Fragmentation of chloroperoxides: Hypochlorite-mediated dehydration of hydroperoxyacetals to esters

Article abstract of DOI:10.1016/j.tetlet.2010.08.068

Hypochlorites efficiently dehydrate hydroperoxyacetals to furnish the corresponding esters. The reaction, which can be accomplished with stoichometric Ca(OCl)₂ or with catalytic amounts of t-BuOCl, appears to involve formation and heterolytic fragmentation of secondary chloroperoxides, species not previously described in solution chemistry.

Full text of DOI:10.1016/j.tetlet.2010.08.068

Tetrahedron Letters 51 (2010) 5615–5617
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Tetrahedron Letters
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Fragmentation of chloroperoxides: hypochlorite-mediated dehydration
of hydroperoxyacetals to esters
⇑
Thomas J. Fisher, Patrick H. Dussault
Department of Chemistry, University of Nebraska–Lincoln, Lincoln, NE 68588-0304, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Hypochlorites efficiently dehydrate hydroperoxyacetals to furnish the corresponding esters. The reaction,
which can be accomplished with stoichometric Ca(OCl)2 or with catalytic amounts of t-BuOCl, appears to
involve formation and heterolytic fragmentation of secondary chloroperoxides, species not previously
described in solution chemistry.
Received 20 July 2010
Revised 17 August 2010
Accepted 19 August 2010
Available online 25 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Hypochlorite
Hydroperoxyacetal
Chloroperoxide
Fragmentation
Ester
1. Introduction
The dehydration proved compatible with a free primary alcohol
(entry 4) or a chloroethyl acetal (entry 8). Little reaction was ob-
Hydroperoxyacetals, readily available intermediates,1 are sub-
strates for a number of useful fragmentations, including Fe(II)-med-
iated cleavage to alkoxy radicals,1c,2 heterolytic C–O bond
migrations of tertiary peresters, or persulfonates (Criegee rear-
rangement),3 and the base-promoted dehydration of hydroperoxy-
acetals, or derived peresters, or persulfonates.1c,4,5 In the course of
investigations into the addition of oxygen nucleophiles to ozonoly-
sis-derived carbonyl oxides,6 we observed the rapid dehydration
of secondary hydroperoxyacetals in the presence of commercial
bleach.7 We now report that Ca(OCl)2, t-BuOCl, and trichloroisoc-
yanuric acid mediate the rapid heterolytic dehydration of hydroper-
oxyacetals through the apparent intermediacy of secondary
chloroperoxides, species whose solution chemistry has not been
previously described.
served with aq NaOCl.
Comparable yields were available with t-BuOCl (Table 2).9 Reac-
tions, although conducted for the same duration as for Ca(OCl)2,
were now complete within 1 min (TLC).10 The rate and yield were
not affected by protection from laboratory light (entry 2), use of
CH2Cl2 as solvent (entry 3), or the presence of acid (entry 4). How-
ever, the presence of methanol slowed reactions considerably (not
shown). Dehydration could be conducted with catalytic (0.25 equiv)
quantities of t-BuOCl (entries 5 and 8), although the reactions now
required 15 min for completion.
Table 1
Fragmentation of hydroperoxyacetals with Ca(OCl)2
1.3 eq Ca(OCl)2
CH3CN, 10 min, rt
O
2. Results and discussion
OOH
OR2
H
R1
OR2
R1
Most of the substrates employed in this study were prepared
via ozonolysis of alkenes in the presence of an alcohol.1a Addition
of Ca(OCl)2 (1.3 equiv) to CH3CN solutions of hydroperoxyacetals
1a–h furnished esters 2a–h (Table 1) after evaporation of solvent
and filtration through a short silica column.7,8 The reaction could
also be conducted in CH3OH/CH2Cl2; however the reaction in
CH2Cl2, THF, or toluene was limited by the solubility of Ca(OCl)2.
