Transition-metal-free highly efficient synthesis of 2-pyridones from β-keto amides and ynals

Article abstract of DOI:10.1016/j.tetlet.2019.04.001

A convenient and efficient annulation reaction was developed, affording 2-pyridones in good to excellent yields. A variety of substituted β-keto amides and ynals were well tolerated, and especially the transformation produced water as only by-product unde

Full text of DOI:10.1016/j.tetlet.2019.04.001

Accepted Manuscript
Transition-metal-free highly efficient synthesis of 2-pyridones from β-keto
amides and ynals
Zhengwang Chen, Jiayang Liu, Caiju Jin, Qi Tan, Min Ye
PII:
S0040-4039(19)30313-2
https://doi.org/10.1016/j.tetlet.2019.04.001
TETL 50716
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
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31 March 2019
2 April 2019
Please cite this article as: Chen, Z., Liu, J., Jin, C., Tan, Q., Ye, M., Transition-metal-free highly efficient synthesis
of 2-pyridones from β-keto amides and ynals, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.04.001
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Tetrahedron Letters
Transition-metal-free highly efficient synthesis of 2-pyridones from β-keto amides
and ynals
Zhengwang Chen,* Jiayang Liu,§ Caiju Jin,§ Qi Tan and Min Ye*
Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University, Ganzhou, Jiangxi, 341000, PR China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A convenient and efficient annulation reaction was developed, affording 2-pyridones in good to
excellent yields. A variety of substituted β-keto amides and ynals were well tolerated, and
especially the transformation produced water as only by-product under transition-metal-free
conditions. Furthermore, the conjugated enyneamides were achieved from β-cyano amides and
ynals in high yields.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
Pyridone
Ynal
Annulation reaction
Enyneamide
Substituted pyridones, as attractive structural units, are
commonly found in organic chemistry and natural products with
interesting structural properties and remarkable bioactivity
profiles.1 They have exhibited promising biological activities,
such as antibacterial, antifungal, cytotoxic and insecticidal
activity.2 As a result, many well-documented modern approaches
have been developed for the construction of pyridone derivatives
over the past decades. Two regular methods for the preparation
of 2-pyridones involve the modification of the heterocycles3 and
the establishment of the heterocyclic skeleton from acyclic
starting materials.4 Transition-metal-catalyzed annulation
reactions containing Ru,5 Rh,6 Pd,7 Au,8 and Co9 complexes have
received significant attention for the formation of 2-pyridones in
recent years. Despite the significant advancement, there are still
some drawbacks, such as expensive transition metal and ligand,
stoichiometric excess of strong oxidant and additive, complex
substrates and multi-step reactions. Considering the important
application of 2-pyridone frameworks in pharmaceutical
industry, continuing to explore a simple and complementary
transformation involving high efficiency and practicability from
readily accessible precursors is vital to the synthetic chemistry
community.
Owing to the rising global environmental issue, transition-
metal-free system has been attracted significant attention.10 These
transformations have several advantages, such as low price, non-
toxicity, operational simplicity, good functional group tolerance
and environmentally friendliness. Ynals, as readily available and
valuable building blocks, have been considered as versatile
substrates in organic synthesis. In particular, they have been
extensively utilized in many cyclization reactions for the
construction of diverse heterocyclic compounds.11 Very recently,
we have described a highly efficient catalyst-free approach for
the synthesis of 3-acylated indolizines from 2-pyridylacetates and
ynals.12 As part of this continuing project accessing to nitrogen-
containing heterocycles from other binucleophilic reagents and
ynals, here we present a simple and efficient protocol toward 2-
pyridones from β-keto amides and ynals through successive
Michael addition and intermolecular dehydration process under
transition-metal-catalyzed conditions (Scheme 1). It is important
to note that, Constantieux’s group reported an efficient synthesis
of 2-pyridones from β-keto amides and ynols via cooperative
organocatalysis and metal catalysis.13
Scheme 1. The synthesis of 2-pyridones via intermolecular
dehydration from β-keto amides and ynals
Optimization of the reaction conditions was established by
varying base, solvent, and temperature (Table 1). At the
beginning of our study, acetoacetanilide (1a) and
phenylpropiolaldehyde (2a) were chosen as the model substrates
to evaluate the reaction conditions. Various commonly used
inorganic and organic bases were tested. In general, inorganic
bases were more effective than organic bases, and we were
pleased to find K2CO3 was the most suitable base and gave the
desired product in 85% yield (Table 1, entries 1-10). The control
experiment showed that the base was indispensable in the
process, no product was formed without the addition of the base
(Table 1, entry 11). Then a variety of solvents were screened at
o
100 or 65 C. The results indicated that the solvents played an
important role, and THF was found to afford the desired product
with the isolated yield improved to 95% (Table 1, entries 12-18).

