Synthesis and X-ray crystal structure determinations of pyrrolidine-2,4-diones 2-imnopyrrolidin-5-ones and 1,3-oxazine-2,4-diones derived from acetoacetanilides

Article abstract of DOI:10.3987/COM-05-10568

Commercially available acetoacetanilides may, after initial alkylation, be cyclized to pyrrolidine-2,5-diones by reaction with ethyl bromoacetate or cyclized to 5-iminopyrrolidin-2-ones with chloroacetonitrile. Reaction with ethyl chloroformate gives 1,3-

Full text of DOI:10.3987/COM-05-10568

HETEROCYCLES, Vol. 68, No. 3, 2006
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HETEROCYCLES, Vol. 68, No. 3, 2006, pp. 465 - 474. © The Japan Institute of Heterocyclic Chemistry
Received, 20th September, 2005, Accepted, 10th February, 2006, Published online, 14th February, 2006. COM-05-10568
SYNTHESIS AND X-RAY CRYSTAL STRUCTURE
DETERMINATIONS OF PYRROLIDINE-2,4-DIONES,
2-IMINOPYRROLIDIN-5-ONES AND 1,3-OXAZINE-2,4-DIONES
DERIVED FROM ACETOACETANILIDES
Thomas Duff,1 John P. James,1* and Helge Müller-Bunz2
1National Institute for Cellular Biotechnology, School of Chemical Sciences,
2
Dublin City University, Glasnevin, Dublin 9, Ireland
School of
Chemistry and Chemical Biology, University College Dublin, Dublin 4, Ireland
Email: paraic.james@dcu.ie
Abstract – Commercially available acetoacetanilides may, after initial alkylation,
be cyclized to pyrrolidine-2,5-diones by reaction with ethyl bromoacetate or
cyclized to 5-iminopyrrolidin-2-ones with chloroacetonitrile. Reaction with
ethyl chloroformate gives 1,3-oxazine-2,4-diones. Several examples of these
reactions using different alkyl groups are described.
products were confirmed by X-Ray crystallography.
The structures of the
INTRODUCTION
There remains considerable ongoing research into the area of small heterocycle synthesis from readily
available starting materials. The use of alkylated acetoacetanilides as precursors to substituted
β-lactams has previously been reported by this group.1 Herein, the preparation of three heterocycles,
namely pyrrolidine-2,5-diones (succinimides), 2-iminopyrrolidin-5-ones and 1,3-oxazine-2,4-diones are
described. Succinimides have attracted attention for a wide range of potential applications including
enzyme inhibitors,2 anti convulsants,3-5 Tat HIV-1 inhibitors,6a irreversible protease inhibitors6b and
5-HT1A receptor ligands.7
Succinimides have previously been prepared by numerous methods
including the condensation of amines with derivatives of succinic anhydride, Diels-Alder and ene
reactions of maleimides and Stobbe type condensations. More recently new derivatives have been

