Oxidative povarov reaction via sp3 C-H oxidation of N-benzylanilines induced by catalytic radical cation salt: Synthesis of 2,4-diarylquinoline derivatives

Article abstract of DOI:10.1021/acs.orglett.5b00244

Oxidative Povarov reaction of N-benzylanilines was realized under catalytic radical cation salt induced conditions. The mechanism studies revealed that a radical intermediate was involved in this catalytic oxidation. This method provides a new way to synthesize 2,4-diarylquinoline derivatives.

Full text of DOI:10.1021/acs.orglett.5b00244

Letter
pubs.acs.org/OrgLett
Oxidative Povarov Reaction via sp3 C−H Oxidation of
N‑Benzylanilines Induced by Catalytic Radical Cation Salt: Synthesis
of 2,4-Diarylquinoline Derivatives
Jing Liu, Fang Liu, Yingzu Zhu, Xingge Ma, and Xiaodong Jia*
Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education and Gansu Key Laboratory of Polymer
Materials, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, China
S
* Supporting Information
ABSTRACT: Oxidative Povarov reaction of N-benzylanilines was
realized under catalytic radical cation salt induced conditions. The
mechanism studies revealed that a radical intermediate was involved in
this catalytic oxidation. This method provides a new way to synthesize
2,4-diarylquinoline derivatives.
irect C−H functionalization is a widely utilized method
D
for the efficient and selective formation of C−C bonds.
Since the pioneering work of Murahashi1 and Li,2 cross-
dehydrogenative coupling (CDC) has attracted considerable
interest among synthetic organic chemists because it does not
require prefunctionalization of substrates and is more atom
economic and environmentally friendly. Inspired by this new
concept, more and more CDC reactions have emerged. Among
these reactions, the oxidative coupling of tetrahydroisoquino-
lines has been studied extensively. In 2004, Li reported the first
example of a CDC reaction between N-phenyltetrahydroiso-
quinoline and phenylacetylene catalyzed by a copper complex.2a
The author proposed a reasonable mechanism to rationalize the
formation of products in which the generated iminium
intermediate is intercepted by a nucleophile, affording a
Mannich-type addition product. Since then, the study of
CDC reactions has primarily concentrated on the functionaliza-
tion of tetrahydroisoquinoline derivatives, and a variety of
different nucleophiles have been employed (Figure 1, reaction
1).3 Recently, this area still remains hot, and some new
nucleophiles have been developed.4 For example, Wang and co-
workers used DDQ/quinine catalysis-promoted oxidative
coupling of tetrahydroisoquinoline with α,β-unsaturated γ-
butyrolactam to achieve asymmetric CDCs.4a Xiao’s group
reported an unprecedented Ir-catalyzed intramolecular dehy-
drogenative coupling to construct a CC bond.4b Zhou’s
group achieved a novel version of the CDC reaction in which
diazo compounds were employed as nucleophiles under
photoredox catalysts, providing a series of β-amino-α-diazo
adducts.4c Moreover, some new catalyst systems have been
developed to initiate CDC reactions. The CDC reaction
between tertiary amines and nitroalkanes was realized by Wu
and co-workers under an oxygen atmosphere in water simply by
using graphene-supported RuO2 as the catalyst.4d Molecular
iodine could also be used to catalyze CDCs in the presence of
hydrogen peroxide.4e In 2014, Lou et al. employed
triphenylcarbenium perchlorate (Ph3CClO4) as an efficient
oxidant to activate an sp3 C−H bond adjacent to a nitrogen
Figure 1. Different variants of CDC reactions.
atom.4f Despite the use of different nucleophiles and new
catalysts, the development of new types of CDC reactions is
still in high demand.
