Visible-Light-Induced 1,3-Aminopyridylation of [1.1.1]Propellane with N-Aminopyridinium Salts

Article abstract of DOI:10.1002/anie.202016156

Through the formation of an electron donor–acceptor (EDA) complex, strain-release aminopyridylation of [1.1.1]propellane with N-aminopyridinium salts as bifunctional reagents enabled the direct installation of amino and pyridyl groups onto bicyclo[1.1.1]pentane (BCP) frameworks in the absence of an external photocatalyst. The robustness of this method to synthesize 1,3-aminopyridylated BCPs under mild and metal-free conditions is highlighted by the late-stage modification of structurally complex biorelevant molecules. Moreover, the strategy was extended to P-centered and CF₃ radicals for the unprecedented incorporation of such functional groups with pyridine across the BCP core in a three-component coupling. This practical method lays the foundation for the straightforward construction of new valuable C4-pyridine-functionalized BCP chemical entities, thus significantly expanding the range of accessibility of BCP-type bioisosteres for applications in drug discovery.

Full text of DOI:10.1002/anie.202016156

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7873–7879
International Edition: doi.org/10.1002/anie.202016156
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Hot Paper
Visible-Light-Induced 1,3-Aminopyridylation of [1.1.1]Propellane with
N-Aminopyridinium Salts
Sanghoon Shin, Seojin Lee, Wonjun Choi, Namhoon Kim, and Sungwoo Hong*
Dedicated to Professor Phil Ho Lee on the occasion of his 60th birthday
[5]
À
Abstract: Through the formation of an electron donor– where the internal central C C bond of [1.1.1]propellane
acceptor (EDA) complex, strain-release aminopyridylation of
[1.1.1]propellane with N-aminopyridinium salts as bifunc-
tional reagents enabled the direct installation of amino and
pyridyl groups onto bicyclo[1.1.1]pentane (BCP) frameworks
in the absence of an external photocatalyst. The robustness of
this method to synthesize 1,3-aminopyridylated BCPs under
mild and metal-free conditions is highlighted by the late-stage
modification of structurally complex biorelevant molecules.
Moreover, the strategy was extended to P-centered and CF3
radicals for the unprecedented incorporation of such func-
tional groups with pyridine across the BCP core in a three-
component coupling. This practical method lays the founda-
tion for the straightforward construction of new valuable C4-
pyridine-functionalized BCP chemical entities, thus signifi-
cantly expanding the range of accessibility of BCP-type
bioisosteres for applications in drug discovery.
can be readily cleaved under an anionic strain-release
approach[6] and, more recently, a radical pathway affording
the requisite substituted BCPA compounds (Scheme 1B).[7]
Baran et al. disclosed the strain-release amination of propel-
lane by employing deprotonated dialkyl amines to access
monosubstituted BCPAs.[6a,b] The Gleason group has extend-
ed this approach to the synthesis of 1,3-disubstituted BCPAs
by trapping alkyl electrophiles with in situ generated meta-
lated intermediates (a).[6c] Despite the advances, this protocol
is limited to benzylic amines as the source of N-nucleophiles
because BCP-Grignard reagents have to be accumulated
before trapping with electrophiles. Uchiyama and co-workers
achieved iron-catalyzed radical carboamination of propellane
using azodicarboxylate as a radical acceptor to access 1,3-
disubstituted BCP-hydrazines (b).[7a] Recently, the MacMillan
group reported the elegant three-component radical coupling
of propellane, where BCP radical intermediates were inter-
cepted by amine nucleophiles under dual photoredox/copper
Introduction
The strategic replacement of an aromatic ring with
unconventional structural bioisosteres can provide unique
opportunities in pharmaceutical chemistry to enhance the
physicochemical properties of drug candidates while main-
taining comparable levels of activity.[1] Recently, a strained
bicyclo[1.1.1]pentane (BCP) scaffold has received increased
attention in medicinal chemistry as a nonclassical bioisostere
of arenes and internal alkynes due to its unique structural and
conformational rigidity.[2] Importantly, the isosteric replace-
ment strategy is of significant interest for circumventing
deleterious metabolic processes of an aniline moiety.[3]
Accordingly, bicyclo[1.1.1]pentylamine (BCPA) has been
extensively targeted as a prominent aniline bioisostere by
creating unexplored druglike chemical space with varying
levels of synthetic utility (Scheme 1A).[4] From a synthetic
point of view, propellane can be efficiently aminated by ring-
opening functionalization at the BCP bridgehead positions,
[*] S. Shin, S. Lee, W. Choi, Dr. N. Kim, Prof. Dr. S. Hong
Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 34141 (Republic of Korea)
and
Center for Catalytic Hydrocarbon Functionalizations
Institute for Basic Science (IBS)
Daejeon 34141 (Republic of Korea)
E-mail: hongorg@kaist.ac.kr
Scheme 1. A) Bioisosteric replacement of aniline. B) Strategies for the
formation of 1,3-disubstituted BCPAs. C) Design plan: A single-step
approach to 1,3-aminopyridylated BCPs using N-aminopyridinium salts
as bifunctional reagents and divergent functionalization.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202016156.
