Facile access to 3-alkyl-substituted 3-hydroperoxy-2,4-pyrrolidinediones using manganese(III)-catalyzed aerobic oxidation

Article abstract of DOI:10.1080/00397911.2010.528129

3-Alkyl-substituted 2,4-pyrrolidinediones were directly oxidized under very mild manganese(III)-catalyzed aerobic oxidation conditions to give the corresponding 3-hydroperoxy-2,4-pyrrolidinediones in quantitative yields. The scope and limitations for the

Full text of DOI:10.1080/00397911.2010.528129

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Facile Access to 3-Alkyl-Substituted
3-Hydroperoxy-2,4-pyrrolidinediones
Using Manganese(III)-Catalyzed Aerobic
Oxidation
M. Aminul Haque a & Hiroshi Nishino a
a Department of Chemistry, Graduate School of Science and
Technology, Kumamoto University, Kumamoto, Japan
Accepted author version posted online: 10 Aug 2011.Version of
record first published: 17 Oct 2011.
To cite this article: M. Aminul Haque & Hiroshi Nishino (2012): Facile Access to 3-Alkyl-Substituted
3-Hydroperoxy-2,4-pyrrolidinediones Using Manganese(III)-Catalyzed Aerobic Oxidation, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
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Synthetic Communications1, 42: 608–619, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.528129
FACILE ACCESS TO 3-ALKYL-SUBSTITUTED
3-HYDROPEROXY-2,4-PYRROLIDINEDIONES USING
MANGANESE(III)-CATALYZED AEROBIC OXIDATION
M. Aminul Haque and Hiroshi Nishino
Department of Chemistry, Graduate School of Science and Technology,
Kumamoto University, Kumamoto, Japan
GRAPHICAL ABSTRACT
Abstract 3-Alkyl-substituted 2,4-pyrrolidinediones were directly oxidized under very
mild manganese(III)-catalyzed aerobic oxidation conditions to give the corresponding
3-hydroperoxy-2,4-pyrrolidinediones in quantitative yields. The scope and limitations for
the synthesis of the hydroperoxyprrolidinediones are described.
Keywords Aerobic oxidation; catalytic oxidation; hydroperoxidation; hydroperoxypyr-
rolidinediones; manganese(III) acetate; 2,4-pyrrolidinediones
INTRODUCTION
Hydroperoxides are known as the first intermediate for the oxidative decompo-
sition of unsaturated higher fatty acids in vivo, are normally unstable, and thus are
successively oxidized into degradation products.[1] Some heterocyclic hydroperoxides
function as antitumor,[2] antimalarial,[3] antibiotic,[4] antibacterial,[4] and anti-
inflammatory agents.[5] Therefore, the synthesis of new heterocyclic hydroperoxides
is important from the viewpoint of determining their activities, even though they
may be unstable. We previously reported that the manganese(III)-catalyzed oxidation
of 4-monosubstituted 1,2-diphenylpyrazolidine-3,5-diones gave the corresponding
4-hydroperoxypyrazolidinediones (Scheme 1).[6a] Because the reaction is quite simple
and convenient for the synthesis of hydroperoxides, we attempted to apply the hydro-
peroxidation to 3-alkyl-substituted 2,4-pyrrolidinediones to synthesize new types of
heterocyclic hydroperoxides.
Received August 19, 2010.
Address correspondence to H. Nishino, Department of Chemistry, Graduate School of Science and
Technology, Kumamoto University, Kurokami 2-39-1, Kumamoto 860-8555, Japan. E-mail: nishino@
sci.kumamoto-u.ac.jp
608

3-HYDROPEROXY-2,4-PYRROLIDINEDIONES
609
Scheme 1. Manganese(III)-catalyzed direct hydroperoxidation of pyrazolidinediones.
