Environmentally Responsible and Cost-Effective Synthesis of the Antimalarial Drug Pyronaridine.

Two routes to the antimalarial drug Pyronaridine are described. The first is a linear sequence that includes a two-step, one-pot transformation in an aqueous surfactant medium, leading to an overall yield of 87%. Alternatively, a convergent route utilizes a telescoped three-step sequence involving an initial neat reaction, followed by two steps performed under aqueous micellar catalysis conditions affording Pyronaridine in 95% overall yield. Comparisons to existing literature performed exclusively in organic solvents reveal a 5-fold decrease in environmental impact as measured by E Factors.

High Turnover Pd/C Catalyst for Nitro Group Reductions in Water. One-Pot Sequences and Syntheses of Pharmaceutical Intermediates.

Commercially available Pd/C can be used as a catalyst for nitro group reductions with only 0.4 mol % Pd loading. The reaction can be performed using either silane as a transfer hydrogenating agent or simply a hydrogen balloon (∼1 atm pressure). With this technology, a series of nitro compounds was reduced to the desired amines in high chemical yields. Both the catalyst and surfactant were recycled several times without loss of reactivity.

Copper-Catalyzed Asymmetric Reductions of Aryl/Heteroaryl Ketones under Mild Aqueous Micellar Conditions.

Enantioselective syntheses of nonracemic secondary alcohols have been achieved in an aqueous micellar medium via copper-catalyzed (Cu(OAc)2·H2O/(R)-3,4,5-MeO-MeO-BIPHEP) reduction of aryl/heteroaryl ketones. This methodology serves as a green protocol to access enantio-enriched alcohols under mild conditions (0-22 °C) using a base metal catalyst, together with an inexpensive, innocuous, and convenient stoichiometric hydride source (PMHS). The secondary alcohol products are formed in good to excellent yields with ee values greater than 90%.

A sustainable approach towards the three-component synthesis of unsubstituted 1H-imidazoles in the water at ambient conditions.

A green protocol for the synthesis of unsubstituted imidazoles has been demonstrated herein. The reaction is realized using commercially available lipase enzyme, porcine pancreas lipase (PPL) in water. The reaction conditions are selective and mild which helped to tolerate a wide variety of functional groups to give the desired products in good chemical yields.[Formula: see text].

Mild and Robust Stille Reactions in Water using Parts Per Million Levels of a Triphenylphosphine-Based Palladacycle.

An inexpensive and new triphenylphosphine-based palladacycle has been developed as a pre-catalyst, leading to highly effective Stille cross-coupling reactions in water under mild reaction conditions. Only 500-1000 ppm of Pd suffices for couplings involving a variety of aryl/heteroaryl halides with aryl/hetaryl stannanes. Several drug intermediates can be prepared using this catalyst in aqueous nanoreactors formed by 2 wt % Brij-30 in water.

Chemoselective Reductive Aminations in Aqueous Nanoreactors Using Parts per Million Level Pd/C Catalysis.

Condensation in recyclable water between aldehydes or ketones and amines occurs smoothly within the hydrophobic cores of nanomicelles, resulting in imine formation that is subject to subsequent reduction leading, overall, to reductive amination. This micellar technology enables the synthesis of several types of pharmaceuticals, a new procedure that relies on only 2000 ppm (0.20 mol %) palladium from commercially available Pd/C. A broad range of substrates can be used under mild conditions, leading to high chemical yields of the desired secondary and tertiary amines.

Sustainable and Cost-Effective Suzuki-Miyaura Couplings toward the Key Biaryl Subunits of Arylex and Rinskor Active.

Challenging Suzuki-Miyaura cross couplings associated with novel crop protection active ingredients from Corteva Agriscience, Arylex and Rinskor, can be performed in water using parts per million (ppm) levels of a Pd catalyst. Each coupling required a distinct set of reaction conditions to achieve maximum selectivities and chemical yields. By way of comparison, this chemistry is not only performed under environmentally responsible aqueous micellar conditions, but also involves lowering loadings (3-5 times) of endangered palladium than used previously to attain a more sustainable process.

Recent advances in Cu-catalyzed C(sp3)-Si and C(sp3)-B bond formation.

Numerous reactions generating C-Si and C-B bonds are in focus owing to the importance of incorporating silicon or boron into new or existing drugs, in addition to their use as building blocks in cross-coupling reactions en route to various targets of both natural and unnatural origins. In this review, recent protocols relying on copper-catalyzed sp3 carbon-silicon and carbon-boron bond-forming reactions are discussed.

A new, substituted palladacycle for ppm level Pd-catalyzed Suzuki-Miyaura cross couplings in water.

A newly engineered palladacycle that contains substituents on the biphenyl rings along with the ligand HandaPhos is especially well-matched to an aqueous micellar medium, enabling valued Suzuki-Miyaura couplings to be run not only in water under mild conditions, but at 300 ppm of Pd catalyst. This general methodology has been applied to several targets in the pharmaceutical area. Multiple recyclings of the aqueous reaction mixture involving both the same as well as different coupling partners is demonstrated. Low temperature microscopy (cryo-TEM) indicates the nature and size of the particles acting as nanoreactors. Importantly, given the low loadings of Pd invested per reaction, ICP-MS analyses of residual palladium in the products shows levels to be expected that are well within FDA allowable limits.

