. Scope of Heteroarene N-Oxides
plausible mechanism for copper/photocatalytic decarboxyla-
tion coupling is proposed as presented in Figure 3. First, under
a
The reactions were carried out using 1a (0.3 mmol, 1.5 equiv), 2
(0.2 mmol, 1.0 equiv), CuCl (0.2 equiv), BPhen (0.3 equiv), and
DCM (2.0 mL). Isolated yields based on heteroarene N-oxides.
diversity of quinoline N-oxides were proven to be suitable
for this transformation, affording the corresponding products
4a−d in good to excellent yields. To our delight, many other
heteroarene N-oxides, such as quinoxaline N-oxide 2e,
phenanthridine N-oxide 2f, and bipyridine N-oxide 2g, reacted
well and gave good yields. Furthermore, we observed that
pyridine N-oxides with a phenyl or cyano group at position C-2
or C-3 were also appropriate substrates, affording the desired
products 4h−k in moderate to good yields. When pyridine N-
oxide with an ester group at position C-4 was used for this
reaction, alkylation product 4l was obtained in a yield of 18%.
To further explore the practicality of this method for
synthesizing complex molecules and modifying drug molecules,
we conducted the following experiments (Scheme 3). First, we
used hydroxy-protected quinine N-oxide 2n to investigate the
ability of this method to alkylate N-heteroarene drugs. When
hypervalent iodine(III) cyclohexanoate 1a was used as the
alkylation reagent, a 58% yield of coupling product 5a could be
obtained and the sensitive group was not affected (Scheme 3a).
Next, we tried to make the hypervalent iodine(III) containing
drug molecule 1m through decarboxylation as an alkylating
reagent by this strategy. Luckily, we successfully decarboxy-
lated dehydrocholic acid and coupled it with quinoline N-oxide
2a to give the desired product 5b in 45% yield (Scheme 3b).
Finally, a more complicated system with multiple active centers
was attempted by the decarboxylation of a drug containing
carboxylic acid and coupling with N-heteroarene drugs.
Gratifyingly, decarboxylation of dehydrocholic acid and
coupling with hydroxy-protected quinine N-oxide provided
the target product 5c in a yield of 35% (Scheme 3c).
Figure 3. Proposed mechanism for visible light/copper-catalyzed
decarboxylation coupling.
visible light irradiation, copper complex LnCuIX enters the
photoexcited [LnCuIX]* A, which reduces hypervalent iodine-
(III) carboxylate 1 leading to an alkyl radical (R•)8b,c,9a and
LnCuIIX(O2CR) B12g,i through a single-electron transfer (SET)
process. Then position C-2 of heteroarene N-oxide 2a
preferentially undergoes metallization to generate copper(II)
species C.12j Next, the R radical is captured to provide
copper(III) active species D. Finally, after reductive elimi-
nation, coupling product 3 is obtained and copper(I) complex
LnCuIX is liberated. In addition, a TEMPO trapping
experiment supported this radical process (see the Supporting
Information for details).
On the basis of relevant reports,11,12 including photocatalysis
by a copper complex with a bidentate nitrogen ligand12a,f and
our experimental results (Table 1, entries 8, 12, and 13), a
In summary, we have developed a new and practical method
for the decarboxylation coupling reaction using copper as a
photocatalyst in place of a noble metal photocatalyst, wherein
C
https://dx.doi.org/10.1021/acs.orglett.0c03382
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
the hypervalent iodine(III) carboxylate serves as an alkylating
agent. The reaction was suitable for primary, secondary, and
tertiary alkyl carboxylic acids and was compatible with sensitive
functional groups, such as alkenyl and alkynyl groups. In
addition, various heteroarene N-oxides, including quinoline,
phenanthridine, quinoxaline, bipyridine, and pyridine, were
suitable for this reaction, affording the desired product in
moderate to excellent yield with high site selectivity. Notably,
this method allows coupling of a carboxyl-containing drug
molecule to a nitrogen-containing heteroarene drug molecule.
It provides a viable solution to the late-stage functionalization
of drugs and is expected to provide easy access to new
multifunctional drugs.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge Northwestern Polytech-
nical University, the Fundamental Research Funds for the
Central Universities, the Natural Science Foundation of
Jiangsu Province (BK20171463), the grant of MOE-Tier 1
[M4012045.110 RG12/18-(S)], the students’ project of
Nanjing Tech University for innovation and entrepreneurship
training program (2020DC0397), Nanjing Tech University,
and Nanyang Technological University for the generous
financial support.
