Ruthenium-catalyzed cyclization of anilides with substituted propiolates or acrylates: An efficient route to 2-quinolinones

Article abstract of DOI:10.1021/ol501548e

A Ru-catalyzed cyclization of anilides with propiolates or acrylates affording 2-quinolinones having diverse functional groups in good to excellent yields is described. Later, 2-quinolinones were converted into 3-halo-2-quinolinones and 2-chloroquinolines

Full text of DOI:10.1021/ol501548e

Letter
pubs.acs.org/OrgLett
Ruthenium-Catalyzed Cyclization of Anilides with Substituted
Propiolates or Acrylates: An Efficient Route to 2‑Quinolinones
Rajendran Manikandan and Masilamani Jeganmohan*
Department of Chemistry, Indian Institute of Science Education and Research, Pune 411021, India
S
* Supporting Information
ABSTRACT: A Ru-catalyzed cyclization of anilides with
propiolates or acrylates affording 2-quinolinones having
diverse functional groups in good to excellent yields is
described. Later, 2-quinolinones were converted into 3-halo-2-
quinolinones and 2-chloroquinolines. The proposed mecha-
nism was strongly supported by experimental evidence and
deuterium labeling studies.
2-Quinolinones are a naturally occurring heterocyclic moiety. It
shows a broad range of biological activities including antibiotic,
anticancer, antiviral, and antihypersensitivity.1 This core is also
present in various natural products (Figure 1).2 2-Quinolinones
electrophilic cyclization of ortho-alkynyl anilides (eq 1c).6c Doi
reported the synthesis of 2-quinolinones through a Pd-catalyzed
intramolecular amidation of phenyl substituted enamides (eq
1d).6d Very recently, Alper reported the synthesis of 2-
quinolinones via the oxidative cyclocarbonylation of 2-vinyl
anilines with CO in the presence of a Pd catalyst (eq 1e).6e In
most of these methods, a preactivated species, such as C−X or
C−M having starting material, is required to synthesize the key
starting materials. In the meantime, the synthesis of 2-
quinolinones are also achieved by the other protocols without
a metal catalyst.7
Figure 1. Selected biologically active 2-quinolinones.
are also efficient fluorescent markers for amino acids, peptides,
amino carbohydrates, and amino polysaccharides (Figure 1).3
Also, 2-quinolinones are key synthetic intermediates for
synthesizing 2-halo, 2-alkoxy, and 2-amino substituted quino-
lines.4
As a result, various synthetic methods are reported in the
literature for the synthesis of 2-quinolinone derivatives.5−7
Traditionally, 2-quinolinone derivatives are prepared by the acid-
mediated intramolecular cyclization of β-keto anilides (Knorr
synthesis) and a base-mediated intramolecular aldol condensa-
tion of 2-aminophenyl substituted carbonyl compounds (Fried-
lander synthesis).5 Recently, 2-quinolinones were efficiently
prepared via Pd catalysis.6 Larock reported the synthesis of 3,4-
disubstituted quinolinones by a Pd-catalyzed carbonylative
annulation of 2-iodoanilides with alkynes and CO (eq 1a).6a
Manley reported a Pd-catalyzed amidation of ortho-halo
acetophenone with alkyl amides leading to 4-substituted
quinolinones (eq 1b).6b Fujiwara reported the synthesis of 4-
substituted quinolinones via a Pd-catalyzed intramolecular
Transition-metal-catalyzed cyclization of heteroatom substi-
tuted aromatics with a carbon−carbon π-component via
chelation-assisted C−H bond activation is a powerful method
to synthesize heterocyclic molecules in one pot.8 In this method,
a preactivated species such as C−X or C−M having starting
material is not required to activate the carbon of the aromatic
moiety. By using this method, various heterocyclic compounds
were synthesized efficiently in a highly atom economical and
environmentally friendly manner.8 But, the synthesis of 2-
Received: May 29, 2014
© XXXX American Chemical Society
A
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Letter
quinolinone derivatives via a chelation-assisted C−H bond
activation pathway is limited in the literature. Herein, we wish to
report the synthesis of 4-substituted-2-quinolinone derivatives
from easily available starting materials via a Ru-catalyzed
cyclization of anilides with substituted propiolates. By using
acrylates instead of propiolates, unsubstituted 2-quinolinone
derivatives were prepared. Later, a halo group such as Cl or Br
