Photoinduced Palladium-Catalyzed Intermolecular Radical Cascade Cyclization of N-Arylacrylamides with Unactivated Alkyl Bromides

Article abstract of DOI:10.1021/acs.orglett.1c01698

A mild visible-light-induced Pd-catalyzed intermolecular radical cascade reaction of N-arylacrylamides with unactivated alkyl bromides is disclosed. Photoexcited Pd complexes transfer a single electron in this protocol, and hybrid alkyl Pd-radical species

Full text of DOI:10.1021/acs.orglett.1c01698

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Letter
Photoinduced Palladium-Catalyzed Intermolecular Radical Cascade
Cyclization of N‑Arylacrylamides with Unactivated Alkyl Bromides
Juan Du, Xing Wang, Hongling Wang, Jinhu Wei, Xuan Huang, Jun Song, and Junmin Zhang*
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ABSTRACT: A mild visible-light-induced Pd-catalyzed intermo-
lecular radical cascade reaction of N-arylacrylamides with
unactivated alkyl bromides is disclosed. Photoexcited Pd
complexes transfer a single electron in this protocol, and hybrid
alkyl Pd-radical species are involved as the key reaction
intermediates. Sophisticated bioactive oxindole derivatives bearing
various substituents and substitution patterns can be efficiently
afforded through this approach.
alladium-catalyzed organic transformations are a signifi-
under mild reaction conditions (Scheme 1c). It worth noting
Pcant part of organometallic chemistry. They are not only that the Yu10a and Cheng10b groups have demonstrated
1
multicomponent reactions of allylamines/anilines with CO2.
Despite the significant achievements obtained in the photo-
excited Pd-catalyzed radical cyclization reactions, the inter-
molecular cascade cyclization of aromatic C(sp2)−H bonds
with unactivated alkyl halides remains unexplored.
efficiently used to construct carbon−carbon and carbon−
heteroatom bonds but also play essential roles in many fields,
such as pharmaceutical synthesis, materials application, and
biological science.2 However, in comparison to aryl/alkenyl
halides, the application of alkyl halides is more challenging in
palladium-catalyzed cross-coupling reactions, while this issue
can be solved through palladium catalysis involving single-
electron transfer (SET).3 Traditionally, Pd-catalyzed radical
reactions with alkyl halides usually require additional photo-
sensitizers, oxidants, or high temperature (Scheme 1a).3b,h,i,4
The use of simple Pd complexes as part of the photosensors
instead of the classical photoredox catalysts for visible-light-
induced organic transformations has recently received much
attention.3d−g,i
In Pd-catalyzed photoredox reactions, the Pd catalysts are
generally activated to their excited states by visible light and
are also involved in the Pd-bonded covalent intermediates to
participate in the catalytic cycles in the absence of traditional
photoredox catalysts.5 In 2016, Gevorgyan and co-workers
disclosed a Pd-catalyzed 1,5-hydrogen atom transfer (HAT)
process for a photoinduced intramolecular radical cyclization
reaction.6 The intramolecular C−H arylation of amides was
realized by the same research group via a Pd-catalyzed
photoredox C(sp2)−O bond cleavage process under mild
conditions.7 Glorius and co-workers also envisioned the redox-
neutral dicarbofunctionalization of olefins via a photoinduced
C(sp2)−Br bond cleavage/Baldwin-type cyclization/tertiary
radical coupling cascade under the catalysis of a Pd complex
(Scheme 1b).8 In addition, the Yu9a and Liang9b groups have
respectively reported the photoexcited Pd-catalyzed intra-
molecular alkylation of (hetero) aryl/alkene C(sp2)−H bonds
Herein, we report a visible-light-induced Pd-catalyzed
intermolecular cyclization of N-arylacrylamides. The alkyl
halides are activated through this protocol to generate hybrid
alkyl palladium radical intermediates, which can react with
another substrate and then undergo an intramolecular radical
cascade cyclization. The readily available, inexpensive Pd-
(PPh3)4 was used as the sole reaction catalyst. Structurally
significant oxindoles and 3,4-dihydroquinolinones with various
substitution patterns are afforded in moderate to good yields.
