Ru-Catalyzed Regioselective Cascade Annulation of Acrylamides with 2-Alkynoates for the Synthesis of Various 6-Oxo Nicotinic Acid Esters

Article abstract of DOI:10.1021/acs.joc.8b02783

Ru-catalyzed regioselective cascade annulation of acrylamides with 2-alkynoates via aza-Michael/C-H activation sequence for the synthesis of various 6-oxo nicotinic acid esters is described. The regioselectivity of the protocol has been confirmed by performing silver mediated protodecarboxylation of the corresponding 6-oxo nicotinic acid to furnish 2-pyridone. The developed protocol is copper or silver salt-free and uses inexpensive, safe, and environmentally benign peroxide-based "oxone" as the sole oxidant. A redox-neutral version of the protocol is also demonstrated.

Full text of DOI:10.1021/acs.joc.8b02783

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Article
Ru#Catalyzed Regioselective Cascade Annulation of Acrylamides with
2-Alkynoates for the Synthesis of Various 6-Oxo Nicotinic Acid Esters
Dnyaneshwar Nilkanth Garad, and Santosh B. Mhaske
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02783 • Publication Date (Web): 15 Jan 2019
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The Journal of Organic Chemistry
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Ru‒Catalyzed Regioselective Cascade Annulation of Acrylamides with 2-
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Alkynoates for the Synthesis of Various 6-Oxo Nicotinic Acid Esters
Dnyaneshwar N. Garad†‡ and Santosh B. Mhaske†‡*
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†Division of Organic Chemistry, CSIR-National Chemical Laboratory, Pune- 411008, India
‡Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India
Supporting Information Placeholder
ABSTRACT: Ru‒catalyzed regioselective cascade an-
nulation of acrylamides with 2-alkynoates via aza-
Michael/C‒H activation sequence for the synthesis of
various 6-oxo nicotinic acid esters is described. The re-
gioselectivity of the protocol has been confirmed by
performing silver mediated protodecarboxylation of the
corresponding 6-oxo nicotinic acid to furnish 2-pyridone.
The developed protocol is copper or silver salt-free and
uses inexpensive, safe, and environmentally benign per-
oxide-based ‘Oxone’ as the sole oxidant. Redox-neutral
version of the protocol is also demonstrated.
INTRODUCTION
N-heterocycles.5 Transition-metal-catalyzed oxidative annula-
tion of amides with alkynes by C-H bond activation is one of
the most commonly used methods for the synthesis of pyrido-
nes6 and isoquinolones.7 Oxidative annulation of benzamides
with alkynes have been explored more than that of acryla-
mides using various metal catalysts.
Pyridone is an ubiquitous scaffold in biologically active mole-
cules.1 In particular, 6-oxo nicotinic acid esters and hydroxy-
pyridinecarboxylic acids constitute biologically important
class of compounds.2 They are used for metal chelation thera-
py because of their good binding capacity towards alumi-
num(III) and iron(III). Milrinone, ciclopirox, pirfenidone, cyt-
isine, flavipucine, camptothecin (CPT) and perampanel are
some of the important natural products and pharmaceuticals
featuring pyridone core1-3 (Fig.1). As a result, several methods
for the selective preparation of these heterocycles and their
derivatives are reported in the literature.1a,b,2a,4 Among these
Previously, ruthenium and rhodium catalytic systems have
been employed on acrylamides and unsymmetrical alkynes for
the regioselective synthesis of β-alkyl pyridones (Scheme 1,
eq 1).6e,f Recently, Fan and co-workers reported Rh-catalyzed
redox neutral annulation protocol for the annulation of benzoyl
and acryloyl hydroxamates with ynoates possessing a tertiary
propargyl alcohol for the regioselective synthesis of -lactone
ring-fused pyridones (Scheme 1, eq 2).8 The regioselectivity of
this protocol was accomplished by the chelation of metal cata-
lyst with hydroxyl group present in the ynoates. The literature
known strategies5-8 mostly follow C-H activation/alkyne inser-
tion sequence to form C‒C bond followed by C‒N bond for-
mation via reductive elimination to get 3-alkyl substituted
pyridones. We envisioned that RuCl2(p-cymene) catalyzed
reaction might follow aza-Michael/C‒H activation sequence
with 2-alkynoates due to the high electron withdrawing nature
of the ester moiety to accomplish complete reverse regioselec-
tivity on contrary to the known ruthenium or rhodium cata-
lyzed protocols with aryl(alkyl)acetylenes. In this context, we
have developed a protocol for inverse regioselective oxidative
annulation of acrylamides with 2-alkynoates for the synthesis
of various 6-oxo nicotinic acid esters (α-alkyl pyridones) using
ruthenium catalysis (Scheme 1 eq 3). We further describe few
Figure 1. Selected Pyridone Containing Natural Products and
Drugs
Methods, C‒H Bond activation has emerged as a cost and
step-economical tool for the synthesis of the pyridone class of
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Scheme 1. Annulation of Acrylamides with unsymmetrical
Page 2 of 8
KOAc additive and nonmetallic oxidant K2S2O8 was used with
Ru-catalyst [RuCl2(p-cymene)]2, a substantial increment in the
yield was observed (entry 4). Pleasingly, a clean reaction was
observed (entry 5) when catalytic [RuCl2(p-cymene)]2 and
KOAc along with Oxone was used as the oxidant. The known
annulation protocols usually require stoichiometric amounts of
mostly metallic oxidants, which compromises the overall sus-
tainable nature of C−H bond activation process.5,6 The use of
inexpensive and non-metallic oxidants in such protocols is still
rare.9 Herein, we have demonstrated its use in the regioselec-
tive annulation protocol using ruthenium catalysis. Further
deviation in the reaction temperature (entries 6, 7) or variation
in the catalyst loading (entries 8-10) did not show considerable
improvement in the yield. The probable reason for the low
yield of this transformation could be the instability of the start-
ing materials at a higher temperature under the present condi-
tions and volatile nature of 2a. To check the stability of al-
kynoates we subjected 2a to our reaction condition in the ab-
sence of 1a and observed decomposition of 2a. Only 45% of
2a could be recovered after 24 h. Thus, the optimum condition
for this transformation is as follows: [RuCl2(p-cym)]2 (5
mol%), KOAc (10 mol%), Oxone (2 equiv) in 1,4-dioxane at
110 oC.
