Direct Synthesis of Quinolines via Co(III)-Catalyzed and DMSO-Involved C-H Activation/Cyclization of Anilines with Alkynes

Article abstract of DOI:10.1021/acs.orglett.7b03673

A unique Co(III)-catalyzed and DMSO-involved C-H activation/cyclization of simple, cheap, and easily available anilines with alkynes for direct and highly efficient synthesis of privileged quinolines with exclusive regioselectivity and broad substrate/functional group tolerance and in good to excellent yields, where DMSO was employed as both the solvent and the C₁ building block of quinoline products, is reported. Mechanistic experiments revealed that the versatile reaction might employ the 2-vinylbenzenamine species as the active intermediate.

Full text of DOI:10.1021/acs.orglett.7b03673

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Synthesis of Quinolines via Co(III)-Catalyzed and DMSO-
Involved C−H Activation/Cyclization of Anilines with Alkynes
Xuefeng Xu,† Yurong Yang,‡ Xu Zhang,*,† and Wei Yi*,‡
†College of Chemistry and Pharmaceutical Engineering, Nanyang Normal University, Nanyang 473061, China
‡Key Laboratory of Molecular Clinical Pharmacology & Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou,
Guangdong 511436, China
S
* Supporting Information
ABSTRACT: A unique Co(III)-catalyzed and DMSO-involved
C−H activation/cyclization of simple, cheap, and easily available
anilines with alkynes for direct and highly efficient synthesis of
privileged quinolines with exclusive regioselectivity and broad
substrate/functional group tolerance and in good to excellent
yields, where DMSO was employed as both the solvent and the C1
building block of quinoline products, is reported. Mechanistic experiments revealed that the versatile reaction might employ the
2-vinylbenzenamine species as the active intermediate.
uinoline represents a ubiquitous structural motif that is
example, in 2015, the Li group reported a beautiful Co(III)-
catalyzed redox-neutral annulative coupling of amides with
alkynes for synthesis of quinolines, in which the acetamino
group was used as the versatile BDG (Scheme 1a).11 Afterward,
the Balaraman group revealed a rhodium-catalyzed C−H
activation strategy which employed unprotected anilines and
Q found in a broad range of biologically active compounds
and pharmaceuticals.1 Recognizing the great importance of
quinoline and its derivatives, the development of efficient
methods toward their synthesis has attracted considerable
attention. As a result, a number of named reactions have been
developed, such as Skraup,2 Doebner−von Miller,3 Conrad−
Limpach,4 Pfitzinger,5 and Friedlander concentration synthe-
̈
Scheme 1. Quinoline Synthesis via Transition Metal-
Catalyzed C−H Annulation of Anilines with Alkynes/
Ketones
ses.6 However, by reviewing these classical procedures, they still
suffer from harsh conditions, corrosive reagents, and a limited
substrate scope. Alternatively, a recently popular C−H bond
functionalization strategy has emerged as one of the most
powerful tools for the step- and atom-economical construction
of quinoline framework. Indeed, numerous versatile protocols
have been disclosed by second-row transition metals such as
Rh, Ru, Pd, Au, Ag, etc.7 Despite this compelling progress, it
would be ideal to directly build the quinoline motif via earth-
abundant and inexpensive first row transition-metal-catalyzed
C−H bond functionalization strategy in view of green and
sustainable chemistry. In this regard, a few seminal examples
have been reported.8
Recently, cobalt-catalyzed C−H functionalization has gained
significant attention due to its distinctive properties, including
abundance and inexpensiveness, outstanding reactivity and
selectivity, and excellent substrate/functional group tolerance.9
In general, the assistance of a proximal directing group (DG) is
typically required for achieving the cobalt-catalyzed C−H bond
activation.9,10 However, the DG cannot be removed simulta-
neously in C−H activation reactions and thus often leaves a
chemical trace in the final products, limiting their structural
diversity.
To overcome the aforementioned limitation, one recent
emerging strategy to develop an innovative bifunctional-
directing group (BDG) which acts as both a DG and a basic
component of products has attracted much attention. For
Received: November 27, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03673
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electron-deficient alkynes to build quinoline products, where
CO gas or paraformaldehyde was employed as one carbon
source (Scheme 1b).12 Recently, our group has also described a
similar Co(III)-catalyzed C−H activation strategy for one-pot
construction of a quinoline framework (Scheme 1c).13 Very
recently, Singh and Jadhav described an elegant FeCl3-catalyzed
oxidative annulation promoted by K2S2O8 involving anilines,
aryl ketones, and DMSO as a methine equivalent giving direct
access to 4-arylquinolines (Scheme 1d).14 Compared to
paraformaldehyde, indeed, DMSO is more feasible due to its
rather low cost, relative stability, and low toxicity. However, in
sharp contrast with that using DMSO as the precursor for the
introduction of various functional groups such as the sulfonyl
group,15 formyl group,16 methylthio,17 and cyano substitu-
ents,18 the examples that employed DMSO as a one carbon
source to directly construct heterocyclic compounds still
remain underexplored.14,19
displayed that employing both AgNTf2 and K2S2O8 as co-
additives was optimal, giving the product 3a in 85% isolated
yield (entry 5). The control experiments demonstrated that the
omission of either the catalyst or cocatalytic additives led to a
significant decrease in the product yield (entries 11−14).
