Efficient Synthesis of N-Substituted 2,4-Azepandione Ring System as an Active Intermediate for Heterocyclic Syntheses

Article abstract of DOI:10.1002/jhet.2709

An improved efficient synthesis for 2,4-azepandiones (3, 8, and 14) could be achieved by a careful control of the reaction conditions to cyclize ethyl 4-(N-acetylarylamino) butanoate (1, 7, and 13), respectively. The ethyl 4-arylamino butanoate (9 or 12) was prepared by stirring the ethyl 4-bromobutanoate and substituted anilines at room temperature. Then, they were acetylated with acetyl chloride and triethylamine under the conditions that avoid the formation of 2-pyrrolidinone derivatives 10. Due to the rapid decomposition of the acetylated product (7 or 13) to its starting material (9 or 12), the reaction mixture is directly transferred without workup to the next cyclization step. The azepandione synthesis is favored by using a weak base at low temperature, where it is in a competition with the other modes of ring closure. The structures of the new compounds were supported by correct analytical and spectral data.

Full text of DOI:10.1002/jhet.2709

Month 2016
Efficient Synthesis of N-Substituted 2,4-Azepandione Ring System as an
Active Intermediate for Heterocyclic Syntheses
a
a
b
a
*
Mohamed A. Waly, Shiam A. Yossif, Ismail T. Ibrahim, and Mamdouh A. Sofan
aChemistry Department, Faculty of Science, Damietta University, New Damietta 34517, Egypt
bHot Laboratories Center, Atomic Energy Authority, Cairo, Egypt
*
E-mail: masofan1953@du.edu.eg
Received March 22, 2016
DOI 10.1002/jhet.2709
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
An improved efficient synthesis for 2,4-azepandiones (3, 8, and 14) could be achieved by a careful con-
trol of the reaction conditions to cyclize ethyl 4-(N-acetylarylamino) butanoate (1, 7, and 13), respectively.
The ethyl 4-arylamino butanoate (9 or 12) was prepared by stirring the ethyl 4-bromobutanoate and
substituted anilines at room temperature. Then, they were acetylated with acetyl chloride and triethylamine
under the conditions that avoid the formation of 2-pyrrolidinone derivatives 10. Due to the rapid decompo-
sition of the acetylated product (7 or 13) to its starting material (9 or 12), the reaction mixture is directly
transferred without workup to the next cyclization step. The azepandione synthesis is favored by using a
weak base at low temperature, where it is in a competition with the other modes of ring closure. The struc-
tures of the new compounds were supported by correct analytical and spectral data.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
bicyclic oxazolo[4,5-c]azepine or thiazolo[4,5-c]azepine
ring systems [7], which act as a selective inhibitor of
phosphoinositide 3-kinase [8]. Drazepinone is a potential nat-
ural herbicide [9] and the new diacetylenic natural products;
montiporyne A–F compounds exhibit bioactivity against cer-
tain solid tumor cells [10]. In addition, the pyrroloazepine ring
systems containing pyridinone derivative were reported as
mitogen-activated protein kinase-inhibiting compounds [11].
A number of novel fused thienoazepine derivatives have
been prepared and identified as potent inhibitors of MEK
[12]. Moreover, the nucleosides containing a 5:7 fused ring
system as a nucleobase, also known as ring- expanded nu-
cleosides (RENs), are very interesting molecular mimics of
purine nucleosides, and most of them possess significant bi-
ological activities because of their interference with the en-
zymes involved in the purine metabolism [13].
The seven-membered lactam systems were shown to be
active on the central nervous system. The anticonvulsant
active 4-substituted and 6-substituted caprolactams have
more optimal log (partition coefficient) characteristics than
the parent caprolactam itself [1,2]. Some allyl ether deriv-
atives, which induced considerable muscular depression
or paralysis, have been synthesized [3]. Also, thioketene
derivatives have been used as therapeutic or prophylactic
agent for hepatic diseases [4].
2,4-Azepindione ring was found in the skeleton of the
anti cancer heterocyclic alkaloids, ceratamines A and B
(Fig. 1), and their analogues, which were recently identi-
fied in a screen for compounds that arrest cells in mitosis
[5,6]. Also, it represents the consecutive building of the
© 2016 Wiley Periodicals, Inc.

M. A. Waly, S. A. Yossif, I. T. Ibrahim, and M. A. Sofan
Vol 000
run a competitive study between different ring sizes and uti-
lization of the reaction conditions to obtain a seven-
membered ring.
Therefore, we carried out the cyclization of the ethyl N-
acetyl-N-(o-carbomethoxy phenyl)aminobutanoate 1 using
sodium methoxide in toluene containing methanol and ob-
tained a white crystalline product (mp 158°C) in 61%
yield. This product is different than the previously reported
one by Proctor et al. (mp 192°C) [23a]. The 1H-NMR spec-
trum of this material revealed a singlet signal at δ 3.75ppm
corresponding to methyl ester protons and two exchange-
able proton signals at δ 6.10 and 12.8ppm that appeared
as a broad band. These signals were attributed to vinylic
and hydroxyl protons, respectively. This implies that the
two protons on C-3 underwent enolization via the tauto-
meric form 4. Also, the microanalysis showed that this
compound has molecular formula C14H15NO4. Hence, the
product of our cyclization reaction of 1 is the 2,4-
azepandione derivative 3. On the other hand, structure 3
was supported as the reaction product by running compet-
itive experiments to cyclize precursor 1 at different condi-
tions. These experiments lead us to verify the centers that
have the great potentialities for nucleophilic attack and un-
derstand the nature and versatility of this incidental cycli-
zation of 4-(N-acetylarylamino) butanoate ester to the
2,4-azepandione derivatives.