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Alkynes/2-Alkynoates
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control reactions, which shed some light on the regioselectivi-
ty and mechanism of this transformation.
RESULTS AND DISCUSSION
After having optimal conditions in hand, we turned our at-
tention to the evaluation of the scope of the reaction (Scheme
2). The protocol has been generalized to access varyingly sub-
We began to optimize the oxidative coupling by employing N-
phenyl acrylamide (1a) and ethyl 2-butynoate (2a, Table 1).
First, we attempted the literature known oxidative annulation
conditions6f with [RuCl2(p-cymene)]2 catalyst and copper ace-
tate in t-amyl alcohol but ended up in the complex reaction
mixture, and the expected product 3a was not observed (entry
1). Interestingly, the change in the solvent from t-amyl alcohol
to DCE resulted in the expected product formation though in
Scheme 2. Ru-Catalyzed Annulation of Various Acryla-
mides with ethyl 2-butynoatea,b
Table 1. Optimization Studies
catalyst additive
(mol%) (equiv)
solvent/temp
(oC)
oxidant
(equiv)
entrya,b
1
Resultc
--
5
-
Cu(OAc)2 (2)
Cu(OAc)2 (2)
TAA/120
DCE/100
2
3
5
5
5
5
5
5
2
-
-
18%
22%
35%
45%
35%
40%
30%
46%
44%
Cu(OAc)2 (2) 1,4-dioxane/110
4
KOAc (0.1) K2S2O8 (2)
KOAc (0.1) Oxone (2)
KOAc (0.1) Oxone (2)
KOAc (0.1) Oxone (2)
KOAc (0.1) Oxone (2)
1,4-dioxane/110
1,4-dioxane/110
1,4-dioxane/100
1,4-dioxane/120
1,4-dioxane/110
1,4-dioxane/110
1,4-dioxane/110
5
6
7
8
9
10 KOAc (0.1) Oxone (2)
10
20 KOAc (0.1) Oxone (2)
b
aSelected entries. Reaction conditions: 1a (0.3 mmol), 2a (0.6
mmol), [RuCl2(p-cym)]2 (5 mol%), KOAc (10 mol%), oxidant
o
(0.6 mmol), 1,4 dioxane (3 mL) in glass tube for 30 h at 110 C.
cIsolated yield. TAA = t-amyl alcohol.
aReaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), [RuCl2(p-
low yield (entry 2). Remarkably, single regioisomer formation
was observed in the reaction. When the reaction was per-
formed in 1,4-dioxane at 110 C, little improvement in the
cym)]2 (5 mol%), KOAc (10 mol%), Oxone (0.6 mmol), 1,4 diox-
o
c
ane (3 mL) in glass tube for 30 h at 110 C. bIsolated yield. 10
o
d
e
mmol scale reaction, Reaction with N-Acetyl acrylamide, Reac-
tion was carried out at 120 oC in sealed tube for 40 h.
yield was observed (entry 3). To our delight, when 10 mol%
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stituted 6-oxo nicotinic acid esters. Initially, N-aryl substituted
reaction of N-phenyl acrylamide and ethyl 2-pentynoate con-
ceded pyridone 3m in moderate yield. As observed above in
the substrate scope studies (Scheme 2) N-methyl acrylamide
furnished the highest yield of pyridone 3h, hence for further
studies N-methyl acrylamide was chosen as a fixed substrate
and reacted with various alkynoates. The pyridones with vari-
ous substituents at the second position such as ethyl 3n, decyl
3o, cyclopropyl 3p, and cyclopentyl 3q were synthesized in
low to moderate yields from the corresponding alkynoates. For
the synthesis of pyridones, 3p and 3q also higher temperature
and more time was required, and these reactions were per-
formed in a sealed tube. Probably, steric hindrance of cyclo-
propyl and cyclopentyl rings of 2-alkynoate affects the rate of
annulation.
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pyridones were synthesized using various N-aryl substituted
acrylamides and ethyl 2-butynoate (2a). As mentioned in the
optimization studies, the N-phenyl substituted acrylamide fur-
nished pyridone 3a in 45% yield. We also performed the reac-
tion of 1a with 2a at the 10 mmol scale and observed con-
sistency in the yield (44%) of 3a. The N-(p-tolyl) substituted
acrylamide delivered pyridone 3b in moderate yield under the
developed protocol. The N-(3-(trifluoromethyl) phe-
nyl)acrylamide and N-(3-fluorophenyl)acrylamide smoothly
underwent oxidative annulation with 2a and furnished the
corresponding pyridones 3c and 3d respectively in acceptable
yields. Electron withdrawing ester group and electron releas-
ing methoxy group at the para position of phenyl ring attached
to the nitrogen of acrylamide did not affect much on annula-
tion reaction and analogous pyridones 3e and 3f were obtained
in modest yields. Various N-alkyl substituted acrylamides
have also been used for the oxidative annulation with 2a and
resulted into formation of N-benzyl 3g, N-Methyl 3h, and N-
propyl 3i pyridones in better yields as compared to the N-aryl
acrylamides. The NMR yield of the crude reaction mixture of
3h is consistent with the isolated yield (see SI). Whereas, an-
nulation of acrylamide and alkynoate 2a produced pyridone 3j
in 30% yield. The formation of pyridone 3j was also observed
when N-acetyl acrylamide was used as the substrate. Acetyl
group deprotection was observed under these conditions and
3j was isolated in 25% yield. The data of 3j is in agreement
with the literature report,10 which confirms the regioselectivity
of our protocol. The effect of substituents on the various posi-
tion of N-methyl acrylamide was also studied and varyingly
methyl substituted pyridones 3k and 3l were synthesized with
reasonable yields. It should be noted that for the synthesis of
pyridones 3k and 3l, a higher reaction temperature and longer
reaction time were required and these reactions were per-
formed in a sealed tube. The higher temperature required for
these substrates may be due to the steric effect of methyl sub-
stituents at the β-position of acrylamides.
