Rhodium(III)-Catalyzed Annulation of Pyridinones with Alkynes via Double C-H Activation: A Route to Functionalized Quinolizinones

Article abstract of DOI:10.1021/acs.orglett.7b01159

A Rh(III)-catalyzed oxidative annulation of pyridin-2(1H)-ones with alkynes via double C-H activation to produce highly functionalized 4H-quinolizin-4-ones is disclosed. This reaction features easily available starting materials, simple manipulation, a relatively wide substrate scope, and good functional group tolerance. The application of this protocol is demonstrated by the synthesis of a known fluorescent quinolizino[3,4,5,6-ija]quinolinium salt.

Full text of DOI:10.1021/acs.orglett.7b01159

Letter
pubs.acs.org/OrgLett
Rhodium(III)-Catalyzed Annulation of Pyridinones with Alkynes via
Double C−H Activation: A Route to Functionalized Quinolizinones
Juan Li, Yudong Yang, Zhigang Wang, Boya Feng, and Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29
Wangjiang Road, Chengdu 610064, P. R. China
S
* Supporting Information
ABSTRACT: A Rh(III)-catalyzed oxidative annulation of
pyridin-2(1H)-ones with alkynes via double C−H activation
to produce highly functionalized 4H-quinolizin-4-ones is
disclosed. This reaction features easily available starting
materials, simple manipulation, a relatively wide substrate
scope, and good functional group tolerance. The application of
this protocol is demonstrated by the synthesis of a known fluorescent quinolizino[3,4,5,6-ija]quinolinium salt.
N-Heteroaryl scaffolds are frequently found in a large number
of natural products, pharmaceuticals, agrochemicals, and
organic materials.1 Owing to their broad application, numerous
methods have been developed for the synthesis of N-
heteroaromatics, especially π-extended N-heteroarenes.2 Qui-
nolizinones are a kind of N-heterocycles that have received
much attention with broad applications as treatments for
Alzheimer’s disease, HIV, Type 2 diabetes, and Mg2+ selective
fluorescent probes.3 However, facile approaches to 4H-
quinolizin-4-ones are extremely rare. The known routes to
4H-quinolizin-4-ones include condensation of ylidenemalono-
dinitriles with quinoline 1-oxides, tandem condensation of α-
substituted picolines with β,β-dichloropropenals and cycliza-
tion, thermal cyclization of α-butenynyl substituted pyridine N-
oxides, intramolecular vinylketene cyclization, addition of
malonic esters to alkynylpyridines, sequential multicomponent
reaction/allylation/Heck reaction, tandem Horner−Wads-
worth−Emmons olefination/cyclization of β-ketopyridines
with phosphonoacetate, sequential N-alkylation of 6-halo-2-
pyridones/Stille cross-coupling/ring-closing metathesis/palla-
dium-catalyzed dehydrogenation reaction, and thermal intra-
molecular cyclization of (η4-vinyketene)-Fe(CO)3 complexes.4
Recently, Huang revealed a highly efficient palladium-catalyzed
intramolecular cyclocarbonylation of allylamines with CO by
C−N bond activation to construct diverse substituted 4H-
quinolizin-4-ones (Scheme 1, eq 1).5 Despite significant
progress, these reported methods typically suffer from narrow
substrate scope, tedious synthetic procedure, and uneasily
available or complex substrates. Thus, the development of a
straightforward and efficient approach to quinolizinones is still
in high demand.
Scheme 1. Transition-Metal-Catalyzed Synthesis of
Quinolizinones via C−N Activation or C−H Activation
functional group tolerance.7 Herein we describe a facile
Rh(III)-catalyzed oxidative cyclization of pyridin-2(1H)-one
derivatives with alkynes for the synthesis of 4H-quinolizin-4-
ones, including π-extended 4H-quinolizin-4-ones (Scheme 1, eq
2).
Our investigation began with the annulation of (E)-1-
styrylpyridin-2(1H)-one (1a) with diphenylacetylene (2a) in
the presence of [Cp*RhCl2]2 (5 mol %), Cu(OAc)2 (1.0
equiv), and PivOH (20 equiv) in N,N-dimethylacetamide
(DMAc) at 120 °C for 24 h under N2 (Scheme 2; Table S1).
