Iodine as a catalyst for efficient conversion of ketones to gem-dihydroperoxides by aqueous hydrogen peroxide

Article abstract of DOI:10.1021/ol060590r

Iodine has been shown to be an efficient catalyst for the selective dihydroperoxidation of ketones with aqueous hydrogen peroxide. Ketones were directly converted to their corresponding gem-dihydroperoxides using a "green" oxidant (30% aq H₂O₂) and a simple catalyst (iodine) under neutral conditions in acetonitrile. The yield of hydroperoxidation of various cyclic ketones was 60-98% including androstane-3,17-dione, and acyclic ketones were converted with a similar efficiency.

Full text of DOI:10.1021/ol060590r

ORGANIC
LETTERS
2006
Vol. 8, No. 12
2491-2494
Iodine as a Catalyst for Efficient
Conversion of Ketones to
gem-Dihydroperoxides by Aqueous
Hydrogen Peroxide
Katja Zˇ
mitek,† Marko Zupan,‡ Stojan Stavber,† and Jernej Iskra*,†
Laboratory of Organic and Bioorganic Chemistry, “Jozˇef Stefan” Institute, JamoVa 39,
Ljubljana, SloVenia, and Faculty of Chemistry and Chemical Technology, UniVersity of
Ljubljana, AsˇkercˇeVa 5, Ljubljana, SloVenia
jernej.iskra@ijs.si
Received March 10, 2006
ABSTRACT
Iodine has been shown to be an efficient catalyst for the selective dihydroperoxidation of ketones with aqueous hydrogen peroxide. Ketones
were directly converted to their corresponding gem-dihydroperoxides using a “green” oxidant (30% aq H2O2) and a simple catalyst (iodine)
under neutral conditions in acetonitrile. The yield of hydroperoxidation of various cyclic ketones was 60−98% including androstane-3,17-
dione, and acyclic ketones were converted with a similar efficiency.
In recent years, an increasing resistance of malaria parasites
to commonly used alkaloidal drugs and the discovery of the
antimalarial properties of artemisinin1 have boosted interest
in organic peroxides as potential antimalarials.2 Dihydro-
peroxides are key intermediates in the synthesis of many
classes of peroxides, such as tetraoxanes3-6 and other
tetraoxacycloalkanes,7-9 macrocyclic endoperoxides,10,11and
acyclic analogues with a variety of functional groups.12
Organic peroxides are also valuable chemicals that serve as
radical initiators and oxidants.13,14
The three major synthetic paths for the synthesis of gem-
dihydroperoxides are: (1) ozonolysis of ketone enol ethers
or R-olefins in the presence of H2O2;8,9 (2) reaction of ketals
with H2O2 in the presence of tungstic acid15 or BF3‚Et2O,16
and (3) peroxidation of ketones using an acidic solvent17 or,
in reactions of cholic acid derivates,5,6 a catalyst. Synthesis
of primary gem-dihydroperoxides (DHPs) has been achieved
† “Jozˇef Stefan” Institute.
‡ University of Ljubljana.
(1) Antimalarial Chemotherapy; Rosenthal, P. J., Ed.; Humana Press:
Totowa, New Jersey, 2001.
(2) Tang, Y. Q.; Dong, Y. X.; Vennerstrom, J. L. Med. Res. ReV. 2004,
24, 425.
(3) Iskra, J.; Bonnet-Delpon, D.; Begue, J. P. Tetrahedron Lett. 2003,
44, 6309.
(4) Terent’ev, A. O.; Kutkin, A. V.; Starikova, Z. A.; Antipin, M. Y.;
Ogibin, Y. N.; Nikishina, G. I. Synthesis 2004, 2356.
(5) Opsenica, D.; Pocsfalvi, G.; Juranic, Z.; Tinant, B.; Declercq, J. P.;
Kyle, D. E.; Milhous, W. K.; Solaja, B. A. J. Med. Chem. 2000, 43, 3274.
(6) Todorovic, N. M.; Stefanovic, M.; Tinant, B.; Declercq, J. P.; Makler,
M. T.; Solaja, B. A. Steroids 1996, 61, 688.
(7) Tsuchiya, K.; Hamada, Y.; Masuyama, A.; Nojima, M.; McCullough,
K. J.; Kim, H. S.; Shibata, Y.; Wataya, Y. Tetrahedron Lett. 1999, 40,
4077.
(9) Kim, H. S.; Tsuchiya, K.; Shibata, Y.; Wataya, Y.; Ushigoe, Y.;
Masuyama, A.; Nojima, M.; McCullough, K. J. J. Chem. Soc., Perkin Trans.
1 1999, 1867.
(10) McCullough, K. J.; Ito, T.; Tokuyasu, T.; Masuyama, A.; Nojima,
M. Tetrahedron Lett. 2001, 42, 5529.
(11) Ito, T.; Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough,
K. J. Tetrahedron 2003, 59, 525.
(12) Hamada, Y.; Tokuhara, H.; Masuyama, A.; Nojima, M.; Kim, H.
S.; Ono, K.; Ogura, N.; Wataya, Y. J. Med. Chem. 2002, 45, 1374.
(13) Peroxide chemistry: mechanistic and preparatiVe aspects of oxygen
transfer; Adam, W., Ed.; Wiley-VCH: Weinheim, 2000.
(14) Organic Peroxides; Ando, W., Ed.; John Wiley & Sons: Chichester,
1992.
(15) Jefford, C. W.; Li, W.; Jaber, A.; Boukouvalas, J. Synth. Commun.
1990, 20, 2589.
(8) Kim, H. S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.; Hamada,
Y.; Tsuchiya, K.; Masuyama, A.; Nojima, M.; McCullough, K. J. J. Med.
Chem. 2001, 44, 2357.
(16) Terent’ev, A. O.; Kutkin, A. V.; Troizky, N. A.; Ogibin, Y. N.;
Nikishin, G. I. Synthesis 2005, 2215.
(17) Ledaal, T.; Solbjor, T. Acta Chem. Scand. 1967, 21, 1658.
10.1021/ol060590r CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/09/2006

