Convenient synthesis of geminal bishydroperoxides by the reaction of ketones with hydrogen peroxide

Article abstract of DOI:10.1080/00397910701226384

A convenient procedure was developed for the synthesis of geminal bishydroperoxides by the sulfuric acid-catalyzed reaction of ketones with hydrogen peroxide in THF. Gem-bishydroperoxides were prepared by the reactions of five- to seven-membered cycloalkanones without additional purification in 80-95% yields with a purity of more than 95%; their acyclic analogs were prepared in 43-72% yields. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701226384

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Convenient Synthesis of Geminal
Bishydroperoxides by the Reaction of
Ketones with Hydrogen Peroxide
A. O. Terent'ev a , M. M. Platonov a , Y. N. Ogibin a & G. I. Nikishin a
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, Moscow, Russia
Published online: 13 Apr 2007.
To cite this article: A. O. Terent'ev , M. M. Platonov , Y. N. Ogibin & G. I. Nikishin (2007): Convenient
Synthesis of Geminal Bishydroperoxides by the Reaction of Ketones with Hydrogen Peroxide, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 37:8,
1281-1287
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Synthetic Communicationsw, 37: 1281–1287, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701226384
Convenient Synthesis of Geminal
Bishydroperoxides by the Reaction of
Ketones with Hydrogen Peroxide
A. O. Terent’ev, M. M. Platonov, Y. N. Ogibin, and
G. I. Nikishin
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, Moscow, Russia
Abstract: A convenient procedure was developed for the synthesis of geminal
bishydroperoxides by the sulfuric acid–catalyzed reaction of ketones with hydrogen
peroxide in THF. Gem-bishydroperoxides were prepared by the reactions of five- to
seven-membered cycloalkanones without additional purification in 80–95% yields
with a purity of more than 95%; their acyclic analogs were prepared in 43–72% yields.
Keywords: Alkanones, cycloalkanones, gem-bishydroperoxides, hydrogen peroxide,
hydroperoxidation, tetrahydrofuran
INTRODUCTION
In recent years, organic geminal bishydroperoxides and derived 1,2,4,5-
tetraoxanes have attracted considerable interest because of their antimalarial
activity.[1–8] In addition, gem-bishydroperoxides can find use as radical
polymerization initiators[9] and in the synthesis of dicarboxylic acid esters.[10]
There are three general procedures for the synthesis of gem-bishydro-
peroxides: the reaction of ketones with H2O2 in HCO2H, EtCO2H,
MeCN,[7,8,11–13] or trifluoroethanol (the reaction is catalyzed by methyl-
trioxorhenium);[14] ozonation of enol ethers in the presence of H2O2;[6–8]
Received in the U.K. April 24, 2006
Address correspondence to A. O. Terent’ev, N. D. Zelinsky Institute of Organic
Chemistry, Russian Academy of Sciences, 47 Leninsky prosp., 119991, Moscow,
Russia. E-mail: terentev@ioc.ac.ru
1281

