Phase Separation As a Strategy Toward Controlling Dilution Effects in Macrocyclic Glaser-Hay Couplings

Abstract

Macrocycles are abundant in numerous chemical applications, however the traditional strategy for the preparation of these compounds remains cumbersome and environmentally damaging; involving tedious reaction set-ups and extremely dilute reaction media. The development of a macrocyclization strategy conducted at high concentrations is described which exploits phase separation of the catalyst and substrate, as a strategy to control dilution effects. Sequestering a copper catalyst in a highly polar and/or hydrophilic phase can be achieved using a hydrophilic ligand, T-PEG(1900), a PEGylated TMEDA derivative. Similarly, phase separation is possible when suitable copper complexes are soluble in PEG(400), a green and efficient solvent which can be utilized in biphasic mixtures for promoting macrocyclization at high concentrations. The latter phase separation technique can be exploited for the synthesis of a wide range of industrially relevant macrocycles with varying ring sizes and functional groups.

Macrocycles: lessons from the distant past, recent developments, and future directions

“…7 A clever solution that bypasses the need for slow-addition/high-dilution involves phase separation of the macrocyclization catalyst from its substrate. 8 An exhaustive treatment of the known methods of cyclization is not the goal of this perspective as it will be almost impossible to deliver an adequate discussion of all available methodologies. Most of these methods are merely performed with the goal of inducing intramolecular reactivity and are not conceptually different from linear molecule synthesis.…”

Gold-Catalyzed Oxidative Coupling of Alkynes toward the Synthesis of Cyclic Conjugated Diynes

“…A significant breakthrough of CCD synthesis was the recent work reported by Collins and coworkers using a phase-transfer system. 28–30 In their work, a mixture of MeOH and PEG-400 (4:1) was used to generate a heterogeneous bi-phasic reaction environment. Although the exact mechanism remains uncertain, they proposed that the bi-phase environment allowed the formation of a metal-acetylide at the solvent interface and prevented intermolecular polymerization.…”

Triphenylene discotic liquid crystal trimers synthesized by Co2(CO)8-catalyzed terminal alkyne [2 + 2 + 2] cycloaddition

“…The undec-10-yn-1-yl p -toluenesulfonate was prepared by LiAlH 4 reduction of the acid and tosylation of the alcohol [53–54]. Then monomers 2 and 3a–c were synthesized by the direct esterification or etherification reaction between phenol 1 and 10-undecynoic acid, undec-10-yn-1-yl p -toluenesulfonate, 5-chloro-1-pentyne, propargyl bromide, respectively.…”

“…All the other reagents and solvents were commercial products and used without further purification unless otherwise noted. 10-Undecyn-1-yl p -toluenesulfonate [53–54], 2-hydroxy-3,6,7,10,11-pentakis(pentyloxy)triphenylene [52] were synthesized as described in the reported methods.…”