Finally, changing Cp*Co(CO)I2 to other well-known cobalt
species also obviously inhibited the process (entries 15−17).
With the optimal reaction conditions in hand, the scope of
the reaction with respect to various anilines was evaluated
initially (Scheme 2); the results showed that the reaction
a
Scheme 2. Scope of Aniline
Motivated by the aforementioned information and in
continuation of our interest in transition-metal-catalyzed C−
H functionalization, we herein report, for the first time, a
Co(III)-catalyzed and DMSO-involved C−H activation/cycli-
zation of anilines with alkynes for one-pot synthesis of
quinolines, in which DMSO was employed as both the solvent
and the C1 building block of quinoline products (Scheme 1e).
We initiated our studies by testing different reaction
conditions for the desired synthesis of quinoline 3a (Table
1). To our delight, the anticipated 3a was smoothly detected in
DMSO and isolated with 64% yield, when simple aniline (1a)
and phenylacetylene (2a) were employed as model substrates,
and Cp*CoI2(CO), AgSbF6, and K2S2O8 were selected as the
catalytic system (Table 1, entry 1). Encouraged by this finding,
we next investigated the effects of additives for this reaction
optimization. As shown in entries 2−12, the brief screening
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), Cp*Co(CO)I2
(5.0 mol %), AgNTf2 (20 mol %), K2S2O8 (1.5 equiv), DMSO (2 mL),
120 °C, 8 h, reaction kettle in air, isolated yield after chromatography.
proceeded smoothly to give the desired products in high yields,
and the electronic and steric effects of the substituents on the
anilines had no obvious influence on the efficiency of the
reaction. For example, anilines bearing the either electron-
donating (Me, t-Bu) or electron-withdrawing (F, Br)
substituents at the ortho-position all showed good compatibility,
and the corresponding products 3b−e were obtained in 77−
82% yields. Similarly, meta- and para-substituted anilines also
successfully afforded the corresponding quinoline products 3f−
3r with excellent yields (up to 91%). It was worth emphasizing
that, for meta-substituted anilines, the sole regioisomer was
detected, in which the C−H activation reaction exclusively
occurred at a less-hindered ortho-position. Notably, the
polyaromatic naphthalene substrates were also well tolerated
with the Co(III)-catalyzed system as exemplified by the
successful synthesis of 3s. Finally, large-size aminoglutethimide
and 4-morpholinobenzenamine were also viable substrates,
providing the desired products 3t and 3u in 71% and 85%
yields, respectively.
The scope of alkynes was next examined (Scheme 3). A wide
variety of phenyl-functionalized terminal alkynes bearing various
substituents either at the ortho-, meta-, or para- position on the
benzene ring all gave the corresponding products with excellent
regioselectivity and in moderate to excellent yields (68−95%)
(4a−4p). Both electron-donating (Me, OMe, Et, n-Pr, t-Bu,
N(CH3)2) and -withdrawing (F, Cl, Br, I, CF3) groups that
attached at the benzene ring part of alkynes were all well
tolerated. Interestingly, the phenyl group of alkynes could also
be extended to the heteroaryl moiety, such as 2-ethynylfuran, 2-
ethynylthiophene, and 3-ethynylpyridine substituents, deliver-
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst
additive A
additive B
yield (%)
1
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
Cp*Co(CO)I2
−
AgSbF6
AgOAc
AgOTf
Ag2CO3
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
AgNTf2
−
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
(NH4)2S2O8
Na2S2O8
H2O2
64
32
54
0
2
3
4
5
85
0
6
7
40
0
8
9
TBHP
35
37
0
10
11
12
13
14
15
16
17
DTBP
−
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
34
21
0
AgNTf2
−
−
Co(OAc)2
AgNTf2
AgNTf2
AgNTf2
17
0
Co(acac)2
CoI2
62
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Cp*Co(CO)I2
(5.0 mol %), additive A (20 mol %), additive B (1.5 equiv), DMSO (2
mL), 120 °C, 8 h, reaction kettle in air. Isolated yield after
b
chromatography.