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catalysis (c).[7b] In addition, the photocatalytic strategy used
for N-centered radical addition to propellane was first
demonstrated by the Leonori group, in which a range of
external SOMOphiles, such as halide, sulfur, and selenium,
could be efficiently installed on the BCPA building blocks
(d).[7c]
construction of 1,3-aminopyridylated BCP products. Under
these settings, our initial studies surveyed various anions to
determine the abilities to promote photolysis of pyridinium
salts (for the screens of various wavelengths, the Supporting
Information for details). Upon addition of sodium acetate to
pyridinium salt 2a in acetonitrile, a photolytic pyridine
product was observed, indicating that the photoinduced
SET took place between 2a and acetate anions to trigger
the amidyl radical. We observed that 2a could be photo-
reduced by the addition of acetate anions under visible light
irradiation (427 nm), leading to the generation of 2-phenyl-
pyridine and 2a’. The formation of 2a’ indicated that the
amidyl radical was readily generated by photolysis and
underwent the 1,2-hydrogen atom transfer (HAT) process[18]
that was intercepted by the pyridinium segment [Eq. (1)]. The
addition of more soluble additives such as tetrabutylammo-
nium bromide (TBAB) and tetrabutylammonium acetate
(TBAOAc) exhibited a dramatic enhancement in the absorp-
tion (Figure 1) and led to substantial decomposition of 2a (see
Scheme 5e). Considering the radical chain propagation path-
way, less soluble inorganic base (NaOAc) in acetonitrile
solution is most suitable for the proposed EDA-complex-
driven transformation with only minimal sacrifice of starting
substrate 2a.
Considering the utility of BCPA and pyridyl groups in the
pharmaceutical industry,[3,4,8] the development of a method
for the efficient synthesis of 1,3-aminopyridyl-functionalized
BCP scaffolds is highly demanded for the rapid construction
of complex and druglike BCP targets. In general, the
preparation of heteroaryl-functionalized BCPAs requires
further elaboration of BCPA-halide intermediates with
prefuntionalized heteroarenes,[9] thus limiting their wide
application to lead optimization in medicinal chemistry. In
this context, the goal of this work is to develop a new strategy
to efficiently access 1,3-aminopyridylated BCP scaffolds from
the direct transformation of propellane in a controllable and
selective manner. In previous work, our laboratory has
demonstrated that N-aminopyridinium salts can be efficiently
leveraged as bifunctional reagents[10] in a visible-light-enabled
platform for the difunctionalization of alkenes to directly
access amine- and pyridine-containing molecules.[11] In view
of our previous experience on the use of pyridinium salts and
the susceptibility of propellane to radical opening, we were
intrigued by the possibility of embracing the intrinsic
À
reactivity of the strained C C bond in propellane by using
N-aminopyridinium salts in strain-release settings (Scheme
1C). We speculated that the reaction could proceed through
the generation of an amidyl radical[12,13] and subsequent BCP
radical trapping of a pyridyl ring at the C4 position[14,15] to
yield complex 1,3-aminopyridylated BCP products through
a radical-chain propagation pathway. Recently, strategies
exploiting electron donor–acceptor (EDA) complexes have
been widely explored to drive a new pattern of visible-light-
induced transformations without requiring an external photo-
catalyst.[16] We reasoned that the photochemically formed
amidyl radical by the single-electron transfer (SET) process
of the EDA complex[17] could readily engage in the cross-
coupling process with propellane. We speculated that the
resulting BCP radical would trap a pyridine group over
another propellane if the cross-coupling process between
BCP radical and N-aminopyridinium salt could be fast. Here,
we report a strategy for the visible-light-driven 1,3-amino-
pyridylation of propellane employing various N-aminopyr-
idinium salts as bifunctional reagents under photocatalyst-
free conditions, which allows the direct introduction of amide
and pyridyl functionality across the BCP core. Furthermore,
this strategy could be extended to a divergent functionaliza-
tion with P-centered and CF3 radicals through three-compo-
nent cascade reactions, thereby enabling the diversification of
synthetically valuable 1,3-disubstituted BCP-building blocks.