Entry
Substrate
R1
R2
Product
Yielda
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
Octyl
Octyl
Octyl
Octyl
AcO(CH2)8
BnO(CH2)3
Ph(CH2)2
Octyl
Me
Et
i-Pr
(CH2)2OH
Me
Me
Me
(CH2)2Cl
2a
2b
2c
2d
2e
2f
75% (91)
86% (90)
83% (93)
83% (86)
85% (93)
81% (94)
80% (93)
82% (92)
1g
1h
2g
2h
⇑
Corresponding author. Tel.: +1 402 472 6951; fax: +1 402 472 9402.
E-mail address: pdussault1@unl.edu (P.H. Dussault).
a
Isolated yields on 0.5 mmol or (5 mmol) scale.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.068

5616
T. J. Fisher, P. H. Dussault / Tetrahedron Letters 51 (2010) 5615–5617
Table 2
The conversion of the chloroperoxides to esters could in princi-
Fragmentation of hydroperoxyacetals with t-BuOCl
ple proceed through either homolytic or heterolytic pathways
(Scheme 4), and several additional experiments were conducted
to discriminate between these possibilities (Scheme 5).
t-BuOCl
(0.25 - 1.2 eq)
CH3CN, rt
O
OOH
O
H
O
Chloroperoxides are reported to undergo homolytic scission to
generate ROOÅ and ClÅ.12,13 For this reason, we initially hypothe-
sized the dehydrations involved a radical chain initiated by
abstraction of the acetal C–H; the resulting carbon radical would
be expected to fragment to the product ester and a propagating
radical (ÅOCl). However, the dehydrations were insensitive to the
presence or the absence of visible light and did not occur in the
presence of PhI(OTFA)2, a reagent known to promote peroxyl rad-
ical formation.14 Perhaps most convincingly, dehydration of 1k, a
hydroperoxyacetal substrate incorporating a fast radical clock
(Scheme 5), proceeded with no detectable formation of ring-
opened products.15
Entry
Substrate
t-BuOCl (equiv)
t (min)
Product
Yielda (%)
1
1a
1a
1a
1a
1a
1b
1d
1e
1h
1.2
1.2
1.2
1.2
0.25
1.2
1.2
0.25
1.2
10
10
10
10
15
10
10
15
10
2a
2a
2a
2a
2a
2b
2d
2e
2h
77
77
79
84
78
85
84
85
84
2b
3c
4d
5
6
7
8
9
a
b
c
Isolated yields on 0.5 mmol scale.
Protected from light (Al foil over flask).
CH2Cl2 as solvent.
The potential role of alkoxy radicals was probed with hydroper-
oxyacetals 1l and 1m16 (Scheme 5); the
a-oxygenated alkoxy
d
Added HOAc (P2 equiv).
radicals derived from either substrate would be expected to readily
undergo b-scission.17 However, both 1l and 1m undergo dehydra-
tion with no signs of radical cleavage. In contrast, a hydroperoxyk-
etal unable to dehydrate (1n) undergoes a much slower (30 min)
reaction to furnish chloroalkanoate 3, the product of alkoxy radical
cleavage.
The results support fragmentation through the heterolytic path-
way illustrated in Scheme 4, presumably through a mechanism
analogous to Criegee or Hock fragmentation (activation of hydro-
peroxides by protonation or Lewis acid complexation).3,18 The
specificity for migration of hydrogen relative to Ph or Bn (1j, 1l)
under nonbasic conditions is interesting. However, as has recently
been demonstrated for Baeyer–Villiger rearrangements of alkoxyb-
romanes derived from hemiacetals,19 the nature of the activating
No reaction was observed between t-BuOCl and a silylated
hydroperoxyacetal (1i, Scheme 1). However, a secondary hydroper-
oxide (1j)11 underwent rapid dehydration; the low yield likely
reflects product volatility. Dehydration of secondary allylic hydro-
peroxides (not shown) required excess t-BuOCl and furnished the
expected
a,b-unsaturated ketones as mixtures with significant
amounts of byproducts lacking unsaturation.
