Multigram Synthesis Research Articles

Iron-polyphenol nanomaterial removes fluoride and methylene blue dye from water and promotes plant growth

Iron-Polyphenols are attractive as adsorbents as polyphenols are abundant in plants and tend to form high-surface-area nanoparticles with metal. However, reports on the large-scale synthesis and adsorption properties are rather limited. We are reporting a multi-gram scale synthesis of a nanostructured material from tannic acid and iron(II) salt. Tannic acid (TA) is a plant polyphenol available in abundant quantities. Analysis and spectroscopic studies of the material confirm the composition as a Fe(III) complex of TA (Fe: TA ~ 9:1) with 25% of iron is in the divalent state. The material has a relatively high surface area (99.6 m2/g). It adsorbs both anionic fluoride and cationic methylene blue (MB) from aqueous solutions. It adsorbs 66% fluoride from contaminated natural water at pH ~7 (C0 4.4 mg/L, dose 3 g/L). It removes 99% methylene blue (MB) dye from an aqueous solution at pH 7 (C0 150 mg/L, dose 4 g/L). The equilibrium study and salt addition experiments suggest that the fluoride removal depends on surface charge and binding with iron. MB can be desorbed using salts of cations with a higher charge. Several reports showed that materials from plant sources could be harmful to plant growth, thereby limiting the use of the adsorbent. We found that tannic acid alone stunts the growth of Mung bean (Vigna radiata) plants, but plants did show significant growth when grown with the material reported here (shoot, 155%, root 200%, twice daily 1 mL of 1 mg/mL).

Front Cover: Fluorine‐Containing sp3‐Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents (Eur. J. Org. Chem. 15/2022)

The Front Cover shows examples of fluoro-substituted pyrazoles and pyrimidines with saturated heterocyclic substituents – advanced building blocks for organic and medicinal chemistry synthesized by a group of chemists from Kyiv, Ukraine. An efficient approach to the multigram preparation of sp3-enriched fluorinated building blocks bearing protected azetidine, pyrrolidine, piperidine, or cyclohexanone moieties and transformations of these useful intermediates into the nitrogen heterocycles mentioned above are described. The authors thank Mr. Andriy Yakymenko for the photo of rapeseed fields used as a background, Mr. Bohdan Vaschenko and Ms. Vladyslava Prykhodko for their help with picture preparation. More information can be found in the Research Article by O. O. Grygorenko et al.

4-Nitropyrazolin-5-ones as Readily Available Fungicides of the Novel Structural Type for Crop Protection: Atom-Efficient Scalable Synthesis and Key Structural Features Responsible for Activity.

The development of new types of fungicides for agriculture and medicine is highly desirable due to the uprising fungal resistance against commonly used compounds. Herein, 4-substituted-4-nitropyrazolin-5-ones (nitropyrazolones) were proposed as highly active fungicides of the novel structural type. The first scalable and practical method for the nitropyrazolone synthesis was proposed, which is atom-efficient, is applicable for the multigram scale synthesis, and allows for production of a wide variety of nitropyrazolones with high yields and purity. The synthesized compounds demonstrated high fungicidal activity against the broad spectrum of phytopathogenic fungi (Venturia inaequalis, Rhizoctonia solani, Fusarium oxysporum, Fusarium moniliforme, Bipolaris sorokiniana, and Sclerotinia sclerotiorum). Their mycelium growth inhibiting activity was comparable or superior to that of kresoxim-methyl. In vitro activity against Staphyloccocus aureus, Candida albicans, and Aspergillus niger revealed that nitropyrazolones are promising candidates against human pathogens. The key factors for the manifestation of high fungicidal activity were established to be an aromatic substituent on the N1 atom and small substituents, such as methyl, at the C3 and C4 positions of the pyrazolone ring.

Fluorine‐Containing sp3‐Enriched Building Blocks for the Multigram Synthesis of Fluorinated Pyrazoles and Pyrimidines with (Hetero)aliphatic Substituents

AbstractEfficient approaches to the gram‐scale synthesis of fluorinated pyrazoles and pyrimidines bearing saturated (hetero)cyclic substituents are described. The methods rely on the heterocyclizations of sp3‐enriched β‐bromo‐α,α‐difluoroketones and fluorinated enaminones (in turn prepared from saturated heterocyclic α‐fluoroketones), respectively; these compounds themselves are useful synthetic intermediates that have been prepared on multigram scale for the first time. LogP and aqueous solubility measurements, as well as lead‐likeness assessment using the Nelson's LLAMA tool show that the 19 synthesized sp3‐enriched fluorinated building blocks meet the lead‐oriented synthesis criteria.

