Radical Annulation of 2-Cyanoaryl Acrylamides via C=C Double Bond Cleavage: Access to Amino-Substituted 2-Quinolones

Article abstract of DOI:10.1021/acs.orglett.1c02281

A novel annulation of 2-cyanoaryl acrylamides via C=C double bond cleavage has been developed for facile and efficient access to a broad spectrum of functionalized 4-amino-2-quinolones, which are important N-heterocycles. In this transformation, the solvent THF is demonstrated to play a crucial role, and the addition of alkyl radicals to nitrile, 1,5-hydride shift, and cleavage of the C-C bond are involved in the mechanism.

Full text of DOI:10.1021/acs.orglett.1c02281

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Letter
Radical Annulation of 2‑Cyanoaryl Acrylamides via CC Double
Bond Cleavage: Access to Amino-Substituted 2‑Quinolones
Wen-Jin Xia, Tai-Gang Fan, Zhi-Wei Zhao, Xin Chen, Xiang-Xiang Wang, and Ya-Min Li*
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ABSTRACT: A novel annulation of 2-cyanoaryl acrylamides via CC double
bond cleavage has been developed for facile and efficient access to a broad
spectrum of functionalized 4-amino-2-quinolones, which are important N-
heterocycles. In this transformation, the solvent THF is demonstrated to play a
crucial role, and the addition of alkyl radicals to nitrile, 1,5-hydride shift, and
cleavage of the C−C bond are involved in the mechanism.
itriles are important in organic synthesis due to their
versatility in functional group transformations.1 For
molecules, and pharmaceuticals9 and is also a useful synthetic
intermediate for the construction of complex molecules.10
Various synthetic methods for 2-quinolones have been
developed,11−13 and representative approaches include cycliza-
tion reactions11 and the derivatization of quinolones.12 Despite
these advances, most of them suffer from the use of noble
metal catalysts, strongly acidic or basic reaction conditions, and
limited substrate scope. Thus, developing simple and efficient
methods for the production of 2-quinolones still represents a
desirable target. As part of our ongoing interest in radical
cyclization,14 we herein report a new radical annulation of 2-
cyanoaryl acrylamides via CC double bond cleavage, for the
synthesis of valuable 4-amino-2-quinolones (Scheme 1).
N
example, nitriles can be converted into α-multisubstituted
primary amines via nucleophilic addition, which is one of the
most common approaches to such compounds. A variety of
nucleophiles, most of which are preformed organometallic
reagents, such as Grignards, organolithiums, and boranes, have
been employed in this transformation.2 Nitriles are also
classical radical acceptors, forming iminyl radicals by the
addition of radical species to the cyano group, which can be
further transformed into imines.3 Such radical additions
provide great opportunities for the synthesis of ketones, N-
heterocycles and other CN double bond moieties;4 however,
the formation of primary amines via radical addition to nitriles
has not been well-developed to date.