1282
A. O. Terent’ev et al.
and hydroperoxidation of ketals catalyzed by tungstic acid[15] or boron tri-
fluoride complexes.[16,17] The former two methods produce gem-bishydro-
peroxides, for example, from 4-tert-butylcyclohexanone, cycloheptanone,
cyclododecanone, adamantanone, and enol ethers [such as, for example,
1-(methoxymethylene)cyclododecane, 1-tert-butyl-4-(methoxymethylene)cy-
clohexane, and 2-(methoxymethylene)adamantane], in moderate yields. Only
bishydroperoxide derived from 4-methylcyclohexanone was prepared in
good yield.[14] The use of ozonation is limited to enol ethers and alkenes
containing no ozone-sensitive groups. Gem-bishydroperoxides can be syn-
thesized in high yields (70–95%) only according to the last method.[15,16]
The drawback of this method is that it requires the preliminary transform-
ation of ketones into ketals. Hence, the development of more elaborate
methods for the synthesis of geminal bishydroperoxides is an important
issue.
RESULTS AND DISCUSSION
In the present study, we describe a modified procedure for the synthesis of bishy-
droperoxides based on the sulfuric acid–catalyzed reaction of ketones with
hydrogen peroxide (Table 1). This method is simpler, less laborious, and in
most cases gives the target products in higher yields than the previously
mentioned procedures. The distinguishing feature of the new method is that
the reactionof carbonyl compounds with H2O2 is performed in THF. Apparently,
THF efficiently solvates gem-bishydroperoxides, thus hindering their further
transformations, and consequently provides high selectivity of the synthesis,
substantially increases the yields, and improves the purity (Scheme 1).
Geminal bishydroperoxides 1–5 were prepared under the previously
mentioned conditions from five- to seven-membered cyclic ketones
without additional purification in 80–95% yields (see Table 1) with a
purity of 95%. The yield of gem-bishydroperoxide 8 containing the adaman-
tane fragment was 78%. Acyclic carbonyl compounds were transformed into
peroxides 9, 10, and 11 in 43%, 67%, and 72% yields, respectively. In the
analogous reactions performed in HCO2H, EtCO2H, or MeCN, the yields of
peroxides 1–5 were at most 50%, with the complete conversion of the
starting carbonyl compounds being achieved.[7,8,11–13] The complete conver-
sion of five- to seven-membered cycloalkanones, adamantan-2-one, and 4-
methylpentan-2-one in the presence of an eight- to ten-fold molar excess
of H2O2 and in the presence of 0.3–0.6 equiv of H2SO4 [thin-layer chroma-
tography (TLC) control] was obtained after 2–3 h. As exemplified by hydro-
peroxidation of cyclohexanone 2, a decrease in the amount of H2O2 to a
four-fold molar excess led to a decrease in the yield of bishydroperoxide
to 73%. Neither an increase in the amount of H2O2 to a 14-fold excess
and an increase in the amount of H2SO4 to an equimolar ratio nor an
increase in the reaction time to 6 h made it possible to bring the reactions

Geminal Bishydroperoxides
1283
Table 1. Synthesis of gem-bishydroperoxides 1–11 by the H2SO4-catalyzed reac-
tions of ketones with H2O2 in a THF–water system at 15–208C
Mole of
Mole of
Time H2O2 / mole
H2SO4 /
mole of
ketone
Conversion
of ketone
(%)
Yield
(%)
Gem-bishydroperoxide
(h)
of ketone
2
8
0.3
100
80
2
2
8
4
0.3
0.3
100
100
81a
73
2
3
3
4
8
10
10
14
0.3
0.6
0.4
0.8
100
100
100
60
90
95a
86
39
6
3
14
10
0.8
0.7
45
12
78
100
3
6
10
10
0.5
1
100
85
67
43
2
10
0.5
100
72
aExperiments on the synthesis of 1,1-dihydroperoxycyclohexane and 1,1-dihydro-
peroxy-4- tert-butylcyclohexane were scaled with an increase in the amounts of the
reagents by a factor of 10.

1284
A. O. Terent’ev et al.
Scheme 1. Reagents and conditions: THF, H2O2 (37% solution, 8–14 equiv), H2SO4
(0.3–1 equiv), 2–6 h, 15–208C.
of cyclooctanone, cyclododecanone, and undecane-6-one to completion.
Gem-bisperoxides 6, 7, and 10 were obtained in 39, 12, and 43% yields,
respectively.
The structures of the resulting bishydroperoxides were established by 1H
and 13C NMR spectroscopy; in particular, the 13C NMR spectra show signals
at d 110–122 typical of the sp3-hybridized carbon atom bearing two oxygen
functions and are consistent with the known spectra of these compounds.
To summarize, we developed a convenient procedure for the selective
synthesis of geminal bishydroperoxides with medium-sized rings. The latter
can easily be prepared according to this method under laboratory conditions
in yields of up to 95% in amounts larger than tens of grams. The method
can easily be scaled, which can provide the basis for the use of bishydroper-
oxides as polymerization initiators.
EXPERIMENTAL
The NMR spectra were recorded on Bruker WM-250 (250.13 MHz for 1H and
1
62.9 MHz for 13C) and Bruker AC-200 (200.13 MHz for H and 50.32 MHz
for 13C) spectrometers in CDCl3. The TLC analysis was carried out using
Silufol UV-254 chromatographic plates. Flash chromatography was
performed using 63- to 200-mesh silica gel (Merk).
The melting points were determined on a Kofler hot-stage apparatus and
are uncorrected.
Cycloalkanones, adamantanone, 4-methylpentane-2-one, undecane-6-
one, and hexane-2-one were purchased from Acros. A 37% aqueous
hydrogen peroxide solution, 98% H2SO4, and the solvents THF, CH2Cl2,
Et2O, and petroleum ether (PE) (40–708C) of high-purity grade were used
without additional purification.
Caution: Bishydroperoxides 1–3, 5, 9, and 11 are shock- and friction-
sensitive and, consequently, should be handled with care. These compounds
can be decomposed explosively on heating to 1008C or greater temperatures.
Synthesis of gem-Bishydroperoxides 1–11 (General Procedure)
Concentrated H2SO4 (0.3–1 mol per mol of ketone) was dissolved in a
mixture of a 37% aqueous H2O2 solution (8- to 14-fold molar excess with

