Manganese(III)-catalyzed facile direct hydroperoxidation of some heterocyclic 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/ol034939b

(Matix presented) The aerobic oxidation of 4-monosubstituted 1,2-diphenylpyrazolidine-3,5-diones 1 was carried out in the presence of a catalytic amount of manganese(III) acetate to quantitatively give the corresponding 4-hydroperoxypyrazolidinediones 2.

Full text of DOI:10.1021/ol034939b

ORGANIC
LETTERS
2003
Vol. 5, No. 16
2887-2890
Manganese(III)-Catalyzed Facile Direct
Hydroperoxidation of Some Heterocyclic
1,3-Dicarbonyl Compounds
Md. Taifur Rahman† and Hiroshi Nishino*
Department of Materials and Life Sciences, Graduate School of Science and
Technology, and Department of Chemistry, Faculty of Science, Kumamoto UniVersity,
Kurokami, Kumamoto 860-8555, Japan
nishino@aster.sci.kumamoto-u.ac.jp
Received May 29, 2003
ABSTRACT
The aerobic oxidation of 4-monosubstituted 1,2-diphenylpyrazolidine-3,5-diones 1 was carried out in the presence of a catalytic amount of
manganese(III) acetate to quantitatively give the corresponding 4-hydroperoxypyrazolidinediones 2. A similar autoxidation of the 5-monosubstituted
barbituric acids 5 and 3-butyl-4-hydroxy-2-quinolinone 7 also gave the corresponding hydroperoxides 5 and 8, respectively, in moderate to
excellent yields.
4-Butyl-1,2-diphenylpyrazolidine-3,5-dione (phenylbutazone
I), a nonsteroidal antiinflammatory drug, is an efficient
reducing cofactor for the peroxidase activity of prostaglandin
H synthase.1 Phenylbutazone I inhibits the production of lipid
mediators causing inflammation but paradoxically performs
this via the intermediacy of the peroxyl radical and hydro-
peroxide, which may themselves be proinflammatory. In
isolated heart preparations of guinea pigs and rabbit hearts
in vivo, 4-butyl-4-hydroperoxy-1,2-diphenylpyrazolidine-3,5-
dione (II) shows a significantly stronger cardiodepressive
and coronary constricting effect compared to phenylbutazone
I itself, 4-butyl-4-hydroxy-1,2-diphenylpyrazolidine-3,5-di-
one (III), and the ring-opened decomposition product of the
hydroperoxide II.2 These phenomena could shed light on the
significance of the hydroperoxylated phenylbutazone II
regarding the antiinflammatory or other biological activities
of phenylbutazone I, e.g., rheumatoid arthritis,3 and could
explain the side effects such as gastric irritation and toxicity
associated with phenylbutazone I. A number of reagents have
been utilized for the introduction of an oxygen functionality
at the 2-position of the 1,3-dicarbonyl compounds, e.g., lead-
(IV) acetate,4 MoOPH,5 percarboxylic acids,6 dimethyldiox-
irane,7 manganese(II) acetate,8 cerium(III) chloride,9 cobalt-
(II) chloride,10 ammonium cerium(IV) nitrate (CAN),11 and
cesium salts.12 However, in all of these cases, only the
(3) (a) Rechenberg, H. K. V. Phenylbutazone, 2nd ed.; Edward Arnold,
Ltd.: London, 1962. (b) Chauhan, S. M. S.; Srinivas, K. A.; Mohapatra, P.
P. Ind. J. Chem. 1999, 31B, 724-725 and references therein.
(4) Demir, A. S.; Jeganathan, A. Synthesis 1992, 235-247.
(5) MoOPH ) MoO5‚Pyridine‚HMPA. Vedejs, E.; Engler, D. A.;
Telschow, J. E. J. Org. Chem. 1978, 43, 188-196.
(6) Hubert, A. J.; Starcher, P. S. J. Chem. Soc. C 1968, 2500-2502.
(7) Adam, W.; Smerz, A. K. Tetrahedron 1996, 52, 5799-5804.
(8) Christoffers, J. J. Org. Chem. 1999, 64, 7668-7669.
(9) (a) Christoffers, J.; Wenner, T. SynLett 2002, 119-121. (b) Chris-
toffers, J.; Werner, T.; Unger, S.; Frey, W. Eur. J. Org. Chem. 2003, 425-
431.
† Department of Materials and Life Sciences, Graduate School of Science
and Technology.
(1) (a) Reed, G. A.; Griffin, I. O.; Eling, T. E. Mol. Pharmacol. 1985,
27, 109-114. (b) Vennerstorm, J. L.; Holmes, T. J., Jr. J. Med. Chem.