Moreover, the determination of all cyclization products
as a result of systematic changes in the reaction conditions
(the base, solvent, and temperature) accurately will need a
particular emphasis. The effect of changing of the base,
solvent, and temperature was summarized in Table 1.
In the light of the previous data, a possible mechanism
was suggested in Scheme 2, which illustrates the most fa-
vored mode of ring closure because of the deprotonation
of the acetyl group to the carbanion 2 that attacks the ethyl
ester in 7-Exo-Trig fashion [26].
Figure 1. Ceratamine alkaloids as anticancer drug.
Based on the aforementioned biological significance, the
2,4-azepandione moiety became the focus of our attention.
We have recently published a review article including the
synthesis and biological activity for 2,4-azepandione ring
system [14]. The 2,4-azepandione ring was synthesized by
several procedures including one-nitrogen ring expansion
such as Beckmann rearrangement for α,β-unsaturated cyclo-
hexanone oxime derivatives with acids [15–18], thermal
Curtius rearrangement, and acidic Schmidt rearrangement
for the azidocyclohexanone derivatives [19,20]. The photo-
chemical irradiation (one-carbon ring expansion) of a solu-
tion of 2,4-dioxopyridine derivative through a Pyrex filter
with high-pressure mercury lamp yielded 2,4-azepenedione
derivatives [21]. Also, we have published a new synthetic
method for the 2,4-azepandione ring by intramolecular con-
densation of the N-acetyl-N-phenylaminobutanoate moiety
with sodium hydride and 15-Crown-5 as a phase transfer cat-
alyst (Scheme 1) [22].
In the present work, 2,4-azepandione was synthesized
by intramolecular cyclization of ethyl N-acetyl-N-
arylaminobutanoate, also the effect of the aromatic ring
substituents has been studied.
RESULTS AND DISCUSSION
The earlier reported cyclization reactions of methyl N-
acetylanthranilate were carried out with a wide variety of
bases and solvents at a suitable temperature (120°C) to give
2,4-quinolindiones [23,24]. These cyclization reactions
need nonaqueous solvents and a fully substituted nitrogen
atom in anthranilic acid ester to avoid the intramolecular
hydrogen bonding between amidic-NH and carbonyl-
oxygen atom of the ester group [25]. The anions that gener-
ated from the N-acetyl compounds can act as electron
donors for Dieckmann-like condensation reactions. The
cyclization reaction of N-acetylanthranilic acid ester to form
six-membered ring was subjected to further investigation to
Furthermore, there are three predictable routes for ring
closure of compound 1. These are the condensation of N-
acetyl carbanion either with butanoate ester to form 2,4-
Table 1
Effect of changing base, solvent, and temperature on the cyclization yield.
Product %
Base
Solvent
Temp. (°C)
3
5
6
NaOCH3
NaOCH3
Methanol
Toluene/
methanol
Toluene
Toluene
Toluene
Toluene
Toluene
80
80–120
80.2
61
—
—
—
—
Scheme 1
NaOCH3
NaH
NaH
t-BuOK
t-BuOK
80–120
40
80
25
80–120
64.8
—
—
40
—
8.7
8.8
83.6
—
17.4
79
—
41
—
87.2
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DOI 10.1002/jhet

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Efficient Synthesis of N-Substituted 2,4-Azepandione Ring System as an Active
Intermediate for Heterocyclic Syntheses
Scheme 2
1-Benzazepine derivative 6 was produced under kineti-
cally controlled conditions (equilibrium) at low tempera-
ture (40°C). The reaction equilibrium shifted to the
forward direction in the absence of alcohol and at low tem-
perature. The structure of this compound was established
previously by the formation of the anion at room tempera-
ture followed by refluxing for 24h [27].
For insuring this apparent cyclization (N-acetyl and
butanoate group to form the 2,4-azepandione ring system)
without competitive feature and studying the effect of sub-
stituents on aromatic nitrogen, structure 7 with different
p-aromatic substituents was synthesized and subjected to
cyclization forming the corresponding 2,4-azepandione
derivative 8 (Scheme 4).
Initially, concerning the conditions of the synthesis of
compound 7 and its cyclization to 2,4-azepandione deriva-
tive 8, heating of ethyl 4-bromobutanoate with aniline,
p-toluidine, and/or p-chloroaniline under the same condi-
tions that described for the synthesis of 1 [28] failed to give
ethyl 4-(N-arylamino) butanoate 9a–c as a target product and
yielded the N-aryl-2-pyrrolidinone 10a–c (Scheme 5). Also,
stirring of the ethyl 4-bromobutanoate with anilines in tetra-
hydrofuran at room temperature in the presence of anhydrous
sodium carbonate or triethyl amine afforded the opened
structures 9, but the reactions did not complete and the unde-
sired 2-pyrrolidinones 10 appeared again at a long time
(3days). In continuation of our trials, sodium iodide was
added to the mixture at the beginning of the reaction, which
transferred to a dark place. The 4-arylaminobutanoate esters
9 were obtained in quite good yields after a relatively shorter
time (24h). We thought that sodium iodide accelerates the
nucleophilic substitution reaction with 4-bromobutanoate.
Finally, stirring of the reactants at room temperature without
solvent in the presence of an equivalent amount of
azepandione derivative 3 (route a) or with the aromatic
ester to give 2,4-quinolindione derivative 5 (route b) and
the Dieckmann condensation to produce 1-benzazepine
derivative 6 (route c) (Scheme 3).
Dieckmann condensations are reversible, and the ring
opening of the β-keto ester is accelerated by the presence
of some alcohol in the reaction medium. The N-acetyl con-
densation (Dieckmann-like condensation) in the present
investigation is irreversible, and the product is stable under
the reaction conditions. The 2,4-azepandione (3, route a)
was preferred where the reaction was performed in the
presence of sodium methoxide as a base and methanol as
a solvent. The Dieckmann condensation was retarded
under these reaction conditions. When the reaction mixture
was free from alcohol, the yield varied according to the
kind of base and temperature used (Table 1).
