Oxygen versus Carbon as the Site of Alkylation

SECTION 1.7. OXYGEN VERSUS CARBON AS THE SITE OF ALKYLATION 

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 0-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. 

0-Alkylation is most pronounced when the enolate is dissociated. When the potassium salt of ethyl acetoacetate is treated with diethyl sulfate in the polar aprotic solvent HMPA, the major product (83%) is the 0-alkylated one. In THF, where ion clustering occurs, all of the product is C-alkylated. In butanol, where the acetoacetate 

Similar effects are also seen with enolates of simple ketones. For isopropyl phenyl ketone, the inclusion of one equivalent of 12-crown-4 in a DME solution of the lithium enolate changes the C/O-alkylation ratio from 1.2 1 to 1 3, with methyl sulfate as the alkylating agent. With methyl iodide as the alkylating agent, C-alkylation is strongly favored with or without 12-crown-4. 

Higher C/O-alkylation ratios are observed with alkyl halides than with alkyl sulfonates and sulfates. The highest C/O-alkylation ratios are obtained with alkyl iodides. For ethylation of the potassium salt of ethyl acetoacetate in HMPA, the product compositions shown below were obtained.47 

Enolate anions are ambident nucleophiles. Alkylation of an enolate may occur at either carbon or oxygen. 

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON. ENOLATES AND ENAMINES 

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