Functionalization of α-C(sp3)?H Bonds in Amides Using Radical Translocating Arylating Groups

Article abstract of DOI:10.1002/anie.202013275

α-C?H arylation of N-alkylamides using 2-iodoarylsulfonyl radical translocating arylating (RTA) groups is reported. The method allows the construction of α-quaternary carbon centers in amides. Various mono- and disubstituted RTA-groups are applied to the arylation of primary, secondary, and tertiary α-C(sp³)?H-bonds. These radical transformations proceed in good to excellent yields and the cascades comprise a 1,6-hydrogen atom transfer, followed by a 1,4-aryl migration with subsequent SO₂ extrusion.

Full text of DOI:10.1002/anie.202013275

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Functionalization of α-C(sp3)‒H Bonds in Amides Using Radical
Translocating Arylating Groups
Authors: Niklas Radhoff and Armido Studer
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.202013275
Link to VoR: https://doi.org/10.1002/anie.202013275

10.1002/anie.202013275
Angewandte Chemie International Edition
COMMUNICATION
Functionalization of -C(sp3)‒H Bonds in Amides Using Radical
Translocating Arylating Groups
Niklas Radhoff and Armido Studer*[a]
[a]
N. Radhoff, Prof. Dr. A. Studer
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität
Corrensstraße 40, 48149 Münster (Germany)
E-mail: studer@uni-muenster.de
Supporting information for this article is given via a link at the end of the document.
Abstract: α-C-H arylation of N-alkylamides using 2-iodoarylsulfonyl
radical translocating arylating (RTA) groups is reported. The method
allows the construction of α-quaternary carbon centers in amides.
Various mono- and disubstituted RTA-groups are applied to the
arylation of primary, secondary and tertiary -C(sp3)−H-bonds. These
radical transformations proceed in good to excellent yields and the
cascades comprise a 1,6-hydrogen atom transfer, followed by a
1,4-aryl migration with subsequent SO2-extrusion.
Nevado group used acrylamides as radical acceptors, where an
initial conjugate radical addition is followed by a 1,4-aryl migration
reaction to an intermediately generated -amide radical to install
an -aryl substituent (Scheme 1b).[11a-c]
The functionalization of C‒H bonds has attracted great attention
in synthesis during the last 30 years.[1] In this context, the principle
of directed functionalization is a highly valuable strategy and
many protocols for C(sp2)‒H functionalization using
transition-metals (TM) as mediators or catalysts have been
developed.[1c-d,2] However, TM-catalyzed processes for remote
arylation of C(sp3)‒H bonds are relatively scarce.[1b,3]
Complementary to TM-mediated processes, remote radical C−H
functionalization via selective hydrogen atom transfer (HAT)
processes has been established.[1c,4] HAT can be achieved to
reactive N-centered radicals, as early documented by the
pioneering studies of Hofmann[5a]
, .
Löffler and Freytag[5b]
Moreover, reactive C-radicals can also be applied for HAT-
mediated remote C(sp3)‒H functionalization. The group of Curran
introduced in the late 1980s the elegant concept of protecting
radical translocating groups by installing aryl radical precursors
as protecting groups for alcohols and amines.[6] The formation of
a transient aryl radical then triggers a selective 1,5-HAT to
generate the corresponding translocated C-radical that in turn can
be trapped, eventually leading to a remote C−H functionalization.
In recent years, radical aryl migration reactions[7] induced by
1,n-HAT processes have emerged as a powerful tool for the
regioselective arylation of C(sp3)−H bonds.[8] Along these lines,
our group developed a method for remote radical C(sp3)‒H
arylation of alcohols using 2-iodoarylsulfonyl chlorides as radical
translocating arylating groups (RTA, Scheme 1a).[9] Generation of
an aryl radical in the corresponding sulfonates followed by
selective 1,7-HAT, 1,5-aryl migration and desulfonylation
provided -arylated alcohols in moderate to good yields.
