A simple, efficient and versatile synthesis of primary gem-dihydroperoxides from aldehydes and hydrogen peroxide

Article abstract of DOI:10.1016/j.tetlet.2008.11.055

Aldehydes were efficiently converted directly into the corresponding gem-dihydroperoxides (DHPs) on treatment with aqueous 70% H₂O₂ in a biphasic system with ether catalyzed by camphorsulfonic acid. The synthesis represents the most versatile access to this class of compounds.

Full text of DOI:10.1016/j.tetlet.2008.11.055

Tetrahedron Letters 50 (2009) 524–526
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple, efficient and versatile synthesis of primary gem-dihydroperoxides
from aldehydes and hydrogen peroxide
*
*
Alexander Bunge, Hans-Jürgen Hamann , Jürgen Liebscher
Institut für Chemie, Humboldt-Universität zu Berlin, Brook-Taylor-Straße 2, D-12489 Berlin, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Aldehydes were efficiently converted directly into the corresponding gem-dihydroperoxides (DHPs) on
Received 2 October 2008
Revised 7 November 2008
Accepted 14 November 2008
Available online 20 November 2008
treatment with aqueous 70% H
The synthesis represents the most versatile access to this class of compounds.
Ó 2008 Elsevier Ltd. All rights reserved.
2 2
O in a biphasic system with ether catalyzed by camphorsulfonic acid.
Keywords:
Aldehydes
gem-Dihydroperoxides
Aqueous hydrogen peroxide
Acid catalysis
1
4
The interest in gem-dihydroperoxides 1 (DHPs) has increased
peroxide in THF under acid catalysis, and by Dussault et al. using
rhenium(VII)oxide in acetonitrile.
1
5
sharply in recent years due to their relevance to peroxidic anti-
1
,2
malaria compounds.
They are useful intermediates in the
3,4
synthesis of tetroxanes and their analogues, and very recently
R1
OH
they have also been utilized as epoxidation reagent for
urated ketones.
The methods for preparing gem-DHPs have been reviewed. The
most straightforward way for preparing gem-dihydroperoxides is
the reaction of hydrogen peroxide with ketones or aldehydes.
However, in most cases, mixtures of peroxidic products were
a
,b-unsat-
OOH
5
C H15CH
7
6
R2
OOH
OOH
2
1
7
,8
obtained.
As the first example of geminal dihydroperoxides,
Remarkably, no conversion of aliphatic aldehydes to DHPs has
been reported so far. Using the reaction conditions under which
benzaldehyde was transformed into the gem-DHP, octanal was
converted into corresponding hydroxy-hydroperoxide 2,12 that is,
just an addition of one molecule of hydrogen peroxide to the
carbonyl group occurred. The same compound 2 and additional
hydroxy-hydroperoxides were already obtained by Rieche in
1931 on treatment of the corresponding aldehydes with ethereal
9
Ledaal and Solbjor isolated 1,1-dihydroperoxycyclododecane
when cyclododecanone was treated with 34% aqueous hydrogen
peroxide under acidic conditions. Later on, other ketones were
used in the presence of formic acid, but DHPs were obtained in
1
0
lower yields.
A more general way for preparing DHPs from ketones is the use
of 30% aqueous H with iodine as catalyst and acetonitrile as sol-
This method was also applied to aromatic aldehydes
affording 55–76% yield of the corresponding primary DHPs.
2 2
O
1
1,12
16
vent.
H O .
2
2
Very few alternative methods to obtain primary gem-DHPs have
been known so far. We obtained primary DHPs from cyclic benzo-
condensed secondary alcohols by acid-catalyzed treatment with
H O under rearrangement. Ozonolysis of enol ethers in the pres-
2 2
2 2
ence of ethereal H O yielded primary gem-DHPs. So far, this has
been the only more general synthetic procedure described to
obtain primary gem-DHPs.
The synthesis of DHPs is limited by their stability and depends
on their structure. 2,2-Dihydroperoxypropane readily decomposes.