RESULTS AND DISCUSSION
3-Alkyl-substituted 2,4-pyrrolidinediones were prepared by the Dieckmann
condensation of N-alkanoyl-N-alkylglycinates, which were produced by the reaction
of a-bromoacetate with alkylamines followed by alkanoylation with the correspond-
ing alkanoyl chloride.[7] The 2,4-pyrrolidinediones exist as an enol form in an aprotic
polar solvent, such as dimethylsulfoxide (DMSO-d6).[8]
With the 3-substituted 2,4-pyrrolidinediones in hand, we explored the hydro-
peroxidation of 2,4-pyrrolidinedione (R1 ¼ Bn, R2 ¼ Me). The reaction was carried
out in glacial acetic acid at room temperature using a stoichiometric amount of
manganese(III) acetate. After 2 h, the oxidant was consumed and the desired hydro-
peroxide was obtained in 65% yield (Scheme 2 and Table 1, entry 1). Because the
product seemed to be decomposed by the manganese(III) oxidant,[6] the reaction
using a catalytic amount of manganese(III) acetate was next examined. The reaction
was carried out under similar conditions and quenched by adding water after 14 h,
giving the corresponding hydroperoxide in a modest yield (entry 2), probably as a
result of the instability of the product in the solvent. The reaction under an oxygen
atmosphere also gave a similar result (entry 3). Finally, we found the optimum
reaction conditions; that is, the reaction was conducted at room temperature in
air for 2 h using a catalytic amount of manganese(III) acetate and produced the
hydroperoxide in 94% yield (entry 4).
1
A broad singlet signal (1H) in the H NMR spectrum of the hydroperoxide
(R1 ¼ Bn, R2 ¼ Me) appeared at d 11.28 ppm and a broad absorption band appeared
at 3400–3000 cmꢀ1 in the infrared (IR) spectrum, which were assigned to a hydroper-
oxy group because the product in dichloromethane showed a positive potassium
1
iodide–starch test. The H NMR spectrum also showed two doublets at d 4.79
and 4.64 (J ¼ 14.7 Hz) due to the H-5 methylene protons of the pyrrolidinedione.
The 13C NMR spectrum revealed two carbonyl carbons at d 204.1 and 171.3 ppm
and in the IR spectrum at 1786 and 1666 cmꢀ1 assigned to a keto group and amide
Scheme 2. Manganese(III)-catalyzed aerobic oxidation of 3-alkyl-substituted 2,4-pyrrolidinediones.

610
M. A. HAQUE AND H. NISHINO
Table 1. Reaction of 3-substituted 2,4-pyrrolidinediones in the presence of manganese(III) acetatea
(%)c
b
Entry
Pyrrolidinedione
Sub.=Mn(OAc)3
T (h)
Product
1
1:1
2
65
2
3
4
1:0.1
1:0.1
1:0.1
14
2
68
70d
94
2
5
6
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
2
2
95
98
93
96
91
90
7
2
8
2
9
1.5
1.5
1.5
10
11
95
(Continued )

3-HYDROPEROXY-2,4-PYRROLIDINEDIONES
611
Table 1. Continued
Entry
12
Pyrrolidinedione
Sub.=Mn(OAc)3
T (h)
1.5
Product
(%)c
b
1:0.1
90
96
99
99
98
95
97
13
14
15
16
17
18
19
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1.5
1.5
1.5
1.5
1.5
1.5
1.5
98
(Continued )

612
M. A. HAQUE AND H. NISHINO
Table 1. Continued
(%)c
b
Entry
Pyrrolidinedione
Sub.=Mn(OAc)3
T (h)
1.5
Product
20
21
22
1:0.1
Comp. mix.e
1:0.1
1:0.1
2
2
n.r.f
Comp. mix.e
aThe reaction of 2,4-pyrrolidinediones (1 mmol) was carried out in acetic acid (25 mL) at ambient
temperature in air.
bMolar ratio.
cThe yield based on the amount of 2,4-pyrrolidinedione.
dThe reaction was conducted under an oxygen atmosphere (1 atm).
eThe reaction gave an intractable mixture.
fThe reaction did not occur and the substrate was recovered.
carbonyl group, respectively. The high-resolution fast atom bombardment (FAB)
mass spectrum also agreed with the exact mass. As a result, the structure of the pro-
duct was determined to be 1-benzyl-3-hydroperoxy-3-methylpyrrolidine-2,4-dione.
Although the product crystallized from diethyl ether=hexane provided single crys-
tals, unfortunately, the crystals did not survive during the x-ray diffraction measure-
ment.
To expand the scope of this reaction with respect to the 2,4-pyrrolidinediones,
the reaction of various 3-alkylsubstituted 2,4-pyrrolidinediones (R1 ¼ Bu, t-Bu, or
i-Pr, R2 ¼ Et, Pr, Bu, or hexyl) was conducted under the optimized reaction
conditions mentioned previously, and similar hydroperoxides were obtained in
comparable yields (entries 5–19). Although the hydroperoxides were obtained as
colorless solids, except for the 1-butyl-3-hydroperoxypyrrolidine-2,4-dione as a
liquid, the products gradually decomposed at ambient temperature in air within 2
or 3 days along with the evolution of gas and even when stored in a refrigerator
at ꢀ20 ꢁC for a half year.