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prepared from three component Ugi type reaction of alkyl isocyanates and isopropylidene Meldrum’s acid
in the presence of either pyrrole, indoles or phenols.8-9
An unsual reaction was discovered by
Furukawa10 involving the solvent free reaction of α-oxoketene O,N-acetals with maleic anhydride and
allows the introduction of a carbonyl functionality at C3.
Literature reports for the synthesis of 2-iminopyrrolidin-5-ones are much scarcer than their succinimide
counterparts. A few papers describe their preparation11-13 by alkoxide catalysed ring opening of
3-cyanosuccinimides to give an open chain intermediate which spontaneously ring closes by reaction at
the cyano group.
As a class of compounds 1,3-oxazine-2,4-diones have received less attention though
The methods used in their preparation included rearrangement of a
some have been reported.
2-hydroxy-2-phenylazo-γ-butyrolactone using BF3Et2O,14 or by rearrangement of an 1,3-oxazine-2-one
using excess Bu2BOTf,15 by reaction of diketene with urethane followed by cyclization with conc
H2SO4,16 or from ethyl acetoacetate by reaction with N,N-dialkyl-ureas in AcOH/(Ac)2O.17
They were
also prepared by reaction of diketene with nitrourea in pyridine,18 by reaction of malonyl dichlorides
with isocyanates19 or by the cyclization of α,α-disubstituted β-carbamoyloxypropionic acids with
SOCl2/pyridine.20 None of these three classes of compounds have been prepared according to the methods
described below.
RESULTS AND DISCUSSION
When 1, (Y = H, Cl Scheme 1) was alkylated with simple alkyl halides such as ethyl or methyl iodide,
the only products isolated were the C3-alkylated mono- or disubstituted acetoacetanilides (6) according as
one or two moles of the reagents were used
The introduction of an ethoxycarbonylmethyl group at the
C3 position was achieved by reaction of 1 with ethyl bromoacetate to give the desired product (5).
However, stepwise alklations at the C3 position using firstly methyl iodide for example, followed by
ethyl bromoacetate lead to the isolation of pyrrolidine-2,5-diones (succinimides) (3) in moderate yield.
When ethyl cloroformate was used in the alkylation step the six membered 1,3-oxazine-2,4-dione ring
system (4) was formed (Figure 1). These are stepwise alkylation/cyclizations with the final product
depending on the alkylating reagent used. The mechanisms for the formation of products (3 and 4) from
monosubstituted acetoacetanilides differ with respect to the initial site of alkylation with the
consequential cyclizations being similar in both cases. In the case of 3 the mechanism involves the
alkylation of an enol oxygen followed by intramolecular cyclisation. The formation of 4 involves
alkylation on carbon followed by cyclisation. Another variation of this reaction involves the use of
bromoacetonitrile as the alkylating reagent. Thus when 6 (R =H, Y = H) was treated with
bromoacetonitrile and base there was formed 2-iminopyrrolidin-5-one (7).
Reversal of the

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467
alkylation sequence where ethyl bromoacetate was first used to obtain 5, followed by alkylation with propyl
iodide, also gave 3 as in the conversion of 5A to 3B. Crystal structures have been obtained for each of the
three classes of compound prepared and are shown in Figure 2. The data analysis for the crystal structure
of 7 indicates that the methyl group at C10 is disordered.
NH
O
Y
O
O
Me
BrCH2CN/NaH
N
Me
N
Et
H
Y
Et
R
O
(6) R = H or Et, Y =H
EtI/NaH
(7) Y = H
O
O
Y
Me
N
O
O
O
1. R-X/NaH
BrCH CO Et/NaH
R
Y
Me
N
2.
2
2
H
1
(3A) R = Butyl, X = I, Y = OMe
(3B) R = Propyl, X = I, Y = OMe
(3C) R = Benzyl, X = Cl, Y = Cl
(3D) R = Methyl, X = I, Y = Cl
(3E) R = Ethyl, X = I, Y =H
1. R-X/NaH
2.
ClCO2Et/NaH
BrCH2CO2Et/NaH
BuI/NaH(5A
(3B)
Me
R
O
O
O
Y
N
O
O
Me
EtO2C
N
H
Y
(4A) R = Butyl, X = I, Y = OMe
(4B) R = Methyl, X = I, Y = Cl
(4C) R = Benzyl, X = Cl, Y = Cl
(5A) Y = OMe
(5B) Y = Cl
FIGURE 1

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HETEROCYCLES, Vol. 68, No. 3, 2006
O1
O2
C7
C11
C10
C12
C11
C2
C5
N1
C9
C3
C4
C8
C1
C6
C10
C13
C8
C12
O3
C9
C4
Cl1
C14
C13
C18
C18
C19
O2
C7
C17
C16
Cl
C14
C15
C3
C1
N
C15
C16
C2
C17
O1
O3
C5
C6
(4C)
(3C)
C3
C12
C2
C1
O1
C4
C5
C11
N1
C8
C6
C7
C10
C14
C13
N2
C9
O2
(7)
FIGURE 2
EXPERIMENTAL
Acetoacetanisidine, 4-chloroacetoacetanilide, ethyl bromoacetate, ethyl chloroformate and all alkyl
halides were purchased from Sigma Aldrich and used as received. Acetone was dried and distilled before
use. Melting points were determined using a Griffin melting point apparatus and are uncorrected.

