Coupling of 1-alkyl-2-(bromomethyl)aziridines with heteroatom-centered nucleophiles towards 2-[(heteroatom)methyl]aziridines

The reactivity of 1-alkyl-2-(bromomethyl)aziridines with respect to different types of oxygen-, nitrogen- and sulphur-centered nucleophiles has been evaluated, pointing to the conclusion that these substrates can be applied successfully as synthetic equivalents for the aziridinylmethyl cation synthon towards the corresponding 2-[(heteroatom)methyl]aziridines in good yields

An update on the synthesis and reactivity of spiro-fused β-lactams

Beta-Lactam ring-containing compounds play a pivotal role in drug design and synthetic chemistry. Spirocyclic beta-lactams, representing an important beta-lactam subclass, have recently attracted considerable interest with respect to new synthetic methodologies and pharmacological applications. The aim of this manuscript is to review the recent progress made in this field, covering publications disseminated between 2011 to 2018 concerning the synthesis and application of spirocyclic beta-lactams. In the first part, new approaches to the synthesis of spirocyclic beta-lactams, including Staudinger synthesis, cyclization and transformation reactions, will be presented. The reactivity and biological properties of spiro-beta-lactams will be described in the second and third part, respectively

Microwave-assisted regioselective ring opening of non-activated aziridines by lithium aluminium hydride

A new synthetic protocol for the LiAlH4-promoted reduction of non-activated aziridines under microwave conditions was developed. Thus, ring opening of 2-(acetoxymethyl)aziridines provided the corresponding beta-amino alcohols, which were then used as eligible substrates in the synthesis of 5-methylmorpholin-2-ones via condensation with glyoxal in THF. The same procedure was applied for the preparation of novel 5(R)- and 5(S)-methylmorpholin-2-ones starting from the corresponding enantiopure 2-(hydroxymethyl)aziridines. Additionally, 2-(methoxymethyl)- and 2-(phenoxymethyl)aziridines were treated with LiAlH4 under microwave irradiation, giving rise to either isopropylamines or 1-methoxypropan-2-amines depending on the reaction conditions

Synthesis and reactivity of 4-(trifluoromethyl)azetidin-2-ones

Because of the beneficial effect of a trifluoromethyl group on the biological properties of bioactive compounds on the one hand and the versatile synthetic potential of beta-lactams on the other hand, 4-CF3-beta-lactams comprises interesting entities for the preparation of a large variety of CF3-substituted nitrogen-containing target structures with promising biological characteristics. In this review, we present an overview of different building block approach-based routes toward the synthesis of 4-(trifluoromethyl)azetidin-2-ones and the application of the "beta-lactam synthon method" for the synthesis of a diverse set of (a)cyclic CF3-substituted molecules by means of ring-opening and ring-transformation reactions

Rhodium-catalysed hydroformylation of N-(2-propenyl)-β-lactams as a key step in the synthesis of functionalised N-[4-(2-oxoazetidin-1-yl)but-1-enyl]acetamides

Biologically relevant functionalised N-[4-(2-oxoazetidin-1-yl)but-1-enyl]acetamides have been prepared in a two-step approach starting from N-(2-propenyl)-beta-lactams, involving initial rhodium-catalysed hydroformylation followed by subjection of the obtained aldehydes to Staudinger reaction conditions after initial imination

Intramolecular pi-pi stacking interactions in 2-substituted N,N-dibenzylaziridinium ions and their regioselectivity in nucleophilic ring-opening reactions

The ring opening of 2-substituted N,N-dibenzylaziridinium ions by bromide is known to occur exclusively at the Substituted aziridine carbon atom via ail S(N)2 mechanism, whereas the opposite regioselectivity has been observed as the main pathway for ring opening by fluoride. Similarly, the hydride-induced ring opening of 2-substituted N,N-dibenzylaziridinium ions has been shown to take place solely at the less hindered position. To gain insight into the main factors causing this difference in regioselectivity, a thorough and detailed computational analysis was performed on the hydride- and halide-induced ring openings of l-benzyl-l-(alpha-(R)-methylbenzyl)-2(S)-(phenoxymethyl)aziridinium bromide. Intramolecular pi-pi stacking interactions in the aziridinium System were investigated at a range of levels that enable a proper description of dispersive interactions; a T-stacking conformer was found to be the most stable. Ring-opening mechanisms were investigated with it variety of DFT and high level ab initio methods to test the robustness of the energetics along the pathway in terms of the electronic level of theory. The necessity to utilize explicit solvent molecules to solvate halide ions was clearly shown; the potential energy surfaces for nonsolvated and solvated cases differed dramatically. It was shown that in the presence of a kinetically viable route, product distribution will be dictated by the energetically preferred pathway; this was observed in the case of hard nucleophiles (both hydride donors and fluoride). However, For the highly polarizable soft nucleophile (bromide), it was shown that in the absence of a large energy difference between transition states leading to competing pathways, the formation of the thermodynamic product is likely to be the driving force. Distortion/interaction analysis on the transition states has shown a considerable difference in interaction energies for the solvated fluoride case, pointing to the fact that sterics plays a major role in the outcome, whereas for the bromide this difference was insignificant, suggesting bromide is less influenced by the difference in sterics