Redox-Neutral Couplings between Amides and Alkynes via Cobalt(III)-Catalyzed C-H Activation

Article abstract of DOI:10.1021/acs.orglett.5b03629

C-H activation assisted by a bifunctional directing group has allowed the construction of heterocycles. This is ideally catalyzed by earth-abundant and eco-friendly transition metals. We report Co(III)-catalyzed redox-neutral coupling between arenes and alkynes using an NH amide as an electrophilic directing group. The redox-neutral C-H activation/coupling afforded quinolines with water as the sole byproduct.

Full text of DOI:10.1021/acs.orglett.5b03629

Letter
pubs.acs.org/OrgLett
Redox-Neutral Couplings between Amides and Alkynes via
Cobalt(III)-Catalyzed C−H Activation
Lingheng Kong, Songjie Yu, Xukai Zhou, and Xingwei Li*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
S
* Supporting Information
ABSTRACT: C−H activation assisted by a bifunctional
directing group has allowed the construction of heterocycles.
This is ideally catalyzed by earth-abundant and eco-friendly
transition metals. We report Co(III)-catalyzed redox-neutral
coupling between arenes and alkynes using an NH amide as an
electrophilic directing group. The redox-neutral C−H activation/coupling afforded quinolines with water as the sole byproduct.
Scheme 1. C−H Activation for the Synthesis of Heterocycles
he past decades have witnessed significant progress in
Tmetal-catalyzed C−H bond activation as an advantageous
strategy in the construction of complex molecules.1 The ubiquity
of C−H bonds and highly atom- and step-economic trans-
formations in C−H activation have attracted increasing attention
in utilizing arenes as direct substrates. The activation of
unreactive arene C−H bonds typically requires the assistance
of a proximal directing group.1,2 However, in most cases, the
directing group (DG) only exhibited a ligating effect or acted as a
simple nucleophile in postcoupling transformations. Thus, the
DG was carried over to the final product with limited functional
diversity. To overcome this limitation, functionalizable DGs with
nucleophlicity, electrophilicity, and redox property have been
designed.3 Electrophilic DGs are bifunctional in that they consist
of a nucleophilic coordinating site and an electrophilic center.
This discrepancy has been reconciled in recent work by Cheng,4
Glorius,5 Shi,6 and others7 in Rh(III)-catalyzed C−H activation.
However, reports in this regard remain limited, particularly in the
context of heterocycle synthesis.8
Recently, cost-effective Cp*Co(III) complexes have been
increasingly employed as highly efficient catalysts for the C−H
activation of arenes, as in the reports by Kanai,9 Glorius,10
Ackermann,11 Ellman,12 Daugulis,13 Chang,14 and others,15
where the DGs are single-functional and Co(III)-catalyzed
annulation reactions are rare.9e,11c,15c We reasoned that bifunc-
tional DGs with low electrophilicity can be viable in facilitating
cyclization reactions when the electrophilicity is enhanced by
Lewis acidic metals. With Lewis acidity higher than that of their
Rh(III) and Ir(III) congeners, Cp*Co(III) catalysts are expected
to meet the criteria by activating both C−H bonds and the
bifunctional DG. Amides are readily available DGs, and the
bifunctionality of amides has been established in C−H activation
systems, leading to annulation.6,9b,16,17 In particular, Wang, Yu,
and co-workers recently reported the synthesis of pyridines via [4
+ 2] annulation between enamides and alkynes (Scheme 1).17
On the other hand, while access to isoquinolines has been
extensively explored in Rh- and Ru-catalyzed C−H activation,18
examples of quinoline synthesis via a C−H activation pathway
are very limited,19 especially under redox-neutral conditions. We
now report Co(III)-catalyzed, redox-neutral couplings between
amides and alkynes, leading to efficient synthesis of quinolines.