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After having studied the substrate scope of oxidative annu-
lation protocol with the external oxidant, we decided to study
oxidant free annulation reaction of acrylamides and 2-
alkynoates (Scheme 4). One solution to overcome the use of
an external oxidizing reagent involves the development of
redox-neutral versions with hydroxamates.7f,g When the N-
methoxy acrylamide 1n was reacted with ethyl 2-butynoate
(2a) at room temperature without external oxidant, the corre-
sponding N-H free pyridone 3j was obtained in 45% yield.
Comparison of the NMR spectral data of 3j with those de-
scribed in the literature10 for this compound confirms the
structure of this latter compound and the regioselectivity of the
Scheme 4. Ru-Catalyzed Redox-Neutral Annulation of N-
Methoxy Acrylamide with 2-Alkynoates
ruthenium-catalyzed annulation. The N-H free pyridone 3r
was also synthesized by employing redox neutral strategy us-
ing N-methoxy acrylamide 1n and ethyl 2-pentynoate as sub-
strates. Here, the substrate itself acts as an oxidant and no ex-
ternal oxidant is required for these reactions.
After having studied the substrate scope with respect to
various N-substituted acrylamides, we decided to study the
substrate scope with various 2-alkynoates (Scheme 3). The
The developed protocol worked very well with various
acrylamides but unfortunately, it did not work with ben-
zamides. The regioselectivity of our protocol was also con-
firmed by synthesizing 6-methyl-1-phenylpyridin-2(1H)-one
(Scheme 5A). Initially, ester hydrolysis of pyridone 3a was
carried out using aqueous NaOH in ethanol to obtain acid 4a
in excellent yield. The acid 4a was then subjected under vari-
ous protodecarboxylation conditions. Under the silver car-
bonate mediated condition in N,N-dimethylacetamide it fur-
nished the pyridone 5a in 42% yield. The NMR spectral data
of compound 5a were consistent with those described in the
literature.11 This reconfirms our hypothesis and regioselectivi-
ty of this protocol. Additionally it shows utility of our method
for the synthesis of 2-oxopyridones. The direct synthesis of 2-
oxopyridones using phenyl acetylene/ethyl propiolate was not
possible under the developed condition, which demonstrates
the importance of the present protocol. During the substrate
scope study, we utilized 2-alkynoates having α-hydrogens. We
were curious to know the outcome of the protocol in the ab-
sence of α-hydrogen. Interestingly, when R4 of 2-alkynoates is
phenyl/tertiary butyl/ester (Scheme 5B), the expected products
were not observed, which could be mostly due to ste-
Scheme 3. Ru-Catalyzed Annulation of N-Me/Ph Acryla-
mides with 2-Alkynoatesa,b
aReaction conditions: 1a/h (0.3 mmol), 2 (0.6 mmol), [RuCl2(p-
cym)]2 (5 mol%), KOAc (10 mol%), Oxone (0.6 mmol), 1,4 diox-
o
c
ane (3 mL) in glass tube for 30 h at 110 C. bIsolated yield. Re-
action was carried out at 120 oC in a sealed tube for 40 h.
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ric/electronic factors. However, the protocol works well when
CONCLUSION
R4 is the primary or secondary alkyl group, which suggests
that the possible involvement of allene intermediates in the
reaction cannot be ruled out. The HRMS study of the reaction
mixture was also carried out to detect the possible intermedi-
ates of the reaction (Scheme 5C), and interestingly M+H peak
of ruthenacycle II was detected by HRMS analysis.
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In summary, Ruthenium catalyzed reverse regioselective an-
nulation of acrylamides with alkynes than that of ar-
yl(alkyl)acetylenes has been developed. The reverse regiose-
lectivity and tentative mechanism is supported by controlled
experiments. The annulation protocol is further extended as
the redox neutral process, where the substrate acts as an oxi-
dant for the metal catalyst. Diverse novel 6-oxo nicotinic acid
esters have been synthesized using the developed protocol.
Further improvement in the protocol to access various 6-oxo
nicotinic acid esters in higher yields and its application in the
synthesis of natural products and bioactive molecules is under
progress in our laboratory.
Scheme 5. Control Reactions
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EXPERIMENTAL SECTION
General Information. All reagents and solvents were used as
received from commercial sources unless otherwise noted. All
experiments were carried out under an argon atmosphere in a
glass tube with side arm or Teflon screw cap glass tube. Alu-
minum plates precoated with silica gel 60 PF254, 0.25 mm or
0.5 mm were utilized for thin-layer chromatography (TLC).