was introduced at the C-3 position of 4-substituted-2-
quinolinones in the presence of NBS or NCS. Further, highly
useful 2-chloroquinolines were prepared from 2-quinolinones in
the presence of POCl3. It is important to point out that the
anilines or enamines reacted with alkynes in the presence of a
rhodium or Ru catalyst furnishing indole and pyrrole derivatives.9
The cyclization of 3,4-dimethoxy acetanilide (1a) with ethyl-2-
butynoate (2a) in the presence of [{RuCl2(p-cymene)}2] (5.0
mol %), AgSbF6 (20 mol %), and pivalic acid (10.0 equiv) in i-
PrOH at 130 °C for 24 h gave 4-methyl substituted-2-
quinolinone 3aa in 86% isolated yield (Scheme 1) (for the
Table 1. Cyclization of Substituted Anilides 1b−m with Ethyl-
a
2-butynoate (2a)
Scheme 1. Cyclization of 3,4-Dimethoxy Acetanilide (1a) with
Ethyl-2-butynoate (2a)
detailed optimization studies, see Supporting Information (SI) in
Table S1). The ortho C−H bond activation of substrate 1a is very
selective, and the activation selectively takes place at a sterically
less hindered side. The cyclization reaction was also tested with
anilines having other removable directing groups at the nitrogen
atom such as sulfonamide (NH−SO2Me) and aryl urea
(NHCONMe2) instead of (NHCOMe). However, in the
reaction, no cyclization product was observed.
a
Method A: 1b−e, 1l, and 1m (100 mg) were treated with ethyl-2-
butynoate (2a) (1.5 equiv), [{RuCl2(p-cymene)}2] (0.05 equiv),
AgSbF6 (0.20 equiv), and pivalic acid (10.0 equiv) in i-PrOH (2.5 mL)
at 130 °C for 24 h. Method B: 1f−k (100 mg) were treated with ethyl-
2-butynoate (2a) (1.5 equiv), [{RuCl2(p-cymene)}2] (0.05 equiv),
and AgSbF6 (0.20 equiv) in AcOH (3.0 mL) at 130 °C for 24 h.
b
Isolated yield.
heteroaromatic thiophene-2-acetamine (1m) also efficiently
reacted with 2a, affording the cyclization product 3ma in an
excellent 83% yield (entry 12).
The scope of the reaction was further tested with unsym-
metrical acetanilides 1n−p (Scheme 2). In all these reactions, a
The scope of the cyclization was examined with various
substituted anilides 1b−p with ethyl-2-butynoate (2a) (Table 1).
In all these reactions, the expected 4-methyl substituted 2-
quinolinone derivatives were observed in good to excellent
yields. In addition, the reaction was compatible with various
sensitive functional groups such as OMe, F, Cl, Br, NO2, ester,
keto, and OH substituted anilides. The reaction of electron-
donating groups such as OMe, Me, and OH substituted anilides
1b−e with 2a gave the corresponding quinolinones 3ba−ea in an
excellent 81%, 79%, 76%, and 80% yield, respectively (entries 1−
4). But, the conditions using i-PrOH/pivalic acid as the solvent
was not superior for halogen and electron-withdrawing group
substituted anilides 1f−k. For these substrates, acetic acid as the
solvent proved superior to pivalic acid/i-PrOH (for the detailed
optimization studies, see SI in Table S2). Under these modified
reaction conditions, F-, Cl-, and Br-substituted anilides 1f−h
provided products 3fa−ha in 62%, 64%, and 69% yields,
respectively (entries 5−7). A less reactive electron-withdrawing
group such as keto, ester, and nitro substituted anilides 1i−k also
efficiently participated in the reaction using AcOH as the solvent,
giving quinolinone derivatives 3ia−ka in 66%, 71%, and 69%
yields, respectively (entries 8−10). It is important to note that, in
the substrates 1i−j, the C−H bond activation selectively takes
place at the ortho position to the NHCOMe group and the keto
and ester groups remain intact. Sterically hindered ortho-
methoxy acetanilide 1l was also involved in the reaction, yielding
product 3la in 77% yield (entry 11). Very interestingly,
Scheme 2. Regioselective Studies
less hindered ortho C−H bond of anilide participated in the
reaction in a highly regioselective manner. Meta hydroxy 1n and
methoxy 1o acetanilides underwent cyclization with 2a, giving
the corresponding 2-quinolinone derivatives 3na and 3oa in
excellent 88% and 86% yields, respectively. It is important to note
that the compound 3na is used as a reference material for study
and analysis of carcinogenicity and quinolone metabolism
B
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Letter
activity.11 2-Naphthyl acetamide (1p) also efficiently reacted
with 2a, providing quinolinone derivative 3pa in 76% yield.