All-carbon -quaternary amides are valuable compounds in
pharmacological chemistry since they can express biological
activity for example as anti-nausea (Netupitant®) and spasmolytic
agents[10]. Recently, three different strategies were introduced for
the -arylation of amides proceeding via an aryl migration
reaction either using radical or ionic chemistry. Importantly, these
methods allow for the construction of quaternary C-centers. The
Scheme 1. C-arylation using radical and ionic chemistry. a) Remote C−H
arylation of unactivated C(sp3)−H-bonds using radical translocating arylating
(RTA) groups.[9] b) Radical -arylation of prefunctionalized amides.[11a-c,12] c)
Stereoselective anionic remote α-C(sp3)‒H arylation of amino acids.[13] d) This
work: Remote radical C(sp3)‒H arylation of amides under construction of an all-
carbon-quaternary center.
The groups of Zhang and Wang developed a similar protocol:
Reduction of an -haloamide under photoredox conditions leads
to the corresponding -amide radical that engages in an aryl
migration reaction (Scheme 1b).[12] Of note, both strategies rely
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202013275
Angewandte Chemie International Edition
COMMUNICATION
on -prefunctionalized amide derivatives. In 2018, the group of
Clayden introduced a protocol for the stereoselective -C(sp3)−H
arylation of amino acid derivatives using an anionic 1,4-aryl
migration strategy (Scheme 1c).[13]
syringe pump) in refluxing benzene for 6 h (Table 1, entry 1).
Instead, oxindole 3a as a product of an homolytic aromatic
substitution[11a] of an intermediate amidyl radical was isolated in
38% yield. fac-Ir(ppy)3 is known to reductively generate aryl
radicals from aryl iodides at room temperature under irradiation
with visible light.[14] Pleasingly, irradiation of 1a in the presence of
the Ir-photocatalyst (1 mol%) and Cs2CO3 (3.0 equiv) as an
additive with two blue LEDs (456 nm and 467 nm) for 16 h at room
temperature in acetonitrile provided the desired α-phenylated
amide 2a in 73% yield and oxindole 3a was not identified (Table
1, entry 2, Method A). Lowering the amount of Cs2CO3 afforded
worse results (Table 1, entries 3-5). Notably, without added
Cs2CO3, starting material could quantitatively be recovered (Table
1, entry 6). Blue light and also the Ir-catalyst are both essential for
a successful transformation (Table 1, entries 7-8). Switching the
light source to a CFL lamp led to significantly lower yield (entry 9,
Table 1). Moreover, the nature of the counterion of the carbonate
was found to be crucial for the reaction outcome as the use of
Na2CO3 and K2CO3 led to lower yields of amide 2a (entries 10-11,
Table 1). However, catalyst-free -arylation is feasible upon
irradiation of a solution of 1a in acetonitrile (1 molar) with UV-light
(254 nm) and the targeted product 2a was isolated in 82% yield
(Table 1, entry 9, Method B). With two different methods A and B
in hand, the substrate scope was investigated.
Herein we introduce radical -C(sp3)−H arylation of amides using
N-alkyl-ortho-iodoarylsulfonamide-based RTA-chemistry. The
RTA-groups are easily incorporated into various carboxylic acid
derivatives bearing an -C(sp3)−H bond via amidation of the
corresponding acid chlorides with an aryl sulfonamide. The
resulting sulfonamides can be converted to -arylated amides in
a radical cascade comprising aryl radical generation, selective
1,6-HAT followed by 1,4-aryl migration and reductive
desulfonylation. Primary, secondary and also tertiary C(sp3)−H
bonds, that are highly challenging for C(sp3)−H arylation using
transition metal-mediated processes[8a,9]
,
are efficiently
functionalized by this cascade. In contrast to the previous radical
based approaches where prefunctionalized amides were used as
substrates (see Scheme 1b),[11a-c,12] the introduced process
operates on -unfunctionalized amides.
Table 1. Reaction optimization.
Entry
1[a,c]
2
Initiator/PC
AIBN (30)
Ir(ppy)3 (1)
Ir(ppy)3 (1)
Ir(ppy)3 (1)
Ir(ppy)3 (1)
Ir(ppy)3 (1)
None
Additive
Light Source
None
Yield 2a
n.i.
Bu3SnH (1.3)
Cs2CO3 (3.0)
Cs2CO3 (2.0)
Cs2CO3 (1.2)
Cs2CO3 (0.5)
/
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
blue LEDs
None
73%[b]
67%
3
4
30%
5
19%
6
n.i.
