Synthesis of asymmetric peroxides: Transition metal (Cu, Fe, Mn, Co) catalyzed peroxidation of β-dicarbonyl compounds with tert -butyl hydroperoxide

Article abstract of DOI:10.1021/jo100793j

(Figure presented) The transition metal (Cu, Fe, Mn, Co) catalyzed peroxidation of β-dicarbonyl compounds at the α position by tert-butyl hydroperoxide was discovered. A selective, experimentally convenient, and gram-scale method was developed for the syn

Full text of DOI:10.1021/jo100793j

pubs.acs.org/joc
Synthesis of Asymmetric Peroxides: Transition Metal (Cu, Fe, Mn, Co)
Catalyzed Peroxidation of β-Dicarbonyl Compounds
with tert-Butyl Hydroperoxide
Alexander O. Terent’ev,*,† Dmitry A. Borisov,† Ivan A. Yaremenko,†
Vladimir V. Chernyshev,‡,§ and Gennady I. Nikishin†
†N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky prosp.,
119991 Moscow, Russian Federation, ‡Department of Chemistry, Moscow State University,
119992 Moscow, Russian Federation, and A. N. Frumkin Institute of Physical Chemistry
and Electrochemistry, 31 Leninsky prosp., 119991 Moscow, Russian Federation
§
terentev@ioc.ac.ru
Received April 26, 2010
The transition metal (Cu, Fe, Mn, Co) catalyzed peroxidation of β-dicarbonyl compounds at the
R position by tert-butyl hydroperoxide was discovered. A selective, experimentally convenient, and
gram-scale method was developed for the synthesis of R-peroxidated derivatives of β-diketones,
β-keto esters, and diethyl malonate. Virtually stoichiometric (2-3/1) molar ratios of tert-butyl
hydroperoxide and a dicarbonyl compound were used in the reactions with β-diketones and β-keto
esters. The target compounds were synthesized in the highest yields from β-keto esters (45-90%) and
in somewhat lower yields from β-diketones (46-75%) and malonates (37-67%).
Introduction
or higher than that of artemisinin.4 Peroxides having anti-
tumor5 or growth-regulatory activity6 were also documented.
In the past decades, organic peroxides have received con-
siderable attention from chemists and drug design experts
because of their potential as drugs for the treatment of para-
sitic diseases, such as malaria1,2 and helminth infections.3
Considerable progress has been made in the design of effective
peroxide antimalarial drugs. Thus, the natural peroxide art-
emisinin and its semisynthetic derivatives are widely used in
medicine. Some synthetic peroxides exhibit activity equal to
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DOI: 10.1021/jo100793j
r
Published on Web 06/30/2010
J. Org. Chem. 2010, 75, 5065–5071 5065
2010 American Chemical Society

Terent’ev et al.
JOCArticle
As a result of their availability and high efficiency, organic
peroxides play a leading part as radical polymerization ini-
tiators in the industrial synthesis of such polymeric materials
as polyacrylates, polystyrene, styrene-containing rubbers,
and high-pressure polyethylene and are also used as cross-
linking agents.
The design of peroxide-based explosives is of particular
interest. Triacetone triperoxide is one of the most sensitive
known explosives with an explosive power similar to that of
trinitrotoluene.7 Peroxide derivatives of other lower ketones
and aldehydes can also be of interest as high-energy substances.
The present study is a continuation of our research on the
peroxidation of β-dicarbonyl compounds.8 It was found for
the first time that transition metals (Cu, Fe, Mn, and Co)
catalyze the selective peroxidation of β-dicarbonyl compounds
at the R position by tert-butyl hydroperoxide.
catalyzed by metal salts and their complexes: copper,10 cobalt,11
and iron,12 including Gif13 and metalloporphyrin14 catalysis.
Peroxides were synthesized in high yields by the peroxidation
of amines, amides, and lactams catalyzed by ruthenium salts.15
Hydroxylation reactions of β-dicarbonyl compounds at
the R position, which are related to the peroxidation dis-
covered in the present study, were extensively studied in the
past two decades. Generally, the oxidation was carried out
with the use of peracids,16 dimethyldioxirane,17 hydrogen
peroxide,18 or oxygen.19 In the studies with the use of oxygen,
the formation of peroxide compounds was observed in the
following cases: the oxidation of ring-containing β-diketones
by singlet oxygen,19a reactions with the use of the CeCl3/O2
system,19b and reactions of nitrogen-containing heterocyc-
lic compounds bearing a β-dicarbonyl fragment with the
Mn(OAc)2/O2 system19c
The transition metal (Cu, Mn, Co)/hydroperoxide system
was used for the first time by Kharasch in the synthesis of
peroxides from alkenes, ketones, and tertiary amines more
than six decades ago.9 Since that time, the research on and
application of this peroxidation method have been documen-
ted in numerous publications. The formation of peroxides
has been observed in various reactions of hydroperoxides
Results and Discussion
In the present study, we found that the transition metal
(Cu, Co, Mn, Fe)/tert-butyl hydroperoxide system can be
used for the peroxidation of β-dicarbonyl compounds at the
R position. The peroxidation of β-dicarbonyl compounds
occurs with high selectivity, does not require the use of a sub-
stantial excess of the reactants, and is easily scaled. R-Substituted
β-keto esters 1a-f, β-diketones 2a,b,d,e,g,h, and β-diesters
3a,e,f,h were used as the starting compounds for the synthesis
of target peroxides 4a-f, 5a,b,d,e,g,h, and 6a,e,f,h (Scheme 1).
