Alkylation of Aldehydes, Esters, Amides, and Nitriles

SECTION 1.8. ALKYLATION OF ALDEHYDES, ESTERS, AMIDES, AND NITRILES 

Among the alkylation reactions of compounds capable of forming enolates, those of ketones have been most widely studied and used. Similar reactions of aldehydes, esters, and nitriles have also been developed. Alkylation of aldehyde enolates is not very common. One limitation is the fact that aldehydes are rapidly converted to aldol condensation products by base (see Chapter 2 for more discussion of this reaction). Only when the enolate can be rapidly and quantitatively formed is aldol condensation avoided. Success has been reported using potassium amide in liquid ammonia or potassium hydride in tetrahydrofuran.  

CHAPTER 1 ALKYLATION OF NUCLEOPHILIC CARBON. ENOLATES AND ENAMINES 

Alkylation via enamines or enamine anions provides a more general method for alkylation of aldehydes. These reactions will be discussed in Section 1.9. 

Carboxylic acids can be directly alkylated by conversion to dianions by two equivalents of LDA. The dianions are alkylated at the a-carbon as would be expected.  

A method for enantioselective s)mthesis of carboxylic acid derivatives is based on alkylation of the enolates of A-acyl oxazolidinones. The lithium enolates have the structures shown because of the tendency for the metal cation to form a chelate. 

In 4 the upper face is shielded by the isopropyl group whereas in 5 the lower face is shielded by the methyl and phenyl groups. As a result, alkylation of the two derivatives gives products of the opposite configuration. Subsequent hydrolysis or alcoholysis provides acids or esters in enantiomerically enriched form. The initial alkylation product 

---

In contrast to facile a-alkylation of carbonyl compounds, a-arylation or alkenylation of carbonyl compounds has been considered to be a difficult reaction. Recently, a big breakthrough has occurred, and methods for the smooth a-arylation or alkenylation of carbonyl compounds have been developed [1]. Active methylene compounds, ketones, aldehydes, esters, amides and nitriles are now a-arylated easily not only with aryl iodides, but also with bromides and even chlorides. These reactions will lead to wide-ranging applications. A typical example of a synthetic application of the innovative reactions is a new preparative method for a-arylated carboxylic acids, such as ibuprofen (1) and naproxen, by direct a-arylation of acetate or propionate. 

Alkylation of Aldehydes, Esters, Carboxylic Acids, Amides, and Nitriles... 

Compared with other synthetic intermediates, enolates show a decreased reactivity. The differences in reactivity are most striking in reactions with alkylating agents [1] and epoxides [6]. The reactivities of the various types of enolates towards alkyl halides decrease in the order C=C(0 )NR2 (amide-enolate) C=C(0 )0R (ester enolate) C=CO (ketone-enolate). Metallated nitriles, imines, and S,S-acetals are, in general, much better nucleophiles than enolates in alkylations and ft-hydroxyalkylations [1], Furthermore, the alkylation of aldehyde and ketone enolates usually does not stop after the mono-functionalization [12]. The decreased reactivity of (especially) aldehyde and ketone enolates also appears in thiolations with disulfides [2]. A solution of lithiated cyclohexanone in THF does not react at 20°C with CH3SSCH3 [1,2]. 

Ketones, esters, and nitriles can all be alkylated using LDA or related dialkyl-amide bases in THE. Aldehydes, however, rarely give high yields of pure products because their enolate ions undergo carbonyl condensation reactions instead of alkylation. (We ll study this condensation reaction in the next chapter.) Some specific examples of alkylation reactions are shown. 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Epoxides also participate in the Ritter reaction with nitriles. An investigation of the ring opening of several alkyl-substituted glycidic esters and amides 181 showed that this transformation occurs with inversion and is completely regiospecific. ° Esters appeared to be somewhat more reactive than amides. However, phenyl-substituted glycidic esters and amides 184 are almost totally nonstereoselective. In addition, the oxazolines 186 are isolated in low yield due to the propensity of intermediate 185 to generate an aldehyde byproduct 187 (Scheme 8.53). 

The lower members of the homologous series of 1. Alcohols 2. Aldehydes 3. Ketones 4. Acids 5. Esters 6. Phenols 7. Anhydrides 8. Amines 9. Nitriles 10. Polyhydroxy phenols 1. Polybasic acids and hydro-oxy acids. 2. Glycols, poly-hydric alcohols, polyhydroxy aldehydes and ketones (sugars) 3. Some amides, ammo acids, di-and polyamino compounds, amino alcohols 4. Sulphonic acids 5. Sulphinic acids 6. Salts 1. Acids 2. Phenols 3. Imides 4. Some primary and secondary nitro compounds oximes 5. Mercaptans and thiophenols 6. Sulphonic acids, sulphinic acids, sulphuric acids, and sul-phonamides 7. Some diketones and (3-keto esters 1. Primary amines 2. Secondary aliphatic and aryl-alkyl amines 3. Aliphatic and some aryl-alkyl tertiary amines 4. Hydrazines 1. Unsaturated hydrocarbons 2. Some poly-alkylated aromatic hydrocarbons 3. Alcohols 4. Aldehydes 5. Ketones 6. Esters 7. Anhydrides 8. Ethers and acetals 9. Lactones 10. Acyl halides 1. Saturated aliphatic hydrocarbons Cyclic paraffin hydrocarbons 3. Aromatic hydrocarbons 4. Halogen derivatives of 1, 2 and 3 5. Diaryl ethers 1. Nitro compounds (tertiary) 2. Amides and derivatives of aldehydes and ketones 3. Nitriles 4. Negatively substituted amines 5. Nitroso, azo, hy-drazo, and other intermediate reduction products of nitro com-pounds 6. Sulphones, sul-phonamides of secondary amines, sulphides, sulphates and other Sulphur compounds... 

---