HETEROCYCLES, Vol. 68, No. 3, 2006
469
Infrared spectra were recorded on a Perkin-Elmer 2000FT-IR spectrometer.
NMR spectra were
1
recorded on a Bruker AC 400 NMR spectrophotometer operating at 400 MHz for H NMR and at 100
MHz for 13C NMR. The 1H and 13C NMR chemical shifts (ppm) are relative to TMS and all coupling
constants (J) are in Hertz (Hz). The electrospray m/s spectral data were aquired using a Bruker LCQ
Esquire, the samples being introduced as solutions in MeOH or MeCN.
X-Ray crystallographic data
"CCDC 269713 (3C), CCDC 272231 (4C) and CCDC 272233 (7) contains the supplementary
crystallographic data for this paper. These can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk)".
Preparation of alpha substituted acetoacetanilides and acetoacetanisidines .
These compounds were prepared according to a general procedure as follows.
A solution of acetoacetanisidine or 4-chloroacetoacetanilide (0.02 mol) was heated under reflux in
acetone (200 mL) containing anhydrous K2CO3 (2.76 g, 0.02 mol).
To this was added the appropriate
alkyl halide (0.02 mole) (Figure 1) and the reaction was heated under reflux overnight. After removal of
the solid potassium carbonate, the filtrate was concentrated to an oil. The oil was purified by column
chromatography using SiO2 and a mixture of EtOAc and hexane as eluant (50%:50% by volume). The
monosubstituted products were obtained in yields of 50–70% along with small quantities of disubstituted
products and unreacted starting materials. Compound (5A) was prepared according to the literature
procedure.21
General procedure for the preparation of 1,3-oxazine-2,4-diones (4)
A solution of the monosubstituted acetoacetanilide (4 mmol) in acetone (80 mL) was treated with NaH
(60 % dispersion in oil, 200 mg, 5 mmol), followed by ethyl chloroformate (0.5 mL, 5 mmol). The
reaction mixture was heated under reflux overnight, concentrated to an oil and subjected to column
chromatography using SiO2 and a mixture of EtOAc and hexane as eluant (50%:50% by volume) to give
the cyclized products.
Synthesis of 5-Butyl-3-(4-methoxyphenyl)-6-methyl[1,3]oxazine-2,4-dione (4A)
Following column chromatography using SiO2 and a mixture of EtOAc and hexane as eluant (50%:50%
by volume) the major component was isolated as a white crystalline solid (750 mg, 69%). mp 98-1000C
(EtOH). IR (KBr) 1773, 1683, 1517, 1401, 1256, 1026, 841 cm-1. 1H NMR (CDCl3), δ 0.95 (3H, t, CH3, J

