Regioselectivity of epoxide ring opening

Epoxides, in contrast to ethers, readily undergo nucleophilic attack, resulting in ring opening and relief of strain. Ring opening proceeds by a different mechanism, and may lead to different products, depending on reaction conditions. 

With strong nucleophiles such as methoxide, ring opening follows an Sn2 mechanism. Examine the next to lowest-unoccupied molecular orbital (LUMO+1) for propylene oxide. On which carbon is it most heavily concentrated Is this also the least crowded carbon (Examine a spacefilling model for propylene oxide.) What should be the product of Sn2 addition  

With weak nucleophiles such as methanol, and in the presence of acid, the reaction proceeds via nucleophilic attack on the protonated epoxide. Examine the LUMO of protonatedpropylene oxide. Does this properly identify the site for nucleophilic attack which will lead to the observed product (Hint The most accessible parts of the LUMO are best identified by simultaneously displaying the molecule as a space-filling model and the LUMO as a mesh surface.) 

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The regioselectivity of epoxide ring opening by amines can occasionally be modified by using a lithium amide instead of the amine. In the example sketched in... 

Scheme4.74. Reagent-controlled regioselectivity of epoxide ring opening with amines [332],...

The regioselectivity of epoxide ring opening by CH3O" in methanol is controlled by the same features as the S 2 displacement reactions we considered in Chapter 10. The nucleophilic methoxide anion regioselectively attacks the least hindered carbon atom. That is, it attacks the primary rather than the tertiary carbon atom of 2,2-dimethyloxirane in the rate-determining step. This intermediate alkoxide then abstracts a proton from the solvent in a rapid second step that regenerates the methoxide base. 

Thermolysis of a solution of epoxide 79 and l,3-thiazole-5(477)-thione derivative 80 in xylene led to the formation of three cycloadducts in 85% overall yield (22). It was expected that the geminal cyano groups of the epoxide would control the regioselectivity of the ring opening such that the anionic terminus of the dipole would be localized on that carbon. Regiochemical control led to a very selective... 

Rough guidelines for the prediction of regioselectivity in epoxide ring openings are summarized in Scheme 4.60. Under neutral or basic reaction conditions alkyl-or aryl-substituted epoxides react with most nucleophiles at the less substituted carbon atom [248-253]. Under acidic reaction conditions, however, product mixtures or preferential attack at the most substituted carbon atom can be observed. Acids can usually be used to enhance the reactivity of epoxides and to promote substitution at the site of an epoxide which forms a carbocation more readily. 

We explained in Chapter 15 that Sn2 reactions adjacent to carbonyl groups are very fast. The regioselectivity of the ring opening of a cyclic sulfate, like that of an epoxide, is directed by the competition between relative rates of two nucleophilic substitution reactions. Benzylic and carbonyl-substituted positions usually open faster. There is more discussion of the regioselectivity of epoxide opening on p. 351. 

SCHEME 35.5. A combination of asymmetric epoxidation and regioselective intramolecular epoxide ring-opening strategies for the total synthesis of (—)-dysiherbaine. 

Displacement of the 3-hydroxyl group of 74 was carried out with Et2NSF3 (DAST) (DAST - diethylaminosulfur trifluoride) in dichloromethane. The expected fluorinated product 75 on treatment with aqueous perchloric acid led to regioselective epoxide ring opening to give 76, which on treatment with hydrazine hydrate at 100 °C for 18 h yielded 3,4-dihydroxy-8-oxo-octahydropyridazino[l,6-r/][l,2,4]triazine-l-carboxylic acid phenylamide 77 (Scheme 3) <1997T9357>. 

Two classes of structures containing azido- and aziridino-hydroxyl-(3-lactam (I and II, respectively, Fig. 21) have been prepared by means of a stereo- and regioselective epoxide ring opening reaction [296],... 

The products 125 and 126 are formed with complete regioselectivity, suggesting involvement of an epoxide ring-opened intermediate. Product ratios vary systematically, depending on the steric properties of the epoxides. As the size of the epoxide substituents increases, the amount of the five-membered ring compounds 126 in the reaction mixture decreases appreciably125. 

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