Visible-Light-Triggered Iodinations Facilitated by Weak Electrostatic Interaction of N-Heterocyclic Carbenes

Article abstract of DOI:10.1021/acs.orglett.0c02523

N-heterocyclic carbenes (NHCs) are well-known as ligands and organocatalysts, but there is no recognition for their catalytic role as a stabilizer through electrostatic interaction rather than electron donation. By utilizing the electrostatic interaction, we herein describe the success of a visible-light-triggered radical-radical cross-coupling of N-alkenoxypyridinium salts and NaI, giving a variety of α-iodo ketones. Computational studies characterize the stabilization role of NHCs.

Full text of DOI:10.1021/acs.orglett.0c02523

pubs.acs.org/OrgLett
Letter
Visible-Light-Triggered Iodinations Facilitated by Weak Electrostatic
Interaction of N‑Heterocyclic Carbenes
He Sheng, Qiang Liu, Xiao-Di Su, Yu Lu, Zhi-Xiang Wang,* and Xiang-Yu Chen*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02523
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: N-heterocyclic carbenes (NHCs) are well-known as
ligands and organocatalysts, but there is no recognition for their
catalytic role as a stabilizer through electrostatic interaction rather
than electron donation. By utilizing the electrostatic interaction, we
herein describe the success of a visible-light-triggered radical−radical
cross-coupling of N-alkenoxypyridinium salts and NaI, giving a
variety of α-iodo ketones. Computational studies characterize the stabilization role of NHCs.
s ligands and organocatalysts, N-heterocyclic carbenes
(NHCs) serve a prominent role in developing novel
addition, the generated iodine radical could be stabilized by the
NHC,14 which may benefit the subsequent radical−radical
coupling.
A
catalytic processes.1 Recently, there has been emerging interest
in harnessing the synergistic interplay of NHCs2 and
photochemistry3 to discover new activation modes that offer
more efficient and selective alternatives to orthodox
approaches. In 2012, Rovis and co-workers first reported the
photoredox/NHC dual-catalyzed α-acylation of tertiary amines
with aldehydes.4 Very recently, significant progress has been
achieved in the field of cooperative NHC catalysis and light
activation by the research groups of Sun,5 Ye,6 Hopkinson,7
Scheidt,8 and Studer.9 All these strategies were based on the
formation of NHC-derived intermediates,10 which can directly
react with partners under the excitation of light (Scheme 1A).
As such, these approaches often require judiciously choosing
the carbonyl compounds to generate the NHC-derived
intermediates and the corresponding reaction partners, which
could be an impediment to the reaction generality. Addition-
ally, expensive metal-based photocatalysts or harmful UV-light
were generally required for these transformations. In this
context, the discovery of new applications of NHCs with the
excitation of visible light which allows flexible and various
substitution patterns is of great value and highly desirable.
The interaction between Lewis bases and alkali metal cations
plays an important role in organic synthesis, catalysis, and
medicinal chemistry.11 In 2017, Krieck and Westerhausen and
co-workers established that the electrostatic interaction of
NHC and NaI enabled the construction of new architectures
(Scheme 1B).12 In this study, we drew inspiration from the
photochemistry of an electron donor−acceptor (EDA)
complex,13 which serves as an alternative and complementary
approach to photoredox catalysis to avoid using expensive
metal complexes and organic dyes. As shown in Scheme 1C,
we hypothesized that the NHC-stabilized NaI can form an
EDA complex with an electron acceptor, which could be
activated by visible light to undergo single electron transfer
(SET), generating an alkyl radical and iodine radical. In
Iodine compounds have versatile applications in various
synthetically important bond formations, synthesis of drugs,
contrastors, and radioactively labeled markers.15 In 2015, Li
and co-workers developed an elegant UV-light-induced
approach to aryl iodides via the radical coupling of sodium
iodide.16 Recently, Fu and Shang reported a novel PPh3/NaI
mediated photocatalytic decarboxylative alkylation via PPh3−I•
species, in which the cation−π interaction of PPh3 and Na+
was crucial for the EDA complex formation. Intriguingly, no
iodination product was observed in their system.17
With this knowledge, a mixture of N-alkenoxypyridinium
salt18 and NaI in MeCN was irradiated with blue LEDs (λ =
455 nm) at room temperature. The iodination product 2 was
obtained in 51% yield, while no reaction was observed in the
absence of light (Scheme 2A), indicating the formation of an
EDA complex between 1 and NaI. Encouraged by this
promising result, we envisioned that our hypothesis could be
devised to improve the efficiency of the iodinations, and we
were pleased to find that the desired product 2 was obtained in