A similar reaction of 1-ethyl-2,4-pyrrolidinedione (R1 ¼ Et, R2 ¼ Me) gave an
intractable mixture and the corresponding hydroperoxide was not isolated (entry 20).
This is probably because of the instability of the product as well as the substrate, since
1-methyl-2,4-pyrrolidinedione (R1 ¼ R2 ¼ Me) was also prepared by a manner similar
to that mentioned previously but in a poor yield because of its instability. The reaction

3-HYDROPEROXY-2,4-PYRROLIDINEDIONES
613
Scheme 3. Catalytic oxidation pathway.
of 2,4-pyrrolidinediones with 3-phenyl and 3-ethoxycarbonyl groups also failed. The
3-phenyl-substituted 2,4-pyrrolidinedione (R1 ¼ Bn, R2 ¼ Ph) has a solubility problem
and it did not dissolve even in acetic acid, ethanol, and chloroform at room tempera-
ture. Therefore, the reaction did not occur and the pyrrolidinedione was recovered
(entry 21). The 2,4-pyrrolidinedione-3-carboxylate (R1 ¼ Bn, R2 ¼ CO2Et) gave an
intractable mixture (entry 22). The pyrrolidinedione radical at C-3 might be labilized
by the ethoxycarbonyl group such as an electron-withdrawing group (vide infra).
The mechanism for the formation of the hydroperoxides could be explained
by the manganese(III)-catalyzed aerobic oxidation, similar to the production of
the 4-hydroperoxypyrazolidinediones.[6a] The mechanism is outlined in Scheme 3.
The alkyl group (R2) substituted at C-3 must be essential for the formation of the
pyrrolidinedione radical followed by capturing molecular oxygen.
In summary, we have demonstrated the facile hydroperoxidation of 3-alkyl-
substituted 2,4-pyrrolidinediones under manganese(III)-catalyzed aerobic oxidation
conditions, although the 3-hydroperoxypyrrolidine-2,4-diones were not stable at
ambient temperature in air except for the N-benzyl-protected hydroperoxypyrrolidi-
nedione (R1 ¼ Bn, R2 ¼ Me). The oxidation of the 2,4-pyrrolidinediones having a
small N-protecting group, such as the methyl and ethyl group, and an electron-
withdrawing group at the C-3 position, such as ethoxycarbonyl group, produced a
complex mixture, and the attempted isolation of the hydroperoxide was unsuccess-
ful. The reaction of 3-phenyl-substituted 2,4-pyrrolidinedione did not proceed
because of poor solubility in acetic acid under the reaction conditions.
EXPERIMENTAL
Materials
1
The NMR spectra were measured at 300 MHz and 500 MHz for H and at
75 Hz and 125 Hz for 13C, respectively, with tetramethylsilane as the internal stan-
dard. The chemical shifts are reported in parts per million (ppm) and the coupling
constants in hertz. The IR spectral data are expressed in centimetersꢀ1. The electron
impact mass spectrometry (EIMS) spectra were recorded at the ionizing voltage of
70 eV. The high-resolution mass spectra (HRMS) were measured and the elemental
analyses were performed at the Analytical Center of Kumamoto University,
Kumamoto, Japan.

614
M. A. HAQUE AND H. NISHINO
Preparation of 2,4-Pyrrolidinediones[7]
Propanoyl chloride (1.65 mL; 19.2 mmol) was added dropwise to a mixture of
ethyl (benzylamino)acetate (3.22 mL, 17.4 mmol)[7a,b] and triethylamine (4.85 mL,
34.8 mmol) in CHCl3 (25 mL) at 0 ꢁC over 15 min. After stirring for another 1.5 h
at room temperature, the mixture was diluted with CHCl3 to 50 mL; washed with
a 5% aqueous acetic acid solution (25 mL), water (50 mL), and brine (25 mL); dried
over anhydrous MgSO4; and then concentrated to dryness, affording the liquid pro-
panoyl-protected (benzylamino)acetate with sufficient purity for use in the next step.
The prepared propanoyl-protected (benzylamino)acetate (2.5 g, 10.03 mmol)
in tetrahydrofuran (50 mL) was added dropwise to a refluxing suspension of NaH
(60% dispersion in mineral oil) (500 mg, 11.03 mmol) and tetrahydrofuran (50 mL)
in a 300-mL, three-necked flask. After this addition, the mixture was continuously
heated under reflux for 12 h. A pale yellow solid was formed during the heating
and then filtered under suction. The obtained solid was dissolved in a minimum
volume of water and very carefully acidified with 2 M H2SO4, giving 1-benzyl-3-
methyl-2,4-pyrrolidinedione (keto form) as a crude precipitate. The precipitate was
purified by silica-gel column chromatography, eluting with a mixture of ethyl acetate
and hexane followed by recrystallization using the appropriate solvent. The other 2,4-
pyrrolidinediones were prepared by a manner similar to that described previously.