REFERENCES
■
(1) (a) Balzarini, J.; Stevens, M.; Andrei, G.; Snoeck, R.; Strunk, R.;
Pierce, J. B.; Lacadie, J. A.; De Clercq, E.; Pannecouque, C. Pyridine
Oxide Derivatives: Structure-Activity Relationship for Inhibition of
Human Immunodeficiency Virus and Cytomegalovirus Replication in
Cell Culture. Helv. Chim. Acta 2002, 85, 2961−2974. (b) Stevens, M.;
Pannecouque, C.; De Clercq, E.; Balzarini, J. Inhibition of Human
Immunodeficiency Virus by a New Class of Pyridine Oxide
Derivatives. Antimicrob. Agents Chemother. 2003, 47, 2951−2957.
(c) Hwang, J.-T.; Greenberg, M. M.; Fuchs, T.; Gates, K. S. Reaction
of the Hypoxia-Selective Antitumor Agent Tirapazamine with a C1’-
Radical in Single-Stranded and Double-Stranded DNA: The Drug and
its Metabolites Can Serve as Surrogates for Molecular Oxygen in
Radical-Mediated DNA Damage Reactions. Biochemistry 1999, 38,
14248−14255. (d) Dowers, T. S.; Rock, D. A.; Rock, D. A.; Perkins,
B. N. S.; Jones, J. P. An Analysis of the Regioselectivity of Aromatic
Hydroxylation and N-Oxygenation by Cytochrome P450 Enzymes.
Drug Metab. Dispos. 2004, 32, 328−332. (e) Balzarini, J.; Stevens, M.;
De Clercq, E.; Schols, D.; Pannecouque, C. Pyridine N-Oxide
Derivatives: Unusual Anti-HIV Compounds with Multiple Mecha-
nisms of Antiviral Action. J. Antimicrob. Chemother. 2005, 55, 135−
138. (f) Andreev, V. P.; Korvacheva, E. G.; Nizhnik, Y. P. Effect of
Pyridine and Quinoline N-Oxides on Microsomal Na,K-Atpase
Activity. Pharm. Chem. J. 2006, 40, 347−348.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03382.
Synthetic procedures, mechanistic studies, and NMR
data (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
Jie-Sheng Tian − Institute of Advanced Synthesis (IAS),
Northwestern Polytechnical University (NPU), Xi’an 710072,
China; Yangtze River Delta Research Institute of Northwestern
Polytechnical University, Taicang, Jiangsu 215400, China;
Institute of Advanced Synthesis (IAS), Nanjing Tech University
(NanjingTech), Nanjing 211816, P. R. China;
Email: ias_jstian@njtech.edu.cn
Teck-Peng Loh − Institute of Advanced Synthesis (IAS),
Northwestern Polytechnical University (NPU), Xi’an 710072,
China; Yangtze River Delta Research Institute of Northwestern
Polytechnical University, Taicang, Jiangsu 215400, China;
Institute of Advanced Synthesis (IAS), Nanjing Tech University
(NanjingTech), Nanjing 211816, P. R. China; Division of
Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University,
Singapore 637371; orcid.org/0000-0002-2936-337X;
Email: teckpeng@ntu.edu.sg
(2) (a) Eberbach, W.; Maier, W. Heterocyclic Synthesis by
Electrocyclization of Extended Dipoles: A Novel Access to the
Indolizine and Quinolizine Systems. Tetrahedron Lett. 1989, 30,
́
́
5591−5594. (b) Alcazar, J.; Alonso, J. M.; Bartolome, J. M.; Iturrino,
L.; Matesanz, E. Synthesis of Novel 3-Substituted-2,3-Dihydro-1,4-
Dioxino[2,3-B]Pyridines as Potential New Scaffolds for Drug
Discovery: Selective Introduction of Substituents on the Pyridine
Ring. Tetrahedron Lett. 2003, 44, 8983−8986. (c) Kanyiva, K. S.;
Nakao, Y.; Hiyama, T. Nickel-Catalyzed Addition of Pyridine-N-
oxides across Alkynes. Angew. Chem., Int. Ed. 2007, 46, 8872−8874.
