Transformation of a spirobarbituric acid via aminobarbituric acid-hydantoin rearrangement

Article abstract of DOI:10.1002/jhet.5570430346

A successful application of the aminobarbituric acid-hydantoin rearrangement to produce a bicyclic carbamoylhydantoin from an intermediate spirobarbituric acid is reported. 7a-Phenylcarbamoyl-tetrahydro-1H-pyrrolo[1,2- c]imidazole-1,3(2H)-dione (8) was obtained in a one-pot multistep reaction of 1-acetyl-2,2-bis(ethoxycarbonyl)pyrrolidine (5) and phenylurea in the presence of sodium ethoxide. Under less severe conditions, 5 and phenylurea were reacted to afford 1-acetyl-7-phenyl-triaza[4,5]decane-6,8,10-trione (6). The structural elucidation of the bicyclic hydantoin 8 and the spirobarbituric acid 6 was based on relevant nmr signals in accordance with those of reference compounds, i.e. monocyclic hydantoins 4a,b and acetamidobarbituric acids 2a-c. The latter compounds were newly prepared from diethyl acetamidomalonates 1 and phenylurea.

Full text of DOI:10.1002/jhet.5570430346

May-Jun 2006
807
Transformation of a Spirobarbituric Acid
via Aminobarbituric Acid-Hydantoin Rearrangement
Agnieszka Ambroꢀak and Michael Gütschow*
Pharmaceutical Institute, Poppelsdorf, University of Bonn, Kreuzbergweg 26, D-53115 Bonn, Germany
Received September 17, 2005
NaOEt in EtOH
0.24 M, 1.2 equiv),
8 °C, 5 h
O
(
7
Ph
O
N
N
N
O
O
O
Me
N
H
Ph
O
OEt
N
HN
+
O
NaOEt in EtOH
(1.3 M, 4 equiv),
O
O
OEt
H
2
N
Ph
Me
N
H
120 °C, 8 h
O
N
H
O
A successful application of the aminobarbituric acid-hydantoin rearrangement to produce a bicyclic
carbamoylhydantoin from an intermediate spirobarbituric acid is reported. 7a-Phenylcarbamoyl-
tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione (8) was obtained in a one-pot multistep reaction of
1
-acetyl-2,2-bis(ethoxycarbonyl)pyrrolidine (5) and phenylurea in the presence of sodium ethoxide. Under
less severe conditions, 5 and phenylurea were reacted to afford 1-acetyl-7-phenyl-triaza[4,5]decane-6,8,10-
trione (6). The structural elucidation of the bicyclic hydantoin 8 and the spirobarbituric acid 6 was based
on relevant nmr signals in accordance with those of reference compounds, i.e. monocyclic hydantoins 4a,b
and acetamidobarbituric acids 2a-c. The latter compounds were newly prepared from diethyl
acetamidomalonates 1 and phenylurea.
J. Heterocyclic Chem., 43, 807 (2006).
Hydantoins have been the subject of considerable
interest in drug discovery because of their wide range of
biological activities. With four possible points of
diversity, this heterocyclic structure represents
of the amino group at the intermediate isocyanate [3,4].
Compared to alkyl ureas, the reaction of aryl ureas with 1
gives rise to the rearrangement to hydantoins under less
rigorous conditions [3,4]. Therefore, the synthesis of 1-
phenyl acetamidobarbituric acids 2 is not so straight-
forward. In order to prepare both 2, as well as 4-phenyl-
carbamoyl hydantoins 4, we have studied the reaction of
three diethyl acetamidomalonates (1a-c) with phenylurea.
Moreover, the application of these reactions to the
pyrrolidine substrate 5 (Scheme 2) was investigated.
The synthesis of the 5-ethyl hydantoin 4b (Scheme 1)
was carried out according to the described method [4] in
the presence of sodium ethoxide in ethanol in a sealed
tube at 120 °C. Next it was examined whether ethanol
could be replaced by higher-boiling 1-butanol and thus
sodium ethoxide by butoxide to allow for a reaction
process in an open vessel. This was indeed the case, and
4a was obtained from 1a by this method. Both 4a and 4b
were then used as reference compounds to investigate the
reactions of phenylurea with alkylated diethyl acetamido-
malonates 1a and 1b under less severe conditions.