85% yield in the presence of precatalyst A. A catalyst screening
showed that other precatalysts B−D and PPh3 gave poorer
yields. The reaction outcome was further improved to 92%
yield by using LiNTf2 as an ion exchange additive to increase
the solubility of NHC salt (Scheme 2B). Unfortunately, further
optimization of the catalyst loading (10 mol %) gave a
decreased 65% yield. To understand this radical−radical
Received: July 29, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02523
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
Scheme 1. Motivation and Synthetic Strategy
Scheme 2. Optimization of the Reaction Conditions
coupling process, we turned to characterize the EDA complex
and the role of the NHC. While neither N-alkenoxypyridinium
salt 1 nor NaI showed significant UV/vis absorption in the
visible region of the spectra, an obvious red shift of absorption
was observed in the spectrum of the reaction mixture 1 and
NaI, supporting the formation of an EDA complex (Scheme
2C, left). The addition of NHC A further enhanced the red
shift of absorption, thus facilitating the EDA complex
formation. The plausible mechanism shown in Scheme 2C
(right) would possibly explain the role of NHC. Irradiation of
EDA complex of 1 and NaI generates the alkyl radical, iodine
radical, and 2,6-lutidine. The following radical−radical
coupling gives the iodination product. Concomitantly, the
NHC is formed via deprotonation of the corresponding
azolium salt by the in situ generation of 2,6-lutidine. The
electrostatic interaction of NHC···NaI would facilitate the
formation of the EDA complex. In addition, the 2c−3e
interaction of NHC could stabilize the generated iodine
radical, thus improving the efficiency of the iodinations.
With the optimized conditions in hand, we subsequently
examined the generality of the method (Scheme 3). We
successfully converted a range of unfunctional alkenoxy-
pyridiniums into the corresponding α-iodo ketones, with
acyclic and cyclic alkyl groups being tolerated (2−8). The
substrates with various functional groups, such as ether (9),
esters (10−12), amide (13), dimethyl malonate (14), chlorine
(15 and 16), and sulfonyl (17) groups, also proceeded well
without an apparent change in the yield. This was also true for
the alkenyl substituents but gave a somewhat decreased yield
(18 and 19). In addition, the di-iodination product 20 was
successfully prepared in 50% yield by using a substrate bearing
the OTs group. This was also true for the substrates bearing
aryl groups, providing the products 21−24 in 42−69% yield.
To further gain insight into the reaction mechanism, we
performed density functional theory (DFT) and time-depend-
ent DFT (TDDFT) calculations (see Supporting Information
(SI) section 5 for computational details), using truncated
NHC and alkenoxypyridinium (namely, NHC and 1a+,
respectively).19 According to the computational results, Figure
1A illustrates our proposed catalytic cycle. On the ground state
(S0), 1a+, NaI, and NHC first form a ternary EDA complex
gIM. Note that the bond distances of Na−I (3.08 Å) and
(NHC)C−Na (2.48 Å) in gIM are close to those (3.03 and
2.50 Å, respectively) in the crystal structure of the NHC−
NaI−THF system (Scheme 1B). The N−O bond cleavage in
gIM requires a barrier of 34.7 kcal/mol (Figure S1 in the SI
section 5). The high barrier rationalizes why the reaction could
not take place in the absence of blue light irradiation (supra
infra).
B
https://dx.doi.org/10.1021/acs.orglett.0c02523
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 3. Scope of the Reaction
Figure 1. Computational results (A−D). Key bond lengths in C are
given in angstroms and NBO charges in e. Binding energies in D are
given in kcal/mol, and absorption wavelengths, in nm.
a
Yield of isolated products 2−24 after chromatography.
resultant two radicals combine, affording the α-iodo ketone
product.
The HOMO and LUMO of gIM are dominated by an
iodine lone pair and a π* orbital of 1a+, respectively (Figure
1B). The LUMO features somewhat antibonding character on
the N−O bond, thus a transition of an electron to LUMO
would favor the cleavage of the bond to generate radicals.
TDDFT calculation indicated that the vertical excitation of an
electron from HOMO to LUMO results in the first excited
state (S1) costs 72.6 kcal/mol (394.4 nm). Relaxing the
structure of gIM in the S1 state gave the photoactivated EDA
complex gIM*. The next process is to cleave the N−O bond in
gIM*, which presumably proceeds via a transition state but
attempts to locate the transition state in the S1 state were
unsuccessful. Nevertheless, a potential energy surface (PES)
scan with the N−O bond as the reaction coordinate
demonstrates that gIM* is only a very shallow minimum in
the S1 state (Table S1 in SI section 5). Thus, under light
irradiation, the N−O bond can be broken facilely, leading to a
weakly bonded diradical (DIRA) and releasing lutidine.
