Nucleophilic Substitutions with Amines

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. 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Biosynthesis usually occurs under reductive and nucleophilic reaction conditions. Weak bases and acids are employed in nature as reagents or as catalysts.  

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G. Aromatic Nucleophilic Substitution with Amines in which the... 

Chlorinated cyclopenta-l,2,3-dithiazole 44 is susceptible to nucleophilic substitution with amines, and in all cases only the 5-chlorine atom of dithiazole 44 is substituted (Scheme 24). The selectivity in these reactions is apparently due to the activation of the c/r-position to the cyano group of the dithiazole 44, which is a unique feature of this compound <2005EJ05055>. 

Nitro-6-chloropyridazine 1-oxide reacts with nucleophiles with displacement of the 6-chlorine atom (even with acetyl bromide), except with sodium methoxide. Merer, the 3-nitro group is diplaced. Nucleophilic substitution with amines was investigated for various monoalkoxydihalo-or dialkoxyhalopyridazines. Normally, the chlorine atom is replaced, but in 3-chloro-4,6-dialkoxy- or 4-alkoxy-3,6-dichloropyridazines the alkoxy group may be replaced preferentially or concurrently. The 6-chlorine atom of methyl (3,6-dichloropyridazin-4-yl)-acetate was displaced by hydrazine or on hydrolysis. ... 

The product 208 may be as drawn or it too may be a pyridone 209 but in any case it reacts with POCl3 to give the chloro-compound 210 and then by nucleophilic substitution with amines such as benzylamine to give, after reduction, the diamine 212 from which the benzyl group could be removed to give 204. 

The linking of pyrimidines to a resin support has also been applied to the synthesis of pteridine 20 (Scheme 12.7). Oxidative cleavage with dimethyldioxirane followed by nucleophilic substitution with amines, azides, or water provided a traceless synthesis of the compound. 

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