Product mixtures were obtained which contained the
corresponding hydantoins 4a and 4b, respectively,
besides the desired acetamidobarbituric acids 2a and 2b,
respectively, and the latter compounds could be isolated.
The purification of 2a and 2b was achieved by single
recrystallizations from ethanol. The new 2-acetamido-1-
a
significant molecular scaffold in combinatorial chemistry;
see [1] for a review and [2] for some recent publications
on hydantoin chemistry. In a previous report, we have
described the aminobarbituric acid-hydantoin rearrange-
ment as an attractive synthetic entry to tri- and tetra-
substituted 5-carbamoylhydantoins [3]. 1,5-Disubstituted
barbituric acids with an additional amino group at
position 5 undergo a base-catalyzed ring contraction to
afford 5-carbamoylhydantoins in which the substituent at
the carbamoyl moiety originates from the 1-substituent at
the nitrogen of the parent barbituric acid. A special case
of the rearrangement comprises the conversion of
barbituric acids with an unsubstituted 5-amino group (e.g.
3
) to 5,5-disubstituted hydantoins with two unsubstituted
ring nitrogens (e.g. 4, Scheme 1). Barbituric acids with a
-NH substituent (e.g. 3) could either be prepared by a
5
2
route via corresponding 5-azido derivatives [4,5], or
formed as intermediates of the one-pot synthesis using
substituted diethyl acetamidomalonates (1) and ureas as
starting materials [4]. The latter transformation includes
the cyclocondensation to 5-acetamidobarbituric acids (e.g.
2
), deacetylation, deprotonation at the ring nitrogen, ring
opening and recyclization due to the nucleophilic attack

8
08
A. Ambroꢀak and M. Gütschow
Vol 43
Scheme 1
O
O
NaOEt in EtOH (0.24 M, 1.2 equiv),
8 °C, 3-7 h
R
Ph
O
7
Me
N
N
H
O
4
N
H
2
2a-c
O
O
R
Ph
O
Me
N
OEt
HN
H N
H
+
O
OEt
NaOEt in EtOH (0.8 M, 4 equiv),
20 °C, 5 h; ref [3]
or
2
1
1a-c
O
O
NaOBu in BuOH (0.8 M, 4 equiv),
reflux, 5 h
R
R
Ph
O
Ph
N
N
NH
H
2
N
H
2
a: R = Me
b: R = Et
c: R = H
O
N
H
O
4
N
H
2
O
3
4a,b
phenylbarbituric acid (2c) was similarly prepared from 1c
and phenylurea. However, our attempts to synthesize a
corresponding hydantoin with a 5-phenylcarbamoyl rest
as the only substituent failed.
8, can be envisaged as a result of an undesired
decarbamoylation of 8, either through direct attack of the
nucleophile ethoxide or through the repulsion of phenyl
isocyanate via an E1cB mechanism and subsequent
reaction with ethoxide.
The proline-derived diester 5 [6,7] (Scheme 2) was
prepared from 1c (Scheme 1) and 1,3-dibromopropane
with benzyltriethylammonium chloride as phase transfer
catalyst [7]. The utilization of 5 as the substrate of the
aforementioned conversions let us anticipate interesting
products. Actually, the spirobarbituric acid 6 was ob-
tained from 5 and phenylurea (Scheme 2). Some other
spirobarbituric acids with a dihydropyrrole [8] or a pyrrol-
idinone unit [9] are known. In N(1), N(3)-unsubstituted
barbituric acids, the spiro-connected pyrrolidinone moiety
was recently designed as a constrained linker structure to
facilitate inhibition of matrix metalloproteinases [10].
The formation of
8 involves ring closure and
deacetylation of the 'protected' aminobarbituric acid 6.
The key step to 8 is the ring-opening/recyclization of the
intermediate spiro compound 7, thus the transformation of
the spiro-connected five-membered cycle to an anellated
ring.
