Site-Selective Remote Radical C?H Functionalization of Unactivated C?H Bonds in Amides Using Sulfone Reagents

Article abstract of DOI:10.1002/anie.201807455

A general and practical strategy for remote site-selective functionalization of unactivated aliphatic C?H bonds in various amides by radical chemistry is introduced. C?H bond functionalization is achieved by using the readily installed N-allylsulfonyl moiety as an N-radical precursor. The in situ generated N-radical engages in intramolecular 1,5-hydrogen atom transfer to generate a translocated C radical which is subsequently trapped with various sulfone reagents to afford the corresponding C?H functionalized amides. The generality of the approach is documented by the successful remote C?N₃, C?Cl, C?Br, C?SCF₃, C?SPh, and C?C bond formation. Unactivated tertiary and secondary C?H bonds, as well as activated primary C?H bonds, can be readily functionalized by this method.

Full text of DOI:10.1002/anie.201807455

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Accepted Article
Title: Site-selective Radical Remote C-H Functionalization of
Unactivated C-H Bonds in Amides with Sulfone Reagents
Authors: Yong Xia, Lin Wang, and Armido Studer
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201807455
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Site-selective Radical Remote CH Functionalization of
Unactivated CH Bonds in Amides with Sulfone Reagents
Yong Xia, Lin Wang and Armido Studer*
Abstract: A general and practical strategy for remote site-selective
functionalization of unactivated aliphatic CH bonds in various
amides via radical chemistry is introduced. CH bond
functionalization is achieved by using the readily installed N-
allylsulfonyl moiety as a N-radical precursor. The in situ generated
N-radical engages in intramolecular 1,5-hydrogen atom transfer to
generate a translocated C-radical which is subsequently trapped
with various sulfone reagents to afford the corresponding CH
functionalized amides. The generality of the approach is
documented by the successful remote CN3, CCl, CBr, CSCF3,
SPh and CC bond formation. Unactivated tertiary and secondary
CH bonds as well as activated primary CH bonds can be readily
functionalized applying this method.
cyclizations.[7] Encouraged by these results, we hypothesized
that such a strategy can also be applied to site-selective remote
CH functionalization via 1,5-HAT. Along these lines, we aimed
to realize the remote azidation, chlorination, bromination,
trifluoromethylthiolation,
phenylthiolation,
cyanation
and
alkenylation going beyond standard HLF-type reactions
(Scheme 1c). In contrast to typical HLF-processes, where one
radical precursor provides only a single product, our approach
offers accessing various products starting from
a single
precursor by simply varying the radical trapping reagent XSO2R’.
Considering diversity oriented synthesis, the chosen amidyl
radical precursor must be accessible in larger scale, stable and
storable for longer time. By looking at these prerequisites, we
regarded allylsulfonamides as ideal candidates and disclose
herein our findings.
In recent years, the functionalization of C(sp3)H bonds has
become an important and intensively investigated research area,
since it allows for streamlined synthesis of target compounds
and for late-stage modification of complex structures.[1] These
efforts have led to the development of advanced methodologies
and new strategies have become available for CH
functionalization
at
unactivated sites.
Among them,
regioselective CH modification using intramolecular 1,5-
hydrogen atom transfer (HAT) to in situ generated amidyl
radicals has been recognized as a simple and powerful
approach, as it allows for site-selective generation of reactive δ-
carbon radicals (Scheme 1a).[2,3] Amide-mediated remote radical
CH functionalization finds its roots in the classical
Hofmann−Lꢀffler−Freytag (HLF) reaction,[4] where exciting
developments have been achieved over the past years.[2,3] Along
these lines, studies have mostly focused on CH halogenation
reactions (chlorination, bromination and iodination), but other
transformations have been explored less intensively.[5,6]
A
drawback is the need of using strong oxidants to generate N-
halogenated amides applied as N-radical precursors. Moreover,
these N-haloamides are generally unstable, have to be prepared
in situ and are at the same time also electrophilic halogenation
reagents, limiting their general applicability. With respect to
diversity oriented synthesis, this strategy has further limitations
since each amidyl radical precursor provides only a single type
of δ-halogenated product amide (Scheme 1b). Thus, the
development of a general protocol for remote diversity oriented
site-selective radical CH functionalization is still demanded.