In the context of this peroxidation reaction, it should be
noted that in the past decade β-dicarbonyl compounds have
found use in oxidative coupling with alkanes, alkenes, amines,
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JOCArticle
SCHEME 1. Synthesis of R-tert-Butylperoxy-β-dicarbonyl
Compounds 4-6
best result was obtained under the conditions when one
additional portion of the catalyst and tert-butyl hydroper-
oxide was added 30 min after the beginning of the reaction
(entries 8 and 10). In these reactions, we achieved conver-
sions of 94% and 85% and obtained compound 4a in 48%
and 67% yield, respectively (with respect to the reactant
used). Apparently, the repeated addition of the catalyst and
tert-butyl hydroperoxide leads to a decrease in their con-
sumption in side reactions.
Since we failed to achieve the complete conversion of dike-
tone 1a and a high yield of 4a in the reactions catalyzed by
Cu(OAc)2 H2O, the subsequent experiments (entries 11-18)
3
were performed with the use of other salts, such as Cu-
(ClO4)2 6H2O and Cu(BF4)2 6H2O (with the strong electron-
withdrawing anion). In the reaction catalyzed by Cu(ClO4)2
3
3
3
6H2O, the complete conversion of dicarbonyl compound 1a was
observed, and the target peroxide 4a was prepared in 90% yield
(entries 13 and 14). Application of dry ButOOH practically has
no effect on the yield of the peroxide 4a (entry 14, footnote d).
esters, and compounds containing the benzyl group.20 In
some studies, the coupling reactions were carried out with the
use of tert-butyl hydroperoxide,20b-d bis(tert-butyl) peroxide,20d
or tert-butyl perbenzoate20d,e as oxidants in the presence of
catalytic amounts of transition metal (Cu, Fe, Co) salts. As a
result of the high selectivity of these reactions, the formation
of peroxides of β-dicarbonyl compounds was observed in none
of the studies. In this context, the coupling of β-dicarbonyl
compounds with tert-butyl hydroperoxide that acts simulta-
neously as the oxidant and the second reaction component
was unexpected.
The present study was performed in several steps. First, we
examined the possibility of performing the peroxidation of
these compounds by investigating the reactions of R-benzyl-
substituted derivatives of acetoacetic ester 1a, acetylacetone
2a, and malonic ester 3a and optimized the reaction condi-
tions (the reagent ratio, the nature of the catalyst, and the sol-
vent). Then we synthesized a series of asymmetric peroxides
with the aim of evaluating the scope of the reaction and pre-
paring the previously unknown compounds.
The experiment with the use of Cu(BF4)2 6H2O (entry 18)
3
also gave a good result (yield of 4a was 79%). In the reactions
catalyzed by the copper salts Cu(acac)2, CuCl, CuCl2 2H2O,
3
and CuSO4 5H2O (entries 19-23), the manganese salt Mn-
3
(OAc)2 4H2O (entry 24), and the iron salts FeCl3, Fe(acac)3
3
(entries 25 and 26), we did not obtain satisfactory results.
In addition to the experimental results presented in Table 1,
we carried out reactions with the use of the salts Co(OAc)2,
Co(ClO4)2 6H2O, Co(acac)2, CoCl2 6H2O, H7[P(Mo2O7)6]
3
3
3
nH2O, and RuCl3 nH2O as the catalysts under the condi-
3
tions of the best experiment (entry 13). In the presence of Co-
containing catalysts, peroxide 4a was obtained only in trace
amounts. The reactions catalyzed by Mo- or Ru-containing
compounds did not afford 4a at all. The formation of per-
oxide 4a was not observed also in the reactions catalyzed by
main-group metal perchlorates (MgClO4 and KClO4).
R-Benzylacetylacetone 2a (the structural analogue of keto
ester 1a) was also used for the optimization of the peroxida-
tion with tert-butyl hydroperoxide. In this case, we obtained
R-benzyl-R-tert-butylperoxyacetylacetone 5a (Table 2).
