Thermal-induced dimerization cyclization of ethyl N-(styrylcarbamoyl) acetates: Formation of 4-hydroxy-2(1H)-pyridone-3- carboxamide derivatives

Article abstract of DOI:10.1080/00397911.2013.878360

Thermal-induced dimerization cyclization of ethyl N-(styrylcarbamoyl) acetate derivatives has been investigated, leading to 4-hydroxy-2(1H)-pyridone- 3-carboxamide derivatives with good yields in diphenyl ether on 200-210 °C. Ethyl N-(styrylcarbamoyl)acet

Full text of DOI:10.1080/00397911.2013.878360

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Thermal-Induced Dimerization
Cyclization of Ethyl N-
(Styrylcarbamoyl)acetates: Formation
of 4-Hydroxy-2(1H)-pyridone-3-
carboxamide Derivatives
Sheng-Yin Zhao a , Bao-Shuo Liu a , Jing Huang a , Shao-Hua Cheng a
Yun-xia Deng a & Zhi-Yu Shao a
,
a Department of Chemistry , Donghua University , Shanghai , China
Accepted author version posted online: 04 Apr 2014.Published
online: 09 Jun 2014.
To cite this article: Sheng-Yin Zhao , Bao-Shuo Liu , Jing Huang , Shao-Hua Cheng , Yun-xia Deng &
Zhi-Yu Shao (2014) Thermal-Induced Dimerization Cyclization of Ethyl N-(Styrylcarbamoyl)acetates:
Formation of 4-Hydroxy-2(1H)-pyridone-3- carboxamide Derivatives, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:14, 2066-2075,
DOI: 10.1080/00397911.2013.878360
To link to this article: http://dx.doi.org/10.1080/00397911.2013.878360
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Synthetic Communications1, 44: 2066–2075, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.878360
THERMAL-INDUCED DIMERIZATION CYCLIZATION
OF ETHYL N-(STYRYLCARBAMOYL)ACETATES:
FORMATION OF 4-HYDROXY-2(1H)-PYRIDONE-3-
CARBOXAMIDE DERIVATIVES
Sheng-Yin Zhao, Bao-Shuo Liu, Jing Huang,
Shao-Hua Cheng, Yun-xia Deng, and Zhi-Yu Shao
Department of Chemistry, Donghua University, Shanghai, China
GRAPHICAL ABSTRACT
Abstract Thermal-induced dimerization cyclization of ethyl N-(styrylcarbamoyl)acetate
derivatives has been investigated, leading to 4-hydroxy-2(1H)-pyridone-3-carboxamide deri-
vatives with good yields in diphenyl ether on 200–210 ꢀC. Ethyl N-(styrylcarbamoyl)acetate
derivatives readily provided the intermolecular cyclization products 4-hydroxy-2(1H)-pyri-
done-3-carboxylates on reflux in xylene. In addition, several related 3-acetyl-4-hydroxy-
5-phenylpyridin-2(1H)-ones have been prepared. It provided an efficient preparation of
4-hydroxy-2(1H)-pyridone-3-carboxamide derivatives.
Keywords Ethyl N-(styrylcarbamoyl)acetate; 4-hydroxy-2(1H)-pyridone-3-carboxamide;
intramolecular thermal cyclization
INTRODUCTION
4-Hydroxy-2-pyridones are embedded as common structural units of many
natural products. They exhibit good to excellent biological activities such as antifun-
gal, antibacterial, and cytotoxic activities.[1] Representative examples are the pigments
Received October 4, 2013.
Address correspondence to Sheng-Yin Zhao, Department of Chemistry, Donghua University,
Shanghai 201620, China. E-mail: syzhao8@dhu.edu.cn
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
2066