(d) Campeau, L.-C.; Stuart, D. R.; Leclerc, J.-P.; Bertrand-Laperle,
M.; Villemure, E.; Sun, H.-Y.; Lasserre, S.; Guimond, N.; Lecavallier,
M.; Fagnou, K. Palladium-Catalyzed Direct Arylation of Azine and
Azole N-Oxides: Reaction Development, Scope and Applications in
Synthesis. J. Am. Chem. Soc. 2009, 131, 3291−3306. (e) Londregan,
A. T.; Jennings, S.; Wei, L. General and Mild Preparation of 2-
Aminopyridines. Org. Lett. 2010, 12, 5254−5257. (f) Wu, Z.; Song,
H.; Cui, X.; Pi, C.; Du, W.; Wu, Y. Sulfonylation of Quinoline N-
Oxides with Aryl Sulfonyl Chlorides via Copper-Catalyzed C-H
Bonds Activation. Org. Lett. 2013, 15, 1270−1273. (g) Zhu, C.; Yi,
M.; Wei, D.; Chen, X.; Wu, Y.; Cui, X. Copper-Catalyzed Direct
Amination of Quinoline N-Oxides via C-H Bond Activation under
Mild Conditions. Org. Lett. 2014, 16, 1840−1843.
Authors
Duan-Yang Liu − Institute of Advanced Synthesis (IAS),
Nanjing Tech University (NanjingTech), Nanjing 211816, P.
R. China
Xu Liu − Institute of Advanced Synthesis (IAS), Nanjing Tech
University (NanjingTech), Nanjing 211816, P. R. China
Yan Gao − Institute of Advanced Synthesis (IAS), Northwestern
Polytechnical University (NPU), Xi’an 710072, China; Yangtze
River Delta Research Institute of Northwestern Polytechnical
University, Taicang, Jiangsu 215400, China
Chao-Qun Wang − Institute of Advanced Synthesis (IAS),
Nanjing Tech University (NanjingTech), Nanjing 211816, P.
R. China
́
(3) (a) Barluenga, J.; Bernad, P. L., Jr; Concellon, J. Total
Diastereoselective Synthesis of Chromium Cyelopropylcarbene
Complexes. Tetrahedron Lett. 1995, 36, 3937−3940. (b) Ye, L.;
Cui, L.; Zhang, G.; Zhang, L. Alkynes as Equivalents of α-Diazo
Ketones in Generating α-Oxo Metal Carbenes: A Gold-Catalyzed
Expedient Synthesis of Dihydrofuran-3-ones. J. Am. Chem. Soc. 2010,
132, 3258−3259. (c) Zheng, Z.; Yu, Z.; Luo, N.; Han, X.
Tautomerism-Dependent Ring Construction of N-Heterocyclic
Compounds from the Reactions of 1-Alkynyl Fischer Carbene
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03382
Notes
The authors declare no competing financial interest.
D
https://dx.doi.org/10.1021/acs.orglett.0c03382
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Complexes and Substituted Pyrazolinones. J. Org. Chem. 2006, 71,
9695−9700. (d) Luo, Y.; Zhang, G.; Hwang, E. S.; Wilcoxon, T. A.;
Zhang, L. Gold-Catalyzed Regioselective Oxidation of Terminal
Allenes: Formation of α-Methanesulfonyloxy Methyl Ketones.
Beilstein J. Org. Chem. 2011, 7, 596−600.
Dai, J.-J.; Xu, J.; Xu, H.-J. Visible-Light-Induced C2 Alkylation of
Pyridine N-Oxides. J. Org. Chem. 2017, 82, 2059−2066. (e) Zhou,
W.; Miura, T.; Murakami, M. Photocatalyzed ortho-Alkylation of
Pyridine N-Oxides through Alkene Cleavage. Angew. Chem., Int. Ed.
2018, 57, 5139−5142; Angew. Chem. 2018, 130, 5233−5236.