Scheme 1
Table 1. Optimization of Reaction Conditions for I2-Catalyzed
Hydroperoxidation of 3-Decanone 4 with 30% aq H2O2
n (mmol)
entry
4
H2O2
I2
concd 4 (M) time (h) conv. (%)a
only by ozonolysis8,9 and by hydroperoxide rearrangement
of selected bicyclic alcohols.18 Drawbacks of these methods
are the need for the prior synthesis of the starting substrates,
the use of highly concentrated H2O2, the need for excess
acid, moderate yields, and the restricted substrate range. In
addition, the selectivity of ozonolysis is poor and cannot be
used for substrates containing ozone-sensitive groups. Be-
cause of these limitations, new, more efficient, and broad
spectrum methods for the synthesis of DHPs are sought.
Our goal was to find a new approach to synthesize DHPs,
starting directly from the carbonyl compound, using com-
mercially available 30% H2O2 while avoiding the use of an
acid if possible. Because molecular iodine has proven a
useful Lewis acid catalyst for the activation of carbonyl
compounds, including for acetalization reactions,19-21 we
envisaged that iodine would benefit the peroxidation reac-
tions of such compounds.
An acid and methyltrioxorhenium (MTO) catalyzed reac-
tion of 4-substituted cyclohexanones with 30% H2O2 in
trifluoroethanol (TFE) led to the formation of tetraoxanes,
but only in the case of 4-methylcyclohexanone does a similar
reaction without acid yield gem-dihydroperoxide.3,22 Using
I2 instead of (MTO), we performed the reaction with 4-tert-
butyl cyclohexanone 1 in TFE using 10 mol % of I2 as the
catalyst. DHP 2 was formed in 80% yield as determined from
the 1H NMR spectra of the crude reaction mixture. We also
investigated whether the use of TFE in combination with I2
was a requirement of whether other solvents could be used.
Therefore, reactions of 1 with 3 equiv of 30% aq H2O2 and
10 mol % of molecular iodine in different solvents and
without a solvent were performed. After 24 h at room
temperature in water, in N,N-dimethylformamide, and with-
out solvent, the reactions were not selective and yielded
varying mixtures of hydroperoxides with low conversion
(48%, 55%, and 13%). Surprisingly, the reaction in aceto-
nitrile gave 90% of DHP 2 in the crude reaction mixture
(Scheme 1). The reaction in methanol was also selective,
but instead of DHP, the monoperoxy ketal 3 was formed in
78% yield (70% after isolation). Given this, acetonitrile was
deemed the optimal solvent for the synthesis of DHPs and
further optimization of the reaction was made in this solvent.
Because the synthesis of acyclic DHPs is more problematic
than that of cyclohexyl DHPs, we selected 3-decanone 4 as
1
2
3
4
5
6
7
8
1
1
1
1
1
1
1
1
3
4
4
4
4
4
10
10
0.1
0.1
0.2
0.5
0.1
0.1
0.1
0.1
0.5
0.5
0.5
0.5
0.1
0.1
0.1
0.1
5
24
24
24
24
67
24
67
22
31
27
13
81
59
59
61
a Conversions to DHP determined from 1H NMR spectra of the crude
reaction mixture.
a test compound to determine the optimal reaction conditions.
The amount of I2 and H2O2, the reaction time, and the
concentration of the reagents were varied. The reaction
conditions, which worked well for the synthesis of the
peroxide 2, resulted in a low conversion (22%) of 4 into the
dihydroperoxide 5 (Table 1, entry 1), and further modification
of the conditions was required to enhance the yield. Table 1
shows how an increase in the amount of H2O2 and an
extended reaction time (24 h) resulted in an increased yield
of DHP 5 (entry 2), whereas an increase in the amount of I2
decreased the yield (entries 3 and 4). Further dilution of the
reaction mixture brought about a significant improvement
in the conversion of ketone 4 to DHP. In a 0.1 M solution
of ketone 4 (entry 5), the conversion was 50% higher than
in a 0.5 M solution. A reaction time of 67 h (entry 6) did
not bring about any further improvement. On the contrary,
it lowered the conversion to DHP, which is probably due to
its decomposition with time. A supplementary increase in
the amount of H2O2 (entry 7) resulted in a deterioration of
conversion (lower yield) to DHP 5.
The best results for the synthesis of DHP 5 were achieved
using a 0.1 M solution of ketone 4 in acetonitrile, 4 equiv
of 30% aq H2O2, and 10 mol % of I2 at room temperature
for 24 h. To determine the limitations of the method, we
tested the efficiency of this transformation on various
cycloalkanones, acyclic ketones, and aldehydes.
Table 2 gives the results obtained for cyclic ketones.
Cyclohexanones show the highest reactivity requiring only
5 h for an efficient conversion to DHPs. Conversion of Me-
substituted cyclohexanones was affected by the steric
environment around the reaction site, as the yield decreased
from 98% for 4-Me-cyclohexyl DHP 12 to 93% for 3-Me
10 and to 80% for 2-Me 8. Also, 4-t-Bu-cyclohexanone 1,
cycloheptanone 14, cyclododecanone 16, and androstane-
3,17-dione 20 were converted to DHP in good yields, and
the cyclopentyl 6 and 2-adamantyl 18 dihydroperoxides
required a higher reaction concentration to be formed
efficiently.
(18) Hamann, H. J.; Liebscher, J. Synlett 2001, 96.
(19) Basu, M. K.; Samajdar, S.; Becker, F. F.; Banik, B. K. Synlett 2002,
319.
(20) Karimi, B.; Golshani, B. Synthesis 2002, 784.
(21) Banik, B. K.; Chapa, M.; Marquez, J.; Cardona, M. Tetrahedron
Lett. 2005, 46, 2341.
(22) Zmitek, K.; Stavber, S.; Zupan, M.; Bonnet-Delpon, D.; Iskra, J.
Tetrahedron 2006, 62, 1479.
2492
Org. Lett., Vol. 8, No. 12, 2006

