ORGANIC
LETTERS
2004
Vol. 6, No. 20
3609-3611
1,2,4-Trioxepanes: Redox-Cleavable
Protection for Carbonyl Groups
Aqeel Ahmed and Patrick H. Dussault*
Department of Chemistry, UniVersity of Nebraska-Lincoln,
Lincoln, Nebraska 68588-0304
Received July 31, 2004
ABSTRACT
1,2,4-trioxepanes, readily prepared and easily handled derivatives of aldehydes and ketones, are stable to a variety of synthetic conditions and
yet easily deblocked with Zn/HOAc or Mg/MeOH to regenerate the parent carbonyl. Trioxepanes may provide an alternative to 1,3-dithianes for
acid-stable protection of carbonyl groups.
In the course of efforts directed toward synthesis of peroxide
natural products, we recently investigated acetalization of
1,3-hydroperoxyalcohols. Although this known conversion
proceeded readily,1 the resulting 1,2,4-trioxepanes proved to
be so acid-stable as to preclude deprotection under conditions
compatible with the preservation of the peroxide group. This
stability, while frustrating from the perspective of peroxide
synthesis, was intriguing in the context of a new strategy
for carbonyl protection. We now demonstrate the efficient
conversion of aldehydes and ketones to 3,3-dialkyl-1,2,4-
trioxepanes, the stability of these cyclic peroxyacetals toward
a variety of synthetic conditions, and the regeneration of
carbonyl compounds under mild reductive conditions.2
Our initial choice of a protection reagent was based upon
a known reagent, 3-triethylsilylperoxy-3-methyl-1-butanol 1,
available via cobalt-mediated reductive oxygenation3 of
3-methyl-3-buten-1-ol (Table 1). The use of a tertiary
peroxide was expected to facilitate reagent synthesis and also
Table 1. Preparation of Reagent
catalyst
solvent
CH2Cl2
1 (R ) H)
2 (R ) SiEt3)
27%
30-35%
30%
50%
40%
25%
5%
5%
5%
1-2%
18%
Co(acac)2
EtOH
EtOH/CH2Cl2
ClCH2CH2Cl
EtOH
Co(thd)2
CH2Cl2
20%
(1) Oh, C. H.; Kang, J. H. Tetrahedron Lett. 1998, 39, 2771. Dussault,
P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett. 2002, 4, 4591. Adam,
W.; Duran, N. J. Chem. Soc., Chem. Commun. 1972, 789.
(2) We also briefly investigated the known reaction of carbonyls with
2-hydroperoxy-1-alkanols (Kerr, B.; McCullough, K. J. J. Chem. Soc., Chem.
Commun. 1985, 590. Subramanyam, V.; Brizuela, C. L.; Soloway, A. H. J.
Chem. Soc., Chem. Commun. 1976, 508. O’Neill, P. M.; Pugh, M.; Davies,
J.; Ward, S. A.; Park, B. K. Tetrahedron Lett. 2001, 42, 4569), but the
resulting 1,2,4-trioxanes were formed in lower yield and were less stable
compared with the corresponding 1,2,4-trioxepanes.
to enhance the stability of both the reagent and the derived
trioxepanes toward base-promoted fragmentation.4 The de-
sired reagent (1) was accompanied by variable amounts of
the bissilylated analogue (2); the best results were obtained
with the bulky diketonate Co(thd)2.5 Although pure samples
of 1 are available via chromatography, the crude reaction
(3) Isayama, S.; Mukaiyama, T. Chem. Lett. 1989, 573. Tokuyasu, T.;
Kunikawa, S.; Masuyama, A.; Nojima, M. Org. Lett. 2002, 4, 3595. Ito,
T.; Tokuyasu, T.; Masuyama, A.; Nojima, M.; McCullough, K. J.
Tetrahedron 2003, 59, 525.
(4) Kropf, H., Nurnburg, W. In Methods in Organic Chemistry:
Organische Peroxo-Verbindungen; Kropf, H., Ed.; George Thieme Ver-
lag: Stuttgart, 1988; Vol. E13, p 1968.
10.1021/ol048484h CCC: $27.50
© 2004 American Chemical Society
Published on Web 09/10/2004