Subsequently, the diradical dissociates, giving the C2H5C(O)-
Although gIM* is only a shallow minima in the S1 state, the
location of the excited EDA complex facilitates the character-
ization of the photoactivation process. When the NBO charge
populations of gIM and gIM* are compared in Figure 1C, the
excitation increases the charge on iodine from −0.96 to
−0.14e, while it decreases the total charge on the lutidine
fragment from 0.99 to 0.04e. The charge variations indicate
that the photoactivation promotes SET from iodide to the
lutidine moiety of 1a+. Compared to gIM, because the electron
redistribution weakens the Coulomb attraction between Na+
and I− and the Coulomb repulsion between Na+ and the 1a+
moiety, the Na−I bond is elongated from 3.08 to 3.40 Å and
the Na−O bond is shortened from 2.69 to 2.37 Å. In line with
our expectation (supra infra), the N−O bond is indeed
elongated from 1.37 to 1.44 Å, which favors the cleavage of the
bond. The charges on NHC and the carbenic carbon remain
nearly unchanged, indicating no significant electron donation
between them.
CH2 radical and a radical ion NHC-NaI•+ which then
It is interesting that NHC A significantly outperforms other
Lewis bases. After understanding the model system, we next
considered real systems. Individual reactants (NaI, NHC A-D,
•
−
interacts with NTf2 to give an NHC-stabilized iodine radical
(NHC-I•) via 2c−3e bonding and NaNTf2. Finally, the
C
https://dx.doi.org/10.1021/acs.orglett.0c02523
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
PPh3, and 1) are all inactive to blue light with absorption
wavelengths (<300 nm), but the EDA complexes shown in
Figure 1C have significantly increased the absorption wave-
length (>380.0 nm). The calculated wavelengths are in
reasonable agreement with the wavelength (455 nm) of the
blue light we used, considering the accuracy of the TDDFT
method which we estimated probably to have an error bar of
50 nm.20 In addition, the increased wavelengths are consistent
with the observed red shift shown in Scheme 2C. As compared
in Figure 1D, the Lewis bases only affect the wavelengths
slightly but the stabilities of the EDA complexes substantially.
In the absence of an NHC, coordination of two acetonitrile
solvent molecules to sodium is optimal for the formation of the
complexes. In the presence of an NHC, the complex with
NHC A is more stable than others with NHCs B−D, which
could be a reason for the inferiority of these NHCs.
advantages of NHC A over PPh3 could be the causes why
NHC A outperforms PPh3 in our reaction.
In summary, we have developed a photocatalytic cross-
coupling of N-alkenoxypyridinium salts and sodium iodide to
afford various α-iodo ketones. Our DFT studies characterize
that the electrostatic interaction of NHC−Na+ facilitates the
formation of the EDA complex. In addition, NHC also
stabilizes the generated iodine radical via 2c−3e bonding. We
anticipate that the presented synthetic method could be
applied in the pharmaceutical and organic chemistry arenas.
The unveiling of the method of NHC in stabilizing EDA
complexes and the mechanistic understanding of the photo-
activation process could enrich the photochemistry of EDA
complexes and inspire the new development of visible light-
induced radical reactions.
ASSOCIATED CONTENT
* Supporting Information
Compared to NHC A, PPh3 forms a less stable EDA
complex (ΔG = 4.3 versus −3.2 kcal/mol of NHC A). Figure 2
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02523.
Experimental details, DFT calculations, characterization
data, and spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Zhi-Xiang Wang − School of Chemical Sciences, University of
the Chinese Academy of Sciences, Beijing 100049, China;
orcid.org/0000-0001-5815-3032; Email: zxwang@
ucas.ac.cn
Xiang-Yu Chen − School of Chemical Sciences, University of the
Chinese Academy of Sciences, Beijing 100049, China;
orcid.org/0000-0002-0383-0910; Email: chenxiangyu20@
ucas.ac.cn
Authors
He Sheng − School of Chemical Sciences, University of the
Chinese Academy of Sciences, Beijing 100049, China
Qiang Liu − School of Chemical Sciences, University of the
Chinese Academy of Sciences, Beijing 100049, China
Xiao-Di Su − School of Chemical Sciences, University of the
Chinese Academy of Sciences, Beijing 100049, China
Yu Lu − School of Chemical Sciences, University of the Chinese
Academy of Sciences, Beijing 100049, China
Figure 2. (A) Electrostatic potential maps of NHC A (left) and PPh3
(right). Red areas represent negative electrostatic potential to attract
underneath positive Na+. (B) EDA complexes of NHC A and PPh3
with NaI. (C) Complexes of NHC A and PPh3 with NaI. In (B) and
(C), key bond lengths in black are given in angstroms and the NBO
charges in red are given in e. Binding energies (ΔG) are relative to
their separate components.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02523
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
compares the structures of the EDA complexes of NHC A and
PPh3. In the former, NHC A forms an “umbrella” to optimally
interact with Na+ via electrostatic interaction, which is not the
case for the EDA complexes of PPh3, as well as those of NHC
B−D, emphasizing the importance of the geometrical unique-
ness of NHC A. We further compared the binding energies of
NHC A and PPh3 with NaI. The large binding energy (−5.3
kcal/mol) of NHC A validates the stabilization effect of NHCs
on NaI salt via electrostatic interaction. PPh3 even has a
positive binding energy (1.5 kcal/mol) with NaI. In addition,
NHC A is stronger than PPh3 in stabilizing the iodine radical
■
This paper is dedicated to the memory of Prof. Dieter Enders.
