Epoxidation of aldehydes

An alternate strategy for the synthesis of epoxides is by the reaction of sulfonium ylides with aldehydes. Aggarwal and coworkers have developed a catalytic asymmetric variant of this process using camphorsulphonic acid-derived sulfonium ylides such as (4.130) and (4.131). ° 

This reaction proceeds with high ee using aromatic aldehydes such as benzalde-hyde (4.138) and derivatives using tosyl hydrazone salt (4.139) and thus has utility in the synthesis of enantiopure stilbene oxide derivatives. High ees are also obtained with some heteroaromatic aldehydes such as 2-furaldehyde (4.140). Basic heteroaromatic aldehydes are poor substrates and the reaction proceeds with low yield and/or diastereoselectivity using aliphatic aldehydes and most a,(3-enones as substrates. These limitations have been overcome using a stoichiometric variant of this process. 

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Epoxidation of aldehydes and ketones is the most profound utility of the Corey-Chaykovsky reaction. As noted in section 1.1.1, for an a,P-unsaturated carbonyl compound, 1 adds preferentially to the olefin to provide the cyclopropane derivative. On the other hand, the more reactive 2 generally undergoes the methylene transfer to the carbonyl, giving rise to the corresponding epoxide. For instance, treatment of P-ionone (26) with 2, derived from trimethylsulfonium chloride and NaOH in the presence of a phase-transfer catalyst Et4BnNCl, gave rise to vinyl epoxide 27 exclusively. ... 

The sulfur ylide-mediated epoxidation of aldehydes has been thoroughly investigated [70, 71]. The chiral sulfur ylides reported by Aggarwal have been most broadly applicable, and a catalytic, asymmetric process yielding aromatic transepoxides has been developed [72]. In this process, the sulfur ylides are produced in situ from diazo compounds, generated in turn from tosylhydrazone salts (Scheme 9.15) [73],... 

Scheme 10.38 Rh-catalysed epoxidations of aldehydes by tosylhydrazones with sulfide.

Scheme 10.39 Ferrocenyl sulfide-catalysed epoxidations of aldehydes.

An alternative to the synthesis of epoxides is the reaction of sulfur ylide with aldehydes and ketones.107 This is a carbon-carbon bond formation reaction and may offer a method complementary to the oxidative processes described thus far. The formation of sulfur ylide involves a chiral sulfide and a carbene or carbenoid, and the general reaction procedure for epoxidation of aldehydes may involve the application of a sulfide, an aldehyde, or a carbene precursor as well as a copper salt. This reaction may also be considered as a thiol acetal-mediated carbene addition to carbonyl groups in the aldehyde. 

In the design of chiral sulfides for sulfur ylide-mediated asymmetric epoxidation of aldehydes, two factors are important. First, a single sulfur ylide should be produced. Otherwise, the diastereomeric sulfur ylides may react with aldehydes in different ways and thus cause a drop in stereoselectivity. This may be achieved by choosing a rigid cyclic structure to make one of the lone pairs more accessible than the other. Second, the structure should be amenable to structural modification in order to study the electronic and steric effects of the sulfur on the enantioselectivity of the epoxidation reaction. 

Aggarwal et al.108 reported excellent results with the catalytic asymmetric epoxidation of aldehydes. As shown in Scheme 4-52, a series of thioacetals 137 was prepared from hydroxy thiol 136 and the corresponding carbonyl compound. Among them, compound 138, derived from 136 and acetaldehyde, proved to be the best catalyst for asymmetric epoxidation of aldehydes. 

This reaction is very sensitive to water because in the presence of water and a metal salt (such as copper salt) the thioacetal tends to decompose, and this may reduce the amount of thioacetal available for epoxidation. When water is excluded from all the reagents, the reaction can be carried out in the presence of a catalytic amount of thioacetal. Otherwise, a stoichiometric amount of thioacetal compound is required. Scheme 4 53 summarizes the epoxidation of aldehydes using 138 as the chiral-inducing reagent. Excellent enantioselectivities are obtained in most cases. 

Scheme 7. Proposed mechanism for Aggarwal s catalytic epoxidation of aldehydes. [Adapted from (90).]...

Scheme 6.30 Typical epoxides obtained from the Corey-Chaykovsky epoxidation of aldehydes catalyzed by urea 16.

Morita-Baylis-Hillman-reaction [6.4] Epoxidation of aldehydes [6.8]... 

Aggarwal, V. K., Ford, J. G., Fonquerna, S., Adams, H., Jones, R. V. H., Fieldhouse, R. Catalytic Asymmetric Epoxidation of Aldehydes. Optimization, Mechanism, and Discovery of Stereoelectronic Control Involving a Combination of Anomeric and Cieplak Effects in Sulfur Ylide Epoxidations with Chiral 1,3-Oxathianes. J. Am. Chem. Soc. 1998, 120, 8328-8339. 

Thus far, discussion has centered around the reaction of alkenes with a source of electrophilic oxygen as a route to epoxides [the C=C + O protocol]. However, a second general approach is represented by the reaction of carbonyl compounds with amphophilic carbon centers [the C=0 + C protocol]. For example, sulfonium yhdes are known to convert aldehydes and ketones to epoxides much recent work has focused on asymmetric induction using this methodology, a topic which has been the subject of a concise review in the past year <04ACR611>. As an illustration, the D-mannitol derived chiral sulfide 42 serves as a useful chiral auxiliary in the sulfonium methylide epoxidation of aldehydes to provide terminal monosubstituted oxiranes (e.g., 44) in fair to excellent yield and good enantiomeric excess <04CC1076>. 

Figure 4.10 Catalytic cycle of the sulfonium ylide catalysed epoxidation of aldehydes...

The direct rhodium-catalysed cyclopropanation is limited to relatively electron-rich alkenes, as the metallocarbenoids formed in situ are electrophilic, j garwal and coworkers have developed a strategy for the catalytic enantioselective epoxidation of aldehydes utilising catalytic quantities of enantiomerically pure sulfides such as... 

As mentioned previously, the Aggarwal group has utilized the Bamford-Stevens reaction as a method to in situ generate diazo compounds 33 and further trap out these in a subsequent reaction. This in situ concept was initially tested on the sulfur-ylide 37 mediated epoxidation of aldehydes 39. "... 

Pereira A, Martin C, Maya C, Belderrain TR, Perez PJ. An effective dual copper- and sulfide-catalytic system for the epoxidation of aldehydes with phenyldiazomethane. Adv Synth Catal. 2013 355 2942-2951. 

Transfer of chirality in epoxidation of aldehyde with ylide 2... 

Scheme 20.3 Sulfide-catalyzed enantioselective epoxidation of aldehydes.

Enantioselective Suljur Ylide Catalysis SS3 Table 20.1 Enantioselective epoxidation of aldehydes with sulfide 13. 

In catalytic epoxidation reactions an alternative to the ylide generation method via alkylation/deprotonation is the transition metal-mediated carbene transfer from diazo compounds to sulfide catalysts. In 1994, Aggarwal and coworkers employed this method in the enantioselective catalytic epoxidation of aldehydes [25]. Using 20mol% of non-racemic sulfide 17 and lmol% of Rh2(OAc)4 together with the slow addition of PhCHN2, a 58% yield and 11% ee were obtained in the epoxidation of benzaldehyde (Scheme 20.10). The enantioselectivity was similar to the results obtained by Breau and Durst using preformed sulfonium salts [26]. 

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