Column chromatographic purifications were carried out on
flash silica gel (240−400 mesh) using petroleum ether and
ethyl acetate as the eluents. The H and 13C{1H}NMR spectra
1
were recorded on 400 MHz and 100 MHz NMR spectrometer,
respectively, in CDCl3 or DMSO-d6. Chemical shifts were
reported as δ values from standard peaks. The mass spectra
were taken on an LC−MS (ESI) mass spectrometer. High-
resolution mass spectrometry (HRMS) was performed on a
TOF/Q-TOF mass spectrometer. N-alkyl and N-alkoxy substi-
tuted acrylamides,12 N-aryl substituted acrylamides13 and
commercially unavailable 2-alkynoate14 starting materials
were prepared according to literature procedures.
A plausible reaction mechanism is proposed based on the
above experimental outcome (Scheme 6) and literature re-
ports.7d,e Initially, ligand exchange of ruthenium catalyst and
EXPERIMENTAL PROCEDURES FOR RU‒
CATALYZED ANNULATION
Scheme 6. Proposed Mechanism
General Procedure-1. To a mixture of [RuCl2(p-cymene)]2
(0.015 mmol; 9.2 mg) and KOAc (0.03 mmol; 3 mg) in a glass
tube with side arm was added 1,4-dioxane (3 mL; 0.1M) under
argon atmosphere and the reaction mixture was stirred for 1 h
at room temperature (rt). Acrylamide 1a-m (0.3 mmol), 2-
alkynoate 2a-e (0.6 mmol) and Oxone (0.6 mmol; 185 mg)
were added to the above mixture and the glass tube was placed
o
in a preheated oil bath at 110 C for stipulated time. The pro-
gress of the reaction was monitored by TLC. After complete
consumption of acrylamide 1a-m (30-40 h), the reaction mix-
ture was cooled to rt, diluted with ethyl acetate, filtered
through a short pad of celite, and the filtrate was evaporated
under vacuo to dryness. The resulting residue was purified by
column chromatography to afford pure pyridones 3a-q.
General Procedure-2. To a mixture of [RuCl2(p-cymene)]2
(0.015 mmol; 9.2 mg) and KOAc (0.03 mmol; 3 mg) in glass
tube with side arm was added 1,4-dioxane (3 mL; 0.1M) under
argon atmosphere and the reaction mixture was stirred for 1 h
at rt. Acrylamide 1n (0.3 mmol) and 2-alkynoate 2a/b (0.6
mmol) were added to the above mixture and it was stirred at rt.
The progress of the reaction was monitored by TLC. After
complete consumption of acrylamide 1n (24 h), the reaction
mixture was diluted with ethyl acetate, filtered through a short
pad of celite, and the filtrate was evaporated under vacuo to
dryness. The resulting residue was purified by column chro-
matography to afford pure pyridones 3j/r.
amide N-directed C-H bond activation of acrylamide 1 forms
ruthenacycle I followed by insertion of alkynoate 2 by azami-
chael type of addition to furnish the ruthenacycle intermediate
II (detected by HRMS when R1 = R4 = Me). Product 3 could
be formed after reductive elimination of metal from ruthena-
cycle II. The oxidation of Ru(0) to Ru(II) by Oxone makes the
active catalyst available for further catalytic cycles.
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Procedure for the Preparation of Pyridone 3a on 10 mmol
Hz), 131.3 (d, J = 8.6 Hz), 123.8 (d, J = 2.9 Hz), 117.4, 116.4
(d, J = 20.1 Hz), 115.7 (d, J = 23 Hz), 109.5, 61.1, 19.6, 14.3;
HRMS (ESI-TOF) m/z: [M+H]+ calcd for C15H15O3NF
276.1030, found 276.1028.
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Scale. To a mixture of [RuCl2(p-cymene)]2 (0.5 mmol; 306
mg) and KOAc (1 mmol; 98 mg) in a two-neck round-bottom
flask was added 1,4-dioxane (100 mL; 0.1M) under argon
atmosphere and the reaction mixture was stirred for 1 h at rt.
N-Phenyl arylamide (1a, 10 mmol; 1.47 gm), ethyl 2-
butynoate (2a, 20 mmol; 2.24 mL) and Oxone (20 mmol; 6.15
gm) were added to the above mixture and the glass tube was
placed in preheated oil bath at 110 oC for 30 h. The progress of
the reaction was monitored by TLC. After complete consump-
tion of acrylamide 1a (30 h) the reaction mixture was cooled
to rt, diluted with ethyl acetate, filtered through short pad of
celite, and the filtrate was evaporated under vacuo to dryness.
The resulting residue was purified by column chromatography
to afford pure pyridone 3a (1.13 g; 44%).
Ethyl 1-(4-(methoxycarbonyl) phenyl)-2-methyl-6-oxo-1,6-
dihydropyridine-3-carboxylate (3e). According to the general
procedure-1, the title compound 3e was obtained as a thick
oil (44 mg; 47% yield); reaction time: 30 h; Rf: 0.5 (2:3
EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.23
(d, J = 8.7 Hz, 2H), 7.99 (d, J = 10.1 Hz, 1H), 7.27 (d, J = 8.7
Hz, 2H), 6.54 (d, J = 9.6 Hz, 1H), 4.32 (q, J = 7.3 Hz, 2H),
3.96 (s, 3H), 2.37 (s, 3H), 1.38 (t, J = 7.3 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 165.96, 165.4, 162.98,
153.2, 142.4, 140.7, 131.4, 130.96, 128.1, 117.4, 109.5, 61.1,
52.4, 19.7, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C17H18O5N 316.1179, found 316.1178.
