Alkylation primary amines

Reduction of phenylacetone in the presence of methylamine rather than ammonia gives methamphetamine (53), an agent similar in action to the primary amine. Alkylation of 53 with benzyl chloride affords the analog, benzphetamine (54). ... 

Preparation of primary amines Alkyl halide reacts with sodium amide (NaNH2) to give 1° amine via Sn2 reaction. The reaction mechanism for the formation of 1° amine is similar to the formation of nitrile. 

Primary amines are obtained from ammonia, and secondary amines from primary amines. Alkylating agent must have good S 2 reactivity. Limitations are discussed in Section 23-9D. 

We end this chapter with a simple commercial synthesis of a drug molecule described as a dopaminergic antagonist. It uses four reactions that you have met conjugate addition of an enolate to acrylonitrile reduction of CN to a primary amine alkylation and reduction of the amide. There is another reaction involved—cyclization to an amide—but this occurs spontaneously. These reactions may be simple but they are important. 

The synthesis of this scaffold requires a set of diverse anthranilic acids 71, of which only a few are commercially available. A variety of these was prepared by nucleophilic substitution of 2-chlorobenzoic acid 70 with a range of primary amines (alkyl, benzyl, phenyl). These anthranilic acids 71 were bound to a polysty-rene/triethyleneglycol chloroformate resin through the amine group (72). Amidation of the carboxylic acid function gave 73 and reaction at 125 °C in DMF gave the cyclized product 74 (Scheme 20) [33]. 

The synthesis, physical and chemical properties of sulphamides have been the subject of various reviews down through the years333-338. Sowada339 has summarized the three main synthetic routes in the preparation of sulphamides as follows (a) reaction of primary amines (alkyl or aryl) with sulphuryl chloride (b) reaction of primary amines with chlorosulphonic acid (c) reaction of primary amines (alkyl, cycloalkyl and aryl) with sulphamide. 

Aryl iodides, bromides, chlorides, triflates and some tosylates are used for the arylamine synthesis. Secondary (dialkyl, alicyclic, alkyl-aryl, and diarylamines) and primary amines (alkyl and arylamines) participate in the reaction with different reactivity. In general, more basic and less bulky amines react faster. 

Enders D, Schubert H. Enantioselective synthesis of beta-substituted primary amines -alkylation reductive amination of aldehydes via samp-hydrazones. Angew. Chem. Int. Ed. Eng. 1984 23 365-366. 

The preparation of pure primary amines by the interaction of alkyl halides and ammonia is very difficult, because the primary amine which is formed reacts with unchanged alkyl halide to give the secondary amine the latter... 

Amines are powerful nucleophiles which react under neutral or slightly basic conditions with several electron-accepting carbon reagents. The reaction of alkyl halides with amines is useful for the preparation of tertiary amines or quaternary ammonium salts. The conversion of primary amines into secondary amines is usually not feasible since the secondary amine tends towards further alkylation. 

The alkyl azide 118 is reduced to a primary amine by the Pd on carbon-catalyzed reaction of ammonium formate in MeOH at room temperature. No racemization takes place with chiral azides[l 11,112]. 

Amines are named m two mam ways m the lUPAC system either as alkylamines or as alkanamines When primary amines are named as alkylamines the ending amine IS added to the name of the alkyl group that bears the nitrogen When named as alkan amines the alkyl group is named as an alkane and the e ending replaced by amine... 

Although this reaction is useful for preparing a ammo acids (Table 22 3 fifth entry) it IS not a general method for the synthesis of amines Its major limitation is that the expected primary amine product is itself a nucleophile and competes with ammonia for the alkyl halide... 

Because alkylation of ammonia can lead to a complex mixture of products it is used to prepare primary amines only when the starting alkyl halide is not particularly expensive and the desired amine can be easily separated from the other components of the reaction mixture... 

Among compounds other than simple alkyl halides a halo ketones and a halo esters have been employed as substrates m the Gabriel synthesis Alkyl p toluenesul fonate esters have also been used Because phthalimide can undergo only a single alkyl ation the formation of secondary and tertiary amines does not occur and the Gabriel synthesis is a valuable procedure for the laboratory preparation of primary amines... 

Because nitriles can be prepared from alkyl halides by nucleophilic substitution with cyanide ion the overall process RX RC=N RCH2NH2 leads to primary amines that have one more carbon atom than the starting alkyl halide... 

In this general equation R and R may be either alkyl or aryl groups When R = H the product is a primary amine... 

Ammonia can act as a nucleophile toward primary and some secondary alkyl halides to give primary alkylamines Yields tend to be modest because the primary amine IS itself a nucleophile and undergoes alkylation Alkylation of ammonia can lead to a mixture containing a primary amine a secondary amine a tertiary amine and a quaternary ammonium salt... 

Nitrosation (Section 22 15) Nitrosation of amines occurs when sodium nitrite is added to a solution containing an amine and an acid Primary amines y e d alkyl diazonium salts Alkyl diazonium salts are very unstable and yield carbo cation derived products Aryl diazonium salts are exceedingly useful synthetic in termediates Their reactions are de scribed in Table 22 7... 

Primary amine (Section 22 1) An amine with a single alkyl or aryl substituent and two hydrogens an amine of the type RNH2 (pnmary alkylamine) or ArNH2 (primary aryl amine)... 

Ritter Reaction (Method 4). A small but important class of amines are manufactured by the Ritter reaction. These are the amines in which the nitrogen atom is adjacent to a tertiary alkyl group. In the Ritter reaction a substituted olefin such as isobutylene reacts with hydrogen cyanide under acidic conditions (12). The resulting formamide is then hydroly2ed to the parent primary amine. Typically sulfuric acid is used in this transformation of an olefin to an amine. Stoichiometric quantities of sulfate salts are produced along with the desired amine. 

Reductive amination of cyclohexanone using primary and secondary aHphatic amines provides A/-alkylated cyclohexylamines. Dehydration to imine for the primary amines, to endocycHc enamine for the secondary amines is usually performed in situ prior to hydrogenation in batch processing. Alternatively, reduction of the /V-a1ky1ani1ines may be performed, as for /V,/V-dimethy1 cyclohexyl amine from /V, /V- di m e th y1 a n i1 i n e [121 -69-7] (12,13). One-step routes from phenol and the alkylamine (14) have also been practiced. 

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