We initiated our studies with the development of a synthetic
method to access quinolines. Traditional quinoline syntheses
such as the Doebner−Von Miller, Skraup, Combes, Knorr, and
Friedlander methods typically suffered from harsh conditions,
necessity of using toxic and corrosive reagents, and a limited
substrate scope.20 We began our quinoline synthesis using
acetanilide (1a) and diphenylacetylene (2a) as model substrates
(Table 1). When the reaction was conducted in DCE using
[Cp*CoCl2]2/AgSbF6 (4 mol %/20 mol %) as the catalyst at 130
°C, the desired quinoline 3aa was isolated in only 35% yield as a
result of dehydrative annulation (entry 1). The silver additive had
a significant impact on the reaction efficiency. Switching the
additive to AgNTf2 improved the yield to 43% (entry 2), but
essentially no product was detected when other additives such as
AgOAc, AgOTf, and AgOPiv were used (entries 4−6). Solvent
screening revealed that DCE was the most efficient medium
(entries 7 and 8). The amount of the silver additive had a
significant effect on the reaction efficiency. While moderate yield
was observed using 0.5 equiv of AgNTf2, the yield was
Received: December 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03629
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Letter
a
which is often problematic in C−H activation systems, is also
compatible, albeit with lower yield (3ia). Various meta
substituents such as methyl (3ka), methoxy (3la), chloro
(3ma), bromo (3na), and CF3 (3oa) groups were fully tolerated,
and in these cases, C−H activation occurred at the less-hindered
position. In contrast to the high selectivity, the coupling of N-(3-
fluorophenyl)acetamide afforded a mixture of regioisomeric
products (3pa and 3pa′) in 1.2:1 ratio and in 81% total yield as a
result of the reduced steric bulk of the fluoro group. The C−H
activation reaction is not limited to a monosubstituted arene, and
2,3-disubstituted acetanilides also reacted under optimized
conditions to afford the desired products (3wa and 3xa) in
good yields and high regioselectivity (>17:1). Meanwhile, amides
bearing other acyl groups (3qa, 3ra, 3sa, and 3ta) also coupled
efficiently to provide the quinolines in 60−81% yields. In
contrast, pivaloyl (3ua) and trifluoroacetyl (3va) amides failed to
undergo any coupling, indicating that the electronic and steric
effects of the acyl group played an important role.
Table 1. Screening of Reaction Conditions
b
entry
cat. (mol %)
additive (mol %)
solvent
yield (%)
1
2
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (4)
[Cp*CoCl2]2 (6)
[Cp*CoCl2]2 (8)
AgNTf2 (20)
AgSbF6 (20)
AgNTf2 (20)
AgOAc (20)
AgOTf (20)
AgOPiv (20)
AgNTf2 (20)
AgNTf2 (20)
AgNTf2 (50)
AgNTf2 (100)
AgNTf2 (100)
AgNTf2 (100)
DCE
DCE
DCE
DCE
DCE
DCE
dioxane
PhCl
DCE
DCE
DCE
DCE
<5
35
43
<5
<5
<5
<5
<5
51
80
93
90
3
4
5
6
7
8
9
10
11
12
We next investigated the scope of the alkyne in the coupling
with 1a (Scheme 3). Symmetrically substituted diarylacetylenes
a
Reaction conditions: acetanilide 1a (0.2 mmol), 2a (0.24 mmol),
solvent (4 mL), 130 °C, 16 h, sealed tube under air. Isolated yield
b
a b
,
Scheme 3. Scope of Alkyne Substrates
after chromatography.
dramatically improved when 6 mol % of [Cp*CoCl2]2 and
AgNTf2 (1 equiv) was used (entry 11), where a stoichiometric
amount of AgNTf2 likely serves as both a halide scavenger
(catalyst activation) and a Lewis acid (activation of the carbonyl
group). Notably, no extrusion of air was necessary. Furthermore,
when the scale of the reaction was enlarged to 1 mmol with a
reduced catalyst loading (3 mol %), product 3aa was isolated in
moderate yield (60%). In comparison, essentially no desired
reaction was observed when the Ru-catalyzed conditions that
proved optimal for the coupling between enamides and alkynes
were employed.17
With the establishment of the optimized conditions, the scope
and generality of the reactions were next evaluated (Scheme 2). It
was found that a range of acetanilide bearing various electron-
donating, -withdrawing, and halogen substituents at the para
positions all coupled smoothly with 2a, and the quinoline
products were isolated in 34−94% yields. A para-nitro group,
a
Reaction conditions: acetanilide (0.2 mmol), alkynes (0.24 mmol),
[Cp*CoCl2]2 (6 mol %), AgNTf2 (1 equiv), DCE (4 mL), 130 °C, 16
b
c
h, sealed tube under air. Isolated yield. Alkyne (0.3 mmol) was used.