Scheme 1. Annulation of 2-Cyanoaryl Acrylamides
As a fundamental chemical transformation, the cleavage of
CC double bonds is one of the most efficient tools for
furnishing complex molecules that would otherwise be
inaccessible by other methods.5 For instance, ring-closing
metathesis (RCM) processes6 and oxidative cleavage7 offer
facile approaches to various large cyclic hydrocarbons and
carbonyl compounds. Recently, the construction of hetero-
cyclic skeletons through radical CC double bond cleavage
have drawn much attention.8 Rueping and co-workers
developed a photoredox catalyzed CC double bond cleavage
reaction of α,β-unsaturated ketones, leading to indole-3-
carboxaldehyde derivatives.8a Wan, Sheng, and co-workers
reported the copper-catalyzed synthesis of 2-aroylbenzothia-
zoles via cleavage of the enaminone CC double bond.8b
Copper-catalyzed alkene aminooxygenation/oxidative carbon−
carbon bond cleavage for access to lactams and lactones has
also been developed by Wdowik and Chemler.8c Yan and his
co-workers have also described the formation of C2-
substituted indoles, through the simultaneous radical cleavage
CC and CC bonds.8d
We initially chose N-(2-cyanophenyl)-N-methylmethacryla-
mide (1a) for establishing an effective reaction system. To our
delight, when amine 1a was subjected to 1.0 equiv of dicumyl
peroxide (DCP) in THF at 100 °C for 8 h, the desired amino
quinolinone 2a was obtained in 60% yield (Table 1, entry 1),
the structure of which was identified by single-crystal X-ray
diffraction analysis. Subsequently, different oxidants including
Received: July 8, 2021
Published: July 27, 2021
2-Quinolone is an important heterocyclic scaffold which can
be found in many natural products, biologically active
https://doi.org/10.1021/acs.orglett.1c02281
© 2021 American Chemical Society
Org. Lett. 2021, 23, 6158−6163
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a
a,b
Table 1. Optimization of Reaction Conditions
Scheme 2. Substrate Scope
b
entry
oxidant (equiv)
solvent
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
acetone
PhCl
hexane
dioxane
di-n-butyl ether
tetrahydropyran
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
DCP (1)
8
8
8
8
8
8
8
8
24
24
24
8
8
8
8
8
8
8
60
53
56
84
0
DTBP (1)
TBPB (1)
TBHP (1)
BPO (1)
K2S2O8 (1)
0
0
TBHP (2)
TBHP (0.5)
TBHP (0.1)
TBHP (0.5)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
89
87
65
34
0
0
0
0
c
11
12
13
14
15
16
17
18
43
39
23
a
Reaction conditions: 1a (0.3 mmol) and an oxidant in solvent (2
b
c
mL) at 100 °C under air. Isolated yield. Reacted at 70 °C.
di-tert-butyl peroxide (DTBP), tert-butyl peroxybenzoate
(TBPB), tert-butyl hydroperoxide (TBHP, 70% aqueous
solution), benzoyl peroxide (BPO), and K2S2O8 were
evaluated; TBHP proved to be the most efficient oxidant,
and no product was detected in the absence of any oxidant
(Table 1, entries 2−7). The effect of the loading of TBHP was
also investigated, and the result indicates that 2.0 equiv of
TBHP is optimal, generating product 2a in 89% yield (Table 1,
entry 8). The reaction can also occur in the presence of either
substoichiometric or catalytic amounts of TBHP. When 1a was
treated with 0.5 equiv of TBHP for 24 h, product 2a was
obtained in 87% yield (Table 1, entry 9), while reducing the
amount of TBHP to 0.1 equiv resulted in an obviously
decreased yield of 65% (Table 1, entry 10). When this
cyclization was performed at 70 °C, 2a was obtained in only
34% yield (Table 1, entry 11). It was also found that
employing THF as solvent is important for this transformation
because no reaction occurred when CH3CN, acetone, PhCl
and hexane were used as solvent (Table 1, entries 12−15).
Using other ether solvents such as 1,4-dioxane, di-n-butyl
ether, and tetrahydropyran resulted in low yields (Table 1,
entries 16−18).
With the optimal reaction conditions identified, the
substrate scope of this cyclization was investigated (Scheme
2). Different N-protecting groups were initially examined, and
the results revealed that 2-cyanoaryl acrylamides with methyl,
benzyl, and ester substituents were compatible with this
transformation, affording the amino quinolinones 2a−2c in
good yields; however, N-acetyl, N-tosyl, and unprotected N−H
substrates were not suitable for the cyclization due to the low
reactivity of 1d and 1f and for decomposition of 1e. For the
aryl moiety, various aryl acrylamides bearing electron-with-
drawing or electron-donating groups on the aryl ring, such as
methyl, methoxyl, fluoro, chloro, bromo, trifluoromethyl,
a
Reaction conditions: 1 (0.30 mmol) and TBHP (0.5 equiv) in 2 mL
b
c
of THF at 100 °C for 24 h. Isolated yield. The reaction was
performed in the presence of 7.5 mmol of 1a. Reaction conditions: 1
(0.30 mmol) and TBHP (2.0 equiv) in 2 mL of THF at 100 °C for 8
h. Reaction conditions: 1 (0.30 mmol) and TBHP (2.0 equiv) in 2
d
e
mL of THF at 110 °C for 12 h.
acetyl, and ester groups, were well tolerated with the
cyclization (2g−2cc). Alkynols, alkynes, and heteroarene-
substituted phenyl acrylamides also gave the corresponding
amino quinolinones in reasonable yields (2r, 2s, 2t, and 2z).