Geminal Bishydroperoxides
1285
respect to ketone) and THF (20–25 mL). Then the corresponding ketone (1 g,
5.5–11.9 mmol) was added with vigorous stirring at 15–208C over 15 min.
The reaction mixture was stirred for 2–6 h, and then CH2Cl2 (80 mL) and a
saturated aqueous NaHCO3 solution were added to adjust pH to 7–8. The
organic layer was separated, washed with water (4 ꢀ 3 mL), dried over
MgSO4, and filtered. Dichloromethane was evaporated at 7–10 mmHg, the
residues of THF and H2O2 were removed in vacuo (0.2–1 mmHg) at room
temperature for 3–4 h, and bishydroperoxides 1–11 were isolated. Analyti-
cally pure samples of bishydroperoxides were isolated by flash chromato-
graphy using PE/Et2O ¼ 80/20 as the eluent. The characteristics of 1–11
are given next.
Data
1
1,1-Dihydroperoxycyclopentane (1).[15] Oil. H NMR (d, ppm): 1.58–2.05
(m, 8H, CH2), 9.80–10.05 (br. s., 2H, OOH). 13C NMR (d, ppm): 24.4,
33.0 (CH2), 122.1 (C).
1,1-Dihydroperoxycyclohexane (2).[15] White crystals; mp 48–508C (Et2O).
1
Mp15 48–498C. H NMR (d, ppm): 1.32–1.61 (m, 6H, CH2), 1.72–1.91
(m, 4H, C–CH2), 9.45–9.65 (br. s., 2H, OOH). 13C NMR (d, ppm): 22.3,
25.2, 29.3 (CH2), 110.4 (C).
1,1-Dihydroperoxy-4-methylcyclohexane (3). White crystals; mp 53–558C
1
(Et2O). H NMR (d, ppm): 0.92 (m, 3H, CH3), 1.1–1.71 (m, 7H, CH2),
2.11–2.29 (m, 2H, C–CH2), 8.90–9.50 (br. s., 2H, OOH). 13C NMR (d,
ppm): 21.3 (CH3), 29.0, 30.5, 31.5 (CH, CH2), 110.8 (C). Anal. calcd. for
C7H1404: C, 51.84; H, 8.70. Found C, 52.12; H, 8.87.
1,1-Dihydroperoxy-4-tert-butylcyclohexane (4).[7] White crystals; mp 81–
82.58C (Et2O). Mp[7] 83–848C (Et2O–hexane). 1H NMR (d, ppm): 0.85
(s, 9H, CH3), 0.98–1.78 (m, 7H, CH, CH2), 2.24–2.35 (m, 2H, CH2),
9.25–9.40 (br. s., 2H, OOH). 13C NMR (d, ppm): 23.4 (CH2), 27.6 (CH3),
29.8 (CH2), 32.4 (C-Me), 47.5 (CH), 111.1 (C).
1,1-Dihydroperoxycycloheptane (5).[7] White crystals; mp 55–578C (Et2O).
1H NMR (d, ppm): 1.28–1.65 (m, 8H, CH2), 1.70–2.03 (m, 4H, C-CH2),
9.60–9.80 (br. s., 2H, OOH). 13C NMR (d, ppm): 22.6, 29.7, 32.7 (CH2),
115.7 (C).
1,1-Dihydroperoxycylooctane (6).[7] Oil.1H NMR (d, ppm): 1.21–1.99
(m, 14H, CH2), 9.59–9.70 (br. s., 2H, OOH). 13C NMR (d, ppm): 21.7,
24.8, 27.1, 27.8 (CH2), 114.0 (C).