N-allylsulfonamides were first used by Zard as precursors for
N-radicals for the preparation of lactams via amidyl radical
Scheme 1. Remote CH functionalization via 1,5-HAT to amidyl radicals.
Initial studies were devoted to remote CH functionalization of
alkylamine derived sulfonamide 1a as a model substrate, first
addressing remote CH azidation[8] (Table 1, for preparation of
all starting sulfonamides, see the Supporting Information). Three
azides 2a-c were tested as C-radical trapping reagents in
combination with α,α′-azobisisobutyronitrile (AIBN) as radical
initiator in dichloroethane (DCE). Whereas radical azidation with
benzenesulfonylazide (2b)[9] and Zhdankin reagent (IBX-N3,
[a]
Dr. Y. Xia, L. Wang and Prof. Dr. A. Studer
Organisch-ChemischesInstitut, WestfälischeWilhelms-Universität
Corrensstrasse40, 48149 Münster (Germany)
E-mail:studer@uni-muenster.de
2c)[10]
is
well
established,
the
use
of
trifluoromethanesulfonylazide (TfN3, 2a) for this purpose is
unprecedented. By using TfN3 as the N3-source, -CH azidation
occurred and the targeted amide 3a was obtained in promising
20% yield (entry 1). With 2b and 2c, lower yields were noted
(entries 2, 3) and TfN3 was therefore selected for further
Y. X. and L. W. contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201807455
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optimization. Yield significantly increased to 63% by replacing
AIBN with BPO (entry 4) and a further improvement was
achieved with DLP as an initiator (80%, entry 5). Solvent
screening revealed chloroform to be the ideal solvent for this
transformation (88%, entries 6-8). The N-protecting group was
varied next and we found that replacing the benzoyl group by
electron-poorer or electron-richer aroyl groups led to worse
results (3b, 72%; 3c, 67%, entries 9 and 10). A moderate yield
was noted for the Cbz-protected sulfonamide 1d (entry 11) and
the pivaloylated congener 1e provided 3e also in good yield
(entry 12). Based on these screenings, all further studies were
conducted on benzoylated amides.
Table 1. Reaction optimization.[a]
Entry
1
SM
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
Initiator
AIBN
AIBN
AIBN
BPO
DLP
Azide2
Solvent
DCE
Yield (%)
20 (3a)
TfN3 (2a)
PhSO2N3 (2b)
IBX-N3 (2c)
TfN3 (2a)
TfN3 (2a)
TfN3 (2a)
TfN3 (2a)
TfN3 (2a)
TfN3 (2a)
TfN3 (2a)
TfN3 (2a)
TfN3 (2a)
2
DCE
13 (3a)
3
DCE
<5 (3a)
4
DCE l
DCE
63 (3a)
5
80 (3a)
6
DLP
CH3CN
EtOAc
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
78 (3a)
7
DLP
17 (3a)
8
DLP
88[c] (3a)
72[c] (3b)
67[c] (3c)
52[c] (3d)
81[c] (3e)
9
DLP
10
11
12
DLP
Scheme 2. Variation of sulfonamides (Reaction conditions: 1 (0.2 mmol), 2a
(0.4mmol, 2.0 equiv) and DLP (16.0 mg, 20 mol%) in CHCl3 (0.5 mL) were
stirred at 80 °C for 24 h. Yields given correspond to isolated yields.)
DLP
DLP
Next, we turned our attention to the more challenging
azidation of unactivated secondary CH bonds and found that all
N-protected sulfonamides 3n-x tested engaged in this
transformation. Amides 1n-p bearing short and long alkyl chains
were good substrates (3n-p). Ring azidation can be achieved,
as documented by the successful preparation of 3q and 3r.
