Alkene syn dihydroxylation with malonoyl peroxides

Article abstract of DOI:10.1021/ja1066674

Cyclopropyl malonoyl peroxide (1), which can be prepared in a single step from the commercially available diacid, is an effective reagent for the dihydroxylation of alkenes. Reaction of 1 with an alkene in the presence of 1 equiv of water at 40 °C followed by alkaline hydrolysis leads to the corresponding diol (40-93%). With 1,2-disubstituted alkenes, the reaction proceeds with syn selectivity (3:1 to >50:1). A mechanism consistent with the experimental findings that is supported by oxygen-labeling studies is proposed.

Full text of DOI:10.1021/ja1066674

Published on Web 09/24/2010
Alkene Syn Dihydroxylation with Malonoyl Peroxides
James C. Griffith,† Kevin M. Jones,† Sylvain Picon,† Michael J. Rawling,† Benson M. Kariuki,†
Matthew Campbell,‡ and Nicholas C. O. Tomkinson*,†
School of Chemistry, Main Building, Cardiff UniVersity, Park Place, Cardiff CF10 3AT, U.K., and GlaxoSmithKline
Medicines Research Centre, Gunnels Wood Road, SteVenage SG1 2NY, U.K.
Received August 17, 2010; E-mail: tomkinsonnc@cardiff.ac.uk
Several features of this novel dihydroxylation procedure deserve
comment. The reaction proceeds under mild conditions in the
Abstract: Cyclopropyl malonoyl peroxide (1), which can be pre-
pared in a single step from the commercially available diacid, is an
presence of air and moisture. For the majority of alkenes examined,
effective reagent for the dihydroxylation of alkenes. Reaction of 1
the diol product required no column chromatography, and diacid 7
with an alkene in the presence of 1 equiv of water at 40 °C followed
by alkaline hydrolysis leads to the corresponding diol (40-93%).
With 1,2-disubstituted alkenes, the reaction proceeds with syn
selectivity (3:1 to >50:1). A mechanism consistent with the experi-
mental findings that is supported by oxygen-labeling studies is
proposed.
was recycled through workup. Although we recommend safe
working procedures for peroxides, in our hands 1 proved to be
insensitive to shock and direct heating and was bench-stable. The
combination of easily handled reagent and mild reaction conditions
renders the overall process highly practical.
The relative rates of reaction of peroxides 1-3 with styrene are
shown in Figure 1. Interestingly, this revealed a marked change in
reactivity through simple modification of the peroxide structure,
with cyclopropyl malonoyl peroxide 1 emerging as the most
effective.
The dihydroxylation of alkenes is a fundamental transformation in
organic synthesis. A range of methods have been reported for the
preparation of syn-1,2-diols;1 however, the OsO4-catalyzed procedure
developed by Sharpless and co-workers is most commonly employed.2
Despite the widespread popularity of this reaction, the toxicity of
osmium and high levels of inorganic waste represent important
limitations that have hindered its application on an industrial scale.3
For these reasons, the development of a metal-free dihydroxylation
procedure provides a challenging and highly attractive target.
Peroxides are known to be highly reactive and serve as versatile
reagents in synthesis.4 Examples of a peroxide reagent capable of
syn dihydroxylation are rare.5 Isolated reports have shown that
phthaloyl peroxide dihydroxylates a limited number of alkenes, but
the explosive nature of this compound has limited its use in
synthesis.5a We reasoned that a class of stable cyclic acyl peroxides
may provide the basis of a metal-free dihydroxylation procedure.
Herein we report that cyclopropyl malonoyl peroxide (1) is an
effective reagent for alkene syn dihydroxylation.
Development of the reaction between peroxides 1-3 and styrene
was initially examined by varying the solvent, time, temperature,
additive, and peroxide stoichiometry. Optimized conditions involved
addition of 1 (1.2 equiv) to styrene in the presence of 1 equiv of
water to give two intermediate esters 4 and 5 in a roughly 1:1 ratio.
Removal of the solvent followed by hydrolysis of the crude reaction
mixture provided diol 6 (89%) and diacid 7 (87%) (eq 1). Recovered
7 can be converted to peroxide 1 (77%) in a single step.
Figure 1. Relative rates for the reaction of peroxides 1-3 with styrene. All
of the reactions were performed in CHCl3 (0.6 M) at 40 °C in the presence of
H2O (1.0 equiv). (9) peroxide 1; (2) peroxide 2; (b) peroxide 3.
An explanation for the enhanced rate observed with 1 came from
X-ray crystallography (Figure 2). For each peroxide 1-3, the five-
membered cyclic peroxide unit adopts a planar conformation with
nearly identical O-O bond lengths. The major difference among
1-3 is the OC-C-CO bond angle. As the size of the spirocyclic
ring decreases from five to four to three, the OC-C-CO bond
angle increases from 102.34(17)° (3) to 107.56(19)° (1). This
increases the ring strain of the peroxide and is manifested by the
† Cardiff University.
‡ GlaxoSmithKline Medicines Research Centre.
Figure 2. X-ray structural data for peroxides 1-3.
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10.1021/ja1066674  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 14409–14411 14409