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= 7.2), 1.40 (2H, m, CH2, J = 7.2), 1.47 (2H, m, CH2, J = 7.0), 2.30 (3H, s, CH3), 2.40 (2H, m, CH2, J =
7.6), 3.80 (3H, s, OCH3), 7.00 (2H, d, 2 x Ar CH, J = 6.8), 7.20 (2H, d, 2 x Ar CH, J = 6.6). 13C NMR
(CDCl3) δ 14.2, 17.3, 55.9 (3 x CH3), 22.9, 25.3, 31.2 (3 x CH2), 115.2, 129.4 (2 x Ar CH), 113.0 127.0,
149.4, 160.2, 160.5, 162.9 (6 x qC). Anal. Calcd for C16H19NO4: C, 66.43; H; 6.6, N; 4.84, Found: C,
66.3; H, 6.58; N, 4.76. ESMS (MeOH CV +40 V) m/z 312 ([M + Na+]+, 100%).
Synthesis of 5,6-Dimethyl-3-(4-chlorophenyl)[1,3]oxazine-2,4-dione (4B)
Following chromatography using SiO2 and a mixture of EtOAc and hexane as eluant (50%:50% by
volume) the major component was isolated as a white solid (120 mg, 27%). mp 155-157oC (EtOH). IR
(KBr) 1765, 1690, 1585, 1420, 1230, 998, 832 cm-1. 1H NMR (CDCl3), δ 2.0 (3H, s, CH3), 2.30 (3H, s,
CH3), 7.20 (2H, d, 2 x Ar CH, J = 6.8), 7.50 (2H, d, 2 x Ar CH, J = 6.8). 13C NMR (CDCl3) δ 10.7 (CH3),
17.5 (CH3), 129.8, 130.2 (2 x Ar CH), 108.5, 133.0, 135.5, 148.8, 160.5, 162.7 (6 x qC). Anal. Calcd for
C12H10NO3Cl: C, 57.3; H, 3.98; N, 5.56. Found: C, 56.82; H, 3.94; N, 5.49. ESMS (MeOH CV +20 V)
m/z 274 ([M + Na+]+, 100%).
Synthesis of 5-Methyl-3-(4-chlorophenyl)-6-benzyl-[1,3]oxazine-2,4-dione (4C)
The oil was diluted with 10 mL of ethyl acetate and then with 200 mL of hexane and chilled in a freezer
overnight. A white crystalline product was filtered. (520 mg, 24%) mp 148-1500C (EtOH). IR (KBr)
1761, 1681, 1492, 1404, 1231, 1091, 752 cm-1. 1H NMR (CDCl3), δ 2.25 (3H, s, CH3), 3.70 (2H, s,
CH2), 7.0-7.2 (7H, m, 7 x Ar CH), 7.40 (2H, d, 2 x Ar CH, J = 6.6). 13C NMR (CDCl3) δ 17.9 (CH3), 31.0
(CH2), 127.2, 128.8, 129.2, 129.8, 130.2 (5 x Ar CH), 112.4, 132.8, 135.6, 138.5, 148.5, 162.2, 162.5 (7 x
qC). Anal. Calcd for C18H14NO3Cl: C, 65.95; H, 4.27; N, 4.27. Found: C; 65.76, H; 4.23, N; 4.10.
ESMS (MeCN CV +36 V) m/z 350 ([M + Na+]+, 100%).
General procedure for the preparation of pyrolidine-2,5-diones (3)
A solution of the monosubstituted acetoacetanilide (6 mmol) in acetone (80 mL) was treated with NaH
(60 % dispersion in oil, 400 mg, 10 mmol), followed by ethylbromoacetate (1.1 mL, 10 mmol). The
reaction mixture was heated under reflux overnight, concentrated to an oil which was subjected to column
chromatography (see individual entries) to give the cyclised products.
Synthesis of 3-Acetyl-3-butyl-1-(4-methoxyphenyl)-pyrolidine-2,5-dione (3A)
Following column chromatography using SiO2 and a mixture of EtOAc and hexane as eluant (50%:50%
by volume) the product eluted as the fastest eluting component. 3A was obtained as a white crystalline
solid (500 mg, 28%). mp 78-80oC (EtOH). IR (KBr) 2960,1701, 1520, 1394, 1248, 1184, 1031, 818 cm-1.