CYCLIZATION OF ETHYL N-(STYRYLCARBAMOYL)ACETATES
2067
Tenellin, Ilicicolin H, Farunosone A, and the related Bassianin isolated from the
insect pathogenic fungus Beauveria bassianna.[2] Ilicicolin H is an nonribosomal
peptides (NRPS)-polyketide hybrid discovered in 1971 from the ‘‘imperfect fungus’’
Cylindrocladium ilicicola MFC-870 and is a potent antifungal group. It has a tetracyc-
lic structure laced with various functional groups.[3] Recently, it was shown that
Ilicicolin H’s antifungal activity was due to inhibiting the yeast cytochrome bc1 com-
plex by interacting at the Qn site of the complex.[4] The class of compounds has
stimulated a great deal of research interest on synthetic methodology for chemists
because of their structural novelty, molecular diversity, and promising biological
activities. Further optimization by chemical and biological modification to improve
their biological and physiochemical profiles was developed. A series of oxime, hydro-
azone, pyrazole, isoxzaole, and 2,4,5-oxadiazocine Illicicolin H analogs were synthe-
sized and evaluated for their antifungal activity.[5–8] However, all of the structural
modifications were focused on the 4-position of 4-hydroxy-2(1H)-pyridone moiety
in Ilicicolin H.
Ilicicolin H is a potent antifungal agent but lacks in vivo efficacy due to its
strong plasma binding.[6] Recently, our group became interested in the synthesis
and structural modification of Illicicolin H (Fig. 1).[1a,9] Generally, 4-hydroxy-2
(1H)-pyridone-3-carboxylate moiety was constructed by thermal cyclization of ethyl
N-(styrylcarbamoyl)acetate derivatives.[10] Subsequently, a few natural alkaloids
with 3-acetyl-4-hydroxy-2(1H)-pyridone moieties were synthesized following this
protocol.[11] 3-Acylpyridin-2(1H)-ones were also obtained from the hydrolysis
of isoxazolo[4,3-c]pyridin-4-one scaffold.[12] First, we tried to synthesize ethyl
4-hydroxy-2(1H)-pyridone-3-carboxylate derivatives and related 3-acetyl-4-hydroxy-
2-pyridiones for antifungal activity evaluation. Rigby et al. developed a general and
efficient preparation of functionalized 4-hydroxy-2(1H)-pyridones from the reaction
of readily available a, b-unsaturated isocyanates with various enolates ester and
thermal cyclization of the ethyl N-(styrylcarbamoyl)acetates.[10] So, our initial prep-
aration was performed according to Rigby’s procedure. However, limited substrates
(only one example for the synthesis of ethyl 4-hydroxy-2(1H)-pyridone-3-carboxylate
was given) were used in Rigby’s methodology in 1986. Another careful study was not
conducted until now. We found that this procedure provided an efficient synthetic
strategy to prepare 3-acetyl-4-hydroxy-2(1H)-pyridiones. It is unsuitable to prepare
ethyl 4-hydroxy-2(1H)-pyridone-3-carboxylate derivatives by cyclization of ethyl
N-(styrylcarbamoyl)acetate in diphenyl ether at 200–210 ꢀC. (E)-4-Hydroxy-2-oxo-5-
(4-phenyl)-N-styryl-1,2-dihydropyridine-3-carboxamides was isolated and elucidated
as main product. Herein, we report the results of our investigation of thermal-induced
dimerization cyclization of ethyl N-(styrylcarbamoyl)acetate derivatives.
Figure 1. Structural modification of Ilicicolin H.

2068
S.-Y. ZHAO ET AL.
RESULTS AND DISCUSSION
Cinnamic acid derivatives were used as starting materials. The target
compounds were synthesized according to the route shown in Scheme 1. A series of
synthetic procedures were developed for the synthesis of acyl azides 2 from aromatic
acids using triphosgene[13] or chloroformate ester and sodium azide.[14] A facile syn-
thesis was used in the preparation of the title compounds. Cinnamoyl azides 2 were
easily obtained by treating cinnamic acids with diphenyl phosphorazidate (DPPA)
in toluene in the presence of triethylamine (80% yields). Then, they are subjected to
thermally induced Curtius rearrangement to provide isocyanates 3.[8] Without further
purification, isocyanates 3 were treated with enolates of diethyl malonate to give
diethyl N-(styrylcarbamoyl)malonates 5 as white solids. With compounds 5 in hand,
we hoped the desired ethyl 4-hydroxy-2(1H)-pyridone-3-carboxylates 7 could be
obtained by thermal cyclization of compounds 5 in diphenyl ether. However, this
reaction failed. For example, after the completion of thermally induced cyclization
of compounds 5a, a white solid was precipitated, isolated, and carried out spectral
1
detection. H NMR spectrum data showed that no hydrogen signals were exhibited
in the range of 2–6 ppm. The data suggested the ethyl group did not exist in this
obtained compound. 13C NMR data suggested that this compound should contain
20 carbons. Our desired product contained 14 carbon atoms a difference of 6 carbons.
Scheme 1. Synthetic route for 4-hydroxy-2(1H)-pyridone-3-carboxamides and ethyl 4-hydroxy-2(1-
H)-pyridione-3-carboxylates.