2,4-Quinolindione derivative 5 was the thermodynami-
cally controlled product, and the yield was increased when
a stronger base and elevated temperature were applied dur-
ing the cyclization process and its structure had been deter-
mined and established [23a].
Scheme 4
Scheme 3
Journal of Heterocyclic Chemistry
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M. A. Waly, S. A. Yossif, I. T. Ibrahim, and M. A. Sofan
Vol 000
Scheme 5
triethylamine produced the N-arylaminobutanoate ester
derivatives 9. The workup for the reaction mixture should
be completed with careful treatment during the extraction
step of the products and evaporation of the solvent at room
temperature under reduced pressure to avoid the cyclization
reaction again.
structure 11. The intensity of this peak was reduced on
prolonged treatment with D2O.
For the ortho aniline substituents such as structure 12, the
ethyl 4-(o-chlorophenylamino)butanoate 12b was prepared
in a similar procedure to its para substituted analogue 9c
(i.e., the reaction completed at room temperature), while
the 4-(o-methylphenylamino)butanoate derivative 12a
needed to heat the reactants in THF at 80°C and this is due
to the steric hindrance exhibited by o-methyl group. The IR
data for the aminobutanoate ester 12 showed the presence
of both NH and C=O groups stretching, while the 1H-
NMR spectral data supported the presence of exchangeable
NH proton at δ 3.603 and 3.998 ppm for 12a and 12b,
respectively.
Unfortunately, the ortho substituted phenylaminobutanoate
proceeds in the same behavior as the para substituted deriva-
tives during the acetylation step to compound 13. They were
hydrolyzed in water and decomposed on heating. So, they
were acetylated within the cyclization step with sodium hy-
dride in THF to the corresponding 2,4-azepandione 14
(Scheme 6).
The 1H-NMR data showed the presence of NH proton as a
broad singlet signal at δ 3.55ppm for compounds 9a and 9b
and at δ 3.62ppm in the case of compound 9c, and all of them
were exchanged on treatment with D2O. The 1H-NMR spec-
trum for compound 10 revealed the disappearance of the ester
and NH protons and the presence of three methylene protons
as were pointed in experimental section for each substituent.
Attempting acetylation of compound 9 by refluxing with
acetic anhydride failed to give the acetylated compound 7
and produced again the cyclized compound 10, while stir-
ring with acetyl chloride in THF under nitrogen afforded a
new product (TLC). Unfortunately, this product was
decomposed during rapid workup by addition to cold water
or left in the normal atmosphere and returned back to the
starting material 9. But, this problem could be avoided by
transferring the reaction mixture directly to the next cycli-
zation step without workup.
Also, compound 14 exists in the 1,3-diketone structure,
and the C-3 protons appeared as a singlet at δ 2.958 and
In spite of the cyclization of precursor 7 with sodium
methoxide in toluene, sodium hydride in toluene or DMF
was failed; it could be cyclized to give the desired 2,4-
azepandione derivative 8 in the presence of the 15-
Crown-5 ether (Scheme 5). The 15-Crown-5 leads to the
separation of the ions and simplifies the carbanion intramo-
lecular nucleophilic addition to the ester group. Cyclization
in THF as a solvent did not require Crown ether because it
has a dual effect as a solvent and does the same role of the
Crown ether. So, it was a suitable solvent for the syntheses
of the target compound 8.
Scheme 6
The 2,4-azepandiones 8 preferred to exist in the keto
form, because their IR spectra showed the absorption
1
bands of the amidic and carbonyl groups. The H-NMR
spectrum supported this structure by showing two protons
as a singlet signals for characterizing C-3 protons without
indication to the vinylic and OH protons in its enolic
Journal of Heterocyclic Chemistry
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Month 2016
Efficient Synthesis of N-Substituted 2,4-Azepandione Ring System as an Active
Intermediate for Heterocyclic Syntheses
3.340 ppm for 14a and 14b, respectively. But they were
completely exchanged on prolonged treatment with D2O.
material was extracted with cold water (30 mL × 3).
The aqueous layer was separated and acidified with
dil. HCl to afford the product azepandione derivative
(3) (1.7 g, 61%).
CONCLUSIONS
ii. In methanol: compound (1) (3g, 0.01mol) in dry meth-
anol (20mL) was added dropwise with stirring during
15min to sodium methoxide (from 0.23g Na in 20-mL
methanol) at room temperature. The reaction mixture
was heated under reflux for 5h. It was concentrated un-
der reduced pressure to nearly 10-mL methanol and left
to cool, and cold water (30mL) was added. After acidi-
fying with diluted HCl, the solid precipitate was filtrated
off, dried, and recrystallized from toluene to afford the
product azepandione derivative (3) in 80.2% yield.
iii. In toluene: precursor (1) (3g, 0.01mol) in dry toluene
(30 mL) was added dropwise with stirring during
15min to sodium methoxide (from 0.23 g of Na in
0.23-mL methanol) in dry toluene (20 mL) at 80°C.
The reaction mixture was heated under reflux for 5 h
at 120°C. After cooling, the solid material was ex-
tracted with cold water (30 ×3 mL). The aqueous layer
was separated and acidified with dil. HCl to afford a
solid product, which was filtrated and washed with cold
95% ethanol (15 mL). According to TLC investigation,
the precipitate consists of two compounds that could be
separated by chromatography on silica gel using (ethanol
3%+ chloroform) mixture and identified as the
azepandione (3) (1.68g, 64.8% yield) and the 2,4-
quinolinedione derivative (5) (0.24 g, 8.7%). The aqueous
filtrate was extracted with chloroform (30 mL × 3) and
dried over sodium sulfate. The chloroform was distilled,
and the residue was dried under reduced pressure. The
elemental and spectral data indicated that this residue is
the benzazepine (6) (0.48 g, 17.4%).