Based on the observation of our initial studies, the
reaction was next optimized by monitoring the reactivity of
propellane 1 and N-aminopyridinium salt 2a under light
irradiation at room temperature, as shown in Table 1. After
screening the parameters, the desired product 3a was
successfully produced in an acetonitrile solvent system with
sodium acetate as a base under blue LED irradiation in the
absence of an external photocatalyst, thus indicating that the
overall proposed process was effectively operating (entry 1).
Other electron donors, such as bromide, show diminished
Results and Discussion
Before starting the optimization of the postulated strat-
egy, we decided to evaluate the behavior of N-aminopyridi-
nium salt 2a on an EDA complex for the one-step, modular
Figure 1. Absorption spectra of 2a and mixtures of 2a and additives.
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Table 1: Strain-release aminopyridylation of [1.1.1]propellane.[a]
valuable BCP building blocks. Specifically, substrates bearing
both electron-rich and electron-deficient substituents in the
aryl group were suitable to yield the desired products (3l–3o).
Halogen-substituted substrates were tolerated in reaction
conditions, thus enabling further synthetic functionalization
at various positions (3p–3r). The applicability of the current
protocol to other arenes, such as naphthyl and thiophenyl
scaffolds, was also examined, and the desired products were
produced in a similar fashion (3s–3u). Notably, this method
could be expanded to substrates containing alkylsulfonyl
amides, such as methyl, cyclopropyl, and phthalimide groups,
to generate synthetically valuable BCPA building blocks (3v–
3x). Given the importance of the carboxamide group for
diverse structures of BCPA moieties, the suitability of this
transformation was subsequently investigated to further
expand scope generality. We were pleased to find that the
carboxamide group was well tolerated under our standard
reaction conditions, affording corresponding product 3y. The
applicability of the current method is further highlighted by
late-stage modifications of pharmaceutically relevant mole-
cules. Pleasingly, structurally complex substrates camphor
(3z) and pyridine-based drugs, such as pyriproxyfen (3aa) and
vismodegib (3ab), were rapidly modified with propellane to
deliver new drug derivatives with excellent regioselectivity,
demonstrating broad functional group tolerance.
During these investigations, we discovered that an amidyl
radical could rapidly engage in intermolecular HAT to form
a phosphinoyl radical when diphenylphosphine oxide was
added.[20] Therefore, we speculated that the generated phos-
phinoyl radical could provide a unique opportunity to
develop the divergent three-component assembly of 1,3-
phosphinoyl and pyridyl-functionalized BCPs, where the
extruded amidyl radical serves as an efficient HATreagent.[13]
To corroborate this scenario, we investigated the catalyst-free
three-component reaction of propellane by employing pyr-
idinium salt 2 and diphenylphosphine oxide 4 under blue
LED irradiation at room temperature, as illustrated in
Scheme 3. To our delight, this approach can be successfully
applied to cascade phosphinoylation/pyridylation under the
slightly modified conditions where TBAB was added as an
electron donor to induce the formation of the pyridinium salt–
bromide EDA complex. Among the bases screened, KHCO3
was more effective than NaOAc in this reaction (see the
Supporting Information for details). Having the optimized
reaction condition in hand, we next examined the scope of
pyridine derivatives and phosphine oxides to extend the
generality of the current three-component phosphorylative
pyridylation protocol. A range of N-aminopyridinium salts
were employed in this transformation and successfully con-
verted to the desired products (5a–5c). In addition, reactions
of tolyl-substituted phosphine oxides smoothly afforded the
desired product 5d and 5e. Moreover, we observed that
pyridine-based drug pyriproxyfen could be successfully em-
ployed for the late-stage functionalization with this protocol
(5 f). Notably, phosphinoyl radicals preferentially react with
[1.1.1]propellane to install pyridyl and phosphorus groups,
and only trace amounts of 1,3-aminopyridylated BCPs were
observed under the reaction conditions.