In this case, as in the peroxidation of keto ester 1a (Table 1),
the copper salts Cu(ClO4)2 and Cu(BF4)2 proved to be the
catalysts of choice (entries 2-8). In these reactions, the com-
plete conversion of 2a was achieved, and R-benzyl-R-tert-
butylperoxyacetylacetone 5a was obtained in 73% (entry 6)
and 69% (entry 8) yields. The main difference of the peroxi-
dation of diketone 2a from that of keto ester 1a is that the
cobalt salts CoCl2 6H2O, Co(acac)2, andCo(ClO4)2 6H2O can
We chose R-benzylacetoacetic ester 1a as one of the main
reactants for the optimization of the conditions of peroxida-
tion. This reactant contains two centers, CH and PhCH2,
active in oxidative reactions (Table 1). The reaction of ester
1a with tert-butyl hydroperoxide afforded R-benzyl-R-tert-
butylperoxyacetoacetic ester 4a.
The reactions were performed with the copper salts Cu-
(OAc)2 H2O, Cu(ClO4)2 6H2O, Cu(BF4)2 6H2O, Cu(acac)2,
3
3
3
CuCl, CuCl2 2H2O, and CuSO4 5H2O (entries 1-23), the man-
3
3
ganesesaltMn(OAc)2 4H2O (entry 24), and the iron salts FeCl3
3
3
3
and Fe(acac)3 (entries 25 and 26). In all of the reactions presen-
ted in Table 1, the peroxidation occurred selectively at the CH
fragment, whereas the benzyl CH2 fragment remained intact.
According to entries 1-4, acetonitrile proved to be the
solvent of choice for the peroxidation; neither acetic acid nor
ethanol are suitable for this purpose.
also catalyze the peroxidation (entries 10-12). The iron salts
Fe(acac)3 and FeCl3 (entries 13 and 14) and the manganese salt
Mn(OAc)2 4H2O (entry 15) are ineffective as the catalysts.
3
In addition to the experiments presented in Table 2, we
tested the catalysts H7[P(Mo2O7)6] nH2O and RuCl3 nH2O
3
3
under the optimized conditions (see entry 5). These catalysts
proved to be ineffective in the peroxidation of diketone 2a.
On the whole, diketone 2a is characterized by higher reac-
tivity compared to keto ester 1a. The peroxidation of 2a can
be performed with the use of a wide range of metal salts and,
under analogous reaction conditions, the complete conver-
sion of 2a is achieved 2-4 times faster compared to 1a.
Diethyl R-benzylmalonate 3a (the structural analogue of 1a
and 2a) was used as the third starting compound for the optimi-
zation of the conditions of peroxidation. The reaction of this
In entries 5-10, we evaluated the effect of the amount of
the catalyst Cu(OAc)2 H2O (varied from 0.05 to 0.2 mol of
the catalyst per mole of 1a) and the order of its addition on
the conversion and the yield of the target peroxide 4a. The
3
(20) (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335–344. (b) Li, Z.; Li, C.-J.
J. Am. Chem. Soc. 2006, 128, 56–57. (c) Yoo, W.-J.; Li, C.-J. J. Org. Chem.
2006, 71, 6266–6268. (d) Li, Z.; Cao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2007,
46, 6505–6507. (e) Borduas, N.; Powell, D. A. J. Org. Chem. 2008, 73, 7822–
7825. (f) Correia, C. A.; Li, C.-J. Tetrahedron Lett. 2010, 51, 1172–1175.