Several features in the nmr spectra for 6 and 8 allowed
for their structural elucidation and were in accordance
with the monocyclic analogues 2 and 4, respectively. In
1
3
the C nmr spectra of barbituric acids 2 and 6 the first
carbonyl resonance appeared at 149-152 ppm (urea CO),
Scheme 2
O
2
Ph
O
NaOEt in EtOH (0.24 M, 1.2 equiv),
1
N
6
N
78 °C, 5 h
O
O
Me
N
H
8
6
O
1
Ph
O
OEt
N
2
HN
+
O
O
Me
OEt
2
H N
5
O
O
NaOEt in EtOH (1.3 M, 4 equiv),
20 °C, 8 h
Ph
O
Ph
1
N
N
H
N
HN
6
O
N
H
1 N
3
O O
H
7
8
1
3
When 5 and phenylurea were reacted under more
rigorous conditions the bicyclic hydantoin 8 was directly
attained. The product 8 was accompanied by ethyl N-
phenylcarbamate. Its formation, and thus the low yield of
and the C nmr shifts of the other three carbonyl carbons
occurred close together at 167-171 ppm. In contrast, the
1
3
C nmr spectra of carbamoyl hydantoins 4 and 8 showed
three distinct carbonyl signals at 156-161 ppm (urea CO),

May-Jun 2006
Transformation of a Spirobarbituric Acid
809
1
64-166 ppm (carbamoyl CO), and 171-174 ppm.
1.2 equivalents). The mixture was refluxed for 3 hours and
evaporated under reduced pressure. The yellow oily residue was
dissolved in water (120 ml) and acidified to pH 2-3 by dropwise
addition of cold 2 M hydrochloric acid. After cooling for 2 days at
Expectedly, the nmr shifts of the phenyl protons depended
on its position either at an imide (in 2 and 6) or amide
nitrogen (in 4 and 8). In the latter case, the signals
appeared apart from each other at 7.1-7.2 ppm (H-4'), 7.3
ppm (H-3'), and 7.6-7.7 ppm (H-2'). The C nmr spectra
of 2 and 6 exhibited signals for the phenyl carbons at 129
ppm (C-4'), 129-130 ppm (C-2', C-3'), and 135 ppm (C-
5
°C, the crude product precipitated as a mixture of 5-methyl-5-
phenylcarbamoylhydantoin (4a) and 5-acetamido-5-methyl-1-
1
3
1
phenylbarbituric acid (2a) as it was confirmed by spectral data ( H
13
nmr, C nmr) and thin-layer chromatography. Recrystallization
from ethanol yielded 3.54 g (32 %) of 2a as white crystals, mp >
1
1
3
2
50 °C (dec.); H nmr (DMSO-d , 500 MHz): ꢀ 1.65 (s, 3H, 5-
1
'). The pattern of the corresponding C nmr signals in
6
CH ), 1.86 (s, 3H, COCH ), 7.18-7.21 (m, 2H, H-2'), 7.38-7.49
3
3
the case of 4 and 8 was clearly different with four distinct
signals at 121 ppm (C-2'), 124 ppm (C-4'), 129 ppm (C-
3
(
m, 3H, H-3', H-4'), 9.20 (s, 1H, NHCOCH ), 11.73 (s, 1H, NH);
3
13
C nmr (DMSO-d , 125 MHz): ꢀ 21.24 (COCH ), 22.33 (CH ),
6
3
3
'), and 138 ppm (C-3).
In summary, we have examined the ethoxide-promoted
5
1
9.05 (C-5), 128.69 (C-4'), 128.88, 129.10 (C-2', C-3'), 135.01 (C-
'), 149.72 (C-2), 170.29, 170.31, 170.98 (C-4, C-6, COCH ); ms:
3
+
+
+
formation of 8 from 5 and phenylurea in the course of a
one-pot multistep reaction. This is the first example of
the aminobarbituric acid-hydantoin rearrangement in
which a cyclic secondary amine (in structure 7) served as
the nucleophile for the intramolecular trapping of a
postulated intermediate isocyanate. As a consequence,
the nitrogen of the attacking amino group becomes the
bridgehead nitrogen of the newly formed anellated
m/z 275 (95 %, M ), 233 (10 %, M – CH CO), 114 (82 %, M –
CH2CO – C6H5NCO), 93 (100 %, C6H7N ).
