Photocatalytic Vicinal Aminopyridylation of Methyl Ketones by a Double Umpolung Strategy

Article abstract of DOI:10.1002/anie.202008435

A photocatalytic double umpolung strategy for the vicinal aminopyridylation of ketones was developed using pyridinium N?N ylides. The inversion of the polarity of the pyridinium N?N ylides by single-electron oxidation successfully enables radical-mediated 1,3-dipolar cycloadditions with enolsilanes formed in situ from ketones, followed by homolytic cleavage of the N?N bond. Intriguingly, the nucleophilic amino and electrophilic pyridyl groups in the ylides can be installed at the nucleophilic α-position and electrophilic carbonyl carbon, respectively, which are typically inaccessible by their innate polarity-driven reactivity. This method accommodates a broad scope, and the utility was further demonstrated by the late-stage functionalization of complex biorelevant molecules. Moreover, the strategy can be successfully applied to enamides.

Full text of DOI:10.1002/anie.202008435

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Photocatalytic Vicinal Aminopyridylation of Methyl Ketones by a
Double Umpolung Strategy
Authors: Honggu Im, Wonjun Choi, and Sungwoo Hong
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202008435
Link to VoR: https://doi.org/10.1002/anie.202008435

10.1002/anie.202008435
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Photochemistry
Photocatalytic Vicinal Aminopyridylation of Methyl Ketones by a Double
Umpolung Strategy **
Honggu Im,a,b Wonjun Choi,a,b and Sungwoo Hong*,b,a
Abstract: A photocatalytic double umpolung strategy for the vicinal
aminopyridylation of ketones was developed using pyridinium N–N
ylides. The inversion of the polarity of the pyridinium N–N ylides by
single-electron oxidation successfully enables radical-mediated 1,3-
dipolar cycloadditions with enolsilanes formed in situ from ketones,
followed by homolytic cleavage of the N–N bond. Intriguingly, the
nucleophilic amino and electrophilic pyridyl groups in the ylides can
be installed at the nucleophilic α-position and electrophilic carbonyl
carbon, respectively, which are typically inaccessible by their innate
polarity-driven reactivity. This method accommodates a broad scope,
and the utility was further demonstrated by the late-stage
functionalization of complex biorelevant molecules. Moreover, the
strategy can be successfully applied to enamides.
K
etones are widely used as versatile synthons in organic synthesis,
and a variety of reactions have been developed utilizing electrophilic
carbonyl group and nucleophilic -carbon.[1] For example, the
nucleophilic addition of organometallic reagents to carbonyl carbons
represents a powerful synthetic tool for the construction of carbon-
carbon bonds (Scheme 1a).[2] However, the conventional strategy
faces some chemoselectivity issues caused by using strong
nucleophiles or bases, which limit the range of tolerated functional
groups. Alternatively, umpolung strategies[3] via polarity inversions
of carbonyl groups have been used for accessing molecules with
functionalities that would be difficult to access using the natural
polarity of carbonyl compounds.[4,5] In particular, moving from a two-
electron paradigm to a radical reactivity pattern[6] could provide the
desired degree of chemoselectivity and functional group tolerance.
For example, the silyl enol ether can serve as a versatile reactive
species that allows radical addition for the selective α-
functionalization of carbonyl groups.[7] Unfortunately, radical-polar
crossover reactions[8] with enolsilanes are typically terminated by
oxidation to the carbocation because the oxidation potential of the
generated α-silyloxy carbon radical is sufficiently low to yield α-
functionalized carbonyl products.[9] As such, this approach is
generally limited to the α-functionalization of carbonyl compounds,
and 1,2-difunctionalization of enolsilanes remains highly challenging.
In this context, one of the potential problems to overcome when
developing difunctionalizations of ketone-derived silyl enol ethers
lies in the rapid trapping of the α-silyloxy carbon radical with a
reactive coupling partner before it undergoes oxidative termination.
Scheme 1.
Design plan: double umpolung strategy for the 1,2-
aminopyridylation of ketones.