1987, 30, 563-567.
(2) Mentz, V. P.; Schulz, M.; Kluge, R. Arzneim.-Forsch. 1987, 37,
1229-1232.
(10) Baucherel, X.; Levoirier, E.; Uziel, J.; Juge, S. Tetrahedron Lett.
2000, 41, 1385-1387.
(11) Nair, V.; Nair, L. G.; Mathew, J. Tetrahedron Lett. 1998, 39, 2801-
2804.
(12) Watanabe, T.; Ishikawa, T. Tetrahedron Lett. 1999, 40, 7795-7798.
10.1021/ol034939b CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/11/2003

hydroxyl functionality could be introduced at the 2-position
of the 1,3-dicarbonyl compounds.
When these autoxidation reactions were carried out for a
longer reaction period in acetic acid or ethanol with a
catalytic amount of manganese(III) acetate or utilizing CAN,
a substantial amount of the hydroxylated pyrazolidinediones
3 was formed (entries 11-14). Copper(II) acetate as the
catalyst was not effective for the autoxidation (entry 15). In
addition, the formed hydroperoxides 2 were stable in sunlight
or visible light,14 and the reduction of 2 (R ) Me, Et, Pr,
i-Pr) with triphenylphosphine in diethyl ether gave the
corresponding 3 in 97, 98, 97, and 96% yields, respectively.
To examine the applicability of the manganese(III) acetate-
catalyzed R-hydroperoxidation of other biologically impor-
tant heterocyclic 1,3-dicarbonyl compounds, the reaction of
5-monosubstituted barbituric acids 4 (R ) Bn, i-Pr, 4-
MeOC6H4CH2, 2-MeOC6H4CH2, 2-naphthyl-CH2)15 and 3-bu-
tyl-4-hydroxy-2-quinolinone 716 was carried out under similar
aerobic conditions, and very similar autoxidation results were
obtained, giving the corresponding hydroperoxides 5 (Scheme
2 and Table 2) and 8 (Scheme 3), respectively, in excellent
During the course of our current investigation of the
manganese(III) acetate-catalyzed oxidative functionalization
of pyrazolidine-3,5-diones to synthesize a variety of deriva-
tives with potent biological activity, we found that stirring a
1 mM solution of different 4-monoalkylpyrazolidine-3,5-
diones 1 (R ) Me, Et, Pr, i-Pr, Bu, t-Bu, Bn, and cyclopentyl)
in acetic acid in the presence of a catalytic amount of
manganese(III) acetate under an aerobic atmosphere gave
the hydroperoxylated products 2 in quantitative yields
(Scheme 1 and Table 1, entries 2-10).13
Scheme 1
Scheme 2
When no catalyst was used, there was no conversion of 1
to 2 (entry 1), which implies that manganese(III) acetate is
essential for the catalytic hydroperoxidation. All the products
2 in dichloromethane showed a positive potassium iodide-
starch test. The structural assignment of 2 was based on the
1H NMR, 13C NMR, and IR spectra and finally X-ray
crystallography.
or moderate yields. All of the compounds 5 and 8 also tested
positive for the hydroperoxyl group using the potassium
iodide-starch paper.
In the case of the barbituric acids 4, stirring for a long
reaction time or using CAN as the catalyst also led to the
formation of hydroxybarbituric acids 6 (Table 2, entries
Table 1. Aerobic Oxidation of 4-Alkyl-1,2-diphenylpyrazolidine-3,5-diones 1 in the Presence of a Catalysta
yield (%)b
entry
R group of 1
catalyst
1:catalyst
solvent
temp (°C)
time (h)
2
3
1
2
i-Pr
i-Pr
i-Pr
Me
Et
Pr
Bu
t-Bu
Bn
Cpd
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
none
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
EtOH
MeOH
AcOH
23
23
23
23
23
23
23
23
23
23
23
23
23
0
3
2
2
2
2
2
2
recovery of 1 (100)
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
CANe
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.1
1:0.2
1:0.28
1:1
97
96
95
95
99
99
95
97
99
3c
4
5
6
7
8
9
10
11
12
13
14
15
10 min
2
2
12
27
3
87
52
54
35
8
46
41
55
1
15
Cu(OAc)2
1:0.2
23
recovery of 1 (94)
a Reaction of 1 (1 mmol) was carried out in air. b Isolated yield based on the pyrazolidinedione 1 used. c Reaction was carried out in the dark. d Cp )
cyclopentyl. e Ammonium cerium(IV) nitrate.
