A facile catalyst-free synthesis of gem-dihydroperoxides with aqueous hydrogen peroxide

Article abstract of DOI:10.1039/b917056a

gem-Dihydroperoxides were easily obtained from the corresponding carbonyl compounds in high yields through a catalyst-free method with aqueous H ₂O₂ (35%) in 1,2-dimethoxyethane at room temperature.

Full text of DOI:10.1039/b917056a

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A facile catalyst-free synthesis of gem-dihydroperoxides
with aqueous hydrogen peroxidew
Norihiro Tada, Lei Cui, Hiroaki Okubo, Tsuyoshi Miura and
Akichika Itoh*
Received (in Cambridge, UK) 18th August 2009, Accepted 9th December 2009
First published as an Advance Article on the web 14th January 2010
DOI: 10.1039/b917056a
gem-Dihydroperoxides were easily obtained from the corresponding
carbonyl compounds in high yields through a catalyst-free method
with aqueous H2O2 (35%) in 1,2-dimethoxyethane at room
temperature.
5 equiv. of hydrogen peroxide was necessary to produce the
product in satisfying yield, and lower yields of the product
were observed when using 3 or 4 equiv. of hydrogen peroxide
(entries 10 and 11).
Table 2 shows the scope and limitations of this synthesis
with various carbonyl compounds under the optimized reaction
conditions.21 Cyclic ketones, including 2-adamantanone and
aliphatic ketones, except acetophenone, produced the corres-
ponding gem-dihydroperoxides in good to excellent yields
(entries 1–10 and 13). p-Anisaldehyde, an aromatic aldehyde,
also produced the corresponding gem-dihydroperoxide in
high yield; however, dodecanal, an aliphatic aldehyde,
Artemisinin, isolated from Artemisia annua which has been
used as a traditional Chinese herbal remedy, shows effective
antimalarial activity against multidrug resistant malaria.1
Since the endoperoxide bridge structure of artemisinin is
crucial for antimalarial activity,1d various types of organic
peroxides have been designed and synthesized as candidates
for antimalarial drugs.1c Thus, organic gem-dihydroperoxides
and their derived peroxides have attracted a great deal of
attention as potential antimalarial active compounds against
the background of the building up of resistance of malaria
parasites to alkaloid medicines. However, from the view point
of organic synthesis, gem-dihydroperoxides have been known
to play an important role as key intermediates in the synthesis
of trioxanes,2 tetraoxanes3 and endoperoxides,4 as an initiator
for radical polymerization,5 and as an oxidant for epoxidation6
and sulfoxidation.7 Generally, gem-dihydroperoxides can be
synthesized from ketone enol ethers, a-olefins, ketones or
ketals with hydrogen peroxide in the presence of a catalyst
such as acids, heavy-metals or halogens;8–19 however, we have
noticed to the best of our knowledge a lack of reports on
catalyst-free synthesis of gem-dihydroperoxides from ketones
and aldehydes with hydrogen peroxide. Although a catalyst or
promoter such as metals and acids have been believed to be
essential for preparation of gem-dihydroperoxides with hydrogen
peroxide, unusually we have found a facile catalyst-free
synthetic method for gem-dihydroperoxides in dimethoxy-
ethane (DME) with 35% aqueous hydrogen peroxide.20 Here,
we report a detailed study of reaction conditions and scope
and limitations of this new synthesis.
showed
a varied reactivity, and hydroxyhydroperoxide
was obtained in 78% yield as reported in a previous paper
(entry 11).15,19a
The role of DME is not clear; however, we believe that the
nucleophilicity of H2O2 for carbonyl compounds is enhanced
by the chelating effect of DME with the hydrogen of H2O2 to
afford the dihydroperoxides.
In conclusion, we have developed a convenient method
for the preparation of gem-dihydroperoxides with 35% H2O2
(5 equiv.) in DME at room temperature without any catalyst.
DME is a good solvent for dihydroperoxidation of several
carbonyl compounds. This novel synthetic method is environment-
friendly and economical due to non-use of catalysts involving
metals or acids. Further application of this oxidation and a
mechanistic study are in progress in our laboratory.