To our delight, the annulated product 7,8,9-triphenyl-4H-
quinolizin-4-one 3a was obtained in 63% yield (Table S1, entry
1). Only a trace amount of 3a was detected in the absence of
Cu(OAc)2 (Table S1, entry 3). Switching the solvent to DMF
Transition-metal-catalyzed C−H activation/cyclization with
alkynes has proved to be a powerful tool to construct a variety
of heterocycles and carbocycles.6 In particular, Rh(III)-
catalyzed oxidative annulation of arenes or alkenes with alkynes
has been regarded as an effective strategy to synthesize a variety
of highly functionalized cyclic compounds owing to high atom
and step economy, a broad substrate scope, and good
Received: April 17, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01159
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Letter
undergo the cyclization reaction to give the desired products in
moderate to excellent yields. The 2-pyridinone derivatives with
electronically differentiated groups at different positions of the
pyridinone skeleton were compatible with the standard reaction
conditions (Scheme 3, 3b−3e). The tolerance of functional
groups at the terminal position of the alkene was also studied,
exemplified by the ester and 2-furanyl substituted substrates
(Scheme 3, 3f and 3g). However, the attempt with an alkyl
substituted substrate (R2 = CH3) under the standard conditions
only gave a low yield of the desired product (Scheme 3, 3h).
This reaction also showed a relatively broad scope of alkynes.
Diphenylacetylenes bearing both the electron-donating and
-withdrawing groups were successfully engaged in this trans-
formation (Scheme 3, 3i−3o). Functional groups such as
methyl, methoxy, fluoro, chloro, trifluoromethyl, and ester were
tolerated under the standard reaction conditions. In addition,
dialkyl alkynes were also competent substrates in this reaction,
giving 4H-quinolizin-4-ones in acceptable yields (Scheme 3, 3p
and 3q). A reaction with alkyl aryl alkyne was carried out,
delivering two regioisomers 3r and 3r′ in a total yield of 55%
with a ratio of 5:3.
Scheme 2. Optimization of the Reaction Conditions
resulted in a similar yield, while other solvents such as DMSO,
DCE, dioxane, toluene, and MeOH proved to be much less
effective (Table S1, entries 4−10). PivOH often works as a
proton shuttle to facilitate the deprotonation process in C−H
activation. The amount of PivOH showed a significant
influence on the yield of this transformation (Table S1, entries
1 and 11−15). The addition of 10 equiv of PivOH proved to be
the best, affording 3a in 82% yield (Table S1, entry 15). AcOH
was less effective (Table S1, entry 16), and almost no desired
product was observed when TFA and TsOH·H2O were
attempted (Table S1, entries 17 and 18). The reaction did
not proceed in the absence of the Rh(III) catalyst (Table S1,
entry 19). Finally, the optimal reaction conditions consisted of
[Cp*RhCl2]2 (5.0 mol %), Cu(OAc)2 (1.0 equiv), and PivOH
(10 equiv) in DMAc (0.5 mL) at 120 °C under N2 for 24 h
(Table S1, entry 15).
This strategy was successfully extended to the annulation of
N-arylpyridin-2(1H)-ones with alkynes, in which the activation
of an aromatic C−H bond instead of an olefinic C−H bond
occurred (Scheme 4). For these reactions, 20 equiv of PivOH
were employed to provide the best results. Likewise, this
With the optimized conditions in hand, we next investigated
the substrate scope of this reaction. As summarized in Scheme
3, a variety of N-vinylpyridin-2(1H)-ones could smoothly
Scheme 4. Annulation of N-Arylpyridin-2(1H)-ones with
Alkynes
Scheme 3. Annulation of N-Vinylpyridin-2(1H)-ones with
Alkynes
a
a
a
Reaction conditions: 1 (0.20 mmol), 2 (0.30 mmol, 1.5 equiv),
a
[Cp*RhCl2]2 (0.01 mmol), Cu(OAc)2 (0.20 mmol), and PivOH (2.0
Reaction conditions: 4 (0.20 mmol), 2 (0.30 mmol, 1.5 equiv),
mmol) were stirred in DMAc (0.5 mL) at 120 °C for 24 h under N2.
1 mmol scale.
[Cp*RhCl2]2 (0.01 mmol), Cu(OAc)2 (0.20 mmol), and PivOH (4.0
mmol) were stirred in DMAc (0.5 mL) at 120 °C for 24 h under N2.
b
B
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Letter
catalytic system exhibited a relatively broad substrate scope for
both N-arylpyridin-2(1H)-ones and alkynes, giving a variety of
4H-benzoquinolizin-4-ones in moderate to excellent yields.
