Direct synthesis of 2-aryl-4-quinolones via transition-metal-free intramolecular oxidative C(sp3)-H/C(sp3)-H coupling

Article abstract of DOI:10.1021/acs.orglett.5b00248

A novel, metal-free oxidative intramolecular Mannich reaction was developed between secondary amines and unmodified ketones, affording a simple and direct access to a broad range of 2-arylquinolin-4(1H)-ones through C(sp³)-H activation/C(sp³)-C(sp³) bond formation from readily available N-arylmethyl-2-aminophenylketones, using TEMPO as the oxidant and KO^tBu as the base.

Full text of DOI:10.1021/acs.orglett.5b00248

Letter
pubs.acs.org/OrgLett
Direct Synthesis of 2‑Aryl-4-quinolones via Transition-Metal-Free
Intramolecular Oxidative C(sp3)−H/C(sp3)−H Coupling
Wei Hu,† Jian-Ping Lin,† Li-Rui Song, and Ya-Qiu Long*
CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi
Road, Shanghai 201203, China
S
* Supporting Information
ABSTRACT: A novel, metal-free oxidative intramolecular
Mannich reaction was developed between secondary amines
and unmodified ketones, affording a simple and direct access
to a broad range of 2-arylquinolin-4(1H)-ones through
C(sp3)−H activation/C(sp3)−C(sp3) bond formation from
readily available N-arylmethyl-2-aminophenylketones, using
TEMPO as the oxidant and KOtBu as the base.
4-Quinolone has been well recognized as a privileged scaffold
prevalent in a vast array of natural products and biologically
active compounds,1 typically constituting an important category
of marketed antibacterial agents.2 More recently, certain 2-
substituted-4-quinolones and compounds containing these
motifs have been studied as potential treatments for a range
of diseases as they exhibit antimitotic,3 antiviral,4 antimalarial,5
xanthine oxidase, and cathepsins inhibitory activities.6 It is also
a versatile synthetic intermediate because the quinolin-4(1H)-
one contains several reactive centers (positions 1, 3, and 4) for
facile derivatization and can also enable different degrees of
unsaturation. Therefore, various methods have been developed
for the synthesis of this valuable scaffold,7 and approaches
based on cyclocondensation, such as the Niementowski,8
Conrad−Limpach,9 and Camps cyclizations,10 are widely
employed. However, most of these methods suffer from harsh
reaction conditions (high temperature and/or strong bases or
acids) and the limitation of substrate scope. Several improved
procedures were reported to make use of transition-metal
catalysis10b,c,11 or tandem reactions from o-haloaryl acetylenic
ketones/amines or o-alkynylbenzamides/aldehydes,12 providing
milder routes toward 2-substituted-4-quinolones (Scheme 1),
but still requiring special starting materials, multistep
procedures, and long reaction time.
Scheme 1. Synthetic Approaches toward 2-Aryl-4-quinolones
As part of our continuing interest in green chemistry
construction of drug-like heterocyclic scaffolds using a cross-
dehydrogenative-coupling (CDC) strategy,13 we recently
reported an elegant and robust synthesis for quinazolines and
benzimidazoles via metal-free direct oxidative C−H function-
alization,14 featuring straightforwardness, atom-economical
nature, and environmental friendliness. As an extension of
this approach, herein we report a novel synthesis of diverse 2-
aryl-4-quinolone derivatives via a TEMPO-promoted intra-
molecular oxidative Mannich reaction from simple N-
arylmethyl-2-aminophenyl ketones (Scheme 1). The oxidative
Mannich reaction is an attractive approach to achieve the
challenging two C(sp3)−H bond couplings, with successful
examples only on tertiary amines and glycine derivatives as
substrates.13c,d Almost all tertiary-amine substrates that under-
went the CDC reaction efficiently were tetrahydroisoquinoline
derivatives. And the glycine derivatives required the assistance
of transition-metal catalysts and extra secondary amines. To the
best of our knowledge, this is the first report on a transition-
metal-free oxidative Mannich reaction between a secondary
amine and an unmodified ketone, affording a simple and direct
access to a broad range of 2-arylquinolin-4(1H)-ones via a
tandem oxidative C(sp3)−H/C(sp3)−H coupling and aroma-
tization.