Table 1 Study of reaction conditions
Table 1 shows the results of optimization of reaction
conditions for the synthesis of gem-dihydroperoxides using
4-tert-butylcyclohexanone as a test substrate. The reaction
conditions were examined with 5 equiv. of aqueous H2O2
(35%) under an argon atmosphere at room temperature, and
among our trials, DME was found to be the most suitable
solvent. (entries 1–9). Although the reason seems unclear yet,
Entry
Solvent
H2O2 (equiv.)
Yield (%)a
1
2
3
4
5
6
7
8
MeOH
CH2Cl2
Et2O
Toluene
AcOEt
t-BuOMe
MeCN
i-PrOH
DME
5
5
5
5
5
5
5
5
5
4
3
21
24
49
59
80
82
85
87
100
92
64
9
10
11
DME
DME
Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi,
Gifu 502-8585, Japan. E-mail: itoha@gifu-pu.ac.jp
w Electronic supplementary information (ESI) available: Experimental
procedure, NMR spectra and ICP analysis data. See DOI: 10.1039/
b917056a
a
Yields were determined by 1H NMR spectroscopy with an internal
standard (1,1,2,2,-tetrachloroethane).
ꢀc
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Table 2 Synthesis of gem-dihydroperoxides
Entry
1
Substrate
Time/h
20
Product
Yield (%)a
99
2
3
10
10
73
90
4
5
6
15
15
1
89
65
81
7
8
1
57
84
20
9
5
5
5
80
10
11
78
78b
12
5
5
85
13
13b
Isolated yields. b 1H NMR spectroscopy yields are indicated as the peroxides decomposed under preparative TLC.
a
2 A. P. Ramirez, A. M. Thomas and K. A. Woerpel, Org. Lett.,
2009, 11, 507.
Notes and references
1 (a) A. Masuyama, J. M. Wu, M. Nojima, H. S. Kim and Y. Wataya,
Mini-Rev. Med. Chem., 2005, 5, 1035; (b) Y. Q. Tang, Y. X. Dong
and J. L. Vennerstrom, Med. Res. Rev., 2004, 24, 425; (c) J. Wiesner,
R. Ortmann, H. Jomaa and M. Schlitzer, Angew. Chem., Int. Ed.,
2003, 42, 5274; (d) K. Borstnik, I. H. Paik, T. A. Shapiro and
G. H. Posner, Int. J. Parasitol., 2002, 32, 1661.
3 (a) K. Zmitek, S. Stavber, M. Zupan, D. Bonnet-Delpon,
S. Charneau, P. Grellier and J. Iskra, Bioorg. Med. Chem., 2006,
14, 7790; (b) I. Opsenica, N. Terzic
M. Lehnig, P. Eilbracht, B. Tinant, Z. Juranic
Y. S. Yang, D. S. Diaz, P. L. Smith, W. K. Milhous,
´
, D. Opsenica, G. Angelovski,
´
, K. S. Smith,
D. Dokovic
´
and B. A. Solaja, J. Med. Chem., 2006, 49, 3790;
ꢀc
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(c) K. Zmitek, S. Stavber, M. Zupan, D. Bonnet-Delpon and
J. Iskra, Tetrahedron, 2006, 62, 1479; (d) A. O. Terent’ev,
A. V. Kutkin, Z. A. Starikova, M. Y. Antipin, Y. N. Ogibin and
G. I. Nikishin, Synthesis, 2004, 2356; (e) J. Iskra, D. Bonnet-
43, 3274; (b) N. M. Todorovic, M. Stefanovic, B. Tinant,
J. P. Declercq, M. T. Makler and B. A. Solaja, Steroids, 1996,
61, 688.
11 A. O. Terent’ev, A. V. Kutkin, M. M. Platonov, Y. N. Ogibin and
G. I. Nikisin, Tetrahedron Lett., 2003, 44, 7359.
12 A. Ramirez and K. A. Woerpel, Org. Lett., 2005, 7, 4617.
13 A. O. Terent’ev, M. M. Platonov, Y. N. Ogibin and G. I. Nikisin,
Synth. Commun., 2007, 37, 1281.