Next, the scope of the catalytic reaction was examined with
substituted alkynes 2b−f (Scheme 3). Thus, methyl-2-hexynoate
with 4a. To increase the yield, the reaction of anilides 1 with 4a
was done in the presence of [{RuCl2(p-cymene)}2] (5.0 mol %),
AgSbF6 (20 mol %), and Cu(OAc)2·H2O (1.5 equiv) in DCE at
110 °C. After that, 0.5 mL of 30% HCl was added into the
reaction mixture directly and further allowed to stir at 130 °C.
Under the reaction conditions, the cyclization products 5ba−5ka
were observed in 64%, 60%, 54%, 56%, 46%, and 48% yields,
respectively (Table 2). In the substrate, 4-acetyl acetanilide (1i),
the C−H bond activation takes place only ortho to NHCOMe.
Scheme 3. Scope of Substituted Propiolates
Table 2. Cyclization of Substituted Anilides 1 with Methyl
a
Acrylate (4a)
(2b), methyl-2-octynoate (2c), and ethyl 4-methoxybut-2-
ynoate (2d) nicely reacted with 1a to give the corresponding
quinolinone derivatives 3ab−3ad in 81%, 79%, and 62% yields,
respectively. The structure of compound 3ac was confirmed by a
single-crystal X-ray diffraction (see SI). Ethylphenyl propiolate
(2e) also reacted with 1a providing 4-aryl substituted
quinolinone 3ae in 41% yield. However, in the reaction, the
other alkyne regioisomer product 3ae′ was observed in 32%
yield. It is important to note that the 4-aryl-2-quinolinone unit
was present in various natural products and medicinal
compounds.12 A terminal alkyne, ethyl propiolate (2f), was
also compatible for the reaction. However, in the reaction,
quinolinone derivative 3af was observed only in 10% yield.
The alkyne cyclization reaction prompted us to explore the
possibility of cyclization of anilides 1 with acrylates 4a−c. Thus,
we have tried the cyclization of 1a with methyl acrylate (4a)
under the optimized reaction conditions (Scheme 4). In the
a
All reactions were carried out using 1 (100 mg), 4a (1.5 equiv),
[{RuCl2(p-cymene)}2] (0.05 equiv), AgSbF6 (0.20 equiv), and
Cu(OAc)2·H2O (1.5 equiv) in DCE (2.5 mL) at 110 °C for 12 h.
After that, 30% of HCl was added and heated at 130 °C for 10 h.
b
c
Isolated yield. The first step was allowed for only 5 h. After that, 30%
of HCl was added and heated at 130 °C for 5 h.
