Macrocyclization Reactions at High Concentration (≥0.2M): The Role of Catalysis

Abstract

The synthesis of macrocycles is fundamental to obtain useful quantities of this unique family of organic compounds. However, most current syntheses still require highly diluted conditions (generally < 0.1M), which makes the synthesis extremely inefficient in the reactor volume. Here we review, quantify, and analyze the few synthetic methods for macrocycles reported so far where the reaction solution is at ≥ 0.2 M concentration. Parametrization of the results with the Emac (efficiency macrocyclization) index unveils that catalytic methods are much more efficient than non-catalyzed methods. Beyond this conclusion, the present study also shows clear evidence that high-concentration macrocyclization reactions are not only possible but necessary, and suggests the use of catalytic reactions, including solid catalysts and in-flow reactions, to develop macrocyclization reactions under high concentration conditions.

Quinoxaline-based azamacrocycles: synthesis, AIE behavior and acidochromism

“…Among the results reported above the reaction with bis(2-aminoethyl)amine (N 3 C 4 ) drew our attention because of the almost quantitative yield (92%) obtained in the runs using PhPF- t Bu ligand. Macrocyclizations driven by transition metal catalyzed (TMC) reaction can give yields above 50, sometimes even 70–75%, 63,76,77 but extremely rarely any higher. Similar or even lower yields are typical for successive formation of macrocycles through reactions which do not need in TMC.…”

“…Our synthetic strategy to prepare macrocycles N 2 C n O x Q and N y C n Q relies on a transition metal-catalyzed macrocyclization reaction in which linear diamines with N and O atoms in the alkyl chain become linkers between two aryl residues of the quinoxaline backbone, as depicted in Scheme 1. [61][62][63] The main step of this strategy involves two consecutive Buchwald-Hartwig amination reactions performed in a one-pot fashion.…”

Alkene Cross‐Metathesis with 2,5‐Dimethyl‐2,4‐Hexadiene Enables Isobutylenyl/Prenyl Functionalizations and Rubber Valorization

“…The alkene cross-metathesis reaction has become an indispensable tool in modern organic synthesis, with application in complex product and polymer synthesis, to name a few. [1][2][3] The resulting alkenes find applications, for instance, as lubricants, plasticizers, cosmetics or insecticides, [4][5][6][7][8][9] and industry relies more and more in the cross-metathesis reactions for chemical production. [10,11] However, the synthesis of well-defined tertiary and quaternary alkenes is still undeveloped respect to secondary ones, which is particularly worrying considering that some of the most abundant functional groups in natural products are isobutylenyl and prenyl alkenes.…”