1286
A. O. Terent’ev et al.
1,1-Dihydroperoxycyclododecane (7).[7,11,15] White crystals; mp 138–
[7]
1
1408C (Et2O). Mp
140–1418C (benzene). H NMR (d, ppm): 1.21–1.82
(m, 22H, CH2), 9.98–10.04 (br. s., 2H, OOH). 13C NMR (d, ppm): 20.0,
22.2, 22.5, 26.4, 26.5, 27.4 (CH2), 113.6 (C).
2,2-Dihydroperoxyadamantane (8).[7] White crystals are slowly decom-
posed on heating to 86–888C or higher temperatures. Mp[7] 144–1458C
(Et2O–hexane). H NMR (d, ppm): 1.21–1.89 (m, 12H, CH2, CH), 2.32–
1
2.42 (m, 2H, CH), 9.65–9.85 (br. s., 2H, OOH). 13C NMR (d, ppm): 27.0,
31.2, 33.7, 37.0 (CH, CH2), 112.6 (C).
2,2-Dihydroperoxy-4-methylpentane (9). Oil. 1H NMR (d, ppm): 0.96
(d, 6H, CH3, J ¼ 6.7 Hz), 1.42 (s, 3H, CH3), 1.65–1.90 (m, 3H, CH2, CH),
9.20–9.45 (br. s., 2H, OOH). 13C NMR (d, ppm): 17.9 (CH), 23.7, 24.2
(CH3), 41.3 (CH2), 112.7 (C). Anal. calcd. for C6H1404: C, 48.17; H, 9.55.
Found C, 47.99; H, 9.40.
6,6-Dihydroperoxyundecane (10). Oil. 1H NMR (d, ppm): 0.86 (t, 6H, CH3,
J ¼ 7.2 Hz), 1.19–1.46 (m, 12H, CH2), 1.58–1.68 (m, 4H, CH2), 9.22–9.65
(br. s., 2H, OOH). 13C NMR (d, ppm): 13.8 (CH3), 22.4, 23.1, 29.2, 31.8
(CH2), 114.6 (C). Anal. calcd. for C11H2404: C, 59.97; H, 10.98. Found C,
59.73; H, 10.69.
1
2,2-Dihydroperoxyhexane (11). Oil. H NMR (d, ppm): 0.88 (t, 3H, CH3,
J ¼ 7.2 Hz), 1.21–1.44 (m, 7H, CH2, CH3), 1.65–1.75 (m, 2H, CH2),
9.31–9.58 (br. s., 2H, OOH). 13C NMR (d, ppm): 13.8 (CH3), 17.7, 22.7,
25.9, 32.7 (CH2), 112.7 (C). Anal. calcd. for C6H1404: C, 47.99; H, 9.40.
Found C, 47.75; H, 9.55.
ACKNOWLEDGMENT
This work is supported by the Program for Support of Leading Scientific
Schools of the Russian Federation (Grant No. 5022.2006.3) and the Russian
Science Support Foundation.
REFERENCES
1. Kim, H.-S.; Shibata, Y.; Wataya, Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M.
Synthesis and antimalarial activity of cyclic peroxides, 1,2,4,5,7-pentoxocanes
and 1,2,4,5-tetroxanes. J. Med. Chem. 1999, 42, 2604–2609.
2. Vennerstrom, J. L.; Fu, H.-N.; Ellis, W. Y.; Ager, A. L.; Wood, J. K.;
Andersen, S. L.; Gerena, L.; Milhous, W. K. Dispiro-1,2,4,5-tetraoxanes: A new
class of antimalarial peroxides. J. Med. Chem. 1992, 35, 3023–3027.