The fragmentation can be combined with alkene ozonolysis to
afford a convenient one-pot synthesis of esters (Scheme 2).
The fragmentation is likely to involve the initial formation of
chloroperoxides, species previously prepared only in tertiary sys-
tems.12 The intermediacy of ROOCl is consistent with the lack of
reaction of silylated hydroperoxyacetal 1i. In an effort to access
chloroperoxides with reagents other than hypochlorites, we
discovered that commercially available trichloroisocyanuric acid
promotes the dehydrative fragmentation as or more efficiently
than t-BuOCl (Scheme 3).
Homolytic fragmentation
•OCl
O
O
OCl
OOCl
OR
H
X•
OMe
OR
Heterolytic fragmentation
t-BuOCl,
OOTBS
CH3CN, rt
H
HOCl
NR
O
O
O
OCl
O
OCl
H
C8H17 OMe
1i
OR
OR
OR
t-BuOCl
CH3CN, rt, 10 min
40%
OOH
Ph Me
Ph Me
Scheme 4. Mechanistic possibilities.
2j
1j
Scheme 1. Substrates other than hydroperoxyacetals.
t-BuOCl,
CH3CN,
OOH
O
rt, 10 min
Ph
2k H
OMe
Ph
1k
OMe
O
i. O3, MeOH/CH2Cl2,
-78 °C;
80%
H
C8H17 OMe
2a (56%)
C8H17
ii. Ca(OCl)2 (1.3 eq)
O
OOH
" "
64%
Ph
Ph
OMe
O
OMe
2l
1l
Scheme 2. Application in tandem with ozonolysis.
O
O
" "
78%
OOH
2m
1m
t-BuOCl,
CH3CN,
rt, 30 min
O
N
O
Cl
Cl
CH2Cl2, rt,
10 min
O
N
N
OOH
OMe
H
OOH
OMe
Cl
Cl
O
octyl
1a
OMe
2a
93%
tBu
CO2Me
26%
tBu
3
1n
lacks
a-H
(0.15 eq)
Scheme 3. Dehydration with trichloroisocyanuric acid.
Scheme 5. Additional substrates.

T. J. Fisher, P. H. Dussault / Tetrahedron Letters 51 (2010) 5615–5617
5617
4. (a) Ellam, R. M.; Padbury, J. M. J. Chem. Soc., Chem. Commun. 1972, 1086; Base-
promoted fragmentation of hydroperoxyacetals is likely involved in a direct
ozonolytic conversion of terminal alkenes to methyl esters: (b) Marshall, J. A.;
Garofalo, A. W. J. Org. Chem. 1993, 58, 3675; Evano, G.. In Science of Synthesis;
Panek, J. S., Ed.; Thieme: Stuttgart, 2007; Vol. 20b, pp 795–797.
5. Thompson, Q. E. J. Org. Chem. 1962, 27, 4498; Claus, R. E.; Schreiber, S. L. Org.
Synth. 1986, 64, 150.
6. Schwartz, C.; Raible, J.; Mott, K.; Dussault, P. H. Tetrahedron 2006, 62, 10747.
7. 2.0 weight equiv of commercial solid bleach (ꢀ65% purity) delivers
1.3 mol equiv of Ca(OCl)2; other components include NaCl, CaCl2, Ca(ClO3)2,
and water.
reagents can have
a strong influence on rearrangements to
electron-deficient oxygen. The proposed mechanism predicts the
regeneration of HOCl,20 and is consistent with the high conversion
obtained in the presence of substoichiometric t-BuOCl or trichlo-
roisocyanuric acid. The results may be of relevance to atmospheric
decomposition of primary chloroperoxides.21
3. Conclusions
8. Typical procedure for reactions with Ca(OCl)2: To a flame-dried 8 mL vial
equipped with stirbar and screw-top septa cap containing technical grade
Ca(OCl)2 (1.3 equiv, 1.0 mmol, 143 mg of 65% reagent) is added CH3CN (2 mL).
