Mild and efficient Re(VII)-catalyzed synthesis of 1,1-dihydroperoxides

Article abstract of DOI:10.1021/ol801859c

(Chemical Equation Presented) Re₂O₇ in CH ₃CN is a remarkably efficient and mild catalyst for the peroxyacetalization of ketones, aldehydes, or acetals by H₂O ₂ to generate 1,1-dihydroperoxides. Me₃SiOReO₃ and methyl rhenium trioxide (MTO) are also effective catalysts under these reaction conditions.

Full text of DOI:10.1021/ol801859c

ORGANIC
LETTERS
2008
Vol. 10, No. 20
4577-4579
Mild and Efficient Re(VII)-Catalyzed
Synthesis of 1,1-Dihydroperoxides
Prasanta Ghorai and Patrick H. Dussault*
Department of Chemistry, UniVersity of NebraskasLincoln,
Lincoln, Nebraska 68588-0304
pdussault1@unl.edu
Received August 9, 2008
ABSTRACT
Re2O7 in CH3CN is a remarkably efficient and mild catalyst for the peroxyacetalization of ketones, aldehydes, or acetals by H2O2 to generate
1,1-dihydroperoxides. Me3SiOReO3 and methyl rhenium trioxide (MTO) are also effective catalysts under these reaction conditions.
1,1- or gem-dihydroperoxides are stable derivatives of
ketones and aldehydes1 and important intermediates in the
synthesis of a number of classes of peroxides, including
tetraoxanes,2 silatetraoxanes,3 spirobisperoxyketals,4 bisper-
oxyketals,5 and 1,2,4,5-tetraoxacycloalkanes.6 Dihydroper-
oxides have also been employed as initiators for radical
polymerization reactions,7 as reagents for nucleophilic ep-
oxidations and oxidations,8,9 and as precursors for synthesis
of dicarboxylic acid diesters.10 We now report that Re2O7-
catalyzed peroxyacetalization of ketones and aldehydes
furnishes 1,1-dihydroperoxides in high yields and with a
broader substrate scope than any existing catalyst system.11
Of the methods described for the synthesis of 1,1-
dihydroperoxides, most have significant limitations.1 The
direct reaction of ketones with commercial grades of aq.
H2O2, in either the presence or the absence of formic acid,6,12
proceeds in modest yield.1 The reaction of H2O2 with enol
ethers, ketals, aldehydes, or ketones in the presence of strong
Bro¨nsted or Lewis acids is widely applied13-16 but can face
problems with heterolytic rearrangements.17,18 Iodine-
promoted peroxyacetalization proceeds under mild conditions
and achieves good yields19 but requires long reaction times
and is likely limited to saturated substrates. The use of ceric
ammonium nitrate as a catalyst requires a large excess of
H2O2 and may be limited by the sensitivity of the substrate
(1) For a review, see: (a) Zmitek, K.; Zupan, M.; Iskra, J. Org. Biomol.
Chem. 2007, 5, 3895. (b) Kropf, H.; Nu¨rnberg, W. In Methoden der
Organischen Chemie, E13; Kropf, H., Ed.; Thieme, 1988; v. 1, 548.
(2) Dong, Y. Mini-ReV. Med. Chem. 2002, 2, 113–123. Terent’ev, A. O.;
Kutkin, A. V.; Starikova, Z. A.; Antipin, M. Y.; Ogibin, Y. N.; Nikishina,
G. I. Synthesis 2004, 2356. Amewu, R.; Stachulski, A. V.; Ward, S. A.;
Berry, N. G.; Bray, P. G.; Davies, J.; Labat, G.; Vivas, L.; O’Neill, P. M.
Org. Biomol. Chem. 2006, 4, 4431.
(3) Terent’ev, A. O.; Platonov, M. M.; Tursina, A. I.; Chernyshev, V. V.;
Nikishin, G. I. J. Org. Chem. 2008, 73, 3169.
(11) Standard procedures are described in the Supporting Informa-
tion.
(4) Ghorai, P.; Dussault, P. H.; Hu, C. Org. Lett. 2008, 10, 2401. Zhang,
Q.; Li, Y.; Wu, Y.-K. Chin. J. Chem. 2007, 25, 1304.