B
DOI: 10.1021/acs.orglett.7b03673
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Scope of Alkynes
Scheme 4. Mechanistic Studies
predicted, the product 3a was obtained smoothly in 72% yield
(Scheme 4b, below). Moreover, the kinetic isotope effect was
measured to shed more light on the C−H activation process
(Scheme 4c), and a small value for the kinetic isotope effect
(KIE = 1.22) was monitored from two independent, side-by-
side experiments, revealing that the C−H bond cleavage was
unlikely involved in the turnover limiting step. No reaction was
observed when 2,6-dimethylaniline and N-methyleneaniline
were respectively employed as the substrate with the reaction of
phenylacetylene (Scheme 4d).
a
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Cp*Co(CO)I2
(5.0 mol %), AgNTf2 (20 mol %), K2S2O8 (1.5 equiv), DMSO (2 mL),
120 °C, 8 h, reaction kettle in air, isolated yield after chromatography.
ing the corresponding quinoline products in good yield (for 4q,
79%; 4r, 81%; and for 4s, 79%). It should be noted that the
substituted acetylenes, such as cyclohexylacetylene (1t),
ethynylnaphthalene (1u−v), N-porargylphthalimide (1w), and
ethynylferrocen (1x), could be accommodated in the catalytic
system, thus giving their corresponding products 4s−x in
moderate to good yields. This methodology could be extended
to internal alkynes as well. For example, the reaction of 1v with
1,2-diphenylethyne or diethyl but-2-ynedioate worked well in
DMSO to deliver the expected products 4z and 4a−a in 60%
and 71% yields, respectively.
Considering the remarkably broad substrate scope displayed
by the Co(III) catalytic system, we performed a series of
control experiments to probe the possible reaction mechanism
(Scheme 4). Initially, by using DMSO-d6 to replace DMSO, the
deuterated product 3m was formed in 84% yield with more
than 99% incorporation of deuterium (Scheme 4a), which
provided clear evidence that DMSO was not only used as the
solvent but also acted as the C1 in this reaction. Further, when
the reaction was performed in methylphenylsulfoxide under
otherwise identical conditions (Scheme 4b, above), both
product 3a and 2-vinylbenzenamine species 5 were isolated
in 12% and 14% yield, respectively, suggesting that 5 might be
employed as an active intermediate for this transformation. To
further confirm this, the treatment of 2-styrylphenylamine with
DMSO under the standard conditions was carried out. As
On the basis of our experimental results and previous
reports, a plausible catalytic cycle is depicted in Scheme 5. First,
the active cationic Co(III) catalyst is generated upon treatment
of Cp*Co(Co)I2 with AgNTf2, which coordinated with aniline,
followed by the EAS pathway and then ortho-metalation to
afford the intermediate A. More polarized carbon−cobalt in
intermediate A should favor 1,2-regioselective insertion20 of an
alkyne leading to intermediate B. In the presence of K2S2O8,
the DMSO is activated by K2S2O8 to give C, which couples
with B to produce the intermediate D. Subsequently, D is
oxidized to give an imine species E with the elimination of
HSMe, followed by Co−C migratory insertion to provide the
intermediate F. Finally, protonolysis of F delivers the final
product 3a with the release of the active Co(III) catalyst.
In conclusion, we have developed the first example of
Co(III)-catalyzed and DMSO-involved C−H activation/cycli-
zation of anilines with alkynes for direct and highly efficient
synthesis of privileged quinolines, in which DMSO was
employed as both the solvent and the C1 building block.
Experimental investigations revealed that this transformation
might be initiated with the C−H activation process and use 2-
vinylbenzenamine species as the active intermediate. Consid-
ering the simple, cheap, and easily available starting materials,
the valuable structures of the products, mild reaction
conditions, exclusive regioselectivity, and excellent substrate/
C
DOI: 10.1021/acs.orglett.7b03673
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03673.
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Experimental procedures, characterization of products,
1
and copies of H and 13C NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(13) Xu, X.; Yang, Y.; Chen, X.; Zhang, Z.; Yi, W. Org. Biomol. Chem.
2017, 15, 9061.
*E-mail: yiwei@gzhmu.edu.cn.
*E-mail: zhangxuedu@126.com.
ORCID
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Xu Zhang: 0000-0002-3588-3240
Wei Yi: 0000-0001-7936-9326
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the National Natural Science Foundation of
China (21502100 and 81502909) and Guangdong Natural
Science Funds for Distinguished Young Scholar
(2017A030306031) for financial support on this study.
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DOI: 10.1021/acs.orglett.7b03673
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