1-Benzyl-4-hydroxy-3-methyl-3-pyrrolin-2-one (Enol Form)
Rf ¼ 0.57 (EtOAc=hexane ¼ 9:1 v=v); colorless needles (from ethanol=hexane);
1
ꢁ
=
mp 146–150 C; IR (CHCl3) n 1784 and 1697 (C O); H NMR (DMSO-d6) d 10.65
=
(1H, s, OH), 7.15–7.35 (5H, m, arom H), 4.46 (2H, s, CH2-C O), 3.63 (2H, s,
PhCH2), 1.58 (3H, s, Me); C NMR (DMSO-d6) d 173.2 (C-2, C O), 164.8 (C-4),
13
=
138.4, 128.6, 127.4, 127.1 (arom C), 100.2 (C-3), 49.0 (C-5, CH2), 44.6 (PhCH2),
6.4 (Me). FAB HRMS (acetone=NBA) calcd. for C12H14NO2 204.1025 (M þ H).
Found 204.1002.
General Procedure
Manganese(III) acetate dehydrate (26.8 mg; 0.1 mmol) was added to a solution
of the 2,4-pyrrolidinedione (1 mmol) in glacial acetic acid (25 mL). The mixture was
stirred at room temperature in air for 1.5–2 h, and then the reaction was quenched by
adding water (25 mL) to the mixture. The aqueous reaction mixture was extracted
three times with CH2Cl2 (30 mL). The combined extract was washed with water
and then a saturated aqueous solution of sodium hydrogencarbonate, dried over
anhydrous magnesium sulfate, and concentrated to dryness. Although the product
was almost pure, it was further purified by silica-gel flash column chromatography,
eluting with EtOAc=hexane (8:2 v=v) if needed.
1-Benzyl-3-hydroperoxy-3-methylpyrrolidine-2,4-dione
Yield (221.1 mg, 94%); Rf ¼ 0.67 (EtOAc=hexane ¼ 8:2 v=v); colorless blocks
(from Et2O=hexane); mp 78–79 ꢁC; IR (CHCl3) n 3400–3000 (OOH), 1786, 1666

3-HYDROPEROXY-2,4-PYRROLIDINEDIONES
615
1
=
(C O); H NMR (CDCl3) d 11.28 (1H, s, OOH), 7.36–7.27 (5H, m, arom H), 4.79
(1H, d, J ¼ 14.7 Hz, CH2), 4.64 (1H, d, J ¼ 14.7 Hz, CH2), 3.75 (2H, s, CH2), 1.39
13
=
=
(3H, s, Me); C NMR (CDCl3) d 204.1 (C-4, C O), 171.3 (C-2, C O), 134.0,
129.1, 128.4, 128.3 (arom C), 82.5 (C-3), 53.4 (C-5, CH2), 46.8 (PhCH2), 16.7
(Me). FAB HRMS (acetone=NBA) calcd. for C12H14NO4 236.0923 (M þ H). Found
236.0935.
1-Benzyl-3-ethyl-3-hydroperoxypyrrolidine-2,4-dione
Yield (236.8 mg, 95%); Rf ¼ 0.53 (EtOAc=hexane ¼ 6:4 v=v); colorless solid; mp
1
ꢁ
=
72–76 C; IR (CHCl3) n 3500–3100 (OOH), 1782, 1693 (C O); H NMR (CDCl3)
11.45 (1H, s, OOH), 7.38–7.26 (5H, m, arom H), 4.73 (2H, s, CH2), 3.74 (1H, d,
J ¼ 17.7 Hz, CH2), 3.64 (1H, d, J ¼ 17.7 Hz, CH2), 1.85 (2H, q, J ¼ 7.4 Hz, CH2),
13
=
0.89 (3H, t, J ¼ 7.4 Hz, Me); C NMR (CDCl3) 204.7 (C-4, C O), 171.0 (C-2,
=
C O), 134.2, 129.1, 128.4, (arom C), 86.1 (C-3), 54.1 (C-5, CH2), 46.8 (PhCH2),
25.1 (CH2), 16.70 (Me). FAB HRMS (acetone=NBA) calcd. for C13H15NO4Na
272.0899 (M þ Na). Found 272.0906.