Supported by the University of the Chinese Academy of
Sciences, National Natural Science Foundation of China (No.
21773240).
REFERENCES
■
(1) (a) Enders, D.; Niemeier, O.; Henseler, A. Organocatalysis by N-
Heterocyclic Carbenes. Chem. Rev. 2007, 107, 5606−5655. (b) Bode,
J. W. Carbene Catalysis: An Internal Affair. Nat. Chem. 2013, 5, 813−
815. (c) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. An
Overview of N-Heterocyclic Carbenes. Nature 2014, 510, 485−496.
̇
̇
(PPh3 + A−I → PPh3−I + A + 4.1 kcal/mol). These
D
https://dx.doi.org/10.1021/acs.orglett.0c02523
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(d) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis, T.
Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes.
Chem. Rev. 2015, 115, 9307−9387. (e) Reyes, E.; Uria, U.; Carrillo,
L.; Vicario, J. L. Enantioselective Cascade Reactions under N-
Heterocyclic Carbene Catalysis. Synthesis 2017, 49, 451−471.
(f) Zhang, C.; Hooper, J. F.; Lupton, D. W. N-Heterocyclic Carbene
Catalysis via the α,β-Unsaturated Acyl Azolium. ACS Catal. 2017, 7,
2583−2596. (g) Murauski, K. J. R.; Jaworski, A. A.; Scheidt, K. A. A
continuing challenge: N-heterocyclic carbene-catalyzed syntheses of γ-
butyrolactones. Chem. Soc. Rev. 2018, 47, 1773−1782. (h) Chen, X.-
Y.; Liu, Q.; Chauhan, P.; Enders, D. N-Heterocyclic Carbene
Catalysis via Azolium Dienolates: An Efficient Strategy for Remote
Enantioselective Functionalizations. Angew. Chem., Int. Ed. 2018, 57,
3862−3873. (i) Mondal, S.; Yetra, S. R.; Mukherjee, S.; Biju, A. T.
NHC-Catalyzed Generation of α,β-Unsaturated Acylazoliums for the
Enantioselective Synthesis of Heterocycles and Carbocycles. Acc.
Chem. Res. 2019, 52, 425−436. (j) Chen, X.-Y.; Gao, Z.-H.; Ye, S.
Bifunctional N-Heterocyclic Carbenes Derived from l-Pyroglutamic
Acid and Their Applications in Enantioselective Organocatalysis. Acc.
Chem. Res. 2020, 53, 690−702.
(2) (a) Guin, J.; De Sarkar, S.; Grimme, S.; Studer, A. Biomimetic
Carbene-Catalyzed Oxidations of Aldehydes Using TEMPO. Angew.
Chem., Int. Ed. 2008, 47, 8727−8730. (b) Du, Y.; Wang, Y.; Li, X.;
Shao, Y.; Li, G.; Webster, R. D.; Chi, Y. R. N-Heterocyclic Carbene
Organocatalytic Reductive β,β-Coupling Reactions of Nitroalkenes via
Radical Intermediates. Org. Lett. 2014, 16, 5678−5681. (c) White, N.
A.; Rovis, T. Enantioselective N-Heterocyclic Carbene-Catalyzed β-
Hydroxylation of Enals Using Nitroarenes: An Atom Transfer
Reaction That Proceeds via Single Electron Transfer. J. Am. Chem.
Soc. 2014, 136, 14674−14677. (d) White, N. A.; Rovis, T. Oxidatively
Initiated NHC-Catalyzed Enantioselective Synthesis of 3,4-Disub-
stituted Cyclopentanones from Enals. J. Am. Chem. Soc. 2015, 137,
10112−10115. (e) Zhang, Y.; Du, Y.; Huang, Z.; Xu, J.; Wu, X.;
Wang, Y.; Wang, M.; Yang, S.; Webster, R. D.; Chi, Y. R. N-
Heterocyclic Carbene-Catalyzed Radical Reactions for Highly
Enantioselective β-Hydroxylation of Enals. J. Am. Chem. Soc. 2015,
137, 2416−2419. (f) Chen, X.-Y.; Chen, K.-Q.; Sun, D.-Q.; Ye, S. N-
Heterocyclic carbene-catalyzed oxidative [3 + 2] annulation of
dioxindoles and enals: cross coupling of homoenolate and enolate.