However, a stabilization by interaction with diphosphinoyl donors
1
3
Das et al. developed an efficient method for the synthesis of
gem-DHPs from the corresponding ketones and aldehydes using
1
7
5
0% aqueous H
2
O
2
and a catalytic amount of ceric ammonium ni-
1
0
trate (CAN). However, for primary gem-DHPs the method seems
to be limited to aromatic aldehydes, which must not be electron
poor. Recently, two other methods for the synthesis of gem-DHPs
were published by Terent’ev et al., applying a solution of hydrogen
*
Corresponding authors. Tel.: +49 30 2093 7550; fax: +49 30 2093 7552 (J.L.).
E-mail address: liebscher@chemie.hu-berlin.de (J. Liebscher).
1
8
was reported. Very recently, we isolated the hitherto unknown
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.055

A. Bunge et al. / Tetrahedron Letters 50 (2009) 524–526
525
ethane-1,1-dihydroperoxide and propane-1,1-dihydroperoxide by
reaction of cyclic epoxyketones with hydrogen peroxide.1 Despite
the very high oxygen content (the former has the highest value
achieved so far), the compounds are remarkably stable. These find-
ings prompted us to search for a convenient synthesis of primary
gem-DHPs starting directly from the corresponding aldehydes.
Here we report on our preliminary results.
for example, concentration, and the signal can also vary in shape
(usually not sharp, but broad in varying extents). The C NMR
spectra of peroxides 5 are similar to those of the gem-DHPs 4,
9
13
but most signals are doubled due to the formation of diastereo-
1
mers. In the H NMR spectra of 5, the intensity relation of the
hydroperoxy proton and the CH-proton is 1:1, contrary to the 2:1
ratio of the gem-DHPs 4.
Hydrogen peroxide is commonly used in aqueous form, but
ethereal solutions can be prepared and used as well. In the latter
case, concentrations are generally lower due to the method of
preparation. Since the application of ethereal hydrogen peroxide
to aldehydes led only to the formation of perhydrates, that is,
only one molecule of hydrogen peroxide entered the aldehyde,
The products formed from lower aldehydes up to the butanals
could be isolated by column chromatography relatively easily.
Products 4 derived from higher aliphatic aldehydes were difficult
to separate from the substrates and side products. C NMR data
of such crude mixtures showed also the formation of perhydrates
analogous to 3, which exhibit the typical hydroperoxycarbon signal
shifted towards higher field by about 7–10 ppm in comparison
with 4. Changing of the solvent used for chromatography from
cyclohexane/ethylacetate to dichloromethane/methanol helped to
overcome this problem.
1
3
1
6
2 2
we tried now to use aqueous H O (70%) and diethylether as a
biphasic system in the presence of catalytic amounts of camphor-
sulfonic acid (CSA). This hitherto unpublished method was origi-
2
0
nally developed by us for transforming ketones into gem-DHPs
and was now applied to various aldehydes to obtain the envisaged
primary gem-DHPs (Scheme 1, Table 1). The reaction was run at
room temperature for 16–40 h and worked remarkably well. The
reaction mixtures contained some starting material in all cases (ex-
cept for the lower aldehydes, where probably evaporation occured)
even at longer reaction times. This could be explained by the for-
mation of an equilibrium between starting material and product.
In addition, the yield might have been further lowered to a small
extent by decomposition of the product into the aldehyde 3 during
chromatography.
Both acyclic and cyclic aliphatic aldehydes 3 afforded the
desired gem-DHPs 4 in moderate to good yields. It should be noted
that using paraldehyde instead of acetaldehyde did not afford any
peroxidic products at all. In most cases, small amounts of bishydr-
operoxy peroxides 5 were detected as by-products by TLC. In some
cases (5a, 5c and 5d), they were also isolated and characterized by
NMR spectra.
2 2
Lowering the concentration of aqueous H O from 70% to 40%
resulted in lower yields as shown in the case of the DHP 4d (42%
vs 64%, entry 5). The present method was also applied to the
hydroperoxidation of aromatic aldehydes such as benzaldehyde
(entry 10) leading to 77% yield of 4i.
The behaviour of chloral 6 under these hydroperoxidation
conditions is completely different from that of other aldehydes 3.
Instead of the expected DHP 8, the dihydroxyperoxide 7 was
isolated (Scheme 2). Even by increasing the amount of H
(16 equiv instead of 4 equiv), the only product detected was 7.
