Co(III)-Catalyzed Enaminone-Directed C-H Amidation for Quinolone Synthesis

Article abstract of DOI:10.1021/acs.orglett.7b00968

We report herein the development of a Co(III)-catalyzed enaminone-directed C-H amidation method for synthetic access to quinolones, an important heterocyclic scaffold for diverse pharmaceutically active structures. The C-H coupling with dioxazolones and subsequent deacylation of an installed amide group allow consecutive C-N coupling generation of quinolones with wide-ranging compatible substituent patterns.

Full text of DOI:10.1021/acs.orglett.7b00968

Letter
pubs.acs.org/OrgLett
Co(III)-Catalyzed Enaminone-Directed C−H Amidation for Quinolone
Synthesis
Pengfei Shi, Lili Wang, Kehao Chen, Jie Wang, and Jin Zhu*
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing National Laboratory of
Microstructures, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing 210023, China
S
* Supporting Information
ABSTRACT: We report herein the development of a Co(III)-catalyzed
enaminone-directed C−H amidation method for synthetic access to quinolones,
an important heterocyclic scaffold for diverse pharmaceutically active structures.
The C−H coupling with dioxazolones and subsequent deacylation of an installed
amide group allow consecutive C−N coupling generation of quinolones with wide-ranging compatible substituent patterns.
a b
,
Table 1. Optimization of Reaction Conditions
he quinolin-4(1H)-one (abbreviated herein as quinolone)
Tmoiety is a nitrogen-containing heterocycle that serves as a
privileged core structure for diverse pharmaceutically active
reagents (Scheme 1). Their demonstrated therapeutic properties
include antibacterial,1 antiviral,2 antimalarial,3 and anticancer4
activities. For example, norfloxacin has been approved for the
treatment of urinary tract infections.5 Nedocromil is a mast cell
stabilizer that acts to prevent breathing problems caused by
asthma.6 Ivacaftor is a drug used to treat cystic fibrosis in people
with certain mutations in the cystic fibrosis transmembrane
conductance regulator gene.7 Elvitegravir is an integrase inhibitor
used to treat HIV infection.8 Therefore, increasing efforts have
been devoted to the development of efficient protocols for the
synthesis of this valuable scaffold. Notable synthetic methods
include (1) Conrad-Limpach9 and Niementowski10 reactions,
involving an initial condensation of amines and carboxyl
derivatives and a subsequent cyclization step; (2) the base-
promoted cyclization of N-(ketoaryl)amides, known as the
Camps cyclization;11 (3) synthesis using transition metals,12
including palladium-catalyzed carbonylation, titanium-mediated
reductive coupling, and ruthenium-catalyzed reduction reac-
tions; and (4) cyclization of 2-nitrophenyl enaminone under
catalytic transfer hydrogenation conditions.13 Unfortunately,
entry
additive (mol %)
solvent
DCE
yield (%)
1
2
AgSbF6 (10)/KOAc (100)
AgSbF6 (10)/AgOAc (100)
AgSbF6 (10)/HOAc (100)
31
DCE
DCE
DCE
DCE
DCE
64
3
62
4
trace
0
5
no [Cp*Co(CO)l2]/AgSbF6 (10)
AgSbF6 (10)
6
88
7
AgSbF6 (10)
CF3CH2OH
1,4-dioxane
toluene
THF
19
8
AgSbF6 (10)
37
9
AgSbF6 (10)
trace
31
10
11
12
13
AgSbF6 (10)
AgBF4 (10)
DCE
92
AgPF6 (10)
DCE
88
AgNTf2 (10)
DCE
85
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), [Cp*Co(CO)-
b
l2] (5 mol %), solvent (2 mL). Isolated yields.
these methods can require cumbersome preassembly of a
complex set of functional groups, involve harsh reaction
conditions, and suffer from a limited substrate scope. Therefore,
it is highly desirable to develop new, convenient, and efficient
approaches for the synthesis of quinolones from simple starting
materials.
Scheme 1. Quinolone Structure and Popular Drugs
Containing the Quinolone Unit
Transition-metal-catalyzed C−H functionalization promises
shortened reaction steps and has recently been explored for
building desired valuable C−C/C−heteroatom bonds or
heterocyclic skeletons.14 The activation of arene C−H bonds
typically entails the presence of a proximal directing group.15 The
effective utilization of this strategy16 has permitted efficient
construction of a diverse range of heterocycles, including
Received: March 31, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b00968
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a b
,
Scheme 2. Substrate Scope for Enaminones
Scheme 4. Proposed Catalytic Cycle
a
Conditions: 1a−1p (0.2 mmol), 2a (0.3 mmol), DCE (2 mL).
Isolated yields.
b
a b
,
Scheme 3. Substrate Scope for Dioxazolones
ab
,
Table 2. Synthesis of Quinolones
a
b
Conditions: 1a (0.2 mmol), 2 (0.3 mmol), DCE (2 mL). Isolated
c
yields. The reaction was conducted with [Cp*Co(CO)l2] (10 mol
%), AgBF4 (20 mol %), DCE (2 mL) at 80 °C for 12 h.
isoquinolines,17 isoquinolones,18 indoles,14c,19 etc.20 Despite the
advances, directing groups reported thus far are still limited with
respect to the synthesis of certain important heterocyclic
skeletons. For example, no directed C−H functionalization
method has been documented for the synthesis of quinolones.
Recently, we have launched a synthetic program with
enaminones acting as the directing group for C−H functionaliza-
tion.21 The unique push−pull electronic structure22 has allowed