Chem. Sci. 2017, 8, 1936−1941. (g) Wu, X.; Zhang, Y.; Wang, Y.; Ke,
J.; Jeret, M.; Reddi, R. N.; Yang, S.; Song, B.-A.; Chi, Y. R. Polyhalides
as Efficient and Mild Oxidants for Oxidative Carbene Organocatalysis
by Radical Processes. Angew. Chem., Int. Ed. 2017, 56, 2942−2946.
(h) Zhao, K.; Enders, D. Merging N-Heterocyclic Carbene Catalysis
and Single Electron Transfer: A New Strategy for Asymmetric
Transformations. Angew. Chem., Int. Ed. 2017, 56, 3754−3756.
(i) Ishii, T.; Ota, K.; Nagao, K.; Ohmiya, H. N-Heterocyclic Carbene-
Catalyzed Radical Relay Enabling Vicinal Alkylacylation of Alkenes. J.
Am. Chem. Soc. 2019, 141, 14073−14077. (j) Ishii, T.; Kakeno, Y.;
Nagao, K.; Ohmiya, H. N-Heterocyclic Carbene-Catalyzed Decar-
boxylative Alkylation of Aldehydes. J. Am. Chem. Soc. 2019, 141,
3854−3858. (k) Song, R.; Chi, Y. R. N-Heterocyclic Carbene
Catalyzed Radical Coupling of Aldehydes with Redox-Active Esters.
Angew. Chem., Int. Ed. 2019, 58, 8628−8630. (l) Regnier, V.; Romero,
E. A.; Molton, F.; Jazzar, R.; Bertrand, G.; Martin, D. What Are the
Radical Intermediates in Oxidative N-Heterocyclic Carbene Organo-
catalysis? J. Am. Chem. Soc. 2019, 141, 1109−1117. (m) Kim, I.; Im,
H.; Lee, H.; Hong, S. N-Heterocyclic carbene-catalyzed deaminative
cross-coupling of aldehydes with Katritzky pyridinium salts. Chem. Sci.
2020, 11, 3192−3197. (n) Ohmiya, H.; Kakeno, Y. N-Heterocyclic
Carbene-Based Catalysis Enabling Cross-Coupling Reactions. ACS
Catal. 2020, 10, 6862−6869. (o) Kakeno, Y.; Kusakabe, M.; Nagao,
K.; Ohmiya, H. Direct Synthesis of Dialkyl Ketones from Aliphatic
Aldehydes through Radical N-Heterocyclic Carbene Catalysis. ACS
Catal. 2020, 10, 8524−8529. (p) Chen, K.-Q.; Sheng, H.; Liu, Q.;
Shao, P.-L.; Chen, X.-Y. N-Heterocyclic Carbene-Catalyzed Radical
Reactions. Sci. China: Chem. 2020.
2, 527−532. (b) Narayanam, J. M. R.; Stephenson, C. R. J. Visible
light photoredox catalysis: applications in organic synthesis. Chem.
Soc. Rev. 2011, 40, 102−113. (c) Prier, C. K.; Rankic, D. A.;
MacMillan, D. W. C. Visible Light Photoredox Catalysis with
Transition Metal Complexes: Applications in Organic Synthesis.
Chem. Rev. 2013, 113, 5322−5363. (d) Twilton, J.; Le, C.; Zhang, P.;
Shaw, M. H.; Evans, R. W.; MacMillan, D. W. C. The merger of
transition metal and photocatalysis. Nat. Rev. Chem. 2017, 1, 0052.
(e) Brenninger, C.; Jolliffe, J. D.; Bach, T. Chromophore Activation of
α,β-Unsaturated Carbonyl Compounds and Its Application to
Enantioselective Photochemical Reactions. Angew. Chem., Int. Ed.
2018, 57, 14338−14349. (f) Silvi, M.; Melchiorre, P. Enhancing the
potential of enantioselective organocatalysis with light. Nature 2018,
̈
554, 41−49. (g) Zou, Y.-Q.; Hormann, F. M.; Bach, T. Iminium and
enamine catalysis in enantioselective photochemical reactions. Chem.
Soc. Rev. 2018, 47, 278−290. (h) Chen, Y.; Lu, L.-Q.; Yu, D.-G.; Zhu,
C.-J.; Xiao, W.-J. Visible light-driven organic photochemical synthesis
in China. Sci. China: Chem. 2019, 62, 24−57. (i) Kancherla, R.;
Muralirajan, K.; Sagadevan, A.; Rueping, M. Visible Light-Induced
Excited-State Transition-Metal Catalysis. Trends Chem. 2019, 1, 510−
523. (j) McAtee, R. C.; McClain, E. J.; Stephenson, C. R. J.