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Ethyl
2-methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-
carboxylate (3a). According to the general procedure-1, the
title compound 3a was obtained as a thick oil (35 mg; 45%
Ethyl
1-(4-methoxyphenyl)-2-methyl-6-oxo-1,6-
dihydropyridine-3-carboxylate (3f). According to the general
procedure-1, the title compound 3f was obtained as a thick oil
(39 mg; 45% yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc:
1
yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); H
NMR (400 MHz, CDCl3) δ (ppm) 7.98 (d, J = 9.8 Hz, 1H),
7.55 (t, J = 7.3 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.16 (d, J =
7.3 Hz, 2H), 6.53 (d, J = 9.8 Hz, 1H), 4.32 (q, J = 6.7 Hz, 2H),
2.37 (s, 3H), 1.37 (t, J = 6.7 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 165.5, 163.3, 153.9, 140.4, 138.4, 130,
129.1, 127.7, 117.3, 109.2, 60.9, 19.7, 14.3; HRMS (ESI-
TOF) m/z: [M+Na]+ calcd for C15H15O3NNa 280.0944, found
280.0943.
1
Pet. ether); H NMR (400 MHz, CDCl3) δ (ppm) 7.97 (d, J =
9.6 Hz, 1H), 7.09-7.03 (m, 4H), 6.54 (d, J = 9.6 Hz, 1H), 4.32
(q, J = 6.9 Hz, 2H), 3.86 (s, 3H), 2.40 (s, 3H), 1.38 (t, J = 6.9
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.6,
163.6, 159.8, 154.4, 140.4, 130.9, 128.7, 117.2, 115.2, 109.3,
60.9, 55.5, 19.7, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C16H18O4N 288.1230, found 288.1227.
Ethyl
2-methyl-6-oxo-1-(p-tolyl)-1,6-dihydropyridine-3-
Ethyl
1-benzyl-2-methyl-6-oxo-1,6-dihydropyridine-3-
carboxylate (3b). According to the general procedure-1, the
title compound 3b was obtained as a thick oil (34 mg; 42%
carboxylate (3g). According to the general procedure-1, the
title compound 3g was obtained as a thick oil (45 mg; 55%
1
1
yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); H
yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); H
NMR (400 MHz, CDCl3) δ (ppm) 7.97 (d, J = 9.6 Hz, 1H),
7.34 (d, J = 8.7 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 6.53 (d, J =
9.2 Hz, 1H), 4.31 (q, J = 7.3 Hz, 2H), 2.43 (s, 3H), 2.38 (s,
3H), 1.37 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 165.6, 163.4, 154.2, 140.3, 139.1, 135.7,
130.7, 127.4, 117.2, 109.2, 60.9, 21.2, 19.7, 14.3; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C16H18O3N 272.1281, found
272.1280.
NMR (400 MHz, CDCl3) δ (ppm) 7.94 (d, J = 9.6 Hz, 1H),
7.35-7.25 (m, 3H), 7.13 (d, J = 7.3 Hz, 2H), 6.56 (d, J = 9.6
Hz, 1H), 5.45 (s, 2H), 4.29 (q, J = 6.9 Hz, 2H), 2.72 (s, 3H),
1.36 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
(ppm) 165.7, 163.2, 153.9, 140.1, 135.7, 128.9, 127.5, 126.3,
116.6, 109.9, 60.96, 47.5, 17.7, 14.3; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C16H18O3N 272.1281, found 272.1279.
Ethyl 1,2-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate
(3h). According to the general procedure-1, the title com-
pound 3h was obtained as a thick oil (34 mg; 58% yield); reac-
tion time: 30 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); 1H NMR (400
MHz, CDCl3) δ (ppm) 7.87 (d, J = 9.8 Hz, 1H), 6.45 (d, J =
9.8 Hz, 1H), 4.29 (q, J = 7.3 Hz, 2H), 3.60 (s, 3H), 2.78 (s,
3H), 1.35 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 165.7, 163.2, 153.6, 139.6, 116, 109.6, 60.9,
31.6, 17.9, 14.2; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C10H14O3N 196.0968, found 196.0967.
Ethyl
2-methyl-6-oxo-1-(3-(trifluoromethyl)phenyl)-1,6-
dihydropyridine-3-carboxylate (3c). According to the general
procedure-1, the title compound 3c was obtained as a thick
oil (46 mg; 47% yield); reaction time: 30 h; Rf: 0.5 (2:3
EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ (ppm) 8.01
(d, J = 9.8 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.70 (t, J = 7.9
Hz, 1H), 7.47 (s, 1H), 7.40 (d, J = 7.9 Hz, 1H), 6.55 (d, J = 9.8
Hz, 1H), 4.33 (q, J = 7.3 Hz, 2H), 2.37 (s, 3H), 1.38 (t, J = 7.3
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.3,
163, 153.2, 140.9, 138.9, 132.7 (q, J = 33 Hz), 131.6, 130.7,
126.2 (q, J = 3 Hz), 125.1 (q, J = 3 Hz), 123.3 (q, J = 273 Hz),
117.5, 109.9, 61.1, 19.8, 14.3; HRMS (ESI-TOF) m/z:
[M+Na]+ calcd for C16H14O3NF3Na 348.0818, found 348.0815.
Ethyl
2-methyl-6-oxo-1-propyl-1,6-dihydropyridine-3-
carboxylate (3i). According to the general procedure-1, the
title compound 3i was obtained as a thick oil (32 mg; 48%
1
yield); reaction time: 30 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); H
Ethyl 1-(3-fluorophenyl)-2-methyl-6-oxo-1,6-dihydropyridine-
3-carboxylate (3d). According to the general procedure-1,
the title compound 3d was obtained as a thick oil (35 mg; 42%
NMR (400 MHz, CDCl3) δ (ppm) 7.84 (d, J = 9.8 Hz, 1H),
6.42 (d, J = 9.8 Hz, 1H), 4.28 (q, J = 7.3 Hz, 2H), 4.06 (t, J =
7.3 Hz, 2H), 2.80 (s, 3H), 1.77-1.64 (m, 2H), 1.35 (t, J = 7.3
Hz, 3H), 1.01 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 165.8, 162.9, 153, 139.6, 116.5, 109.5, 60.9,
46.2, 21.6, 17.2, 14.3, 11.3; HRMS (ESI-TOF) m/z: [M+H]+
calcd for C12H18O3N 224.1281, found 224.1280.