the exploitation of the enaminone system for Rh(III)-catalyzed
C−C coupling and synthesis of naphthalenes. We are interested
in the extension of the reactivity profile of enaminones to C−
heteroatom coupling en route to the synthesis of heterocycles. In
addition, our synthetic endeavor also aims at the development of
viable catalysis with earth-abundant metal species. We now
report herein Co(III)-catalyzed, enaminone-directed C−H
amidation, using 1,4,2-dioxazol-5-ones23 (abbreviated as dioxa-
zolones herein) as the coupling partners, for the synthesis of
quinolones.
a
Conditions: 1) 1 (0.2 mmol), 2k (0.3 mmol), [Cp*Co(CO)l2] (10
mol %), AgBF4 (20 mol %), DCE (2 mL), 80 °C, 12 h; 2) 4k, 5b−5o
(0.1 mmol), 1.2 N HCl (2 mL), reflux, 9 h; 3) 4k, 5b−5o (0.1 mmol),
TMSOTf (1.45 equiv), Cy2NMe (1.4 equiv), CH2Cl2, 0 °C to rt, 2 h.
b
Isolated yields.
no-1-phenylprop-2-en-1-one (1a) with 3-phenyl-1,4,2-dioxazol-
5-one (2a). Initial screening of the reaction conditions with
[Cp*Co(CO)I2],24 AgSbF6, and additionally either KOAc,
AgOAc, or HOAc leads to the low-yield production of 3a after
12 h of reaction in dichloroethane (DCE) (Table 1, entries 1−3).
Essentially no conversion is observed in the absence of
[Cp*Co(CO)I2] and AgSbF6 (entries 4 and 5), suggesting,
most likely, that a cationic Co(III) complex is involved in the
Reaction development was initiated with the screening of
experimental conditions for the coupling of (E)-3-dimethylami-
B
DOI: 10.1021/acs.orglett.7b00968
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Letter
catalytic cycle. With AgSbF6 loaded as the sole additive, the yield
of 3a is increased to 88% (entry 6). The switching of solvent from
DCE to various other reaction media (entries 6−10) proves
DCE as the optimum solvent. Further examination of the effect
of silver salt (entries 6, 11−13) indicates that AgBF4 gives the
best result (entry 11), with the optimized product yield reaching
92%.
Under the obtained optimal reaction conditions mentioned
above, we explored the applicability of diversely substituted
enaminones 1a−1p in the transformation by adopting 2a as the
representative reaction partner (Scheme 2). The para-
substituted enaminones, bearing both electron-donating sub-
stituents (1b, Me; 1c, OMe; 1k, Ph) and electron-withdrawing
substituents (1d, F; 1e, Cl; 1f, Br; 1g, I; 1h, CF3; 1i, COOMe; 1j,
CN), exhibit excellent reactivity. The reaction proceeds
effectively for meta-substituted enaminones (1l, OMe; 1m, Cl),
resulting in the production of a single regioisomer. Substitution
in the ortho-position as in 1n proves to be compatible with the
synthesis. The reaction can also be applied to disubstituted (1o)
and polycyclic (1p) substrates, and the corresponding products
are acquired in moderate yields.
hydrochloric acid solutions25 or trimethylsilyl trifluoromethane-
sulfonate (TMSOTf)/N,N-dicyclohexylmethylamine
(Cy2NMe),26 enabling the synthesis of a diverse range of
quinolone derivatives (6a−6h, 6j, 6k, 6o) (Table 2).
In conclusion, we have developed herein an efficient Co(III)-
catalyzed enaminone-directed C−H amidation method for
synthetic access to quinolones. The distinct reactivity between
the alkene moiety of the enaminone group and the amino group
generated by deacylation of the amide group has allowed the
incorporation of a diverse range of substituent patterns into the
quinolone molecular skeleton. Given the unique electron push−
pull property exhibited by the enaminones, we anticipate that this
valuable synthon will further prove its utility in more C−H
functionalization reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b00968.
Experimental and synthetic details (PDF)
1H and 13C NMR data (PDF)
With the enaminone substrate scope explored, we next
examined the substrate scope for dioxazolones (2b−2n), with
1a employed as the reaction partner (Scheme 3). Dioxazolone
reagents bearing different electron-donating (2b, 2c, 2i, 2j) and
electron-withdrawing (2d−2h) groups at different positions of
the phenyl ring can all couple smoothly with 1a. Substituents on
the dioxazolones are not limited to aromatic structures, as ethyl
(2k), butyl (2l), tert-butyl (2m), and benzylic (2n) substitution
also allows the delivery of respective target products effectively.
Several experiments were then conducted to examine the C−
H activation process. A competition reaction was performed to
evaluate the electronic preference for the transformation (see
Supporting Information). A one-pot reaction between 1b/1d
and 2a reveals a preferred reaction for electron-rich 1b (product
distribution: 3b/3d = 2.27), providing evidence for an
electrophilic aromatic substitution pathway. A large kinetic
isotope effect (kH/kD = 4) is observed in an experiment between
1a/1a-d5 and 2a, suggesting that C−H activation is turnover-
limiting.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jinz@nju.edu.cn.
ORCID
Jin Zhu: 0000-0003-4681-7895
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Natural
Science Foundation of China (21425415, 21274058) and the
National Basic Research Program of China (2015CB856303).
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In the presence of AgBF4, a cationic Co(III) species (I) is
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