CYCLIZATION OF ETHYL N-(STYRYLCARBAMOYL)ACETATES
2069
On the other hand, we supposed the intermolecular cyclization of ethyl N-(styrylcar-
bamoyl) acetate happened in diphenyl ether on 200–210 ꢀC. Furthermore, the
electron impact (EI) mass spectrum of this compound showed a molecular ion at
332(Mþ). High-resolution mass spectrography suggested the formula was
C20H16N2O3. On the basis of spectral data, its structure was assigned to (E)-4-
hydroxy-5-(4-cholorophenyl)-N-styryl-2-oxo-1,2-dihydropyridine-3-carboxamide 6a.
To get more information about this cyclization reaction, a series of substrates was
used. The cyclization productions 6a–6d were obtained with 50–60% yield after being
heated in phenyl ether at 200–210 ꢀC.
In the next step, we turn our attention to investigate the influence of reaction
temperature on the yield of product 6a and product 7a. A series of solvents with low
boiling points were chosen for this cyclization reaction, such as toluene, xylene,
diethyleneglycoldiethyl ether, diethyleneglycoldimethyl ether, and so on (Table 1).
Our results suggested the yield of compounds 7a increased with the decrease of
the reaction temperature. Isolated yield of compounds 7a is around 12–61%. For
instance, xylene was chose as solvent. Product 6a and product 7a were obtained in
15% and 61% yields, respectively.
Thermal-induced dimerization cyclization of ethyl N-(styrylcarbamoyl)acetate
derivatives were carried out in diphenyl ether at 200–210 ꢀC. The effect of substitute
group on the reaction yield was discussed in Table 2. Electron-rich group in phenyl
ring can favor the reaction. For example, compound 5b with methoxyl group pro-
vided the compound 6b in 70% yield. Compound 6d was obtained with 50% yield
when the nitro group was introduced in the compound 5d.
Based on these experimental results, a plausible mechanism is shown in
Scheme 2. Initially, compound 5a was subjected to intramolecular electrophilic
addition to give the intermediate 8 under the xylene reflux condition. The compound
8 eliminates the ethoxyl group to form a 4-hydroxy-2(1H)-pyridinone ring 7a in the
heating condition. However, intermolecular cyclization happened in the diphenyl
ether at greater reaction temperature. The compounds 5a contain active hydrogen
atom between two ethoxycarbonyl groups. First, the carbon attacked the carbonyl
Table 1. Influence of reaction temperature on cyclization of ethyl N-(styrylcarbamoyl)acetates
Reaction
time
Product 6a
yield (%)b
Product 7a
yield (%)b
Entrya
Solvent
1
2
3
4
Diphenyl ether (200–210 ꢀC)
Diethyleneglycoldiethyl ether (reflux)
Diethyleneglycoldimethyl ether (reflux)
Xylene (reflux)
5 min
30 min
2 h
65
55
45
15
12
25
30
61
12 h
aReaction conditions: compounds 5a (2.0 mmol) was stirred in solvent for the time indicated in Table 1.
bIsolated yield with column chromatography.

2070
S.-Y. ZHAO ET AL.
Table 2. Thermally induced dimerization cyclization of ethyl N-(styrylcarbamoyl)acetates
Entrya
R1
Reaction time (min)
Yield (%)b
6a
6b
6c
6d
H
OCH3
Cl
5
5
60
70
55
51
5
10
NO2
aReaction conditions: compounds 5 (2.0 mmol) was stirred in diphenyl ether at 200–210 ꢀC for the time
indicated in Table 2.
bIsolated yield with column chromatography.
Scheme 2. Plausible mechanism of the formation of compounds 7a and 6a.