As part of our ongoing research program,5 we focused on
two aspects: (1) developing new catalysts to achieve catalytic
oxidation of sp3 C−H bonds while avoiding over use of a
stoichiometric oxidant and (2) not only constructing new C−C
bonds via C−H functionalization but also building useful and
important heterocyclic skeletons. On the basis of these goals,
we reported in 2012 the first example of C−H activation of an
sp3 C−H bond prompted by catalytic radical cation salts in the
presence of O2, providing a series of quinoline derivatives
(Figure 1, reaction 2).5a Furthermore, if 1,3-dicarbonyls were
used as the acceptor of the generated α-amino radical, 1,4-
dihydropyridines (1,4-DHPs) could be constructed through a
Received: January 28, 2015
Published: March 10, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00244
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Organic Letters
Letter
fragment-reassembly process (Figure 1, reaction 2).5d Inspired
by these results, we questioned whether the sp3 C−H oxidation
of tertiary amines could also be prompted by radical cation
salts. Tetrahydroisoquinolines show good reactivity toward C−
H functionalization and were studied extensively. However, in
most cases, N-aryl groups were needed to stabilize the iminium
intermediate in which the N-aryl group acts as an auxiliary
group instead of a functionalized group to participate in CDC
reactions. Thus, we wanted to know that if its linear analogues,
N-benzylanilines, have similar reactivity under oxidative
conditions and if an N-aryl group can not only be a stabilizer
but also participate in a CDC reaction. Therefore, when N-
benzylaniline was oxidized smoothly, an imine (or iminium)
intermediate would be generated, which is a good aza-diene to
undergo a Povarov reaction with dienophiles (Figure 1,
reaction 3). If our hypothesis is feasible, an oxidative Povarov
reaction could be achieved via sp3 C−H oxidation induced by
catalytic radical cation salt to realize the synthesis of quinoline
derivatives.
was obtained (entry 3). When TBPA and CAN were premixed,
a characteristic dark blue solution was afforded, indicating the
formation of the corresponding radical cation. Then, when the
blue solution was added dropwise to a mixture of 1a and 2a, the
quinoline product was afforded in 88% yield (entry 4), which
suggested generation of the radical cation was crucial to prompt
efficient transformation. Because TBPA+. can efficiently induce
a Povarov reaction between imines and alkenes,6 we tried the
reaction in the absence of InCl3. The oxidative Povarov reaction
occurred smoothly, giving 3a in excellent yield (entry 5).
Further optimization of the conditions showed that the reaction
was significantly affected by catalyst loading and diminished
yields were obtained (entries 6 and 7). Next, a solvent screen
revealed that halogenated solvents were deleterious to this
reaction (entries 8−10). Higher temperature resulted in
complicated products, and the desired product was given in
lower yield (entry 11). To test the role of dioxygen, the
reaction was conducted under argon atmosphere, but only 9%
1
yield was obtained by crude product H NMR. This result
With these ideas in mind, we used the reaction of N-benzyl-
4-methoxylaniline 1a with styrene 2a as a model reaction to test
the possibility of an oxidative Povarov reaction (Table 1). As
implied that O2 was pivotal to oxidation of the sp3 C−H bond.
Under the optimized reaction conditions, we then inves-
tigated scopes of the oxidative Povarov reaction by using
various N-arylbenzylamines and styrenes. We first examined the
substituent effect on the benzene ring connected to the
nitrogen atom in the N-arylbenzylamines (Scheme 1). The
a
Table 1. Optimization of Reaction Conditions
a
Scheme 1. Reaction of N-Benzylanilines with Styrene
TBPA+.
additive
temp
b
entry
(mol %)
(mol %)
solvent
CH3CN
(°C)
yield (%)
1
10
20
InCl3(10)
InCl3(10)
InCl3(10)
InCl3(10)
none
60
60
60
60
60
60
60
60
60
60
80
60
41
90
39
88
2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
c
3
20
d
4
20
e
5
10
5
95 (87)
22
6
none
7
2
none
22
8
10
10
10
10
10
none
NR
9
none
CHCl3
NR
10
11
12
none
ClCH2CH2Cl
CH3CN
CH3CN
trace
36
none
f
none
9
a
Unless otherwise specified, the reaction was carried out with 1a (0.1
mmol) and 2a (0.15 mmol) in the presence of TBPA+. and anhydrous
solvent (1.0 mL) for 72 h. Yield of crude product by 1H NMR using
1,3,5-trimethoxylbenzene as an internal standard. CAN (20 mol %)
a
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), TBPA+. (10 mol
b
%), MeCN (2 mL), 60 °C under O2 for 24 h, isolated yield.