However, diastereoselectivity was low in both cases (1,2-
induction and 1,3-induction). As expected, diastereoselectivity
was also low for the open-chain systems (see 3s, 3t). 1,5-HAT
was still favored over the 1,6-HAT even in the case of 1t bearing
a δ-secondary CH bond along with an ε-tertiary CH bond
(84% combined yield, regioselectivity = 9:1). The remote radical
azidation tolerates different functional groups including ester,
silyl ether, azido, and cyano groups (3u-x, 38-69%). We also
addressed azidation of primary C(sp3)H bonds and found that
[a] Reaction conditions: 1a (0.1 mmol), 2 (0.2 mmol, 2.0 equiv) and initiator (20
mol%), in solvent (0.5 mL) were stirred at 80 °C for 24 h.[b] NMR yield using
CH2Br2 as an internal standard. [c] Isolated yield at 0.2 mmol scale. AIBN =
α,α′-azobisisobutyronitrile; BPO
= dibenzoyl peroxide; DLP = dilauroyl
peroxide; IBA-N3 = azidobenziodoxolone.
We then investigated the reaction scope by varying the
starting sulfonamides, keeping azide 2a as the azidyl transfer
reagent (Scheme 2). As expected, azidation worked well for
functionalization of tertiary CH bonds providing azidoamides 3f-
m in good yields (58-89%). 1,5-HAT occurred completely site-
selectively in all these cases and azidation of the additional
tertiary CH bond in 1g was not observed.
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AIBN (20 mol%) in MeCN (1.0 mL) were stirred at 85 °C for 24 h. Yields given
correspond to isolated yields.)
functionalization of substrate 1y was possible, albeit in low yield
(3y, 24%). However, for activated methyl groups, such as in
sulfonamide 1z bearing an oxygen atom at the γ-position, the
1,5-HAT process followed by azidation occurred smoothly to
give 3z in 74% yield.
The synthetic value of the method was further documented by
azidation of more complex bioactive relevant compounds. N-
protected pregabalin[11] was selectively functionalized to give
azide 3aa in 42% yield. CH modification of a (-)-menthol
derived amine provided 3ab in 67% yield with complete site-
selectivity. (+)-Dehydroabietylamine,[12] which shows antitumor
and antimalarial activity, could also be chemically modified to
give regioselectively the C10-azidation product 3ac with
complete diastereocontrol in 45% yield.
To document the diversity of our approach, related radical
remote CH functionalizations varying the sulfone-type radical
trapping reagent were studied. Selective halogenation of
unactivated C−H bonds is an important transformation.[13] We
found that chlorination could be realized by using the
commercial trifluoromethanesulfonyl chloride as the chloride
source under slightly modified reaction conditions (Scheme 3a,
5a-c). By simply switching to trifluoromethanesulfonyl bromide
as trapping reagent, CH bromination could also be achieved
(see 5d).
Due to the electronegativity and high lipophilicity of the
trifluoromethylthiyl group (SCF3), chemical modification by
trifluoromethylthiolation has attracted much attention.[14] However,
to our knowledge, there are no reports on amide-mediated
radical remote site-selective CH trifluoromethylthiolation. Due
to its ready accessibility, we decided to use S-(trifluoromethyl)
benzenesulfonothioate (PhSO2SCF3)[15] in place of the likely
more reactive S-(trifluoromethyl) trifluoromethylsulfonothioate
(CF3SO2SCF3) as the SCF3 source. Gratifyingly, the radical CH
functionalization
proceeded
smoothly
and
trifluoromethylthiolation of tertiary, secondary, as well as
activated primary CH bonds was achieved in good yields (5e-h,
72-89%).
Moreover,
by
using
commercial
S-phenyl
benzenesulfonothioate (PhSO2SPh),[16] CH phenylsulfenylation
was possible, as documented by the successful preparation of
5i-h (42-76%). Notably, the remote HLF-type sulfenylation of
unactivated C(sp3)H bonds is also unprecedented.
Next, we investigated CH cyanation due to the high synthetic
versatility offered by the cyano group in downstream
chemistry.[17] By using commercially available tosyl cyanide
(TsCN) as a radical acceptor,[18] the remote cyanation of tertiary,
secondary, and activated primary CH bonds occurred with
complete regiocontrol in good yields (5m-p, 68-89%), further
documenting the generality of our approach.
We then tested whether this type of substrate can also be
used for remote C-H alkenylation. To this end, reagents 4f and
4g were reacted under optimized conditions with sulfonamide 1a
(Scheme 3b). We found that the cascade worked with
significantly lower efficiency as compared to the other
functionalizations described above. C-radical addition to the
alkenylsulfones 4f and 4g is slow and mainly reduction of the
translocated C-radical was observed. We therefore switched to
acetonitrile as the solvent and could obtain the trans-β-
styrenylated product 5q, albeit in a moderate 27% yield. A
similar result was achieved using the cis-alkenylsulfone 4g
(34%). It is obvious that both isomers 4f and 4g lead to the
same stereoisomer 5q, since β-elimination of the adduct radical
generating the corresponding aminosulfonyl radical occurs with
complete trans-selectivity.
