Primary alkyl reactions with epoxides

Alkyl halides (particularly bromides) undergo oxidative addition with activated copper powder, prepared from Cu(I) salts with lithium naphthalenide, to give alkylcopper species10. The alkyl halides may be functionalized with ester, nitrile and chloro functions ketone and epoxide functions may also be tolerated in some cases11. The resulting alkylcopper species have been shown to react efficiently with acid chlorides, enones (conjugate addition) and (less efficiently) with primary alkyl iodides and allylic and benzylic bromides (equations 5 and 6). If a suitable ring size can be made, intramolecular reactions with epoxides and ketones are realized. 

The reactions with epoxides occurred at 0° producing 2-trimethylsiloxyalkyl phenyl tellurium derivatives. The ring opening is stcrcospccific in favor of rraws-siloxy tellurium compounds and regiospecific in favor of primary alkyl tellurium compounds2. 

A wide repertoire of cleavage reactions demonstrates the synthetic potential of the pseudoephedrine amides, providing access to chiral a-branched carboxylic acids, aldehydes, ketones or primary alcohols with recovery of the auxiliary (Scheme 2). Moreover, efficient alkylation reactions utilizing epoxides and epoxide-derived electrophiles open up a route to chiral y-lactones and y-hydroxy ketones. [7]... 

Most often, the application of cyanohydrin acetonide couplings to a natural product synthesis calls for coupling with a primary alkyl halide. This has proven successful in every instance. However, on occasion, alkylations of more hindered epoxides or hindered alkyl halides are desirable. These reactions are less dependable. 

These complexes are effective catalysts in epoxidation reactions with H2O2 and alkyl hydroperoxides. Several detailed mechanistic studies have been carried out in particular, it has been shown that, when the alkyl chain contains a double bond, no autoepoxidation is observed both in the solid state and in solution. Nevertheless, if f-BuOOH is added, the epoxidation of the olefinic moiety immediately takes place. Therefore, it has been suggested that these complexes are not the active species in the oxygen transfer step to the substrate, but they behave as catalysts for the primary peroxidic oxidant. On the basis of kinetic, spectroscopic and theoretical studies, the authors provided a mechanism, whose key steps are sketched in Scheme 12. In this context a major role appears to be played by the fluxionality of the particular ligands used . ... 

Lithiation of 2-bromo-3,3-disubstituted-methylenecyclopropanes by metal halogen exchange reaction with EtLi in ether, followed by alkylation with epoxides, gave selectively ring-alkylated /8-alcohols, derived from attack at the epoxide primary carbon (equation 299). When R1 R2 a mixture of isomers is obtained369. 

Lithiation of compound 560 with s-BuLi-TMEDA in THF at —78 °C following an inverse addition protocol provided the anion 561. It reacts with primary alkyl iodides and triflates, silyl chlorides, diphenyl disulfide, epoxides, aldehydes, ketones, imines, acyl chlorides, isocyanates and sulfonyl fluorides to yield the expected compounds 562 (Scheme 152). The transmetallation of compound 561 with ZnBr2 allowed the palladium-catalyzed cross-coupling reaction with aryl and vinyl bromides837. When the reaction was quenched with 1,2-dibromotetrafluoroethane, the corresponding bromide 562 (X = Br) is obtained838. 

The alkylation of compounds 591 and 592 can be performed with primary alkyl bromides and iodides824,865,866,871 887. This procedure, followed by different transformations of the alkylated products, has been applied extensively in organic synthesis. However, the alkylation with epoxides gave very poor yields with intermediates 591 and 592, so they have to be transmetallated to low-order cuprates 594888 and 595889 in order to undergo reaction with these electrophiles in THF at 0 to 20 °C. 

While alkylation of sulfonyl-stabilized oxiranyllithiums with primary alkyl triflates proceeds in high yield, the reaction towards epoxides is relatively slow ( 2 h) and the decomposition of oxiranyllithium is marked, such that it decreases the yield, especially in the case of a Z-isomer (eq 7 and 8). Addition of boron trifluoride diethyl etherate promotes this epoxide-epoxide coupling reaction. One of the diastereoisomers of eq 8 has been elaborated via 5-endo cyclization into a marine tetrahydrofuran isolated from a brown alga. ... 

A publication discussing the uses of reactive arsonium ylides for the stereospecific preparation of epoxides draws attention to the fact that arsonium salts are less readily prepared than phosphonium salts because of the poorer nucleophilicity of arsenic compared to phosphorus, and suggests methods for obtaining them. Primary salts were made from alkyl triflates, while a-branched salts were prepared from alkyldiphenylarsines, obtained from iodo compounds as, for example, in equation 23. Reaction of alkyl halides with arsines to form arsonium salts is also promoted by the presence of silver tetra-fluoroborate . 

As will be discussed later in this chapter, although the alkylation reaction is in almost all cases reasonably successful with methyl iodide and primary alkyl halides, ethylene oxide and terminal epoxides, it is... 

The key step in all these transformations is without doubt the reaction of l-lithio-l,3-dithianes with organic halides and epoxides. The alkylation usually proceeds extremely rapidly with primary alkyl iodides (-78 C, 0.2 h) and with allylic and benzylic halides - - (Scheme 59, entry a) but is much slower with secondary alkyl iodides and bromides. The reaction is best carried out at low temperature in order to obtain good yields by lowering the competitive elimination reaction it has been found to proceed with inversion of the configuration at the asymmetric carbon when optically active alkyl halides are used. ... 

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