7
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Cs2CO3 (3.0)
Na2CO3 (3.0)
K2CO3 (3.0)
/
n.i.
8[c]
9
Ir(ppy)3 (1)
Ir(ppy)3 (1)
Ir(ppy)3 (1)
Ir(ppy)3 (1)
None
n.i.
CFL
37%
10
11
12
blue LEDs
blue LEDs
254 nm
22%
Scheme 2. Substrate scope - variation of the N-substituent R. Reaction scale
between 0.1 M and 0.25 M. Isolated yields. [a] Reaction time: 72 h.
10%
94% (82%[b]
)
We first studied the influence of the N-substituent R on the
reaction outcome (Scheme 2). Sulfonamides 1a-c bearing a
secondary N-alkyl group provided the corresponding
-phenylated amides 2a-c in good yields using the milder
Ir-mediated process (Method A, 73-85%). Good yields for 2a and
2b were also achieved upon simple UV-irradiation in the absence
of the catalyst and additive (Method B, 82% and 63%). The
transformation of sulfonamide 1a to amide 2a was also feasible
on a gram-scale (59% yield). The sterically less hindered
N-methyl amide 2d afforded the targeted 3d in 77% using method
A. However, the catalyst-free variant did not provide a good result
Reactions were conducted under an argon atmosphere on a 0.1 mmol scale.
Blue LEDs: 456 nm and 467 nm. CFL = compact fluorescent lamp. Yields were
determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as internal
standard. [a] In benzene at 95°C for 6 h. Addition of tin hydride by syringe pump
over 2 h. Isolated yield of oxindole 3a: 38%. [b] Isolated Yield. [c] In the dark.
n.i. = not identified.
Optimization was conducted with N-((2-iodophenyl)sulfonyl)-N-
isopropyl-isobutyramide (1a) as the model substrate (Table 1).
The desired arylation product 2a was not detected by
GC-MS-analysis upon reacting 1a with azobis(isobutyronitrile)
(AIBN, 0.3 equiv) and Bu3SnH (1.2 equiv, added over 2 h via
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202013275
Angewandte Chemie International Edition
COMMUNICATION
in this particular case (13%). In contrast, the N-benzyl-substituted
sulfonamide 1e was not a good substrate for the Ir-catalyzed
process (24%), whereas method B afforded an acceptable yield
(56%). The N-phenyl sulfonamide 1f delivered only 24% product
2f using method A and with method B, 2f was not identified.
Conformational effects exerted by the N-substituents likely play a
role in these transformations. Along these lines, the unsubstituted
sulfonamide 1f did not provide the target 2g using either method
A or B and the same result was noted for the Weinreb-type
substrate 1h.
2s (56%) has also been successfully prepared following our
approach. However, the 2-pyridyl derivative 2t and the thienyl
amide 2u were formed in traces only. The targeted migration
product was not observed for the para-imide substrate 1v. Instead,
N,S-heterocycle 2’v was formed in 76% yield via 1,6-HAT
followed by a homolytic aromatic substitution reaction.
Scheme 4. Substrate scope – primary, secondary and tertiary -amide radicals.
Reaction scale: 0.1 − 0.15 mmol. Isolated yields.
Next, we studied the effect of the -substituents in amides of type
1 on the novel cascade using method A (Scheme 4). Switching
from the parent -dimethyl derivative 1a to the
-methyl--propyl congener 1w did not affect the yield and 2w
was isolated in 81% yield. With the sterically even more hindered
-isopropyl--methyl amide 1x, yield remained good (2x, 72%)
and a similar result was obtained for the cyclic amide 1y. We also
addressed the synthesis of -diarylated amides using
-aryl--methyl amides 1z-1ad as substrates. For steric reasons
and also for electronic reasons (reactions proceed through more
stabilized -amide radicals) these -arylations are even more
challenging. We were pleased to find that all tested
transformations proceeded, albeit with slightly lower efficiencies.
Electronic effects of the -aryl substituent could be observed.