d
Only the major isomer was shown.
bearing halogen or methyl groups at the para and meta positions
gave the desired products 3ab−3af in 58−94% yield. The alkynes
can also be extended to heteroaryl substitution with di(2-
thienyl)acetylene with excellent yield (3ag, 96%). In addition,
unsymmetrical alkynes displayed good to high reactivity and
moderate to high regioselectivity. Of note, couplings for alkyl-
and aryl-disubstituted alkynes gave excellent yields (3ak−3am,
88−95%) and high regioselectivities (8−11:1), while other
unsymmetrical alkynes offered high reactivity but lower
regioselectivity.
a b
,
Scheme 2. Scope of Amide Substrates
To demonstrate the synthetic utility, a derivatization reaction
was carried out for a quinoline product. Treatment of quinoline
3aa with m-CPBA led to the quantitative formation of the
corresponding quinoline N-oxide. A functionalized acetophe-
none (4) was isolated in high yield via a Rh(III)-catalyzed C−H
activation with subsequent O-atom transfer (Scheme 4).21
To shed light on the mechanism, the kinetic isotope effect was
studied by two side-by-side reactions using 1a and 1a-d5 under
the standard conditions, from which a kH/kD value of 3.4 was
1
a
obtained on the basis of H NMR analysis (Scheme 5). In
Reaction conditions: amide (0.2 mmol), alkyne (0.24 mmol),
addition, the competitive coupling of an equimolar mixture of 1a
and 1a-d5 with diphenylacetylene gave a consistent value of kH/
kD = 5.3. These results indicated that C−H activation is likely
[Cp*CoCl2]2 (6 mol %), AgNTf2 (1.0 equiv), DCE (4.0 mL), 130
°C, 16 h, sealed tube under air. Isolated yield. With 4 mol % of
catalyst.
b
c
B
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Letter
group, forming a Co(III) alkoxide species III. This migratory
insertion is favored by the enhanced electrophilicity of the amide
carbonyl assisted by the stoichiometric amount of AgNTf2.
Protonolysis of the Co−O bond produces a tertiary alcohol and
regenerates the active catalyst, and the final product was released
upon dehydration of the tertiary alcohol.
Scheme 4. Transformations of a Coupled Product
In conclusion, we have developed Cp*Co(III)-catalyzed
redox-neutral annulative couplings for the synthesis of quinolines
between amides and alkynes via a C−H activation pathway. The
reactions proceeded with high functional compatibility. Amides
bearing various functional groups are viable substrates, and a
wide range of aryl-, hetero-, and ester-substituted alkynes have
been established as efficient coupling partners in the reactions.
The coupling system represents a rare synthesis of quinolines via
a C−H activation process. This efficient and concise protocol to
access important quinoline scaffolds may find applications in the
synthesis of complex products.
Scheme 5. Mechanistic Studies
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03629.
General experimental procedures, characterization details,
and 1H and 13C NMR spectra of new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
involved in the turnover-limiting step. To further investigate the
electronic preference of the reaction, competitive coupling of 1b
and 1h differing in electronic effects was performed, and the
coupling was favored for the more electron-rich substrate (1b).
Furthermore, to probe if the annulation proceeded with the
intermediacy of an olefin, styrene 5 was prepared and subjected
to the standard reaction conditions. No desired product was
observed; instead, an indoline was generated in good yield
(Scheme 5). This indicates that the reaction did not proceed via
initial full hydroarylation and subsequent cyclization.
*E-mail: xwli@dicp.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the NSFC (Nos. 21525208 and
21472186) and the Dalian Institute of Chemical Physics,
Chinese Academy of Sciences is gratefully acknowledged.
On the basis of our mechanistic experiments and previous
reports,14a a plausible catalytic cycle is depicted in Scheme 6. The
active cationic Co(III) catalyst is generated upon treatment of
[Cp*CoCl2]2 with AgNTf2. Cobalt-mediated C−H bond
activation of acetanilide affords a six-membered metallacyclic
intermediate I.14a Alkyne coordination and migratory insertion
of the aryl group generates a Co(III) alkenyl species II. The Co−
C bond of II undergoes migratory insertion into the carbonyl
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