Key results of the condition optimization are summarized in
Table 1. The reaction was carried out with N-arylacrylamide
(1a) and alkyl bromide (2a) used as the model substrates. To
our delight, the oxindole product 3a could be afforded in 81%
yield in the presence of a stoichiometric amount of cesium
carbonate in 1,4-dioxane (entry 1). Replacing the Pd(PPh3)4
catalyst with PdCl2 or Pd(OAc)2 led to little formation of the
desired product 3a (entry 2). The addition of frequently used
phosphine ligands such as PPh3, Xantphos, and BINAP did not
further increase the reaction yields (entry 3). Decreasing the
Received: May 20, 2021
Published: July 8, 2021
https://doi.org/10.1021/acs.orglett.1c01698
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5631−5635
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afforded in a decreased yield when the light source was
switched to white LEDs (entry 5). No desired product was
obtained without the use of light, Pd(Ph3)4, or base (entries
6−8). It is worth noting that the addition of TEMPO
completely inhibited the formation of the product 3a (entry 9).
When alkyl chloride or alkyl iodine was used instead of alkyl
bromide as the substrate to participate in the reaction, the
yields were significantly decreased (entries 11 and 12); alkyl
fluoride was found to be an unsuccessful substrate (entry 10).
To examine the generality of our established method, we
studied the substrate scope of N-arylacrylamide 1 and alkyl
bromide 2 bearing various substituents and substitution
patterns (Tables 2 and 3).
Scheme 1. Pd-Catalyzed Radical Cascade Cyclization
a
Table 2. Scope of the N-Arylacrylamides 1 and 4
a
Table 1. Optimization of Conditions
b
entry
variation from the standard conditions
none
yield (%)
1
81
2
3
4
5
PdCl2 or Pd (OAc)2 as catalyst
adding 10 mol % PPh3/rac-BINAP/Xantphos
5 mol % Pd(PPh3)4
white light as light source
no light
trace
50/42/78
55
60
0
6
7
8
9
10
11
12
no Pd(PPh3)4
no base
adding TEMPO (1.5 equiv)
cyclohexyl fluoride instead of 2a
cyclohexyl chloride instead of 2a
cyclohexyl iodine instead of 2a
0
0
0
trace
19
58
a
Unless otherwise specified, the reactions were carried out using 1a
(0.1 mmol), 2a (0.15 mmol), Cs2CO3 (0.2 mmol), Pd(PPh3)4 (10
mol %), 450 nm LEDs, and 1,4-dioxane (1.0 mL) at room
temperature for 12 h under nitrogen. Addition of 10 mol %
Xantphos as ligand. A mixture of two regioisomeric α/β isomers in a
ratio of 2/1 determined by crude H NMR analysis. Diastereomeric
ratio (dr) determined by crude H NMR analysis.
b
c
d
1
a
1
Unless otherwise specified, the reactions were carried out using 1a
(0.1 mmol), 2a (0.15 mmol), Cs2CO3 (0.2 mmol), Pd(PPh3)4 (10
mol %), 450 nm LEDs and 1,4-dioxane (1.0 mL) at room temperature
for 12 h under nitrogen.Abbreviations: LED, light-emitting diode;
First, the N-arylacrylamide substrates 1 possessing different
N substituents (Me, Pr, Ph, Bn) worked well in the reaction
b
TEMPO, 2,2,6,6-tetramethylpiperidine-1-oxyl. Isolated yield of 3a.
i
(Table 2, 3a−d). Both electron-donating and electron-
withdrawing substituents at the para position of the aniline
moiety were well tolerated in this transformation (3e−j).