A solution of the hydroperoxy acetal (1.0 equiv, 0.50 mmol) in CH3CN (1 ml) is
added as a single portion via syringe. The reaction is stirred vigorously for
10 min at which time the partially heterogeneous solution is filtered through a
short plug of silica. The reaction vial is rinsed with a small amount of CH2Cl2
and this solution is also filtered through the silica plug. The silica plug is rinsed
with another small portion of CH2Cl2 and the filtrate is concentrated.
9. Mintz, M. J.; Walling, C. Org. Synth. 1969, 49, 9.
We have developed a new fragmentation of hydroperoxyacetals
to esters based upon heterolytic fragmentation of intermediate
chloroperoxides.
CAUTION: While we experienced no hazards in the course of this
work, any preparative work with peroxides should be conducted
with an awareness of the potential for spontaneous and exother-
mic decomposition reactions.22
10. Typical procedure for reactions with t-BuOCl: To a flame dried 8 mL vial
equipped with stirbar and screw-top septa cap containing t-BuOCl (1.2 equiv,
0.6 mmol, 65 mg) is added CH3CN (2 mL). The hydroperoxy acetal (1 equiv,
0.5 mmol) is dissolved in CH3CN (1 mL) and added in one portion via syringe.
The reaction is stirred vigorously for 10 min and then worked up as before.
11. Prepared by Ag(I)-mediated displacement: Cookson, P. G.; Davies, A. G.;
Roberts, B. P. J. Chem. Soc., Chem. Commun. 1976, 1022.
Acknowledgments
This research was funded by NSF(CH-0749916) and the Nebras-
ka Research Initiative and conducted in facilities remodeled with
support from NIH (RR016544-01). NMR spectra were acquired, in
part, on spectrometers purchased with NSF support (MRI
0079750 and CHE 0091975). We thank Dr. Chris Schwartz and Pro-
fessor Stephen DiMagno for helpful discussions.
12. Osipov, A. N.; Panasenko, O. M.; Chekanov, A. V.; Arnhold, J. Free Radical Res.
2002, 36, 749.
13. Marwah, P.; Marwah, A.; Lardy, H. A. Green Chem. 2004, 6, 570.
14. Ochiai, M.; Ito, T.; Takahashi, H.; Nakanishi, A.; Toyonari, M.; Suleda, T.; Goto,
S.; Shiro, M. J. Am. Chem. Soc. 1996, 118, 7716; Milas, N. A.; Plesnicar, B. J. Am.
Chem. Soc. 1968, 90, 4450.
Supplementary data
15. k
opening P 1011/s for the unsubstituted 2-phenylcyclopropyl methyl radical:
TadicBiadatti, M. H. L.; Newcomb, M. J. Chem. Soc., Perkin Trans. 2 1996, 1467.
16. 1m was prepared via addition of H2O2 to dihydropyran: Milas, N. A.; Peeler, R.
L., Jr.; Mageli, O. L. J. Am. Chem. Soc. 1954, 76, 2322.
1H and 13C NMR spectra for 1a–i, 1k–n, 2a–I, 2k–m, 3. Supple-
mentary data associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.08.068.
17. b-Scission of oxygenated alkoxy radicals: Orlando, J. J.; Tyndall, G. S.;
Wallington, T. J. Chem. Rev. 2003, 103, 4657; Erhardt, S.; Macgregor, S. A.;
McCullough, K. J.; Savill, K.; Taylor, B. J. Org. Lett. 2007, 9, 5569.
18. Hock, H.; Kropf, H. Angew. Chem. 1957, 69, 313; Dussault, P. H.; Lee, H. J.; Liu, X.
Perkin. 1 2000, 3006.
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