1-Benzyl-3-hydroperoxy-3-propylpyrrolidine-2,4-dione
Yield (258.0 mg, 98%); Rf ¼ 0.54 (EtOAc=hexane ¼ 5:5 v=v); colorless solid; mp
1
ꢁ
=
112 C; IR (CHCl3) n 3400–3100 (OOH), 1784, 1693 (C O); H NMR (CDCl3)
11.62 (1H, s, OOH), 7.37–7.27 (5H, m, arom H), 4.76 (1H, d, J ¼ 14.7, CH2), 4.67
(1H, d, J ¼ 14.7 Hz, CH2), 3.74 (1H, d, J ¼ 17.7, CH2), 3.64 (1H, d, J ¼ 17.4 Hz,
CH2), 1.75 (2H, t, J ¼ 8.4 Hz, CH2), 1.31 (2H, m, CH2), 0.88 (3H, t, J ¼ 7.4 Hz,
13
=
=
Me); C NMR (CDCl3) 204.8 (C-4, C O), 171.1 (C-2, C O), 134.2, 129.1, 128.4,
128.3 (arom C), 85.7 (C-3), 54.1 (C-5, CH2), 46.8 (PhCH2), 33.5, 15.9 (CH2), 14.1
(Me). FAB HRMS (acetone=NBA) calcd. for C14H17NO4Na 286.1055 (M þ Na).
Found 286.1032.
1-Benzyl-3-butyl-3-hydroperoxypyrrolidine-2,4-dione
Yield (257.9 mg, 93%); Rf ¼ 0.58 (EtOAc=hexane ¼ 5:5 v=v); colorless solid; mp
1
ꢁ
=
80–81 C; IR (CHCl3) n 3400–3100 (OOH), 1784, 1695 (C O); H NMR (CDCl3)
11.37 (1H, s, OOH), 7.38–7.26 (5H, m, arom H), 4.72 (2H, s, CH2), 3.74 (1H, d,
J ¼ 17.6 Hz, CH2), 3.64 (1H, d, J ¼ 17.6 Hz, CH2), 1.79 (2H, t, J ¼ 8.1 Hz, CH2),
1.18 (4H, m, 2CH2), 0.84 (3H, t, J ¼ 6.9 Hz, Me); 13C NMR (CDCl3) 204.8 (C-4,
=
=
C O), 171.0 (C-2, C O), 134.2, 129.1, 128.4, 128.3 (arom C), 85.7 (C-3), 54.1
(C-5, CH2), 46.8 (PhCH2), 31.4, 24.4, 22.8 (CH2), 13.6 (Me). FAB HRMS (acet-
one=NBA) calcd. for C15H19NO4Na 300.1212 (M þ Na). Found 300.1219.
1-Benzyl-3-hexyl-3-hydroperoxypyrrolidine-2,4-dione
Yield (293.2 mg, 96%); Rf ¼ 0.60 (EtOAc=hexane ¼ 4:6 v=v); colorless solid; mp
1
ꢁ
=
78–80 C; IR (CHCl3) n 3400–3100 (OOH), 1784, 1691 (C O); H NMR (CDCl3)
11.56 (1H, s, OOH), 7.38–7.27 (5H, m, arom H), 4.75 (1H, d, J ¼ 15.0 Hz, CH2),
4.69 (1H, d, J ¼ 15.0 Hz, CH2), 3.75 (1H, d, J ¼ 18.0 Hz, CH2), 3.64 (1H, d,

616
M. A. HAQUE AND H. NISHINO
J ¼ 18.0 Hz, CH2), 1.78 (2H, t, J ¼ 7.8 Hz, CH2), 1.21 (8H, m, 4xCH2), 0.85 (3H, t,
13
=
=
J ¼ 6.5 Hz, Me); C NMR (CDCl3) 204.8 (C-4, C O), 171.1 (C-2, C O), 134.2,
129.1, 128.4, 128.3 (arom C), 85.7 (C-3), 54.1 (C-5, CH2), 46.8 (PhCH2), 31.6,
31.3, 29.2, 22.4 (2C) (CH2), 14.0 (Me). FAB HRMS (acetone=NBA) calcd. for
C17H23NO4Na 328.1525 (M þ Na). Found 328.1493.