Sustainable ppm level palladium-catalyzed aminations in nanoreactors under mild, aqueous conditions.

A 1 : 1 Pd : ligand complex, [t-BuXPhos(Pd-π-cinnamyl)]OTf, has been identified as a highly robust pre-catalyst for amination reactions leading to diarylamines, where loadings of metal are typically at 1000 ppm Pd, run in water at temperatures between rt and 45 °C. The protocol is exceptionally simple, is readily scaled, and compares very favorably vs. traditional amination conditions. It has also been shown to successfully lead to key intermediates associated with several physiologically active compounds.

Structure of Nanoparticles Derived from Designer Surfactant TPGS-750-M in Water, As Used in Organic Synthesis.

Using density functional theory and the COSMO-RS implicit solvent model, we predict the structure and physical chemical properties of nanomicelles derived from the designer surfactant TPGS-750-M used in organic synthesis. We predict that the influence of chain length of the PEG region is low, while the termination of the PEG chain (-OH vs.-OCH3 ) plays a very large role. The interfacial tension is considerably lower between the micellar and water phases for the -OH than the -OCH3 terminated surfactant, and our calculations reproduce the large difference observed in average particle size as a function of PEG chain termination. We propose a structure for the nanoparticles formed by TPGS-750-M in water that is consistent with a ≈50 nm average diameter, which is significantly larger than a single micelle. According to the calculations, each nanoparticle would consist of 30-40 aggregated TPGS-750-M micelles forming a compartmentalized nanoparticle, with considerable amounts of water in the PEG region. The whole particle is stabilized by vitamin E succinate at the nanoparticle-water interface. In the presence of Zn dust or powder, the surfactant collides with the Zn surface, and by interactions with the hydrophobic inner cores, form organozinc species that are protected from the surrounding water. This explains why highly moisture-sensitive Negishi-like couplings take place in surfactant-water systems.

Sustainable HandaPhos-ppm Palladium Technology for Copper-Free Sonogashira Couplings in Water under Mild Conditions.

Complexation of ca. 1000 ppm Pd(OAc)2 with the ligand HandaPhos (1-1.5:1) leads to a precatalyst that efficiently mediates Sonogashira couplings in aqueous nanomicelles under very mild conditions. Neither copper nor organic solvent is required in the reaction medium, and the product can be isolated directly from the reaction flask, leaving behind a reaction mixture that can be recycled without additional additives.

Unsupported Nanoporous Gold Catalyst for Chemoselective Hydrogenation Reactions under Low Pressure: Effect of Residual Silver on the Reaction.

For the first time, H-H dissociation on an unsupported nanoporous gold (AuNPore) surface is reported for chemoselective hydrogenation of C≡C, C═C, C═N, and C═O bonds under mild conditions (8 atm H2 pressure, 90 °C). Silver doping in AuNPore, which was inevitable for its preparation through a process of dealloying of Au-Ag alloy, exhibited a remarkable difference in catalytic activity between two catalysts, Au>99Ag1NPore and Au90Ag10NPore.The former was more active and the latter less active in H2 hydrogenation, while the reverse tendency was observed for O2 oxidation. This marked contrast between H2 reduction and O2 oxidation is discussed. Further, Au>99Ag1NPore showed a high chemoselectivity toward reduction of terminal alkynes in the presence of internal alkynes which was not achieved using supported gold nanoparticle catalysts and other previously known methods. Reductive amination, which has great significance in synthesis of amines due to its atom-economical nature, was also realized using Au>99Ag1NPore, and the Au>99Ag1NPore/H2 system showed a preference for the reduction of aldehydes in the presence of imines. In addition to this high chemoselectivity, easy recovery and high reusability of AuNPore make it a promising heterogeneous catalyst for hydrogenation reactions.

Chemoselective reduction of α,ß-unsaturated aldehydes using an unsupported nanoporous gold catalyst.

The remarkable effect of an unsupported nanoporous gold catalyst (AuNPore) on chemoselective hydrogenation of α,ß-unsaturated aldehydes using silane has been described. Enals can be reduced with excellent selectivity, giving the corresponding allylic alcohols in good to high chemical yields.

Exclusive chemoselective reduction of imines in the coexistence of aldehydes using AuNPore catalyst.

Aldimines (R(1)HC═NR(2)) were reduced in the coexistence of aldehydes (R(1)CHO) with 100% chemoselectivity by the use of AuNPore giving corresponding amines (R(1)H2C-NHR(2)) in high chemical yields.

Gold nanoparticle (AuNPs) and gold nanopore (AuNPore) catalysts in organic synthesis.

Organic synthesis using gold has gained tremendous attention in last few years, especially heterogeneous gold catalysis based on gold nanoparticles has made its place in almost all organic reactions, because of the robust and green nature of gold catalysts. In this context, gold nanopore (AuNPore) with a 3D metal framework is giving a new dimension to heterogeneous gold catalysts. Interestingly, AuNPore chemistry is proving better than gold nanoparticles based chemistry. In this review, along with recent advances, major discoveries in heterogeneous gold catalysis are discussed.