Better yields were achieved with the more electron rich
para-alkyl-phenyl amides and products 2ac and 2ad were
isolated in 64% yield. Notable, substrate 1ad is a readily prepared
Ibuprofene®-derived amide. Lower yields were noted for the
para-fluoro and para-chloro derivatives (43-48%), whereas the
corresponding bromide 2ab was isolated in 62% yield. Our
method also tolerates an α-methoxy substituent as documented
by the successful preparation of 2ae (63%).
Scheme 3. Substrate scope - variation of the radical translocating arylating
group. Reaction scale: 0.1 − 0.25 mmol. Isolated yields.
To investigate the effect of the migrating aryl moiety on the
reaction efficiency, various N-isopropyl sulfonamides 1i-s were
prepared (see SI). For this study, only method A was chosen
(Scheme 3). We could show that meta- and para-mono-
substituted phenyl groups bearing electron donating (methyl and
methoxy) and withdrawing (chloro and trifluoromethyl) engaged in
the transformation and the products 2i-2m were isolated in 48-
79% yields. Arylsulfonamides 1n-1p containing doubly
substituted phenyl groups could be successfully transformed to
the corresponding -arylated amides 2n-2p (62-72%) and also
the -naphthyl-substituted amides 2q (73%) and 2r (68%) were
accessible via this approach. The latter also shows the
compatibility of amine functional groups with the applied
conditions. The amide core of the anti-nausea agent Netupitant®
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202013275
Angewandte Chemie International Edition
COMMUNICATION
2-
We continued the studies by addressing the -arylation of
-monosubstituted amides. -Phenylation with amide 1ag
occurred highly efficiently and targeted 2ag was isolated in
excellent 93% yield. A lower yield was achieved for the -phenoxy
derivative 2af, likely due to the increased stability of the
corresponding intermediate -amide radical. Not surprisingly,
steric effects at the -position play a role and the highest yield
was obtained for the -unsubstituted amide 1ah where the
product 2ah was isolated in 95% yield. This is in line with the fact
that only traces of the sterically highly hindered product 2ai were
observed by GC- and ESI-MS. Moreover, the large stabilization of
the corresponding intermediate bisbenzylic α-amide radical also
contributes to the suppression of the attempted -phenylation in
1ai.[15]
oxidation of CO3 with the [IrIV]-complex with concomitant
generation the carbonate radical anion.[16,17] This also explains
why more than one equivalent of Cs2CO3 is required. Moreover,
cyclovoltammetry studies of cesium carbonate in acetonitrile
support the feasibility of the reaction of Cs2CO3 with the
[IrIV]-complex (see SI).
In method B, the aryl radical R-1 is generated by UV-induced
homolyis of the C−I bond in 1a. As for method A, 1,6-HAT is
followed by 1,4-phenyl migration to give after SO2-extrusion the
amidyl radical R-4. Reduction by acetonitrile via intermolecular
HAT finally provides the product 2a.[12,18] That reduction step
could experimentally be further supported. Hence, UV-light
(254 nm) irradiation of 1a in deuterated acetonitrile provided
amide 2a-D with >95% deuterium incorporation (see SI).
In summary, two protocols for arylation of α-C(sp3)−H bonds in
amides starting from easily accessible substrates was introduced.
Reactions proceed in good to excellent yields via
a
1,6-HAT/1,4-aryl migration/desulfonylation sequence. These
radical translocation arylation cascades show broad substrate
scope. Importantly, the introduced method allows for construction
of all carbon quaternary centers but secondary and primary
-amide C(sp3)−H bonds can also be functionalized. Considering
the Ir-catalyzed process, inexpensive and environmentally benign
cesium carbonate acts as the terminal reductant. Although less
general and not as mild, a transition-metal free variant for this
transformation was also developed.
Acknowledgements
We thank the WWU Mꢀnster and the European Research Council
(ERC Advanced Grant Agreement no. 692640) for financial
support.
Keywords: Radical • Aryl Migration • Hydrogen Atom Transfer •
Visible light catalysis
Scheme 5. Suggested mechanism for the remote arylation of α-C(sp3)−H amide
bonds via a 1,6-HAT/1,4-aryl migration/desulfonylation cascade.
[1]
Selected Reviews regarding (Remote) C−H-bond functionalization: a) X.