Scheme 3. Variation of sulfone reagents (Reaction conditions for a: 1 (0.2
mmol), 2 (0.8 mmol, 4.0 equiv) and DLP (20 mol%) in CHCl3 (0.5 mL) were
stirred at 80 °C for 24 h; for b: 1a (0.2 mmol), 2 (0.4 mmol, 2.0 equiv) and
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In summary, we have presented a method for radical
C(sp3)H functionalization of unactivated CH bonds in various
benzamides. Site-selective remote radical generation is
achieved via 1,5-HAT to in situ generated amidyl radicals. The
allylsulfonamide moiety serves as a stable and valuable amidyl
radical precursor entity, which is easily attached to the substrate.
In contrast to most HLF-type reactions, various functionalities
can be introduced at the remotely generated C-radical by simply
varying the radical trapping reagents some of which are
commercially available. Hence, one type of amidyl radical
precursor allows preparing a series of functionalized products.
This is shown for azidation, chlorination, bromination,
trfluoromethylthiolation,
phenylthiolation
and
cyanation.
Substrate scope is broad, as cascades work efficiently for CH
modification of unactivated tertiary, secondary, as well as
activated primary CH bonds. The potential of this method is
further documented by the late-stage C(sp3)−H functionalization
of complex and biologically relevant compounds. Moreover, the
strategy introduced can also be applied to the -CH
functionalization of amides.
Scheme 4. Suggested mechanism for azidation of 1a to give 3a.
The suggested mechanism is presented exemplarily for
azidation of 1a to 3a in Scheme 4. Halogenations, alkyl/aryl
thiolations, cyanations and alkenylations proceed in analogy.
Initiation occurs by thermal decomposition of DLP to provide the
corresponding alkyl radical which is azidated to give
undecylazide, SO2 and the trifluoromethyl radical.[19] The latter
adds to the allylsulfonyl moiety in 1a to give after fragmentation
of allylCF3 the amidosulfonyl radical A. SO2 fragmentation then
leads to the amidyl radical B, which in turn undergoes 1,5-HAT
to generate the tertiary C-radical C. Azidation with TfN3 via
addition/elimination/fragmentation eventually provides product
3a along with SO2 and the chain carrying trifluoromethyl radical.
In case of reagents 4c, 4d and 4e the chains are sustained by
an arylsulfonyl radical.
Finally, we could show that our strategy can also be applied to
the -CH azidation of amides, significantly expanding the
substrate scope. The starting amides 6a-d were readily
prepared by N-acylation of N-methyl-allylsulfonamide with the
corresponding acid chloride (see SI for preparation of 6a-d).
Site-selective azidation was achieved at the -position under our
standard conditions with reagent 2a and DLP as initiator in
CHCl3 (Scheme 5). Tertiary and secondary CH bonds in these
amides could be chemically modified to deliver the products 7a-
din 71-81% yields.
Acknowledgements
This work was financially supported by the Deutsche
Forschungsgemeinschaft (DFG) and the China Scholarship
Council (stipend to L. W.).
Keywords: azidation • radical C-H functionalization • cyanation •
sulfenylation• trifluoromethylthiolation
[1]
a) J. Yuan, C. Liu, A. Lei, Chem. Commun. 2015, 51, 1394; b) J. F.
Hartwig, M. A. Larsen, ACS Cent. Sci. 2016, 2, 281; c) J. C. K. Chu, T.
Rovis, Angew. Chem. Int. Ed. 2018, 57, 62; Angew. Chem. 2018, 130,
64.
[2]
[3]
a) H. Yi, G. Zhang, H. Wang, Z. Huang, J. Wang, A. K. Singh, A. Lei,
Chem. Rev. 2017, 117, 9016; b) D. Ravelli, M. Fagnoni, T. Fukuyama,
T. Nishikawa, I. Ryu, ACS Catal. 2018, 8, 701.
a) L. M. Stateman, K. M. Nakafuku, D. A. Nagib, Synthesis 2018, 50,
1569; b) J. Robertson, J. Pillai, R. K. Lush, Chem. Soc. Rev. 2001, 30,
94; c) S. Chiba, H. Chen, Org. Biomol. Chem. 2014, 12, 4051; d) S. Z.