To address current limitations, our inspiration to reach the goal of
ketone difunctionalization stems from
a [3+2]-cycloaddition
approach[10] to impose a conformational preference on the coupling
of transient radical species with electrophilic coupling partners. We
questioned whether this mechanistic approach could be applied to the
aminopyridylation of carbonyl compounds where pyridinium N–N
ylides containing both electrophilic and nucleophilic subunits[11] are
employed as bifunctional reagents.[12] In principle, the addition of a
Lewis basic N–N ylide to the nucleophilic α-carbon of a ketone or the
reaction of an electrophilic carbonyl carbon with an electrophilic
pyridinium subunit are fundamentally problematic in two-electron
addition pathways[13] due to the polarity mismatch, which requires an
umpolung strategy contrary to their innate polarity-driven reactivity.
In addition, we thought that the inversion of the polarity of pyridinium
N–N ylides by photocatalytic single-electron oxidation[14] would
more efficiently drive the overall reactions because the instability of
the radical cations generated from the enolsilanes rapidly results in
the elimination of silyl cations to produce the parent carbonyl groups.
In our working hypothesis, the C2 position of an electrophilic
pyridinium subunit[15] could promptly intercept the resulting α-
silyloxy carbon radical in an intramolecular manner to form a 5-
membered cycloadduct that would subsequently undergo homolytic
cleavage of the N–N bond to deliver the 1,2-aminopyridylation
product. If successful, this method would be remarkable in its ability
to install a nucleophilic amino and an electrophilic pyridyl group at
the reaction sites of ketones contrary to their innate polarity. Herein,
we report a double umpolung strategy for the C2-selective
aminopyridylation of ketones through radical-mediated 1,3-dipolar
[]
H. Im, W. Choi, Prof. Dr. S. Hong
aDepartment of Chemistry, Korea Advanced Institute of
Science and Technology (KAIST), Daejeon 34141 (Republic
of Korea)
bCenter for Catalytic Hydrocarbon Functionalizations, Institute
for Basic Science (IBS), Daejeon 34141 (Republic of Korea)
E-mail: hongorg@kaist.ac.kr
[] Supporting information for this article is available on the
WWW under http://www.angewandte.org.
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202008435
Angewandte Chemie International Edition
cycloaddition using pyridinium N–N ylides (Scheme 1b). Moreover,
this reaction was applied to access pyridylated 1,2-diamino
compounds starting from enamides.
such as pyridine (4n and 4o), quinoline (4p), and pyrazine (4q)
moieties, which underwent smooth reaction to produce the
corresponding products under the current reaction conditions.
Furthermore, this protocol can be extended to alkyl ketones to deliver
desired products 4r, 4s, and 4t.
To test the viability of the envisioned strategy, we explored the
reaction using ketone 1a and pyridinium N–N ylide 2a as model
substrates under photoredox catalysis (Table 1). Our preliminary
Considering the importance of N-heteroarenes in drug discovery
studies revealed that a one-pot, two-step procedure was more efficient, and organic materials,[18] we next evaluated the scope with respect to
enabling the aminopyridylation of ketone 1a. After an extensive
screening of reaction parameters, we were pleased to find that the use
of an Ir photocatalyst initiated the vicinal aminopyridylation of
ketone 1a to generate targeted 1,2-difunctionalized product 3a in 82%
yield (entry 1). Intriguingly, radical trapping with 2a occurs
exclusively at the C2 position of the pyridine core. Treatment of the
crude mixture with tetrabutylammonium fluoride (TBAF) led to the
complete conversion of 3a into target product 4a (entry 2). The
evaluation of various photocatalysts revealed that the transformation
was best conducted with [Ir(dF(CF3)ppy)2(5,5’-d(CF3)bpy)]PF6 ([Ir])
(2.5 mol%) (entries 3 and 4). We examined the influence of the
the pyridinium N–N ylides and the utility of the current protocol was
further magnified by transformations of various N-heteroarenes
containing either electron-donating or electron-withdrawing
substituents. Pyridines bearing various substituents, such as alkyl (5b-
5d), ether (5e), cyano (5f), and benzoyl (5g) at the C4-position,
effectively engaged in this aminopyridylation to afford the desired
products. With respect to pyridine substrates bearing aryl, alkyl,
halogen, electron-withdrawing ester, and benzoyl groups at the C3-
position, radical addition preferentially gives C–C bond formation at
the sterically less congested C6 position of the pyridine core over the
competing C2-position (5h-5j and 5o-5q). In the case of the C3/C5
di-substituted pyridine core, the regiomixture of aminopyridylated
product 5r was obtained. Next, the C2-phenyl substituted pyridinium
ylide was shown to be a suitable substrate and provided the desired
product 5s. We subsequently investigated the utility of our method by
exploring other heteroarenium ylides. Impressively, quinoline,
isoquinoline, and benzoquinoline scaffolds are all capable substrates
for this transformation, and the pyridyl C–H addition to the carbonyl
carbons took place exclusively at the C2 position of the pyridine core,
highlighting the exquisite regiocontrol of this strategy.