1-Butyl-3-hydroperoxy-3-methylpyrrolidine-2,4-dione
Yield (183.0 mg, 91%); Rf ¼ 0.52 (EtOAc=hexane ¼ 6:4 v=v); colorless liquid; IR
1
=
(CHCl3) n 3400–3100 (OOH), 1784, 1693 (C O); H NMR (CDCl3) 11.75 (1H, s,
OOH), 3.90 (2H, s, CH2), 3.53 (2H, t, J ¼ 6.9 Hz, CH2), 1.60 (2H, m, CH2), 1.36
(2H, m, CH2), 1.35 (3H, s, CH3), 0.96 (3H, t, J ¼ 7.2 Hz, Me); 13C NMR (CDCl3)
=
=
204.9 (C-4, C O), 171.3 (C-2, C O), 82.2 (C-3), 53.9 (C-5, CH2), 42.6, 28.6, 19.9
(CH2), 16.6, 13.7 (Me). FAB HRMS (acetone=NBA) calcd. for C9H15NO4Na
224.0899 (M þ Na). Found 224.0897.
1-Butyl-3-ethyl-3-hydroperoxypyrrolidine-2,4-dione
Yield (193.7 mg 90%); Rf ¼ 0.66 (EtOAc=hexane ¼ 6:4 v=v); colorless liquid; IR
1
=
(CHCl3) n 3400–3100 (OOH), 1782, 1689 (C O); H NMR (CDCl3) 11.85 (1H, s,
OOH), 3.90 (1H, d, J ¼ 18.0 Hz, CH2), 3.83 (1H, d, J ¼ 18.0 Hz, CH2), 3.63 (1H,
m, CH2), 3.48 (1H, m, CH2), 1.79 (2H, q, J ¼ 7.2 Hz, CH2), 1.61 (2H, m, CH2),
1.39 (2H, m, CH2), 0.96 (3H, t, J ¼ 7.2 Hz, Me), 0.88 (3H, t, J ¼ 7.5 Hz, Me); 13C
=
=
NMR (CDCl3) 205.3 (C-4, C O), 170.7 (C-2, C O), 85.7 (C-3), 54.5 (C-5, CH2),
42.6, 28.4, 24.6, 19.7 (CH2), 13.4, 6.7 (Me). FAB HRMS (acetone=NBA) calcd.
for C10H17NO4Na 238.1055 (M þ Na). Found 238.1036.
1,3-Dibutyl-3-hydroperoxypyrrolidine-2,4-dione
Yield (231.1 mg, 95%); Rf ¼ 0.53 (EtOAc=hexane ¼ 5:5 v=v); colorless liquid;
IR (CHCl3) n 3400–3100 (OOH), 1784, 1689 (C O); 1H NMR (CDCl3) 11.85
=
(1H, s, OOH), 3.88 (1H, d, J ¼ 18.0 Hz, CH2), 3.83 (1H, d, J ¼ 18.0 Hz, CH2), 3.61
(1H, m, CH2), 3.48 (1H, m, CH2), 1.73 (2H, t, J ¼ 7.8 Hz, CH2), 1.59 (2H, m,
CH2), 1.37 (2H, m, CH2), 1.25 (4H, m, 2CH2), 0.96 (3H, t, J ¼ 7.2 Hz, Me), 0.85
13
=
=
(3H, t, J ¼ 6.8 Hz, Me); C NMR (CDCl3) 205.3 (C-4, C O), 170.8 (C-2, C O),
85.3 (C-3), 54.4 (C-5, CH2), 42.3, 30.9, 28.3, 24.2, 22.5, 19.6 (CH2), 13.4, 13.3
(Me). FAB HRMS (acetone=NBA) calcd. for C12H21NO4Na 266.1368 (M þ Na).
Found 266.1375.
1-(t-Butyl)-3-hydroperoxy-3-methylpyrrolidine-2,4-dione
Yield (181.0 mg, 90%); Rf ¼ 0.55 (EtOAc=hexane ¼ 7:3 v=v); colorless solid; mp
1
ꢁ
=
99–100 C; IR (CHCl3) n 3400–3100 (OOH), 1782, 1697 (C O); H NMR (CDCl3)
11.27 (1H, s, OOH), 3.94 (2H, s, CH2-C O), 1.49 (9H, s, t-Bu), 1.32 (3H, s, Me); 13C
=
=
=
NMR (CDCl3) 205.3 (C-4, C O), 171.5 (C-2, C O), 83.2 (C-3), 55.8 (>C<), 52.8
(C-5, CH2), 28.1 (3CH3), 16.9 (Me). FAB HRMS (acetone=NBA) calcd. for
C9H16NO4 202.1079 (M þ H). Found 202.1069.