Chen, K. M. Engle, D. Wang, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48,
5094 – 5114; Angew. Chem. 2009, 121, 5196 – 5217; b) J. Yamaguchi,
A.D. Yamaguchi, K. Itami, Angew. Chem. Int. Ed. 2012, 51, 8960 – 9009;
Angew. Chem. 2012, 124, 9092 – 9142; c) M. Zhang, Y. Zhang, X. Jie,
H. Zhao, G. Li, W. Su, Org. Chem. Front. 2014, 1, 843 – 895; d) J. C. K.
Chu, T. Rovis, Angew. Chem. Int. Ed. 2018, 57, 62 – 101; Angew. Chem.
2018, 130, 64 – 105; e) L. M. Stateman, K. M. Nakafuku, D. A. Nagib,
Synthesis 2018, 50, 1569 – 1586.
Plausible mechanisms for methods A and B are presented in
Scheme 5. Considering method A, the aryl radical R-1 is
reductively generated by oxidative quenching of the photoexcited
IrIII-catalyst.[14]
Stern-Volmer
fluorescence
quenching
experiments with model substrate 1a and the photocatalyst
support the oxidative quenching of the photocatalyst (see SI).
Radical R-1 then undergoes a selective 1,6-HAT to give the
translocated -amide radical R-2. Ipso-attack of R-2 at the arene
moiety of the RTA-group leads to the cyclohexadienyl radical R-3.
Rearomatization completing the aryl migration and extrusion of
SO2 lead to the amidyl radical R-4.[11a-c,12] Reduction of the amidyl
radical by the excited [IrIII]-catalyst and protonation by traces of
water which is present in the reaction mixture eventually provide
product 2a. To further support the suggested mechanism,
reaction was repeated in deuterated acetonitrile. As no deuterium
incorporation into the N−H bond of the amide 2a was observed,
hydrogen abstraction from the solvent is not likely. When
deuterium oxide (20 equiv) was added to the reaction mixture,
deuterium incorporation (>95% ND) in 2a was obtained under
standard conditions. The [IrIII]-catalyst is regenerated upon
[2]
For selected examples see: a) I. Moritani, Y. Fujiwara, Tetrahedron Lett.
1967, 12, 1119 – 1120; b) B. Trost, F. D. Toste, J. Am. Chem. Soc. 1996,
118, 6305 – 6306; c) C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura, Y.
Fujiwara, Science 2000, 287, 1992 – 1995; d) T. Yokota, M. Tani, S.
Sakaguchi, Y. Ishii, J. Am. Chem. Soc. 2003, 125, 1476 – 1477; e) G.
Cai, Y. Fu, Y. Li, X. Wan, Z. Shi, J. Am. Chem. Soc. 2007, 129, 7666 –
7673, f) L. Desai, K. Stowers, M. S. Sanford, J. Am. Chem. Soc. 2008,
130, 13285 – 13293.
[3]
a) J. He, M. Wasa, K.S.L. Chan, Q. Shao, J.-Q. Yu, Chem. Rev. 2017,
117, 8754 – 8786: b) O. Daugulis, J. Roane, L. Trane, Acc. Chem. Res.
2015, 48, 1053 – 1064; c) T.G. Saint-Denis, R.-Y. Zhu, G. Chen, Q.-F.
Wu, J.-Q. Yu, Science 2018, 359, eaao4798; d) G. Chen, W. Gong, Z.
Zhuang, M. S. Andrä, Y.-Q. Chen, X. Hong, Y.-F. Yang, T. Liu, K.N. Houk,
J.-Q. Yu, Science 2016, 353, 1023 – 1027; e) J.J. Topszewski, P.J.
Cabrera, N.I. Saper, M.S. Sanford, Nature 2016, 531, 220 – 224; f) Y.
Liu, H. Ge, Nat. Chem. 2017, 9, 26 – 32; g) G.-F. Wu, P.-X. Shen, J. He,
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202013275
Angewandte Chemie International Edition
COMMUNICATION
X.-B. Wang, F. Zhang, Q. Shao, R.-Y. Zhu, C. Mapelli, J.X. Qiao, M.A.
Maiensheim, P. Liu, M.-Y. Ngai, Angew. Chem. Int. Ed.
10.1002/anie.202009490.
Ross, J.-Q. Yu, Science 2017, 355, 499 – 503.