However, only a trace amount of product was detected with N-
catalyst loading of Pd(PPh3)4 resulted in a drop in the product
yield (entry 4). Light played a significant role in this Pd-
catalyzed alkylarylative reaction, since the product 3a was
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a
primary alkyl bromides also worked well (6h,i). Notably,
alkyl iodides were also tolerated in this reaction (6g, 3a).
3,3-Disubstituted oxindoles are valuable structure motifs that
widely exist in biologically active natural products, alkaloids,
and pharmaceutical agents.11 The multicyclic oxindole
products (3 and 6) obtained from our reactions are readily
available in synthetic transformations to give sophisticated
functional molecules. Note that the photoexcited Pd catalytic
transformation can be carried out on a gram scale without
obvious erosions of the product yields (Scheme 2a). Further
Table 3. Scope of the Unactivated Alkyl Bromides 2
Scheme 2. Applications of the Synthetic Methodology
a
Unless otherwise specified, the reactions were carried out using 1a
(0.1 mmol), 2a (0.15 mmol), Cs2CO3 (0.2 mmol), Pd(PPh3)4 (10
mol %), 450 nm LEDs, and 1,4-dioxane (1.0 mL) at room
temperature for 12 h under nitrogen.
arylacrylamides bearing Br/I at the para position. The possible
reason is that the aryl radicals could be generated from aryl
iodide/bromide under photoinduced Pd catalysis,6b,8a which
resulted in more complicated reactions. In addition, the steric
effect of ortho substituents had little influence on this reaction,
with the corresponding products being afforded in 49−85%
yields (3k−n). The N-arylacrylamide 1 bearing a m-CH3 group
on its aryl ring could also give the desired product 3o in a
satisfactory yield. Switching the phenyl ring on 1a into a
naphthyl ring led to product 3p in a moderate yield. Replacing
the CH3 on the α-position of the acrylamide moiety of 1a with
a Ph group resulted in a drop of the product yield (3q). When
the R3 group of N-arylacrylamides 1 was a hydrogen atom,
none of the desired product was observed. Finally, molecules
containing internal CC double bonds were evaluated under
the typical reaction conditions (Table 2b). N-Methyl-N-
arylcinnamamides (4a−c) were found to be effective
substrates, and the corresponding six-membered-ring products
5a−c were smoothly afforded (Table 2) in acceptable yields
and with good dr values.
synthetic applications of photoinduced tandem reactions with
the complicated functional molecules 7 and 9 were tested. It
was found that the radicals underwent cascade reactions to
afford the desired oxindoles 8 and 10, respectively (Scheme
2b). The synthetic utility of this protocol was also used in the
preparation of alkyl-substituted oxindole derivative 3r in 61%
yield, which could be readily converted into alkyl analogues of
naturally existing ( )-physovenine (Scheme 2c).12 This family
of alkaloids exhibits inhibitory activity against acetylcholines-
terase and tutyrylcholinesterase.13
Subsequently, the scope of alkyl halides with 1a was
evaluated (Table 3). Secondary alkyl bromides, including
cyclic and acyclic species, all reacted effectively (6a−e). tert-
Alkyl bromides were conveniently converted into the desired
products in 26−64% yields (6f,g). Replacing 1-bromoada-
mantane with 2-bromo-2-methylpropane led to a dramatic
decrease in the corresponding product yields. Moreover,
To gain insights into this alkylation reaction, several control
experiments were conducted. The radical scavenger TEMPO
was introduced into the reaction system of N-arylacrylamide 1a
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with alkyl bromide 2a. No alkylated oxindole was detected. In
addition, the radical trapping product 1-(cyclohexyloxy)-
2,2,6,6-tetramethylpiperidine (13) was observed in 40% yield
(Scheme 3a). Convincing evidence could be obtained through
AUTHOR INFORMATION
■
Corresponding Author
Junmin Zhang − International Joint Research Centre for
Molecular Science, College of Chemistry and Environmental
