Aminoalkylation of Thiophene The Mannich Reaction

Thiophene was successfully aminoalkylated for the first time [152] by heating thiophene with formaldehyde and ammonium chloride in 45% yield, together with several side products [21]. 

It was shown that thiophene 70 is the most reactive and thiophene 69 is the least reactive in Mannich reactions [153]. Moreover, mixed aminomethyl thiophenes 71 could also obtained by this simple method [153]. 

Direct nucleophilic substitution on a thiophene ring is rather limited. It proceeds only with highly reactive substrates - thiophenes possessing strong electron-withdrawing groups like nitro - or with highly reactive nucleophiles. 

It was recognised early that halogenonitrothiophenes possess a higher reactivity to nucleophiles than the corresponding benzene derivatives [155]. Since then, nucleophilic substitutions of thiophenes have been well studied [156-161]. 

In most cases, nitrothiophenes or bromo-substituted nitrothiophenes have been used as the substrates for aromatic nucleophilic substitutiOTi. Both bromo and nitro groups can be substituted by oxygen, nitrogen or sulfur nucleophiles [156]. 

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