Alkyl anion synthons

Although this method is aot a geaeral procedure, bemg specific for ct-nitroketoues, k has several merits to avoid the use of toxic reageuts such as organodn compounds Functionalized ketones have been prepared by this denitration reaction, in which functionalized nitroalkanes are used as alkyl anion synthons For example, 3-nitropropanal ethylene acetal can be used as synthon of the 3-oxo-propyl anion and 1,4-dicarbonyl compounds are prepared, as shovm In Eq 7 88... 

An extensive review on the use of nitroalkanes as alkyl anion synthons has appeared415. 

Ballini, R. and Rosini, G. 1988. Functionalized nitroalkanes as useful reagents for alkyl anion synthons. Synthesis, 11 833 7. 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

Formaldehyde anion synthon ( CHO). The anion of 1 (n-BuLi, THF, 0°) is readily alkylated, particularly by primary halides. The products can he converted into aldehydes under very mild conditions. Oxidation with m-chloroperbenzoic acid gives an unstable sulfoxide, which undergoes an sila-Pummerer rearrangement to an acetal. Addition of water liberates the free aldehyde. Epoxides can also be used as electrophiles.2 3 Example ... 

Cyanohydrin derivatives have also been widely used as acyl anion synthons. They are prepared from carbonyl compounds by addition of hydrogen cyanide. A very useful variant is to use trimethylsilyl cyanide with an aldehyde to produce a trimethylsilyloxy cyanide. The cyano group acidifies the a position (pKA 25) and the a proton can be removed by a strong base. Alkylation of the anion and unmasking of the hydroxy group cause elimination of cyanide and re-formation of the carbonyl group. 

A C—N disconnection of a primary amine gives rise to the carbocation and amide anion synthons. It might be predicted therefore that treatment of an alkyl halide with ammonia (reagents equivalent to the above synthons) under pressure would constitute a suitable synthesis of a primary amine. In practice, however, the yield is poor since a mixture of all three classes of amines, together with some of the quaternary ammonium salt, is obtained, owing to more ready further alkylation of the sequentially formed products. 

An alternative reagent equivalent for the amide anion synthon is the potassium salt of phthalimide which can only react with one molecular proportion of alkyl halide. The resulting JV-alkylphthalimide is then cleaved to the primary amine (the Gabriel synthesis). The preliminary preparation of potassium phthalimide (from a solution of phthalimide in absolute ethanol and potassium hydroxide in 75% ethanol) may be avoided in some cases by boiling phthalimide with the halide in the presence of anhydrous potassium carbonate. The cleavage of the JV-substituted phthalimide is best effected by reaction with hydrazine hydrate and then heating the reaction mixture with hydrochloric acid. The insoluble phthalylhydrazide is filtered off, leaving the amine hydrochloride in solution from which the amine may be liberated and isolated in the appropriate manner. 

A sequence in which a carbonyl group has been masked as a sulfur derivative, alkylated with an electrophile, and then revealed again is a nucleophilic acylation. These nucleophilic equivalents of carbonyl compounds are known as acyl anion equivalents. In the retrosynthetic terms of Chapter 50 they are d1 reagents corresponding to the acyl anion synthon. 

Aldehyde synthesis. Aldehydes are obtained through alkylation under solid-liquid biphasic conditions followed by reduction with LiAlH4 and Hg(II)-promoted hydrolysis. Thus the bissulfonyl methanes are a formyl anion synthon. 

Ketones. The reagent (1) is a propenoyl anion synthon. After alkylation, enones are released. On the other hand, the adducts undergo allylic displacement with Grignard reagents, and on hydrolytic workup, ketones are formed. The possibility of creating a-bromoalkyl ketones, 1,4-diketones, 2-ethoxy-2-cyclopentenones, and a-keto enamines bespeaks for the versatility of this synthesis. 

Alkylations. -Lithiocarbonyl synthons and propargyl anions are generated from the bromides by reacting with BuTeLi and then BuLi. (Z)-l,3-Butadien-l-yllithium is available from P-(organotelluro)acroleins. 

Two groups have reported the use of phenylthiomethyltrimethylsilane as a formyl anion synthon. Alkylation of the lithium anion may be accomplished in THF, or in hexane containing TMEDA. A distinct advantage of this formyl synthon is the ease of unmasking the aldehyde via a sila-Pummerer rearrangement (Scheme 6). However, as steric crowding about the intermediate sulphoxide... 

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