Entry
Change from standard conditions
Yield [%][b]
1
2
3
4
5
6
7
8
9
none
75 (74)[c]
17
29
trace
trace
70
50
13
0
0
TBAB instead of NaOAc
TBAOAc instead of NaOAc
without base
MeCN instead of pentane stock
benzene instead of pentane stock
467 nm instead of 427 nm
525 nm instead of 427 nm
dark
10
with TEMPO (2.0 equiv)
[a] Reactions were performed by using 1 (0.05 mmol in 0.4 M pentane
solution), 2a (2.0 equiv) and NaOAc (2.0 equiv) in MeCN (0.5 mL)
under irradiation using blue LEDs (427 nm, 40 W) at room temperature
for 12 h under N2. [b] Yields were determined by 1H NMR spectroscopy.
[c] Yield of the isolated product. TEMPO=(2,2,6,6-tetramethylpiperidin-
1-yl)oxyl.
yield (entry 2), probably because of the side reaction between
a bromo radical and 1. Among the solvents screened,
acetonitrile and pentane cosolvent systems were optimal
(entries 5 and 6). We next investigated the influence of the
light source, and blue LEDs (427 nm, 40 W) gave the highest
yield. The longer wavelength under green LED irradiation
also resulted in product 3a, albeit in diminished yield
(entries 7 and 8). As expected, control experiments confirmed
that visible light is critical for this transformation (entry 9).
The reaction was completely terminated using the radical
scavenger TEMPO, supporting the radical-mediated mecha-
nism (entry 10).
With the optimized reaction conditions for strain-release
aminopyridylation, we set out to investigate the generality of
this protocol, as summarized in Scheme 2. First, a series of
pyridinium substrates with various substituents (methyl,
trifluoromethyl, methoxy, bromo, and fluoro group) on the
phenyl rings reacted well to furnish the 1,3-aminopyridylated
BCP products with excellent C4-selectivity (3b–3 f).[13,14]
Importantly, the bromide group was tolerable under the
standard reaction conditions to provide product 3e,[19] thus
providing an opportunity for further functionalization. Fur-
ther exploration demonstrated that pyridine-, picoline-, and
lutidine-substituted BCPAs (3g–3j) were readily produced
with similar reactivity under the reaction conditions. In
general, C2-substituted N-aminopyridinium salts give C4
products exclusively whereas substrates bearing no C2 sub-
stituent provide a modest preference (3g and 3j). We next
investigated the utility of our method by exploring other
heteroarenes such as quinolinium salts. Unfortunately, only
trace amounts of desired products (< 5%) were observed.
Considering the importance of sulfonamide in medicinal
chemistry and materials science, we next assessed the applic-
ability of this method with respect to the N-sulfonamide unit,
and we found that a broad range of sulfonamide groups could
be incorporated into the propellane substrate to afford
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Scheme 2. Substrate scope of strain-release aminopyridylation. Reactions were performed by using 1 (0.1 mmol in 0.4 M pentane solution), 2
(2.0 equiv) and NaOAc (2.0 equiv) in MeCN (1.0 mL) under irradiation using blue LEDs (427 nm, 40 W) at room temperature for 12 h under N2.
Yields are for the isolated product. [a] The reaction was carried out on a 1.0 mmol scale. [b] DMSO was used instead of MeCN; NaHCO3 was
used instead of NaOAc.
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Scheme 4. Substrate scope of cascade trifluoromethyl pyridylation.
