C and O-Alkylation

The leaving group in the alkylating reagent has a major effect on whether C- or O-alkylation occurs. In the case of the lithium enolate of acetophenone, for example, C-alkylation is predominant with methyl iodide, but C- and O-alkylation occur to approximately equal extents with dimethyl sulfate. The C- versus O-alkylation ratio has also been studied for the potassium salt of ethyl acetoacetate as a function of both solvent and leaving group. ... 

Alkylation of p-oxophosphonates, using a procedure analogous to 6.2.19.A, produces both C- and O-alkylated products [74] in ratios varying from ca. 2 1 to 5 1 depending on the alkylating agent and the structure of the p-oxophosphonate. 

The data in Table 7 obtained with equimolar amounts of the polymeric catalysts and the 2-naphthoxide ion should be more reliable because all of the reactive anion is contained within the polymer. These conditions (expts 7-9) gave 100 % O-alkylation, indicating that the active site environment of the polystyrene-bound tri-n-butylphos-phonium ion/naphthoxide ion pair or aggregate is aprotic even with the 60%RS polymer. However, the common benzyltrimethylammonium ion found in commercial ion exchange resins is more hydrophilic, giving both C- and O-alkylation (expts 10 and 11 of Table 7). 

The extent of C-alkylation as a side reaction in etherification varies about 1% of allyl 2-allylphenyl ether is formed when phenol is used in the acetone and potassium carbonate method with allyl bromide with cinnamyl bromide or 7,7-dimethylallyl bromide the extent of C-alkylar tion is greater.16 A complicated mixture of C- and O-alkylation products results from the treatment of phenol with 4-bromo-2-hexene and 4-chloro-2-hexene. 9 4-Hexenylresordnol has been obtained in about 40% yield from the reaction of l-bromo-2-hexene, resorcinol, and potassium carbonate in boiling acetone.99 An appreciable amount of C-alkylation occurs when 2,6-dimethyIphenol is treated with allyl bromide and sodium ethoxide in ethanol.70 Since, in general, the ampunt of C-alkylation is greatly increased by carrying out the alkylation on the sodium salt of the phenol in benzene,16 this method is unsuitable for the preparar tion of allyl aryl ethers. 

Based on the above results it was assumed that both C- and O-alkylation are kinetical-ly controlled processes, i.e. that pathway a in equation 15 is effectively irreversible68. 

The solvolysis of alkyl chlorides and aralkyl p-nitrobenzoates in phenol, an ambident nucleophile, gave C- and O-alkylated phenols. The logarithm of the ratio of product concentrations was found to be a linear function of the logarithm of the solvolytic rate constant for the particular substrate. 

Exposure of I to another efficient dienophile, quinone II, yielded the abnormal product III. This compound shows signs of C- and O-alkylation processes that call for the operation of a mechanism other than the normal [2+4] cycloaddition. 1,4-Benzoquinone is not only susceptible to Diels-Alder operations but also to Michael-type 1,4 additions. In this case the required nucleophile would be the vinyl ether portion of I while the alkyl dithiane group would remain unaltered throughout the sequence. Its role would be limited to provide substantial stabilization to the carbenium ion in V. The second C-alkylation step that would lead to four- and six-membered ring structures VI and IV, respectively, is overcome by proton transfer and D-alkylation to yield III (see Scheme 13.2). 

The reaction of propargyl carbonate 187 with 2,5-hexanedione-3,4-dicarboxylate (203) for 7 h catalyzed by [Pd2(dba)3] and dppe afforded methylenecyclobutane 204 by double C-alkylation, and 3-methylenedihydropyran derivative 205 by C- and O-alkylations, in 52% and 42% yields, respectively (Scheme 11-54). The cyclobutane 204 is a product of a... 

In general, there is significant competition between C- and O-alkylation when the equilibrium concentration of the enol tautomer is relatively high, as in the case of 1,3-cyclohexanedione. ... 

Methoxybenzo[ >] thiophene may be obtained (90%) by methylation of thiooxindole with Me2S04-NaH in hexamethylphosphoric triamide (HMPA)206 alkylation by other reagents gives a complex mixture of C- and O-alkyl derivatives and ring-opened products.267... 

F -Anion exchange resins. Fluoride ion immobilized on strongly basic anion exchange resins, particularly Amberlyst A27 and Dowex MSA-1, promote the various reactions that have been found to be promoted by alkali metal or tetraalkylammonium fluorides, such as C- and O-alkylation, sulfenylation, and Michael additions. 

Williams and McClymont described detailed studies of the alkylation and acylation of 5-(l,3-dithian-2-yl)oxazole 932. The authors showed from deuterium incorporation studies that sequential deprotonation of 932 occurred first at C(2) and then at the dithiane carbon atom. Thus treatment of 932 with excess LiHMDS followed by an alkylating agent afforded exclusively the side chain alkyl analogues 933 (Scheme 1.249, Table 1.67). Reactive electrophiles, e.g., CH3I and TMSCl afforded complex mixtures of C- and O-alkylated products derived from the acyclic isocyanovinyllithium alkoxides 938a and 938b (discussed below), whereas secondary alkyl halides were unreactive. 

Substrates which are precursors of ambidentate anions, i.e. carbonyl compounds or phenols, can undergo both C- and O-alkylation Under PTC conditions, the C-/0-alkylation ratio depends on a number of factors, such as ion pair association, anion conformation, solvation at oxygen or carbon, and nature of the alkylating agent... 

Scheme 8.93. A generalized depiction of the possiblities of C- and O-alkylation of an enolate anion. C-alkylation is generally preferred, although varying amounts of O-alkylation can be produced by judicious choice of metal-base, leaving group combinations.

Regio- and stereo-selectivity in the intramolecular cyclization of enolates derived from 4,5-, 5,6-, and 6,7-epoxy-1-phenylalkan-l-ones (18a,b-2 a,b) has been explored. Competition between C- and O-alkylation routes have been discussed. The LHMDS-Sc(OTf)3 protocol seems to be a valuable tool for obtaining the corresponding y-hydroxy ketones stereoselectively from (18a,b) and (20a,b) whereas (19a,b) reacted cleanly only under alternative basic conditions, and yielded products of O-alkylation. 

Phenolate anions are ambident ions and as such may suffer both C- and O-alkylation [26]. Very small changes in free energy usually separate the alternate routes in such reactions and it requires somewhat less than 3 k-calories of free energy to... 

Picolyl alkyl and aryl ketones have attracted attention because of their chelating and bactericidal properties . In the solid state they exist in the enolic forms (6) and in solution as equilibrium mixtures . Some C-aroyl-2-phenacylpyridines exist in two hydrogen-bond-stabilized enolic forms , (7) and (8). Both C- and O-alkylation and -acylation of these... 

Alkylation.—Potassium enolates of aldehydes can be prepared by reaction of the aldehyde with potassium hydride in tetrahydrofuran. Reaction of these enolates with activated primary bromides (allyl or benzyl) and methyl iodide gives rise to C-alkylated products exclusively secondary alkyl iodides afford mixtures of C-and O-alkylated products. ... 

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