3-HYDROPEROXY-2,4-PYRROLIDINEDIONES
617
1-(t-Butyl)-3-ethyl-3-hydroperoxypyrrolidine-2,4-dione
Yield (206.6 mg, 96%); Rf ¼ 0.64 (EtOAc=hexane ¼ 4:6 v=v); colorless solid; mp
1
ꢁ
=
130–131 C; IR (CHCl3) n 3500–3200 (OOH), 1780, 1695 (C O); H NMR (CDCl3)
12.34 (1H, s, OOH), 4.08 (1H, d, J ¼ 18.3 Hz, CH2), 3.97 (1H, d, J ¼ 18.3 Hz, CH2),
1.58 (2H, q, J ¼ 7.5 Hz, CH2), 1.41 (9H, s, t-Bu), 0.77 (3H, t, J ¼ 7.5 Hz, Me); 13C
=
=
NMR (CDCl3) 207.7 (C-4, C O), 169.2 (C-2, C O), 85.3 (C-3), 54.5 (>C<), 53.3
(C-5, CH2), 27.1 (3Me), 24.6 (CH2), 16.9 (Me). FAB HRMS (acetone=NBA) calcd.
for C10H17NO4Na 238.1055 (M þ Na). Found 238.1045.
1-(t-Butyl)-3-hydroperoxy-3-propylpyrrolidine-2,4-dione
Yield (227.1 mg, 99%); Rf ¼ 0.44 (EtOAc=hexane ¼ 4:6 v=v); colorless solid; mp
1
ꢁ
=
112–113 C; IR (CHCl3) n 3450–3050 (OOH), 1782, 1685 (C O); H NMR (CDCl3)
11.59 (1H, s, OOH), 3.95 (1H, d, J ¼ 17.8 Hz, CH2), 3.84 (1H, d, J ¼ 17.8 Hz, CH2),
1.69 (2H, t, J ¼ 8.4 Hz, CH2), 1.49 (9H, s, t-Bu), 1.29 (2H, m, CH2), 0.88 (3H, t,
13
=
=
J ¼ 7.1 Hz, Me); C NMR (CDCl3) 205.7 (C-4, C O), 171.3 (C-2, C O), 86.5
(C-3), 55.8 (>C<), 53.3 (C-5, CH2), 33.7 (CH2), 27.5 (3Me), 15.9 (CH2), 14.1
(Me). FAB HRMS (acetone=NBA) calcd. for C11H20NO4 230.1392 (M þ H). Found
230.1042.
1-(t-Butyl)-3-butyl-3-hydroperoxypyrrolidine-2,4-dione
Yield (240.9 mg, 99%); Rf ¼ 0.58 (EtOAc=hexane ¼ 4:6 v=v); colorless solid; mp
1
ꢁ
=
87–88 C; IR (CHCl3) n 3400–3100 (OOH), 1782, 1685 (C O); H NMR (CDCl3)
11.47 (1H, s, OOH), 3.95 (H, d, J ¼ 18.0 Hz, CH2), 3.83 (1H, d, J ¼ 18.0 Hz, CH2),
1.72 (2H, t, J ¼ 7.2 Hz, CH2), 1.49 (9H, s, t-Bu), 1.25 (4H, m, 2CH2), 0.82 (3H, t,
13
=
=
J ¼ 7.1 Hz, Me); C NMR (CDCl3) 205.8 (C-4, C O), 171.2 (C-2, C O), 86.4
(C-3), 55.8 (>C<), 53.6 (C-5, CH2), 31.4 (CH2), 27.5 (3Me), 24.4, 22.7 (CH2), 13.5
(Me). FAB HRMS (acetone=NBA) calcd. for C12H22NO4 244.1549 (M þ H). Found
244.1521.
1-(t-Butyl)-3-hexyl-3-hydroperoxypyrrolidine-2,4-dione
Yield (276.9 mg, 98%); Rf ¼ 0.45 (EtOAc=hexane ¼ 3:7 v=v); colorless solid; mp
1
ꢁ
=
94 C; IR (CHCl3) n 3400–3100 (OOH), 1780, 1685 (C O); H NMR (CDCl3) 11.20
(1H, s, OOH), 3.94 (H, d, J ¼ 17.4 Hz, CH2), 3.83 (1H, d, J ¼ 17.4 Hz, CH2), 1.71
(2H, m, CH2), 1.49 (9H, s, t-Bu), 1.27 (8H, m, 4CH2), 0.85 (3H, t, J ¼ 6.9 Hz,
13
=
=
Me); C NMR (CDCl3) 205.7 (C-4, C O), 171.3 (C-2, C O), 86.6 (C-3), 55.9
(>C<), 53.6 (C-5, CH2), 31.8, 31.3, 29.2 (CH2), 27.6 (3Me), 22.4, 22.3 (CH2),
13.97 (Me). FAB HRMS (acetone=NBA) calcd. for C14H26NO4 272.1862 (M þ H).