To further demonstrate the broad applicability in a more complex
setting, the late-stage modifications of medicinally relevant
molecules possessing various functional groups were explored.
Noteworthy, menthol, estradiol, and celestolide derivatives were
readily accommodated under the photoredox conditions, affording the
desired products 6a-6c. Likewise, structurally complex pyridine-
containing drugs such as abiraterone, and bisacodyl, reacted smoothly,
and aminopyridylation products 6d and 6e were formed, highlighting
the broad functional group tolerance
silylation
source,
and
tert-butyldimethylsilyl
trifluoromethanesulfonate (TBSOTf) was found to be most effective
(entry 5). The choice of base was critical for the overall reaction
efficiency, and 2,6-lutidine gave the best performance. For example,
the use of triethylamine failed to afford any of the desired product,
probably because of its facile oxidation by single-electron transfer
(SET) (entry 6).[16] Among the screened solvents, dichloromethane
(DCM) was found to be the most suitable solvent for this reaction. As
expected, control experiments verified the necessity of light
irradiation and the photocatalyst for the current transformation
(entries 7 and 8). A radical scavenger experiment showed that 2,2,6,6-
Tetramethylpiperidine 1-oxyl (TEMPO) inhibited the formation of
the product, and TEMPO-ylide adduct could be detected.[17]
Table 1: Optimization of the reaction conditions.[a,b]
Encouraged by these exciting results, we next evaluated the
compatibility of this light-driven method with enamides. To
demonstrate this hypothesis, we prepared enamides derived from
ketones and hydroxyl amine salts, as shown in Table 3. To our delight,
this strategy can be successfully applied to enamides 7 to achieve
umpolung aminopyridylation, and 3,6-di-tert-butyl-9-mesityl-10-
phenylacridin-10-ium tetrafluoroborate (Mes-Acr+, 5.0 mol%) was
more effective than [Ir] (see Scheme S6, Figure S5, and Figure S10
in the Supporting Information for details). For example, the reaction
of 7a successfully afforded amino pyridylated product 8a. Aryl
enamides substituted with tert-butyl, trifluoromethyl, and
trifluoromethoxy on the aryl rings worked well under the same
reaction conditions (8b-8d). Notably, reaction with alkyl enamide 7e
was also successful to generate amino pyridylated product 8e.
Likewise, aminopyridylation was successful with pyridinium N–N
ylides containing substituents, such as benzoyl, ether, and phenyl
groups on pyridyl rings (8f-8i). Furthermore, isoquinolinium N-ylide
participated successfully to provide product 8j. These excellent
results support the potential wide applicability of the current
procedure in the construction of synthetically useful pyridine-tethered
diamino building blocks.[19]
Entry
1
Deviation from standard conditions
No change
Yield 3a/4a (%)[b]
82/0
0/80
38/0
<5/0
55/5
0/0
2
Workup with TBAF
3
Mes-Acr+ instead of [Ir]
4
TPT instead of [Ir]
5
TMSOTf instead of TBSOTf
Et3N instead of 2,6-lutidine
No catalyst
6
7[c]
8[d]
9[e]
0/0
No light
0/0
Addition of TEMPO 2.0 equiv
0/0
[a] After preactivation of 1a (0.1 mmol) with TBSOTf (1.1 equiv), 2,6-lutidine (1.25
equiv) in DCM (0.1 M) at 0 oC to rt under N2 for 5 h, 2a (1.5 equiv) and
[Ir(dF(CF3)ppy)2(5,5’-d(CF3)bpy)]PF6 (2.5 mol%) was added, and the reaction
mixture was stirred under blue LEDs at 5 oC for 15 h. [b] Ar = 4-methylbenzoate.
PG = protecting group.
With the optimized conditions presented in Table 1, we explored
the substrate scope to determine the generality of the current
methodology. We were pleased to find that this protocol was
amenable to a variety of ketones, as summarized in Table 2.