Geminal Bishydroperoxides
1287
3. Jefford, C. W. Peroxidic antimalarials. Adv. Drug Res. 1997, 29, 271–320.
4. Dong, Y.; Matile, H.; Chollet, J.; Kaminsky, R.; Wood, J. K.; Vennerstrom, J. L.
Synthesis and antimalarial activity of 11 dispiro-1,2,4,5-tetraoxane analogues of
WR 148999: 7,8,15,16-Tetraoxadispiro[5.2.5.2]hexadecanes substituted at the 1
and 10 positions with unsaturated and polar functional groups. J. Med. Chem.
1999, 42, 1477–1480.
5. Hamada, Y.; Tokuhara, H.; Masuyama, A.; Nojima, M.; Kim, H.-S.; Ono, K.;
Ogura, N.; Wataya, Y. Synthesis and notable antimalarial activity of acyclic
peroxides, 1-(alkyldioxy)-1-(methyldioxy)cyclododecanes. J. Med. Chem. 2002,
45, 1374–1378.
6. Kim, H.-S.; Tsuchiya, K.; Shibata, Y.; Wataya, Y.; Ushigoe, Y.; Masuyama, A.;
Nojima, M.; McCullough, K. Synthetic methods for unsymmetrically substituted
1,2,4,5-tetroxanes and of 1,2,4,5,7-pentoxocanes. J. Chem. Soc., Perkin Trans.1
1999, 1867–1870.
7. Kim, H.-S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.; Hamada, Y.;
Tsuchiya, K.; Masuyama, A.; Nojima, M.; McCullough, K. Synthesis and antima-
larial activity of novel medium-sized 1,2,4,5-tetraoxacycloalkanes. J. Med. Chem.
2001, 44, 2357–2361.
8. Tsuchiya, K.; Hamada, Y.; Masuyama, A.; Nojima, M.; McCullough, K. J.;
Kim, H.-S.; Shibata, Y.; Wataya, Y. Synthesis, crystal structure and anti-
malarial activity of novel spiro-1,2,4,5-tetraoxacycloalkanes. Tetrahedron Lett.
1999, 40, 4077–4080.
9. Hansma, H.; Schroeder, A. AKZO N.V. Composition containing a cyclohexanone
peroxide and a solvent. Belg. Patent 868,681; 1978. Chem. Abstr. 1979, 90,
153037a.
10. Terent’ev, A. O.; Platonov, M. M.; Kutkin, A. V. A new oxidation process: Trans-
formation of gem-bishydroperoxides in esters. Cent Eur. J. Chem. 2006, 4,
207–215.
¨
11. Ledaal, T.; Solbjor, T. 1,1-Dihydroperoxycyclododecane. Acta Chem. Scand.
1967, 21, 1658–1659.
˚
12. Dasnes, T.; Ledaal, T. New cyclotridecane peroxides. Acta Chem. Scand. 1971, 25,
1906–1907.
13. Kropf, H. In Methoden der organische Chemie (Houben-Weyl). Bd. E13 (part 1).
Kropf, H., Ed.; Thieme: Stuttgart, 1988, pp. 548–551.
14. Iskra, J.; Bonnet-Delpon, D.; Begue, J.-P. One-pot synthesis of non-symmetric
tetraoxanes with the H2O2/MTO/fluorous alcohol system. Tetrahedron Lett.
2003, 44, 6309–6312.
15. Jefford, C. W.; Amer Jaber, Y. L.; Boukouvalas, J. A new method for the synthesis
of gem-dihydroperoxides. Synth. Commun. 1990, 20, 2589–2596.
16. Terent’ev, A. O.; Kutkin, A. V.; Platonov, M. M.; Ogibin, Y. N.; Nikishin, G. I. A
new method for the synthesis of bishydroperoxides based on a reaction of ketals
with hydrogen peroxide catalyzed by boron trifluoride complexes. Tetrahedron
Lett. 2003, 44, 7359–7363.
17. Terent’ev, A. O.; Kutkin, A. V.; Platonov, M. M.; Starikova, Z. A.; Ogibin, Y. N.;
Nikishin, G. I. Synthesis of 1,10-bishydroperoxydi(cycloalkyl)peroxide by homo-
coupling of 11–15-membered gem-bis(hydroperoxy)cycloalkanes in the
presence of boron trifluoride. Izv. Akad Nauk, Ser. Khim. 2005, 1182–1185;
Russ. Chem. Bull. 2005, 54, 1214–1218 (Engl. transl.).