Found 272.1857.
3-Hydroperoxy-3-methyl-1-(i-propyl)pyrrolidine-2,4-dione
Yield (177.8 mg, 95%); Rf ¼ 0.41 (EtOAc=hexane ¼ 7:3 v=v); colorless solid; mp
1
ꢁ
=
82–84 C; IR (CHCl3) n 3400–3100 (OOH), 1784, 1685 (C O); H NMR (CDCl3)
11.65 (1H, s, OOH), 4.66 (1H, sept, J ¼ 6.6 Hz, CH), 3.87 (1H, d, J ¼ 17.7 Hz,

618
M. A. HAQUE AND H. NISHINO
CH2), 3.80 (1H, d, J ¼ 17.7 Hz, CH2), 1.32 (3H, s, Me), 1.25 (3H, d, J ¼ 6.6 Hz, Me),
13
=
1.22 (3H, d, J ¼ 6.6 Hz, Me); C NMR (CDCl3) 204.9 (C-4, C O), 170.5 (C-2,
=
C O), 82.6 (C-3), 49.0 (C-5, CH2), 43.1 (CH), 19.43, 18.88, 16.36 (Me). FAB HRMS
(acetone=NBA) calcd. for C8H13NO4Na 210.0742 (M þ Na). Found 210.0740.
3-Ethyl-3-hydroperoxy-1-(i-propyl)pyrrolidine-2,4-dione
Yield (195.2 mg, 97%); Rf ¼ 0.50 (EtOAc=hexane ¼ 7:3 v=v); colorless solid; mp
1
ꢁ
=
63–65 C; IR (CHCl3) n 3600–3100 (OOH), 1782, 1685 (C O); H NMR (CDCl3)
11.66 (1H, s, OOH), 4.69 (1H, sept, J ¼ 6.6 Hz, CH), 3.85 (1H, d, J ¼ 17.4 Hz,
CH2), 3.71 (1H, d, J ¼ 17.4 Hz, CH2), 1.79 (2H, q, J ¼ 7.3 Hz, CH2), 1.26 (3H, d,
J ¼ 6.6 Hz, Me), 1.23 (3H, d, J ¼ 6.6 Hz, Me), 0.78 (3H, t, J ¼ 7.3 Hz, Me); 13C
=
=
NMR (CDCl3) 205.3 (C-4, C O), 170.1 (C-2, C O), 86.4 (C-3), 49.7 (C-5, CH2),
43.1 (CH), 24.7 (CH2), 19.7, 18.9, 6.8 (Me). FAB HRMS (acetone=NBA) calcd.
for C9H15NO4Na 224.0899 (M þ Na). Found 224.0895.
3-Hydroperoxy-1-(i-propyl)-3-propylpyrrolidine-2,4-dione
Yield (211.0 mg, 98%); Rf ¼ 0.59 (EtOAc=hexane ¼ 7:3 v=v); colorless solid; mp
1
ꢁ
=
78 C; IR (CHCl3) n 3600–3100 (OOH), 1782, 1685 (C O); H NMR (CDCl3) 11.71
(1H, s, OOH), 4.68 (1H, sept, J ¼ 6.6 Hz, CH), 3.85 (1H, d, J ¼ 17.7 Hz, CH2), 3.72
(1H, d, J ¼ 17.7 Hz, CH2), 1.71 (2H, t, J ¼ 8.4 Hz, CH2), 1.30 (2H, m, CH2), 1.26
(3H, d, J ¼ 6.6 Hz, Me), 1.22 (3H, d, J ¼ 6.6 Hz, Me), 0.88 (3H, t, J ¼ 7.2 Hz, Me);
13
=
=
C NMR (CDCl3) 205.3 (C-4, C O), 170.2 (C-2, C O), 86.0 (C-3), 49.7 (C-5,
CH2), 43.0 (CH), 33.3 (CH2), 19.6, 18.9 (Me), 15.9 (CH2), 14.0 (Me). FAB HRMS
(acetone=NBA) calcd. for C10H17NO4Na 238.1055 (M þ Na). Found 238.1044.
ACKNOWLEDGMENT
This research was supported by a Grant-in-Aid for Scientific Research (C),
No. 19550046, from the Japan Society for the Promotion of Science.
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