A broadly applicable mild method for the synthesis of gem-diperoxides from corresponding Ketones or 1,3-dioxolanes

Article abstract of DOI:10.1021/ol900262t

Ketones or ketals were readily converted into the corresponding gem-dihydroperoxides in high yields by treatment with ethereal H ₂O₂ at ambient temperature in the presence of 2-5 mol % of phosphomolybdic acid.

Full text of DOI:10.1021/ol900262t

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1615-1618
A Broadly Applicable Mild Method for
the Synthesis of gem-Diperoxides from
Corresponding Ketones or
1,3-Dioxolanes
Yun Li, Hong-Dong Hao, Qi Zhang, and Yikang Wu*
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, China
yikangwu@mail.sioc.ac.cn
Received February 8, 2009
ABSTRACT
Ketones or ketals were readily converted into the corresponding gem-dihydroperoxides in high yields by treatment with ethereal H2O2 at
ambient temperature in the presence of 2-5 mol % of phosphomolybdic acid.
Following the worldwide recognition of qinghaosu1 (QHS,
artemisinin, 1) as a potent and fast-acting antimalarial agent in
the 1980s, many new organic peroxides of various structural
types have been designed and synthesized in a global effort to
develop novel agents against multidrug resistant malaria. As a
consequence, an impressive number of man-made peroxides
with high potency in at least in vitro tests were discovered,
strongly suggesting that incorporation of peroxy bonds into the
structures of organic molecules is indeed a very promising
approach to the generation of new antimalarials.
One of the salient structural features2 shared by many
known antimalarial cyclic organic peroxides is the gem-
Figure 1. Qinghaosu and some antimalarial gem-diperoxides.
peroxy linkage (Figure 1), which presumably is at least one
of the main stimuli for the current interest3 in the synthesis
of gem-peroxyketals. To date, at least 10 different protocols
have been documented in the literature for converting
ketones/ketals into corresponding gem-peroxides through
reaction with H2O2. Most of them used a Bro¨nsted or Lewis
acid, such as HCO2H (used as solvent),3a F3CCO2H (12 mol
equiv),3b conc. H2SO4 (0.3-1.0 mol equiv),3c H2WO4 (1.0
mol equiv),3d NaHSO4-SiO2 (ca. 0.2 mol equiv),3e F3B·OEt2
(0.2-0.4 mol equiv),3f or camphorsulfonic acid (CSA, along
(1) (a) Liu, J.-M.; Ni, M.-Y.; Fan, J.-F.; Tu, Y.-Y.; Wu, Z.-H.; Wu,
Y.-L.; Chou, W.-S. Acta Chim. Sin. 1979, 37, 129–143. (Chem. Abstr. 1980,
92, 94594w). (b) Klayman, D. L. Science 1985, 228, 1049–1055. (c) Haynes,
R. K.; Vonwiller, S. C. Acc. Chem. Res. 1997, 30, 73–79. (d) Vroman,
J. A.; Alvim-Gaston, M.; Avery, M. A. Curr. Pharm. Des. 1999, 5, 101–
138. (e) Robert, A.; Dechy-Cabaret, O.; Cazalles, J. M.; Meunier, B. Acc.
Chem. Res. 2002, 35, 167–174. (f) Li, Y.; Wu, Y.-L. Curr. Med. Chem.
2003, 10, 2197–2230. (g) O’Neill, P. M.; Posner, G. H. J. Med. Chem.
2004, 47, 2945–2964. (h) Posner, G. H.; O’Neill, P. M. Acc. Chem. Res.
2004, 37, 397–404. (i) Tang, Y.; Dong, Y.; Vennerstrom, J. L. Med. Res.
ReV. 2004, 24, 425–448. (j) Muraleedharan, K. M.; Avery, M. A.
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10.1021/ol900262t CCC: $40.75
Published on Web 03/11/2009
2009 American Chemical Society