C O M M U N I C A T I O N S
Scheme 1. Possible Mechanistic Course of the Reaction
Table 2. Stereoselectivity of the Dihydroxylationa
Table 1. Scope of the Dihydroxylationa
a Yields quoted are isolated yields. All reactions were run in
duplicate. Stereoselectivities were determined by 1H NMR spectroscopy
of the crude reaction mixture, with relative stereochemistries determined
by comparison to material prepared by Sharpless dihydroxylation.
b Reaction was conducted at 0 °C.
Diastereoselectivity was examined with a series of 1,2-
disubstituted alkenes (Table 2). trans-Stilbene substrates gave
selectivities in excess of 30:1 (entries 1-3 and 5). Consistent
with the proposed mechanism (i.e., 8), cis-stilbene gave the syn-
dihydroxylated product in a lower 3:1 ratio (entry 4), whereas
incorporation of the alkene within a ring resulted in exclusive
formation of the syn product (entry 6). ꢀ-Methylstyrene deriva-
tives also gave the products with excellent stereoselectivity (g10:
1) (entries 7-10), providing a powerful and versatile method
for selective alkene functionalization.
We have described an effective and highly practical method for
the syn dihydroxylation of alkenes. The reaction is operationally
simple and transition-metal-free and does not require the rigorous
exclusion of moisture or air. Current efforts are focusing on a
catalytic variant of this transformation.
Caution! Peroxides are particularly dangerous. These proce-
dures should be carried out only by knowledgeable laboratory
workers.
a Yields quoted are isolated yields. All reactions were run in
Acknowledgment. The authors thank Leverhulme Trust, EPSRC,
and GlaxoSmithKline for financial support and the Mass Spec-
trometry Service, Swansea, for high-resolution spectra. We are
indebted to Professor Barry Carpenter for enthusiastic and insightful
discussions and Dr. John Brazier for stimulating debate.
duplicate. b Reaction was performed with peroxide 2.
increased reactivity of 1, consistent with differential scanning
calorimetry (DSC) analysis (Supporting Information).
Mechanistically, we believe that reaction of alkene with peroxide
1 leads to 8, which undergoes ring closure to form dioxonium
species 9 (Scheme 1).6 Hydrolysis with the molecule of water
necessary to bring about reaction explains the 1:1 ratio of esters 4
and 5. Additionally, a small amount (4%) of 11 resulting from direct
cyclization of 8 was present in the crude reaction mixture.
Consistent with this proposal, a preliminary investigation using
H218O showed incorporation of the label in the intermediates 4 and
5 and the diacid 7 but not in the final diol product 6.
Pleasingly, the conditions developed above were effective for
the dihydroxylation of a range of alkenes in up to 91% isolated
yield (Table 1). For each reaction, diacid 7 could easily be recovered
through workup.
Supporting Information Available: Experimental procedures,
characterization data, NMR spectra for all compounds, DSC data, and
CIF files for 1-3. This material is available free of charge via the
Internet at http://pubs.acs.org.
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