The preparation of the peroxide 7 from chloral was first re-
2 2
O
2
1
ported by Baeyer and Villiger using Caro’s acid or ethereal
2
2
H
2
O
2
. Popova et al. described a method for the preparation of
the putative DHP 8 by reaction of 6 with a mixture of 30% H
2 2
O
and 102% oleum. However, they obviously isolated the peroxide
7 instead as can be deduced by their determined mp (120–
123 °C) and content of active oxygen (4.75%) fitting to the structure
7. The unusual behaviour of chloral 6 can be explained by the pres-
ence of the strongly withdrawing trichloromethyl group. The
highly electrophilic carbonyl group rapidly undergoes addition of
H O to form hydroxy-hydroperoxide 9, which is resistant to ioni-
2 2
zation and instead undergoes reaction with an additional molecule
chloral to form the stable peroxide 7.
In addition to already known gem-dihydroperoxides (4a, 4b, 4h
and 4i ), the hitherto unknown 1,1-dyhydroperoxides 4c, 4d, 4e, 4f
and 4g could be obtained in this straightforward way. All
gem-DHPs 4 show distinctive signals in the NMR spectra, including
a signal at ca. 110 ppm in the 13C NMR spectrum and one typical
hydroperoxy proton signal (intensity two protons) at ca.
9
.0–9.8 ppm in the 1H NMR spectrum. The chemical shift of the
hydroperoxy proton can, however, vary due to various reasons,
OOH
Cl C
OH
3
R
H O (70%),CSA
8
O
2
2
OOH
R OOH
R
O
+
O
OOH
R
ether, r.t., 16-40 h
OOH
+
H O
2
2
3
5
4
Scheme 1.
H O (70%),CSA
2 2
O
OOH
OH
ether, r.t., 16 h
Cl C
Cl C
3
3
Table 1
Synthesis of primary gem-dihydroperoxides 4 from aldehydes 3
6
9
O
Entry
Aldehyde 3
R
Time (h)
4/yield (%)
5/yield (%)
+
1
2
3
4
5
6
7
8
9
3a
3b
3c
3d
Me
Et
n-Propyl
i-Propyl
16
16
22
21
21
40
16
18
16
16
4a/34
4b/42
4c/63
4d/64
5a/10
Traces
5c/5
5d/5
Traces
0
Traces
Traces
Traces
0
Cl C
6
3
CCl3
a
4d/42
3e
3f
3g
3h
3i
t-Butyl
4e/28
4f/44
4g/33
4h/44
4i/77
Cl C
3
O
O
OH
n-Pentyl
n-Heptyl
Cyclohexyl
Phenyl
OH
7
1
0
a
Using aqueous H
2
O
2
(40%).
Scheme 2.

5
26
A. Bunge et al. / Tetrahedron Letters 50 (2009) 524–526
7. Kharasch, M. S.; Sosnovsky, G. J. Org. Chem. 1958, 23, 1322–1326.
In conclusion, we developed an environmentally benign, simple
8
9
.
.
Criegee, R.; Schnorrenberg, W.; Becke, J. Liebigs Ann. Chem. 1949, 565, 7–21.
Ledaal, T.; Solbjor, T. Acta Chem. Scand. 1967, 21, 1658–1659.
and efficient method for the synthesis of primary aliphatic and aro-
matic gem-dihydroperoxides directly from the corresponding alde-
10. Kim, H. S.; Nagai, Y.; Ono, K.; Begum, K.; Wataya, Y.; Hamada, Y.; Tsuchiya, K.;
hydes by treatment with aqueous H
2
O
2
and a catalytic amount of
Masuyama, A.; Nojima, M.; McCullough, K. J. J. Med. Chem. 2001, 44, 2357–
2361.
CSA in ether solution. This synthesis represents the most versatile
access to this class of compounds. Using this method, we have suc-
cessfully synthesized several aliphatic primary gem-DHPs for the
first time.
1
1
1. Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J. Org. Lett. 2006, 8, 2491–2494.
2. Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J. J. Org. Chem. 2007, 72, 6534–6540.
13. Das, B.; Krishnaiah, M.; Veeranjaneyulu, B.; Ravikanth, B. Tetrahedron Lett.
007, 48, 6286–6289.
4. Terent’ev, A. O.; Platonov, M. M.; Ogibin, Y. N.; Nikishin, G. I. Synth. Commun.
007, 37, 1281–1287.
