An isocyanide ligand for the rapid quenching and efficient removal of copper residues after Cu/TEMPO-catalyzed aerobic alcohol oxidation and atom transfer radical polymerization

Abstract

Transition metal catalysts play a prominent role in modern organic and polymer chemistry, enabling many transformations of academic and industrial significance. However, the use of organometallic catalysts often requires the removal of their residues from reaction products, which is particularly important in the pharmaceutical industry. Therefore, the development of efficient and economical methods for the removal of metal contamination is of critical importance. Herein, we demonstrate that commercially available 1,4-bis(3-isocyanopropyl)piperazine can be used as a highly efficient quenching agent (QA) and copper scavenger in Cu/TEMPO alcohol aerobic oxidation (Stahl oxidation) and atom transfer radical polymerization (ATRP). The addition of QA immediately terminates Cu-mediated reactions under various conditions, forming a copper complex that can be easily separated from both small molecules and macromolecules. The purification protocol for aldehydes is based on the addition of a small amount of silica gel followed by QA and filtration. The use of QA@SiO 2 synthesized in situ results in products with Cu content usually below 5 ppm. Purification of polymers involves only the addition of QA in THF followed by filtration, leading to polymers with very low Cu content, even after ATRP with high catalyst loading. Furthermore, the addition of QA completely prevents oxidative alkyne-alkyne (Glaser) coupling.Although isocyanide QA shows moderate toxicity, it can be easily converted into a non-toxic compound by acid hydrolysis. Scheme 1 (A) Mechanism of Cu/TEMPO alcohol aerobic oxidation (Stahl oxidation). (B) Mechanism of Cu-catalyzed normal ATRP and low-ppm ATRP in the presence of excess reducing agents. 4252 | Chem. Sci., 2020, 11, 4251-4262 This journal isFig. 3 QA reactivity towards the [Cu II (TPMA)Br] + . (A) UV-vis spectra of [Cu II Br 2 ] ¼ 2.5 mM; [TPMA] ¼ 2.5 mM in DMSO at 22 C in air. (B) UV-vis spectra of copper complex after addition of QA (4 equiv.). (C) UV-vis spectra of copper complex after addition of QA (4 equiv.) and AA (10 equiv.). This journal is a Reaction conditions: [monomer]/[EBiB]/[Cu II Br 2 ]/[Me 6 TREN] ¼ 200/1/0.05/0.25 in MeCN, ([MA] ¼ 7.4 M, [nBA] ¼ 4.7 M, [tBA] ¼ 4.6 M, [MMA] ¼ 6.2 M) at 22 C. b Monomer conversion was determined by using 1 H NMR spectroscopy. c Theoretical molecular weight was calculated using the equation M n,th ¼ [M] Â MW M Â a + MW EBiB , where [M], MW M , a, and MW EBiB correspond to initial monomer concentration, molar mass of monomer, conversion, and molar mass of EBiB initiator, respectively. d Molecular weight and dispersity (Đ) were determined by GPC analysis (THF as eluent) calibrated to poly(methyl methacrylate) standards. e Equivalents of QA with respect to Cu II Br 2 . f Copper content was determined by ICP-MS. g ARGET ATRP: ascorbic acid (5 equiv. with respect to Cu II Br 2 ), under anaerobic conditions. h SARA ATRP: 4 cm Cu(0) wire (d ¼ 1 mm, S ¼ 1.27 cm 2 ), under anaerobic conditions. i pATRP: UV irradiation (l ¼ 365 nm), under anaerobic conditions. j pAT...

Principles and Characteristics of Polymerization-Induced Self-Assembly with Various Polymerization Techniques

“…81 Another recent study described a method that utilizes a "Cu scavenger", followed by filtration, on a polymer solution. 82 Nonetheless, such procedures are demanding and would require cross-linked nanoparticles.…”

Large‐Scale Synthesis of a Niche Olefin Metathesis Catalyst Bearing an Unsymmetrical N‐Heterocyclic Carbene (NHC) Ligand and its Application in a Green Pharmaceutical Context

“…For example, the purification procedure consisted of dissolving the crude product (1697 ppm of Ru) in 10 %a queous solution of NaOH at 80 8C, treatment with activated charcoal and precipitationb yd rop-wise addition of concentrated HCl, whichl ed to ap roduct containing 11 ppm of Ru, so actually more than in the case where product 47 precipitated freely after the reaction. An alternative purification protocol, consisting of use of as cavenger developed in our laboratories [41] led to 9.6 ppm of Ru (Table2,e ntry 5).…”

Olefin Metathesis in Continuous Flow Reactor Employing Polar Ruthenium Catalyst and Soluble Metal Scavenger for Instant Purification of Products of Pharmaceutical Interest

“… 33 Building on this foundational concept, we developed a scavenger incorporating two isocyanide groups that can bind efficiently to ruthenium metal, hence reducing the ruthenium content to less than 1 ppm with the usage of minimal amount of silica gel. 22 , 34 − 36 …”

“…In 2007, Diver’s group synthesized a scavenger which contains an isocyanide group that can bind to residual ruthenium allowing for easier product purification via column chromatography . Building on this foundational concept, we developed a scavenger incorporating two isocyanide groups that can bind efficiently to ruthenium metal, hence reducing the ruthenium content to less than 1 ppm with the usage of minimal amount of silica gel. ,− …”

“…Herein, we report a highly efficient ring-closing metathesis (RCM) in flow that uses the commercially available homogeneous StickyCat PF 6 catalyst and SnatchCat scavenger (1,4-bis­(3-isocyanopropyl)­piperazine) ,− to continuously produce advanced functionalized products, resembling in their complexity selected API substances, with low ruthenium content. With this system, without ethylene removal, we conducted a number of RCM reactions of highly functionalized substrates and managed to upscale the flow process to produce 62 g of a Sildenafil analogue in 24 h with a very low ruthenium content of 0.5 ppm with an environmental-friendly green solvent, ethyl acetate.…”