Notably, the heteroarene-containing substrates such as 1-
(thiophen-3-yl)pyridin-2(1H)-one, 1-(thiophen-2-yl)pyridin-
2(1H)-one, and 1,2-bis(5-methylthiophen-2-yl)ethyne worked
well under the standard conditions (Scheme 4, 5g, 5h, and 5w).
An attempt with 1-phenyl-1-propyne led to two isolatable
regioisomers 5n and 5n′ in a total yield of 65% with a 30:7
ratio.
(Scheme 5, eq 6). Additionally, treatment of 4a with 2k with
the electron-donating 4-OMe substituent and 2m with the
electron-drawing 4-CO2Et substituent gave rise to a slightly
preferential formation of 5t, probably because the electron-poor
alkyne could more easily undergo coordination and carbome-
talation (Scheme 5, eq 7).9
On the basis of the above observations and the previous
literature,10 a plausible mechanism is proposed in Scheme 6.
Scheme 6. Plausible Mechanism
To shed light on the reaction mechanism, a series of control
experiments were conducted (Scheme 5). Treatment of 4k with
Scheme 5. Mechanism Study
Initially, cyclometalation of pyridin-2(1H)-one 1 or 4 delivers a
six-membered rhodacycle IM1. Then a rollover cyclometalation
takes place to give a five-membered rhodacyclic intermediate
IM2 possibly owing to the steric hindrance of Cp* and/or the
coordination of the solvent.11 The following alkyne coordina-
tion and migratory insertion produce a seven-membered
rhodacycle IM5 or IM6 (path a). Finally, reductive elimination
of IM5 or IM6 gives the desired product 3 or 5 and releases the
Rh(I) species, which is then reoxidized by Cu(OAc)2 to
regenerate the reactive Rh(III) catalyst. Alternatively, in path b,
an alkyne insertion followed by rollover cyclorhodation is
possibly involved, affording a seven-membered rhodacycle
intermediate IM5.
Recently, azonia aromatic heterocycles have attracted much
attention owing to their great potential applications in organic
functional materials.12 To further demonstrate the utility of this
reaction, quinolizino[3,4,5,6-ija]quinolinium salt 6, which was
reported as a fluorescent molecule,13 was synthesized by
treatment of 5a with either a Cp*Co(III) or Cp*Rh(III)
catalytic system (Scheme 7, eqs 8 and 9). However, the
annulations of compound 3 with diphenylacetylene under
otherwise identical conditions failed (Scheme 7, eq 10). Based
on the previous reports,14 a plausible mechanism is proposed
(see the Supporting Information). Initially, a carbonyl oxygen-
directed C−H activation of compound 5a delivers a six-
membered organometallic intermediate IM7, which could
further undergo alkyne insertion and nucleophilic addition to
the CO bond to give the intermediate IM9. In the presence
of BF3·OEt2, a deoxygenation process might take place to give
the desired product quinolinium salt 6 along with the release of
the metal catalyst.
PivOD in the absence of an alkyne under the standard
conditions led to 20% deuterium incorporation at the two
ortho-positions of the phenyl moiety (Scheme 5, eq 3). This
result indicated a reversible C−H activation was probably
involved in this transformation. However, no H/D exchange
was observed in both the isolated product and recovered
starting material when the same reaction was performed in the
presence of 2a, implying an irreversible alkyne insertion was
likely involved (Scheme 5, eq 4).8 A large kinetic isotope effect
(KIE) value of 6.1 was obtained in the annulation of an
equimolar mixture of 4a and [D5]-4a with diphenylacetylene 2a
under the standard conditions, suggesting that C−H bond
cleavage is likely involved in the rate-determining step (Scheme
5, eq 5). Then the intermolecular competition experiment
between electronically differentiated 4l and 4i was conducted. A
small molar ratio of 1.15:1 between the products 5l and 5i was
obtained, implying an electrophilic aromatic substitution
process is less likely involved in the initial C−H activation
In conclusion, we have developed a Rh(III)-catalyzed
oxidative annulation of pyridin-2(1H)-one derivatives with
C
DOI: 10.1021/acs.orglett.7b01159
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elucidated by the synthesis of fluorescent quinolizino[3,4,5,6-
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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.7b01159.
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Detailed experimental procedures, characterization data,
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1
and copies of H, 13C, and 19F NMR spectra of key
substrates and final products. (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jsyou@scu.edu.cn.
ORCID
Jingsong You: 0000-0002-0493-2388
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the National NSF of
China (No. 21432005) and the Comprehensive Training
Platform of Specialized Laboratory, College of Chemistry,
Sichuan University.
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DOI: 10.1021/acs.orglett.7b01159
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