An efficient synthesis of gem-dihydroperoxides with molecular oxygen and anthracene under light irradiation

Article abstract of DOI:10.1002/adsc.201000357

A new efficient dihydroperoxidation protocol of a wide variety of carbonyl compounds with molecular oxygen, anthracene, and 2-propanol under light irradiation afforded their corresponding gem-dihydroperoxides in high yields.

Full text of DOI:10.1002/adsc.201000357

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DOI: 10.1002/adsc.201000357
An Efficient Synthesis of gem-Dihydroperoxides with Molecular
Oxygen and Anthracene under Light Irradiation
Norihiro Tada,a Lei Cui,a Hiroaki Okubo,a Tsuyoshi Miura,a and Akichika Itoha,*
a
Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
Fax : (+81)-58-230-8108; phone: (+81)-58-230-8108; e-mail: itoha@gifu-pu.ac.jp
Received: May 7, 2010; Revised: August 10, 2010; Published online: October 7, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000357.
Abstract: A new efficient dihydroperoxidation pro-
tocol of a wide variety of carbonyl compounds with
molecular oxygen, anthracene, and 2-propanol
under light irradiation afforded their corresponding
gem-dihydroperoxides in high yields.
es can be established with it. Based on these consider-
ations, we have reported oxidations with molecular
oxygen under light irradiation for various types of re-
actions.[11] In the course of our further studies on ap-
plications of aerobic photooxidation, we found that
gem-dihydroperoxides were obtained from carbonyl
compounds when using molecular oxygen as terminal
oxidant under light irradiation in the presence of a
catalytic amount of anthracene in 2-propanol [Eq.
(1)].
Keywords: anthracene; dihydroperoxides; organo-
catalysis; oxygen; photo-dihydroperoxidation
Organic gem-dihydroperoxides and their derived per-
oxides have attracted a great deal of attention as po-
tential antimalarial active compounds against the
background the increasing resistance of malaria para-
sites to alkaloid medicine, since artemisinin with an
To the best of our knowledge, this reaction is the
endoperoxide bridge structure shows effective antima- first example for the preparation of gem-dihydroper-
larial activity against multidrug-resistant malaria.[1] In oxides from carbonyl compounds with molecular
addition, from the view point of organic synthesis, oxygen as a terminal oxidant. Herein, we report our
gem-dihydroperoxides have been also known to play detailed study, including scope and limitations, of this
an important role as key intermediates in the synthe- synthesis of gem-dihydroperoxides.
sis of various peroxides[2–4] as an initiator for radical
The reaction conditions were examined with molec-
polymerization,[5] and as an oxidant for epoxidation[6] ular oxygen and a catalytic photosensitizer under irra-
and sulfoxidation.[7] Generally, gem-dihydroperoxides diation from a 500 W xenon lamp at room tempera-
can be synthesized from carbonyl compounds or their ture using tert-butylcyclohexanone (1) as a test sub-
derivative with hydrogen peroxide in the presence of strate. Among the typical photosensitizers and sol-
catalysts such as acids, heavy metals and iodine.[8] vents we have examined, anthracene and 2-propanol
Also we have recently reported the convenient cata- were found to be most effective for this reaction, re-
lyst-free synthesis of gem-dihydroperoxides from ke- spectively, and even 2 mol% of the catalyst was
tones and aldehydes with hydrogen peroxide in dime- enough for the smooth progression of this reaction. It
thoxyethane.[9] Hydrogen peroxide is an excellent oxi- is noted that all three factors, light irradiation, anthra-
dant due to its production of water as the only by- cene, and molecular oxygen, were necessary for the
product in oxidation reactions; however, attention is dihydroperoxydation since the product was not ob-
required for handling due to its corrosive and explo- tained without them.[12]
sive properties. On the other hand, molecular oxygen
Table 1 indicates the scope and limitations of this
has attracted much attention because of its (a) ease of synthesis using various ketones under the optimized
handling, (b) involvement in photosynthesis, and (c) reaction conditions mentioned above. Cyclohexanone