Specifically, a broad range of functional groups on the aromatic ring,
such as ester (4a), alkyl (4i and 4j), halides (4c-4e), acetate (4f),
trifluoromethyl (4g), and trifluoromethoxy (4h) groups, were well
tolerated and furnished the desired aminopyridylated products. Next,
we investigated the reaction using N-heteroaryl ketone substrates
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202008435
Angewandte Chemie International Edition
Table 2: Exploration of substrate scope[a]
[a] After preactivation of 1 (0.1 mmol) with TBSOTf (1.1 equiv), and 2,6-lutidine (1.25 equiv) in DCM (0.1 M) at 0 oC to rt under N2 for 5 h, 2 (1.5 equiv) and [Ir] (2.5
mol%) was added, and the reaction mixture was stirred at 5 oC under blue LEDs. After evaporation, TBAF (2.5 equiv) was added to the crude mixture in THF. [b] 3.5
mol% of [Ir] was used. [c] TMSOTf was used instead of TBSOTf. Diastereomeric ratios were determined by 1H NMR.
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202008435
Angewandte Chemie International Edition
Table 3: Scope of enamide derivatives[a]
reaction indicates that the alternative radical chain pathway is likely
to be inefficient.
Figure 1. Plausible reaction mechanism
[a] The reaction was conducted with 7 (0.1 mmol), 2 (1.5 equiv) and Mes-Acr+
BF4- (5 mol%) in DCM (0.1 M) under blue LEDs at 10 oC under N2 atmosphere.
[b] 2.5 mol% of [Ir] was used.
In summary, the visible-light-induced 1,2-aminopyridylation of
ketones via a double umpolung strategy is made possible by
employing pyridinium N–N ylides. The inversion of the polarity of
the pyridinium N–N ylides via SET oxidation is key to the success of
the reaction with silyl enol ethers generated from ketones.
Remarkably, the synthetic advances of this approach were
highlighted by the selective installation of amino and pyridyl groups
into the nucleophilic α-position and electrophilic carbonyl carbon,
respectively. Moreover, this photocatalytic method was applied to
enamides, providing powerful synthons for the synthesis of a variety
of pyridine-tethered diamino building blocks. This study provides a
basis for the development of a new and complementary retrosynthetic
approach for the 1,2-difunctionalization of ketones that would be
difficult to access using their inherent natural polarity.
To gain insight into the reaction mechanism, we conducted a series
of control experiments. First, we conducted Stern–Volmer quenching
studies to clarify the plausible mechanism, which revealed that the
luminescence of the excited photocatalyst is effectively quenched by
pyridinium ylide 2a (see the SI for details). On the other hand, the
excited Ir*-catalyst is barely quenched by enolsilane from 1a, which
indicates that the photocatalytic cycle likely begins with the single-
electron oxidation of the N-aminopyridinium ylide. Next, we noticed
that the reaction of 1a with 2a under an O2 atmosphere gave α-amino
ketone 9, implying that the generated α-silyloxy carbon radical can
be readily oxidized (Scheme 2a). To better understand the radical
addition pathway, malonyl ketoesters 10 were used as substrates.
Notably, alcohol products 11a and 11b were obtained via -C−C
scission[15e] (Scheme 2b), which indicates that the N−N bond
cleavage led to the generation of amidyl radical intermediates.
Received: ((will be filled in by the editorial staff))
Published online on ((will be filled in by the editorial staff))
Acknowledgements
This research was supported financially by Institute for Basic Science
(IBS-R010-A2).
Conflict of interest
The authors declare no conflict of interest.
Keywords: double umpolung • aminopyridylation • bifunctional reagent
• photocatalysis • ketone
[1] Modern Carbonyl Chemistry, Wiley-VCH, Weinheim, 2000.
[2] P.Knochel, Handbook of Functionalized Organometallics:Applications in
Synthesis, Wiley-VCH, 2008; b) S. Kobayashi, K. Manabe, Acc. Chem.
Res. 2002, 35, 209.
Scheme 2. Control experiments.
[3] For selected reviews, see: a) D. Seebach, Angew. Chem. Int. Ed. Engl.
1979, 18, 239; b) R. Brehme, D. Enders, R. Fernandez, J. M. Lassaletta,
Eur. J. Org. Chem. 2007, 5629; c) X. Bugaut, F. Glorius, Chem. Soc. Rev.
2012, 41, 3511; d) J. Streuff, Synthesis 2013, 45, 281.