J. Org. Chem. Vol. 75, No. 15, 2010 5067

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TABLE 1. Transition Metal Salt Catalyzed Peroxidation of R-Benzylacetoacetic Ester 1a with tert-Butyl Hydroperoxidea
moles t-BuOOH
per mole 1a
moles catalyst
per mole 1a
entry
catalyst
reaction time, h
solvent
CH3CN
CH3CN
conv of 1a, %
yield of 4a, %
1
2
3
4
5
6
2
2
2
2
2
3
5
Cu(OAc)2 H2O
3
0.05
0.05
0.05
0.05
0.1
1
2
1
1
1
2
2
67
75
trace
trace
71
77
52
94
85
62
52
0
0
60
50
38
48
33
67
87
Cu(OAc)2 H2O
3
Cu(OAc)2 H2O
3
EtOH
Cu(OAc)2 H2O
3
CH3COOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
EtOH
CH3COOH
CH3CN
CH3CN
CH3CN
CH3CN
Cu(OAc)2 H2O
Cu(OAc)2 H2O
3
0.1
0.1
3
7
Cu(OAc)2 H2O
Cu(OAc)2 H2O
3
8b
9
2 Â 2
2 Â 0.05
2 Â 1
3
2
Cu(OAc)2 H2O
Cu(OAc)2 H2O
0.2
3
3
10b
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
2 Â 2
2 Â 0.1
0.05
0.1
0.1
0.1
0.2
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.1
0.1
0.1
2 Â 0.5
85
100
83
3
2
2
2
3
2
2
2
2
2
2
2
2
2
2
2
2
Cu(ClO4)2 6H2O
3
1
0.5
1
1
1
1
1
1
1
1
1
1
1
1
1
1
Cu(ClO4)2 6H2O
Cu(ClO4)2 6H2O
76
3
100
100
100
trace
trace
100
60
trace
16
43
90 (88)c
90 (87)d
74
3
Cu(ClO4)2 6H2O
Cu(ClO4)2 6H2O
3
3
Cu(ClO4)2 6H2O
Cu(ClO4)2 6H2O
0
0
79
3
3
Cu(BF4)2 6H2O
3
Cu(acac)2
CuCl
CuCl2 2H2O
40
trace
trace
41
14
21
3
CuSO4 5H2O
3
CH3CN/H2O (4:1)
CH3CN/H2O (4:1)
CH3CN
CH3CN
CH3CN
CuSO4 5H2O
3
42
33
50
10
Mn(OAc)2 4H2O
3
FeCl3
Fe(acac)3
24
trace
0.1
aGeneral reaction conditions. The catalyst (0.05-0.2 mol per mole of 1a) and a 70% aqueous ButOOH solution (2-5 mol per mole of 1a) were added
to a solution of keto ester 1a (0.3 g, 1.36 mmol) in the solvent (CH3CN, EtOH, or CH3COOH) (5 mL). The reaction mixture was refluxed for 0.5-2 h (at a
temperature from 79 to 119 °C). bThe catalyst Cu(OAc)2 H2O and a 70% aqueous ButOOH solution were added to the reaction mixture in two portions.
3
The first portion was added in the beginning of the experiment, and another portion was added 1 h (entry 8) or 30 min (entry 10) after the beginning of the
reaction. cThe experiment was carried out under argon. dThe experiment was carried out with the use of dry ButOOH.
TABLE 2. Transition Metal Salt Catalyzed Peroxidation of R-Benzylacetylacetone 2a with tert-Butyl Hydroperoxidea
entry
moles t-BuOOH per mole 2a
catalyst
τ, h
conv of 2a, %
yield of 5a, %
1
2
2
2
2
3
3
5
3
3
3
3
3
3
3
2
Cu(OAc)2 H2O
3
1
1
87
87
100
71
100
100
100
100
38
100
98
trace
45
73
34
51
64
32
71
73
52
69
29
34
24
trace
23
12
15
2b
3
Cu(ClO4)2 6H2O
3
Cu(ClO4)2 6H2O
Cu(ClO4)2 6H2O
0.5
0.5
0.5
0.25
0.5
0.5
1
1
1
1
1
3
4c
5
6
7
8
9
10
11
12
13
14
15
3
Cu(ClO4)2 6H2O
Cu(ClO4)2 6H2O
3
3
Cu(ClO4)2 6H2O
Cu(BF4)2 6H2O
3
3
Cu(acac)2
CoCl2 6H2O
3
Co(acac)2
Co(ClO4)2 6H2O
3
Fe(acac)3
FeCl3
Mn(OAc)2 4H2O
1
1
86
3
aGeneral reaction conditions. The catalyst (13-30 mg, 0.05 mol per mole of 2a) and a 70% aqueous ButOOH solution (0.41-1.03 g, 2-5 mol per mole
of 2a) were added to a solution of diketone 2a (0.3 g, 1.58 mmol) in CH3CN (5 mL). The reaction mixture was refluxed for 0.25-2 h (the temperature of
the reaction mixture was 79-81 °C). bThe reaction was performed with the use of 0.02 mol of Cu(ClO4)2 6H2O per mole of 2a. cThe temperature of the
3
reaction mixture was 58-60 °C.
5068 J. Org. Chem. Vol. 75, No. 15, 2010

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TABLE 3. Copper Perchlorate Catalyzed Peroxidation of Diethyl R-Benzylmalonate 3a with tert-Butyl Hydroperoxidea
entry
moles t-BuOOH per mole 3a
moles catalyst per mole 3a
reaction time, h
conv of 3a, %
yield of 6a, %
1
2
3
4
5
6
7
2
2
5
5
3
5
5
0.1
0.2
0.3
0.3
0.4
0.4
0.5
1
2
1
1.5
1
43
62
87
99
98
98
98
32
41
65
42
59
67
59
1
0.5
aGeneral reaction conditions. The catalyst Cu(ClO4)2Â6H2O (0.1-0.5 mol per mole of 3a) and a 70% aqueous ButOOH solution (2-5 mol per mole
of 3a) were added to a solution of diester 3a (0.3 g, 1.2 mmol) in CH3CN (5 mL). The reaction mixture was refluxed for 0.5-2 h (the temperature of the
reaction mixture was 79-81°C).
compound catalyzed by Cu(ClO4)2 6H2O, which was proved to
compound) oxidizes ButOOH to the ButOO radical (which is
consumed in step B) to form monovalent copper.10a,g,14
3
be the best catalyst for the reactions of keto ester 1a and diketone
2a (Table 3), afforded diethyl R-benzyl-R-tert-butylmalonate 6a.