[4]
For recent examples see: a) H. Jiang, A. Studer, Angew. Chem. Int. Ed.
2018, 57, 1692 – 1696; Angew. Chem. 2018, 130, 1708 – 1712; b) W.
Shu, E. Merino, C. Nevado, ACS Cat. 2018, 8, 6401 – 6406; c) S. M.
Thullen, S. M. Treacy, T. Rovis, J. Am. Chem. Soc. 2019, 141, 14062 –
14067; d) S. Wu, X. Wu, D. Wang, C. Zhu, Angew. Chem. Int. Ed. 2019,
58, 1499 – 1503; Angew. Chem. 2019, 131, 1513 – 1517; e) X. Bao, Q.
Wang, J. Zhu, Nat. Commun. 2019, 10, 769 – 775; f) H. Chen, S. Yu,
Org. Biomol. Chem. 2020, 18, 4519 – 4532; g) G. Kumar, S. Pradhan, I.
Chatterjee, Chem. Asian J. 2020, 15, 651 – 672.
[17] E. H. Doeven, E. M. Zammit, G. J. Barbante, P. S. Francis, N. W. Barnett,
C. F. Hogan, Chem. Sci. 2013, 4, 977 – 982.
[18] a) V. Rey, A. B. Pierini, A. B. Peñéñory, J. Org. Chem. 2008, 74, 1223 –
1230; b) L. Zheng, C. Yang, Z. Xu, F. Gao, W. Xia, J. Org. Chem. 2015,
80, 5730 – 5736.
[5]
[6]
a) A. W. Hofmann, Chem. Ber. 1883, 16, 558 – 560; b) K. Löffler, C.
Freytag, Chem. Ber. 1909, 42, 3427 – 3431.
a) D. P. Curran, D. Kim, H. T. Liu, W. Shen, J. Am. Chem. Soc. 1988,
110, 5900 – 5902; b) D. P. Curran, A. C. Abraham, H. Liu, J. Org. Chem.
1991, 56, 4335 – 4337; c) D. P. Curran, H. Yu, Synthesis 1992, 123 –
127; d) D. P. Curran, J. Xu, J. Am. Chem. Soc. 1996, 118, 3142 – 3147.
a) R. Loven, W.N. Speckamp, Tetrahedron Lett. 1972, 16, 1567 – 1570;
b) M. Bossart, A. Studer, Tetrahedron 2001, 57, 9649 – 9667; c) M.
Bossart, R. Fässler, J. Schoenberger, A. Studer, Eur. J. Org. Chem. 2002,
16, 2742 – 2757; c) Z.-M. Chen, X.-M. Zhang, Y.-Q. Tu, Chem. Soc. Rev.
2015, 44, 5220 – 5245; d) D. Alpers, K. P. Cole, C. R. J. Stephenson,
Angew. Chem. Int. Ed. 2018, 37, 12167 – 12170; Angew. Chem. 2018,
130, 12344 – 12348; e) W. Li, W. Xu, J. Xie, S. You, C. Zhu, Chem. Soc.
Rev. 2018, 47, 654 – 667; f) T. M. Monos, R. C. McAtee, C. R. J.
Stephenson, Science 2018, 361, 1369 – 1373; g) D. M. Whalley, H. A.
Duong, M. F. Greaney, Chem. Eur. J. 2019, 25, 1927 – 1930; h) H. L.
Barlow, P. T. G. Rabet, A. Durie, T. Evans, M. F. Greaney, Org. Lett.
2019, 21(22), 9033 – 9035; i) Z.-S. Wang, Y.-B. Chen, H.-W. Zhang, Z.
Sun, C. Zhu, L.-W- Ye, J. Am. Chem. Soc. 2020, 142, 3636 – 3644; j) J.
Yan, H. W. Cheo, W. K. Teo, X. Shi, H. Wu, S. B. Idres, L.-W. Deng, J.
Wu, J. Am. Chem. Soc. 2020, 142, 11357 – 11392; k) R. Abrams, J.
Clayden, Angew. Chem. Int. Ed. 2020, 59, 11600 – 11606; Angew. Chem.