[4] For selected examples: a) d) D. Seebach, E. J. Corey, J. Org. Chem. 1975,
40, 231; b) B.-T. Grꢀbel, D. Seebach, Synthesis 1977, 357; c) A. B. Smith,
C. M. Adams, Acc. Chem. Res. 2004, 37, 365; d) N. Marion, S.
DíezGonzalez, S. P. Nolan, Angew. Chem. Int. Ed. 2007, 46, 2988; e) D.
M. Flanigan, F. Romanov-Michailidis, N. A. White, T. Rovis, Chem. Rev.
2015, 115, 9307; f) D. E. Lewis, The Wolff-Kishner Reduction and
Related Reactions: Discovery and Development; Elsevier, 2019; g) S.
Wang, B.-Y. Cheng, M. Srsen, B. Kꢀnig, J. Am. Chem. Soc. 2020, 142,
7524.
Based on the mechanistic studies, a plausible catalytic cycle for the
photochemical reaction is illustrated in Figure 1. Pyridinium N−N
ylide 2a undergoes single-electron oxidation with Ir* to afford radical
cation 2a’. The enolsilane I formed in situ from the ketone undergoes
radical addition with 2a’ to generate intermediate II. The C2-position
of the pyridinium segment rapidly traps the α-silyloxy carbon radical
prior to further oxidation, leading to the formation of III. The
resulting intermediate III undergoes deprotonation and subsequent
homolytic cleavage of the N−N bond to yield intermediate IV. The
nitrogen-radical intermediate is reduced by the IrII species to
complete the catalytic cycle, and a protonation event would deliver
silyl ether V. Adding TBAF allowed to achieve the final product in a
one-pot process. The measured quantum yield (Φ = 0.87) of the model
[5] For selected examples of umpolung reactions of -carbonyl carbon: a) J.
Mihelcic, K. D. Moeller, J. Am. Chem. Soc. 2003, 125, 36; b) A. G. Smith,
J. S. Johnson, Org. Lett. 2010, 12, 1784; c) T. Miyoshi, T. Miyakawa, M.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202008435
Angewandte Chemie International Edition
Ueda, O. Miyata, Angew. Chem. Int. Ed. 2011, 50, 928; d) M. N.
VanderWal, A. K. Dilger, D. W. C. MacMillan, Chem. Sci. 2013, 4, 3075;
e) V. Tona, A. Torre, M. Padmanaban, S. Ruider, L. Gonzalez, N. Maulide,
J. Am. Chem. Soc. 2016, 138, 8348; f) T. Yanagi, S. Otsuka, Y. Kasuga,
K. Fujimoto, K. Murakami, K. Nogi, H. Yorimitsu, A. Osuka, J. Am. Chem.
Soc. 2016, 138, 14582; g) X. Li, F. Lin, K. Huang, J. Wei, X. Li, X. Wang,
X. Geng, N. Jiao, Angew. Chem. Int. Ed. 2017, 56, 12307; h) A. Lgcht, L.
J. Patalag, A. U. Augustin, P. G. Jones, D. B. Werz, Angew. Chem. Int. Ed.
2017, 56, 10587; i) D. P. Hari, P. Caramenti, J. Waser, Acc. Chem. Res.
2018, 51, 3212.
8037; f) P.-J. Xia, Z.-P. Ye, Y.-Z. Hu, D. Song, H.-Y. Xiang, X.-Q. Chen,
H. Yang, Org. Lett. 2019, 21, 2658; g) H. Jiang, G. Seidler, A. Studer,
Angew. Chem. Int. Ed. 2019, 58, 16528; h) K. Ohmatsu, T. Nakashima,
M. Sato, T. Ooi, Nat. Commun. 2019, 10, 2706.
[15] For selected examples using electrophilic pyridinium salts: a) X. Ma, H.
