Oxidative [4+2] Cycloaddition of α-(N-Arylamino) Carbonyls with Aryl Alkenes by Multiple C-H Functionalizations and [1,2]-Aryl Shifts

Article abstract of DOI:10.1021/acs.orglett.9b02169

A new, general copper-catalyzed oxidative tandem [4+2] cycloaddition of α-(N-arylamino) carbonyl compounds with aryl alkenes to produce highly substituted quinolines has been developed, which allows the formation of three new C-C bonds through a sequence of multiple C-H functionalizations, annulation, and [1,2]-aryl shifts.

Full text of DOI:10.1021/acs.orglett.9b02169

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxidative [4+2] Cycloaddition of α‑(N‑Arylamino) Carbonyls with
Aryl Alkenes by Multiple C−H Functionalizations and [1,2]-Aryl
Shifts
Wen-Ting Wei,†,‡ Fan Teng,† Yang Li,† Ren-Jie Song,*,† and Jin-Heng Li*,†,‡,§
†Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources Recycle, Nanchang Hangkong University,
Nanchang 330063, China
‡Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal
University, Changsha 410081, China
§State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: A new, general copper-catalyzed oxidative
tandem [4+2] cycloaddition of α-(N-arylamino) carbonyl
compounds with aryl alkenes to produce highly substituted
quinolines has been developed, which allows the formation of
three new C−C bonds through a sequence of multiple C−H
functionalizations, annulation, and [1,2]-aryl shifts.
for the one-pot synthesis of quinolines.3a,b Jia, Wang, and co-
uinolines represent an important class of heterocycles
Q that occur widely as natural products, pharmaceuticals,
workers have established a similar version for quinolines via a
domino C−H functionalization/annulation of glycine deriva-
tives with olefins using the trisarylaminium salt/InCl3/O2
catalytic system.3c,d Recently, Jia and co-workers3e extended
the oxidative tandem annulation method to readily available
1,1-disubstituted olefins, where 3,4-dihydro-quinoline-3-ones
were formed by a consecutive C−H functionalization/C−H
oxidation of various glycines and N-benzylanilines. Although
the construction of the [1,2]-aryl shift products has been
reported, the [1,2]-aryl shift process relied on two special aryl
alkenes. While 1,1-diphenylethylene gave a minor 1,2-Ph shift
product, the other aryl alkene, 1-methoxy-4-(prop-1-en- 2-
yl)benzene, was exclusively converted to the 1,2-aryl (4-
methoxyphenyl) shift product (Scheme 1a). Thus, discovery of
new, general catalytic oxidative strategies for achieving tandem
[4+2] cycloaddition of α-(N-arylamino) carbonyl compounds
with aryl alkenes involving [1,2]-aryl shifts is highly desirable.
Herein, we report a new oxidative tandem [4+2] cyclo-
addition of α-(N-arylamino) carbonyl compounds with aryl
alkenes by means of a copper oxidative catalysis, in which an
unprecedented [1,2]-aryl shift occurs (Scheme 1b).5 The
method is general for various terminal aryl alkenes and
provides new access to highly substituted quinolines through
multiple C−H oxidative functionalization, annulation, and
[1,2]-aryl shift cascades.
and functional materials and serve as useful synthetic building
blocks in synthesis.1,2 The construction of quinoline scaffolds is
arguably one of the most important goals of the synthetic
community and continues to attract the attention of synthetic
chemists.2−4 Attractive methods include the catalytic annula-
tion reactions of aromatic compounds with 2π components
(e.g., alkenes and alkynes) involving C(sp2)−H functionaliza-
tion for targeting these skeleton constructions.3,4 Among them,
the oxidative tandem [4+2] cycloaddition of α-(N-arylamino)
carbonyl compounds with alkenes has proven to be particularly
efficient, which allows the formation of substituted quinolines
via multiple C−H functionalization and annulation cascades
(Scheme 1a).3,4 However, available examples are less
abundant, and a majority of them concern a limited olefin
scope (e.g., monosubstituted and 1,2-disubstituted alkenes).
Mancheno and co-workers first reported an FeCl3-promoted
̃
TEMPO oxoammonium salt-mediated dehydrogenative Povar-
ov/oxidative tandem reaction of N-alkyl anilines with olefins
Scheme 1. [4+2] Cycloaddition of α-(N-Arylamino)
Carbonyl Compounds with Olefins
Our studies began with the [4+2] cycloaddition of 1,1-
diphenylethylene 1a with 1-phenyl-2-(phenylamino)ethanone
2a for optimization of reaction conditions (Table 1).