with 70% H2O2 and only applicable to aldehydes),3g as the
catalyst. Ce(NH4)2(NO3)6 (CAN),3h I2,3i and methyltri-
oxorhenium3j (MTO, prepared from Re2O7) have also been
utilized to promote such transformations. However, as
noted3k by Ghorai and Dussault, none of these methods are
mild enough to be generally applicablesthey all suffer from
one or more of such drawbacks as low yields, slow reactions,
requirement for use of high concentration of H2O2, and
incompatibility with sensitive functionalities.
The recent mild/highly efficient Re2O7 protocol of
Dussault3k does represent a major improvement. However,
new mild/effective methods directly applicable to multifunc-
tionalized substrates are still in great need.
seemed less reactive, and clear-cut discrimination between
two types of ketone carbonyl groups was achieved (entry
12).
Open-chain ketones showed similar reactivity under the
same conditions, resulting in the expected gem-dihydroper-
oxides in excellent yields (entries 13-15). It is interesting
to note that 1,3-dioxolanes, which are more practical protect-
ing groups than those dimethyl ketals, also served very well
as the precursors (entries 16-18). Compared with all the
previous acid-catalyzed protocols, which were effective only
with ketals (mostly dimethyl ones) unless using substantial
amounts of strong acids, the present method should have
better prospects in application.
In our efforts to develop new antimalarial organic perox-
ides, we observed that phosphomolybdic acid (PMA,
H3Mo12O40P·xH2O, a reagent much cheaper than Re2O7) in
ethereal H2O2 could efficiently catalyze the peroxyketal-
ization reaction of ketones/ketals (Scheme 1). The reaction
That common protecting groups such as TBS (tert-
butyldimethylsilyl), MOM (methoxymethyl), PMB (p-meth-
oxybenzyl), Bn (benzyl), and Bz (benzoyl) groups were
tolerated is particularly valuable because construction of gem-
peroxides by direct peroxy ketalization of ketone/ketals
containing common protecting groups in synthetically useful
yields has never been achieved before (to the best of our
knowledge), and there has been only one3d individual
example for olefinic substrates.
4
Scheme 1
As a direct comparison, we also tested conversion of 5f
3e
to 6f under the NaHSO4-SiO2 conditions. No traces of
gem-diperoxides could be detected after 2 h, while the TBS
protecting group was completely hydrolyzed. Similarly, in
an earlier effort to prepare a gem-dihydroperoxide from a
dimethyl ketal using 20 mol % of F3B·OEt2 as the catalyst,
the expected product was formed in 10-40% yield, along
with 35-77% of the corresponding ketone which resulted
from hydrolysis.
In conclusion, a novel mild method using 2-5 mol % of
phosphomolybdic acid (PMA) as the catalyst has been
developed for the synthesis of gem-diperoxides. The lower
acidity and higher catalytic activity of this set of conditions
made it possible for the first time to make gem-diperoxyketals
directly from the ketones/ketals containing such protecting
groups as TBS, MOM, PMB, Bn, and Bz and/or C-C
double5 bonds. The yields are generally high, and the reaction
time in most cases is 3-4 h. 1,3-Dioxolanes, which are
broadly employed protecting groups and might be necessary
usually occurred readily at ambient temperature in the
presence of 0.02-0.05 mol equiv (i.e., 2-5 mol %) of PMA
and resulted in the desired gem-diperoxides in excellent
yields within a few hours.
The results are summarized in Table 1. Cyclic ketones of
different ring sizes all reacted very well (entries 1-3).
Bridged and substituted ketones (entries 4-6 and 9) appeared
to be equally reactive. It is interesting to note that even when
the carbonyl groups were masked as 1,3-dioxolanes, which
usually are more stable/less reactive than dimethyl ketals (the
substrates in some of the previous investigations) and
therefore are more often used as protecting groups, the gem-
peroxides were also formed in high yields.
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When a free ketone and a ketal functionality are both
present in the same molecule, further reactions might follow
(entries 10 and 11), leading to also interesting and potentially
useful cyclic structures. The conjugated carbonyl group
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this work, see the Supporting Information.
(5) The only exception was found in ref 3d (a compound similar to 5r
but without the aromatic ring and the oxygen in the six-membered ring).
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Org. Lett., Vol. 11, No. 7, 2009

Table 1. Formation of gem-Diperoxides Catalyzed by Phosphomolybdic Acida
Org. Lett., Vol. 11, No. 7, 2009
1617

Table 1 Continued
a All runs were performed at ambient temperature in ethereal H2O2 containing the indicated amount (with respect to the starting 5) of phosphomolybdic
acid (H3Mo12O40P·xH2O) with the substrate and H2O2 concentration being 0.2 and 1.0 M, respectively.
in the synthesis of such substrates as 5k and 5r, could also
be directly used in lieu of a free ketone carbonyl group. The
chemistry is compatible with a range of functionalities,
including ester, nitrile, alkyne, alkene (both isolated and
conjugated), and enol ester groups. These advantages, along
with the much lower price of PMA compared with that of
Re2O7, make the present method an attractive means for the
synthesis of gem-dihydroperoxyketals.
20772143) and the Chinese Academy of Sciences (“Knowledge
Innovation”, KJCX2.YW.H08) is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures, physical and spectroscopic data listing, 1H as well
1
as 13C NMR spectra for all new peroxides, and H NMR
for the known peroxides 6a-c and 6u-w. This material
isavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
Acknowledgment. Financial support from the National
Natural Science Foundation of China (20672129, 20621062,
OL900262T
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