Engineering, Shenzhen University, Shenzhen 518060, People’s
Republic of China; orcid.org/0000-0003-4061-8350;
Email: zhangjm@szu.edu.cn
Scheme 3. Control Experiments for Mechanistic
Investigations
Authors
Juan Du − International Joint Research Centre for Molecular
Science, College of Chemistry and Environmental Engineering
and College of Physics and Optoelectronic Engineering,
Shenzhen University, Shenzhen 518060, People’s Republic of
China
Xing Wang − International Joint Research Centre for
Molecular Science, College of Chemistry and Environmental
Engineering, Shenzhen University, Shenzhen 518060, People’s
Republic of China
Hongling Wang − International Joint Research Centre for
Molecular Science, College of Chemistry and Environmental
Engineering, Shenzhen University, Shenzhen 518060, People’s
Republic of China
Jinhu Wei − International Joint Research Centre for Molecular
Science, College of Chemistry and Environmental Engineering,
Shenzhen University, Shenzhen 518060, People’s Republic of
China
Xuan Huang − International Joint Research Centre for
Molecular Science, College of Chemistry and Environmental
Engineering, Shenzhen University, Shenzhen 518060, People’s
Republic of China
Jun Song − College of Physics and Optoelectronic Engineering,
Shenzhen University, Shenzhen 518060, People’s Republic of
China; orcid.org/0000-0002-2321-7064
a radical-clock experiment to support the radical-mediated
reaction mechanism. The radical-mediated ring-opening
product 14 could be afforded in 60% yield from the Pd-
catalyzed alkylarylation reaction when the (bromomethyl)-
cyclopropane 2b was used as the reaction substrate (Scheme
3b). All of these radical probe experiments indicated that this
reaction proceeded through a radical-type mechanism. In
addition, the Gevorgyan group proved that Pd species
undergoes a Pd(0)/Pd(I) catalytic cycle, not a traditional
Pd(0)/Pd(II) catalytic cycle, from the results of isotope
labeling studies in visible-light-induced Pd-catalyzed reac-
tions.6b On the basis of the above results and previous
reports,9a,14 we propose a plausible catalytic cycle involving
radical mechanism (see the Supporting Information for more
details). It starts from a SET from the excited Pd(0) complex
to an alkyl bromide (2); thus, the corresponding hybrid alkyl
Pd-radical species was obtained. Then, the alkyl radical adds to
the alkene of substrates 1, followed by cyclization, with
subsequent deprotonation and rearomatization to obtain the
final product 3, as well as regeneration of the Pd(0) catalyst,
which supported the next cycle.
In conclusion, we have developed an efficient radical cascade
cyclization reaction of N-arylacrylamides and unactivated alkyl
bromides via visible-light-induced Pd-catalysis under mild
reaction conditions. A variety of unactivated tertiary,
secondary, and primary alkyl bromides have been applied in
this reaction to give valuable 3,3-dialkyl-substituted oxindoles
and alkylated 3,4-dihydroquinolin-2(1H)-ones in moderate to
good yields. This methodology features good functional-group
tolerance, commercially available Pd(PPh3)4 as the sole
photocatalyst, and simple and mild conditions and provides
great potential for the practical synthesis of bioactive oxindole
derivatives.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01698
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the National Natural
Science Foundation of China (No. 22001173), the Project of
Department of Education of Guangdong Province (No.
2020KTSCX116), the Basic and Applied Research Foundation
of Guangdong (No. 2019A1515110906), the Shenzhen
S c i e n c e a n d T e c h n o l o g y F o u n d a t i o n ( N o s .
20200812202943001 and KQJSCX20180328100401788),
and the Principal Foundation of Shenzhen University (No.
8570700000307). We gratefully acknowledge support from the
Instrumental Analysis Centre of Shenzhen University.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01698.
Experimental procedures and spectral data for all new
compounds (PDF)
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