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1H NMR (DMSO-d6), δ 0.90 (3H, t, CH3, J = 7.2), 1.20 (2H, m, CH2, J = 6.8), 1.30 (2H, m, CH2, J = 7.0),
2.00 (2H, m, CH2, J = 6.0), 2.30 (3H, s, CH3), 2.70 (1H, d, CH2, J = 18.4), 3.32 (1H, d, CH2, J = 18.4),
3.80 (3H, s, OCH3), 7.0 (2H, d, 2 x Ar CH, J = 6.5), 7.20 (2H, d, 2 x Ar CH, J = 6.8). 13C NMR
(DMSO-d6), δ 14.0, 26.4, 55.7 (3 x CH3), 22.6, 26.3, 34.5, 35.5 (4 x CH2), 114.5, 128.8 (2 x Ar CH), 61.8,
125.0, 160.0, 175.0, 176.2, 203.3 (6 x qC). Anal. Calcd. for C17H21NO4: C, 67.32; H, 6.93; N, 4.62.
Found: C, 67.29; H, 6.97; N, 4.56. ESMS (MeOH CV +40 V) m/z 326 ([M + Na+]+, 100%).
Synthesis of 3-Acetyl-3-propyl-1-(4-methoxyphenyl)pyrolidine-2,5-dione (3B)
Method A
3-Ethoxycarbonylmethylacetoacetanisidine (5) (1.5 g, 5 mmol) was heated under reflux in acetone (100
mL) with K2CO3 (690 mg, 5 mmol) and iodopropane (850 mg, 5 mmol) for 2 days. The usual work up
followed by column chromatography using SiO2 and a mixture of EtOAc and hexane as eluant (50%:50%
by volume) gave the product (the faster eluting component) as a pale yellow solid (300 mg, 21%.)
Method B
3-Propylacetoacetanisidine (5.1 g, 0.02 mol) was heated overnight under reflux in acetone (250 mL) with
K2CO3 (2.8 g, 0.02 mol) and ethyl bromoacetate (2.2 mL, 0.02 mol). Work up gave an oil which was
purified by chromatography using SiO2 and a mixture of EtOAc and hexane as eluant (50%:50% by
volume) as the second fastest component, yielding a white solid (2.5 g, 43%) mp 96-980C (EtOH). IR
(KBr) 2967, 1703, 1520, 1387, 1253, 1188, 1027, 850 cm-1. 1H NMR (DMSO-d6): δ 0.90 (3H, t, CH3, J
= 7.2), 1.30 (2H, m, CH2, J = 7.6), 2.00 (2H, m, CH2, J = 7.6), 2.30 (3H, s, CH3), 2.70 (1H, d, CH2, J =
18.4), 3.32 (1H, d, CH2, J = 18.4), 3.80 (3H, s, OCH3), 7.00 (2H, d, 2 x Ar CH, J = 6.8), 7.20 (2H, d, 2 x
13
Ar CH, J = 7.0). C NMR (DMSO-d6): δ 14.0, 26.4, 55.7 (3 x CH3), 17.7, 35.5, 36.8 (3 x CH2), 114.5,
128.8 (2 x Ar CH), 61.8, 125.0, 159.4, 175.0, 176.2, 203.3 (6 x qC). Anal. Calcd for C16H19NO4: C,
66.43; H, 6.57; N, 4.84. Found: C, 66.31; H, 6.57; N, 4.76. ESMS (MeCN CV +33 V) m/z 312 ([M +
Na+]+, 100%).
Synthesis of 3-Acetyl-3-benzyl-1-(4-chlorophenyl)pyrolidine-2,5-dione (3C)
The oil was purified by column chromatography using SiO2 and a mixture of EtOAc and hexane as eluant
(50%:50% by volume) to give the product as the faster eluting component yielding a white solid (900 mg
1
13%). mp 105-1080C (EtOH). IR (KBr) 3021, 1717, 1493, 1387, 1177, 1091, 829 cm-1. H NMR
(CDCl3): δ 2.60 (3H, s, CH3), 2.70 (1H, d, CH2, J = 18.4), 3.50 (1H, d, CH2, J = 18.4), 3.00 (1H, d, CH2, J
= 18.4 ), 3.76 (1H, d, CH2, J = 18.4), 6.95 (2H, d, 2 x Ar CH, J = 6.8), 7.25 (2H, d, 2 x Ar CH, J = 6.5),
7.30-7.40 (5H, m, 5 x Ar CH). 13C NMR (CDCl3): δ 27.0 (CH3), 34.7 (CH2), 40.5 (CH2), 128.0, 128.5,