larger atom efficiency than that of other oxidants,[10] (3) and its derivatives 1, 5, 7, 9 produced the corre-
and higher environmentally benign oxidation process- sponding gem-dihydroperoxides 2, 4, 6, 8, 10 in good
Adv. Synth. Catal. 2010, 352, 2383 – 2386
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Table 1. Aerobic photosynthesis of gem-dihydroperoxides.
Scheme 1. Plausible reaction path.
dihydroperoxide 22) since they were also good sub-
strates for aerobic photo-oxidation to give the corre-
sponding carboxylic acids (entries 10 and 11).[13] Un-
fortunately, acetophenone (23) was converted to the
corresponding dihydroperoxide only in low yield.
To clarify the mechanism, first we assayed the per-
oxides in solution by iodometry, and found that large
excesses of peroxides were formed in comparison
with the substrate.[14] This result suggests that hydro-
gen peroxide or hydroxy peroxide was formed in the
solution. In addition, the formation of excess amounts
of acetone (2.39 mmol) was detected by 1H NMR
measurements. We have also found that gem-dihydro-
peroxides can be obtained from the carbonyl com-
pounds and aqueous hydrogen peroxide without any
catalyst.[9] Scheme 1 shows the plausible path of this
reaction, which is postulated by considering all of the
results mentioned above and the necessity of 2-propa-
nol, a catalytic amount of anthracene and molecular
oxygen. Hydroxy hydroperoxide 25 was generated
from 2-propanol in the presence of molecular oxygen
and anthracene or dianthracene with irradiation from
the xenon lamp.[15] Hydroxy hydroperoxide 25 or hy-
drogen peroxide (26), that is generated from 25 in
situ, reacts with ketone to generate the gem-dihydro-
peroxide.[16] It has not been clarified yet which path is
operative; however, we believe that hydrogen perox-
ide was generated in situ since bubbling was observed
when catalase was added to this reaction mixture.[17]
In conclusion, we have developed a first facile and
practical method for preparation of gem-dihydroper-
oxides from various carbonyl compounds in the pres-
ence of molecular oxygen and the catalytic amount of
anthracene under photo irradiation. This dihydroper-
[a]
Isolated yields.
[b]
Determined by 1H NMR using tetrachloroethane as an
internal standard.
Octanoic acid (28%) was detected by H NMR.
4-Anisic acid (58%) was detected by H NMR.
[c]
[d]
1
1
to excellent yields (entries 1–5). Cyclooctanone (11) oxidation protocol also seems efficient as environ-
was also converted to the corresponding gem-dihydro- ment friendly. Further application of this dihydroper-
peroxide 12 in high yield (entry 6). 2-Adamantanone oxidation and detailed mechanistic study are now in
(13), having high steric hindrance, was still reactive progress in our laboratory.
and the corresponding gem-dihydroperoxide (14) was
obtained in 81% yield (entry 7). Furthermore, 2-nona-
none (15) and 5-nonanone (17), non-cyclic aliphatic
ketones, produced the corresponding gem-dihydroper-
Experimental Section
oxides in 84 and 77% yields, respectively (entries 8
and 9). On the other hand, aldehydes 19, 21 produced
Caution! Peroxides generated in the reaction mixture may
result in explosion. All preparations should be handled with
low yields of products (hydroperoxyhemiacetal 20 or care on a small scale.
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Adv. Synth. Catal. 2010, 352, 2383 – 2386

An Efficient Synthesis of gem-Dihydroperoxides with Molecular Oxygen and Anthracene
VCH: Weinheim, Germany, 2000; b) H. Hansma, A.
Schrorder, (AKZON.V.), Belgian Patent 868,681, 1978:
Chem. Abstr. 1979, 90, 153037a.
Representative Procedure of Dihydroperoxidation
A dry 2-propanol solution (5 mL) of 4-tert-butylcyclohexa-
none (46.3 mg, 0.30 mmol) and anthracene (1.07 mg,
0.006 mmol) in a pyrex tube equipped with an O2-balloon
was stirred and irradiated externally with a 500 W xenon
lamp, which was set up at a distance of 30 cm, for 10 h. The
temperature of the final stage of this reaction was about
608C. The reaction mixture was concentrated under reduced
pressure, and the pure product was obtained by purification
with preparative TLC: yield: 52.7 mg (86%).
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