c
was added to the reaction solution in the presence of tri(4-
bromophenyl)amine (20 mol %). CAN (20 mol %) and tri(4-
d
substrates bearing electron-donating groups, such as 4-
methoxyl and 4-methyl, underwent smooth reactions with
styrene and afforded the desired products 3a and 3b,
respectively, in good yields (87 and 72%, respectively),
probably due to their higher electron-donating ability to
stabilize the electron-poor intermediate. A free phenolic
hydroxyl group could be tolerated under the oxidative
conditions, resulting in the corresponding product 3c in 47%
yield. Unsubstituted aniline also shows good reactivity (3d),
and no coupling product on the p-position of aniline was
isolated. Introduction of an electron-withdrawing group, such
as 4-bromo, 4-chloro, 4-floro, and 4-nitro led to the desired
products 3e−3h in marginally reduced yields (55−65%). We
were pleased to find that the substrate with the strong electron-
withdrawing group, the nitro group, could also undergo an
bromophenyl)amine (20 mol %) were premixed for 15 min then
e
added to the reaction solution. Yield of the isolated product.
f
Reaction was performed under argon.
desired, the 2,4-diarylquinoline product was obtained in 41%
yield in the presence of 10 mol % tris(4-bromophenyl)aminium
hexachloroantimonate (TBPA+.) and 10 mol % InCl3 (entry 1).
When 20 mol % TBPA+. was added, the yield was increased to
90% (entry 2). As reported previously, cerium(IV) ammonium
nitrate (CAN) can also trigger aerobic oxidation in the
presence of catalytic tris(4-bromophenyl)aminium (TBPA),5e
in which the TBPA radical cation was generated in situ. We
tried this catalyst system in two ways: If CAN was added to the
reaction solution in the presence of 20 mol % TBPA, 39% yield
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Letter
oxidative Povarov reaction with styrene, resulting in the
quinoline product in acceptable yield (3h). In another case,
when 1- and 2-naphthylamine were used, a benzoquinoline
skeleton can be formed in good yields (3j and 3k, respectively).
Next, different benzyl groups were varied to evaluate the
effect of a substituent on the benzyl group (Scheme 2). In
Scheme 3. Reaction of N-Benzyl-4-methylanilines with
Substituted Styrenes
a
Scheme 2. Reaction of N-Benzyl-4-methoxylanilines with
a
Styrene
a
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), TBPA+. (10 mol
%), MeCN (2 mL), 60 °C under O2 for 24 h, isolated yield.
a
Scheme 4. Reaction of N-Benzyl-4-methylanilines with α-
Methylstyrene
Reaction conditions: 1 (0.5 mmol), 2 (0.75 mmol), TBPA+. (10 mol
%), MeCN (2 mL), 60 °C under O2 for 24 h, isolated yield
general, electron-donating groups gave higher yields of the
desired products due to higher stability of the radical
intermediate (3l, 3m, and 3q). When electron-withdrawing
groups, such as 4-bromo and 4-chloro, were connected under
Ar, the oxidative Povarov reaction was less efficient, providing
the quinoline products in lower yields (3n and 3o). The nitro
group exerts a negative effect, and the yield of 3p was decreased
to 29% together with isolation of 4-nitrobenzaldehyde in 37%
yield. The formation of 4-nitrobenzaldehyde was attributed to
oxidation of N-benzylaniline to imine followed by hydrolysis.
This byproduct also supported the Povarov reaction pathway.
The furan-derived substrate is also applicable; however, a low
yield was obtained (3r). Notably, radical cation-prompted
aerobic oxidation can also be applied to oxidation of N-
alkylaniline, yielding the Povarov product 3s in 74% yield.
To further demonstrate the scope of the reaction, we
extended the present protocol to substituted styrenes, and the
results are compiled in Scheme 3. Overall, electron-rich
styrenes gave better results than electron-poor ones, which
supports the participation of an electron-deficient intermediate
(3t−3w). 2-Methylstyrene shows slightly lower reactivity than
4-methylstyrene, giving the quinoline product 3x in 49% yield.
To avoid terminated aromatization, we employed α-methyl-
styrene as a dienphile to test if 1,2,3,4-tetrahydroquinoline
could be obtained (Scheme 4). To our great surprise, the
reaction was inefficient, and a novel product 5 was isolated in
19% yield together with some unidentified products. A
plausible pathway to rationalize the formation of product 5 is
that α-methylstyrene first reacted with the generated imine, and
a 1,2,3,4-tetrahydroquinoline intermediate was generated, but
was followed by further oxidation to imine A. Under the
aerobic oxidation conditions, α-hydrogen of imine A was
oxidized, and a radical intermediate was formed, which was
trapped by dioxygen. Finally, the generated peroxide underwent
elimination of water, leading to product 5. The poor yield of 5
suggests that aromatization might be an important driving force
for terminating the reaction.