(12) Ledaal, T.; Solbjor, T. Acta Chem. Scand. 1967, 21, 1658
(13) H2SO4/ketones: Terent’ev, A. O.; Platonov, M. M.; Ogibin, Y. N.;
Nikishin, G. I. Synth. Commun. 2007, 37, 1281
(14) BF3·Et2O/acetals: Terent’ev, A. O.; Kutkin, A. V.; Platonov, M. M.;
Ogibin, Y. N.; Nikishin, G. I. Tetrahedron Lett. 2003, 44, 7359
(15) Tungstic acid/acetals: Jefford, C. W.; Li, W.; Jaber, A.; Boukou-
valas, J. Synth. Commun. 1990, 20, 2589
(16) NaHSO4/ketones: Das, B.; Veeranjaneyulu, B.; Krishnaiah, M.;
Balasubramanyam, P. J. Mol. Catal. A 2008, 284, 116
(17) Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 737, 7
.
(5) Hamada, Y.; Tokuhara, H.; Masuyama, A.; Nojima, M.; Kim, H. S.;
Ono, K.; Ogura, N.; Wataya, Y. J. Med. Chem. 2002, 45, 1374.
(6) 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. Masuyama, A.; Wu, J.-M.; Nojima, M.; Kim, H.-
S.; Wataya, Y. Mini-ReV. Med. Chem. 2005, 5, 1035.
.
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(7) Hansma, H.; Schroeder, A. AKZO N. V. Belg. Patent 868,681, 1978;
Chem. Abstr. 1979, 90, 153037a.
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(8) Jakka, K.; Liu, J.; Zhao, C.-G. Tetrahedron Lett. 2007, 48, 1395
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(18) (a) Dussault, P. H.; Lee, H-J.; Liu, X. J. Chem. Soc., Perkins Trans.
1 2000, 3006, and references within. (b) Kropf, H. In Methoden der
(9) Saneyoshi, H.; Miyata, K.; Seio, K.; Sekine, M. Tetrahedron Lett.
2006, 47, 8945
(10) Terent’ev, A. O.; Platonov, M. M.; Kutkin, A. V. Cent. Eur.
J. Chem. 2006, 4, 207
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Organischen Chemie, E13; Kropf, H., Ed.; Thieme, 1988; v. 2, 1084
(19) Zmitek, K.; Zupan, M.; Stavber, S.; Iskra, J. Org. Lett. 2006, 8,
2491.
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10.1021/ol801859c CCC: $40.75
Published on Web 09/11/2008
2008 American Chemical Society

or product toward oxidation.20 Ozonolysis of alkenes in the
presence of H2O2 allows preparation of 1,1-dihydroperoxides
under neutral conditions but requires the use of organic
solutions of H2O2 and is limited to ozone-compatible
substrates.4,21
Methyl rhenium trioxide (MTO) catalyzed peroxyacetal-
ization of cycloalkanones and aldehydes has been applied
in tandem with ketalization of the intermediate dihydroper-
oxides as an approach to unsymmetric 1,2,4,5-tetraox-
anes.22-24 However, the method requires fluorinated alcohol
solvents and has not been applied to aliphatic substrates. We
became interested in Re2O7, which has been applied to the
isomerization/deprotection of allyl silyl ethers25 and, in
conjunction with TFAA, the ring opening of THF.26 Silylated
perrhenates are known to catalyze the isomerization of
unsaturated alcohols.27
tive.21-23 Solvent polarity appears important, as the peroxy-
acetalization proceeded more rapidly and in higher yield in
CH3CN compared with CH2Cl2. Conducting the Re2O7-
promoted reaction at 0 °C slowed the reaction but resulted
in a higher yield and the absence of byproducts. Consider-
ations of cost and convenience led us to focus on Re2O7.28,29
Application to the synthesis of cyclic-1,1-dihydroperoxides
is summarized in Table 2. The six- and seven-membered
Table 2. Synthesis of Cycloalkyl-1,1-dihydroperoxides
A preliminary investigation of the peroxyacetalization of
4-t-butylcyclohexanone (1a) with a modest excess of aq.
