Halides, alkyl from amides

As these compounds all possess a nitrogen-containing functional feature, it is worth pointing out that they arise from alkyl halides (or methanesulphonates) in the case of azides and cyanides, or from carboxylic acid chlorides (in the case of amides). 

Olah, G. A., Gupta, B. G. B., Narang, S. C. Synthetic methods and reactions 66. Nitrosonium ion induced preparation of amides from alkyl (arylalkyl) halides with nitriles, a mild and selective Ritter-type reaction. Synthesis 274-276. 

Ester- and amide-substituted radicals bearing an adjacent stereocenter abstract hydrogen with high diastereoselectivity1. The radicals are generated via intra- or intermolecular radical addition to alkenes, halogen abstraction from alkyl halides or reductive cleavage of alkylmercury compounds. Some examples are shown in Table 1. 

Nitriles are commonly available from aldoximes (aldehydes) and amides (carboxylic acids) by dehydration, from alkyl halides by nucleophilic substitution, and from primary amines by oxidation. It is therefore not surprising that these... 

A special problem arises in the preparation of secondary amines. These compounds are highly nucleophilic, and alkylation of an amine with alkyl halides cannot be expected to stop at any specifle stage. Secondary amides, however, can be monoalkylated and lydrolyzed or be reduced to secondary amines (p. 11 If.). In the elegant synthesis of phenyl- phrine an intermediate -hydroxy isocyanate (from a hydrazide and nitrous acid) cyclizes to pve an oxazolidinone which is monomethylated. Treatment with strong acid cleaves the cyclic irethan. 

Both methods of nitrile synthesis—SN2 displacement by CN- on an alkyl halide and amide dehydration—are useful, but the synthesis from amides is more general because it is not limited by steric hindrance. 

Another alternative for preparing a primary amine from an alkyl halide is the Gabriel amine synthesis, which uses a phthalimide alkylation. An imide (—CONHCO—) is similar to a /3-keto ester in that the acidic N-H hydrogen is flanked by two carbonyl groups. Thus, imides are deprotonated by such bases as KOH, and the resultant anions are readily alkylated in a reaction similar to the acetoacetic ester synthesis (Section 22.7). Basic hydrolysis of the N-alkylated imide then yields a primary amine product. The imide hydrolysis step is analogous to the hydrolysis of an amide (Section 21.7). 

A more general method for preparation ofa-amino acids is the amidotnalmatesynthesis, a straightforward extension of the malonic ester synthesis (Section 22.7). The reaction begins with conversion of diethyl acetamidomalonate into an eno-late ion by treatment with base, followed by S 2 alkylation with a primary alkyl halide. Hydrolysis of both the amide protecting group and the esters occurs when the alkylated product is warmed with aqueous acid, and decarboxylation then takes place to vield an a-amino acid. For example aspartic acid can be prepared from, ethyl bromoacetate, BrCh CCHEt ... 

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