Remote Regioselective Radical C-H Functionalization of Unactivated C-H Bonds in Amides: The Synthesis of gem-Difluoroalkenes

Article abstract of DOI:10.1021/acs.orglett.1c01385

The site-selective functionalization of unactivated aliphatic amines is an attractive and challenging synthetic approach. We herein report a general strategy for the remote site-selective functionalization of unactivated C(sp3)-H bonds in amides by photogenerated amidyl radicals to form gem-difluoroalkenes with trifluoromethyl-substituted alkenes. The site selectivity is controlled by a 1,5-hydrogen atom transfer (HAT) process of the amide. This photocatalyzed transformation shows both chemo- and site-selectivity, facilitating the formation of a secondary, tertiary, or quaternary carbon center.

Full text of DOI:10.1021/acs.orglett.1c01385

pubs.acs.org/OrgLett
Letter
Remote Regioselective Radical C−H Functionalization of
Unactivated C−H Bonds in Amides: The Synthesis of gem-
Difluoroalkenes
Qu-Ping Hu, Jing Cheng, Ying Wang, Jie Shi, Bi-Qin Wang, Ping Hu, Ke-Qing Zhao, and Fei Pan*
Cite This: Org. Lett. 2021, 23, 4457−4462
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ABSTRACT: The site-selective functionalization of unactivated aliphatic amines is an attractive and challenging synthetic approach.
We herein report a general strategy for the remote site-selective functionalization of unactivated C(sp3)−H bonds in amides by
photogenerated amidyl radicals to form gem-difluoroalkenes with trifluoromethyl-substituted alkenes. The site selectivity is
controlled by a 1,5-hydrogen atom transfer (HAT) process of the amide. This photocatalyzed transformation shows both chemo-
and site-selectivity, facilitating the formation of a secondary, tertiary, or quaternary carbon center.
Scheme 1. Site and Chemoselective gem-Difluoroallylation
of Inert C(sp3)−H Bonds in Amide
he gem-difluoroalkene moieties are known as versatile
Tprecursors to a variety of organofluorine compounds,
such as monofluoromethylenes, difluoromethylenes, and gem-
difluorocyclopropane groups.1 They are widely used in the
fields of pharmaceuticals, agrochemicals, and materials
science.2 By virtue of their electronic and steric similarity to
aldehydes, ketones, and esters as well as their high metabolic
stability, gem-difluoroalkenes are considered as carbonyl
bioisosteres with a widespread adoption in drug discovery.3
Hereby the development of general and efficient procedures to
synthesize structurally diverse gem-difluoroalkenes has at-
tracted remarkable attention over the past decades.4 The
gem-difluoromethylenation of carbonyl or diazo compounds
offers a general procedure for the preparation of gem-
difluoroalkenes.5 Furthermore, catalytic defluorinative alkyla-
tion, the sequential introduction of an alkyl group into the
CF3-substituted alkene, and β-fluorine elimination provide an
alternative path for gem-difluoroalkene.6 Nevertheless, most
reactions in this process usually require harsh conditions,
which brings challenges for the expansion of the substrate
scope. Recently, photocatalysis7 and transition-metal catalysis8
strategies have been successfully applied in the synthesis of
different gem-difluoroalkenes through the defluorinative cross-
coupling of α-trifluoromethyl alkenes (Scheme 1A).
presented as a mild, site-selective, and efficient strategy to
cleave inert C(sp3)−H bonds, which has been well applied in
The direct functionalization of unactivated C(sp3)−H bonds
renders a step- and atom-economic method for the rapid
construction of various valuable complex molecules.9 However,
on account of their high bond-dissociation energies and
inherently different reactivities, it is difficult to achieve high
selectivity and efficiency to activate the inert C(sp3)−H bonds.
Radical-mediated hydrogen atom transfer (HAT) has
Received: April 22, 2021
Published: May 13, 2021
https://doi.org/10.1021/acs.orglett.1c01385
© 2021 American Chemical Society
Org. Lett. 2021, 23, 4457−4462
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direct C(sp3)−H bond functionalization.10 These reactions
were mediated by the generation of carbon-,11 nitrogen-,12 and
oxygen-13 centered radicals through photocatalysis.
toluene) were investigated, but no improvement of the
reaction yield was observed (entries 9−12). In addition, the
catalyst loading could be decreased to 0.1 mol % without much
influence on the reaction yield, albeit an increased reaction
time (48 h) was needed (entry 13).