H2O2 in CH3CN revealed the formation of useful yields of
the dihydroperoxide (2a) in the presence of MTO, Re2O7,
or Me3SiOReO3 (Table 1); in each case, the desired product
Table 1. Comparison of Re(VII) Catalysts
H2O2
time
(h)
2a
3a
catalyst
MTO
solvent (equiv) temp
(%)a (%)a
CH3CN
CH3CN
CH3CN
CH2Cl2
4
4
2.2
2.2
2.2
rt
rt
0 °C
rt
rt
0.5
0.5
1
0.5
0.5
73
86
95
41
81
3
5
-
30
5
Re2O7
Me3SiOReO3 CH3CN
a Isolated yields.
ring ketones, including adamantanone, provided excellent
yields of the dihydroperoxides in an hour or less. Cyclooc-
tanone reacted slowly and gave the lowest yield within this
group. The reaction of cyclododecanone, while even slower,
furnished the dihydroperoxide in excellent yield. Traces of
bishydroperoxyperoxide dimers were often observed (TLC)
in the crude reaction mixtures but were lost upon chroma-
tography. No products of ring expansion were observed
except for 1d, where the product (2d) was accompanied by
approximately 5% of octalactone.30
With the exception of iodine-catalyzed peroxyacetaliza-
tions,19 preparation of acyclic 1,1-dihydroperoxides has been
problematic, particularly for aldehydes or aryl ketones. This
limitation presumably reflects the tendency of the intermedi-
ate perhydrate or the dihydroperoxides to undergo heterolytic
was accompanied by small amounts of the bishydroperoxy
peroxide (3a). Although higher yields were obtained with
Re2O7 or Me3SiOReO3, the catalytic activity of MTO is
noteworthy, given the lack of a fluorinated alcohol addi-
(20) Das, B.; Krishnaiah, M.; Veeranjaneyulu, B.; Ravikanth, B.
Tetrahedron Lett. 2007, 48, 6286.
(21) 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
(22) Zmitek, K.; Stavber, S.; Zupan, M.; Bonnet-Delpon, D.; Iskra, J.
Tetrahedron 2006, 62, 1479
(23) Atheaya, H.; Khan, S. I.; Mamgain, R.; Rawat, D. S. Bioorg. Med.
Chem. Lett. 2008, 18, 1446
.
.
.
(24) Ellis, G. L.; Amewu, R.; Sabbani, S.; Stocks, P. A.; Shone, A.;
Stanford, D.; Gibbons, P.; Davies, J.; Vivas, L.; Charnaud, S.; Bongard,
E.; Hall, C.; Rimmer, K.; Lozanom, S.; Jesus, M.; Gargallo, D.; Ward,
S. A.; O’Neill, P. M. J. Med. Chem. 2008, 51, 2170
.
(25) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2006, 128, 8142.
(26) Lo, H. C.; Han, H.; D’Souza, L. J.; Sinha, S. C.; Keinan, E. J. Am.
Chem. Soc. 2007, 129, 1247.
(28) As of August 2008, the ratio of $/mol for Re2O7, Me3SiOReO3,
and MTO was 1:2:6.
(29) Allowing the reactions to run for longer periods or at higher
temperatures resulted in slow formation of byproducts.
(30) Gonza´lez-Nu´n˜ez, M. E.; Mello, R.; Olmos, A.; Asensio, G. J. Org.
Chem. 2005, 70, 10879.
(27) Bellemin-Laponnaz, S.; Gisie, H.; Le Ny, J. P.; Osborn, J. A. Angew.
Chem., Int. Ed 1997, 36, 976. Morrill, C.; Grubbs, R. H. J. Am. Chem.
Soc. 2005, 127, 2842.
4578
Org. Lett., Vol. 10, No. 20, 2008

fragmentations.17,18 We were therefore pleased to observe
that the peroxyacetalizations proceed in good to excellent
yield for aliphatic ketones, aromatic aldehydes, and aromatic
ketones (Table 3). Aromatic aldehydes and ketones generally
yields and improved scope relative to more traditional
catalysts points to a different mode of substrate or reagent
activation. This is supported by the activity of MTO, a
catalyst unlikely to generate a potent Bro¨nsted acid under
the reaction conditions. The demonstrated activation of
alcohols by silyl perrhenates27 suggests that our results may
be due to Re(VII) activation of the intermediate perhydrate.