Reactions were performed by using 1 (3.0 equiv in 0.4 M pentane
solution), 2 (0.1 mmol), Umemoto reagent (3.0 equiv), Ir(ppy)3
(2.5 mol%) and CsHCO3 (2.0 equiv) in DMA (1.0 mL) under irradia-
tion using blue LEDs (440 nm, 10 W) at room temperature for 15 h
under N2. Yields are for the isolated product.
substrates. Next, we observed that four cross-coupled prod-
ucts were produced when two different pyridinium salts 2s
and 2h were employed as substrates, implying that the
reaction pathways proceed in the proposed stepwise process
(Scheme 5b). To better understand whether the radical chain
process is involved, light/dark experiments were carried out.
While a fully dark reaction could not generate the desired
product 3a, product formation occurred by chain propagation
under dark conditions after visible-light-induced initiation for
1 h (Scheme 5c). In addition, we observed that the radical
reaction occurred in the dark period (Scheme 5d).[21] Next, we
evaluated the photolysis of pyridinium salt 2a, which could be
reduced by several electron donor anions under blue LED
irradiation to yield a substantial amount of 2-phenylpyridine
(Scheme 5e).
Scheme 3. Substrate scope of cascade phosphinoylation/pyridylation.
Reactions were performed by using 1 (2.0 equiv in 0.4 M pentane
solution), 2 (0.1 mmol), 4 (2.0 equiv), TBAB (1.0 equiv) and KHCO3
(2.0 equiv) in MeCN (1.0 mL) under irradiation using blue LEDs
(440 nm, 40 W) at room temperature for 12 h under N2.
To further highlight the broad applicability of the present
approach, we next explored the compatibility of the method
to the trifluoromethylative pyridylation of propellane, as
illustrated in Scheme 4. To our delight, the desired trifluor-
omethylation product 6a was generated in 43% yield under
the slightly altered reaction conditions (see the Supporting
Information for details). After evaluating different reaction
conditions, the improved result (51%) was obtained when
Ir(ppy)3 was added as an external photocatalyst. With the
optimal conditions in hand, we next investigate the substrate
scope with respect to pyridinium salts to demonstrate the
utility of the current method. Specifically, trifluoromethyl
pyridylation was successful with several N-aminopyridinium
salts bearing substituents such as methoxy and trifluorometh-
yl groups on the aryl ring (6a–6c). Noteworthily, pyridine-
containing drugs, including vismodegib and bisacodyl, under-
went the reaction successfully to afford the corresponding
products 6d and 6e. These results support the potential wide
applicability of the divergent method in the construction of
synthetically valuable 1,3-functionalized BCP building blocks.
To investigate the reaction pathway, several control
experiments were next carried out, as shown in Scheme 5.
First, we observed that the reaction took place selectively at
pyridinium salt 2a to afford BCPA 3a (Scheme 5a) when
both pyridinium salt 2a and 2-methylpyridine were used as
Considering the above observations, the plausible mech-
anism of the current method is shown in Figure 2. Initially,
a small quantity of photoexcited EDA complex I upon
Figure 2. Proposed reaction mechanism.
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amidyl radical adds to the propellane, which cleaves the
central s-bond and provides BCP-radical intermediate III.
Afterward, the BCP radical III is poised for addition to the C4
position of another N-aminopyridinium salt. Next, the
resulting cationic radical species IV undergoes deprotonation
À
followed by cleavage of the N N bond to afford the final
product and amidyl radical II. The generated amidyl radical
initiates a radical chain process. The measured quantum yield
(F = 2.7) using 2d (see the Supporting Information for
details), along with a light–dark cycle experiment, supports
the radical chain propagation mechanism (see the Supporting
Information for details).
Conclusion
In summary, the visible-light-induced strain-release ami-
nopyridylation of propellanes has been developed by employ-
ing N-aminopyridinium salts as bifunctional reagents under
mild reaction conditions. This strategy involves the photo-
active formation of EDA complexes between N-aminopyr-
idinium salts and acetate anions, enabling the direct incorpo-
ration of amino and pyridyl groups onto BCP frameworks
without requiring an external photocatalyst. The present
procedure exhibits a fairly broad substrate scope and offers
a convenient and powerful synthetic tool for accessing 1,3-
aminopyridylated BCPs while controlling the C4-selectivity
of radical addition to the pyridine ring. Furthermore, this
strategy can be extended to P and CF3 radicals, offering the
option of divergence through the three-component assembly
of synthetically valuable BCP chemical entities. Overall, this
versatile method significantly expands the scope of BCP-type
bioisosteres and is expected to stimulate further research
endeavors for applications in medicinal chemistry.