Received: January 26, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Table 1. Condition Screening for the CDC Synthesis of 2-Aryl-quinolones
b
entry
oxidant
base
temp (°C)
solvent
yield % (2a)
1
PhI(OAc)2 (4.0 equiv)
TEMPO (4.0 equiv)
Cu(OAc)2 (2.0 equiv)
TBHP (4.0 equiv)
DDQ (4.0 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
NaOH (4 equiv)
K2CO3 (3 equiv)
Et3N (4 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (3 equiv)
KOtBu (2 equiv)
KOtBu (2 equiv)
KOtBu (2 equiv)
KOtBu (2 equiv)
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
80
DMF
trace
82
2
DMF
3
DMF
3
4
DMF
5
5
DMF
trace
44
6
K2S2O8 (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (4.0 equiv)
TEMPO (2.0 equiv)
TEMPO (0 equiv)
TEMPO (0 equiv)
TEMPO (2.0 equiv)
DMF
7
DMF
trace
trace
trace
98
8
DMF
9
DMF
10
11
12
13
14
15
16
17
18
19
DMSO
dioxane
tBuOH
toluene
DMSO
CH3CN
DMSO
DMSO
DMSO
75
trace
47
97
trace
97
80
68
c
80
41
cd
,
80
DMSO
93
a
b
c
Reaction conditions: 1a (0.02 mmol, 4 mL solvent), oxidant, and base, 6 h. Yields of isolated products are given. Reaction was performed under
d
an Ar atmosphere. Reaction was completed in 4 h.
Our initial efforts commenced with N-benzyl-2-aminoaceto-
phenone 1a as the model substrate, using PhI(OAc)2 as the
oxidant14a and KOtBu as the base (Table 1, entry 1). The
starting material was easily synthetic accessible by either
reductive amination or nucleophilic substitution of substituted
2-aminoacetophenone, enabling structurally diverse substrate
availability. The reaction was performed at 120 °C for 6 h in
DMF. Disappointingly, a trace amount of quinolone product
was detected, and 1a was rapidly decomposed to 1-(2-
aminophenyl)ethanone. So, the oxidant species was screened
first (entries 2−6). Gratifyingly, when TEMPO was used, the
desired quinolone product 2a was obtained in 82% yield (entry
2). Then, careful examination of the solvent and base (entries 2,
7−9, 10−13) revealed that TEMPO in DMSO with KOtBu
served as the best oxidation system, affording 1b in 98% yield
(entry 10). Further survey of the reaction temperature, the
equivalents of the oxidant and base, and the reaction time (for
the details, please see Supporting Information (SI)) identified
entry 16 as an optimized set of conditions, i.e. 2 equiv of
TEMPO as the oxidant and 2 equiv of KOtBu as the base in
DMSO at 80 °C for 6 h to deliver the quinolone 2a in 97%
yield. Interestingly, when searching for an optimal equivalence
of the TEMPO, the oxidative C(sp3)−H/C(sp3)−H coupling
reaction still occurred in the absence of the oxidant (entry 17),
suggesting the DMSO could serve as an oxidant in this
transformation, albeit in a reduced yield. More experiments
were performed to explore the role of the oxygen in the two
oxidation systems under an Ar atmosphere (entries 18−19).
The much lowered yield of the quinolone by the DMSO-only
system indicated that the oxygen played an important
accelerating role in the transformation while the TEMPO
system displayed much higher oxidizing potency.
With the optimized conditions in hand, we explored the
scope and generality of this oxidative coupling protocol
(Scheme 2). We first examined the effect of the R1 substituent
on the acetophenone portion (Scheme 2, products 2a−2f). In
general, both electron-donating and -withdrawing groups on
the phenyl ring were well tolerated to give the corresponding
quinolones 2a−2e in good to excellent yields (85%−98%).
Even the pyridine analog 1f was converted to the
corresponding 2-phenyl-1,6-naphthyridin-4(1H)-one 2f in
90% yield.