In entries 1-7, it was shown that the virtually complete con-
version of diester 3a can be achieved with the use of a 5-fold
molar excess of tert-butyl hydroperoxide in the presence of
the catalyst (30-50 mol %), which is substantially higher
compared to the reactions of keto ester 1a and diketone 2a.
Therefore, a comparison of the reactions of three dicarbo-
nyl compounds 1a, 2a, and 3a under analogous conditions
showed that the keto ester gave the target peroxide 4a in the
highest yield (90%), the peroxidation of the diketone resul-
ted in a lower yield (5a, 73%), whereas the reaction of the
diester produced peroxide 6a in the lowest yield (67%). The
complete conversion of diketone 2a is achieved most rapidly
(15 min), whereas 1 h is required for the complete conversion
of keto ester 1a and diester 3a.
With the aim of evaluating the scope of the peroxidation
with respect to other dicarbonyl compounds and preparing
previously unknown compounds, we synthesized peroxides
4-6 under the optimized reaction conditions (Table 4).
On the basis of the results of the synthesis of structurally
different peroxides in 37-90% yields, it could be expected
that the above-described method for the peroxidation can be
extended to other R-substituted β-dicarbonyl compounds.
Proposed Reaction Mechanism. Taking into account the
data published in the literature,20 it can be suggested that the
peroxidation of β-dicarbonyl compounds I occurs according to
Scheme 2 (as exemplified by the use of copper salts as the cata-
lyst). In step A, β-dicarbonyl compound I and CuII give com-
plex II, which reacts with the ButOO radical (step B) to form the
target peroxide III and CuI. In step C, monovalent copper is
oxidized by tert-butyl hydroperoxide to give CuII and the
ButO radical, which abstracts hydrogen from the tert-butyl
hydroperoxide molecule (step D) to form the ButOO radical (or
its complex with metal),10b,11b,21 which is consumed in the step
B. The ButOO radical can also be generated in the process E,
according to which CuII (as a salt or complex II with a dicarbonyl
The possibility that the reaction occurs through step B (the
transformation of II into III) was confirmed experimentally (see
Supporting Information). Thus, the copper complex, which was
prepared from R-benzylacetylacetone 2a according to a known
method,22 was subjected to peroxidation, resulting in the forma-
tion of peroxide 5a in 44% yield. This experiment, as well as ano-
ther experiment with the use of the copper complex of R-benzyl-
acetylacetone in catalytic amounts (5 mol %, the conversion of
2a was 63%, the yield of 5a was 23%, see Supporting Informa-
tion), partially confirmed step E, according to which complex II
oxidizes tert-butyl hydroperoxide to the ButOO radical.
Apparently, the efficiency of the catalyst Cu(ClO4)2 (like
that of Cu(BF4)2) in the peroxidation is determined primarily
by a combination of three factors. First, copper(II) perchlo-
rate can be involved in the reaction with β-dicarbonyl com-
pounds to form complexes.23,24 As a result, the reaction mixture
contains, in addition to the starting diketone I and Cu(ClO4)2,
complex II. Second, Cu(ClO4)2 acts as a strong oxidant in
acetonitrile;25 this salt is a stronger oxidant compared to Cu-
(NO3)2 and CuCl2.26 As a result of this property, Cu(ClO4)2
rapidly oxidizes tert-butyl hydroperoxide to the ButOO radical.
Third, the efficiency of Cu(ClO4)2 as the catalyst is manifested
in that monovalent copper that is generated (apparently, as
CuClO4) in the step B readily forms the complex with aceto-
nitrile of composition CuClO4 4CH3CN, 27 which is relatively
3
easily oxidized by tert-butyl hydroperoxide to divalent copper
(step C), thus providing its regeneration.
As for the reaction mechanism of peroxidation, it should
be noted that the reactions with unsubstituted acetylacetone,
acetoacetic ester, and malonic ester afford complex mixtures
of products. This is attributed to the fact that compound III
containing the hydrogen atom and the ButOO group in the
(22) Dryden, R.; Winston, A. J. Org. Chem. 1958, 62, 635–637.
