Air- and Moisture-Stable Amphoteric Molecules: Enabling Reagents in Synthesis

Abstract

Researchers continue to develop chemoselective synthesis strategies with the goal of rapidly assembling complex molecules. As one appealing approach, chemists are searching for new building blocks that include multiple functional groups with orthogonal chemical reactivity. Amphoteric molecules that possess nucleophilic and electrophilic sites offer a versatile platform for the development of chemoselective transformations. As part of a program focused on new methods of synthesis, we have been developing this type of reagents. This Account highlights examples of amphoteric molecules developed by our lab since 2006. We have prepared and evaluated aziridine aldehydes, a class of stable unprotected α-amino aldehydes. Structurally, aziridine aldehydes include both a nucleophilic amine nitrogen and an electrophilic aldehyde carbon over the span of three atoms. Under ambient conditions, these compounds exist as homochiral dimers with an aziridine-fused five-membered cyclic hemiaminal structure. We have investigated chemoselective reactions of aziridine aldehydes that involve both the aziridine and aldehyde functionalities. These transformations have produced a variety of densely functionalized nitrogen-containing compounds, including amino aldehydes, 1,2-diamines, reduced hydantoins, C-vinyl or alkynyl aziridines, and macrocyclic peptides. We have also developed air- and moisture-stable α-boryl aldehydes, another class of molecules that are kinetically amphoteric. The α-boryl aldehydes contain a tetracoordinated N-methyliminodiacetyl (MIDA) boryl substituent, which stabilizes the α-metalloid carbonyl system and prevents isomerization to its O-bond enolate form. Primarily taking advantage of chemoselective transformations at the aldehyde functionality, these α-boryl aldehydes have allowed us to synthesize a series of new functionalized boron-containing compounds that are difficult or impossible to prepare using established protocols, such as α-borylcarboxylic acids, boryl alcohols, enol ethers, and enamides. Using α-borylcarboxylic acids as starting materials, we have also prepared several new amphoteric borylated reagents, such as α-boryl isocyanates, isocyanides, and acylboronates. These compounds are versatile building blocks in their own right, enabling the rapid synthesis of other boron-containing molecules.

Borylated oximes: versatile building blocks for organic synthesis

“…For instance, the major product of condensation with aniline is the N -boryl enamine, which is the result of a 1,3-migration of the boryl group from carbon-to-nitrogen. 24,25 This is in contrast to condensation with tert -butylsufinamide, where the C -boryl imine is the major product with N -boryl enamine as the byproduct. Boron migration from carbon-to-nitrogen leads to a decrease in hydrolytic stability and product decomposition.…”

Oxidative Difunctionalization of Alkenyl MIDA Boronates: A Versatile Platform for Halogenated and Trifluoromethylated α‐Boryl Ketones

“…[6] Despite their importance,t he preparation of organoborons is not trivial in organic synthesis and this is particularly true for multi-functionalized organoborons consisting of sensitive functional groups. [9] [7] Hence,t he formation of C-boron enolates (a-boryl carbonyls) provides ag reater challenge to the synthetic chemist.…”

“…[7] Hence,t he formation of C-boron enolates (a-boryl carbonyls) provides ag reater challenge to the synthetic chemist. [9] [9] …”

“…[8] However,t hey have potentially good synthetic value because they are kinetically amphoteric,m eaning that they contain an ucleophilic site adjacent to an electrophilic center (the nucleophilic boronate and the electrophilic carbonyl) and hence exhibit multiple modes of reactivity. [9] Generally,the formation of stable,isolable a-boryl carbonyls remains an underexplored area of research, despite the fact that they have been suggested or (in some cases) shown to be implicated as reactive intermediates in many transformations. [9] One of the simplest examples for the formation of aboryl ketones is the reaction of ylides and boranes (Figure 1a).…”

Synthesis of Previously Inaccessible Borylated Heterocycle Motifs Using Novel Boron‐Containing Amphoteric Molecules

“…[1] These bifunctional structures contain orthogonal nucleophilic and electrophilic functional groups that are stabilized against premature inter-and intramolecular reactions.Our main strategy has been to map nucleophilic carbon and nitrogen functional groups relative to carbon-oxygen double bonds.T he counting system shown in Scheme 1a llows us to refer to different amphoteric environments by enumerating the atoms that separate the nodes of opposing reactivity.The molecules developed thus far include 1,1-, 1,2-, and 1,3-systems. [1] These bifunctional structures contain orthogonal nucleophilic and electrophilic functional groups that are stabilized against premature inter-and intramolecular reactions.Our main strategy has been to map nucleophilic carbon and nitrogen functional groups relative to carbon-oxygen double bonds.T he counting system shown in Scheme 1a llows us to refer to different amphoteric environments by enumerating the atoms that separate the nodes of opposing reactivity.The molecules developed thus far include 1,1-, 1,2-, and 1,3-systems.…”