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129.5, 129.8, 130.2 (5 x Ar CH), 63.2, 130.2, 134.4, 135.2, 173.7, 175.3, 202.3 (7 x qC). Anal. Calcd for
C19H16NO3Cl: C, 66.76; H, 4.68; N, 4.10. Found: C, 66.65, H, 4.63, N, 4.0.
ESMS (MeCN CV +36 V)
m/z 364 ([M + Na+]+, 100%).
Synthesis of 3-Acetyl-3-methyl-1-(4-chlorophenyl)pyrolidin-2,5-dione (3D)
The oil purified by column chromatography using SiO2 and a mixture of EtOAc and hexane as eluant
(50%:50% by volume) to give the product as the faster eluting component as a white solid (300 mg, 20%)
1
mp 102-1050C (EtOH). IR (KBr) 2986, 1706, 1495, 1397, 1200, 1091, 875 cm-1. H NMR (CDCl3): δ
1.73 (3H, s, CH3), 2.40 (3H, s, CH3), 2.53 (1H, d, CH2, J = 18.4), 3.60 (1H, d, CH2, J = 18.4), 7.20 (2H,
m, 2 x Ar CH), 7.43 (2H, m, 2 x Ar CH). 13C NMR (CDCl3): δ 22.3 (CH3), 26.5 (CH3), 38.7 (CH2), 57.9,
130.4, 135.0, 174.0, 176.0, 203.0 (6 x qC), 128.0, 130.0 (2 x Ar CH). Anal. Calcd for C13H12NO3Cl: C,
58.75; H, 4.52; N, 5.27. Found: C, 58.60; H, 4.50; N, 5.15 ESMS (MeOH CV +20 V) m/z 274 ([M +
Na+]+, 100%).
Synthesis of 3-Acetyl-3-ethyl-1-(phenyl)pyrolidine-2,5-dione (3E)
White solid (800 mg, 19%) mp 82-850C (EtOH). IR (KBr) 2984, 1707, 1488, 1395, 1187, 1103, 971,
1
864 cm-1. H NMR (CDCl3): δ 1.00 (3H, t, CH3, J = 7.2), 2.20 (2H, m, CH2), 2.50 (3H, s, CH3, J = 6.8),
2.60 (1H, d, CH2, J = 18.8), 3.70 (1H, d, CH2, J = 18.8), 7.20 (2H, m, 2 x Ar CH), 7.40-7.45 (3H, m, 3 x
Ar CH). 13C NMR (CDCl3): δ 9.30, 26.5 (2 x CH3), 29.0, 35.0 (2 x CH2), 63.2, 132.0, 174.5, 175.7, 203.0
(5 x qC), 126.8,129.2, 129.6 (3 x Ar CH) ). Anal. Calcd for C11H15NO3: C, 68.57; H, 6.12; N, 5.71,
Found: C, 68.56; H, 6.17; N, 5.71. ESMS (MeCN CV +30 V) m/z 268 ([M + Na+]+, 100%).
Synthesis of α-Ethoxycarbonylmethyl-4-chloroacetoacetanilide (5B) Y = Cl
Procedure as for 5A21. White solid (2g, 40%), mp 90-920C. (EtOH). IR (KBr) 3306, 2987, 1708, 1602,
1
1539, 1400, 1338, 1202, 1089, 833 cm-1. H NMR (CDCl3): δ 1.27 (3H, m, CH3, J = 7.4), 2.30 (3H, s,
CH3), 3.00 (2H, m, CH2, J = 8.0), 3.90 (1H, t, CH, J = 6.8), 4.15 (2H, q, CH2, J = 7.2), 7.25 (2H, d, 2 x Ar
CH, J = 7.0), 7.44 (2H, d, 2 x Ar CH, J = 6.8), 8.71 (1H, s, NH). 13C NMR (DMSO-d6): δ 14.5, 29.3, (2 x
CH3), 33.5, 62,0 (2 x CH2), 57.7 (CH), 121.6, 129.4 (2 x Ar CH), 130.2, 136.5, 166.0, 172.5, 204.8 (5 x
qC).
Anal. Calcd for C14H16NO4Cl: C, 56.47; H, 5.38; N, 4.70, Found: C, 56.50; H, 5.25; N, 4.61.
ESMS (MeCN CV +30 V) m/z 320 ([M + Na+]+, 100%).
Synthesis of 3-Acetyl-3-ethyl-5-imino-1-phenyl-pyrrolidin-2-one (7)
3-Ethylacetoacetanilide (6) (3.5 g, 17 mmol) was heated under reflux in acetone (150 mL) with NaH
(60% dispersion, 1g, 25 mmol) and chloroacetonitrile (1.6 mL, 25 mmol) for 16 h. The reaction was