2
+
Anal. Calcd. for C H N O : C, 56.73; H, 4.76; N, 15.27.
13 13
3 4
Found: C, 56.61; H, 5.06; N, 14.94.
5-Acetamido-5-ethyl-1-phenylbarbituric Acid (2b).
Diethyl 2-acetamido-2-ethylmalonate (19.62 g, 80 mmoles)
and phenylurea (10.90 g, 80 mmoles) were added to a 0.24 M
solution of sodium ethoxide in anhydrous ethanol (200 ml, 1.2
equivalents). The mixture was refluxed for 3 hours and
evaporated in vacuo. The yellow oily residue was dissolved in
water (150 ml) and acidified to pH 2-3 by dropwise addition of
cold 2 M hydrochloric acid. After cooling overnight at 5 °C, the
precipitate was isolated by filtration and dried. The crude
product was identified as a mixture of 5-ethyl-5-phenylcarba-
moylhydantoin (4b) and 5-acetamido-5-ethyl-1-phenylbarbituric
acid (2b) by means of nmr and thin-layer chromatography. It
hydantoin (structure 8).
Bicyclic hydantoins have
attracted much attention in medicinal chemistry and
organic synthesis particularly in the preparation of
hydantoin-containing polycyclic scaffolds using solid-
phase methods [1,11]. Several derivatives of the tetra-
hydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione system
have been described. Compound 8, however, is the first
example of a 7a-carbamoyl-substituted derivative of that
system.
was recrystallized from ethanol to give 10.30 g (45 %) of 2b as
1
white crystals, mp > 250 °C (dec.); H nmr (DMSO-d6, 500
MHz): ꢀ 0.97 (t, 3H, J = 7.53 Hz, CH CH ), 1.87 (s, 3H,
2
3
COCH ), 2.02 (q, 2H, J = 7.53 Hz, CH ), 7.14-7.17 (m, 2H, H-
3
2
2
1
'), 7.39-7.50 (m, 3H, H-3', H-4'), 9.11 (s, 1H, NHCOCH ),
3
1
3
EXPERIMENTAL
1.83 (s, 1H, NH); C nmr (DMSO-d , 125 MHz): ꢀ 7.83
6
(
CH CH ), 21.24 (COCH ), 29.71 (CH CH ), 63.10 (C-5),
2 3 3 2 3
Melting points were obtained on a Rapido Boetius apparatus
and are uncorrected. H nmr spectra were recorded on a Bruker
128.74 (C-4'), 129.22, 129.76 (C-2', C-3'), 134.90 (C-1'), 149.86
1
(C-2), 169.65, 170.28, 170.42 (C-4, C-6, COCH ); ms: m/z 289
3
+
+
Avance (500 MHz) or on a Varian Gemini 300 instrument (300
(50 %, M ), 127 (29 %, M – CH CO – C H NCO), 119 (72 %,
3 6 5
1
3
+
+
MHz). C nmr spectra were recorded on a Bruker Avance (125
MHz) or on a Varian Gemini 300 (75 MHz) instrument. Mass
spectra (EI, 70 eV) were measured on a MS-50 A.E.I.
spectrometer. Thin-layer chromatography was carried out using
aluminum sheets coated with silica gel 60 F254 (Merck).
Chromatograms were detected by UV fluorescence and
visualized with FeCl3 (in 0.5 M hydrochloric acid), or
anisaldehyde / ethanol / acetic acid / concentrated sulfuric acid
C H NCO ), 93 (100 %, C H N ).
6 5 6 7
Anal. Calcd. for C H N O : C, 58.13; H, 5.23; N, 14.53.
1
4 15 3 4
Found: C, 58.05; H, 5.27; N, 14.51.
5
-Acetamido-1-phenylbarbituric Acid (2c).
