Nucleophiles reaction with epoxides

The products of epoxidation in vivo depend on the reactivity of the particular epoxide. Stabilized epoxides react with nucleophiles and undergo further enzymic reactions, whereas destabilized ones undergo spontaneous isomerization to phenols. Epoxides are generally reactive intermediates, however, and in a number of cases are known to be responsible for toxicity by reaction with cellular constituents. 

Oxides 28 and 29 react with nucleophiles like p-toluidine, although the reactivities of epoxides 1,4,28, and 29 differ by a factor of less than three. It is interesting that 253 is most stable toward the attack of p-toluidine, showing that the carbocation-stabilizing group does not necessarily facilitate the reaction with nucleophiles. 

Several recent publications describe cleavage of 1,3,2-dioxathiolane. S -dioxides (cyclic sulfates) by halide nucleophiles that furnish halohydrines, which can be used as synthetic intermediates, primarily for preparation of corresponding epoxides or for further reactions with nucleophiles (Table 6). Similar reactions with chloride have been studied for 1,3,2-dioxathiolane J-oxides (cyclic sulfites) <1996ACS832>. 

The analogy between this type of C-C disconnection and 1,2-diX disconnections was explained at the start of this chapter with compounds 5, 6 and 7. The epoxide route works particularly well if the epoxide is mono-substituted as the reaction with nucleophilic carbon should then be regioselective. Alcohol 53 is used in perfumery and can be disconnected 53a at the next-but-one bond to the alcohol group with the idea of using the epoxide 54 made from the but-l-ene. 

The stereochemical outcome of this transformation deserves special comment. Based on established mechanistic grounds, the likely intermediate in this process is the transient 1,2-epoxide, 107 (Eq. 15). Reaction with nucleophiles occurs exclusively at C-l as a result of powerful electronic effects, as evidenced by the exclusive formation of 1-azidoad-ducts 104 and 105. However, the resulting stereochemistry of the 1-sub-stituted-2-hydroxy adducts depends greatly on the reaction conditions. For example, Rebek reported that a cis-1 -methoxy-2-hydroxy adduct was isolated as the major product when bromohydrin 106 was exposed to basic reaction conditions (NaOMe/MeOH).80 In this case the product cis/trcms ratio was found to be inversely proportional to the base concentration, a fact suggesting that the minor trans-adduct arose directly via Sn2 attack on the epoxide 107. To explain the formation of the cis-adduct,... 

Reactions with nucleophiles can result in ring opening and relief of strain. Nucleophiles will attack either of the electrophilic carbons present in an epoxide by an SN2 reaction ... 

Ring opening of epoxides proceeds smoothly by the reaction with nucleophilic selenium species, whereas the opening of larger cyclic ethers, such as THF, does not proceed under normal conditions. As demonstrated in Scheme 1, ring open-... 

Reactions with Nucleophiles. The epoxide is, by far, the more reactive site and a wide variety of nucleophiles have been used (eq 2) to open the ring at C-3 such as HCl (96%), HOAc (>50%), H2S (65% as cyclized product 3-thietanol), HCN (66%), ethanol (90%), t-butanol (86%), phenyl or benzyl thiol (99% or 93%, respectively), and phenyl selenide (generated in situ from the diselenide and sodium hydroxymethyl sulfite) (>55%). If desired, the epoxide is easily formed from the chlorohydrin by treatment with excess KOH or Et3N. 

The reaction of epoxide rings with nucleophiles is important for the synthesis of many biologically active compounds, including albuterol and salmeterol, two bronchodilators used in the treatment of asthma (Figure 9.10). 

Since both classes of agent act by a bimolecular mechanism their rate of reaction with nucleophilic centres will be dependent on the concentration of such centres. Both epoxides and ethyleneimines are more reactive under very acid conditions. Ethyleneimides such as triethylenephosphoramide (TEPA 16) are also more reactive than ethyleneimines because of the electron withdrawing properties of the oxygen atom which makes the methylene group of the ethyl-eneimine ring more susceptible to nucleophilic attack. 

At somewhat higher pH, direct nucleophilic attack of halide ion on diol epoxide 81 (fci[X-]) becomes important, and a rate plateau is reached in which this term is the main one. If the pH is sufficiently low, the pH-dependent equilibrium between halohydrin 131 and diol epoxide 81 (shown in Scheme 41) favors halohydrin, which reacts via an SnI reaction (k3) to form tetrols 129. As the pH is increased, however, the pH-dependent equilibrium between halohydrin 131 and diol epoxide 81 shifts to favor diol epoxide, and there is a resulting rate decrease that gives an inflection point in the pH-rate profile at intermediate pH that resembles those in the profiles in Figs 4 and 5. Rate and product observations are rationalized by the mechanism of Scheme 40, and comparable mechanisms can be expected for reactions of other epoxides susceptible to reaction with nucleophiles. 

As previously noted, one reason for the powerful nature of the Sharpless epoxidation is the ability of the resultant epoxy alcohols to undergo regio- and stereoselective reaction with nucleophiles [1,6-8,39-43], Often, the regiochemistry is determined by the functional group within the substrate [44-71],... 

The Simmons-Smith cyclopropanation reaction Stereochemically controlled epoxidations Regio- and Stereocontrolled Reactions with Nucleophiles Claisen-Cope rearrangements Stereochemistry in the Claisen-Cope rearrangement The Claisen-Ireland rearrangement Pd-catalysed reactions of allylic alcohols Pd-allyl acetate complexes Stereochemistry of Pd-allyl cation complexes Pd and monoepoxides of dienes The control of remote chirality Recent developments Summary... 

Regioselective opening of Sharpless epoxides, that is those (enantio-enriched) derived from allylic alcohols, has major synthetic significance. The usual outcome is opening at C-3, but the reaction with nucleophiles such as azide, cyanide and thiophenoxide, in the presence of trialkyl borates, can be highly selective for attack at C-2. ... 

Review. These products have become of special interest since they are now available in optically pure form by asymmetric dihydroxylation of alkcnes. In addition, the rcgiosclectivity in reactions with nucleophiles can differ from that of epoxides and the yields can be superior. The reference covers literature from 1863 through 1991 (104 references). 

---