Dehydration of primary amides to nitriles in water. Late-stage functionalization and 1-pot multistep chemoenzymatic processes under micellar catalysis conditions
Abstract:Palladium-catalyzed dehydration of primary amides to the corresponding nitriles can be performed in aqueous micelles, without need of significant volumes of organic co-solvent.
“…The hydrophobic pockets in these aggregates hold oleophilic substrates together to “dissolve” them in water, which can resolve the solubility issues of organic substrates in water . Therefore, commercially available surfactants such as sodium dodecyl sulfate (SDS), , hexadecyl trimethyl ammonium bromide (CTAB), , and polyoxyethylene 23 lauryl ether (Brij35) , and newly designed surfactants such as TPGS-750-M, − PS-750-M, − PTS, , and Nok , have been employed to promote a variety of reactions. The morphology of the aggregates is an important concern in the success of reactions because of the great relevance to solubilization and mass transfer of organic substrates.…”
Despite the wide utility of colloidal palladium (Pd) nanoparticle (NP)-catalyzed Suzuki−Miyaura cross-coupling reactions in laboratory and industrial synthesis, the easy construction of colloidal Pd NPs and the detailed role of surfactants remain the focus of attention. Here, we present a simple and sustainable strategy to construct a nanoreactor by connecting micelles with Pd NPs. The strategy enables us to employ a pH-induced morphological transition of sugar-based surfactant aggregates, such as worm-like, spherical, and tubular micelles, to investigate the solubilization of organic substrates. Pd NPs are mainly synthesized by the reduction of phenylboronic acid, further stabilized by the sugar-based surfactant micelles. A kinetic model is established, and the apparent activation energy of this reaction in aqueous micellar solutions is determined to be 46.7 kJ/mol. Notably, the recycled aqueous reaction mixture containing the micelles and Pd NPs can be reused.
“…The hydrophobic pockets in these aggregates hold oleophilic substrates together to “dissolve” them in water, which can resolve the solubility issues of organic substrates in water . Therefore, commercially available surfactants such as sodium dodecyl sulfate (SDS), , hexadecyl trimethyl ammonium bromide (CTAB), , and polyoxyethylene 23 lauryl ether (Brij35) , and newly designed surfactants such as TPGS-750-M, − PS-750-M, − PTS, , and Nok , have been employed to promote a variety of reactions. The morphology of the aggregates is an important concern in the success of reactions because of the great relevance to solubilization and mass transfer of organic substrates.…”
Despite the wide utility of colloidal palladium (Pd) nanoparticle (NP)-catalyzed Suzuki−Miyaura cross-coupling reactions in laboratory and industrial synthesis, the easy construction of colloidal Pd NPs and the detailed role of surfactants remain the focus of attention. Here, we present a simple and sustainable strategy to construct a nanoreactor by connecting micelles with Pd NPs. The strategy enables us to employ a pH-induced morphological transition of sugar-based surfactant aggregates, such as worm-like, spherical, and tubular micelles, to investigate the solubilization of organic substrates. Pd NPs are mainly synthesized by the reduction of phenylboronic acid, further stabilized by the sugar-based surfactant micelles. A kinetic model is established, and the apparent activation energy of this reaction in aqueous micellar solutions is determined to be 46.7 kJ/mol. Notably, the recycled aqueous reaction mixture containing the micelles and Pd NPs can be reused.
“…5 ) 15 . Although Pfizer’s approach to the dehydration of their primary amide relied on the Burgess reagent in chlorinated solvent 15 , 12 could alternatively be smoothly dehydrated applying recently disclosed technology based on an “amide exchange” 27 , 34 ; that is, using commercially available fluoroacetonitrile as the sacrificial acceptor of water under palladium-catalyzed conditions, resulting in nitrile 13 (93%). It is appreciated that fluoroacetonitrile may be undesirable owing to both its cost and the toxicity of the fluoroacetamide by-product.…”
Section: Resultsmentioning
confidence: 99%
“…The strategy selected for the synthesis of nirmatrelvir, therefore, focused on the inherent benefits on scale of a convergent route 26 . Moreover, it seemed advantageous to perform our palladium-catalyzed amide dehydration 27 in this convergent fashion, as subsequent steps provide opportunities to limit the amount of residual palladium in the final API. Fig.…”
Pfizer’s drug for the treatment of patients infected with COVID-19, Paxlovid, contains most notably nirmatrelvir, along with ritonavir. Worldwide demand is projected to be in the hundreds of metric tons per year, to be produced by several generic drug manufacturers. Here we show a 7-step, 3-pot synthesis of the antiviral nirmatrelvir, arriving at the targeted drug in 70% overall yield. Critical amide bond-forming steps utilize new green technology that completely avoids traditional peptide coupling reagents, as well as epimerization of stereocenters. Likewise, dehydration of a primary amide to the corresponding nitrile is performed and avoids use of the Burgess reagent and chlorinated solvents. DFT calculations for various conformers of nirmatrelvir predict that two rotamers about the tertiary amide would be present with an unusually high rotational barrier. Direct comparisons with the original literature procedures highlight both the anticipated decrease in cost and environmental footprint associated with this route, potentially expanding the availability of this important drug worldwide.
“…The product was recovered by extraction, dried with silica, and further purified by column chromatography. A yield of the biaryl product of 96% with >99% ee was achieved [ 152 ]. Building on these capabilities, chemoenzymatic tandem processes to achieve more complex nonracemic products has been pursued.…”
Reducing the use of solvents is an important aim of green chemistry. Using micelles self-assembled from amphiphilic molecules dispersed in water (considered a green solvent) has facilitated reactions of organic compounds. When performing reactions in micelles, the hydrophobic effect can considerably accelerate apparent reaction rates, as well as enhance selectivity. Here, we review micellar reaction media and their potential role in sustainable chemical production. The focus of this review is applications of engineered amphiphilic systems for reactions (surface-active ionic liquids, designer surfactants, and block copolymers) as reaction media. Micelles are a versatile platform for performing a large array of organic chemistries using water as the bulk solvent. Building on this foundation, synthetic sequences combining several reaction steps in one pot have been developed. Telescoping multiple reactions can reduce solvent waste by limiting the volume of solvents, as well as eliminating purification processes. Thus, in particular, we review recent advances in “one-pot” multistep reactions achieved using micellar reaction media with potential applications in medicinal chemistry and agrochemistry. Photocatalyzed reactions in micellar reaction media are also discussed. In addition to the use of micelles, we emphasize the process (steps to isolate the product and reuse the catalyst).
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