Acknowledgements
This research was supported financially by the Institute for
Basic Science (IBS-R010-A2). We thank Dr. Dongwook Kim
(IBS) for XRD analysis.
Conflict of interest
The authors declare no conflict of interest.
Keywords: bicyclo[1.1.1]pentane ·bifunctional reagents ·
photolysis ·pyridinium salts ·strained molecules
[1] a) E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257;
b) Y. P. Auberson, C. Brocklehurst, M. Furegati, T. C. Fessard,
G. Koch, A. Decker, L. L. Vecchia, E. Briard, ChemMedChem
2017, 12, 590.
[2] a) G. M. Locke, S. S. R. Bernhard, M. O. Senge, Chem. Eur. J.
2019, 25, 4590; b) P. K. Mykhailiuk, Org. Biomol. Chem. 2019,
17, 2839; c) N. D. Measom, K. D. Down, D. J. Hirst, C. Jamieson,
E. S. Manas, V. K. Patel, D. O. Somers, ACS Med. Chem. Lett.
2017, 8, 43.
Scheme 5. Control experiments. [a] Reactions were performed by using
2a (0.05 mmol) and NaOAc (1.0 equiv) in MeCN (0.5 mL) under
irradiation with the light source at room temperature for 12 h under
N2. [b] Yields were determined by 1H NMR spectroscopy.
irradiation with blue LEDs undergoes a SET event to yield
electrophilic amidyl radical II. Subsequently, the resulting
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[3] a) J. S. Walsh, G. T. Miwa, Annu. Rev. Pharmacol. Toxicol. 2011,
2020, 53, 1066; e) J. Davies, S. P. Morcillo, J. J. Douglas, D.
51, 145; b) A. S. Kalgutkar, Curr. Med. Chem. 2014, 22, 438.
[4] T. M. Sodano, L. A. Combee, C. R. J. Stephenson, ACS Med.
Chem. Lett. 2020, 11, 1785.
[5] a) A. J. Sterling, A. B. Dürr, R. C. Smith, E. A. Anderson, F.
Duarte, Chem. Sci. 2020, 11, 4895; b) J. A. Milligan, P. Wipf, Nat.
Chem. 2016, 8, 296; c) K. B. Wiberg, S. T. Waddell, J. Am. Chem.
Soc. 1990, 112, 2194; d) K. B. Wiberg, Angew. Chem. Int. Ed.
Engl. 1986, 25, 312; Angew. Chem. 1986, 98, 312.
[6] a) R. Gianatassio, J. M. Lopchuk, J. Wang, C.-M. Pan, L. R.
Malins, L. Prieto, T. A. Brandt, M. R. Collins, G. M. Gallego,
N. W. Sach, J. E. Spangler, H. Zhu, J. Zhu, P. S. Baran, Science
2016, 351, 241; b) J. M. Lopchuk, K. Fjelbye, Y. Kawamata, L. R.
Malins, C. M. Pan, R. Gianatassio, J. Wang, L. Prieto, J. Bradow,
T. A. Brandt, M. R. Collins, J. Elleraas, J. Ewanicki, W. Farrell,
O. O. Fadeyi, G. M. Gallego, J. J. Mousseau, R. Oliver, N. W.
Sach, J. K. Smith, J. E. Spangler, H. Zhu, J. Zhu, P. S. Baran, J.
Am. Chem. Soc. 2017, 139, 3209; c) J. M. E. Hughes, D. A.
Scarlata, A. C.-Y. Chen, J. D. Burch, J. L. Gleason, Org. Lett.
2019, 21, 6800.
Leonori, Chem. Eur. J. 2018, 24, 12154; f) J.-R. Chen, X.-Q. Hu,
L.-Q. Lu, W.-J. Xiao, Chem. Soc. Rev. 2016, 45, 2044.