2
Tetrahedron Letters
The reaction temperatures were also evaluated, and lower
temperatures were disadvantageous to this transformation (Table
1, entries 19 and 20). Therefore, base, solvent and reaction
temperature are all crucial for this transformation.
Table 1. Optimization of reaction conditions for the synthesis
of 2-pyridonepyridione a
Entry
1
2
3
4
5
6
7
8
Base
Cs2CO3
K2CO3
NaOEt
KOH
K3PO4
NaOAc
Et3N
Solvent
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DMF
Temp.
100
100
100
100
100
100
100
100
100
100
100
100
100
100
100
65
Yield (%)b
82
85
56
60
30
21
n.p
18
47
68
n.p
88
n.p
54
n.p
62
98 (95)
28
DABCO
DMAP
DBU
9
10
11
12
13
14
15
16
17
18
19
20
-
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
H2O
DMSO
toluene
CH3CN
THF
EtOH
THF
a Reaction conditions: 1a (0.2 mmol), 2 (0.2 mmol) with K2CO3 (30 mol%) in
THF (1.0 mL) at 65 °C for 10 h; Isolated yield.
65
65
45
25
Scheme 3. Substrate scope of β-keto amides and ynalsa
70
20
THF
a Reaction conditions: 1a (0.2 mmol), 2a (0.2 mmol) with base (30 mol%) in
solvent 1.0 mL for 10 h.
b Isolated yield. n.p=no product.
With the optimized reaction conditions, the substrate scopes
were evaluated, and the results were illustrated in Scheme 2.
Initially, a wide range of ynals proceeded smoothly with
acetoacetanilide (1a) to deliver the corresponding products under
the standard conditions. In general, the reaction has good
functional group tolerance. Ynals with electron-donating and
electron-deficient substituents were all compatible with this
protocol (3b-j). Interestingly, the reaction gave high yield when
ortho ethyl substituted ynal was employed (3c). The substrate
bearing tertiary butyl group generated the product in 72% yield
(3d). Notably, bromide-substituted ynal was suitable substrate
and provided 3h product in excellent yield (3h). In particular,
aryl bromide was easily further functionalized under transition-
metal-catalyzed conditions. The products containing acetyl and
ester groups could be easily converted to other functional groups
and had potential applications in organic synthesis and
pharmaceutical chemistry (3i and 3j). In addition, the heteroaryl
substituted ynal reacted successfully to produce the product in
88% yield (3k). Fortunately, the aliphatic ynal also worked well
in the reaction and afforded the desired product in satisfactory
yield (3l).
a Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol) with K2CO3 (30 mol%) in
Scheme 2. Substrate scope of ynalsa
THF (1.0 mL) at 65 °C for 10 h; Isolated yield. 10 mmol scale of the
b
reaction.
Subsequently, we investigated the scope of β-keto amides
under the standard conditions. Initially the aniline moiety was
explored and the results were indicated in scheme 3. Both the
electron-rich and electron-poor substituents attached to the
benzene ring were favorable in the optimized conditions (4a-e).
The steric hindrance on the benzene ring seemed to have little

effect on the yields (4b and 4c). When the methyl group was
replaced with phenyl group, the corresponding product 4f was
obtained in 91% yield (4f). The aryl, heteroaryl, and aliphatic
substituted ynals were also tested, and the results implied that
this annulation approach can be effective for the 2-pyridone
library (4g-i). It is noteworthy that the alkyl substituted β-keto
amide was also compatible under the standard conditions (4j-l).
The reaction yield decreased to 53% when para acetyl
substituted ynal was applied (4k). To our delighted, the reaction
could be performed on a gram scale, delivered the product in
good yield (4a).
In conclusion, we have developed a convenient and highly
efficient annulation reaction of β-keto amides and ynals.14
A
series of 2-pyridones bearing various functional groups were
obtained in good to excellent yields through a tandem Michael
addition and dehydration process. The merits of this
transformation include transition-metal-free conditions, readily
available reagents, complete regioselectivity, simple operation,
etc. It is noteworthy that water is the only byproduct in this
transformation. Moreover, the conjugated enyneamides were
formed from β-cyano amides and ynals via a nucleophilic 1,2-
addition. Further studies to extend synthetic applications and
detailed mechanism are currently underway in our laboratory.
When the β-keto amide substrates were replaced with β-cyano
amides, and examined the reaction with ynals under the standard
conditions (Scheme 4). To our surprise, the reaction did not form
any products. Interestingly, after some attempts, we found that
the intermolecular dehydration products were produced as a
single regioisomer without the addition of K2CO3. Following the
above results, four examples of conjugated enyneamide synthesis
were demonstrated. Both primary, secondary amides and
aromatic, aliphatic ynals were compatible, and underwent
smoothly to lead to the corresponding products in excellent
yields (5a-d).
Acknowledgements
The authors thank the NSF of Jiangxi Province
(20171ACB21048) and the NSF of Jiangxi Provincial Education
Department (GJJ180756) for financial support.
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/xxx
Scheme 4. The Intermolecular Dehydration of β-Cyano
§
Contribute equally.
Amides and Ynalsa
Corresponding author. Tel: +86 797 8393670; fax: +86 797
8393670; e-mail address:chenzwang@126.com (Z. Chen)
References
a Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol) in THF (1.0 mL) at 65 °C
1
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Tetrahedron Letters
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Transition-Metal-Free Highly Efficient Synthesis of 2-Pyridones from
β-Keto Amides and Ynals
Zhengwang Chen,* Jiayang Liu, Caiju Jin, Qi Tan and Min Ye*
China Key Laboratory of Organo-Pharmaceutical Chemistry of Jiangxi Province, Gannan Normal University,
Ganzhou, Jiangxi, 341000, P.R.

6
Tetrahedron Letters
Highlights:
·Transition-metal-free annulation reaction toward
2-pyridones.
·Convenient conditions and afford products in good
to excellent yields.
·Broad substrate scope and good functional
compatibility.