With the optimized reaction in hand, we first tested the
scope of amides 1a−1n (Scheme 2). Amides bearing a δ-
Knowles,14 Rovis,15 and Meggers16 successfully applied this
methodology to amide substrates coupling to alkenes. These
reactions generally underwent a photoredox-catalyzed oxida-
tion of the pendent amide moiety and a 1,5-HAT process
followed by C-functionalization with Michael acceptors
(Scheme 1B). Despite the notable achievement, the formation
of an amidyl radical from the amide C−H bonds and
applications in the intermolecular transformation of C(sp3)−
H bonds are still scarce.17 Herein we develop a direct gem-
difluoroallylation of inert C(sp3)−H bonds in amides with α-
trifluoromethyl alkenes (Scheme 1C). Mediated by a photo-
catalysis-triggered 1,5-HAT process, gem-difluoroalkenyl-
group-functionalized amides are synthesized in good yields
with high functional group tolerance and high δ-selectivity.
At the outset of this project, we adopted the trifluor-
oacetamide (1a) and α-trifluoromethyl alkene (2a) as the
standard substrates (Table 1). More detailed reaction
a
Scheme 2. Scope with Respect to the Amide
a
Table 1. Variation of Reaction Parameters
b
entry
variation from standard conditions
yield (%)
c
1
none
89 (86)
2
without light
0
3
4
air instead of N2
without 4CzIPN
56
0
5
6
7
Ru(bpy)3Cl2 instead of 4CzIPN
eosin Y instead of 4CzIPN
0
0
0
MesAcr+CIO4 instead of 4CzIPN
−
8
9
10
11
12
13
Ir[dF(CF3)ppy]2(dtbbpy)PF6 instead of 4CzIPN
K2CO3 instead of K3PO4
CS2CO3 instead of K3PO4
DCM instead of MeCN
toluene instead of MeCN
45
54
37
61
13
80
a
Reaction conditions: 1a (0.20 mmol, 1.0 equiv), 2a (0.20 mmol, 1.0
equiv), 4CzIPN (1 mol %), K3PO4 (0.40 mmol, 2.0 equiv), and
0.1 mol % of catalyst for 48 h
MeCN (2.0 mL) under N2 and stirred at rt for 24 h under 30 W blue
LED irradiation. Isolated yields.
a
b
Reaction conditions: 1a (0.10 mmol, 1.0 equiv), 2a (0.10 mmol, 1.0
equiv), 4CzIPN (1 mol %), K3PO4 (0.20 mmol, 2.0 equiv), and
MeCN (1.0 mL) under N2 and stirred at rt for 24 h under 30 W blue
LED irradiation. Yields determined by GC using n-tetradecane as the
b
c
internal standard Isolated yield.
methine carbon were examined at the beginning, and
satisfactory results were obtained (3a−3d). Additionally,
amides bearing a methylene δ-carbon were also functionalized
using this approach in moderate yields, and the δ-selectivity
was retained (3e−3k, 3m, and 3n). For the substrate with
multiple functionalizable sites, only the δ-functionalized
product was selectively obtained (3g). Substrate 1k, with an
oxygen atom adjacent to the δ-C−H bond, reacted smoothly in
this reaction and generated 3k. With one more carbon
substrate 1m, both 1,5- and 1,6-HAT products could be
obtained. What should be of concern is that the primary δ-C−
H bond in substrate 1l that bears an α-substituent to nitrogen
was also competent in the reaction, albeit in slightly lower yield
(3l). The alkene also could be tolerated under the standard
reaction conditions to give the product 3n. Last but not the
least, to demonstrate the synthetic potential of this trans-
formation, the amide substrate derived from steroid 1o was
tested, and the desired product (3o) was obtained in satisfying
yield with high selectivity.
conditions optimization are summarized in Supplementary
Tables S1−S4. After much effort, the standard conditions were
successfully established: A mixture of 1a (0.1 mmol, 1 equiv)
and 2a (0.1 mmol, 1.0 equiv) in MeCN was irradiated with a
30 W blue LED in the presence of 1 mol % of 2,4,5,6-
tetrakis(carbazol-9-yl)-1,3-dicyanobenzene (4CzIPN); K3PO4
(0.2 mmol, 2.0 equiv) was used as the base, and the reaction
was carried out at room temperature. The desired gem-
difluoroallylation product (3a) was isolated in 86% yield as a
single regioisomer (Table 1, entry 1). Control experiments
indicated that the base, light, and inert atmosphere are vital for
this reaction (Table 1, entries 2−4). Photoredox catalysts, such
as Ru(bpy)3Cl2 (entry 5), eosin Y (entry 6), and
MesAcr+ClO4 (entry 7), were unreactive in this reaction
−
system. Ir[dF(CF3)ppy]2(dtbbpy)PF6 showed good catalytic
reactivity but afforded the product in lower yield (entry 8).