(23) El-Ayaan, U.; El-Metwally, N. M.; Youssef, M. M.; El Bialy,
S. A. A. Spectr. Acta Part A 2007, 68, 1278–1286.
(24) Sekine, T.; Inaba, K.; Morimoto, T. Anal. Sci. 1986, 2, 535–540.
(25) (a) Kratochvil, B.; Zatko, D. A.; Markuszewski, R. Anal. Chem. 1966,
38, 770–772. (b) Kratochvil, B.; Quirk, P. F. Anal. Chem. 1970, 42, 492–495.
(c) Mruthyunjaya, H. C.; Murthy, A. R. V. Indian J. Chem. 1969, 7, 403–406.
(26) Mruthyunjaya, H. C.; Murthy, A. R. V. Indian J. Chem. 1973, 11,
481–484.
(21) (a) Minisci, F.; Fontana, F.; Araneo, S.; Recupero, F.; Zhao, L.
Synlett 1996, 119–125. (b) Avila, D. V.; Ingold, K. U.; Lusztyk, J.; Green,
W. H.; Procopio, D. R. J. Am. Chem. Soc. 1995, 117, 2929–2930. (c) Paul, H.;
Small, R. D.; Scaiano, J. C. J. Am. Chem. Soc. 1978, 100, 4520–4527.
(d) Barton, D. H. R.; Le Gloahec, V. N.; Patin, H.; Launay, F. New J.
Chem. 1998, 559–563.
(27) (a) Senne, J. K.; Kratochvil, B. Anal. Chem. 1971, 43, 79–82. (b) Persson,
I.; Penner-Hahn, J. E.; Hodgson, K. O. Inorg. Chem. 1993, 32, 2497–2501.
J. Org. Chem. Vol. 75, No. 15, 2010 5069

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TABLE 4. Structures and Yields of Peroxides 4-6 Derived from β-Dicarbonyl Compounds 1-3
aA 70% aqueous ButOOH solution (2 mol per mole of 1) was added to a solution of ethyl 2-substituted-3-oxobutanoates 1 (0.3 g) and Cu(ClO4)2
3
6H2O (0.1 mol per mole of 1) in CH3CN (5 mL). The reaction mixture was refluxed at 79-81 °C for 1 h. bA 70% aqueous ButOOH solution (3 mol per
mole of 2) was added to a solution of 3-substituted-2,4-dione 2 (0.3 g) and catalyst Cu(ClO4)2 6H2O (0.05 mol per mole of 2) in CH3CN (5 mL). The
reaction mixture was refluxed at 79-81 °C for 15 min. cA 70% aqueous ButOOH solution (5 mol per mole of 3) was added to a solution of diethyl
3
2-substituted malonate 3 (0.3 g) and catalyst Cu(ClO4)2 6H2O (0.4 mol per mole of 3) in CH3CN (5 mL). The reaction mixture was refluxed at 79-81 °C
3
for 1 h. dThe experiments on the synthesis of 4a and 5g were scaled up to 10 times larger amounts of the reactants.
R position apparently gives complex II (R=ButOO) containing
the unstable vinyl peroxide moiety, as well as to the fact that the
second ButOO group can be incorporated into the molecule to
form diperoxides unstable under the reaction conditions.
It is possible that the target peroxides are generated in
insignificant amounts according to the mechanism of recom-
bination of the following radicals: the ButOO radical (or its
complex with metal) and the C-centered radical, which is
formed through the abstraction of hydrogen from the R-CH
fragment of β-dicarbonyl compounds by the ButOO and
ButO radicals9a,10d,11b,13,28 or through the oxidation of the
dicarbonyl compounds by metal ions.29 However, the re-
combination of the radicals is unlikely because the dimers of
dicarbonyl compounds, which are generally formed by the
radical coupling of two C-centered radicals, were not detected,30
and the peroxidation of R-allylacetylacetone 2h was not accom-
panied by its oligomerization. In the experiment on the peroxi-
dation of R-benzylacetoacetic ester 1a in the presence of a 5-fold
molar excess of allyl acetate, the formation of the product of the
radical addition at the CdC bond was not observed; the target
peroxide 4a was obtained in 86% yield (the experiment is
described in Supporting Information). It should be noted that
the radical addition of ketones to compounds containing the
double bond are well-known and are typical of C-centered
radicals generated from ketones.31
(28) Kochi, J. K. Tetrahedron 1962, 18, 483–497.
(29) (a) Citterio, A.; Santi, R.; Fiorani, T.; Strologo, S. J. Org. Chem.
1989, 54, 2703–2712. (b) Santi, R.; Bergamini, F.; Citterio, A.; Sebastiano,
R.; Nicolini, M. J. Org. Chem. 1992, 57, 4250–4255.
(30) (a) Iqbal, J.; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519–564.
(b) Snider, B. B. Chem. Rev. 1996, 96, 339–363. (c) Liu, Y. C.; Romero, J. R.