Illuminating Photoredox Catalysis. Trends Chem. 2019, 1, 111−125.
(k) Wei, Y.; Zhou, Q.-Q.; Tan, F.; Lu, L.-Q.; Xiao, W.-J. Visible-Light-
Driven Organic Photochemical Reactions in the Absence of External
Photocatalysts. Synthesis 2019, 51, 3021−3054. (l) Zhou, Q.-Q.; Zou,
Y.-Q.; Lu, L.-Q.; Xiao, W.-J. Visible-Light-Induced Organic Photo-
chemical Reactions through Energy-Transfer Pathways. Angew. Chem.,
Int. Ed. 2019, 58, 1586−1604.
(4) DiRocco, D. A.; Rovis, T. Catalytic Asymmetric α-Acylation of
Tertiary Amines Mediated by a Dual Catalysis Mode: N-Heterocyclic
Carbene and Photoredox Catalysis. J. Am. Chem. Soc. 2012, 134,
8094−8097.
(5) Yang, W.; Hu, W.; Dong, X.; Li, X.; Sun, J. N-Heterocyclic
Carbene Catalyzed γ-Dihalomethylenation of Enals by Single-Electron
Transfer. Angew. Chem., Int. Ed. 2016, 55, 15783−15786.
(6) (a) Dai, L.; Xia, Z.-H.; Gao, Y.-Y.; Gao, Z.-H.; Ye, S. Visible-
Light-Driven N-Heterocyclic Carbene Catalyzed γ- and ϵ-Alkylation
with Alkyl Radicals. Angew. Chem., Int. Ed. 2019, 58, 18124−18130.
(b) Gao, Z.-H.; Xia, Z.-H.; Dai, L.; Ye, S. N-Heterocyclic Carbene
Catalyzed Photooxidation: Intramolecular Cross Dehydrogenative
Coupling of Tetrahydroisoquinoline-Tethered Aldehydes. Adv. Synth.
Catal. 2020, 362, 1819−1824. (c) Xia, Z.-H.; Dai, L.; Gao, Z.-H.; Ye,
S. N-Heterocyclic carbene/photo-cocatalyzed oxidative Smiles
rearrangement: synthesis of aryl salicylates from O-aryl salicylalde-
hydes. Chem. Commun. 2020, 56, 1525−1528. (d) Dai, L.; Ye, S.
Photo/N-Heterocyclic Carbene Co-catalyzed Ring Opening and γ-
Alkylation of Cyclopropane Enal. Org. Lett. 2020, 22, 986−990.
(7) Mavroskoufis, A.; Rajes, K.; Golz, P.; Agrawal, A.; Ruß, V.;
̈
Gotze, J. P.; Hopkinson, M. N. N-Heterocyclic Carbene Catalyzed
Photoenolization/Diels−Alder Reaction of Acid Fluorides. Angew.
Chem., Int. Ed. 2020, 59, 3190−3194.
(8) Davies, A. V.; Fitzpatrick, K. P.; Betori, R. C.; Scheidt, K. A.
Combined Photoredox and Carbene Catalysis for the Synthesis of
Ketones from Carboxylic Acids. Angew. Chem., Int. Ed. 2020, 59,
9143−9148.
̈
(9) Meng, Q.-Y.; Doben, N.; Studer, A. Cooperative NHC and
Photoredox Catalysis for the Synthesis of β-Trifluoromethylated Alkyl
Aryl Ketones. Angew. Chem., Int. Ed. 2020, DOI: 10.1002/
anie.202008040.
(10) (a) Liu, Q.; Chen, X.-Y. Dual N-heterocyclic carbene/
photocatalysis: a new strategy for radical processes. Org. Chem.
Front. 2020, 7, 2082−2087. (b) Mavroskoufis, A.; Jakob, M.;
Hopkinson, M. N. Light-Promoted Organocatalysis with N-Hetero-
cyclic Carbenes. ChemPhotoChem. 2020, DOI: 10.1002/
cptc.202000120. (c) Liu, J.; Xing, X.-N.; Huang, J.-H.; Lu, L.-Q.;
Xiao, W.-J. Light Opens a New Window for N-Heterocyclic Carbene
Catalysis. Chem. Sci. 2020, DOI: 10.1039/D0SC03595E.
(3) (a) Yoon, T. P.; Ischay, M. A.; Du, J. Visible light photocatalysis
as a greener approach to photochemical synthesis. Nat. Chem. 2010,
(11) (a) Poonia, N. S.; Bajaj, A. V. Coordination chemistry of alkali
and alkaline earth cations. Chem. Rev. 1979, 79, 389−445.