CYCLIZATION OF ETHYL N-(STYRYLCARBAMOYL)ACETATES
2071
group in another molecule to form intermediate 9 by nucleophile addition reaction.
Second, compound 9 was subjected to intramolecular cyclization to give compound
10. Herein, ethanol and diethyl malonate was released from the compunds 10 to
complete this reaction. The structure of compound 6a was confirmed by spectral
analysis.
To elucidate the reaction mechanism of thermally induced dimerization of
ethyl N-(styrylcarbamoyl)acetate derivatives to form 4-hydroxy-2(1H)-pyridone-
3-carboxamide derivatives, compounds 12, prepared from isocynates 3 with
72–85% yield and acetoacetate ethyl esters 11, were heated in diphenyl ether in
200–210 ꢀC to give 3-acetyl-4-hydroxy-5-(4-methoxyphenyl)-2(1H)-pyridinones 13
with 65–79% yield in Scheme 3. No dimerization product was obtained. An enolate
and carbonyl group tautomerization existed in compound 12.[15] We suggested that
enol form, not keto form, existed in this molecule. The crystal structure of
compound 12b provided strong evidence to help understand this reaction mech-
anism. The crystal of compound 12b was obtained by slow evaporation of a 1:1 ethyl
acetate–petroleum ether solution to clarify this mechanism. The x-ray structural
analysis of this compound reported here confirmed the assignment of its structure
determined from spectroscopic data. The stereochemistry of this molecule is stabi-
lized by intramolecular N—H. . .O and O—H. . .O hydrogen bonds (Figure 2). In
Scheme 3. Synthetic route for 3-acetyl-4-hydroxy-2(1H)-pyridiones.
Figure 2. Molecular structure of 12b.

2072
S.-Y. ZHAO ET AL.
the crystal, molecules are linked by weak intermolecular C—Hꢁ ꢁ ꢁO hydrogen bonds.
The layers are further connected into a three-dimensional network by weak p–p
stacking interactions involving neighboring benzene rings. No carbon atom contain-
ing active hydrogen atom exists in this compounds 12. Hence, carbon atom with
acetate ester moiety was unable to attack the carbonyl group in another molecular
to form the dimerization products because of enol form. No thermally induced inter-
molecular dimerization product was observed. So, we supposed the nucleophilic
addition is the key step for intermolecular dimerization cyclization. Further biologi-
cal evaluation and structural optimizing of Illicicolin H are currently under way in
our laboratories.
CONCLUSIONS
We have demonstrated thermally induced intermolecular dimerization cycliza-
tion of ethyl (E)-3-oxo-2-(styrylcarbamoyl)butanoate derivatives to give (E)-4-
hydroxy-5-phenyl-N-styryl-2-oxo-1,2-dihydropyridine-3-carboxamides as main pro-
ducts in diphenyl ether on 200–210 ꢀC. A number of 4-hydroxy-2(1H)-pyridone-
3-carboxylates were synthesized via an intramolecular cyclization of ethyl
N-(styrylcarbamoyl)acetates in xylene at reflux. 3-Acetyl-4-hydroxy-2(1H)-
pyridones were prepared by intramolecular cyclization in diphenyl ether on 200–
210 ꢀC. The preparation procedures of 4-hydroxy-2(1H)-pyridone-3-carboxylates
and 3-acetyl-4-hydroxy-2(1H)-pyridones were simple and gave a satisfactory yield.
Their structures were confirmed by spectra analysis.
EXPERIMENTAL
(E)-Diethyl 2-(Styrylcarbamoyl)malonate 5a
Typical procedure. Triethylamine (10.3 mL, 74.7 mmol) and diphenyl phos-
phorazidate (DPPA, 18.6 g, 67.6 mmol) were added to an ice-cooled solution of cin-
namic acid (10.0 g, 67.6 mmol) in 100 mL toluene. The reactant solution was stirred
at room temperature for 3 h. The acyl azide product was isolated by dilution with
cold water. The organic layer was dried over anhydrous magnesium sulfate, and
the solvent was removed in vacuo to provide the crude product. The acyl azide
was dissolved in 20 mL of benene and heated at reflux until azide decomposition
was complete as monitored by thin-layer chromatography (TLC). The reaction mix-
ture was then cooled to 0 ꢀC, and diethylsodiomalonate (prepared from diethyl mal-
onate (10.3 g, 67.6 mmol) and sodium hydride (2.23 g, 80% dispersion in oil,
74.3 mmol) in toluene (100 mL) at 0 ꢀC) were added. The reaction mixture was
allowed to warm to room temperature over 2 h, quenched with a saturated aqueous
ammonium chloride solution, extracted with ether (3 ꢂ 100 mL), rinsed with brine
(3 ꢂ 100 mL), and dried over anhydrous sodium sulfate. The solvent was removed
in vacuo to give the compound 5a as white crystals.
Spectral data. Yield 83%. White solid, mp 78–80 ꢀC. IR (KBr, n cmꢃ1): 3267,
1
1745, 1652, 1310, 1176, 1036, 924, 693. H NMR (400 MHz, CDCl3) d ¼ 1.30 (t,
J ¼ 7.1 Hz, 3H), 1.32 (t, J ¼ 7.1 Hz, 3H), 4.29 (t, J ¼ 10.7 Hz, 4H), 4.41 (s, 1H),
6.24 (d, J ¼ 14.7 Hz, 1H), 7.18–7.21 (m, 1H), 7.30–7.45(m, 4H), 7.49–7.52 (m, 1H),