Pushing the Limits on the Intestinal Crossing of Metal-Organic Frameworks: An Ex Vivo and In Vivo Detailed Study.

Biocompatible nanoscaled metal–organic frameworks (nanoMOFs) have been widely studied as drug delivery systems (DDSs), through different administration routes, with rare examples in the convenient and commonly used oral administration. So far, the main objective of nanoMOFs as oral DDSs was to increase the bioavailability of the cargo, without considering the MOF intestinal crossing with potential advantages (e.g., increasing drug availability, direct transport to systemic circulation). Thus, we propose to address the direct quantification and visualization of MOFs’ intestinal bypass. For that purpose, we select the microporous Fe-based nanoMOF, MIL-127, exhibiting interesting properties as a nanocarrier (great biocompatibility, large porosity accessible to different drugs, green and multigram scale synthesis, outstanding stability along the gastrointestinal tract). Additionally, the outer surface of MIL-127 was engineered with the biopolymer chitosan (CS@MIL-127) to improve the nanoMOF intestinal permeation. The biocompatibility and intestinal crossing of nanoMOFs is confirmed using a simple and relevant in vivo model, Caenorhabditis elegans; these worms are able to ingest enormous amounts of nanoMOFs (up to 35 g per kg of body weight). Finally, an ex vivo intestinal model (rat) is used to further support the nanoMOFs’ bypass across the intestinal barrier, demonstrating a fast crossing (only 2 h). To the best of our knowledge, this report on the intestinal crossing of intact nanoMOFs sheds light on the safe and efficient application of MOFs as oral DDSs.

Correction to “Multigram Synthesis of Tetrasubstituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow”

Correction to “Multigram Synthesis of Tetrasubstituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow”

Synthesis of α-Aryldiazophosphonates via a Diazo Transfer Reaction.

The simple synthetic procedure for preparation of α-aryl-α-diazophosphonates via a diazo transfer reaction is proposed. Benzylphosphonates reacted with tosyl azide (TsN3) in the presence of potassium tert-butoxide (KOtBu) to afford diazophosphonates in a yield up to 79%. The proposed method is general. The reaction uses easily available starting materials, tolerates various functional groups, and may be applied for multi-gram scale synthesis.

An Optimized Synthesis of Fmoc-l-Homopropargylglycine-OH.

An efficient multigram synthesis of alkynyl amino acid Fmoc-l-homopropargylglycine-OH is described. A double Boc protection is optimized for high material throughput, and the key Seyferth-Gilbert homologation is optimized to avoid racemization. Eighteen grams of the enantiopure (>98% ee) noncanonical amino acid was readily generated for use in solid phase synthesis to make peptides that can be functionalized by copper-assisted alkyne-azide cycloaddition.

Multigram scale preparation of a semi-synthetic N-trifluoroacetyl protected chondroitin disaccharide building block: Towards the stereoselective synthesis of chondroitin sulfates disaccharides

The chemoselective N-trifluoroacetylation of a chondroitin disaccharide obtained from controlled acid hydrolysis of a commercially available polymeric chondroitin sulfate is reported for the first time. We also described the multi-gram scale synthesis of a donor block having a benzylidene moiety further used for the expeditious and stereocontrolled synthesis of glycosides fitted with various aglycons. Stereocontrolled β-glycosylation, sulfation and efficient N-TFA deprotection steps afforded the desired disaccharides in good yields.

Controlled and Predictably Selective Oxidation of Activated and Unactivated C(sp3)-H Bonds Catalyzed by a Molybdenum-Based Metallomicellar Catalyst in Water.

The synthesis of carbonyl derivatives from renewable feedstocks, by direct oxidation/functionalization of activated and unactivated C(sp3)-H bonds under a controlled and predictably selective fashion, especially in late stages, remains a formidable challenge. Herein, for the first time, cost-effective and widely applicable protocols for controlled and predictably selective oxidation of petroleum waste and feedstock ingredients like methyl-/alkylarenes to corresponding value-added carbonyls have been developed, using a surfactant-based oxodiperoxo molybdenum catalyst in water. The methodologies use hydrogen peroxide (H2O2) as an environmentally benign green oxidant, and the reactions preclude the need of any external base, additive, or cocatalyst and can be operated under mild eco-friendly conditions. The developed protocols show a wide substrate scope and eminent functional group tolerance, especially oxidation-liable and reactive boronic acid groups. Upscaled multigram synthesis of complex steroid molecules by late-stage oxidation proves the robustness and practical utility of the current protocol since it employs an inexpensive recyclable catalyst and an easily available oxidant. A plausible mechanism has been proposed with the help of few controlled experiments and kinetic and computational studies.