Dang, J. A. Rose, P. Rablen, S. B. Herzon, J. Am. Chem. Soc. 2017, 139,
5998; b) W. Jo, J. Kim, S. Choi, S. H. Cho, Angew. Chem. Int. Ed. 2016,
55, 9690; c) Y.-T. He, D. Kang, I. Kim, S. Hong, Green Chem. 2018, 20,
5209; d) I. Kim, B. Park, G. Kang, J. Kim, H. Jung, H. Lee, M.-H. Baik,
S. Hong, Angew. Chem. Int. Ed. 2018, 57, 15517; e) W. Zhou, T. Miura,
M. Murakami, Angew. Chem. Int. Ed. 2018, 57, 5139; f) J. Q. Buquoi, J.
M. Lear, X. Gu, D. A. Nagib, ACS Catal. 2019, 9, 5330; g) 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; h) K. Lee, S. Lee, N. Kim, S. Kim,
[6] a) C. P. Jasperse, D. P. Curran, T. L. Fevig, Chem. Rev. 1991, 91, 1237; b)
U. Koert, Angew. Chem. Int. Ed. Engl. 1996, 35, 405; c) A. Studer, Chem.
Eur. J. 2001, 7, 1159; d) J. M. R. Narayanam, C. R. J. Stephenson, Chem.
Soc. Rev. 2011, 40, 102; e) M. Yan, J. C. Lo, J. T. Edwards, P. S. Baran,
J. Am. Chem. Soc. 2016, 138, 12692; f) K. J. Romero, M. S. Galliher, D.
A. Pratt, C. R. J. Stephenson, Chem. Soc. Rev. 2018, 47, 7851; g) L. Pitzer,
J. Luca Schwarz, F. Glorius, Chem. Sci. 2019, 10, 8285.
S.
doi.org/10.1002/anie.202004439.
[16] J. W. Beatty, C. R. J. Stephenson, Acc. Chem. Res. 2015, 48, 1474.
Hong,
Angew.
Chem.
Int.
Ed.
2020,
doi:
[7] a) P. V. Pham, D. A. Nagib, D. W. C. MacMillan, Angew. Chem. Int. Ed.
2011, 50, 6119; b) A. T. Herrmann, L. L. Smith, A. Zakarian, J. Am. Chem.
Soc. 2012, 134, 6976; c) W. Kong, C. Yu, H. An, Q. Song, Org. Lett. 2018,
20, 349; d) G. N. Chernov, V. V. Levin, V. A. Kokorekin, M. Struchkova,
A. D. Dilmana, Adv. Synth. Catal. 2017, 359, 3063; e) Q. Luo, R. Mao, Y.
Zhu, Y. Wang, J. Org. Chem. 2019, 84, 13897; f) M.-C. Fu, R. Shang, B.
Zhao, B. Wang, Y. Fu, Science 2019, 363, 1429; g) D. Spinnato, B.
Schweitzer-Chaput, G. Goti, M. Oseka, P. Melchiorre, Angew. Chem. Int.
Ed. 2020, 59, 9485.
[17] The exact mass of TEMPO-ylide adduct was detected by HRMS (See
supporting information for further detail).
[18] a) A. R. Katritzky, C. W. Rees, E. F. V. Scriven, Comprehensive
Heterocyclic Chemistry II, Vol. 5, Elsevier, 1996; b) J. P. Michael, Nat.
Prod. Rep. 2005, 22, 627; c) M. D. Hill, Chem. Eur. J. 2010, 16, 12052.
[19] a) S. R. S. S. Kotti, C. Timmons, G. Li, Chem. Biol. Drug Des. 2006, 67,
101; b) D. Lucet, T. Le Gall, C. Mioskowski, Angew. Chem. Int. Ed. 1998,
37, 2580.
[8] For selected examples of radical-polar crossover reactions: a) V. R.
Yatham, Y. Shen, R. Martin, Angew. Chem. Int. Ed. 2017, 56, 10915; b)
T. Ju, Q. Fu, J.-H. Ye, Z. Zhang, L.-L. Liao, S.-S. Yan, X.-Y. Tian, S.-P.
Luo, J. Li, D.-G. Yu, Angew. Chem. Int. Ed. 2018, 57, 13897; c) K.
Donabauer, M. Maity, A. L. Berger, G. S. Huff, S. Crespi, B. Kꢀnig, Chem.
Sci. 2019, 10, 5162; d) Q.-Y. Meng, T. E. Schirmer, A. L. Berger, K.
Donabauer, B. Kꢀnig, J. Am. Chem. Soc. 2019, 141, 11393; e) W. P.
Thomas, D. J. Schatz, D. T. George, S. V. Pronin, J. Am. Chem. Soc. 2019,
141, 12246; f) J. L. M. Matos, S. Vasquez-Cespedes, J. Gu, T. Oguma, R.