Zard, Chem. Soc. Rev. 2008, 37, 1603.
[4]
[5]
a) K. Lꢀffler, C. Freytag, Ber. 1909, 42, 3427; b) A. W. Hofmann, Ber.
1883, 16, 558. c) P. Mackiewicz, R. Furstoss, Tetrahedron 1978, 34,
3241; d) R. S. Neale, Synthesis 1971, 1; e) M. E. Wolff, Chem. Rev.
1963, 63, 55.
a) Q. Qin, S. Yu, Org. Lett. 2015, 17, 1894; b) T. Liu, T.-S. Mei, J.-Q.
Yu, J. Am. Chem. Soc. 2015, 137, 5871; c) J. Richers, M. Heilmann, M.
Drees, K. Tiefenbacher, Org. Lett. 2016, 18, 6472; d) E. A. Wappes, S.
C. Fosu, T. C. Chopko, D. A. Nagib, Angew. Chem. Int. Ed. 2016, 55,
9974; Angew. Chem. 2016, 128, 10128.
[6]
For elegant site-selective remote CC bond formation, see: a) G. J.
Choi, Q. Zhu, D. C. Miller, C. J. Gu, R. R. Knowles, Nature 2016, 539,
268; b) J. C. K. Chu, T. Rovis, Nature 2016, 539, 272; c) W. Yuan, Z.
Zhou, L. Gong, E. Meggers, Chem. Commun. 2017, 53, 8964; d) D.-F.
Chen, J. C. K. Chu, T. Rovis, J. Am. Chem. Soc. 2017, 139, 14897; e)
H. Jiang, A. Studer, Angew. Chem. Int. Ed. 2017, 56, 12273; Angew.
Chem. 2017, 129, 12441.
[7]
[8]
C. Mourtrille, S. Z. Zard, Chem. Commun. 2004, 1848.
Scheme 5. -CH azidation of amides (Reaction conditions: 6 (0.2 mmol), 2a
(0.4 mmol, 2.0 equiv) and DLP (16.0 mg, 20 mol%) in CHCl3 (0.5 mL) were
stirred at 80 °C for 24 h. Yields given correspond to isolated yields.)
a) X. Huang, J. T. Groves, ACS Catal. 2016, 6, 751; b) S. Bräse, C. Gil,
K. Knepper, V. Zimmermann, Angew. Chem. Int. Ed. 2005, 44, 5188;
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Angew. Chem. 2005, 117, 5320; c) E. Lallana, R. Riguera, E.
Fernandez-Megia, Angew. Chem. Int. Ed. 2011, 50, 8794; Angew.
Chem. 2011, 123, 8956; d) C. I. Schilling, N. Jung, M. Biskup, U.
Schepers, S. Brase, Chem. Soc. Rev. 2011, 40, 4840; e) E. M. Sletten,
C. R. Bertozzi, Acc. Chem. Res. 2011, 44, 666.
[14] a) X. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 2015, 115, 731; b) X.
Yang, T. Wu, R. J. Phipps, F. D. Toste, Chem. Rev. 2015, 115, 826; c)
C. Ni, M. Hu, J. Hu, Chem. Rev. 2015, 115, 765; d) P. Chauhan, S.
Mahajan, D. Enders, Chem. Rev. 2014, 114, 8807.
[15] For using PhSO2SCF3 as the SCF3 source see, a) H. Li, C. Shan, C.-H.
Tung, Z. Xu, Chem. Sci. 2017, 8, 2610; b) X. Zhao, B. Yang, A. Wei, J.
Sheng, M. Tian, Q. Li, K. Lu, Tetrahedron Letters 2018,59, 1719.
[16] For selected examples using PhSO2SPh as the SPh sourcesee, a) M.