[13] S. Jung, H. Lee, Y. Moon, H.-Y. Jung, S. Hong, ACS Catal. 2019,
9, 9891.
[14] For selected examples of C4-selective functionalization of
pyridinium salts, see: a) K. Lee, S. Lee, N. Kim, S. Kim, S.
Hong, Angew. Chem. Int. Ed. 2020, 59, 13379; Angew. Chem.
2020, 132, 13481; b) N. Kim, C. Lee, T. Kim, S. Hong, Org. Lett.
2019, 21, 9719.
[15] For selected examples of C2-selective alkylation of pyridine N-
oxides and pyridinium salts, see: a) W. Jo, J. Kim, S. Choi, S. H.
Cho, Angew. Chem. Int. Ed. 2016, 55, 9690; Angew. Chem. 2016,
128, 9842; b) C. Hwang, W. Jo, S. H. Cho, Chem. Commun. 2017,
53, 7573; c) W. Zhou, T. Miura, M. Murakami, Angew. Chem. Int.
Ed. 2018, 57, 5139; Angew. Chem. 2018, 130, 5233; d) J.-h. Xu,
W.-b. Wu, J. Wu, Org. Lett. 2019, 21, 5321; e) Y. Moon, W. Lee, S.
Hong, J. Am. Chem. Soc. 2020, 142, 12420; f) J. Jeon, Y. He, S.
Shin, S. Hong, Angew. Chem. Int. Ed. 2020, 59, 281; Angew.
Chem. 2020, 132, 287.
[7] a) J. Kanazawa, K. Maeta, M. Uchiyama, J. Am. Chem. Soc.
2017, 139, 17791; b) X. Zhang, R. T. Smith, C. Le, S. J. McCarver,
B. T. Shireman, N. I. Carruthers, D. W. C. MacMillan, Nature
2020, 580, 220; c) J. H. Kim, A. Ruffoni, Y. S. S. Al-Faiyz, N. S.
Sheikh, D. Leonori, Angew. Chem. Int. Ed. 2020, 59, 8225;
Angew. Chem. 2020, 132, 8302; d) H. Zhang, M. Wang, X. Wu, C.
Zhu, Chin. J. Org. Chem. 2020, 40, 3431; e) Z. Wu, Y. Xu, J. Liu,
X. Wu, C. Zhu, Sci. China Chem. 2020, 63, 1025; for related
a review, see: f) M. M. D. Pramanik, H. Quian, W.-J. Xiao, J.-R.
Chen, Org. Chem. Front. 2020, 7, 2531.
[8] a) R. D. Taylor, M. MacCoss, A. D. G. Lawson, J. Med. Chem.
2014, 57, 5845; b) E. Vitaku, D. T. Smith, J. T. Njardarson, J.
Med. Chem. 2014, 57, 10257.
[9] a) J. Nugent, C. Arroniz, B. R. Shire, A. J. Sterling, H. D.
Pickford, M. L. J. Wong, S. J. Mansfield, D. F. J. Caputo, B.
Owen, J. J. Mousseau, F. Duarte, E. A. Anderson, ACS Catal.
2019, 9, 9568; b) K. Schwärzer, H. Zipse, K. Karaghiosoff, P.
Knochel, Angew. Chem. Int. Ed. 2020, 59, 20235; Angew. Chem.
2020, 132, 20412.
[16] For selected reviews of EDA complexes, see: a) S. V. Rosokha,
J. K. Kochi, Acc. Chem. Res. 2008, 41, 641; b) C. G. S. Lima, T. D.
Lima, M. Duarte, I. D. Jurberg, M. W. Paix¼o, ACS Catal. 2016,
6, 1389; c) A. Postigo, Eur. J. Org. Chem. 2018, 6391; d) G. E. M.
Crisenza, D. Mazzarella, P. Melchiorre, J. Am. Chem. Soc. 2020,
142, 5461.
[17] For selected examples of the use of EDA complexes with
pyridinium salts, see: a) V. Quint, F. Morlet-Savary, J.-F. Lohier,
J. LalevØe, A.-C. Gaumont, S. Lakhdar, J. Am. Chem. Soc. 2016,
138, 7436; b) V. Quint, N. Chouch›ne, M. Askri, J. LalevØe, A.-C.