In conclusion, Re2O7-catalyzed peroxyacetalization offers
a mild, efficient, and broadly applicable method for synthesis
of 1,1-dihydroperoxides which employs an inexpensive
organic solvent and requires only a slight excess of H2O2.32
Application of this methodology for the chemoselective
synthesis of 1,2,4,5-tetraoxanes is in progress.
Table 3. Synthesis of Acyclic 1,1-Dihydroperoxides
substrate
R1
R2
time(h)
product
yield
1i
1j
pentyl
Ph(CH2)2
Bu
Me
Me
Bu
H
H
H
H
H
H
Me
0.5
1
1
6
2
5
5
5
24
24
2i
2j
2k
2l
2m
2n
2o
2p
-
94%
89%
71%
96%
67%
94%
92%
96%
Acknowledgment. This work was funded by NSF CHE
0749916. NMR spectra were acquired, in part, on spectrom-
eters purchased with NSF support (MRI 0079750 and CHE
0091975). A portion of this research was conducted in
facilities remodeled with support from the NIH (RR016544-
01). We thank Prof. Jonathan Vennerstrom (Univ. of
Nebraska-Medical Center) for useful discussions.
1k
1l
1m
1n
1o
1p
Ph
4-MeOPh
2-MeOPh
3-MeOPh
4-ClPh
4-NO2Ph
Ph
a
-
69%
1q
2q
Supporting Information Available: Details regarding
preparation and characterization of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
a Traces of product decomposed during purification.
required longer reaction times; at the extreme, only traces
of product were observed from reaction of 4-nitrobenzalde-
hyde. The lower yields obtained for substrates 1m and 1q
appear due to oligomerization of the electron-rich products
(2m, 2q) under the reaction conditions.
OL801859C
(31) Re207 is described as hydrating to form perrhenic acid, HOReO3,
a greenish-yellow solid we often observed following evaporation of our
aqueous washes: Holleman, A. F.; Wiberg, E. Inorganic Chemistry;
Academic Press: San Diego, 2001; p 1428. Peacock, R. P. In Comp. Inorg.
Chem.; Pergamon: Elmsford, NY, 1973; v. 3. However, the reaction product
of Re207 and water has been crystallographically characterized as a dihydrate
of a binuclear compound in which the two rhenium atoms are bound to six
and four oxygens respectively. Krebs, B. Angew. Chem., Int. Ed. 1968, 7,
308.
Finally, Re2O7 was also found to catalyze the peroxyac-
etalization of benzaldehyde dimethyl acetal (Figure 1),
(32) Caution: While we experienced no problems in the course of this
work, any preparative work with peroxides, particularly those of high active
oxygen content, should be conducted with an awareness of the potential
for spontaneous and exothermic decomposition: (a) Medard, L. A. Accidental
Explosions: Types of ExplosiVe Substances; Ellis Horwood Limited:
Chichester, 1989; Vol. 2. (b) Patnaik, P. A. ComprehensiVe Guide to the
Hazardous Properties of Chemical Substances, 2nd ed.; John Wiley & Sons:
New York, 1999. (c) Shanley, E. S. In Organic Peroxides; Swern, D., Ed.,
Wiley-Interscience: New York, 1970; Vol. 3, p 341. (d) Safety And Handling
Of Organic Peroxides (AS-109); The Society Of The Plastics Industry, Inc.,
August, 1999, www.socplas.org/about/Safety_Guide.pdf. (e) Zabicky, J. In
The Chemistry of the Peroxide Group, v. 2, Rappoport, Z., Ed.; John Wiley
& Sons: Chichester, 2006; pt 2, pp 597-773. (f) Sanchez, J.; Myers, T. N.
Organic Peroxides. In Kirk-Othmer Encyclopedia of Chemical Technology,
5th ed.; John Wiley & Sons: Hoboken, NJ, 2006; v. 18, pp 489-496.
Figure 1. Re(VII)-catalyzed peroxyacetalization of an acetal.
although in lower yield than had been obtained from the
corresponding aldehyde (see Table 3).
Reactions such as the acetal exchange can reasonably be
attributed to Brønsted acid catalysis.31 However, the higher
Org. Lett., Vol. 10, No. 20, 2008
4579