(8) (a) Sakamoto, R.; Kashiwagi, H.; Maruoka, K. The Direct C-H
Difluoromethylation of Heteroarenes Based on the Photolysis of
Hypervalent Iodine(III) Reagents that Contain Difluoroacetoxy
Ligands. Org. Lett. 2017, 19, 5126−5129. (b) Yang, B.; Yu, D.; Xu,
X.-H.; Qing, F.-L. Visible-Light Photoredox Decarboxylation of
Perfluoroarene Iodine(III) Trifluoroacetates for C-H Trifluorome-
thylation of (Hetero)arenes. ACS Catal. 2018, 8, 2839−2843. (c) He,
Z.; Bae, M.; Wu, J.; Jamison, T. F. Synthesis of Highly Functionalized
Polycyclic Quinoxaline Derivatives Using Visible-Light Photoredox
Catalysis. Angew. Chem., Int. Ed. 2014, 53, 14451−14455; Angew.
Chem. 2014, 126, 14679−14683. (d) Budhwan, R.; Yadav, S.;
Murarka, S. Late Stage Functionalization of Heterocycles Using
Hypervalent Iodine(iii) Reagents. Org. Biomol. Chem. 2019, 17,
6326−6341.
(9) (a) Liang, Y.; Zhang, X.; MacMillan, D. W. C. Decarboxylative
Sp3 C−N Coupling via Dual Copper and Photoredox Catalysis.
Nature 2018, 559, 83−88. (b) Watanabe, A.; Miyamoto, K.; Okada,
T.; Asawa, T.; Uchiyama, M. Safer Synthesis of (Diacetoxyiodo)-
arenes Using Sodium Hypochlorite Pentahydrate. J. Org. Chem. 2018,
83, 14262−14268.
(10) (a) Wang, C.; Guo, M.; Qi, R.; Shang, Q.; Liu, Q.; Wang, S.;
Zhao, L.; Wang, R.; Xu, Z. Visible-Light-Driven, Copper-Catalyzed
Decarboxylative C(sp3)-H Alkylation of Glycine and Peptides. Angew.
Chem., Int. Ed. 2018, 57, 15841−15846; Angew. Chem. 2018, 130,
16067−16072. (b) Zhao, W.; Wurz, R. P.; Peters, J. C.; Fu, G. C.
Photoinduced, Copper-Catalyzed Decarboxylative C-N Coupling to
Generate Protected Amines: An Alternative to the Curtius Rearrange-
ment. J. Am. Chem. Soc. 2017, 139, 12153−12156. (c) Paria, S.;
Reiser, O. Copper in Photocatalysis. ChemCatChem 2014, 6, 2477−
2483. (d) Lyu, X.-L.; Huang, S.-S.; Song, H.-J.; Liu, Y.-X.; Wang, Q.-
M. Visible-Light-Induced Copper-Catalyzed Decarboxylative Cou-
pling of Redox-Active Esters with N-Heteroarenes. Org. Lett. 2019,
21, 5728−5732.
(11) (a) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S.
L.; Peters, J. C.; Fu, G. C. Asymmetric Copper-Catalyzed C-N Cross-
Couplings Induced by Visible Light. Science 2016, 351, 681−684.
(b) Do, H.-Q.; Bachman, S.; Bissember, A. C.; Peters, J. C.; Fu, G. C.
Photoinduced, Copper-Catalyzed Alkylation of Amides with Un-
activated Secondary Alkyl Halides at Room Temperature. J. Am.
Chem. Soc. 2014, 136, 2162−2167. (c) Bissember, A. C.; Lundgren, R.
J.; Creutz, S. E.; Peters, J. C.; Fu, G. C. Transition-Metal-Catalyzed
Alkylations of Amines with Alkyl Halides: Photoinduced, Copper-
Catalyzed Couplings of Carbazoles. Angew. Chem., Int. Ed. 2013, 52,
5129−5133; Angew. Chem. 2013, 125, 5233−5237.
(12) (a) Rabet, P. T. G.; Fumagalli, G.; Boyd, S.; Greaney, M. F.
Benzylic C-H Azidation Using the Zhdankin Reagent and a Copper
Photoredox Catalyst. Org. Lett. 2016, 18, 1646−1649. (b) Minozzi,
C.; Caron, A.; Grenier-Petel, J.-C.; Santandrea, J.; Collins, S. K.
Heteroleptic Copper(I)-Based Complexes for Photocatalysis: Combi-
natorial Assembly, Discovery, and Optimization. Angew. Chem., Int.
Ed. 2018, 57, 5477−5481; Angew. Chem. 2018, 130, 5575−5579.
(c) Armaroli, N.; Accorsi, G.; Cardinali, F.; Listorti, A. Photo-
chemistry and Photophysics of Coordination Compounds: Copper.