Gaumont, S. Lakhdar, Org. Chem. Front. 2019, 6, 41; c) S. Jung,
S. Shin, S. Park, S. Hong, J. Am. Chem. Soc. 2020, 142, 11370;
d) I. Kim, S. Park, S. Hong, Org. Lett. 2020, 22, 8730.
[18] a) A. W. Rand, H. Yin, L. Xu, J. Giacoboni, R. Martin-Montero,
C. Romano, J. Montgomery, R. Martin, ACS Catal. 2020, 10,
4671; b) L.-J. Zhong, H.-Y. Wang, X.-H. Ouyang, J.-H. Li, D.-L.
An, Chem. Commun. 2020, 56, 8671; c) J. Zhang, D. Liu, S. Liu,
Y. Ge, Y. Lan, Y. Chen, iScience 2020, 23, 100755.
À
[19] The C1 C3 bond length of 3e was found to be 1.858 Š. For the
[10] For selected examples, see: a) T. M. Monos, R. C. McAtee,
C. R. J. Stephenson, Science 2018, 361, 1369; b) Y. Zhang, H.
Liu, L. Tang, H. J. Tang, L. Wang, C. Zhu, C. Feng, J. Am. Chem.
Soc. 2018, 140, 10695; c) H.-M. Huang, M. Koy, E. Serrano, P. M.
Pflüger, J. L. Schwarz, F. Glorius, Nat. Catal. 2020, 3, 393; d) T.
Patra, P. Bellotti, F. Glorius, Angew. Chem. Int. Ed. 2020, 59,
3172; Angew. Chem. 2020, 132, 3198.
correlation between the C1 –C3 non-bonded distance and the
field/inductive parameters for substituents, see Ref. [7c].
Deposition Number 2046034 (for 3e) contains the supplemen-
tary crystallographic data for this paper. These data are provided
free of charge by the joint Cambridge Crystallographic Data
Centre and Fachinformationszentrum Karlsruhe Access Struc-
tures service www.ccdc.cam.ac.uk/structures.
[11] a) Y. Moon, B. Park, I. Kim, G. Kang, S. Shin, D. Kang, M.-H.
Baik, S. Hong, Nat. Commun. 2019, 10, 4117; b) G. R. Mathi, Y.
Jeong, Y. Moon, S. Hong, Angew. Chem. Int. Ed. 2020, 59, 2049;
Angew. Chem. 2020, 132, 2065; c) H. Im, W. Choi, S. Hong,
Angew. Chem. Int. Ed. 2020, 59, 17511; Angew. Chem. 2020, 132,
17664; d) Y. Kim, K. Lee, G. R. Mathi, I. Kim, S. Hong, Green
Chem. 2019, 21, 2082.
[20] a) I. Kim, G. Kang, K. Lee, B. Park, D. Kang, H. Jung, Y.-T. He,
M.-H. Baik, S. Hong, J. Am. Chem. Soc. 2019, 141, 9239; b) K.
Kim, H. Choi, D. Kang, S. Hong, Org. Lett. 2019, 21, 3417; c) I.
Kim, M. Min, D. Kang, K. Kim, S. Hong, Org. Lett. 2017, 19,
1394.
[21] L. M. Kammer, A. Rahman, T. Opatz, Molecules 2018, 23, 764.
[12] For selected reviews of the generation of an amidyl radical, see:
a) T. Xiong, Q. Zhang, Chem. Soc. Rev. 2016, 45, 3069; b) L. Q.
Nguyen, R. R. Knowles, ACS Catal. 2016, 6, 2894; c) E. C.
Gentry, R. R. Knowles, Acc. Chem. Res. 2016, 49, 1546; d) X.-T.
Yu, Q.-Q. Zhao, J. Chen, W.-J. Xiao, J.-R. Chen, Acc. Chem. Res.
Manuscript received: December 4, 2020
Accepted manuscript online: January 6, 2021
Version of record online: March 1, 2021
Angew. Chem. Int. Ed. 2021, 60, 7873 –7879
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