1
yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); H
NMR (400 MHz, CDCl3) δ (ppm) 7.99 (d, J = 10.1 Hz, 1H),
7.57-7.48 (m, 1H), 7.21 (td, J = 8.2, 2.8 Hz, 1H), 6.98 (dt, J =
7.8, 1 Hz, 1H), 6.94 (dt, J = 8.7, 2.3 Hz, 1H), 6.53 (d, J = 9.6
Hz, 1H), 4.33 (q, J = 6.9 Hz, 2H), 2.40 (s, 3H), 1.38 (t, J = 6.9
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.4,
163.3 (d, J = 249.2 Hz), 163, 153.5, 140.7, 139.7 (d, J = 10.5
Ethyl
2-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate
(3j).10 According to the general procedure-1 and by using
acrylamide and N-acetyl acrylamide, the title compound 3j
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was obtained as a thick oil (16 mg; 30% yield) and (14 mg;
Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.4,
163.5, 157.6, 139.9, 116.1, 108.8, 60.8, 31.9, 31.1, 30.7, 29.8,
29.5, 29.3, 29.2, 28.4, 22.7, 14.3, 14.1; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C19H32O3N 322.2377, found 322.2374.
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25% yield) respectively; reaction time: 30 h; whereas by using
general procedure-2 and N-methoxy acrylamide, the title
compound 3j was obtained as a thick oil (25 mg; 45% yield);
1
reaction time: 24 h; Rf: 0.4 (2:1 EtOAc: Pet. ether); H NMR
Ethyl
2-cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridine-3-
(400 MHz, CDCl3) δ (ppm) 12.92 (bs, 1H), 8.06 (d, J = 9.8
Hz, 1H), 6.43 (d, J = 9.8 Hz, 1H), 4.31 (q, J = 7.3 Hz, 2H),
2.74 (s, 3H), 1.37 (t, J =7.6 Hz, 3H), 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 165.3, 164.8, 152.9, 143, 116, 109.4,
60.8, 19.7, 14.3; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C9H12O3N 182.0812, found 182.0811.
carboxylate (3p). According to the general procedure-1 at
120 oC in the glass tube with screw cap, the title compound 3p
was obtained as a thick oil (18 mg; 28% yield); reaction time:
1
40 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); H NMR (400 MHz,
CDCl3) δ (ppm) 7.63 (d, J = 9.8 Hz, 1H), 6.49 (d, J = 9.8 Hz,
1H), 4.32 (q, J = 7.3 Hz, 2H), 3.74 (s, 3H), 2.05-1.95 (m, 1H),
1.37 (t, J = 7.3 Hz, 3H), 1.23 (apparent q, J = 6.1 Hz, 2H),
0.63 (apparent q, J = 6.1 Hz, 2H); 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 166.4, 163.3, 154.7, 139.1, 117.3, 113.3, 61.2,
32.7, 14.3, 14.25, 9.9; HRMS (ESI-TOF) m/z: [M+H]+ calcd
for C12H16O3N 222.1125, found 222.1124.
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Ethyl 1,2,4-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxylate
o
(3k). According to the general procedure-1 at 120 C in the
glass tube with screw cap, the title compound 3k was obtained
as a thick oil (24 mg; 38% yield); reaction time: 40 h; Rf: 0.5
1
(1:1 EtOAc: Pet. ether); H NMR (400 MHz, CDCl3) δ (ppm)
6.32 (s, 1H), 4.34 (q, J = 7.3 Hz, 2H), 3.52 (s, 3H), 2.39 (s,
3H), 2.17 (s, 3H), 1.37 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 167.8, 162.6, 147.4, 145.7, 117.1,
114.8, 61.4, 31.1, 20.4, 18.5, 14.2; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C11H16O3N 210.1125, found 210.1123.
Ethyl
2-cyclopentyl-1-methyl-6-oxo-1,6-dihydropyridine-3-
carboxylate (3q). According to the general procedure-1 at
120 oC in the glass tube with screw cap, the title compound 3q
was obtained as a thick oil (19 mg; 26% yield); reaction time:
1
40 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); H NMR (400 MHz,
Ethyl
1,2,4,5-tetramethyl-6-oxo-1,6-dihydropyridine-3-
CDCl3) δ (ppm) 7.76 (d, J = 9.9 Hz, 1H), 6.51 (d, J = 9.9 Hz,
1H), 4.40-4.25 (m, 3H), 3.57 (s, 3H), 2.11-1.98 (m, 4H), 1.97-
1.86 (m, 4H), 1.36 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 166.7, 163.97, 158, 140, 116, 111.9,
61.2, 40.1, 34.2, 30.7, 27, 14.2; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C14H20O3N 250.1438, found 250.1436.
carboxylate (3l). According to the general procedure-1 at
120 oC in the glass tube with screw cap, the title compound 3l
was obtained as a thick oil (27 mg; 40% yield); reaction time:
1
40 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); H NMR (400 MHz,
CDCl3) δ (ppm) 4.35 (q, J = 7.3 Hz, 2H), 3.55 (s, 3H), 2.34 (s,
3H), 2.12 (s, 6H), 1.38 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ (ppm) 168.6, 162.9, 141.7, 140.7, 123.8,
115.5, 61.4, 31.7, 18.2, 17.3, 14.2, 13; HRMS (ESI-TOF) m/z:
[M+H]+ calcd for C12H18O3N 224.1281, found 224.1279.
Ethyl 2-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (3r).