2020, 132, 11697 – 11703; l) J. Liu, D. Ba, W. Lv, Y. Chen, Z. Zhao, G.
Cheng, Adv. Synth. Catal. 2020, 362, 213 – 233; m) D. Whalley, H. A.
Duong, M. F. Greaney, Chem. Commun. 2020, 56, 11493 – 11496; n) J.
Yan, H. W. Cheo, W. K. Teo, X. Shi, H. Wu, S. B. Idres, L.-W. Deng, J.
Wu, J. Am. Chem. Soc. 2020, 142, 11357 – 11362.
[7]
[8]
a) X. Wu, M. Wang, L. Huan, D. Wang, J. Wang, C. Zhu, Angew. Chem.
Int. Ed. 2018, 57, 1640 – 1644; Angew. Chem. 2018, 130, 1656 – 1660;
c) X. Wu, H. Zhang, N. Tang, Z. Wu, D. Wang, M. Ji, Y. Xu, M. Wang, C.
Zhu, Nat. Commun. 2018, 9, 3343 – 3350; d) Z. Li, Q. Wang, J. Zhu,
Angew. Chem. Int. Ed. 2018, 57, 13288 – 13292; Angew. Chem. 2018,
130, 13472 – 13476; e) X. Zhang, L. Stateman, D. Nagib, Chem. Sci.
2019, 10, 1207 – 1211; f) X. Wu, C. Zhu, Acc. Chem. Res. 2020, 53,
1620 – 1636.
[9]
F. Friese, C. Mück-Lichtenfeld, A. Studer, Nat. Commun. 2018, 9, 2808
– 2814.
[10] University of Houston System, 2019, Aryl-substituted acetamide and
pyrrolidine-2-one derivatives and their use for the treatment of seizures,
WO2019099760A1.
[11] a) W. Kong, M. Casimiro, E. Merino, C. Nevado, J. Am. Chem. Soc. 2013,
135, 14480 – 14483; b) W. Kong, M. Casimiro, N. Fuentes, E. Merino, C.
Nevado, Angew. Chem. Int. Ed. 2013, 52, 13086 – 13090; Angew. Chem.
2013, 125, 13324 – 13328; c) W. Kong, E. Merino, C. Nevado, Angew.
Chem. Int. Ed. 2014, 53, 5078 – 5082; Angew. Chem. 2014, 126, 5178
– 5182.
[12] Y. Li, B. Hu, W. Dong, X. Xie, J. Wan, Z. Zhang, J. Org. Chem. 2016, 81,
7036 – 7041.
[13] D. J. Leonard, J. W. Ward, J. Clayden, Nature 2018, 562, 105 – 109.
[14] J. D. Nguyen, E. M. D’Amato, J. M. R. Narayanam, C. R. J. Stephenson,
Nat. Chem. 2012, 4, 854 – 859.
[15] D. Leifert, A. Studer, Angew. Chem. Int. Ed. 2020, 59, 74 – 108; Angew.
Chem. 2020, 132, 74 – 110.
[16] B. Zhang, A. Studer, Org. Lett. 2014, 16, 3990 – 3993; b) Angew. Chem.
Int. Ed. 2014, 53, 4910 – 4914; Angew. Chem. 2014, 126, 5010 – 5014;
c) M. Bühl, P. DaBell, D. W. Manley, R. P. McCaughn, J.C. Walton, J.
Am. Chem. Soc. 2015, 137, 16153 – 16162; d) J. W. Lee, S. Lim, D.N.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202013275
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 2:
COMMUNICATION
N. Radhoff, A. Studer
Page No. – Page No.
Multitasking! α-C-H arylation of N-alkylamides using 2-iodoarylsulfonyl radical
translocating arylating (RTA) groups is reported. The RTA group fulfills multiple roles:
a) acts as radical precursor, b) engages in remote C−H activation via hydrogen atom
transfer and c) serves as arylating moiety. The method allows the construction of
α-quaternary carbon centers in amides and shows broad substrate scope. Cascades
can be conducted applying photoredox conditions under blue light irradiation or in the
absence of any catalyst upon UV-irradiation.
Functionalization of -C(sp3)‒H
Bonds in Amides Using Radical
Translocating Arylating Groups
6
This article is protected by copyright. All rights reserved.