15. Ghorai, P.; Dussault, P. H. Org. Lett. 2008, 10, 4577–4579.
2
1
Presently, we are further optimizing the reaction conditions and
investigating the scope and limitations of this method.
Caution : 70% Hydrogen peroxide as well as peroxidic
compounds are potentially explosive and should be handled with
precautions (shields, fume hoods, avoidance of transition metal
salts or heating).
2
1
1
1
6. Rieche, A. Chem. Ber. 1931, 64, 2328–2335.
7. Hamann, H. J.; Liebscher, J. Synlett 2001, 96–98.
8. Pettinari, C.; Marchetti, F.; Cingolani, A.; Drozdov, A.; Troyanov, S. Chem.
Commun. 2000, 1901–1902.
9. Hamann, H. J.; Bunge, A.; Liebscher, J. Chem. Eur. J. 2008, 14, 6849–6851.
20. Bolsinger, J., Diploma thesis, Humboldt-Universität zu Berlin, 2005.
1. Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1900, 33, 2479–2487.
22. Popova, A. A.; Khardin, A. P.; Shreibert, I. V. Mater. Nauch. Konf. Sovnarkhoz
Nizhnevolz. Ekon. Raiona, Volgograd. Politekh. Inst., Volgograd 1965, 2, 18–23;
Chem. Abstr. 1967, 66, 85413.
1
2
3
General procedure: The aldehyde 3 (10 mmol) was dissolved in
diethylether (2 ml) and cooled in an ice bath. After addition of 70%
hydrogen peroxide (2 ml) and camphorsulfonic acid monohydrate
2
(
25 mg, 0.1 mmol), the biphasic system was left to stir over night
2
3. Spectral data for new compounds: Bis(1-hydroperoxyethyl)peroxide 5a:
while the temperature gradually rose to room temperature. The
mixture was diluted with water (30 ml), extracted with diethyl
ether (3 ꢀ 20 ml), and the combined organic layers were washed
with saturated aqueous sodium bicarbonate solution (20 ml). After
drying over sodium sulfate, the solvent was evaporated under
reduced pressure. The residue was purified by column chromato-
graphy (silica gel, cyclohexane–EtOAc or DCM–MeOH) affording
pure 4. Usually traces of 5 were also found, which could be isolated
in some cases.
1
colourless oil (10%); 1:1 mixture of diastereomers; H NMR (CDCl
3
): 9.72 (s,
2H), 5.47–5.40 (m, 2H), 1.47–1.44 (m, 6H); 13C NMR (CDCl
3
): 106.6, 106.5, 14.7,
þ
4 14 6
4
H O N: 172.0816 (M+NH ); found 172.0814.
1
1
4.6; HRMS (ESI) calcd for C
Butane-1,1-dihydroperoxide 4c: colorless oil (63%); H NMR (CDCl
H), 5.30 (t, 1H, J = 6.1 Hz), 1.71 (dd, 2H, J = 6.3, 15.2 Hz), 1.48 (dd, 2H, J = 7.5,
3
): 9.84 (s,
2
13
15.2 Hz), 0.95 (t, 3H, J = 7.4 Hz); C NMR (CDCl
ESI) calcd for
3
): 111.1, 30.5, 18.0, 13.7; HRMS
Cl: 157.0273 (M+Cl ); found 157.0267. Bis(1-
ꢁ
(
C
4
H
10
O
4
hydroperoxybutyl)peroxide 5c: colorless oil (5%); 1:1 mixture of
diastereomers; 1H NMR (CDCl
3
): 9.69 (s, 2H), 5.24–5.29 (m, 2H), 1.73–1.82
(m, 4 H), 1.52 (dd, 4H, J = 7.6, 15.1 Hz), 0.98 (t, 6H, J = 7.4 Hz); C NMR (CDCl
09.8, 30.4, 30.3, 18.1, 13.7; HRMS (ESI) calcd for C Na: 233.0996
M+Na ); found 233.0997. 2-Methyl-propane-1,1-dihydroperoxide 4d: white
1
3
3
):
1
(
8 18 6
H O
+
1
waxy solid (64%); H NMR (CDCl
3
): 8.92 (s, 2H), 4.99 (d, 1H, J = 7.9 Hz), 2.05–
13
Acknowledgements
2.17 (m, 1H), 1.03 (d, 6H, J = 6.8 Hz); C NMR (CDCl ): 115.5, 28.5, 18.2. HRMS
3
ꢁ
(
ESI) calcd for
C
4
H
10
O
4
Cl: 157.0273 (M+Cl ); found 157.0271. Bis(1-
hydroperoxy-2-methyl-propyl)peroxide 5d: colorless oil (5%); 1:1 mixture of
We wish to thank Dipl.-Ing. Angela Thiesies for the very fast
measurement of many NMR samples. We further thank Solvay
Interox GmbH, Bayer Services GmbH & Co. OHG, BASF AG and Sasol
GmbH for the donation of chemicals. A.B. gratefully acknowledges
a grant from Deutsche Forschungsgemeinschaft (DFG).