Table 2. Synthesis of Dihydroperoxides from Cycloalkanones
Table 3. Synthesis of Dihydroperoxides with I2/30% aq H2O2
with I2/30% aq H2O2
a Yield after column chromatography. b Conditions: 1 mmol of ketone,
4 mmol of 30% aq H2O2, 0.1 mmol of I2, 10 mL of MeCN, rt, 24 h.
I2-catalyzed hydroperoxidation with 30% aq H2O2 was
effective for acyclic ketones (Table 3). DHPs were formed
in excellent yields from 3-decanone 4 and 2- and 5-nonanone
25 and 27. Steric effects are again important, and the yield
of DHP from an acyclic ketone with a methyl substituent
on the â-position 30 is lower. Surprisingly, acetophenone
31 was also converted to its DHP, although until now
hydroperoxidation of acetophenone derivatives was not
reported. Although we also investigated the influence of
electron-donating (33, MeO-) and -withdrawing groups (34,
NO2-) on conversion, no DHP was isolated.
Hydroperoxidation of aldehydes is more problematic, and
there exists no corresponding efficient synthetic method to
our knowledge. Thus, we were glad when, with our hydro-
peroxidation protocol, benzaldehyde was converted into the
gem-dihydroperoxide 36a in a 55% yield (isolated). The
effect of electron-donating (35b, MeO-) and -withdrawing
groups (35c, NO2-) on the conversion to DHP proved
remarkable (Scheme 3). The methoxy group in 35b improved
a Yield after column chromatography. b Conditions: 1 mmol of ketone,
4 mmol of 30% aq H2O2, 0.1 mmol of I2, 10 mL of MeCN, rt. c 2 mL of
MeCN. d DHP 13 was synthesized on a few gram scale without any apparent
complications.
Because many synthetic methods for making DHPs start
from ketals, we tested whether there was a difference in the
reactivity between ketones and ketals when using our method.
Conversion of 4-Me-cyclohexanone 12 and its dimethoxy
ketal was determined from the 1H NMR spectra of the crude
reaction mixture. The ketal yielded a slightly lower amount
of DHP (88%) than the ketone (94%). It seems that reactive
ketones and their ketals show similar reactivity for DHP
formation. We also tested the use of ketals for less reactive
5R-cholestan-3-one 22. Its low reactivity is likely to originate
from its low solubility because improved results were
obtained by increasing the reaction time or by adding CH2-
Cl2 to improve solubility (Scheme 2). To overcome this
problem, we used dimethoxy cholestane 23, which is more
soluble than the parent ketone. The result was a good
Scheme 3. Formation of Dihydroperoxides 36 from
Benzaldehydes 35
1
conversion in a shorter reaction time as determined by H
NMR of the crude reaction mixture.6
Scheme 2
the yield of the isolated DHP 36b to 76%, and the nitro group
in 35c inhibited the reaction with no dihydroperoxide being
isolated.
Iodine could be playing a double role as a catalyst,
enhancing the electrophilic character of the carbonyl C-atom
and enhancing the nucleophilic character of hydrogen
Org. Lett., Vol. 8, No. 12, 2006
2493