Diethyl acetamidomalonate 1c (8.68 g, 40 mmoles) and
phenylurea (5.45 g, 40 mmoles) were added to a 0.24 M solution
of sodium ethoxide in anhydrous ethanol (200 ml, 1.2
equivalents). The mixture was refluxed for 7 hours meanwhile a
white precipitate was formed. The mixture was cooled, diluted
with ice-water (50 ml), and the solution was acidified with 6 M
hydrochloric acid. The precipitate was separated by suction
(
1:50:20:2) followed by heating, or iodine / potassium iodide (in
ethanol/ water 1:10) and 2 M hydrochloric acid. Column
chromatography was performed with silica gel 60 G (Merck),
and fractions were analyzed by thin-layer chromatography using
the same solvent. Alkylation of diethyl acetamidomalonate was
carried out according to standard procedures [12].
filtration, washed with water and recrystallized from acetic acid
1
to obtain 8.4 g (80 %) of 2c, mp 252-256 °C; H nmr (DMSO-
d , 300 MHz): ꢀ 1.94 (s, 3H, CH ), 5.25 (d, 1H, J = 6.5 Hz, H-
6
3
5
-Acetamido-5-methyl-1-phenylbarbituric Acid (2a).
5
), 7.19-7.25 (m, 2H, H-2'), 7.43-7.53 (m, 3H, H-3', H-4'), 9.01
1
3
Diethyl 2-acetamido-2-methyl-malonate 1a (9.25 g, 40
(d, 1H, J = 6.5 Hz, NHCOCH ), 11.75 (s, 1H, NH); C nmr
3
mmoles) and phenylurea (5.45 g, 40 mmoles) were added to a
.24 M solution of sodium ethoxide in anhydrous ethanol (200 ml,
(DMSO-d , 75 MHz): ꢀ 22.24 (CH ), 55.66 (C-5), 129.20 (C-
4'), 129.44, 129.70 (C-2', C-3'), 135.69 (C-1'), 151.10 (C-2),
6
3
0

8
10
A. Ambroꢀak and M. Gütschow
Vol 43
1
67.22, 167.72, 170.83 (C-4, C-6, COCH ); ms: m/z 261 (58 %,
(COCH3), 24.16 (C-4), 36.26 (C-3), 48.26 (C-5), 61.97
(CH CH ), 72.30 (C-2), 168.69 (CO-O), 169.22 (CO-N); ms:
3
+
+
+
M ), 219 (100 %, M – CH CO), 119 (17 %, C H NCO ), 93
2
6
5
2
3
+
+
+
+
(17 %, C H N ).
m/z 257 (2 %, M ), 185 (10 %, M – C H O ), 142 (35 %, M -
6
7
3 4 2
+
Anal. Calcd. for C H N O ꢀ 0.1 H O: C, 54.79; H, 4.29;
C H O – CH CO), 112 (42 %, M – C H O ), 70 (100 %,
1
2
11
3
4
2
3 4 2 3 6 7 4
+
N, 15.98. Found: C, 54.76; H, 4.48; N, 15.70.
C H N ).
4 8
5
-Methyl-5-phenylcarbamoylhydantoin (4a).
1-Acetyl-7-phenyl-triaza[4,5]decane-6,8,10-trione (6).
1-Acetyl-2,2-bis(ethoxycarbonyl)pyrrolidine 5 (1.54 g,
Diethyl 2-acetamido-2-methylmalonate 1a (9.25 g, 40
6
mmoles) and phenylurea (5.45 g, 40 mmoles) were added to a
solution of sodium (3.7 g, 160 mmol, 4 equivalents) in
anhydrous butanol (200 ml). The mixture was refluxed for 5
hours under an argon atmosphere. Most of the solvent was
removed under reduced pressure. Water (80 ml) was added, the
mixture was stirred for 2 minutes, and kept at room temperature
for 30 min. The organic layer was removed, and the aqueous
phase was extracted with ethyl acetate (3 ꢀ 20 ml) and then
acidified with 2 M hydrochloric acid. The precipitate was
mmoles) and phenylurea (0.82 g, 6 mmoles) were added to a
0.24 M solution of sodium ethoxide in anhydrous ethanol (30
ml, 1.2 equivalents). The mixture was refluxed for 5 hours.
