Alkylation on Carbon

For reviews of metalalion and electrophilic substitution of amine derivatives adjacent to nitrogen, see Chem Rev 84 471 (1984) 

See page 1778, Section 4, for alkylation on carbon next to the nitrogen of an amide, urethane or phosphorus derivative. 

Highsmith, A. I. Meyers, Advances in Heterocyclic Natural Product Synthesis, Ed. W. H. Pearson, JAI Press, Greenwich, CT (1991) (chiral) 

RMgBr (R=Me, PhCH2, allyl, propargyl, alkynyl, aryl) MeO, c-CgHiaO SiMe3 Angew Int 23 53 (1984) 

RMgX (R = 1 alkyl, aUyl, benzyl, aryl) n-BuO alkyl JCS 123 532 (1923) 

RMgX (R=l°, 2° alkyl allyl benzyl aryl vinylic alkynyl) 

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Vinylogous amides, which have an enamine function in conjugation with a carbonyl group, constitute tridentate systems and thus open the possibility of alkylation on carbon, nitrogen, or oxygen. It has been found that the pyrrolidine enamine of acetylacetone gives rise to a carbon mcthylation but an oxygen ethylation product 41). The alkylation of cyclic 1,3-diketone-derived enamines has been studied 41,283). O Alkylation was found in alcohol solvents and predominant C alkylation in nonprotonic solvents. 

An important task remaining is the stereocontrolled introduction of a methyl group at C-8. When a cold (-78 °C) solution of 14 in THF is treated successively with LDA and methyl iodide and then warmed to -45 °C, intermediate 24 admixed with minor amounts of the C-8 epimer is formed in a yield of 95 %. The action of LDA on 14 generates a lactone enolate which is alkylated on carbon in a diastereoselective fashion with methyl iodide to give 24. It is of no consequence that 24 is contaminated with small amounts of the unwanted C-8 epimer because hydrolysis of the mixture with lithium hydroxide affords, after Jones oxidation of the secondary alcohol, a single keto acid (13) in an overall yield of 80%. Apparently, the undesired diastereoisomer is epimerized to the desired one under the basic conditions of the saponification step. 

V,/V-Bis(trimethylsilyl) alkyl glycinates can be deprotonated and then alkylated on carbon (4) to give homologous a-amino-acid derivatives ... 

Enolate anions are ambident nucleophiles. Alkylation of an enolate can occur at either carbon or oxygen. Because most of the negative charge of an enolate is on the oxygen atom, it might be supposed that O-alkylation would dominate. A number of factors other than charge density affect the C/O-alkylation ratio, and it is normally possible to establish reaction conditions that favor alkylation on carbon. 

Hart et al,172 observed that pyridines cannot be alkylated on carbons bonded to positions 2, 4, or 6 unless the nitrogen atom is first quaternized. 

A few nitro compounds have been obtained in good yields by the interaction of reactive halogen compounds with aci-nitro alkanes. The reaction is usually complicated in that both C- and 0-alkylation occurs. If the stability of the aci form of the nitro compound is high, then the tendency is toward alkylation on carbon rather than on oxygen. An example is the condensation of p-nitrobenzyl chloride with the sodium salt of nitro-ethane to give an 83% yield of 1-p-nitrobenzylnitroethane, P-OjNC.H CHjCHCNOjXIHj. ... 

Enamines, N-C=C, usually alkylate on carbon with this sink, and produce an iminium ion, +N=C-C-R, which is normally hydrolyzed to the ketone in an acidic water workup (the reverse of imine formation. Section 8.5.1). Enamine alkylation example ... 

With anionic allylic sources, highly polar aprotic solvents increase the amount of lone pair alkylation because poor solvent stabilization of the anion leaves the heteroatom end less hindered by solvent. Conversely, groups bound to the heteroatom increase the steric hindrance about it, and therefore decrease the tendency toward heteroatom alkylation. For example, enamines (R2N-C=C) tend to alkylate on carbon rather than nitrogen (as shown in Section 8.4.5). 

If the lithium reagent is large, alkylation on carbon occurs rather than... 

Deprotonation of phenol (P20.2) gives an anion which is equivalent to the enolate anion of cyclohexadienone (P20.3). This can be alkylated on carbon, rather than oxygen, if the reaction conditions are correct. The product ketone (P20.4) can be re-enolised to give o-cresol (P20.5) and the whole process repeated. After the addition of three methyl groups, the product ketone (P20.1) cannot enolise and so the alkylation process ceases (Figure S20). 

In a minor variation, the possession of an appropriately positioned carbonyl group by the phosphonic derivative, can lead to simultaneous expulsion of the phosphinoyl moiety with carbon-carbon double bond formation coupled with cyclization " . Although the ylide 157 can be alkylated on carbon (like the carbanion prepared by Arbuzov and Dunin), with simultaneous expulsion of the diethoxyphosphinoyl moiety (unlike the phosphory-lated carbanion), no reaction takes place between 157 and an aldehyde or ketone. ... 

The first base removes the proton from nitrogen to make an eno late-like intermediate that reacts at nitrogen. Now that the NH is blocked, the second base makes the amide enolate that is alkylated on carbon. 

Carbon Acids. Active methylene compounds, such as mal-onates and 8-keto esters, can be deprotonated with sodium hydride and alkylated on carbon (eqs 12 and 13). Alkylation of Reissert anions is also facile with sodium hydride (eq 14). ... 

Enamines readily undergo Sj 2 reactions with methyl and primary alkyl halides, a-haloketones, and a-haloesters. Enamines are superior to enolate anions for these reactions because they are less basic and consequently give higher ratios of substitution to elimination products. In addition, they also give more alkylation on carbon than do enolate anions. 

In the first reaction (Table 8.6, item 23), alkylation of the anion of cyclohexanone is not reversible. Hence, the question of O-alkylation (Equation 8.35) versus C-alkylation (Equation 8.36) is a kinetic problem (AH° < 0 for both O- and C-alkylation, Table 1.1) and, in principle, the enolate anion of cyclohexanone could alkylate on carbon and/or oxygen. 

As shown in Scheme 9.86, a nonsymmetricaUy substituted carbonyl group can, in principle, produce four different enolate anions (or their corresponding enols). Again, in principle, each of these enolate anions (or enols) could undergo alkylation on carbon or oxygen leading to an intractable mixture of isomers (Problem 9.16). Fortunately, not all isomers form with equal facility. 

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