HETEROCYCLES, Vol. 68, No. 3, 2006
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filtered and the filtrate was then concentrated to an oil and purified by column chromatography using
SiO2 and a mixture of EtOAc and hexane as eluant (50%:50% by volume) to give the product as the
slowest running component along with unreacted material. 7 (920 mg, 22%). mp 100-1150C.(EtOH). IR
(KBr) 3292 (s), 2974, 1706, 1653, 1498, 1416, 1208 1132 cm-1. 1H NMR (CDCl3): δ 1.1 (3H, t, CH3, J =
7.2), 2.20 (2H, m, CH2, J = 7.2), 2.50 (3H, s, CH3), 2.6 (1H, d, CH2, J = 18.8), 3.7 (1H, d, CH2, J =
18.8), 7.2 (2H, m, 2 x Ar CH), 7.4-7.45 (3H, m, 3 x Ar CH). 13C NMR (CDCl3): δ 9.30, 26.5 (2 x CH3),
29.0, 33.6 (2 x CH2), 63.3, 126.8, 132.0, 132.6, 174.5, 203.7 (5 x qC), 127.8,129.5, 130.1 (3 x Ar CH).
Anal. Calcd for C14H16N2O3: C, 68.85; H, 6.55; N, 11.47, Found: C; 68.69, H; 6.61, N; 10.71. ESMS
(MeCN CV +30 V) m/z 267 ([M + Na+]+, 100%).
ACKNOWLEDGEMENTS
This research was supported by the National Institute for Cellular Biotechnology under the Programme
for Research in Third Level Institutions (PRTLI, round 3, 2001–2006).
REFERENCES
1. C. A. Downey, J. Lawler, J. P. James, P. O’Malley, and S. Wolfe, J. Chem. Soc., Chem.
Commun., 1992, 454.
2. (a) W. C. Groutas, M. J. Brubaker, L. S. Chong, R. Venkataraman, H. Huang, J. B. Epp, R. Kuang,
and J. R. Hoidal, Bioorg. Med. Chem., 1995, 3, 375; (b) M. L. Curtin, R. B. Garland, H. R.
Heyman, R. R. Frey, M. R. Michaelides, J. Li, L. J. Pease, K. B. Glaser, P. A. Marcotte, and S. K.
Davidsen, Bioorg. Med. Chem. Lett., 2002, 12, 2919.
3. (a) The Organic Chemistry of Drug Synthesis, Vol 1. p. 227. (b) M. Park, J. Lee, and J. Choi,
Bioorg. Med. Chem. Lett., 1996, 6, 1297 (c) R. L. Hudkins, D. L. DeHaven-Hudkins, and P. Doukas,
Bioorg. Med. Chem. Lett., 1997, 7, 979.
4. J. Obniska and A. Zagorska, Farmaco, 2003, 58, 1227.
5. B. Malawska, Curr. Top. Med. Chem., 2005, 5, 69.
6. (a) M. Montembault, G. Vo-Thanh, A. Deyine, V. Fargeas, M. Villiéras, A. Adjou, D. Dubreuil, D.
Esquieu, C. Grégoire, S. Opi, J-M. Pelopenese, G. Campbell, J. Watkins, J. deMareuil, |A-M.
Aubertin, C. Bailly, E. Loret, and J. Lebreton, Bioorg. Med. Chem. Lett., 2004, 14, 1543.
(b) A. D. Abell and M. D. Oldham, J. Org. Chem., 1997, 62, 1509.
7. M. Pawlowski, G. Chlon, J. Obniska, A. Zejc, S. Cgarakchieva-Minol, and M. J. Mokrosz,
Farmaco, 2000, 55, 461.

474
HETEROCYCLES, Vol. 68, No. 3, 2006
8.
9.
I. Yavari and A. Habibi, Pol. J. Chem., 2004, 78, 71 (and refs cited therein).
I. Yavari and A. Habibi, Synthesis, 2004, 989.
10. I. Furukawa, T. Abe, H. Fujisawa, and T. Ohta, Tetrahedron, 1997, 53, 17643.
11. A. Foucaud and G. Barret, Tetrahedron Lett., 1968, 1075.
12. G. Barret and A. Foucaud, Bull. Soc. Chim. Fr., 1968, 11, 4594.
13. A. Foucaud and G. Barret, Bull. Soc. Chim. Fr., 1969, 8, 2836.
14. D. H. R. Barton and W. Liu, J. Chem. Soc., Chem. Commun., 1997, 571.
15. T. R. Abbas, J. I. G. Cadogan, A. A. Doyle, I. Gosney, P. K. G. Hodgson, G. E. Howells, A. N.
Hulme, S. Parsons, and I. H. Sadler, Tetrahedron Lett., 1997, 38, 4917.
16. T. Kato, U. Izumi, and N. Katagiri, J. Heterocycl. Chem., 1978, 15, 1475.
17. S. Ahmed, R. Lofthouse, and G. Shaw, J. Chem. Soc., Perkin Trans. 1, 1976, 1969.
18. M. Yogo, K. Hirota, and S. Senda, J. Chem. Soc., Perkin Trans. 1, 1982, 473.
19. K. Hirota and S. Senda, J. Heterocycl. Chem., 1981, 18, 1095.
20. E. Testa, L. Fontanella, G. Cristiani, and G. Gallo, J. Org. Chem., 1959, 24, 1928.
21. P. S. Raman and M. A. Ashrof, Current Science, 1979, 48, 583.