To illuminate the reaction mechanism, we performed several
control experiments (Scheme 5). The reaction between imine
Scheme 5. Control Experiments
and styrene was conducted under the standard reaction
conditions, and the quinoline product was isolated in 42%
yield (Scheme 5, reaction 1). This result suggested that an
imine might be the intermediate involved in the oxidative
Povarov reaction. The lower yield compared to that of the
reaction of 1a and 2a was due to the decomposition of imine,
which is in high concentration under the radical cation-induced
condition.6a In the presence of one equiv of the radical inhibitor
TEMPO, the reaction was completely inhibited (Scheme 5,
reaction 2). A competition reaction was performed between 2a
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Organic Letters
Letter
1
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and 2c. From the crude product H NMR, the ratio of the
product mixture is ∼1:2. This result supports the idea that an
electron-deficient intermediate is involved in the reaction, and
an electron-rich dienophile is more reactive in the process of
Povarov cyclization.
On the basis of the experimental results and literature
reports, a radical intermediate-mediated mechanism was
proposed (Scheme 6). The N-benzylaniline was oxidized by
(4) For recent progress on CDCs, see: (a) Ma, Y.; Zhang, G.; Zhang,
J.; Yang, D.; Wang, R. Org. Lett. 2014, 16, 5358. (b) Nie, S.-Z.; Sun, X.;
Wei, W.-T.; Zhang, X.-J.; Yan, M.; Xiao, J.-L. Org. Lett. 2013, 15, 2394.
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X.; Peng, F.-F.; Liu, J.; Huo, C.-D.; Wang, X.-C.; Jia, X.-D. J. Org.
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(e) Liu, J.; Wang, Y.-X.; Yu, L.-L.; Huo, C.-D.; Wang, X.-C.; Jia, X.-D.
Adv. Synth. Catal. 2014, 356, 3214.
Scheme 6. Proposed Mechanism of a Radical Cation-
Prompted Oxidative Povarov Reaction
the radical cation salt TBPA+. in the presence of dioxygen,
yielding a radical intermediate, which was oxidized to the
corresponding imine (Scheme 6, path a). Then, a TBPA+.-
induced Povarov reaction occurred, resulting in the formation
of 1,2,3,4-tetrahydroquinoline. After further aromatization, the
desired quinoline product was generated. However, another
pathway might also be possible (Scheme 6, path b). The radical
intermediate adds to the double bond of styrene directly,
followed by radical addition to the phenyl group. After further
oxidation and aromatization, the quinoline derivative was
afforded. At this stage, one of these two pathways cannot fully
be ruled out.
(6) For radical cation-induced Povarov reactions, see: (a) Jia, X.-D.;
Lin, H.-C.; Huo, C.-D.; Zhang, W.; Lu, J.-M.; Yang, L.; Zhao, G.-Y.;
̈
Liu, Z.-L. Synlett 2003, 1707. (b) Jia, X.-D.; Han, B.; Zhang, W.; Jin,
X.-L.; Liu, Z.-L. Synthesis 2006, 2831. (c) Jia, X.-D.; Qing, C.; Huo, C.-
D.; Peng, F.-F.; Wang, X.-C. Tetrahedron Lett. 2012, 53, 7140. (d) Jia,
X.-D.; Peng, F.-F.; Qing, C.; Huo, C.-D.; Wang, Y.-X.; Wang, X.-C.
Tetrahedron Lett. 2013, 54, 4950. (e) Jia, X.-D.; Ren, Y.; Huo, C.-D.;
Wang, W.-J.; Chen, X.-N.; Xu, X.-L.; Wang, X.-C. Tetrahedron Lett.
2010, 51, 6779. (f) Han, B.; Jia, X.-D.; Jin, X.-L.; Zhou, Y.-L.; Yang, L.;
Liu, Z.-L.; Yu, W. Tetrahedron Lett. 2006, 47, 3545.
In conclusion, we demonstrated an efficient sp3 C−H
oxidation of N-benzylaniline derivatives under aerobic con-
ditions prompted by a catalytic radical cation salt. This method
provides a new way of conducting CDC reactions to achieve
not only C−C bond formation but also construction of useful
quinoline skeletons. Further applications of this reaction and
synthesis of heterocycles are currently underway in our
laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jiaxd1975@163.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the Natural Science
Foundation of China (NSFC, Grant 21362030).
■
REFERENCES
■
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DOI: 10.1021/acs.orglett.5b00244
Org. Lett. 2015, 17, 1409−1412