According to the general procedure-2, the title compound 3r
was obtained as a thick oil (23 mg; 40% yield); reaction time:
1
24 h; Rf: 0.4 (2:1 EtOAc: Pet. ether); H NMR (400 MHz,
Ethyl
2-ethyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-
CDCl3) δ (ppm) 12.68 (bs, 1H), 8.03 (d, J = 9.9 Hz, 1H), 6.42
(d, J = 9.2 Hz, 1H), 4.32 (q, J = 7.6 Hz, 2H), 3.11 (q, J = 7.6
Hz, 2H), 1.37 (t, J = 7.6 Hz, 3H), 1.34 (t, J = 7.6 Hz, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 165.5, 164.7,
158.2, 143.1, 116.4, 108.2, 60.8, 26.1, 14.2, 13.9; HRMS
(ESI-TOF) m/z: [M+H]+ calcd for C10H14O3N 196.0968, found
196.0968.
carboxylate (3m). According to the general procedure-1, the
title compound 3m was obtained as a thick oil (31 mg; 38%
1
yield); reaction time: 30 h; Rf: 0.5 (2:3 EtOAc: Pet. ether); H
NMR (400 MHz, CDCl3) δ (ppm) 8.01 (d, J = 9.8 Hz, 1H),
7.59-7.47 (m, 3H), 7.20 (d, J = 6.8 Hz, 2H), 6.52 (d, J = 9.8
Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 2.84 (q, J = 6.8 Hz, 2H),
1.38 (t, J = 7.5 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H); 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 165, 163.5, 159.4, 140.9,
137.9, 129.7, 129.1, 128.2, 117.3, 108.2, 60.9, 24.8, 14.3,
13.7; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C16H18O3N
272.1281, found 272.1279.
2-Methyl-6-oxo-1-phenyl-1,6-dihydropyridine-3-carboxylic
acid (4a). To a round bottom flask containing the solution of
ester 3a (1 mmol, 257 mg) in EtOH (20 mL) was added 2N
aqueous NaOH (10 mL) at rt. The resulting mixture was
stirred at rt until completion of the reaction (2h). The reaction
mixture was then diluted with water and transferred to a sepa-
rating funnel and washed with ethyl acetate (2 x 5 mL). The
aqueous layer was acidified to pH 2 with dil. HCl and extract-
ed with EtOAc (3 x 20 mL). The organic layer was dried over
Na2SO4 and evaporated under vacuo to dryness to afford pure
acid 4a (202 mg; 88% yield), which was used in the next step
without further purification. 1H NMR (400 MHz, DMSO-d6) δ
(ppm) 12.77 (bs, 1H), 7.94 (d, J = 9.8 Hz, 1H), 7.55 (t, J = 7.3
Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.28 (d, J = 7.3 Hz, 2H),
6.40 (d, J = 9.8 Hz, 1H), 2.28 (s, 3H); 13C{1H} NMR (100
MHz, DMSO-d6) δ (ppm) 166.8, 162.2, 153.9, 140.9, 138.6,
129.6, 128.7, 128.2, 116.4, 108.7, 19.4; HRMS (ESI-TOF)
m/z: [M+H]+ calcd for C13H12O3N 230.0812, found 230.0810.
Ethyl
2-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-
carboxylate (3n). According to the general procedure-1, the
title compound 3n was obtained as a thick oil (25 mg; 40%
1
yield); reaction time: 30 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); H
NMR (400 MHz, CDCl3) δ (ppm) 7.89 (d, J = 9.8 Hz, 1H),
6.45 (d, J = 9.2 Hz, 1H), 4.29 (q, J = 6.7 Hz, 2H), 3.64 (s, 3H),
3.22 (q, J = 7.3 Hz, 2H), 1.36 (t, J = 6.7 Hz, 3H), 1.30 (t, J
=7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
165.3, 163.4, 158.2, 139.9, 116.2, 108.7, 60.8, 30.96, 24, 14.2,
12.5; HRMS (ESI-TOF) m/z: [M+H]+ calcd for C11H16O3N
210.1125, found 210.1123.
Ethyl
2-decyl-1-methyl-6-oxo-1,6-dihydropyridine-3-
carboxylate (3o). According to the general procedure-1, the
title compound 3o was obtained as a thick oil (34 mg; 35%
6-Methyl-1-phenylpyridin-2(1H)-one (5a).11 A glass tube with
side arm was charged with acid 4a (0.1 mmol, 23 mg),
Ag2CO3 (0.2 mmol, 55 mg), PivOH (0.15 mmol, 15 µL),
Na2CO3 (0.4 mmol, 43 mg) and DMA (1 mL). The glass tube
was placed in preheated oil bath at 120 oC for 24 h. After 24 h,
the reaction was cooled to rt, diluted with ethyl acetate and
1
yield); reaction time: 30 h; Rf: 0.5 (1:1 EtOAc: Pet. ether); H
NMR (400 MHz, CDCl3) δ (ppm) 7.89 (d, J = 9.8 Hz, 1H),
6.44 (d, J = 9.8 Hz, 1H), 4.29 (q, J = 6.7 Hz, 2H), 3.63 (s, 3H),
3.16 (t, J =7.3 Hz, 2H), 1.66-1.57 (m, 2H), 1.51-1.43 (m, 2H),
1.36 (t, J = 7.3 Hz, 3H), 1.31-1.22 (m, 12H), 0.89 (t, J = 6.7
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The Journal of Organic Chemistry
proaches. Nat. Prod. Rep. 2010, 27, 1168–1185. (g) Otsubo, K.;
filtered through a short pad of celite. The filtrate was washed
two times with water, dried over Na2SO4 and evaporated under
vacuo to dryness. The resulting residue was purified by col-
umn chromatography to afford pure pyridone 5a (8 mg; 42%);
Rf: 0.3 (1:1 EtOAc: Pet. ether); 1H NMR (400 MHz, CDCl3) δ
(ppm) 7.56-7.50 (m, 2H), 7.48-7.43 (m, 1H), 7.31 (dd, J = 9.2,
6.9 Hz, 1H), 7.23-7.18 (m, 2H), 6.55 (d, J = 9.2 Hz, 1H), 6.11
(d, J = 6.9 Hz, 1H), 1.96 (s, 3H); 13C{1H} NMR (100 MHz,
CDCl3) δ (ppm) 164, 146.4, 139.6, 138.8, 129.8, 128.8, 127.8,
118.5, 106.1, 21.6; HRMS (ESI-TOF) m/z: [M+H]+ calcd for
C12H12ON 186.0913, found 186.0914.