Tetrahedron Lett. 1995, 36, 8757–8760. (d) Bukhtiarov, A. V.; Golyshin,
V. N.; Tomilov, A. P.; Kuz’min, O. V. J. Gen. Chem. USSR (Engl. Transl.)
1988, 58, 139–146.; Zh. Obshch. Khim. 1988, 58, 157-165. (e) Vessels, J. T.;
Janicki, S. Z.; Petillo, P. A. Org. Lett. 2000, 2, 73–76.
(31) (a) Vinogradov, M. V.; Verenchikiov, S. P.; Nikishin, G. I. Izv. Akad.
Nauk. SSSR, Ser. Khim. 1971, 200–201. (b)Snider, B. B.;Kwon, T.J. Org. Chem.
1990, 55, 1965–1968. (c) Cali-skan, R; Pekel, T.; Watson, W. H.; Balci, M.
Tetrahedron Lett. 2005, 46, 6227–6230. (d) Nair, V.; Mathew, J.; Prabhakaran, J.
Chem. Soc. Rev. 1997, 127–132. (e) Ogibin, Yu. N.; Terent’ev, A. O.; Ananikov,
V. P.; Nikishin, G. I. Russ. Chem. Bull., Int. Ed. 2001, 50, 2149–2155. (f) Hirase,
K.; Iwahama, T.; Sakaguchi, S.; Ishii, Y. J. Org. Chem. 2002, 67, 970–973.
5070 J. Org. Chem. Vol. 75, No. 15, 2010

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SCHEME 2. Proposed Reaction Mechanism of Peroxidation of
β-Dicarbonyl Compounds Exemplified by the Use of Copper Salts
As the Catalyst
Experimental Section
Caution: Although we have encountered no difficulties in
working with peroxides, precautions, such as the use of shields,
fume hoods, and the avoidance of transition metal salts, heating,
and shaking, should be taken whenever possible.
Synthesis of Ethyl 2-Benzyl-2-(tert-butylperoxy)-3-oxobuta-
noate 4a (entry 13, Table 1). A 70% aqueous ButOOH solution
(0.35 g, 2.72 mmol, 2 mol per mole of 1a) was added to a solution
of 2-benzyl-3-oxobutanoate 1a (0.3 g, 1.36 mmol) and Cu(ClO4)2
3
6H2O (0.05 g, 0.136 mmol, 0.1 mol per mole of 1a) in CH3CN
(5 mL). The reaction mixture was refluxed at 79-81 °C for 1 h,
cooled to 20-25 °C, poured into water (40 mL), stirred, and
extracted with CH2Cl2 (3 Â 10 mL). The combined extracts were
washed with water (3 Â 10 mL), dried over Na2SO4, and filtered.
The filtrate was evaporated using a water-jet vacuum pump. The
residue was chromatographed using a petroleum ether-ethyl
acetate system with an increase in the fraction of the latter solvent
from 0 to 20%. Product 4a was obtained in 90% yield (0.38 g, 1.23
mmol). Colorless oil. Rf=0.68 (TLC, hexane-ethyl acetate, 5:1).
1H NMR (300.13 MHz, CDCl3), δ:1.21(t, 3H, J=7.3 Hz), 1.30 (s,
9H), 1.89 (s, 3H), 3.44 (dd, 2H, J=13.9, 69.7 Hz), 4.10-4.23 (m,
2H), 7.16-7.26 (m, 5H). 13C NMR (75.48 MHz, CDCl3), δ: 13.8,
26.5, 27.0, 37.1, 61.5, 81.0, 92.6, 126.6, 127.9, 130.6, 134.9, 167.5,
203.4. Anal. Calcd for C17H24O5: C, 66.21; H, 7.84. Found: C,
66.32; H, 7.89.
Establishment of the Structures of the Peroxides. Peroxides
4a-c,e-f, 5b,d,e,g,h, and 6e,g,h are liquids. Peroxides 4d, 5a,
b, and 6a are solid compounds with mp varying from 34 to
36 °C (5a) to 109-110 °C (5b). The structures of these com-
pounds were established by 1H and 13C NMR spectroscopy,
mass spectrometry, and elemental analysis. The 13C NMR
spectra show characteristic signals for the carbon atoms of
the COOC(CH3)3 fragment at δ 85.41-97.16, 80.37- 81.79,
and 26.19-26.69. The retention of the characteristic signals
of the CdO group at δ 165.86-206.92 is important evidence
that this group remains intact in the reaction with tert-butyl
hydroperoxide. In the 1H NMR spectra, the absence of the
signal for the hydrogen atom of the R-CH fragment and the
presence of the signals of the CH3CO (δ 1.89- 2.24) and
C(CH3)3 (δ 1.23- 1.33) groups are the most characteristic data.