Gratifyingly, the reaction of alkene 1a with substrate 2a,
Received: June 23, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02169
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Variation of the Aryl Alkenes (1) and α-(N-
a
Arylamino) Carbonyl Compounds (2)
entry
[Cu] (mol %)
[O]
DTBP
solvent
T (°C) yield (%)
1
2
3
4
5
6
7
8
Cu(OTf)2 (20)
CuCl2 (20)
CuBr2 (20)
Cu(OAc)2 (20)
CuOTf (20)
Fe(OTf)3 (20)
−
Cu(OTf)2 (10)
Cu(OTf)2 (40)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
Cu(OTf)2 (20)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMF
toluene
PhCl
PhCl
PhCl
PhCl
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
130
100
120
69
10
12
51
10
10
0
23
68
6
42
72
10
62
0
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
TBHP
TBPB
PhI(OAc)2
O2
9
10
11
12
13
14
15
16
17
18
PhCl
PhCl
PhCl
PhCl
0
0
70
23
68
−
DTBP
DTBP
DTBP
b
19
20
c
PhCl
a
Reaction conditions: 1a (0.3 mmol), 2a (0.36 mmol), [M], [O] (4
b
c
equiv), solvent (1 mL), argon, 24 h. Recovery of 1a of >67%. 1a (1
g, 5.56 mmol) and PhCl (5 mL) for 48 h.
Cu(OTf)2, and di-tert-butyl peroxide (DTBP) in MeCN at 120
°C for 24 h unexpectedly afforded the [1,2]-Ph shift product
3aa6 in 69% yield (entry 1). Although other Cu and Fe salts,
including CuCl2, CuBr2, Cu(OAc)2, CuOTf, and Fe(OTf)3,
displayed catalytic activity, they were less efficient than
Cu(OTf)2 (entries 2−6, respectively). Both the Cu catalyst
and the peroxide oxidant are crucial, as omission of each led to
no cycloaddition reaction (entries 7 and 17). While a smaller
amount (10 mol %) of Cu(OTf)2 had a negative effect (entry
8), a larger amount (40 mol %) of Cu(OTf)2 gave no obvious
improvement in yield (entry 9). Screening the effect of
solvents revealed that the use of DMF and toluene showed
lower reactivity (entries 10 and 11, respectively) but the use of
the PhCl solvent slightly increased the yield from 69% (entry
1) to 72% yield (entry 12). Other peroxides, tert-butyl
hydroperoxide (TBHP) and tert-butyl perbenzoate (TBPB),
were inferior to DTBP (entries 13 and 14, respectively), and
PhI(OAc)2 and O2 were inert (entries 15 and 16, respectively).
The effect of the reaction temperature was found to affect the
reaction. Using 130 °C did not improve the yield (entry 18),
but at 100 °C, the yield of 3aa decreased dramatically (entry
19). The reaction could be applied to a 1 g scale of alkene 1a,
furnishing 3aa in good yield (entry 20).
a
Reaction conditions: 1 (0.3 mmol), 2 (0.36 mmol), Cu(OTf)2 (20
mol %), DTBP (4 equiv), PhCl (1 mL), 120 °C, argon, 24 h.
(3ab−ak). While p-Me-substituted substrate 2b furnished 3ab
in 84% yield, m- and o-Me-substituted substrates 2g and 2i
afforded 3ag and 3ai in 67% and 60% yields, respectively.
Interestingly, halogen-substituted substrates 2d, 2e, and 2h
were highly reactive, giving halo-possessing products 3ad, 3ae,
and 3ah, respectively, in moderate to good yields. Substrates 2f
and 2j with an electron-withdrawing CF3 group were smoothly
converted to 3af and 3aj, respectively. The bulky 2,5-diMe-
substitued substrate 2k also produced 3ak in 62% yield. The
reaction with 1-(3,4-dichlorophenyl)-2-(phenylamino)-
ethanone 2l or 2-(phenylamino)-1-(thiophen-2-yl)ethanone
2m was performed successfully (3al or 3am, respectively).
Unfortunately, 1-(phenylamino)propan-2-one 2n had no
reactivity (3an). The optimal conditions were found to be
applicable to α-(N-phenylamino) ester 2o, giving 3ao in 72%
yield.
Under the optimal reaction conditions, the scope of this
[4+2] cycloaddition protocol with regard to both alkenes 1
and α-(N-arylamino) carbonyl compounds 2 was next
investigated (Scheme 2). The generality of α-(N-arylamino)
carbonyl compounds 2 in the presence of alkyne 1a,
Cu(OTf)2, and DTBP was initially explored (Scheme 2).