CYCLIZATION OF ETHYL N-(STYRYLCARBAMOYL)ACETATES
2073
9.22 (d, J ¼ 10.3 Hz, 1H). 13C NMR (101 MHz, CDCl3): d ¼ 13.9, 58.7, 63.0, 115.1,
121.7, 125.7, 126.9, 128.6, 135.7, 159.4, 165.4. HRMS-EI: [M]þ calc. for C16H19NO5
305.1263; found 305.1262.
(E)-4-Hydroxy-2-oxo-5-phenyl-N-styryl-1,2-dihydropyridine-3-
carboxamide 6a
Typical procedure. Compounds 5a (0.4 g, 1.3 mol) were stirred in diphenyl
ether (5 mL) at 200–210 ꢀC for 5 min. The reaction mixture was cooled to room tem-
perature. The precipitate was collected and washed with ethyl acetate and n-hexane
(1:2) to give the compound 6a as colorless solid.
Spectral data. Yield 62%. Colorless solid, mp 258–260 ꢀC. IR (KBr, n cmꢃ1):
3331, 3030, 2850, 1665, 1587, 1287, 752, 692. 1H NMR (400 MHz, DMSO-d6):
d ¼ 6.50 (d, J ¼ 10.8 Hz, 1H), 7.19 (s, 1H), 7.52–7.21 (m, 9H), 7.57 (t, J ¼ 10.8 Hz,
1H), 7.67 (s, 1H), 12.27(s, 1H), 12.35 (d, 1H), 15.90 (s, 1H). 13C NMR (101 MHz,
DMSO-d6): d ¼ 97.7, 114.2, 116.0, 121.3, 126.1, 127.3, 127.8, 128.7, 129.1, 129.7,
133.2, 136.3, 139.2, 163.1, 168.5, 173.4. MS (EI, 70 eV): m=z ¼ 333 (M þ 1), 332
(Mþ), 214, 120, 119, 118, 117, 91. HRMS (EI): calc. for C20H16N2O3[M]þ
332.1161; found 332.1162.
Ethyl 4-Hydroxy-2-oxo-5-phenyl-1,2-dihydropyridine-3-carboxylate 7a
Typical procedure. Compounds 5a (0.4 g, 1.3 mol) were refluxed in xylene
(20 mL) for 12 h. The solvent was removed in vacuo to give an oil. The residue
was purified by column chromatography (ethyl acetate = hexane ¼ 1:6) to give the
compound 7a as white solid.
Spectral data. Yield 60%. White solid, mp 187–190 ꢀC. IR (KBr, n cmꢃ1):
3125: 2981, 2358, 1660, 1548, 1200, 813, 763, 697. H NMR (400 MHz, DMSO-d6):
1
d ¼ 1.30 (t, 3H), 4.53 (q, 2H), 7.32–7.34 (m, 1H), 7.38–7.41 (m, 2H), 7.44–7.46 (m,
2H), 7.59 (s, 1H), 11.71 (s, 1H), 13.67 (s, 1H). 13C NMR (101 MHz, DMSO-d6):
d ¼ 14.5, 61.7, 98.8, 111.9, 127.6, 128.6, 129.4, 133.6, 140.0, 159.7, 172.3, 172.6.
MS (EI, 70 eV): m=z ¼ 259 (Mþ), 214, 213, 145, 144, 119, 112, 89. HRMS: calc.
for C14H13NO4 [M]þ 259.0845, found 259.0847. This compound was reported in
literature.[16]
FUNDING
The authors acknowledge financial support from the National Natural Science
Foundation of China (Grant 21072029) and Shanghai Municipal Natural Science
Foundation (Grant 10ZR1400700).
SUPPORTING INFORMATION
Full experimental details and 1H NMR and13C NMR spectra data for all of the
compounds can be accessed on the publisher’s website.

2074
S.-Y. ZHAO ET AL.
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