In conclusion, iodine-catalyzed hydroperoxidation of cyclic
and acyclic ketones with aqueous H2O2 in acetonitrile is a
straightforward and efficient method for the synthesis of gem-
dihydroperoxides and the reaction is conducted directly from
carbonyl compounds in a neutral medium with a readily
available low-cost oxidant and catalyst. Further work on this
method and transformations of DHP to potentially bioactive
endoperoxides is underway, and studies with 18O-labeled
H2O2 and other nucleophiles will provide further insight into
the mechanism of this interesting reaction.
Scheme 4
Acknowledgment. This research has been supported by
the Ministry of Higher Education, Science and Technology
of the Republic of Slovenia and the Young Researcher
program (K.Zˇ.) of the Republic of Slovenia. The authors are
grateful to I. Pravst, the staff of the National NMR Centre
at the National Institute of Chemistry in Ljubljana (A. Gacˇesˇa
and J. Plavec), and the staff of the Mass Spectroscopy Centre
at the JSI (B. Kralj, D. Zˇigon) and to T. Stipanovicˇ and Prof.
B. Stanovnik for some elemental combustion analysis.
peroxide. Furthermore, iodine assists in the rehybridization
of the sp3 C-atom into the sp2 one and thus enables the second
addition of a nucleophile or rearrangement (Scheme 4). The
neutral conditions of this reaction seem to be crucial for
further substitution by a nucleophile (H2O2 and MeOH) and
do not lead to a Baeyer-Villiger rearrangement of this
Criegee intermediate as proposed for acid- and BF3-catalyzed
reactions.23,24 Neutral conditions also prevent the acid-
catalyzed enolization of the starting ketone that would
otherwise lead to R-iodination of ketone.25
Supporting Information Available: Data on general
synthetic procedures for DHP and characterization of sub-
stances. This material is available free of charge via the
Internet at http://pubs.acs.org.
(23) Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 737, 7.
(24) Carlqvist, P.; Eklund, R.; Brinck, T. J. Org. Chem. 2001, 66, 1193.
(25) Jereb, M.; Iskra, J.; Zupan, M.; Stavber, S. Lett. Org. Chem. 2005,
2, 465.
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