Multigram Synthesis of Tetrasubstituted Dihydrobenzofuran GSK973 Enabled by High-Throughput Experimentation and a Claisen Rearrangement in Flow

This article describes two routes toward the synthesis of cis or trans C2,3,5,7-tetrasubstituted dihydrobenzofurans as potent and selective bromodomain and extra-terminal BD2 inhibitors, followed by the optimization of the synthesis of the lead molecule GSK973 to support pre-clinical efficacy and safety studies. The use of flow chemistry for a Claisen rearrangement, extensive optimization of the fluorination step, and high-yielding aminocarbonylation were key to generate the required 50 g of material. The identified new route also represents a robust starting point for further optimization.

An improved procedure for the synthesis of fourteen 4-OH and 3-MeO-4OH metabolites of fentanyl analogues from two intermediates on multi-gram scale

Fentanyl analogues have appeared on the recreational drug market during the last ten years and caused many fatal overdoses around the world due to their high potencies. Their metabolites are of great interest for toxicology, metabolism and identification studies. According to the literature, fentanyl analogues with similar structures have similar metabolism profile. Therefore, a synthetic route that enables synthesis of the corresponding metabolites for several fentanyl analogues would be valuable. Fentanyl analogue metabolites are often polar and tailing on silica gel. Hence, the purification of these substances could be challengeable. In this work, a general synthetic route was developed and described for the multi-gram scale synthesis of 14 potential metabolites of seven fentanyl analogues. The synthetic route is concise and optimized, does not require any use of silica gel purification and is therefore convenient for large-scale synthesis. The overall yields of the metabolites were in the range of 25–57%.

Highly stereoselective multigram scale synthesis of (3S,4S)-Statine and (3S,4S)-N-Benzylstatine

Statins are essential naturally occurring β-hydroxy-γ-amino acids and (3S,4S)-Statine, derived from L-Leucine, is found in important aspartic proteases inhibitors like Pepstatin A. We developed a new synthesis of (3S,4S)-Statine based on the highly diastereoselective reduction of N,N-Boc/Benzyl protected β-ketoester intermediate. This Boc/Benzyl protection strategy gives access to either N-Fmoc or N-Benzyl protected (3S,4S)-Statine on multigram scale quantities.

Supramolecular aggregation in sterically encumbered monoarylphosphates and their H-bonded adducts: multigram synthesis of elusive 2,6-di-tert-butylphenyl phosphate

A viable synthetic methodology has been developed for multigram synthesis of bulky 2,6-di-tert-butyphenyl phosphate; its supramolecular association behaviour and those of adducts formed with N-bases is established.

1-(4-Nitrophenyl)-1H-1,2,3-Triazole-4-carbaldehyde: Scalable Synthesis and Its Use in the Preparation of 1-Alkyl-4-Formyl-1,2,3-triazoles

1,2,3-Triazole-4-carbaldehydes are useful synthetic intermediates which may play an important role in the discovery of novel applications of the 1,2,3-triazole moiety. In this work, a one-step multigram scale synthesis of 4-formyl-1-(4-nitrophenyl)-1H-1,2,3-triazole (FNPT) as a preferred reagent for the synthesis of 1-alkyl-4-formyltriazoles is described, making use of the commercially available 3-dimethylaminoacrolein and 4-nitrophenyl azide. Next, the earlier reported reaction of FNPT with alkylamines is further explored, and for hexylamine, the one-pot sequential cycloaddition and Cornforth rearrangement is demonstrated. In addition, a useful protocol for the in situ diazotization of 4-nitroaniline is provided. This facilitated the complete hydrolysis of rearranged 4-iminomethyl-1,2,3-triazoles and allowed for the recycling of 4-nitrophenyl azide.

Synthesis and characterization of an isopropylBippyPhos precatalyst

A review of our high throughput reaction screening data revealed that BippyPhos was frequently associated with successful outcomes in Buchwald – Hartwig amination reactions. A barrier to the wider use of this ligand, particularly among those performing smaller scale work, may be the lack of a readily available precatalyst. We describe the multi-gram synthesis and characterization of isopropylBippyPhos, and its conversion to isopropylBippyPhos Pd G2, a biaryl phosphine precatalyst. We demonstrate the competency of isopropylBippyPhos Pd G2 in palladium catalyzed Buchwald – Hartwig amination reactions and in Suzuki – Miyaura cross coupling reactions.