E
https://dx.doi.org/10.1021/acs.orglett.0c02523
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
(b) Savelyev, A.; Papoian, G. A. Electrostatic, Steric, and Hydration
Interactions Favor Na+ Condensation around DNA Compared with
K+. J. Am. Chem. Soc. 2006, 128, 14506−14518. (c) Daniele, P. G.;
Foti, C.; Gianguzza, A.; Prenesti, E.; Sammartano, S. Weak alkali and
alkaline earth metal complexes of low molecular weight ligands in
aqueous solution. Coord. Chem. Rev. 2008, 252, 1093−1107.
Heteroaryl Ketones. J. Org. Chem. 2018, 83, 10051−10059.
(g) Mathi, G. R.; Jeong, Y.; Moon, Y.; Hong, S. Photochemical
Carbopyridylation of Alkenes Using N-Alkenoxypyridinium Salts as
Bifunctional Reagents. Angew. Chem., Int. Ed. 2020, 59, 2049−2054.
(h) Liu, Q.; Zhang, C.-S.; Sheng, H.; Enders, D.; Wang, Z.-X.; Chen,
X.-Y. Site-Selective Pyridyl Alkyl Ketone Synthesis from N-
Alkenoxypyridiniums through Boekelheide-Type Rearrangements.
Org. Lett. 2020, 22, 5617−5621.
̈
(12) Koch, A.; Gorls, H.; Krieck, S.; Westerhausen, M. Coordination
behavior of bidentate bis(carbenes) at alkali metal bis(trimethylsilyl)-
amides. Dalton. Trans. 2017, 46, 9058−9067.
(13) (a) Lima, C. G. S.; de M. Lima, T.; Duarte, M.; Jurberg, I. D.;
(19) For selected examples of computational investigations of NHC
catalysis, see: (a) Zheng, L.; Wang, Y.; Wei, D.; Qiao, Y. Insights into
N-Heterocyclic Carbene-Catalyzed [4 + 2] Annulation Reaction of
Enals with Nitroalkenes: Mechanisms, Origin of Chemo- and
Stereoselectivity, and Role of Catalyst. Chem. - Asian J. 2016, 11,
3046−3054. (b) Li, X.; Wang, Y.; Wang, Y.; Tang, M.; Qu, L.-B.; Li,
Z.; Wei, D. Insights into the N-Heterocyclic Carbene (NHC)-
Catalyzed Oxidative γ-C(sp3)−H Deprotonation of Alkylenals and
Cascade [4 + 2] Cycloaddition with Alkenylisoxazoles. J. Org. Chem.
2018, 83, 8543−8555. (c) Wang, Y.; Wei, D.; Zhang, W. Recent
Advances on Computational Investigations of N-Heterocyclic
Carbene Catalyzed Cycloaddition/Annulation Reactions: Mechanism
and Origin of Selectivities. ChemCatChem 2018, 10, 338−360. (d) Li,
X.; Xu, J.; Li, S.-J.; Qu, L.-B.; Li, Z.; Chi, Y. R.; Wei, D.; Lan, Y.
Prediction of NHC-catalyzed chemoselective functionalizations of
carbonyl compounds: a general mechanistic map. Chem. Sci. 2020, 11,
7214−7225.
Paixao, M. W. Organic Synthesis Enabled by Light-Irradiation of EDA
̃
Complexes: Theoretical Background and Synthetic Applications. ACS
Catal. 2016, 6, 1389−1407. (b) Postigo, A. Electron Donor-Acceptor
Complexes in Perfluoroalkylation Reactions. Eur. J. Org. Chem. 2018,
́
́
2018, 6391−6404. (c) Arceo, E.; Jurberg, I. D.; Alvarez-Fernandez,
A.; Melchiorre, P. Photochemical activity of a key donor−acceptor
complex can drive stereoselective catalytic α-alkylation of aldehydes.
Nat. Chem. 2013, 5, 750−756. (d) Crisenza, G. E. M.; Mazzarella, D.;
Melchiorre, P. Synthetic Methods Driven by the Photoactivity of
Electron Donor−Acceptor Complexes. J. Am. Chem. Soc. 2020, 142,
5461−5476.
(14) Martin, C. D.; Soleilhavoup, M.; Bertrand, G. Carbene-
stabilized main group radicals and radical ions. Chem. Sci. 2013, 4,
3020−3030.
(15) (a) Seevers, R. H.; Counsell, R. E. Radioiodination techniques
for small organic molecules. Chem. Rev. 1982, 82, 575−590.