A reliable proof of the structures of organic peroxides,
even despite the NMR spectroscopic and elemental analysis
data, is generally a difficult problem. Hence, to determine
with certainty the structures of the peroxides, the structure of
compound 5b was established by X-ray diffraction study (the
molecular structure of 5b is shown in Supporting Informa-
tion), which confirmed the structures of these compounds.
Synthesis of 3-Benzyl-3-(tert-butylperoxy)pentane-2,4-dione
5a (entry 6, Table 2). A 70% aqueous ButOOH solution (0.61 g,
4.74 mmol, 3 mol per mole of 2a) was added to a solution of
3-benzylpentane-2,4-dione 2a (0.3 g, 1.58 mmol) and Cu(ClO4)2
3
6H2O (0.03 g, 0.08 mmol, 0.05 mol per mole of 2a) in CH3CN
(5 mL). The reaction mixture was refluxed at 79-81 °C for 15 min,
cooled to 20-25 °C, poured into water (40 mL), stirred, and ex-
tracted with CH2Cl2 (3 Â 10 mL). The isolation was carried out as
described in entry 13, Table 1. Product 5a was obtained in 73%
yield (0.32 g, 1.15 mmol). Yellowish crystals. Mp=34-36 °C. Rf=
0.74 (TLC, hexane-ethyl acetate, 10:1). 1H NMR (300.13 MHz,
CDCl3), δ: 1.33 (s, 9H), 1.98 (s, 6H), 3.36 (s, 2H), 7.14-7.27 (m,
5H). 13C NMR (75.48 MHz, CDCl3), δ: 26.6, 27.2, 37.1, 81.3, 97.0,
126.7, 128.0, 130.5, 135.0, 203.3. Anal. Calcd for C16H22O4: C,
69.04; H, 7.97. Found: C, 69.10; H, 7.94.
Synthesis of Diethyl 2-Benzyl-2-(tert-butylperoxy)malonate 6a
(entry 6, Table 3). A 70% aqueous ButOOH solution (0.77 g,
6 mmol, 5 mol per mole of 3a) was added to a solution of diethyl
2-benzylmalonate 3a (0.3 g, 1.2 mmol) and Cu(ClO4)2 6H2O
3
(0.178 g, 0.48 mmol, 0.4 mol per mole of 3a) in CH3CN (5 mL).
The reaction mixture was refluxed at 79-81 °C for 1 h, cooled to
20-25 °C, poured into water (40 mL), stirred, and extracted
with CH2Cl2 (3 Â 10 mL). The isolation was carried out as
described in entry 13, Table 1. Product 6a was obtained in 67%
yield (0.27 g, 0.8 mmol). White crystals. Mp =44-45 °C. Rf =
0.37 (TLC, hexane-ethyl acetate, 10:1). 1H NMR (300.13 MHz,
CDCl3), δ: 1.20 (t, 6H, J = 7.3 Hz), 1.29 (s, 9H), 3.50 (s, 2H),
4.11-4.21 (m, 4H), 7.14-7.28 (m, 5H). 13C NMR (75.48 MHz,
CDCl3), δ: 13.9, 26.5, 37.8, 61.6, 81.0, 87.9, 126.8, 127.9, 130.3,
134.9, 166.9. Anal. Calcd for C18H26O6: C, 63.89; H, 7.74.
Found: C, 63.76; H, 7.84.
Conclusion
Transition metal (Cu, Fe, Mn, Co) salts were found to cata-
lyze the peroxidation of R-substituted β-dicarbonyl compounds
at the R position by tert-butyl hydroperoxide. On the basis of
this reaction, we developed a selective and experimentally conve-
nient method for the synthesis of R-tert-butylperoxy-β-dicarbonyl
compounds. The synthesis is easily scaled without a decrease in
the yield of the target peroxides, which can be prepared in gram
amounts. The reactions are performed in acetonitrile with the
use of 5-40 mol % of the catalyst (Cu(ClO4)2 is the catalyst of
choice) and an aqueous solution of tert-butyl hydroperoxide
(2-3 mol per mole of a β-dicarbonyl compound). The reaction
is suitable for structurally different R-substituted β-dicarbonyl
compounds. The target peroxides are obtained in the highest
yields (up to 90%) from β-keto esters and in somewhat lower
yields from β-diketones (up to 75%) and malonates (up to 69%).
Acknowledgment. This work is supported by the Program
for Support of Leading Scientific Schools of the Russian
Federation (Grant NSh 4945.2010.3).
Supporting Information Available: Experimental proce-
dures for the synthesis of 4a-f, 5a,b,d,e,g,h, and 6a,e,f,h, their
1H and 13C NMR spectra, and details of X-ray data for 5b,
including CIF file. This material is available free of charge via
the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5071