A concise review covering updated presence and role of 2-phenethylamines in medicinal chemistry is presented. Open-chain, flexible alicyclic amine derivatives of this motif are enumerated in key therapeutic targets, listing medicinal chemistry hits and appealing screening compounds. Latest reports in discovering new bioactive 2-phenethylamines by research groups are covered too.

The concept of bioisostere replacement is of paramount importance in medicinal chemistry, as it can be employed as a rational to expand bioactive chemical space to tackle lead optimization issues like lack of potency, efficacy, and selectivity or pharmacokinetic/dynamic issues. One of the most important building blocks (in the sense of participating in a vast area of chemical space of biological importance) in medicinal chemistry is the 2-phenethyl moiety, a key component of diverse drug-like entities. Although the core 2-phenethylamine structure has been recognized by the drug discovery community, little attention has been given to the various ring-based rescaffolding procedures that can be conducted with this unit. In this regard, a review on the use of 2-heteroarylethylamines displaying pharmacological activity is reported. A detailed description of flexible, amine-opened motifs is provided, that describes therapeutic targets and other potent bioactive examples, which will be a valuable repository of phenyl, heteroaryl, and other replacement units of high value to the drug discovery community.

2-Arylethylamines are presented in several natural bioactive compounds, as well as in nitrogen-containing drugs. Their ability to surpass the blood–brain barrier makes this family of compounds of especial interest in medicinal chemistry. Asymmetric methodologies towards the synthesis of 2-arylethylamine motives are of great interest due to the challenges they may present. Thus, a concise metal-free review presenting recent advances in the asymmetric synthesis of 2-arylethylamines is presented, covering last-millennium studies, considering different methodologies towards the aforementioned motif, including chiral induction, organocatalysis, organophotocatalysis and enzymatic catalysis.

The 2-arylethylamine motif is very well-known in medicinal chemistry because of its interesting properties when it comes to interacting with the Central Neural System thanks to its ability to pass the blood–brain barrier. This nitrogen-containing family of compounds is of great interest in synthetic organic chemistry and, when it comes to its asymmetric synthesis, great challenges can be faced in order to obtain the chiral purity required in the drug industry. Thus, we provide a concise transition metal review presenting the recent advances in the synthesis of chiral 2-arylethylamines using transition metals as the main catalysts in the introduction of chirality. Both conventional and photocatalysis methods will be covered, considering the main transition metal used in the studies.

The preparation and characterization of a new chiral tertiary dibenzylamine are described. These molecules are well known in the literature for their high neuropharmacological potential. The general synthetic pathway is based on asymmetric Aza–Michael addition of chiral (R)-N-benzyl-N-(α-methylbenzyl)amide to methyl cyclohex-1-en-carboxilate obtaining the β-amino ester, followed by carboxylic acid hydrolysis and subsequent Barton descarboxylation. Interestingly, it is a general synthetic procedure of a wide range of chiral amines by careful choice of insaturated esters and alkylation of the chiral enolate in the initial reaction. The new tertiary dibenzylamine molecule is fully characterized by NMR Spectroscopy (¹H and ¹³C), as well by High-Resolution Mass Spectrometry and Infrared Spectroscopy.

(S)-N¹,N³-dibenzyl-1-cyclohexyl-N¹,N³-bis((R)-1-phenylethyl)propane-1,3-diamine was prepared in good yield by the reduction of the corresponding amide, which was obtained by the addition of a chiral lithium amide to an α,β-unsaturated ester. The target compound was fully characterized by NMR (¹H and ¹³C), high-resolution mass spectrometry and polarimetry.