The synthesis of ethyl 4-[N-acetyl-(p-substituted phenyl)
amino] butanoate could be achieved without its cyclization
to 2-pyrrolidinone derivative by careful controlling of the re-
action conditions, while the ethyl 4-[N-acetyl-(o-substituted
phenyl) amino] butanoate was prepared in situ during the
cyclization step. It was unstable in aqueous conditions or un-
der heating and decomposed to the starting materials. Tetra-
hydrofuran is the suitable solvent for the intramolecular
cyclization with sodium hydride without using a phase trans-
fer catalyst (15-Crown-5), while toluene or N,N-dimethyl
formamide solvent needs the presence of this catalyst.
Especially in the presence of a weak base and at low
temperature, the intramolecular cyclization of the ethyl
4-(N-acetylarylamino)butanoate to 2,4-azepandione deriv-
atives via 7-Exo-Trig mode of ring closure is favored than
the 6-Exo-Trig that gives six-membered ring products.
EXPERIMENTAL
Melting points were obtained on digital Gallen Kamp
melting point apparatus. The IR spectra were recorded on
a Jasco 4100 FTIR spectrophotometer in KBr disks (υ
1
max in cmÀ1). H-NMR and 13C-NMR spectra (CDCl3)
were obtained using Pucker 300-MHZ spectrometer, and
chemical shift values were expressed in δ values (ppm) rel-
ative to that of the solvent. All NH and OH protons were
exchangeable with D2O. Elemental analyses were recorded
on a PERKIN-ELMER 2400 C, H, N elemental analyzer,
Cairo University, and mass spectra were recorded on
Shimadzu QP-2010 Plus. Reaction progress was monitored
by analytical TLC on precoated glass plate (silica gel
60F254-plate-Merck), and the products were visualized by
UV light.
Ethyl 4-[N-acetyl-(o-carbomethoxyphenyl)amino]butanoate
(1) was prepared according to the procedure previously de-
scribed by Proctor et al. [27].
Cyclization procedure for ethyl 4-[N-acetyl-(o-carbome
thoxyphenyl) amino] butanoate (1); synthesis of compounds
3, 5, and 6.
B. Cyclization with sodium hydride:
i. At 40°C: the N-acetylaminobutanoate 1 (3 g, 0.01 mol)
in dry toluene (30 mL) was added dropwise to sodium
hydride (0.89g, 0.02mol, 60%) in dry toluene (30 mL)
at 40°C during 15min with stirring under nitrogen. The
reaction mixture was stirred under reflux at room tem-
perature for overnight. Ethanol (5 mL) and cold water
(30 mL) were added. The solid material was extracted
with cold water (30 × 3 mL). The aqueous layer was
separated and acidified with dil. HCl to afford a solid
product, which was filtrated and washed with cold
95% ethanol (15 mL). According to TLC investigation,
the precipitate consists of one compound, which could
be identified as the 2,4-quinolinedione derivative (5)
(0.62g in 8.8% yield). The aqueous filtrate was ex-
tracted with chloroform (30 mL × 3) and dried over so-
dium sulfate. The chloroform was distilled, and the
residue was dried under reduced pressure to give the
benzazepine derivative (6) (2.54g, 79%).
A. Cyclization with sodium methoxide:
i. In methanol/toluene: the title compound (1) (3g, 0.01mol)
in dry toluene (20 mL) and dry methanol (20mL) was
added dropwise with stirring during 15min to sodium
methoxide (from 0.23g Na in 20-mL methanol) in dry tol-
uene (20mL) at 80°C. The reaction mixture was heated
under reflux for 5h at 120°C. After cooling, the solid
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M. A. Waly, S. A. Yossif, I. T. Ibrahim, and M. A. Sofan
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Ethyl 1-acetyl-5-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-
ii. At 80°C: a solution of 1 (3 g, 0.01 mol) in dry toluene
(30 mL) was added dropwise during 15 min to so-
dium hydride (0.8 g, 0.02 mol, 60%) in dry toluene
(30 mL) with stirring at 80°C under nitrogen. The re-
action mixture was stirred under reflux at this temper-
ature for further 5 h. After cooling and addition of
ethanol (10 mL) and water (50 mL), the aqueous layer
was separated and acidified with dil. HCl to give a
white product 5 (2.3 g, 83.6%).
4-carboxylate (6). bp 140°C at 0.2 mmHg [27]; IR: 1730
(CO, ester), 1690 (CO, ketone), 1630 (CO, amide) cmÀ1
;
1H-NMR: δ 1.11 (q, 3H, CO2CH2CH3), 1.70 (s, 3H,
COCH3), 2.02 (m, 2H, CH2-3), 3.30, 4.55 (2 m, 2H,
CH2À2), 3.71 (d, 1H, CH-4), 4.48 (q, 2H, CO2CH2CH3),
7.11 (m, 4H, ArH), and 12.60 (br., 1H, OH enolic, exch.)
ppm. Anal. Calcd for C15H17NO4 (275.30): C, 65.44; H,
6.22; N, 5.09. Found C, 65.25; H, 5.90; N, 4.80.
The reaction between ethyl 4-bromo butanoate and aniline
derivatives (synthesis of 1-aryl-2-pyrrolidinone 10a–c). To
a suspension of Na2CO3 (1.5eq.) and aniline and/or its
derivative (1eq.) in MeCN (30 mL) was added ethyl 4-
bromobutanoate (0.01mol) and NaI (0.01mol). The reaction
mixture was stirred for 15 h at 20°C and then heated under
reflux until completion (TLC investigation). The solvent was
evaporated under reduced pressure to dryness, and the
residue was partitioned between water (30mL) and ethyl
acetate (30mL×3). The organic layer was separated, washed
with water (30mL), dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure. The reaction
product 10 was purified by chromatography on silica gel
(elution with DCM/MeOH: 99/1 to 90/10).