Several substituents, namely, Me, MeO, Cl, Br, and CF3, on the
aromatic ring of the N-aryl moiety were well tolerated, and the
position effect had a fundamental influence on reactivity
The [4+2] cycloaddition protocol was subjected to a wide
range of 1,1-disubstituted olefins 1b−p (Scheme 2). For
symmetrical 1,1-disubstituted olefins 1b−d that possess the
same two aryl groups, the reaction with substrate 2b,
Cu(OTf)2, and DTBP selectively afforded 3bb−db, respec-
tively, in high yields. In the case of unsymmetrical 1,1-
B
DOI: 10.1021/acs.orglett.9b02169
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
disubstituted olefins 1e−k with two different aryl groups,
which aryl group undergoes the [1,2] shift depends on the
electronic and steric hindrance properties: electron-deficient
aryl groups > electron-rich aryl groups > Ph, and p- and m-
substituted aryl group > Ph > o-substituted aryl groups (3eb−
kb). For example, olefins 1e, 1f, and 1g, bearing a Ph group
and a p-substituted aryl group, mainly gave the p-substituted
aryl-migration products 3eb, 3fb, and 3gb, respectively, as the
major products. Although the m-substituted aryl-migration
product 3hb was the major product from olefin 1h having a Ph
group and an m-substituted aryl group, the ratio of two isomers
was decreased to 2:1. The same version of migration was
observed in the reaction with 1-phenyl-1-(3,4-
dimethylphenyl)ethylene 1j and 1-phenyl-1-(thiophen-2-yl)-
ethylene 1k, which provided selectivity toward 3jb and 3kb,
respectively, mainly through the migrating 3,4-dimethylphenyl
group or the migrating thiophen-2-yl group. Because of the
steric hindrance effect, the migration of the Ph group had
precedence over the o-Me-substituted-aryl group with a 53:1
ratio (3ib). Gratifyingly, a variety of 1-methyl-1-arylethylenes
1l−o worked well and exclusively afforded aryl-migration
products 3la, 3lo, and 3mb−ob in moderate to good yields.
Unfortunately, 1,1-dialkyl alkenes 1p and 1q and α-(N-
arylamino) amide 2p were not viable for the reaction.
To understand the mechanism for the current reaction,
control experiments were performed (Scheme 3). A mixture of
two different 1,1-diaryl olefins 1a and 1b reacted with substrate
2b afforded products 3ab and 3bb, respectively, in which no
cross aryl-migrating products were observed (eq 2). The
results suggest that the [1,2]-aryl shift proceeds via an
intramolecular process. The reaction of olefins 1a with
substrate 2a was completely suppressed when a stoichiometric
amount of the radical inhibitor was used (4 equiv), including
TEMPO, hydroquinone, and BHT (eq 3). The results imply
that the current reaction includes a free radical process, which
was also supported by the intermolecular kinetic isotope effect
experiment (kH/kD = 1.0).7 Notably, a strong high kinetic
isotope effect (kH/kD = 4.0) in the intramolecular experiment
supported the idea that the aromatic C(sp2)−H functionaliza-
tion step is rate-limiting.7
The mechanism for this oxidative [4+2] cycloaddition
protocol was proposed (Scheme 3).3−5,8 Initially, the splitting
of an α-C(sp3)−H bond in substrate 2a with the active CuI
species and DTBP affords alkyl radical A, the CuII(OtBu)
species, and HOtBu under heating.5 Subsequently, the addition
of alkyl radical A across the CC bond in 1,1-diphenyl-
ethylene 1a produces radical intermediate B, followed by
cyclization with the N-aryl ring that gives radical intermediate
C. Single-electron oxidation and continuous oxidative depro-
tonation of intermediate C afford intermediate D,8 which
would subsequently undergo an intramolecular 1,2-Ph shift
that occurs via spiro[2,5]octadienyl radical E to deliver
intermediate F.5 Finally, intermediate F is converted to 3aa
through the single-electron oxidation by the CuII(OtBu)
species.
As shown in Scheme 3, the optimal conditions were also
consistent with terminal and internal aryl olefins 1r and 1t,
giving the corresponding products 3ra and 3tb, respectively, in
moderate yields (eq 1).3 However, aliphatic olefin 1s had no
reactivity for the reaction (3sa).
In summary, we have developed a novel, general copper-
catalyzed oxidative [4+2] cycloaddition of α-(N-arylamino)
carbonyl compounds with aryl alkenes for producing highly
substituted quinolines involving functionalization of multiple
C−H bonds and [1,2]-aryl shifts. This method enables an
unprecedented [1,2]-aryl shift with excellent levels of
selectivity and high atom and step economy and provides
general access to diverse substituted quinoline scaffolds using a
multiple-C−H oxidative radical functionalization strategy.
Scheme 3. Other Alkenes, Control Experiments, and
Possible Mechanism
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b02169.
Experimental details, NMR spectra, and details of the
experiments (PDF)
Accession Codes
CCDC 1417836 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 Authors
*E-mail: srj0731@hnu.edu.cn.
*E-mail: jhli@hnu.edu.cn.
C
DOI: 10.1021/acs.orglett.9b02169
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
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see: (a) Ruchardt, C.; Hecht, R. Chem. Ber. 1965, 98, 2471.
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(b) Studer, A.; Bossart, M. Tetrahedron 2001, 57, 9649. (c) Aureliano
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Ren-Jie Song: 0000-0001-8708-7433
Jin-Heng Li: 0000-0001-7215-7152
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21625203 and 21871126) and the Opening Fund of
KLCBTCMR, Ministry of Education (KLCBTCMR18-02), for
financial support.
(6) CCDC 1417836 (3aa).
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