Water (25 ml) was added to the resulting suspension, followed
by filtration. The filtrate was acidified to pH 1-3 by dropwise
addition of cold 2 M hydrochloric acid. The crude product was
isolated by extraction of the aqueous solution with ethyl acetate
(5 ꢀ 15 ml). The combined organic layers were dried (sodium
sulfate) and evaporated to dryness. The crude product was
collected by filtration and dried to give of 2.9 g (31 %) of 4a,
mp 159-162 °C (ethanol), ref 154-156 °C [4]; H nmr (DMSO-
recrystallized from ethanol to yield 180 mg (10 %) of the
spirobarbituric acid 6 as white crystals, mp 234-236 °C; H nmr
1
1
d , 500 MHz): ꢁ 1.61 (s, 3H, CH ), 7.11-7.17 (m, 1H, H-4'),
(DMSO-d , 500 MHz): ꢁ 2.01 (s, 3H, CH ), 2.08-2.16 (m, 2H,
6
3
6
3
7
.30-7.38 (m, 2H, H-3'), 7.64-7.68 (m, 2H, H-2'), 8.38 (s, 1H,
H-3), 2.32-2.47 (m, 2H, H-4), 3.74 (t, 2H, J = 6.7 Hz, H-2),
7.40-7.48 (m, 5H, phenyl), 11.84 (s, 1H, NH); C nmr (DMSO-
1
3
13
PhNH), 9.76, 10.95 (each s, total 2H, NH); C nmr (DMSO-d6,
25 MHz): ꢁ 21.67 (CH ), 66.63 (C-5), 120.82 (C-2'), 124.26
1
d , 125 MHz): ꢁ 21.52 (CH ), 24.93 (C-3), 37.54 (C-4), 48.71
3
6
3
(
C-4'), 128.67 (C-3'), 138.32 (C-1'), 156.87 (C-2), 165.62
(C-2), 67.93 (C-5), 128.77 (C-4'), 128.92, 129.16 (C-2', C-3'),
134.90 (C-1'), 149.96 (C-8), 168.78, 169.95, 170.42 (C-6, C-10,
(CONHPh), 173.74 (C-4).
+
+
COCH ); ms: m/z 301 (100 %, M ), 258 (58 %, M – CH CO),
3
3
5
-Ethyl-5-phenylcarbamoylhydantoin (4b) [4].
+
1
39 (16 %, M – CH CO – C H NCO), 119 (24 %,
3 6 5
+
+
Diethyl 2-acetamido-2-ethylmalonate 1b (0.98 g, 4 mmoles)
C H NCO ), 93 (25 %, C H N ).
6 5 6 7
and phenylurea (0.55 g, 4 mmoles) were added to a 0.8 M
solution of sodium ethoxide in anhydrous ethanol (20 ml, 4
equivalents). The mixture was stirred in a sealed tube at 120 °C
for 5 hours under an argon atmosphere. The yellow suspension
was evaporated to dryness. The oily residue was dissolved in
water (20 ml), and charcoal and silica gel were added to the
solution. After stirring for 5 minutes and filtration, the filtrate
was acidified to pH 2-3 by dropwise addition of cold 2 M
hydrochloric acid. After cooling overnight, the crude product
Anal. Calcd. for C H N O ꢀ 0.2 H O: C, 59.09; H, 5.09;
15 15 3 4 2
N, 13.78. Found: C, 59.04; H, 5.30; N, 13.41.
7
1
a-Phenylcarbamoyl-tetrahydro-1H-pyrrolo[1,2-c]imidazole-
,3(2H)-dione (8).