Other bases (K2CO3 and Cs2CO3) and solvents (DCM and
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Moreover, we continue to investigate the substrate scope of
this remote C(sp3)−H gem-difluoroallylation with various α-
trifluoromethyl alkenes 2a−2v and amide 1a. As shown in
Scheme 3, various functional-group-substituted α-CF3 alkenes
(4q), and benzofuran (4r), were also suitable for the reaction.
This transformation is not limited to CF3−styrenyl reagents.
The conjugated 2-trifluoromethyl-1,3-enyne could also gen-
erate the desired product (4m), whereas the alkyl-substituted
trifluoromethyl alkene did not work (4s). On the basis of the
good functional group tolerance, we tried to explore the
application of our methodology to the late-stage functionaliza-
tion of structural complex molecules. Three trifluoromethyl
alkenes derived from ibuprofen (4t), gemfibrozil (4u), and
oxaprozin (4v) proceeded smoothly to furnish the final
products in moderate yields.
Scheme 3. Scope with Respect to the α-Trifluoromethyl
a b
,
Alkene
To further assess the practical applicability of the developed
method, we performed the reaction on a gram scale with a
reduced amount of catalyst loading, which afforded the
product in 73% yield. The amide could be easily deprotected
to give the free amine in almost quantitative yield under mild
reaction conditions (Scheme 4).
Scheme 4. Large-Scale and Deprotection Experiments
Furthermore, to gain more insights into the mechanism, the
radical trapping experiments were performed. As shown in
Scheme 5, the addition of 2,2,6,6-tetramethylpiperidin-1-oxyl
Scheme 5. Control Experiment and Proposed Reaction
Pathway
a
Reaction conditions: 1a (0.20 mmol, 1.0 equiv), 2a (0.20 mmol, 1.0
equiv), 4CzIPN (1 mol %), K3PO4 (0.40 mmol, 2.0 equiv), and
MeCN (2.0 mL) under N2,and stirred at rt for 24 h under 30 W blue
b
LED irradiation. Isolated yields.
were recognized as effective radical acceptors for the
defluorinative gem-difluoroallylation of amide. Different
substituted groups on the aryl ring of α-CF3 styrenes did not
considerably affect the reaction, whereas both electron-rich
(4a, 4b, 4j, and 4k) and electron-deficient (4c−4f and 4h)
groups on the aryl ring were well tolerated, and the
corresponding gem-difluoroallylation products were obtained
in good yields. Various functionalities including methylthio
(4a), ester (4d), sulfone (4e), nitrile (4f), ketone (4h), and
amide (4l) had excellent compatibility. The bromo (4g) group
was also tolerated under the standard reaction conditions,
which provides a useful handle for further transformation.
Furthermore, an α-trifluoromethyl alkene with a naphthalene
substituent also underwent the desired reaction to give the
desired products (4n) in good yield. It is worth mentioning
that heteroaromatic groups, such as pyridine (4p), quinoline
(TEMPO) or butylated hydroxytoluene (BHT) completely
shut down the reaction. Both results indicated that there was a
radical pathway for this transformation. On the basis of the
previously described results and previous literature,14−16
a
proposed mechanism for this remote site-selective C(sp3)−H
defluorinative gem-difluoroallylation is proposed in Scheme 5.
Initially, the photoexcitation of 4CzIPN by visible light leads to
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the excited 4CzIPN* complex. Through single-electron
oxidation by the photocatalyst 4CzIPN*, amide B forms an
amidyl radical C. Next, a 1,5-HAT from nitrogen to carbon
generates the carbon-centered radical D. The intermediate D is
trapped by the α-trifluoromethyl alkene, giving the radical
intermediate E. The single-electron reduction of radical E by
4CzIPN•− gives carbanion F and regenerates photocatalyst
4CzIPN. Finally, β-fluoride elimination from carbanion F
generates the desired gem-difluoroallylated product G to finish
the catalytic cycle.
ACKNOWLEDGMENTS
■
We are grateful for the financial support from the National
Natural Science Foundation of China (no. 21901175).
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The Supporting Information is available free of charge at
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Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
Fei Pan − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610068, China; orcid.org/
0000-0002-9015-3013; Email: feipan@sicnu.edu.cn
Authors
Qu-Ping Hu − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Jing Cheng − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Ying Wang − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Jie Shi − College of Chemistry and Materials Science, Sichuan
Normal University, Chengdu 610068, China
Bi-Qin Wang − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Ping Hu − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Ke-Qing Zhao − College of Chemistry and Materials Science,
Sichuan Normal University, Chengdu 610068, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01385
Notes
The authors declare no competing financial interest.
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