Quinolinone derivatives 3aa and 3hc were converted into
useful 2-chloroquinolines 6a and 6b in 79% and 71% yields,
respectively, in the presence of POCl3 in CH3CN at 90 °C for 10
h (Scheme 5). Further, 3aa reacted with NCS or NBS in the
Scheme 5. Transformation of 2-Quinolinones
Scheme 4. Cyclization of 1a with Acrylates 4a−c
reaction, the cyclization product 5aa was observed only in 32%
yield. To increase the yield, we have added 1.50 equiv of
Cu(OAc)2·H2O to the reaction mixture instead of pivalic acid. It
is important to note that Cu(OAc)2·H2O is an efficient oxidant
for the alkenylation reaction of anilides with alkenes.13 However,
using these conditions, product 5aa was observed only in 32%
yield. Then, the reaction was carried out with a 1:1 mixture of
ClCH2CH2Cl (DCE) and i-PrOH solvents. Interestingly,
product 5aa was observed in 76% yield. The cyclization reaction
was also tested with other acrylates such as ethyl acrylate (4b)
and n-butyl acrylate (4c). However, product 5aa was observed in
only 65% and 45% yields, respectively. But, the above reaction
conditions such as Cu(OAc)2·H2O in a 1:1 mixture of solvents is
not suitable for the cyclization of anilides 1b, 1e−g, 1i, and 1k
presence of AIBN (10 mol %) in CCl4 at 90 °C for 2 h, yielding 3-
Cl or Br substituted quinolinones 7a−b in 78% and 83% yields,
respectively. By using 7a−b, various functionalizations can be
undertaken at the 3-carbon of the quinolinone ring.
A possible reaction mechanism is proposed to account for the
present cyclization reaction in Scheme 6. AgSbF6 likely removes
the Cl− ligand from the [{RuCl2(p-cymene)}2] complex,
providing a cationic Ru species 8. Coordination of the carbonyl
group of 1 to the Ru species 8 followed by ortho-metalation
provides ruthenacycle 9. Coordinative insertion of alkyne 2 into
the Ru−C bond of intermediate 9 gives intermediate 10.
C
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Scheme 6. Proposed Mechanism
AUTHOR INFORMATION
Corresponding Author
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*E-mail: mjeganmohan@iiserpune.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the DST (SR/S1/OC-26/2011), India for the support
of this research. R.M. thanks the CSIR for a fellowship.
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Protonation at the Ru−C bond of intermediate 10 by RCOOH
affords ortho-alkenylated anilide 11 and regenerates the Ru
species 8. Later, it could be possible that the carboxylic acid or
solvent i-PrOH accelerates trans−cis isomerization of the double
bond of 11 via Michael addition followed by intramolecular
nucleophilic addition of NHCOMe to the ester moiety followed
by a loss of the acetyl group, leading to cyclic compound 3.14 In
the reaction, organic acid plays multiple roles such as acting as a
proton source, accelerating cis−trans isomerization and
deacylation of anilide to aniline.
To support the multiple roles of organic acid, the reaction of
1a with 2a was carried out in the presence of CD3COOD instead
of pivalic acid under similar reaction conditions. In the reaction,
product d-3aa was observed in 40% yield, in which 73% of
deuterium incorporation was observed at the C-3 carbon of
quinolinone. In the meantime, 71% deuterium incorporation was
also observed at the C-8 carbon of d-3aa. This result clearly
supports that the ortho C−H bond cleavage of anilide 1 is a
reversible process. Further, to support the conversion of product
11 into 3, product 11a was prepared separately and treated with
pivalic acid (10.0 equiv) in i-PrOH at 130 °C for 12 h without a
catalyst. As expected, product 3aa was observed in 75% yield.
But, the same reaction did not produce product 3aa without an
acid source. This result clearly reveals the multiple role of organic
acid in the cyclization reaction.
In conclusion, we demonstrated a Ru-catalyzed cyclization of
anilides with substituted propiolates or acrylates in the presence
of carboxylic acid, which provides 4-substituted-2-quinolinones
and 2-quinolinones in good to excellent yields. 3-Halo-4-
substituted-2-quinolinones and 2-chloroquinolines were pre-
pared using the obtained 2-quinolinones.
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ASSOCIATED CONTENT
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S
* Supporting Information
General experimental procedure, starting materials preparation,
and characterization details. This material is available free of
charge via the Internet at http://pubs.acs.org.
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