diastereomers; 1H NMR (CDCl
3
): 9.81 (s, 2H), 4.89 (dd, 2H, J = 5.1, 8.6 Hz),
2.12–2.25 (m, 2H), 1.07 (d, 12H, J = 6.8 Hz); C NMR (CDCl ): 114.4, 114.3,
13
3
+
28.3, 28.2, 18.6, 18.5; HRMS (ESI) calcd for C
8 18 6
H O Na: 233.0996 (M+Na );
found 233.0995. 2,2-Dimethylpropane-1,1-dihydroperoxide 4e: white solid
1
(
5
9
28%), already melting at room temperature; H NMR (C
6
D
6
): 7.51 (br s, 2H),
13
1
.10 (s, 1H), 0.95 (s, 9H); C NMR (C
6
D
6
): 117.1, 35.6, 25.7; H NMR (CDCl
.80 (br s, 2H), 5.14 (s, 1H), 0.98 (s, 9H); C NMR (CDCl
Cl: 171.0430 (M+Cl ); found: 171.0424. Hexane-
,1-dihydroperoxide 4f: colorless oil (44%); H NMR (CDCl
3
):
13
3
): 117.1, 35.6, 25.5;
ꢁ
HRMS (ESI) calcd for C
5
H
12
O
4
References and notes
1
1
1
4
3
): 9.82 (s, 2H), 5.27 (t,
H, J = 6.0 Hz), 1.71 (dt, 2H, J = 9.0, 6.3 Hz), 1.47–1.38 (m, 2H), 1.33–1.24 (m,
1
2
.
.
Tang, Y. Q.; Dong, Y. X.; Vennerstrom, J. L. Med. Res. Rev. 2004, 24, 425–448.
Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew. Chem., Int. Ed. 2003, 42,
13
H), 0.87 (t, 3H, J = 6.6 Hz); C NMR (CDCl
3
): 111.3, 31.3, 28.4, 24.3, 22.3, 13.8;
Cl: 185.0586 (M+Cl ); found: 185.0586. Octane-
ꢁ
HRMS (ESI) calcd for C
6
H
14
O
4
5
274–5293.
1
,1-dihydroperoxide 4g: colorless oil (33%); white solid when stored in the
3
4
.
.
Iskra, J.; Bonnet-Delpon, D.; Begue, J. P. Tetrahedron Lett. 2003, 44, 6309–6312.
Terent’ev, A. O.; Kutkin, A. V.; Starikova, Z. A.; Antipin, M. Y.; Ogibin, Y. N.;
Nikishina, G. I. Synthesis 2004, 2356–2366.
1
freezer (ꢁ30 °C); H NMR (CDCl
3
): 9.73 (s, 2H), 5.28 (t, 1H, J = 6.0 Hz), 1.72 (dt,
2
H, J = 9.0, 6.0 Hz), 1.49–1.38 (m, 2H), 1.31–1.22 (m, 8H), 0.87 (t, 3H,
13
J = 6.6 Hz); C NMR (CDCl
HRMS (ESI) calcd for C
3
): 111.3, 31.7, 29.2, 29.0, 28.5, 24.6, 22.6, 14.0;
5
6
.
.
Jakka, K.; Liu, J. Y.; Zhao, C. G. Tetrahedron Lett. 2007, 48, 1395–1398.
Zmitek, K.; Zupan, M.; Iskra, J. Org. Biomol. Chem. 2007, 5, 3895–3908.
ꢁ
8
H
18
O
4
Cl: 213.0899 (M+Cl ); found: 213.0892.