Delpon and J.-P. Begue
´ ´
(f) B. A. Solaja, N. Terzic
, Tetrahedron Lett., 2003, 44, 6309;
´
, G. Pocsfalvi, L. Gerena, B. Tinant,
D. Opsenica and W. K. Milhous, J. Med. Chem., 2002, 45, 3331.
4 (a) K. J. McCullough, H. Tokuhara, A. Masuyama and
M. Nojima, Org. Biomol. Chem., 2003, 1, 1522; (b) T. Ito,
T. Tokuyasu, A. Masuyama, M. Nojima and K. J. McCullough,
Tetrahedron, 2003, 59, 525; (c) Y. Hamada, H. Tokuhara,
A. Masuyama, M. Nojima, H.-S. Kim, K. Ono, N. Ogura and
Y. Wataya, J. Med. Chem., 2002, 45, 1374; (d) H.-S. Kim,
Y. Nagai, K. Ono, K. Begum, Y. Wataya, Y. Hamada,
K. Tsuchiya, A. Masuyama, M. Nojima and K. J. McCullough,
J. Med. Chem., 2001, 44, 2357; (e) H. S. Kim, K. Tsuchiya,
Y. Shibata, Y. Wataya, Y. Ushigoe, A. Masuyama, M. Nojima
and K. J. McCullough, J. Chem. Soc., Perkin Trans. 1, 1999, 1867.
5 (a) Peroxide Chemistry: Mechanistic and Preparative Aspects of
Oxygen Transfer, ed. W. Adam, Wiley-VCH, Weinheim,
Germany, 2000; (b) H. Hansma and A. Schrorder, AKZO N. V.
Belg. Patent, 1978, 868, 681; H. Hansma and A. Schrorder, Chem.
Abstr., 1979, 90, 153037a.
14 B.
Das,
B.
Veeranjaneyulu,
M.
Krishnaiah
and
P. Balasubramanyam, J. Mol. Catal. A: Chem., 2008, 284, 116.
15 A. Bunge, H.-J. Hamann and J. Liebscher, Tetrahedron Lett., 2009,
50, 524.
16 B. Das, M. Krishnaiah, B. Veeranjaneyulu and B. Ravikanth,
Tetrahedron Lett., 2007, 48, 6286.
17 P. Ghorai and P. H. Dussault, Org. Lett., 2008, 10, 4577.
18 Y. Li, H.-D. Hao, Q. Zhang and Y. Wu, Org. Lett., 2009, 11,
1615.
19 (a) K. Zmitek, M. Zupan, S. Stavber and J. Iskra, J. Org. Chem.,
2007, 72, 6534; (b) K. Zmitek, M. Zupan, S. Stavber and J. Iskra,
Org. Lett., 2006, 8, 2491.
20 We undertook an ICP analysis of the DME, which was purchased
from Kanto Chemical, for detection of traces of metal species. The
results showed that the amounts of metal species which provided
gem-dihydroperoxides were not contained in the DME (see ESIw).
21 A typical procedure for the dihydroperoxidation is as follows: To a
solution of 4-tert-butylcyclohexanone (46.3 mg, 0.30 mmol) in dry
DME solution (3 mL) was added 35% H2O2 (130 mL, 1.50 mmol)
at room temperature. After stirring at room temperature for 20 h,
the reaction mixture was concentrated under reduced pressure. The
residue was purified by preparative TLC to afford the pure 4-tert-
butylcyclohexylidenebishydroperoxide (60.7 mg, 99%).
6 K. Jakka, J. Liu and C.-G. Zhao, Tetrahedron Lett., 2007, 48, 1395.
7 J. J. P. Selvam, V. Suresh, K. Rajesh, D. C. Babu, N. Suryakiran
and Y. Venkateswarlu, Tetrahedron Lett., 2008, 49, 3463.
8 T. Ledaal and T. Solbjor, Acta Chem. Scand., 1967, 21, 1658.
9 C. W. Jefford, Y. Li, A. Jaber and J. Boukouvalas, Synth. Commun.,
1990, 20, 2589.
´
10 (a) D. Opsenica, G. Pocsfalvi, Z. Juranic, B. Tinant, J. P. Declercq,
D. E. Kyle, W. K. Milhous and B. A. Solaja, J. Med. Chem., 2000,
ꢀc
This journal is The Royal Society of Chemistry 2010
1774 | Chem. Commun., 2010, 46, 1772–1774