Kobayashi, M. Kobayashi, M. Yoshida, Bull. Chem. Soc. Jpn. 1985, 58,
473; b) S. Kim, S. Kim, N. Otsuka, I. Ryu, Angew. Chem. Int. Ed. 2005,
44,6183; Angew. Chem. 2005, 117, 6339; c) W. Kong, H. An, Q. Song,
Chem. Commun. 2017, 53, 8968; d) A.-P. Schaffner, F. Montermini, D.
Pozzi, V. Darmency, E. M. Scanlan, P. Renaud, Adv. Synth. Catal.
2008, 350, 1163.
[9]
a) P. Panchaud, L. Chabaud, Y. Landais, C. Ollivier, P. Renaud, S.
Zigmantas, Chem. Eur. J. 2004, 10, 3606; b) E. Nyfeler, P. Renaud,
Org. Lett. 2008, 10, 985; c) A. Kapat, A. König, F. Montermini, P.
Renaud, J. Am. Chem. Soc. 2011, 133, 13890; d) Y. Zhu, X. Li, X.
Wang, X. Huang, T. Shen, Y. Zhang, X. Sun, M. Zou, S. Song, N. Jiao,
Org. Lett. 2015, 17, 4702; e) C. Liu, X. Wang, Z. Li, L. Cui, C. Li, J. Am.
Chem. Soc. 2015, 137, 9280.
[10] a) V. V. Zhdankin, C. J. Kuehl, A. P. Krasutsky, M. S. Formaneck, J. T.
Bolz, Tetrahedron Letters 1994, 35, 9677; b) V. V. Zhdankin, A. P.
Krasutsky, C. J. Kuehl, A. J. Simonsen, J. K. Woodward, B. Mismash, J.
T. Bolz, J. Am. Chem. Soc. 1996, 118, 5192; c) R. R. Karimov, A.
Sharma, J. F. Hartwig, ACS Cent. Sci. 2016, 2, 715; d) P. T. G. Rabet,
G. Fumagalli, S. Boyd, M. F. Greaney, Org. Lett. 2016, 18, 1646;
[11] T. R. Belliotti, T. Capiris, I. V. Ekhato, J. J. Kinsora, M. J. Field, T. G.
Heffner, L. T. Meltzer, et al. J. Med. Chem. 2005, 48, 2294.
[17] a) J.‐ M. Brunel, I. P. Holmes, Angew. Chem. Int. Ed. 2004, 43, 2752;
Angew. Chem. 2004, 116, 2810; b) Y. Ping, Q. Ding, Y. Peng, ACS
Catal. 2016, 6, 5989.
[18] For selected examples using TsCN as the CN source see, a) J.-M.
Fang, M.-Y. Chen, Tetrahedron Letters 1987,28, 2853; b) S. Kamijo, T.
Hoshikawa, M. Inoue, Org. Lett. 2011, 13, 5928; c) J. Sun, P. Li, L. Guo,
F. Yu, Y.-P. He, L. Chu, Chem. Commun. 2018, 54, 3162.
[12] a) T. D. Aicher, R. E. Damon, J. Koletar, C. C. Vinluan, L. J. Brand, J. P.
Gao, S. S. Shetty, et al. Bioorg. Med. Chem. Lett. 1999, 9, 2223; b) M.
Pirttimaa, A. Nasereddin, D. Kopelyanskiy, M. Kaiser, J. Yli-
Kauhaluoma, K.-M. Oksman-Caldentey, R. Brun, et al. J. Nat. Prod.
2016, 79, 362.
[19] Alternatively the undecyl radical derived from DLP might also directly
react with substrate 1a to initiate the chain.
[13] a) V. Agarwal, Z. D. Miles, J. M. Winter, A. S. Eustaquio, A. A. El
Gamal, B. S. Moore, Chem. Rev. 2017, 117, 5619; b) D. A. Petrone, J.
Ye, M. Lautens, Chem. Rev. 2016, 116, 8003.
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Entry for the Table of Contents (Please choose one layout)
Layout 2:
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Y. Xia, L. Wang, A. Studer
Page No. – Page No.
Site-selective Radical Remote CH
Functionalization of Unactivated CH
Bonds in Amides with Sulfone
Reagents
Diversity-oriented remote radical site selective CH functionalization of
unactivated CH bonds is achieved using stable and readily accessed substrates.
CH functionalization proceeds via 1,5-hydrogen atom transfer (HAT) followed by
trapping with various sulfonyl derivatives.
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