A. Shenvi, J. Am. Chem. Soc. 2018, 140, 16976; g) C. Shu, R. S. Mega, B.
J. Andreassen, A. Noble, V. K. Aggarwal, Angew. Chem. Int. Ed. 2018,
57, 15430; h) C. Shu, A. Noble, V. K. Aggarwal, Angew. Chem., Int. Ed.
2019, 58, 3870.
[9] S. Fukuzumi, M. Fujita, J. Otera, Y. Fujita, J. Am. Chem. Soc. 1992, 114,
10271.
[10] For selected recent examples a) E. Yen-Pon, P. A. Champagne, L.
Plougastel, S. Gabillet, P. Thuery, M. Johnson, G. Muller, G. Pieters, F.
Taran, K. N. Houk, D. Audisio, J. Am. Chem. Soc. 2019, 141, 1435; b) R.
A. Kumar, M. R. Pattanayak, E. Yen-Pon, J. Eliyan, K. Porte, S. Bernard,
M. Riomet, P. Thuery, D. Audisio, F. Taran, Angew. Chem. Int. Ed. 2019,
58,14544; c) H. Jangra, Q. Chen, E. Fuks, I. Zenz, P. Mayer, A. R. Ofial,
H. Zipse, H. Mayr, J. Am. Chem. Soc. 2018, 140, 16758; d) M. S. T.
Morin, D. J. St-Cyr, B. A. Arndtsen, E. H. Krenske, K. N. Houk, J. Am.
Chem. Soc. 2013, 135, 17349.
[11] a) R. Huisgen, R. Grashey, R. Krischke, Tetrahedron Lett. 1962, 9, 387;
b) J. J. Mousseau, J. A. Bull, C. L. Ladd, A. Fortier, D. S. Roman, A. B.
Charette, J. Org. Chem. 2011, 76, 8243; c) S. Ding, Y. Yan, N. Jiao,
Chem. Commun. 2012, 49, 4250; d) A. Kakehi, Heterocycles 2012, 85,
1529; e) K. Miyazawa, T. Koike, M. Akita, Tetrahedron 2016, 72, 7813-
7820.
[12] a) T. M. Monos, R. C. McAtee, C. R. J. Stephenson, Science 2018, 361,
1369; b) J. Yu, Z. Wu, C. Zhu, Angew. Chem. Int. Ed. 2018, 57, 17156;
c) M.Wang, H. Zhang, J. Liu, X. Wu, C. Zhu, Angew. Chem. Int. Ed.
2019, 58, 17646; d) Y. Moon, B. Park, I. Kim, G. Kang, S. Shin, D. Kang,
M.-H. Baik, S. Hong, Nat. Commun. 2019, 10, 4117; e) G. R. Mathi, Y.
Jeong, Y. Moon, S. Hong, Angew. Chem. Int. Ed. 2020, 59, 2049; f) T.
Patra, P. Bellotti, F. Strieth-Kalthoff, F. Glorius, Angew. Chem. Int. Ed.
2020, 59, 3172;.
[13] D. S. Allgauer, P. Mayer, H. Mayr, J. Am. Chem. Soc. 2013, 135, 15216.
[14] For selected recent examples of reductive quenching photocatalysis: a) G.
J. Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature 2016, 539,
268; b) S. B. Lang, R. J. Wiles, C. B. Kelly, G. A. Molander, Angew.
Chem. Int. Ed. 2017, 56, 15073; c) L. Candish, M. Freitag, T. Gensch, F.
Glorius, Chem. Sci. 2017, 8, 3618; d) H. Im, D. Kang, S. Choi, S. Shin,
S. Hong, Org. Lett. 2018, 20, 7437; e) J. P. Phelan, S. B. Lang, J. S.
Compton, C. B. Kelly, G. A. Molander, J. Am. Chem. Soc. 2018, 140,
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202008435
Angewandte Chemie International Edition
Photochemistry
Honggu Im, Wonjun Choi, and Sungwoo
Hong __________ Page – Page
Photocatalytic Vicinal Aminopyridylation
of Methyl Ketones by a Double
Umpolung Strategy
Double umpolung: A photocatalytic strategy for the vicinal aminopyridylation of ketones was
developed using pyridinium N–N ylides as bifunctional reagents. Intriguingly, the synthetic
advances of this approach were highlighted by the selective installation of amino and pyridyl
groups into the nucleophilic α-position and electrophilic carbonyl carbon, respectively.
6
This article is protected by copyright. All rights reserved.