Monosubstituted 3,3‐Difluorocyclopropenes as Bench‐Stable Reagents: Scope and Limitations

AbstractA general approach to gem‐difluorocyclopropenes synthesis based on the reaction of alkynes with Ruppert‐Prakash reagent is reported. The proposed method is evaluated for the synthesis of a wide difluorocyclopropenes scope based on their bench lifespan and hydrolytic stability. The tolerance of the method for common functional groups was shown. Previously unavailable difluorocyclopropenes substituted with aliphatic were prepared using the proposed procedure. The retain of stability was proven by the multigram scale synthesis and further storage in the temperature interval −78 to −4 °C over a year. This makes them attractive building blocks and intermediates for organic synthesis. The reasons for dropping stability were defined. The relations between the structure of the substituents and the stability of the difluorocyclopropene ring were determined and discussed.

Multigram synthesis of N-alkyl bis-ureas for asymmetric hydrogen bonding phase-transfer catalysis.

Fluorine is a key element present in ~35% of agrochemicals and 25% of marketed pharmaceutical drugs. The availability of reliable synthetic protocols to prepare catalysts that allow the efficient incorporation of fluorine in organic molecules is therefore essential for broad applicability. Herein, we report a protocol for the multigram synthesis of two representative enantiopure N-alkyl bis-urea organocatalysts derived from (S)-(-)-1,1'-binaphthyl-2,2'-diamine ((S)-BINAM). These tridentate hydrogen bond donors are highly effective phase-transfer catalysts for solubilizing safe and inexpensive metal alkali fluorides (KF and CsF) in organic solvents for enantioselective nucleophilic fluorinations. The first catalyst, characterized by N-isopropyl substitution, was obtained by using a two-step sequence consisting of reductive amination followed by urea coupling from commercially available starting materials (14 g, 48% yield and 5-d total synthesis time). The second catalyst, featuring N-ethyl alkylation and meta-terphenyl substituents, was accessed via a novel, scalable, convergent route that concluded with the coupling between N-ethylated (S)-BINAM and a preformed isocyanate (52 g and 52% overall yield). On this scale, the synthesis requires ~10 d. This can be reduced to 5 d by performing some steps in parallel. Compared to the previous synthetic route, this protocol avoids the final chromatographic purification and produces the desired catalysts in very high purity and improved yield.

New Route to Battery Grade NaPF6 for Na-Ion Batteries: Expanding the Accessible Concentration.

Sodium-ion batteries represent a promising alternative to lithium-ion systems. However, the rapid growth of sodium-ion battery technology requires a sustainable and scalable synthetic route to high-grade sodium hexafluorophosphate. This work demonstrates a new multi-gram scale synthesis of NaPF6 in which the reaction of ammonium hexafluorophosphate with sodium metal in THF solvent generates the electrolyte salt with the absence of the impurities that are common in commercial material. The high purity of the electrolyte (absence of insoluble NaF) allows for concentrations up to 3 M to be obtained accurately in binary carbonate battery solvent. Electrochemical characterization shows that the degradation dynamics of sodium metal-electrolyte interface are different for more concentrated (>2 M) electrolytes, suggesting that the higher concentration regime (above the conventional 1 M concentration) may be beneficial to battery performance.

Concise Large-Scale Synthesis of Tomatidine, A Potent Antibiotic Natural Product.

Tomatidine has recently generated a lot of interest amongst the pharmacology, medicine, and biology fields of study, especially for its newfound activity as an antibiotic agent capable of targeting multiple strains of bacteria. In the light of its low natural abundance and high cost, an efficient and scalable multi-gram synthesis of tomatidine has been developed. This synthesis uses a Suzuki–Miyaura-type coupling reaction as a key step to graft an enantiopure F-ring side chain to the steroidal scaffold of the natural product, which was accessible from low-cost and commercially available diosgenin. A Lewis acid-mediated spiroketal opening followed by an azide substitution and reduction sequence is employed to generate the spiroaminoketal motif of the natural product. Overall, this synthesis produced 5.2 g in a single pass in 15 total steps and 15.2% yield using a methodology that is atom economical, scalable, and requires no flash chromatography purifications.