2888
Org. Lett., Vol. 5, No. 16, 2003

Scheme 4
Table 2. Manganese(III)-Catalyzed Oxidation of the
5-Substituted 1,3-Dimethylbarbituric Acids 4a
yield (%)b
entry
R group of 4
Bn
Bn
Bn
Bn
Bn
i-Pr
time (h)
5
6
1
2
3
4
5c
6
7
8
9
2
3
5
18
90
88
79
78
47
80
94
94
88
7
18
15
43
30 min
4
4
4
2
4-MeOC6H4CH2
2-MeOC6H4CH2
2-naphthyl-CH2
a Reaction was carried out in glacial acetic acid (30 mL) at 23 °C in air
at the molar ratio of 4 (1 mmol):Mn(OAc)3 ) 1:0.1. b Isolated yield based
on 4 used. c Reaction with CAN was conducted in methanol (30 mL) at 0
°C at the molar ratio of 4 (1 mmol):CAN ) 1:1.
Since the second process would regenerate the catalyst and
it is well-known that metal ions, e.g., Cu(I) or Co(II), can
reduce the peroxyl radical to the corresponding anion,20 we
assumed that a similar reduction could be possible with Mn-
(II) or Ce(III). Therefore, path 2 is probably the major route
to the product. Involvement of the peroxyl radicals, as well
as the hydroperoxide intermediates, during the transition
metal-catalyzed autoxidation of different 1,3-dicarbonyl
compounds has been already proposed;11,18 however, there
is only one report on the detection and identification of such
peroxyl radicals by the electron spin resonance measurement.18d
To the best of our knowledge, there is no report on the
isolation and characterization of 2-hydroperoxy-1,3-dicar-
bonyl compounds via the transition metal-catalyzed autoxi-
dation. The formation of hydroxyl derivatives 3 and 6 can
be attributed to the decomposition of the corresponding
hydroperoxides 2 and 5. We scrutinized several decomposi-
tion reactions of 2 and 5 under different reaction conditions
(Table 3). As a result, we determined that the decomposition
of 2 and 5 is neither thermal21 (Table 3, entry 1) nor
photochemical14 (Table 3, entry 3) in nature; instead,
hydroperoxides 2 and 5 are decomposed to the corresponding
alcohols 3 and 6 by the redox reaction of the Mn(III)/Mn(II)
2-5). Furthermore, the hydroperoxide 5 (R ) Bn) was
deoxygenated with triphenylphosphine in diethyl ether to give
the corresponding 6 in 80% yield.
Scheme 3
To rationalize our experimental result, we presumed that
the formation of the Mn(III)-enolate or Ce(IV)-enolate
complex A in situ undergoing a one-electron transfer to give
the 1,3-dicarbonyl radical B and the reduced metal ions
(Scheme 4).9,17 The 1,3-dicarbonyl radical B could be trapped
by dissolved molecular oxygen in the solution to give the
peroxyl radical C.18 This radical C could either (1) take up
a hydrogen atom from another substrate molecule19 or solvent
or (2) be reduced by Mn(II)17a,b or Ce(III)9 to give the
corresponding hydroperoxyl anion D, which would be
subsequently protonated to give the products 2, 5, and 8.
Table 3. Metal Ion-Mediated Decomposition of
Hydroperoxides 2 and 5a
(13) Reaction was quenched by adding water, and extraction with
dichloromethane, followed by silica gel column chromatographic separation,
gave 2.
ROOH: time, ROH
recovered
entry ROOH
catalyst
catalyst
h
(%)b ROOH (%)
(14) (a) Boyaci, F. G.; Takac¸, S.; O¨ zdamar, T. H. ReV. Chem. Eng. 2000,
16, 249-299. (b) Dannley, R. L.; Jalics, G. J. Org. Chem. 1965, 30, 3848-
3851.
(15) (a) Bojarski, J. T.; Mokrosz, J. L.; Barton, H. J.; Paluchowska, M.
H. In AdVances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Aca-
demic: New York, 1985; Vol. 38, pp 229-297. (b) Jursic, B. S.; Neumann,
D. M. Tetrahedron Lett. 2001, 42, 4103-4107.
(16) (a) Detsi, A.; Bardakos, V.; Markopoulos, J.; Igglessi-Markopoulou,
O. J. Chem. Soc., Perkin Trans. 1 1996, 2909-2313 and references therein.
(b) McQuaid, L. A.; Smith, E. C. R.; Lodge, D.; Pralong, E.; Wikel, J. H.;
Calligaro, D. O.; O’Malley, P. J. J. Med. Chem. 1992, 35, 3423-3425.
(17) (a) Yamada, T.; Iwahara, Y.; Nishino, H.; Kurosawa, K. J. Chem.
