Nucleophilic alkyl substitution epoxides

Azidoalcohols (79, 81) can be accessed directly through the cerium-catalyzed addition of sodium azide onto mono-substituted epoxides. When the substituent is a simple alkyl or aryl group, nucleophilic attack at the more substituted epoxide carbon was observed i.e., 78 -> 79). However, when a phenoxy group was incorporated into the side chain (e.g., 80), a crossover to attack on the unsubstituted methylene carbon was encountered <99SC561>. 

A nucleophile is an electron rich species that reacts with an electrophile. The term electrophile literally means electron-loving , and is an electron-deficient species that can accept an electron pair. A number of nucleophilic substitution reactions can occur with alkyl halides, alcohols and epoxides. However, it can also take place with carboxylic acid derivatives, and is called nucleophilic acyl substitution. 

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. 

The lone pairs may act as nucleophiles in substitution reactions of alkyl halides and sulfonates, in the solvolysis of epoxides, and in addition reactions to carbonyl groups. These reactions often proceed with acid or base catalysis. 

A highly effective catalytic method for alkynylation of epoxides has recently been reported this involves the chelation-controlled alkylation of hetero-substituted epoxides with Mc3A1 and alkynyllithiums via pentacoordinate organoaluminum complexes [82]. For instance, reaction of epoxy ether, (l-benzyloxy)-3-butene oxide (75) in toluene with PhC = CLi under the influence of catalytic MesAl (10 mol%) proceeded smoothly at 0 °C for 5 h to furnish the alkynylation product l-(benzyloxy)-6-phenylhex-5-yn-3-ol (76) in 76 % yield. The yield of the product was very low (3 %) without MeaAl as catalyst under similar conditions. This is the first catalytic procedure for amphiphilic alkylation of epoxides. The participation of pentacoordinate MesAl complexes of epoxy ethers of type 75 is emphasized by comparing the reactivity with the corresponding simple epoxide, 5-phenyl-l-pentene oxide (77), which was not susceptible to nucleophilic attack of PhC s CLi with catalytic Me3Al under similar conditions (Sch. 50). 

Mechanistic studies have been reported on the addition of alkylphosphonic acid reagents (325) to trialkyl-substituted epoxides (326). The addition occurs according to a three-step mechanism starting with rapid nucleophilic attack of the phosphorylated anion on the most alkyl-substituted carbon of oxirane, followed by formation of a dioxaphospholane structure (327) with release of... 

A powerful class of epoxidation reagents in this category are the anions derived from A/-p-tolylsulfo-nylsulfoximines (equation 16). These reagents form epoxides directly upon addition to carbonyl compounds and are available in a number of alkyl substitution patterns. Their chemistry is similar to that of dimethyloxosulfonium methylide, to which they often provide a practical alternative due to their greater nucleophilicity. 

Epoxides can serve as competent electrophiles in the alkylation of a variety of carbanions, as illustrated by the ring opening of cyclohexene oxide (64) with the dianion of phenylacetic acid (77) to produce the y-hydroxy carboxylic acid 78. In this protocol, the dianion is generated using K-butyllithium and a substoichiometric quantity of a secondary amine lithium chloride is also used as a Lewis acid additive to activate the secondary epoxide toward nucleophilic addition. Primary epoxides undergo addition without the use of catalyst—in these cases, the nucleophile attacks at the less substituted position <04EJOC2160>. 

Nucleophilic addition of alkyl lithium to difluorovinyl-substituted epoxide (48) proceeds on the difluoromethylene carbon via the addition-ring opening pathway [16]. However, trimethylaluminum reagent transfers the methyl group at the carbon remote from the difluorinated carbon of 50 presumably via the Lewis acid catalyzed ring opening-addition mechanism as shown in Scheme 2.26. 

Increasing the electron density of the double bond increases the rate of epoxidation because it makes the double bond more nucleophilic. Alkyl substituents increase the electron density of the double bond. Therefore, if a diene is treated with only enough peroxyacid to react with one of the double bonds, it will be the most substituted double bond that is epoxidized. 

Ethers are generally unreactive except with strong acids such as HI and HBr, which leads to cleavage of the ether to an alcohol and an alkyl halide. Epoxides are particularly reactive with nucleophiles, which open the three-membered ring at the less substituted carbon. Epoxides also react with an acid catalyst and weak nucleophiles such as water or alcohols, as well as with cyanide, azide, etc. 

The chemistry of metalated aziridines is far less developed than the chemistry of metalated epoxides, although from what is known [lb], it is obvious that their chemistry is similar. Like metalated epoxides, metalated aziridines can act as classical nucleophiles with a variety of electrophiles to give more highly substituted aziridines (Scheme 5.56, Path A). A small amount is known about how they can act as electrophiles with strong nucleophiles to undergo reductive alkylation (Path B), and undergo C-H insertion reactions (Path C). 

Exclusive trims attack of the nucleophile is also observed with 2,3-epoxycyclopentanones 1559. In contrast to 2-alkyl- and 2-methoxy-substituted cyclopentanones, preferential trans attack to 2,3-epoxycyclopenlanones occurs with alkyl, ethenyl, and ethynyl nucleophiles. Thus, there is no assistance by the epoxidic oxygen for cis attack. Due to the geometry of the molecule, chelation-controlled cis attack is not possible39 60. 

The method is quite useful for particularly active alkyl halides such as allylic, benzylic, and propargylic halides, and for a-halo ethers and esters, but is not very serviceable for ordinary primary and secondary halides. Tertiary halides do not give the reaction at all since, with respect to the halide, this is nucleophilic substitution and elimination predominates. The reaction can also be applied to activated aryl halides (such as 2,4-dinitrochlorobenzene see Chapter 13), to epoxides, " and to activated alkenes such as acrylonitrile. The latter is a Michael type reaction (p. 976) with respect to the alkene. 

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