C. Cyclization with potassium tert. butoxide:
i. Room temperature: the amino-ester 1 (3 g, 0.01mol) in
dry toluene (30 mL) was added to a suspension of po-
tassium tert. butoxide (from potassium 0.4 g in 0.74-
mL tert. butyl alcohol) in dry toluene (30 mL) at room
temperature under nitrogen during 15 min. The reac-
tion mixture was stirred at this temperature for further
48h. After heating under reflux for 3 min, the mixture
was left to cool, and ethanol (5mL) followed by water
(50 mL) was added. The aqueous layer was separated
and acidified with dil. HCl to give a precipitate, which
was filtrated and identified as compound 3 (1.0 g,
40%). The aqueous filtrate was extracted with chloro-
form (30 mL ×3), washed with NaHCO3, and dried
over sodium sulfate. The chloroform was distilled,
and the residue was dried under reduced pressure to
give the benzazepine derivative (6) (1.1 g, 41%).
ii. Refluxing temperature: compound 1 (1.5 g, 0.05mol) in
dry toluene (20 mL) was added to a suspension of potas-
sium tert. butoxide (from potassium 0.2 g in 0.37-mL tert.
butyl alcohol) in dry toluene (20mL) dropwise with stirring
during 15 min under nitrogen. The reaction mixture was
heated under reflux for 3h at 120°C. It was left to cool,
and then ethanol (10 mL) followed by water (50 mL) was
added. The aqueous layer was separated and acidified with
dil. HCl to give compound 5 (1.2 g, 87.2%).
1-Phenylpyrrolidin-2-one (10a). Yield 85.7%, mp 67–
1
69°C; IR: 1671.22 (CO, amide) cmÀ1; H-NMR: δ 2.08
(m, 2H, CH2-4), 2.51 (t, 2H, CH2-3), 3.78 (t, 2H, CH-5),
and 7.29 (m, 5H, ArH) ppm; 13C-NMR: δ 18.04 (C-4),
32.76 (C-3), 48.80 (C-5), 119.99, 124.51, 128.64, 129.26,
139.42 (Ar C), 174.24 (C-2) ppm; ms: m/z 161.05
(21.05%), 106.05 (100%), 91.05 (21.93%), 77.00 (91.22),
65.00 (12.39%), 51 (5.83%). Anal. Calcd for C10H11NO
(161.20): C, 74.51; H, 6.88; N, 8.69%; found: C, 74.26;
H, 6.59; N, 8.81.
1-(p-Tolyl)pyrrolidin-2-one (10b).
Brownish crystals,
yield 90%, mp 82°C; IR: 1687.41 (CO, amide) cmÀ1
;
1H-NMR: δ 2.09 (m, 2H, CH2-4), 2.31 (s, 3H, CH3),
2.54 (t, 2H, CH2-3), 3.78 (t, 2H, CH2-5), and 7.14–7.464
(2 m, 4H, ArH) ppm; 13C-NMR: δ 14.24 (CH3), 17.97
(C-4), 32.66 (C-3), 48.90 (C-5), 113.15, 120.05, 129.31,
134.11, 136.92 (ArC), 174.10 (C-2) ppm; ms: m/z 175.15
(38.73%), 120.15 (100%) 91.05 (21.41%), 79.9
(20.71%), 65.00 (12.06%), 51 (4.42%). Anal. Calcd for
C11H13NO (175.23): C, 75.40; H, 7.48; N, 7.99; found:
C, 75.66; H, 7.74; N, 8.01.
1-(2-Carbomethoxyphenyl)-2,4-azepandione (3). White crystals
(toluene), mp 158°C. IR: 3600 (br., OH, enolic), 1725 (CO,
1
ester), 1640 (CO, amide) cmÀ1; H-NMR: δ 1.91 (m, 2H, C-
6), 2.40 (t, 2H, C-5), 3.75 (s, 3H, CO2Me), 3.85 (t, 2H, C-7),
6.10 (s, 1H, vinyl, exch.), 7.11, 7.50, 8.01 (m, t and d, 4H,
ArH) and 13.10 (br., 1H, OH, enolic, exch.). Anal. Calcd for
C14H15NO4 (261.27): C, 64.36; H, 5.79; N, 5.36. Found: C,
63.95; H, 5.49; N, 6.10.
Ethyl 4-(2,4-dioxo-3,4-dihydroquinolin-1(2H)-yl)butanoate (5).
White needles (toluene and ethanol), mp 192°C (Lit. [21a]
190–192°C); IR: 3400 (br., OH enolic), 1720 (CO, ester),
1-(4-Chlorophenyl)pyrrolidin-2-one (10c). White crystals,
1
yield 75%, mp 90°C; IR: 1689.34 (CO, amide) cmÀ1; H-
NMR: δ 2.08 (m, 2H, CH2-4), 2.53 (t, 2H, CH2-3), 3.76 (t,
2H, C-5), and 7.26–7.52 (2m, 4H, ArH) ppm; 13C-NMR: δ
18.03 (C-4), 32.84 (C-3), 48.84 (C-5), 121.18, 126.42,
128.96, 129.66, 138.22 (C-5), 174.46 (C-2) ppm; ms: m/z
195.05 (38.33%), 142.10 (29.91%), 140.10 (100%), 127.10
(25.54%), 111.05 (15.09%), 80 (12.72%). Anal. Calcd for
C10H10ClNO (195.65): C, 61.39; H, 5.15; Cl, 18.12; N,
7.16; found: C, 61.54; H, 5.70; Cl, 18.35; N, 7.74.
