A practical method for the synthesis of gem-2,2-disubstituted tertiary amines from the corresponding lactams (or amides) is reported. It is based on the reaction of thioiminium ions, easily prepared from lactams and amides with organometallic reagents such allylmagnesium, benzylmagnesium, and primary alkylcerium reagents.

5-Bromo-2-nitropyridine was prepared from the corresponding amine via hydrogen peroxide oxidation in large scale production. This transformation initially showed low conversion, high impurity content and lack of reproducibility in lab trials. Parallel to process development, safety studies were conducted to investigate the stability of oxidant mixture, its composition and the oxidation reaction itself by reaction and adiabatic calorimetry. The resulting robust reaction conditions and appropriate safety boundaries allowed to develop a reproducible, safe protocol for the implementation of this chemistry on large scale, obtaining consistent results throughout the campaign.

Detailed process safety investigation of an old process revealed hidden, previously unnoticed danger. The synthesis of morpholine-adduct 2 was performed under reaction conditions very close to triggering a potentially dangerous runaway reaction. Process modifications such as dilution with an inert solvent allowed gaining better control of the process. Ultimately, improvement in both quality and yield was obtained.

General R 0010An Efficient Method to Convert Lactams and Amides into 2,2-Dialkylated Amines. -The lactams or amides are converted into thioiminium iodides which react with Grignard reagents or primary alkylcerium compounds to give gem-2,2-disubstituted tertiary amines. The bisallylated amines are converted into spirocyclic derivatives by ring-closing metathesis. -(AGOSTI, A.; BRITTO, S.; RENAUD*, P.; Org. Lett. 10 (2008) 7, 1417-1420; Inst. Chem. Biochem., Univ. Bern, CH-3012 Bern, Switz.; Eng.) -Klein 33-109 ,