Heteroaromatic substrates, N-pyridinyl and thienyl acryla-
mides, also reacted smoothly, leading to the corresponding
products 2dd and 2ee in 93% and 91% yield, respectively. In
addition, an indoline derivative was tolerated by the reaction
system, and the tricyclic product 2ff was obtained in 73% yield.
The substrate scope with respect to the substituents on the
olefin was further examined. Acrylamides with various
substituents at the α-position of carbonyl group, such as
ethyl, isopropyl, cyclopentyl, ester, benzyl, phenyl, naphthyl,
and fluoro, smoothly underwent the cyclization, providing the
products 2gg−2nn in moderate to good yields. The substrate
with a monosubstituted olefin (R3 = H) also exhibited high
reactivity and 4-amino-quinolinone 2oo was obtained in 67%
yield. When 7.5 mmol of acrylamide 1a was treated with
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TBHP (2.0 equiv) in THF at 100 °C for 12 h, 4-amino-
quinolinone 2a was obtained in 82% (1.15 g) yield.
Scheme 5. Mechanistic Studies
It was pleasant to find that 2-cyanovinyl acrylamides are also
compatible with this system (Scheme 3), with cyclohexenyl-
a,b
Scheme 3. Substrate Scope
a
Reaction conditions: 1 (0.30 mmol) and TBHP (2.0 equiv) in 2 mL
b
c
of THF at 110 °C for 12 h. Isolated yield. Reaction conditions: 1
(0.30 mmol) and TBHP (0.5 equiv) in 2 mL of THF at 100 °C for 24
h.
and cyclopentenyl-substituted acrylamides showing good
efficiency, providing the corresponding products 2pp−2uu in
reasonable yields. 2-Cyanovinyl acrylamides bearing different
groups substituted at the nitrogen atom or the α-position of
the carbonyl group, including methyl, benzyl, ester, and phenyl
groups, were well tolerated with the cyclization. However,
phenyl-substituted 2-cyanovinyl acrylamide was not a suitable
substrate for this transformation, and only trace amounts of 4-
amino-2-pyridone 2vv were detected due to the decomposition
of substrate. Aliphatic 2-cyanoethyl acrylamide also failed to
form the desired product 2ww.
intermolecular addition of a THF radical to the CC double
bond, and two radical-mediated cyclizations, addition of alkyl
radical to cyano group and radical substitution of iminyl radical
with aromatic ring.14d This result suggests that THF is an
important participant, and the iminyl radical is a key
intermediate in this cyclization.
Subsequently, the annulation of amides bearing an internal
alkene was investigated (Scheme 4). When β-methyl-
Scheme 4. Cyclization of the Substrates with Internal Olefin
To further understand the mechanism, the annulation of
cyclohexene moiety-containing amide 8 was performed, and
the 4-amino-2-quinolinone bearing γ-hydroxyketone 9 was
obtained in 26% yield [eq (4)]. In fact, in addition to the
quinolinone 2a, 5-hydroxypentan-2-one 10 was also isolated in
the model reaction [eq (6)]. These results indicate that the γ-
hydroxyketone is the byproduct of the reaction. Although the
byproduct was successfully identified, the detailed mechanism,
especially the CC double bond cleavage step, is still not
clear. To our delight, in the reaction of acrylamide 4, 5-
hydroxy-1-phenylpentan-2-one 12 was isolated, and 2-
benzylidenetetrahydrofuran 11 was also detected by 1H
NMR and HRMS [eq (6)]. It is already known that 12 can
be generated by hydrolysis of 11.15 Thus, 2-alkenyltetrahy-
drofuran is probably the leaving fragment after cleavage of C
C double bond.