1630 (CO, amide) cmÀ1
;
1H-NMR: δ 1.20 (t, 3H,
CO2CH2CH3), 1.83 (m, 2H, CH2CH2CH2CO2Et), 2.31 (t,
2H, CH2CH2CH2CO2Et), 3.80 (t, 2H, N-CH2CH2À), 4.12
(q, 2H, CO2CH2CH3), 6.16 (s, 1H, vinylic, exch.), 7.17 (m,
4H, ArH), and 11.03 (br, 1H, OH enolic) ppm. Anal. Calcd
for C15H17NO4 (275.30): C, 65.44; H, 6.22; N, 5.09. Found
C, 65.30; H, 6.33; N, 5.23.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
Efficient Synthesis of N-Substituted 2,4-Azepandione Ring System as an Active
Intermediate for Heterocyclic Syntheses
Synthesis of ethyl 4-(substituted phenylamino)butanoate (9a–
c and 12a,b). A mixture of anilines (0.01mol), ethyl 4-
bromobutanoate (0.012mol), and triethylamine (0.012mol)
was stirred at room temperature overnight, and then the
mixture was dissolved in water (50mL). The methylene
chloride extract is washed with water and dried over
sodium sulfate anhydrous. The solvent should be removed
under reduced pressure at room temperature to give the
crude product. Column chromatography purification using
a mixture (methylene chloride:petroleum ether, 1:2) gave
pure 4-anilinobutanoate derivatives 9a–c and 12b.
(m, 2H, N-CH2CH2CH2CO2Et), 2.44 (t, 2H, N-
CH2CH2CH2CO2Et), 3.24 (t, 2H, N-CH2), 3.99 (br, 1H,
NH exch.), 4.10 (q, 2H, CO2CH2CH3), 6.62–7.13 (2 m,
4H, ArH) ppm; 13C-NMR: δ 14.22 (CH3CH2), 29.71 (C-
3), 31.31 (C-2), 43.03 (C-4), 60.55 (CH3CH2), 111.16,
117.19, 119.13, 127.82, 129.40, 143.84 (ArC), 173.26 (c-
1) ppm; ms: m/z 241.00 (26.66%), 196 (8.51%), 142
(31.36%), 140.00 (100%), 127.00 (11.95%), 111.05
(16.57%), 79.95 (27.82%). Anal. Calcd for C12H16ClNO2
(241.71): C, 59.63; H, 6.67; Cl, 14.67; N, 5.79; found: C,
59.56; H, 6.33; Cl, 14.78; N, 5.42.
Ethyl 4-(phenyl amino)butanoate (9a). Yield 82.1%, mp
80°C; IR: 3374.82 (br., NH), 1727.91 (CO, ester) cmÀ1; 1H-
NMR: δ 1.29 (t, 3H, CO2CH2CH3), 1.95 (m, 2H, N-
CH2CH2CH2CO2Et), 2.45 (t, 2H, N-CH2CH2CH2CO2Et),
3.19 (t, 2H, N-CH2), 3.81 (br, 1H, NH exch.), 4.17 (q, 2H,
CO2CH2CH3), 6.64–7.20 (2m, 5H, ArH) ppm; 13C-NMR:
δ 14.27 (CH3CH2), 24.73 (C-3), 31.97 (C-2), 43.29 (C-4),
60.49 (CH3CH2-), 112.73, 117.27, 129.28, 148.26 (ArC),
173.45 (C-1) ppm; ms: m/z 207.15 (17.27%), 162.10
(8.77%), 106.15 (100%), 91.05 (1.75%), 77.05 (17.29%),
65.00 (3.12), 51.00 (5.83). Anal. Calcd for C12H17NO2
(207.13): C, 69.54; H, 8.27; N, 6.76; found: C, 69.23; H,
8.51; N, 6.85.
Ethyl 4-(2-methylphenylamino)butanoate (12a).
After
stirring the mixture of o-toluidine (1.07g, 0.01mol), ethyl
4-bromobutanoate (2.34 g, 0.012 mol), and triethylamine
(1.2 mL, 0.012 mol) at room temperature for 4 h, TLC did
not show any product. Then, it was dissolved in THF
(30 mL) and heated gradually until reached to reflux. The
reaction mixture was heated under refluxing for 8 h. It
was left to cool, poured into cold water, and extracted
with dichloromethane. The organic layer was separated,
washed with dilute aqueous sodium hydrogen carbonate,
dried over sodium sulfate, and evaporated in vacuo to
give crude product. Column chromatography purification
using a mixture (methylene chloride :petroleum ether 40–
60°C, 1:2) gave the pure ethyl 4-(o-tolylamino)butanoate
(12a). Yield 67, IR: 3419.17 (br., NH), 1725.98 (CO,
Ethyl 4-(4-methylphenylamino)butanoate (9b).
Yield
88%, mp 54°C; IR: 3392.17 (br., NH), 1733.76 (CO,
1
ester) cmÀ1; H-NMR: δ 1.27 (t, 3H, CO2CH2CH3), 1.91
1
ester) cmÀ1; H-NMR: δ 1.30 (t, 3H, CO2CH2CH3), 2.04
(m, 2H, N-CH2CH2CH2CO2Et), 2.28 (s, 3H, CH3), 2.35
(t, 2H, N-CH2CH2CH2CO2Et), 3.15 (t, 2H, N-CH2), 3.35
(br., 1H, NH exch.), 4.14 (q, 2H, CO2CH2CH3), 6.55–
7.01 (2 m, 4H, ArH) ppm; 13C-NMR: δ 14.54 (CH3CH2),
22.84 (p-CH3), 25.08 (C-3), 32.23 (C-2), 43.90 (C-4),
60.64 (CH3CH2), 113.20, 113.29, 126.53, 130.02,
130.12, 146.34 (ArC), 173.69 (C-1); ms: m/z 221.15
(33.23%). Anal. Calcd for C13H19NO2 (221.30): C,
70.56; H, 8.65; N, 6.33; found: C, 70.67; H, 8.45; N, 6.12.