1-Acetyl-2,2-bis(ethoxycarbonyl)pyrrolidine 5 (1.54 g,
6
mmoles) and phenylurea (0.82 g, 6 mmoles) were added to a 1.3
M solution of sodium ethoxide in anhydrous ethanol (18.5 ml, 4
equivalents). The mixture was stirred in a sealed tube at 120 °C
for 8 hours under an argon atmosphere. The solution was
evaporated to dryness. A small amount of water was added, and
insoluble material was removed by filtration. The filtrate was
acidified to pH 2-3 by dropwise addition of cold 2 M
hydrochloric acid, and the solution was extracted with ethyl
acetate (5 ꢀ 20 ml). The combined organic layers were dried
(sodium sulfate) and the solvent was removed under reduced
pressure. The oily residue was purified by column chromatog-
raphy (eluent, dichloromethane/ethyl acetate 1:4). Ethyl N-
was collected by filtration to give 0.42 g (42 %) of 4b as
1
colorless crystals; H nmr (DMSO-d , 500 MHz): ꢁ 0.83 (t, 3H,
6
J = 7.35 Hz, CH CH ), 1.97-2.13 (m, 2H, CH CH ), 7.06-7.11
2
3
2
3
(
8
m, 1H, H-4'), 7.28-7.33 (m, 2H, H-3'), 7.61-7.63 (m, 2H, H-2'),
.37 (s, 1H, PhNH), 9.64, 10.93 (each s, total 2H, NH); C nmr
1
3
(
DMSO-d , 125 MHz): ꢁ 7.71 (CH CH ), 27.69 (CH CH ),
6 2 3 2 3
7
0.87 (C-5), 120.83 (C-2'), 124.28 (C-4'), 128.67 (C-3'), 138.23
(C-1'), 157.10 (C-2), 165.02 (CONHPh), 173.87 (C-4).
1
-Acetyl-2,2-bis(ethoxycarbonyl)pyrrolidine (5).
phenylcarbamate was isolated as the fastest leaving fraction (220
1
A mixture of diethyl acetamidomalonate 1c (8.68 g, 40
mg, retention factor 0.84, yellow oil); H nmr (DMSO-d , 500
6
mmoles), 1,3-dibromopropane (16.15 g, 8.12 mL, 80 mmoles),
potassium carbonate (5.53 g, 40 mmoles) and
MHz): ꢁ 1.23 (t, 3H, J = 7.1 Hz, CH ), 4.11 (q, 2H, J = 7.1 Hz,
3
CH ), 6.94-6.98 (m, 1H, H-4'), 7.23-7.27 (m, 2H, H-3'), 7.44-
2
1
3
benzyltriethylammonium chloride (300 mg) in anhydrous
acetonitrile (30 ml) was stirred at reflux for 14 hours. The
resulting suspension was filtrated, and the solvent was removed
under reduced pressure to provide a yellow oily residue. The
crude product was purified by column chromatography (eluent,
7.45 (m, 2H, H-2'), 9.54 (s, 1H, NH); C nmr (DMSO-d , 125
6
MHz): ꢁ 14.64 (CH ), 60.20 (CH ), 118.32 (C-2'), 122.39 (C-4'),
3
2
128.81 (C-3'), 139.37 (C-1'), 153.68 (CO). Compound 8 (60
mg, retention factor 0.65, yellow oil) was obtained in 4 % yield;
1
H nmr (DMSO-d , 500 MHz): ꢁ 1.87-2.06 (m, 2H, H-6), 2.60-
6
dichloromethane/ethyl acetate 1:2 to 1:4) to afford 5.37 g (52 %)
of 5 as an yellow oil; H nmr (deuteriochloroform, 500 MHz): ꢁ
2.64 (m, 1H, H-7), 3.15-3.19 (m, 1H, H-7), 3.57-4.13 (m, 2H, H-
5), 7.07-7.10 (m, 1H, H-4'), 7.29-7.31 (m, 2H, H-3'), 7.64-7.66
1
1
3
1
.26 (t, 6H, J = 0.83 Hz, CH CH ), 1.92-1.99 (m, 2H, 4-H), 2.07
(m, 2H, H-2'), 9.91 (s, 1H, NH); C nmr (DMSO-d , 125
2
3
6
(
6
s, 3H, COCH ), 2.45 (t, 2H, J = 7.1 Hz, H-3), 3.61 (t, 2H, J =
MHz): ꢁ 26.12 (C-6), 30.94 (C-7), 45.25 (C-5), 77.29 (C-7a),
120.72 (C-2'), 124.31 (C-4'), 128.65 (C-3'), 138.27 (C-1'),
160.58 (C-3), 164.64 (CONHPh), 171.78 (C-1).
3
1
3
.9 Hz, H-5), 4.16-4.28 (m, 4H, CH CH );
C nmr
2
3
(deuteriochloroform, 125 MHz): ꢁ 13.96 (CH CH ), 22.40
2 3

May-Jun 2006
Transformation of a Spirobarbituric Acid
811
Acknowledgement.
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(