Then, we investigated the R2 substituent on the benzylamine
portion. A diverse array of substrates bearing electron-donating
or -withdrawing or sterically hindered group substituted
aromatic rings all underwent the oxidative cyclization smoothly
and gave the desired 4-quinolone products in excellent yields
(Scheme 2, products 2g−2q), ensuring a broad range of
substrate scope. The halogen group had little influence on the
reaction (2l−o), thus offering the possibility of introducing
further substituents by additional coupling reactions. Only the
4-methoxy and 2-bromo group caused a slight decrease in the
yield (2i, 71%; 2m, 76%). Heteroaromatic structures were also
competent to produce the 2-heterocycle-4-quinolones effi-
ciently (2p−q). However, an aliphatic substituent cannot be
introduced into the 2-position of 4-quinolone by this protocol
(2r−s), with the isolation of an oxidized cleavage product, i.e. a
benzoic acid derivative instead.
When the 2-aminoacetophenone was extended to 2-amino-
propiophenone, i.e. R3 was the methyl group, the intra-
molecular oxidative Mannich reaction still proceeded in
excellent yields (2t−u, 93−95%). It is also worth noting that
this protocol was readily scaled up to produce grams of
quinolone 2a without loss of yield, demonstrating the
practicability of this procedure (Scheme 3).
B
DOI: 10.1021/acs.orglett.5b00248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
conditions, the quinolone product was obtained in a much
lowered yield (3a, 21% yield), whereas an indole was harvested
as the major product (3b, 57%), implying that the N−H is
involved in the formation of the quinolone. When a methyl
group was appended to the benzylic carbon, the bulky
benzylamine 4 failed to generate annulated product 4a, but
gave an overoxidized product benzoic acid 4b instead,
indicating that the steric hindrance on benzylic C−H is critical
for the conversion. On the other hand, when the ketone α-
position was congested by two methyl groups, the resulting
isobutyrophenone analog 5 just gave 3,3-dimethyl-2-phenyl-2,3-
dihydroquinolin-4(1H)-one 5b, suggesting the quinolone was
formed through sequential annulation and aromatization
reactions. Notably, the kinetic isotope effect (KIE) (KH/KD =
1.73), determined by an intermolecular competition reaction
between 1a and [D7]1a (see SI for the details), indicated that
the cleavage of the benzylic C−H bond was involved in the
product-determining step. But the relatively low KIE value
suggested a two-step mechanism involving a single electron
transfer (SET) from the aniline to TEMPO followed by a
hydrogen-transfer step to ultimately form an iminium
intermediate.14b,15
Scheme 2. Substrate Scope for the Synthesis of
Multisubstituted Quinolones via C(sp3)−H/C(sp3)−H
ab
,
Oxidative Coupling
Taken together, a plausible mechanism is proposed in
Scheme 5. An anilinium radical cation A is generated from an
Scheme 5. Proposed Mechanism for the TEMPO-Promoted
Oxidative Annulation
a
Reaction conditions: 1 (0.5 mmol), KOtBu (1 mmol), TEMPO (1
b
c
mmol), DMSO (10 mL), 80 °C, 6 h. Isolated yields are given. n.d. =
not detected.
Scheme 3. Gram-Scale Production of 2-Aryl-4-quinolone
SET process by TEMPO. This radical species facilitates a
hydrogen transfer from the adjacent carbon to yield an
iminium-type intermediate which is rapidly converted to
imine B and then to an enolate form C under the basic
conditions. After a nucleophilic addition to the imine, the
annulated product D is further oxidized to deliver quinolone
product 2a.
To gain insight into the reaction mechanism, we carried out
several control experiments (Scheme 4). First, when N-
methylated substrate 3 was subjected to the optimized
Scheme 4. Control Experiments
In conclusion, we have developed an efficient, mild, and
green synthesis of structurally diverse 2-arylquinolin-4(1H)-
ones through a metal-free oxidative Mannich reaction from
readily available N-arylmethyl-2-aminophenylketones, using
TEMPO as the oxidant and KOtBu as the base. This is the
first construction of a 4-quinolone scaffold via an oxidative
direct C(sp3)−H/C(sp3)−H coupling under metal-free con-
ditions, featuring atom and step economy, environmental
friendliness, and a broad substrate scope.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, reaction conditions screening,
compound characterization data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
C
DOI: 10.1021/acs.orglett.5b00248
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yqlong@mail.shcnc.ac.cn.
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Author Contributions
†These authors contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (81325020, 81361120410, 81321092, and
81123004).
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