Ethyl 4-(4-chlorophenylamino)butanoate (9c). The product
takes more reaction time (48h), yield 88%, mp 52°C; IR:
(m, 2H, N-CH2CH2CH2CO2Et), 2.26 (s, 3H, CH3), 2.50
(t, 2H, N-CH2CH2CH2CO2Et), 3.29 (t, 2H, NCH2), 3.60
(br., 1H, NH exch.), 4.16 (q, 2H, CO2CH2CH3), 6.71–
7.18 and 7.294 (3m, 4H, ArH) ppm; 13C-NMR: δ 14.49
(o-CH3), 22.64 (CH3CH2), 24.60 (C-3), 32.14 (C-2),
43.51 (C-4), 60.54 (CH3CH2), 115.29, 122.26, 124.97,
129.06, 130.39, 144.70 (ArC), 173.60 (C-1); ms: m/z 225
(100%), 221.05 (M+, 5.65%), 176.05 (1.71%), 119.05
(13.85%), 91.05 (2.29%), 77.00 (2.29%), 65.00 (1.26%),
55.00 (6.03%). Anal. Calcd for C13H19NO2 (221.30): C,
70.56; H, 8.65; N, 6.33; found: C, 70.33; H, 9.00; N, 6.54.
Acetylation of the ethyl 4-(N-arylamino)butanoate derivatives.
a. By acetic anhydride: stirring aminoester 9 (1 g) in acetic
anhydride (5 mL) at room temperature for 4 h did not
give any product. The reaction mixture was heated
under reflux at 50°C for 2 h and then at 100°C for
4 h. After cooling, the reaction mixture was poured
into cold water and extracted with dichloromethane.
The organic layer was separated, washed with dilute
aqueous sodium hydrogen carbonate, dried over
sodium sulfate, and evaporated in vacuo to give crude
product, which was identified as the cyclized
compound 10.
1
3351.68 (br., NH), 1733.69 (CO, ester) cmÀ1; H-NMR: δ
1.26 (t, 3H, CO2CH2CH3), 1.91 (m, 2H, N-CH2CH2
CH2CO2Et), 2.41 (t, 2H, N-CH2CH2CH2CO2Et), 3.14 (t,
2H, N-CH2), 3.68 (br., 1H, NH exch.), 4.14 (q, 2H,
CO2CH2CH3), 6.53–7.11 (2m, 4H, Ar) ppm; 13C-NMR: δ
14.24 (CH3CH2), 28.95 (C-3), 31.89 (C-2), 43.50 (C-4),
60.59 (CH3CH2), 113.86, 116.30, 123.15, 129.12, 144.96,
146.65 (ArC), 173.43 (C-1) ppm; ms: m/z 241.10
(16.85%), 196.95 (17.99%), 142.10 (25.99%), 140.10
(82.18%), 127.00 (100%), 111.05 (6.54%), 79.95
(53.55%). Anal. Calcd for C12H16ClNO2 (241.71): C,
59.63; H, 6.67; Cl, 14.67; N, 5.79; found: C, 60.00; H,
6.55; Cl, 14.22; N, 6.10.
b. By acetyl chloride: a solution of compound 9 (1g), acetyl
chloride (2mL), and triethylamine (1mL) or sodium car-
bonate (1g) in THF (30mL) was stirred at room temper-
ature for 4h. A new product has been formed by TLC
Ethyl 4-[(2-chlorophenyl)amino]butanoate (12b).
Yield
74%, mp 54°C; IR: 3388.32 (br., NH), 1727.56 (CO,
1
ester) cmÀ1; H-NMR: δ 1.26 (t, 3H, CO2CH2CH3), 1.85
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. Waly, S. A. Yossif, I. T. Ibrahim, and M. A. Sofan
Vol 000
1-(4-Chlorophenyl)-2,4-azepandione (8c).
White flacks
investigation, which is completely different than the
cyclized compound 10. The reaction mixture was poured
into cold water and extracted with methylene chloride.
The organic layer was separated, washed with water,
and dried over sodium sulfate anhydrous. The solvent
was removed under reduced pressure at room temperature
to give the crude product. Column chromatography puri-
fication using a mixture (methylene chloride : petroleum
ether 40–60°C, 1:2) gave pure 4-anilinobutanoate deriva-
tive 9 as a result of the hydrolysis of the reaction product.
General procedure for preparation of N-substituted
(light petroleum bp 30–40°C), yield 81%, mp 61°C; IR:
1725.53 (C=O, ketone) and 1644.98 (C=O, amide) cmÀ1
;
1H-NMR: δ 2.14 (q, 2H, CH2-6), 2.59 (t, 2H, CH2-5),
2.88 (s, 2H, CH2-3, exch on prolonged treatment with
D2O), 3.81 (t, 2H, CH2-7) and 7.23–7.56 (m, 4H, ArH)
ppm; 13C-NMR: δ 22.77 (C-6), 32.62 (C-5), 48.70 (C-7),
51.15 (C-3), 121.04, 128.85, 128.90, 129.57, 136.82,
137.94 (C-3), 169.13 (C-2), 174.37 (C-7) ppm; ms: m/z
237.10 (1.66%), 195.05 (22.23%), 142.05 (21.03%),
140.10 (67.44%), 127.10 (2.46%), 111.05 (11.04%),
79.95 (100%). Anal. Calcd for C12H12ClNO2 (237.68): C,
60.64; H, 5.09; Cl, 14.92; N, 5.89, found: C, 60.71; H,
5.32; Cl, 15.11; N, 6.15.
2,4-azepandione(8 or 14).
To a mixture of ethyl 4-(N-
arylamino)butanoate 9 and/or 13 (0.01 mol) in dry THF
(50 mL) and sodium hydride (60%, 0.04mol) at room
temperature, a solution of acetyl chloride (0.01 mol) in
THF (10 mL) was added with stirring under nitrogen
during 10min. The reaction mixture was stirred at this
temperature for 1 h and then at 80°C for another 1 h.
