An efficient method for the construction of polysubstituted 4-pyridones via self-condensation of β-keto amides mediated by P2O5 and catalyzed by zinc bromide

Article abstract of DOI:10.3762/bjoc.9.304

A self-condensation cyclization reaction mediated by phosphorus pentoxide (P₂O₅) and catalyzed by zinc bromide (ZnBr₂) is presented for the synthesis of polysubstituted 4-pyridones and 2-pyridones from β-keto amides. A var

Full text of DOI:10.3762/bjoc.9.304

An efficient method for the construction of
polysubstituted 4-pyridones via self-condensation
of β-keto amides mediated by P2O5
and catalyzed by zinc bromide
Liquan Tan*, Peng Zhou, Cui Chen and Weibing Liu*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 2681–2687.
School of Chemistry and Life Science, Guangdong University of
Petrochemical Technology, 2 Guangdu Road, Maoming 525000,
China
doi:10.3762/bjoc.9.304
Received: 22 September 2013
Accepted: 07 November 2013
Published: 28 November 2013
Email:
Liquan Tan* - mmtlq522@gmail.com; Weibing Liu* -
lwb409@gmail.com
Associate Editor: K. Itami
* Corresponding author
© 2013 Tan et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
β-keto amide; phosphorus pentoxide; 2-pyridones; 4-pyridones;
self-condensation
Abstract
A self-condensation cyclization reaction mediated by phosphorus pentoxide (P2O5) and catalyzed by zinc bromide (ZnBr2) is
presented for the synthesis of polysubstituted 4-pyridones and 2-pyridones from β-keto amides. A variety of β-keto amides are used
in this approach, and a wide range of functionalized 4-pyridones and 2-pyridones were obtained in good to excellent yields. When
employing the N-aryl β-keto amides as the substrates in this protocol, 4-pyridones are resulted, however, when using N-aliphatic-
substituted β-keto amides as the partners of N-aryl β-keto amides under the same conditions, 2-pyridones are afforded.
Introduction
β-Keto amide and their derivatives are desired classes of inter- prompted us to exploit the reactivity of the six different reac-
mediates for the synthesis of nitrogen- and oxygen-containing tive positions of β-keto amides [14-18].
heterocyclic compounds since they possess six reactive sites in
the same molecule (Scheme 1) [1-7]. A lot of reports can be Two groups reported the self-condensation of N-aryl β-keto
found in the literature concerning the construction of different amides. The group of Zhang used Na2S2O8 as the reagent to in-
heterocyclic compounds from β-keto amides by modification of duce this condensation [19] and the group of Ovenden used
the six different reactive positions [8-13]. Our interest in the tosic acid to catalyze this transformation [20]. In this article, we
fields of cleavage or construction of C–C and C–hetero bonds report an improved efficient method for the construction of
using β-keto amides and their derivatives as the substrates polysubstituted 4-pyridones and 2-pyridones via phosphorus
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Scheme 1: The six different reactive positions of β-keto amides.
pentoxide-mediated self-condensation of β-ketobutylanilides Results and Discussion
catalyzed by zinc bromide (Scheme 2). It is well known that In our initial study, 3-oxo-N-phenylbutanamide (1a) was
4-pyridones are one of the most important classes of hetero- selected as a model substrate to optimize the reaction condi-
cyclic compounds as they are a key structural attribute of many tions (Table 1). The preliminary results showed that this self-
bioactive natural products [21-27]. Besides, many of the 4-pyri- condensation cyclization reaction did not occur in the absence
dones have shown interesting biological activities, such as of ZnBr2 (Table 1, entry 1) or P2O5 (Table 1, entry 3) at room
antibacterial [24,28], antitumor [29], antiviral [30], and several temperature. Notable efficacy was achieved when increasing the
other potentially useful activities [27,31].
reaction temperature to 100 °C for 4 h and afforded the desired
Scheme 2: Synthesis of polysubstituted 4-pyridones from β-keto amides.
Table 1: Optimization of reaction conditionsa.
Entry
Solvent
Zn(II) (equiv)
Temp. ( °C)
Yield (%)b
1c
2c
3c,d
4e
5
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
0
rt
0
ZnBr2 (1.0)
ZnBr2 (1.0)
ZnBr2 (1.0)
ZnBr2 (1.0)
ZnBr2 (1.0)
ZnBr2 (0.2)
rt
13
0
rt
100
100
100
100
72
94
94
94
6c
7
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Beilstein J. Org. Chem. 2013, 9, 2681–2687.
Table 1: Optimization of reaction conditionsa. (continued)
8
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Cyclohexane
DCE
ZnBr2 (0.5)
ZnCl2 (0.2)
Zn(OAc)2 (0.2)
ZnO (0.2)
100
94
92
45
0
9
100
10
11
12f
13
14
15
16
17
100
100
ZnBr2 (0.2)
ZnBr2 (0.2)
ZnBr2 (0.2)
ZnBr2 (0.2)
ZnBr2 (0.2)
ZnBr2 (0.2)
100
84
56
81
32
14
30
reflux
reflux
100
DMF
AcOH
100
MeOH
reflux
aAll reactions were carried out with 1a in 0.25 mmol scale and 2 mL solvent; bGC yield; creaction time: 6 h; dwithout P2O5; ereaction time: 2 h; fP2O5:
1.0 equiv.
product 1,4-dihydro-2,6-dimethyl-4-oxo-N,1-diphenylpyridine- ring had no obvious influence on the reaction, including without
3-carboxamide (2a) in 94% GC yield (Table 1, entries 2, 4–6). a substituent or with both an EWG and EDG substituent on the
Results of the screening study of the amount of ZnBr2 and P2O5 benzene ring (Scheme 3), all could be easily converted into
(Table 1, entries 6–8 and 12) indicated that 0.2 equiv of ZnBr2 their corresponding product with good isolated yield. Besides,