Based on the above experimental results and previous
literature reports,14,15 a plausible mechanism for this trans-
formation is proposed as depicted in Scheme 6. The tert-
butoxy radical and hydroxyl radical are initially generated from
TBHP through thermal hemolysis. The hydrogen atom
abstraction of THF by the tert-butoxy or hydroxyl radical
then forms THF radical A, which undergoes addition to the
CC double bond of acrylamide to provide alkyl radical B,
followed by an intramolecular cyclization with the nitrile group
substituted acrylamide 3 served as the substrate, 2a was
isolated in 80% yield. The cleavage of the phenyl-substituted
CC double bond in amide 4 also occurred under this
oxidative system, again giving product 2a in a moderate yield.
To gain insight into the mechanism of this cyclization, a
series of mechanistic experiments were performed (Scheme 5).
It was found that the cyclization was remarkably inhibited by
adding stoichiometric amounts of radical scavengers, 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-ditertbutyl-4-
methylphenol (BHT), into the reaction system, with both
TEMPO-THF and BHT-THF adducts being detected by
HRMS [eqs (1) and (2)]. These results reveal that this
transformation may proceed via a radical pathway, and THF
radical is likely to be involved in the process. Furthermore,
when phenyl-substituted 2-cyanoaryl acrylamide 5 was
employed as a reactant, quinolinone 6 was obtained in 8%
yield, along with 27% yield of a THF moiety-containing N-
polyheterocycle 7 [eq (3)]. The formation of compound 7
from acrylamide 5 is known, and the mechanism includes an
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Authors
Scheme 6. Proposed Mechanism
Wen-Jin Xia − Faculty of Life Science and Technology,
Kunming University of Science and Technology, Kunming
650500, P. R. China
Tai-Gang Fan − Faculty of Life Science and Technology,
Kunming University of Science and Technology, Kunming
650500, P. R. China
Zhi-Wei Zhao − Faculty of Life Science and Technology,
Kunming University of Science and Technology, Kunming
650500, P. R. China
Xin Chen − Faculty of Life Science and Technology, Kunming
University of Science and Technology, Kunming 650500, P.
R. China
Xiang-Xiang Wang − Faculty of Life Science and Technology,
Kunming University of Science and Technology, Kunming
650500, P. R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02281
to give iminyl radical C. Subsequently, intermediate C
undergoes 1,5-hydrogen atom transfer (HAT) to produce
alkyl radical intermediate D,14c which then undergoes β-
cleavage and imine-enamine tautomerism to afford amine
radical intermediate E, along with 2-alkenyltetrahydrofuran F.
Finally, H-abstraction by intermediate E from THF provides 4-
amino-quinolinone 2a and THF radical A. The hydrolysis of 2-
alkenyltetrahydrofuran F forms γ-hydroxyketone 10.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Nos. 21871114 and
21662021).
In summary, we have developed a novel annulation of 2-
cyanoaryl acrylamides via CC double bond cleavage to
construct a wide range of functionalized 4-amino-2-quinolones.
This reaction features acid-, base-, and metal-free, simple
reaction system, utilization of readily available reagents, and
wide substrate scope. The mechanistic study demonstrated
that solvent THF is an important participant, and a radical
pathway is involved in this transformation. Further application
of this reaction are currently underway.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
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Experimental procedures, X-ray crystallography data,
charts of compounds, HRMS spectra, and 1H NMR and
13C NMR spectra of compounds (PDF)
Accession Codes
CCDC 2087528 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Ya-Min Li − Faculty of Life Science and Technology, Kunming
University of Science and Technology, Kunming 650500, P.
R. China; orcid.org/0000-0003-4233-5274;
Email: liym@kust.edu.cn
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