After cooling and adding of ethanol (excess), followed by
ice cold water, the mixture was acidified with dil. HCl
(2 M) and extracted with CHCl3. The organic layer was
separated, washed with dilute aqueous sodium hydrogen
carbonate, and dried over anhydrous sodium sulfate. The
solvent was evaporated to give the crude product, which
purified chromatographically (dichloromethane :ethanol :
ammonia, 300:8:1) to afford 2,4-azepanedione derivative
8 and or 14.
1-(o-Tolyl)-2,4-azepandione (14a).
Oily product, yield
68%; IR 1729.83 (C=O, ketone) and 1648.84 (C=O,
1
amide) cmÀ1; H-NMR: δ 1.92 (q, 2H, CH2-6), 2.29 (t,
2H, CH2-5), 2.32 (s, 3H, CH3), 2.95 (s, 2H, C-3, exch on
prolonged treatment with D2O), 3.69 (t, 2H, CH2-7) and
7.11–7.43 (m, 4H, ArH) ppm; 13C-NMR: δ 17.61 (o-
CH3), 22.44 (C-6), 31.85 (C-5), 47.47 (C-7), 52.46 (C-3),
125.90, 128.75, 129.42, 130.27, 136.16, 140.21 (ArC),
170.84 (C-2), 172.98 (C-4) ppm; ms: m/z 217.10
(3.61%), 177.10 (5.98%), 153.10 (8.17%), 120.10
(14.22%), 91.05 (14.64%), 77.00 (24.56%), 65.00
(11.57%), 55.05 (100%). Anal. Calcd for C13H15NO2
(217.26): C, 71.87; H, 6.96; N, 6.45, found: C, 71.55; H,
7.12; N, 6.63.
1-(2-Chlorophenyl)-2,4-azepandione (14b). Oily product,
yield 78%, IR: 1722.12 (C=O, ketone) and 1656.55 (C=O,
amide) cmÀ1; 1H-NMR: δ 2.17 (q, 2H, CH2-6), 2.31 (t,
2H, CH2-5), 3.34 (s, 2H, CH2-3, exch on prolonged
treatment with D2O), 3.92 (t, 2H, CH2-7), 6.97–7.22 (m,
4H, ArH) ppm; 13C-NMR: δ 22.91 (C-6), 31.59 (C-5),
47.63 (C-7), 51.08 (C-3), 122.77, 128.29, 129.57, 130.16,
132.95, 139.67 (ArC), 169.27 (C-2), 173.02 (C-4); ms:
m/z 237.10 (1.66%), 196.00 (9.92%), 142,05 (31.94%),
140.10 (100%). 127.05 (14.40%), 111.05 (10.27%),
79.95 (27.82%). Anal. Calcd for C12H12ClNO2 (237.68):
C, 60.64; H, 5.09; Cl, 14.92; N, 5.89, found: C, 60.33;
H, 4.92; Cl, 14.55; N, 5.75.
1-Phenyl-2,4-azepandione (8a).
White flacks (light
petroleum bp 30–40°C), yield 79.4%, mp 50°C; IR:
1727.91 (C=O, ketone) and 1598.70 (C=O, amide) cmÀ1
;
1H-NMR: δ 2.17 (q, 2H, CH2-6), 2.23 (t, 2H, C-5), 2.25
(s, 2H, CH2-3, exch on prolonged treatment with D2O),
3.62 (t, 2H, CH2-7) and 7.04 (m, 5H, ArH) ppm; 13C-
NMR: δ 23.09 (C-6), 44.29 (C-5), 48.13 (C-7), 50.08 (C-
3), 119.61, 123.47, 127.82, 127.69, 128.61, 142.90
(ArC), 170.10 (C-2), 172.97 (C-4) ppm; ms: m/z 203.10
(0.14%), 161.10 (27.10%), 106.10 (90.28%), 91.05
(4.36%), 79.95 (100%), 63.95 (48%), 51.00 (10.08).
Anal. Calcd for C12H13NO2 (203.24): C, 71.92; H, 6.45;
N, 6.89, found: C, 72.32; H, 6.63; N, 6.55.
1-(p-Tolyl)-2,4-azepandione (8b).
White flacks (light
petroleum bp 30–40°C), yield 65%, mp 68–70°C; IR:
1737.55 (C=O, ketone) and 1671.68 cmÀ1 (C=O, amide)
cmÀ1 1H-NMR: δ 2.00 (q, 2H, CH2-6), 2.26 (t, 2H,
;
REFERENCES AND NOTES
CH2-5), 2.32 (s, 3H, CH3), 2.49 (s, 2H, CH2-3, exch on
prolonged treatment with D2O), 3.69 (t, 2H, CH2-7),
6.99–7.44 (m, 4H, ArH) ppm; 13C-NMR: δ 18.10 (p-
CH3), 21.01 (C-6), 32.84 (C-5), 48.41 (C-7), 49.07 (C-3),
120.18, 129.36, 133.27, 134.27, 136.61, 137.12 (ArC),
169.09 (C-2), 174.27 (C-4); ms: m/z 217.00 (62.79%),
177.00 (62.79%), 153.00 (90.71%), 120.00 (75.58%),
92.00 (69.77%), 82.00 (97.67%), 66.00 (72.09%), 51.00
(100%). Anal. Calcd for C13H15NO2 (217.26): C, 71.87;
H, 6.96; N, 6.45, found: C, 72.01; H, 6.72; N, 6.19.
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DOI 10.1002/jhet

Month 2016
Efficient Synthesis of N-Substituted 2,4-Azepandione Ring System as an Active
Intermediate for Heterocyclic Syntheses
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Journal of Heterocyclic Chemistry
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