Morita, S.; Uchida, M.; Yamasaki, K.; Kanbe, T.; Shimizu, T. Syn-
thesis and Antiulcer Activity of Optical Isomers of 2-(4-
Chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl] propionic Acid
(Rebamipide). Chem. Pharm. Bull. 1991, 39, 2906‒2909; and ref-
erences cited therein.
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2
3
4
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6
7
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(2) (a) Ferlin, M. G.; Di Marco, V. B.; Dean, A. Synthesis of 1,4-
Dihydro-2-methyl-4-oxo-nicotinic Acid: Ochiai’s Route Failed.
Tetrahedron 2006, 62, 6222‒6227. (b) Di Marco, V. B.; Yokel, R.
A.; Ferlin, M. G.; Tapparo, A.; Bombi, G. G. Evaluation of 3,4-
Hydroxypyridinecarboxylic Acids as Possible Bidentate Chelating
Agents for Aluminium(III): Synthesis and Metal-Ligand Solution
Chemistry. Eur. J. Inorg. Chem. 2002, 2002, 2648–2655.
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HRMS Study of Ruthenacycle (II). A glass tube with side
arm was charged with [RuCl2(p-cymene)] (0.02 mmol; 12 mg)
and KOAc (0.04 mmol; 4 mg) under argon atmosphere. To
this reaction mixture 1,4-dioxane (4 mL; 0.1M) was added and
stirred for 1 h at rt. N-Methyl acrylamide 1h (0.2 mmol), ethyl
2-butynoate 2a (0.4 mmol) and Oxone (0.4 mmol) were added
to the mixture and it was stirred at 110 oC for 1 h. The reaction
mixture was immediately subjected to mass analysis. HRMS
of Ruthenacycle(II) (ESI-TOF) m/z: [M+H]+ calcd for
C20H28O3NRu 432.1107, found 432.1104.
(3) (a) Falb, E.; Ulanenko, K.; Tor, A.; Gottesfeld, R.; Weitman, M.;
Afri, M.; Gottlieb, H.; Hassnerb, A. A Highly Efficient Suzuki–
Miyaura Methylation of Pyridines Leading to the Drug Pirfenidone
and its CD3 Version (SD-560). Green Chem. 2017, 19, 5046‒5053.
(b) Kim E. S.; Keating, G. M. Pirfenidone: A Review of Its Use in
Idiopathic Pulmonary Fibrosis. Drugs 2015, 75, 219–230.
(4) (a) Das, D.; Samanta, R. Iridium(III)-Catalyzed Regiocontrolled
Direct Amidation of Isoquinolones and Pyridones. Adv. Synth.
Catal. 2018, 360, 379–384. (b) Ni, J.; Zhao, H.; Zhang, A. Manga-
nese(I)-Catalyzed C‒H 3,3-Difluoroallylation of Pyridones and In-
doles. Org. Lett. 2017, 19, 3159–3162. (c) Akhtar, M. S.; Shim, J.-
J.; Kim, S. H.; Lee, Y. R. Novel Construction of Diversely Func-
tionalized N-Heteroaryl-2-pyridones via Copper(II)-Catalyzed
[3+2+1] Annulation. New J. Chem. 2017, 41, 13027–13035. (d) Al-
lais, C.; Basle, O.; Grassot, J. -M.; Fontaine, M.; Anguille, S.; Ro-
driguez, J.; Constantieux, T. Cooperative Heterogeneous Organo-
catalysis and Homogeneous Metal Catalysis for the One-Pot Regi-
oselective Synthesis of 2-Pyridones. Adv. Synth. Catal. 2012, 354,
2084‒2088.
(5) (a) Gulias, M.; Mascarenas, J. L. Metal-Catalyzed Annulations
through Activation and Cleavage of C‒H Bonds. Angew. Chem.;
Int. Ed. 2016, 55, 11000–11019. (b) Ackermann, L. Carboxylate-
Assisted Ruthenium-Catalyzed Alkyne Annulations by C‒H/Het‒H
Bond Functionalizations. Acc. Chem. Res. 2014, 47, 281–295. (c)
Zhu, C.; Wang, R.; Falck, J. R. Amide-Directed Tandem C‒C/C‒N
Bond Formation through C‒H Activation. Chem. Asian J. 2012, 7,
1502‒1514. (d) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Ru-
thenium(II)-Catalyzed C−H Bond Activation and Functionaliza-
tion. Chem. Rev. 2012, 112, 5879‒5918.
(6) Selected references for acrylamide annulation: (a) Tulichala, R. N.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
Spectroscopic data (1H, 13C{1H} spectra) of all new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: sb.mhaske@ncl.res.in
ORCID
Santosh B. Mhaske: 0000-0002-5859-0838
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
D.N.G. thanks UGC-New Delhi for the research fellowship, and
S.B.M. gratefully acknowledges generous financial support from
DST-SERB, New Delhi.
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