Epoxidation nucleophilic

In general, conjugate substitution is not nearly as important as the next topic in this chapter— nucleophilic aromatic substitution. Before we describe in detail those reactions that do occur, we need to explain why the most obvious reactions do not occur. 

The simplest and most obvious nucleophilic substitutions on an aromatic ring, such as the displacement of bromide from bromobenzene with hydroxide ion, do not occur. 

Please note—this mechanism is wrong No such reactions are known. You might well ask, Why not  

The reaction looks all right and, if the ring were saturated, it would be all right. 

This is an S j2 reaction, and we know (Chapter 17) that attack must occur in line with the C-Br bond reaction does happen 

Hydroperoxide is a good nucleophile because of the alpha effect interaction of the two lone pairs on adjacent oxygen atoms raises the HOMO of the anion and makes it a better and softer nucleophile than hydroxide. 

Hydroperoxide is also less basic than hydroxide because of the inductive electron-withdrawing effect of the second oxygen atom. Basicity and nucleophilicity usually go hand in hand— not here though. This means that the hydroperoxide anion can be formed by treating hydrogen peroxide with aqueous sodium hydroxide. 

This is what happens when this mixture is added to an enone. First, there is the conjugate addition. 

Ranitidine s right-hand portion is made in a simiiar way from an unsaturated nitro compound. This time the methyi-amine substitution is done first, foiiowed by addition of the rest of the moiecuie. 

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Reactions of oxiranyl anions as nucleophilic epoxides 97YGK176. 

Chiral PTC has been used effectively for making intermediates for drugs. Dolling and coworkers have used 8-R, 9-5, N-(p-trifluoromethylbenzyl) cinchonium bromide to carry out an important asymmetric alkylation, giving 95% ee (Starks, 1987). Nucleophilic epoxidations of enones, Darzens reaction, Michael additions, etc. are some examples of reactions rendered asymmetric through chiral PTCs (Nelson, 1999). 

The stereoselective synthesis of awri-P-amino-a-hydroxy acid derivatives using nucleophilic epoxidation of 1-arytlthio-l-nitroalkenes has been reported (Eq. 4.41).54... 

Porco s synthesis of ( )-kinamycin C (3) constituted the first reported route to any of the diazofluorene antitumor antibiotics. This synthesis invokes several powerful transformations, including a modified Baylis-Hillman reaction, a catalyst-controlled asymmetric nucleophilic epoxidation, and a regioselective epoxide opening to establish the D-ring of the kinamycins. The tetracyclic skeleton was constructed by an... 

The synthesis of the spiroisoxazoline natural product (+ )-calafianin 447 has been reported, using asymmetric nucleophilic epoxidation and nitrile oxide cycloaddition as key steps. Syntheses and spectral analyses of all calafianin stereoisomers lead to unambiguous assignments of relative and absolute stereochemistry (494). 

Asymmetric epoxidation of olefins is an effective approach for the synthesis of enan-tiomerically enriched epoxides. A variety of efficient methods have been developed [1, 2], including Sharpless epoxidation of allylic alcohols [3, 4], metal-catalyzed epoxidation of unfunctionalized olefins [5-10], and nucleophilic epoxidation of electron-deficient olefins [11-14], Dioxiranes and oxazirdinium salts have been proven to be effective oxidation reagents [15-21], Chiral dioxiranes [22-28] and oxaziridinium salts [19] generated in situ with Oxone from ketones and iminium salts, respectively, have been extensively investigated in numerous laboratories and have been shown to be useful toward the asymmetric epoxidation of alkenes. In these epoxidation reactions, only a catalytic amount of ketone or iminium salt is required since they are regenerated upon epoxidation of alkenes (Scheme 1). 

TABLE 12. Nucleophilic epoxidation of vinyl sidfoximines with alkah alkyl peroxides [diastereomeric ratios are given in brackets the yields of the two diastereomers are shown]... 

Optically active 2-alkylidene-l,3-dithiane 1,3-dioxides have been prepared as chiral Michael-type acceptors. It was shown that these compounds react under nucleophilic epoxidation conditions to give diastereoselectively the epoxides. Other heteroatom nucleophiles reacted as well <1998JOC7128, 1999PS(153/4)337>. It was further demonstrated that enolates were also effective nucleophiles for the stereoselective addition to 2-alkylidene-l,3-dithiane 1,3-dioxides (Scheme 48) <20050L4013>. 

Asymmetric epoxidation of a prochiral alkene is an appealing process because two stereogenic centers are established in the course of the reaction. Often, the starting alkene is inexpensive. There have been several interesting recent advances in the asymmetric nucleophilic epoxidation. 

Epoxides are reactive electrophiles, which enable the facile preparation of substituted alcohols by reaction with a broad range of nucleophiles. Epoxides can be prepared on insoluble supports either by epoxidation of alkenes or from aldehydes (Table 15.1). 

The subject has been covered in various discussions [1,78-84] previously but a striking example in this group of reactions is the occurrence of nucleophilic epoxidation. These reactions emphasise the frequently stressed mirror-image relationship of the chemistry of alkenes and their perfluorinated analogues that we have emphasised earlier. Bleaching powder has proved to be... 

The Mannich reaction gave a base that was methylated without isolation to give the salt 58. Elimination with NaHCC>3 gave the enone, nucleophilic epoxidation with HO2- gave the epoxide... 

Two different epoxidation reactions have been studied using chiral phase transfer catalysts. The salts 22 and 23 have been used to catalyse the nucleophilic epoxidation of enones (e.g. 24) to give either enantiomer of epoxides such as 25 (Scheme 9) [17]. Once again, the large 9-anthracenylmethyl substituent is thought to have a profound effect on the enantio selectivity of the process. A similar process has been exploited by Taylor in his approach to the Manumycin antibiotics (e.g. Manumycin C, 26) [18]. Nucleophilic epoxidation of the quinone derivative 27 with tert-butyl hydroperoxide anion, mediated by the cinchonidinium salt la, gave the tx,/ -epoxy ketone 28 in >99.5% ee (Scheme 10). 

The enantio-determining step of nucleophilic additions to a-bromo-a,y -unsaturated ketones is mechanistically similar to those of nucleophilic epoxidations of enones, and asymmetry has also been induced in these processes using chiral phase-transfer catalysts [20]. The addition of the enolate of benzyl a-cyanoacetate to the enone 31, catalysed by the chiral ammonium salt 32, was highly diastereoselective and gave the cyclopropane 33 in 83% ee (Scheme 12). Good enantiomeric excesses have also been observed in reactions involving the anions of nitromethane and an a-cyanosulfone [20]. 

Other electron-poor alkenes generally require nucleophilic epoxidation conditions. These reactions usually proceed via non-concerted pathways (nucleophilic addition followed by epoxide ring closure), and so do not have the advantage of retaining the alkene geometry. Nevertheless, for the trans-epoxide, which is usually the predominant product, several methods exist that afford excellent levels of enantio-selectivity. 

Pradilla et al. have shown that simple p-tolyl vinyl sulfoxides undergo nucleophilic epoxidation with metal alkyl peroxides to give enantiopure sulfinyl oxiranes.138 This process takes place with fair to excellent diastereoselectivities. The same group recently reported the epoxidation of diastereomeric hydroxy vinyl sulfoxides, bearing an additional stereocenter adjacent to the reactive carbon-carbon double bond. Hydroxy vinyl sulfoxides 256 and 258 underwent epoxidation with lithium ferf-butyl peroxide with high anti selectivity. However, when potassium ferf-butyl peroxide was used, only hydroxy vinyl sulfoxide 256 showed anti... 

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