Top Curr. Chem. 2007, 280, 69−115. (d) Kern, J.-M.; Sauvage, J.-P.
Photoassisted C-C Coupling via Electron Transfer to Benzylic Halides
by a Bis(di-imine) Copper(i) Complex. J. Chem. Soc., Chem. Commun.
1987, 546−548. (e) McMillin, D. R.; Kirchhoff, J. R.; Goodwin, K. V.
Exciplex Quenching of Photo-Excited Copper Complexes. Coord.
Chem. Rev. 1985, 64, 83−92. (f) Bagal, D. B.; Kachkovskyi, G.; Knorn,
M.; Rawner, T.; Bhanage, B. M.; Reiser, O. Trifluoromethylchlor-
osulfonylation of Alkenes: Evidence for an Inner-Sphere Mechanism
by a Copper Phenanthroline Photoredox Catalyst. Angew. Chem., Int.
Ed. 2015, 54, 6999−7002; Angew. Chem. 2015, 127, 7105−7108.
(g) Pirtsch, M.; Paria, S.; Matsuno, T.; Isobe, H.; Reiser, O.
(4) (a) Tian, W.-F.; Hu, C.-H.; He, K.-H.; He, X.-Y.; Li, Y. Visible-
Light Photoredox-Catalyzed Decarboxylative Alkylation of Hetero-
arenes Using Carboxylic Acids with Hydrogen Release. Org. Lett.
2019, 21, 6930−6935. (b) Evano, G.; Theunissen, C. Beyond Friedel
and Crafts: Innate Alkylation of C-H Bonds in Arenes. Angew. Chem.,
Int. Ed. 2019, 58, 7558−7598; Angew. Chem. 2019, 131, 7638−7680.
(c) Liu, L.; Pan, N.; Sheng, W.; Su, L.; Liu, L.; Dong, J.; Zhou, Y.; Yin,
S.-F. Visible Light-Induced Regioselective Decarboxylative Alkylation
of the C(sp2)−H Bonds of Non-Aromatic Heterocycles. Adv. Synth.
Catal. 2019, 361, 4126−4132. (d) Buquoi, J. Q.; Lear, J. M.; Gu, X.;
Nagib, D. A. Heteroarene Phosphinylalkylation via a Catalytic,
Polarity-Reversing Radical Cascade. ACS Catal. 2019, 9, 5330−5335.
(e) Ji, J.-J.; Zhu, Z.-Q.; Xiao, L.-J.; Guo, D.; Zhu, X.; Tang, J.; Wu, J.;
Xie, Z.-B.; Le, Z.-G. Photocatalyst-free Decarboxylative Amino-
alkylation of Imidazo[1,2-a]pyridines with N-Aryl Glycines Enabled
by Visible Light. Org. Chem. Front. 2019, 6, 3693−3697. (f) Zhao, H.;
Xu, X.; Yu, H.; Li, B.; Xu, X.; Li, H.; Xu, L.; Fan, Q.; Walsh, P. J.
Rh(I)-Catalyzed C6-Selective Decarbonylative Alkylation of 2-
Pyridones with Alkyl Carboxylic Acids and Anhydrides. Org. Lett.
2020, 22, 4228−4234. (g) Pitre, S. P.; Muuronen, M.; Fishman, D. A.;
Overman, L. E. Tertiary Alcohols as Radical Precursors for the
Introduction of Tertiary Substituents into Heteroarenes. ACS Catal.
2019, 9, 3413−3418.
(5) (a) Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo,
M. Nucleophilic Character of Alkyl RadicalsVI: A New Convenient
Selective Alkylation of Heteroaromatic Bases. Tetrahedron 1971, 27,
3575−3579. (b) Minisci, F.; Vismara, E.; Fontana, F.; Claudia
Nogueira Barbosa, M. A New General Method of Homolytic
Alkylation of Protonated Heteroaromatic Bases by Carboxylic Acids
and Iodosobenzene Diacetate. Tetrahedron Lett. 1989, 30, 4569−
4572.
(6) (a) Dong, J.; Wang, Z.; Wang, X.; Song, H.; Liu, Y.; Wang, Q.
Metal-, Photocatalyst-, and Light-Free Minisci C−H Alkylation of N-
Heteroarenes with Oxalates. J. Org. Chem. 2019, 84, 7532−7540.
