A practical synthesis of N-alkyl-N-arylputrescines and cadaverines

Selectively N-substituted 1,4-diaminobutane (putrescine) and 1,5-diaminopentane (cadaverine) derivatives are of biochemical and pharmacological interest as synthetic analogs of natural polyamines. Several derivatives have been described acting as antibiotics, antineoplastics, antiparasitic agents, and NMDA or cholinergic modulators. In addition, such compounds represent key intermediates for acyclic and heterocyclic polyamine derivatives.N-Aryl putrescines and cadaverines represent a challenge, since the available methods for di and trimethylenediamines are not generally suitable for their higher homologs. The literature regarding N-alkyl-N-arylputrescines and cadaverines is even scarcer.N-Alkylation is conceptually the most straightforward disconnection towards tertiary amines. Although this transformation seems rather simple, the fact that the newly formed amines are also nucleophilic brings about bis and/or polyalkylation byproducts. Therefore, improvement in the selectivity of the reaction would increase the chemical yields and lead to easier purification protocols.In this work we present a practical method for the synthesis of tertiary N-aryltetra and pentamethylenediamines, by selective monoalkylation of N-alkylanilines followed by reduction. The optimized reaction conditions resulted in a simplified procedure, remarkable selectivity in the alkylation step and high global yields of the diamines. We examined in the first place the synthesis of N-methyl-N-phenylputrescine using different reaction conditions (solvent, base, molar ratios) for the N-alkylation step. The best results were obtained using K₂CO₃ as the base, DMF as the solvent and a molar ratio 2:1 between arylamine and halonitrile. In such conditions, selectivity toward the N-alkylation product was complete, allowing for the direct reduction of the crude aminolysis product.    Employing the optimized experimental conditions, a series of N-aryl-N-alkyl cadaverines and putrescines were prepared in high overall yields (64-87%). The sequence employs readily available and inexpensive starting materials, involves two steps and one column purification and represents an advantageous alternative to other synthetic approaches.