Alkylations enolates

In the prostaglandin synthesis shown, silyl enol ether 216, after transmetaJ-lation with Pd(II), undergoes tandem intramolecular and intermolecular alkene insertions to yield 217[205], It should be noted that a different mechanism (palladation of the alkene, rather than palladium enolate formation) has been proposed for this reaction, because the corresponding alkyl enol ethers, instead of the silyl ethers, undergo a similar cyclization[20I],... 

ALKYL-l-ALKYNES, 58, 1 ALKYL ARYL SULFIDES, 58,143 Alkyl aryl thioethers, 58,145 Alkylation, enolates, 56, 52 C-ALKYLATION, phase transfer catalysis... 

Acetals of benzaldehydes may undergo EGA-catalyzed aldol reactions also with alkyl enol ethers, (22) (R = alkyl), as nucleophiles [31] but in contrast to the reaction with enol silyl ethers the threo isomer is favored in this case. 

Scheme 9. Reaction with alkyl enol ethers is unsuccessful for acetals of aliphatic aldehydes [31].

An enantioselective intramolecular Pauson-Khand reaction based on chiral auxiliary-directed 7t-face discrimination in acetylenic 0-alkyl enol ether-dicobalt hexacarbonyl complexes, which proceeds with good yields and high facial diastereoselectivity, has recently been developed by M.A. Pericas, A. Moyano, A.E. Greene and their associates. The method has been applied to an enantioselective formal synthesis of hirsutene. Moreover, the process is stereodivergent and the chiral auxiliary -rran5-2-phenylcyclohexanol- is recovered in a yield as high as 92% [18]. 

Polar protic solvents also possess a pronounced ability to separate ion pairs but are less favorable as solvents for enolate alkylation reactions because they coordinate to both the metal cation and the enolate ion. Solvation of the enolate anion occurs through hydrogen bonding. The solvated enolate is relatively less reactive because the hydrogen-bonded enolate must be disrupted during alkylation. Enolates generated in polar protic solvents such as water, alcohols, or ammonia are therefore less reactive than the same enolate in a polar aprotic solvent such as DMSO. 

Trifluoroalamne cannot be prepared by alkylation of a glycine anion with tri-fluoromethyl halides, since these electrophiles are not able to alkylate enolates. Other approaches have been reported using various substrates, but none is really satisfying. The three main ones are ... 

Silyl enol ethers, enol esters and alkyl enol ethers of ketones and aldehydes can be C-alkylated with reactive alkylating agents in the presence of Lewis acids86-90. However, information regarding the use of these reactions for diastereoselcctive or asymmetric synthesis is still limited. 

Alkylation, enolates, 56, 52 ALKYLATIVE COUPLING, 55, 127 2-Alkyl-l,3-cyclopentanediones, 58, 82 Alkyl 2,2-dimethylpropanethioate, 58, 146 Alkyl disulfides, 58, 142 Alkyl fluoride, 58,77 Alkyl halide, 58, 145... 

F-Teda BF4 is effective for the selective addition of fluorine to steroids in good yield, re-gioselectively and, in many cases, stereoselectively at the 6- and 16-positions, under very mild reaction conditions (Table 7).92 Further, 6 will also efficiently fluorinate silyl and alkyl enolates, enamides, carbanions, a-alkenes and actived aromatic compounds (Table 8). As an extension of this method F-Teda BF+ has been used for the electrophilic fluorination of (fluorovinyl)tin compounds affording terminal fluoroalkenes (see Table 9).88... 

This methodology can be extended to alkylation of (3-silyl-a-alkyl enolates the diastereoselectivity is dependent on the size of the a-alkyl substituent, decreasing as the size of the alkyl group is increased (equation I). 

Keywords Alkylation, enolate, phase transfer, Cinchona alkaloid, arylation, chiral amide base,... 

Alkyl enol ethers and vinyl sulfides may also be oxidatively annulated onto electron-rich aromatic rings (Scheme 71)168. 

Replacing 30a by the bulky alkyl enolate 30b as nucleophile led to an improved enantioselectivity (up to 62% ee) (Scheme 6.16). In both reactions the (S) enantiomer was preferably formed. The organocatalyst derived from cinchonine 31 was more efficient than that derived from cinchonidine [66],... 

All the reactions discussed in this section are SN2 reactions with respect to the alkylating reagent. The most suitable alkylating reagents for enolates and aza enolates are therefore the most reactive alkylating reagents (Section 2.4.4), that is, Mel, Rpr/m—X, and especially H2C=CH—CH2—X and Ar—CH2—X (X = Hal, OTs, OMs). Isopropyl bromide and iodide also can alkylate enolates in some instances. Analogous compounds Rsec—X and R(ert—X either do not react with enolates at all or react via E2 eliminations to afford alkenes. 

Simmons-Smith regioselective cyclopropanation of a-enone alkyl enol ethers also provided 1-alkoxyvinylcyclopropanes in high yields43 . 

In Chapter 17 you saw epoxides acting as electrophiles in Sn2 reactions. They can be used to alkylate enolates providing epoxide opening is assisted by coordination to a Lewis acidic metal ion in this case the lanthanide yttrium(III). The new C-C bond in the product is coloured black. Note that the ketone starting material is unsymmetrical, but has protons only to one side of the carbonyl group, so there is no question over which enolate will form. The base is one of the LDA variants we showed you on p. 668—LHMDS. 

Other known methods for preparing O-alkyl enol ethers include, most notably, alcohol elimination from acetals, double bond isomeri2ation in allylic ethers, reduction of alkoxy enol phosphates, and phosphorane-based condensation approaches.5 These methods, however, suffer from poor stereoselectivity, low yields, or lack of generality, if not a combination of these drawbacks. 

Photocyclization of A -alkylfuran-2-carboxyanilides conducted in inclusion crystals with optically active tartaric acid-derived hosts led to the formation of tricyclic /ra r-dihydrofuran compounds with up to 99% ee <1996JOC6490, 1999JOC2096>. 2-(/>-Alkoxystyryl)furans underwent photocyclization to give 5-(3-oxo-(/ )-butenyl)benzo[ ]furans as the predominant isomers in undehydrated dichloromethane as shown in Equation (59). The intermediate alkyl enol ether could be obtained by performing the reaction in anhydrous benzene <1999OL1039>. 

A furoannulation protocol via dichlorocarbene adducts of alkyl enol ethers has been applied to the synthesis of the furanosesquiterpene pallescensin A (Equation 39) <2006TL6817>. 

B. Alkyl Enol Ethers and Silyl Enol Ethers... 

Whereas alkyl enol ethers easily polymerize upon treatment with electrophilic reagents [202], silylated enol ethers are rapidly desilylated after the electrophilic attack, and regeneration of the carbonyl group prevents polymerization. Therefore, silyl enol ethers are frequently used reagents for synthesizing a-substituted carbonyl compounds (Scheme 45) [200,201,203-205]. 

Alkyl enol ethers polymerize under these conditions, and their reactivity, as that of other strong nucleophiles, has been determined with the LASER flash method (Table 7). Because this method of carbocation generation produces the nucleophilic counterions CL, eventual polymeriza-... 

Scheme 48, which compares silyl and alkyl enol ethers of analogous structure, shows that the two classes of compounds have similar reactivities. Although the rate constants for the bis(p-chlorophenyl)-carbenium... 

The comparable process for alkyl enol ethers involves participation of solvent,residual peiacid or water ° in cleaving the initially formed epoxide.Thus vinyl ether (74) produces the a-hydroxy derivative directly, while (75) provides the dimethoxy acetal. ... 

---