Soc., Perkin Trans. 1 1993, 609-616. (b) Qian, C.-Y.; Nishino, H.;
Kurosawa, K. J. Org. Chem. 1993, 58, 4448-4451. (c) Buono-Core, G.
E.; Chow, Y. L. J. Am. Chem. Soc. 1986, 108, 1234-1239.
1
2
3d
4e
5f
6
2c
2c
2c
2c
2c
5g
none
23
23
23
14
2
2 (100)
Mn(OAc)3
Mn(OAc)3
Mn(OAc)2
CAN
1:0.1
1:0.1
1:1
1:1
1:0.4
3 (47)
3 (47)
3 (25)
3 (47)
6 (40)
2 (32)
2 (33)
2 (66)
2 (33)
5 (50)
Mn(OAc)3
23
a Reaction of 2 and 5 (1 mmol) was carried out at 23 °C in glacial acetic
acid (30 mL) in air except for entry 5. b Isolated yield based on the
hydroperoxide used. c R ) i-Pr. d Reaction was conducted in the dark.
e Reaction was carried out under an argon atmosphere. f Reaction of 2 (1
mmol) was carried out at 0 °C in methanol (30 mL) in air. g R ) Bn.
Org. Lett., Vol. 5, No. 16, 2003
2889

and Ce(IV)/Ce(III) couples, which is typical for the decom-
position of alkylhydroperoxides by manganese and cobalt
ions.22
In summary, we have demonstrated for the first time that
the manganese(III)-catalyzed autoxidation of heterocyclic
1,3-dicarbonyl compounds provided the corresponding hy-
droperoxides in excellent yields. 4-Benzyl-4-hydroperoxy-
1,2-diphenylpyrazolidine-3,5-dione (2, R ) Bn) showed a
weak antimalarial activity.23
Acknowledgment. This research was supported by
Grants-in-Aid for Scientific Research on Priority Areas (A)
“Exploitation of Multi-Element Cyclic Molecules”, Nos.
13029088 and 14044078, from the Ministry of Education,
Culture, Sports, Science and Technology, Japan, and also
by Grants-in-Aid for Scientific Research, Nos. 13640539 and
15550039, from the Japan Society for the Promotion of
Science. We thank Professor Emeritus Kazu Kurosawa,
Kumamoto University, Japan, for his helpful discussions and
suggestions. We also gratefully acknowledge Professor Teruo
Shinmyozu and Dr. Mikio Yasutake, Institute for Materials
Chemistry and Engineering, Kyushu University, Japan, for
their crystallographic assistance and Professor Yusuke
Wataya, Laboratory of Drug Informatics, Faculty of Phar-
maceutical Science, Okayama University, Japan, for his
antimalarial screening testing.
(18) (a) Ohshima, T.; Sodeoka, M.; Shibasaki, M. Tetrahedron Lett. 1993,
34, 8509-8512. (b) Lamarque, L.; Me´ou, A.; Brun, P. Can. J. Chem. 2000,
78, 128-132. (c) Ye, J.-H.; Xue, J.; Ling, K.-Q.; Xu, J.-H. Tetrahedron
Lett. 1999, 40, 1365-1368. (d) Neumann, B.; Mu¨ller, S. C.; Hauser, M. J.
B.; Steinbock, O.; Simoyi, R. H.; Dalal, N. S. J. Am. Chem. Soc. 1995,
117, 6372-6373.
(19) Tona, M.; Guardiola, M.; Fajari, L.; Messeguer, A. Tetrahedron
1995, 51, 10041-10052.
(20) Ling, K.-Q.; Lee, Y.; Macikenas, D.; Protasiewicz, J. D.; Sayre, L.
M. J. Org. Chem. 2003, 68, 1358-1366 and references therein.
(21) (a) Hiatt, R.; Irwin, K. C. J. Org. Chem. 1968, 33, 1436-1441. (b)
Stannett, V.; Mesrobian, R. B. J. Am. Chem. Soc. 1950, 72, 4125-4130.
(22) (a) Sheldon, R. A.; Kochi, J. K. Metal-Catalyzed Oxidations of
Organic Compounds; Academic: New York, 1981. (b) Hiatt, R.; Irwin, K.
C.; Gould, C. W. J. Org. Chem. 1968, 33, 1430-1435. (c) Hirano, K.;
Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2002, 43, 3617-3620.
(23) Antimalarial test was performed at the Laboratory of Drug Infor-
matics, Faculty of Pharmaceutical Science, Okayama University, Japan.
Supporting Information Available: Experimental pro-
cedures and full characterization for compound 2 (R ) Bn)
including a selected X-ray data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL034939B
2890
Org. Lett., Vol. 5, No. 16, 2003