(b) Stavber, S.; Jereb, M.; Zupan, M. Electrophilic Iodination of
Organic Compounds Using Elemental Iodine or Iodides. Synthesis
(20) According to Truhlar et al.’s calibrations: Jacquemin, D.;
̀
Perpete, E. A.; Ciofini, I.; Adamo, C.; Valero, R.; Zhao, Y.; Truhlar, D.
G. Time-Dependent Density Functional Theory “Not Guilty” of
Large Errors for Cyanines. J. Chem. Theory Comput. 2010, 6, 2071−
2085. Regarding TDDFT-M06 calculations for a set of 18 n→p*
transitions of neutral nitroso dyes, the mean unsigned deviation is
0.39 eV. Taking the value into account, the error bar for a wavelength
of 400.0 nm is about 50.0 nm.
̌
2008, 2008, 1487−1513. (c) Podgorsek, A.; Zupan, M.; Iskra, J.
Oxidative Halogenation with “Green” Oxidants: Oxygen and
Hydrogen Peroxide. Angew. Chem., Int. Ed. 2009, 48, 8424−8450.
(d) Parvatkar, P. T.; Parameswaran, P. S.; Tilve, S. G. Recent
Developments in the Synthesis of Five- and Six-Membered Hetero-
cycles Using Molecular Iodine. Chem. - Eur. J. 2012, 18, 5460−5489.
(e) Petrone, D. A.; Ye, J.; Lautens, M. Modern Transition-Metal-
Catalyzed Carbon−Halogen Bond Formation. Chem. Rev. 2016, 116,
8003−8104. (f) Vekariya, R. H.; Balar, C. R.; Sharma, V. S.; Prajapati,
N. P.; Vekariya, M. K.; Sharma, A. S. Preparation of α-Iodocarbonyl
Compounds: An Overall Development. ChemistrySelect 2018, 3,
9189−9203.
(16) (a) Li, L.; Liu, W.; Zeng, H.; Mu, X.; Cosa, G.; Mi, Z.; Li, C.-J.
Photo-induced Metal-Catalyst-Free Aromatic Finkelstein Reaction. J.
Am. Chem. Soc. 2015, 137, 8328−8331. (b) Liu, W.; Yang, X.; Gao,
Y.; Li, C.-J. Simple and Efficient Generation of Aryl Radicals from
Aryl Triflates: Synthesis of Aryl Boronates and Aryl Iodides at Room
Temperature. J. Am. Chem. Soc. 2017, 139, 8621−8627.
(17) (a) Fu, M.-C.; Shang, R.; Zhao, B.; Wang, B.; Fu, Y.
Photocatalytic decarboxylative alkylations mediated by triphenylphos-
phine and sodium iodide. Science 2019, 363, 1429−1434. (b) Noble,
A.; Aggarwal, V. K. Triphenylphosphine and sodium iodide: a new
catalyst combination to rival precious metal complexes in visible light
photoredox catalysis. Sci. China: Chem. 2019, 62, 1083−1084.
(18) (a) Xu, Z.; Chen, H.; Wang, Z.; Ying, A.; Zhang, L. One-Pot
Synthesis of Benzene-Fused Medium-Ring Ketones: Gold Catalysis-
Enabled Enolate Umpolung Reactivity. J. Am. Chem. Soc. 2016, 138,
5515−5518. (b) Xu, Z.; Zhai, R.; Liang, T.; Zhang, L. Efficient One-
Pot Multifunctionalization of Alkynes en Route to α-Alkoxyketones,
α-Thioketones, and α-Thio Thioketals by using an Umpolung
Strategy. Chem. - Eur. J. 2017, 23, 14133−14137. (c) Petrosyan, A.;
Hauptmann, R.; Pospech, J. Heteroarene N-Oxides as Oxygen Source
in Organic Reactions. Eur. J. Org. Chem. 2018, 2018, 5237−5252.
(d) Xia, X.; Chen, B.; Zeng, X.; Xu, B. Synthesis of α-amino ketones
through aminations of umpoled enolates. Org. Biomol. Chem. 2018,
16, 6918−6922. (e) Xia, X.; Chen, B.; Zeng, X.; Xu, B. Synthesis of α-
Trifluoromethylthiolated and α-Thiocyanated Ketones Using Um-
poled Enolates. Adv. Synth. Catal. 2018, 360, 4429−4434. (f) Zhai, R.
L.; Xue, Y. S.; Liang, T.; Mi, J. J.; Xu, Z. Regioselective Arene and
Heteroarene Functionalization: N-Alkenoxypyridinium Salts as
Electrophilic Alkylating Agents for the Synthesis of α-Aryl/α-
F
https://dx.doi.org/10.1021/acs.orglett.0c02523
Org. Lett. XXXX, XXX, XXX−XXX