Recent Advances in the Protection of Amine Functionality: A Review

Abstract

Selective protection of −NH2 functionality has enormous utility and significance in organic synthesis. Amines are nucleophile and basic in nature thus vulnerable to react with an extensive range of reagents, especially oxidizing, alkylating, and carbonyl compounds and therefore can require protection to mask these properties in the multifunctional molecule during chemical reactions. Protection of amine functionality finds important application in peptide synthesis, thus several methodologies have been developed for N‐Protection reaction. Herein, we have reviewed recent advances in the protection of amines (from 2012 till present) in the hope that this will update the current body of knowledge and aid researchers working in this area.

The Discovery of GSK3640254, a Next-Generation Inhibitor of HIV-1 Maturation

“…While the C-17 amine 11 can be obtained in a one-pot reaction from betulinic acid ( 2 ), the Curtius rearrangement of 2 to afford 11 was performed in a stepwise fashion in order to optimize the yield of the transformation. The isocyanate 10 was prepared under standard conditions by heating 2 with diphenylphosphoryl azide (DPPA) in the presence of triethylamine (TEA) in 1,4-dioxane at 100 °C for 26 h with subsequent hydrolysis of 10 accomplished by heating with HCl in 1,4-dioxane at 60 °C for 15 h. − The C-17 amine of 11 was protected by exposure to Boc 2 O, which allowed oxidation of the C-3 alcohol with pyridinium chlorochromate (PCC) to afford 12 . − The C-3 ketone of 12 was converted to the corresponding enol triflate under standard conditions by exposure to PhNTf 2 in the presence of potassium hexamethyldisilazane (KHDMS) in THF at −78 °C. , Subsequent treatment with trifluoroacetic acid (TFA) to unmask the C-17 amine rendered the key intermediate 13 . Alkylation of 13 with 1-(2-chloroethyl)-4-(methylsulfonyl)­piperidine using K 3 PO 4 in the presence of KI at 120 °C afforded 14 , while 15 was obtained from 13 by heating with 2-(1,1-dioxidothiomorpholino)­ethyl­methane­sulfonate and N , N -diisopropyl­ethyl­amine (DIPEA) at 40 °C. − A Suzuki–Miyaura coupling of either 14 or 15 with a boronic ester was followed by unmasking of the carboxylic under basic conditions to provide the targeted final products 9 and 17 – 41 . , …”

“…4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR 3,3a,4,5,5a,5b,6,7,7a,8,11,11a, 11b,12,13,13a,13b- (39). The residue was isolated and purified by prep HPLC (method 8) to give a white solid (99% yield).…”

A Combined Spectroscopic and Computational Study on the Mechanism of Iron-Catalyzed Aminofunctionalization of Olefins Using Hydroxylamine Derived N–O Reagent as the “Amino” Source and “Oxidant”

“… 12 − 18 However, most of the methods developed thus far lead to the installation of a protected form of the amino group, requiring additional and often challenging protecting group manipulations. 19 Moreover, synthesis of unprotected amino functionality poses another serious challenge of product coordination to the metal catalysts, thereby, leading to catalyst deactivation.…”

“…An attractive approach to address this challenge is the direct catalytic amination of organic molecules and has been the subject of intense research efforts. − Nevertheless, most synthetic procedures involve toxic, explosive and/or expensive chemicals and intermediates and, therefore, are not in line with the principles of green chemistry . Inspired by the widely studied iron-based enzymes, biomimetic complexes have opened new avenues for the oxidation and amination of organic substrates. − However, most of the methods developed thus far lead to the installation of a protected form of the amino group, requiring additional and often challenging protecting group manipulations . Moreover, synthesis of unprotected amino functionality poses another serious challenge of product coordination to the metal catalysts, thereby, leading to catalyst deactivation.…”

Ruthenium‐Catalyzed Secondary Amine Formation Studied by Density Functional Theory

“…Accordingly, alcohols are employed as alkylating reagent and the entire concept relies on the use of the well-elaborated reaction portfolio of the carbonyl group. [26,27] Upon catalytic dehydrogenation of the alcohol a carbonyl group and a metal hydride are generated in small amounts. The former undergoes a fast condensation reaction, e. g., with an amine to form an imine and water as by-product.…”