Efficient and Scalable Method for the Selective Alkylation and Acylation of Secondary Amines in the Presence of Primary Amines

Abstract

Selective substitution of secondary amines in the presence of primary amines is performed by using the reaction solvent, methyl isobutylketone (MIBK), as a temporary protecting group for the primary amine. After acylation or alkylation of the secondary amine, the resulting imine intermediate is smoothly hydrolysed, leading to the free primary amine in high yield and purity. This procedure represents a cheap and scalable alternative to multistep methods requiring several protections and deprotections.

Selective Protection of Secondary Amines as the N-Phenyltriazenes. Application to Aminoglycoside Antibiotics

“…1 In particular we were struck by the need for selective protection of disymmetric secondary amines 2 without complications of the NMR spectra by the presence of slowly interconverting conformers. The use of carbamates and amides affords rotamers and thus hinders routine spectral interpretation, 3 while sulphonamides require less than ideal conditions for eventual deprotection.…”

Synthesis, characterization, and evaluation of polyisobutylene‐based imido‐amine‐type dispersants containing exclusively non‐nucleophilic nitrogen

“…As shown in Scheme , the primary amine in 1‐(2‐aminoethyl)piperazine (AEP) was protected by reaction with excess methyl isobutyl ketone (MIBK) . The ketone served as both solvent and protecting group and formed a Schiff base with the primary amine while leaving the secondary amine unreacted.…”

“…First, protection of the primary amine group of 1-(2-aminoethyl)piperazine (AEP) was conducted as outlined by Laduron and coworkers. 33 To a 250 mL 3-neck round-bottom flask equipped with a magnetic stir bar, Dean-Stark apparatus, and nitrogen inlet/outlet were added 6.52 g (50.5 mmol) of AEP and 100 mL of methyl isobutyl ketone (MIBK). The solution was heated to reflux, upon which azeotropic distillation of water, indicative of imine formation, was observed.…”

“…As shown in Scheme 2, the primary amine in 1-(2-aminoethyl)piperazine (AEP) was protected by reaction with excess methyl isobutyl ketone (MIBK). 33 The ketone served as both solvent and protecting group and formed a Schiff base with the primary amine while leaving the secondary amine unreacted. Reaction of AEP with MIBK was monitored both qualitatively by the change in color of the reaction medium from light yellow to dark yellow as well as quantitatively by collection of the water by-product from imine formation in a Dean-Stark apparatus.…”

Evolution of the Process for the Preparation of a Selective ErbB VEGF Receptor Inhibitor

“…This allowed selective alkylation of a secondary amine present within the molecule. 20 Further precedence was garnered from the demonstration that (1R,2R)-2-aminocyclohexanol produces stable Schiff bases with benzaldehyde, in contrast to the (1R,2S)-2-aminocyclohexanol, which yields the oxazolidine (Scheme 12). 21 With this knowledge providing a degree of confidence, the first task at hand was selection of the appropriate aldehyde component.…”