and 1.5 equiv of P2O5 was sufficient for the completion of this the scope of this protocol was further examined by the N-ali-
transformation. In order to improve the efficiency of the reac- phatic-substituted β-keto amides (1n and 1o) (Scheme 4). We
tion, we tested several zinc salts for this reaction (Table 1, found that the reactions did not afford the 4-pyridones, but
entries 7, 9–11). The use of ZnBr2 and ZnCl2 greatly facilitated provided 2-pyridones 2n and 4o with 82% and 81% isolated
the reaction, and both gave 2a in excellent GC yield (Table 1, yield, respectively.
entries 7 and 9). Among the various solvents examined
(Table 1, entries 7, 13–17), dioxane proved to be the most suit- What is the result when employing different β-keto amides? Is it
able solvent for this transformation (Table 1, entry 7). After possible to achieve the cross-condensation products? Therefore,
screening, the optimal reaction conditions were obtained; these we attempted the reactions under the same conditions
are, the mixture of 3-oxo-N-phenylbutanamide 1a with (Scheme 5). We were astonished to find that the results only
0.2 equiv of ZnBr2 and 1.5 equiv of P2O5 reacted in dioxane included the self-condensation products (2a, 2l, 2j) and
(2.0 mL) at 100 °C for 4 h (Table 1, entry 7).
achieved not the cross-condensation products.
To explore the substrate scope and limitations of this self-con- It is well known that Lewis acids can activate β-keto amides
densation cyclization reaction, a range of N-aryl β-keto amides [32]. Under mild conditions, phosphorus pentoxide (P2O5) is
were then examined under the optimal reaction conditions. The often used as the dehydrating agent in organic synthesis for the
results are shown in Scheme 3.
condensation of amines with carbonyl compounds [33,34].
Based on these evidences, a plausible reaction pathway of this
The results indicated that a variety of substituted N-aryl self-condensation cyclization reaction was hypothesized as
acetoacetamides 1a–1k could be easily converted into their shown in Scheme 6. The first step of this transformation
corresponding 4-pyridone 2a–2k. All the reactions proceeded involved the coordination of β-keto amides 1 with ZnBr2 to
smoothly and afforded the desired product in good to excellent activate the carbonyl group and to form intermediates 4 and 5,
isolated yields (72–90%) in 4 h. This transformation appears which was followed by the attack of the lone-pair electrons of
quite tolerant with respect to the positions of the substituents on the amide nitrogen to the carbonyl carbon in the presence of
the aryl group (para-, meta- and ortho-positions). For example, P2O5 and intermediate 6 was formed by eliminating one equiva-
the reactions of N-(2-chlorophenyl)-3-oxobutanamide (1c), lent of H2O. Next, when R is aryl, a 1,3-acyl migration occurred
N-(3-chlorophenyl)-3-oxobutanamide (1d), N-(4-chlorophenyl)- from N to C of intermediate 6 [35-39], and affords imine 7 and
3-oxobutanamide (1e), as well as 3-oxo-N-o-tolylbutanamide its equilibrium compound 8, the subsequent intramolecular
(1j), 3-oxo-N-m-tolylbutanamide (1k) and 3-oxo-N-p-tolylbu- nucleophilic cyclization of intermediate 8 provides the final
tanamide (1l) all lead to their corresponding product (2c, 2d, 2e, product 4-pyridones [20,38]. Alternatively, when R is aliphatic,
2j, 2k and 2l) in good isolated yield. Furthermore, various elec- the 1,3-acyl migration is not observed – maybe the migration
tron-withdrawing groups (EWG) (Cl and CO2Et) and electron- leads to an unstable imine intermediate. Therefore, under the
donating groups (EDG) (Me, OMe and OEt) on the benzene acidic conditions, a cationic species 10 is generated from the
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Beilstein J. Org. Chem. 2013, 9, 2681–2687.
Scheme 3: The scope of the substrates. (Note: All the listed yields are isolated yields.)
Scheme 4: Synthesis of polysubstituted 4-pyridones from N-aliphatic-substituted β-keto amides.
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Beilstein J. Org. Chem. 2013, 9, 2681–2687.
Scheme 5: Construct the cross-condensation products.
Scheme 6: Hypothesized mechanism.
intermediate 6 and the subsequent intramolecular dehydration sequence of intermolecular dehydration of β-keto amides in the
process provides 2-pyridones 11 [19].
presence of phosphorus pentoxide (P2O5), 1,3-acyl migration
and intramolecular dehydration. Comparing to the similar
findings, the simple operation with satisfactory yields, rela-
Conclusion
In summary, we have established an improved efficient syn- tively cheap additive P2O5 and zinc catalyst, and the mild reac-
thetic protocol for the synthesis of 4-pyridone derivatives by a tion conditions are the advantages of this protocol. Further
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Beilstein J. Org. Chem. 2013, 9, 2681–2687.
18.Zhang, Q.; Liu, W.; Chen, C.; Tan, L. Chin. J. Chem. 2013, 31,
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Supporting Information
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Supporting Information File 1
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2005, 68, 1106–1108. doi:10.1021/np050059p
Full experimental details and copies of NMR spectral data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-304-S1.pdf]
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We thank the Guangdong Natural Science Foundation
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