(b) Sutherland, D. R.; Veguillas, M.; Oates, C. L.; Lee, A.-L. Metal-,
Photocatalyst-, and Light-Free, Late-Stage C−H Alkylation of
Heteroarenes and 1,4-Quinones Using Carboxylic Acids. Org. Lett.
2018, 20, 6863−6867. (c) Hong, G.; Yuan, J.; Fu, J.; Pan, G.; Wang,
Z.; Yang, L.; Xiao, Y.; Mao, P.; Zhang, X. Transition-metal-free
Decarboxylative C3-Difluoroarylmethylation of Quinoxalin-2(1H)-
ones with α,α-Difluoroarylacetic Acids. Org. Chem. Front. 2019, 6,
1173−1182. (d) Proctor, R. S. J.; Phipps, R. J. Recent Advances in
Minisci-Type Reactions. Angew. Chem., Int. Ed. 2019, 58, 13666−
13699; Angew. Chem. 2019, 131, 13802−13837. (e) Zhang, X.-Y.;
Weng, W.-Z.; Liang, H.; Yang, H.; Zhang, B. Visible-Light-Initiated,
Photocatalyst-Free Decarboxylative Coupling of Carboxylic Acids
with N-Heterocycles. Org. Lett. 2018, 20, 4686−4690. (f) Garza-
Sanchez, R. A.; Tlahuext-Aca, A.; Tavakoli, G.; Glorius, F. Visible
Light-Mediated Direct Decarboxylative C-H Functionalization of
Heteroarenes. ACS Catal. 2017, 7, 4057−4061. (g) Li, D.; Liang, C.;
Jiang, Z.; Zhang, J.; Zhuo, W.-T.; Zou, F.-Y.; Wang, W.-P.; Gao, G.-L.;
Song, J. Visible-Light-Promoted C2 Selective Arylation of Quinoline
and Pyridine N-Oxides with Diaryliodonium Tetrafluoroborate. J. Org.
Chem. 2020, 85, 2733−2742.
(7) (a) Deng, G.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li, C.-J.
Coupling of Nitrogen Heteroaromatics and Alkanes without
Transition Metals: A New Oxidative Cross-Coupling at C-H/C-H
Bonds. Chem. - Eur. J. 2009, 15, 333−337. (b) Wu, Z.; Pi, C.; Cui, X.;
Bai, J.; Wu, Y. Direct C-2 Alkylation of Quinoline N-Oxides with
Ethers via Palladium-Catalyzed Dehydrogenative Cross-Coupling
Reaction. Adv. Synth. Catal. 2013, 355, 1971−1976. (c) Xiao, B.;
Liu, Z.-J.; Liu, L.; Fu, Y. Palladium-Catalyzed C-H Activation/Cross-
Coupling of Pyridine N-Oxides with Nonactivated Secondary Alkyl
Bromides. J. Am. Chem. Soc. 2013, 135, 616−619. (d) Zhang, W.-M.;
E
https://dx.doi.org/10.1021/acs.orglett.0c03382
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
[Cu(dap)2Cl] As an Efficient Visible-Light-Driven Photoredox
Catalyst in Carbon−Carbon Bond-Forming Reactions. Chem. - Eur.
J. 2012, 18, 7336−7340. (h) Baralle, A.; Fensterbank, L.; Goddard, J.-
P.; Ollivier, C. Aryl Radical Formation by Copper(I) Photocatalyzed
Reduction of Diaryliodonium Salts: NMR Evidence for a CuII/CuI
Mechanism. Chem. - Eur. J. 2013, 19, 10809−10813. (i) Xiao, P.;
́
Dumur, F.; Zhang, J.; Fouassier, J. P.; Gigmes, D.; Lalevee, J. Copper
Complexes in Radical Photoinitiating Systems: Applications to Free
Radical and Cationic Polymerization upon Visible LEDs. Macro-
molecules 2014, 47, 3837−3844. (j) Kianmehr, E.; Gholamhosseyni,
M. Visible-Light-Promoted Copper-Catalyzed Regioselective Benzy-
lation of Pyridine N-Oxides versus Thermal Acylation Reaction with
Toluene Derivatives. Eur. J. Org. Chem. 2018, 13, 1559−1566.
F
https://dx.doi.org/10.1021/acs.orglett.0c03382
Org. Lett. XXXX, XXX, XXX−XXX