Transition-Metal-Free Upscaling of 2,5-Furandicarboxylic Acid Synthesis and Investigation of the Reaction Mechanism.

An environmentally friendly oxidation system has proposed for the practical and scalable production of value-added 2,5-furandicarboxylic acid from 1 kg of 5-hydroxymethylfurfural. The system is composed of a simple base, oxygen, and a green solvent, thereby providing a sustainable and economical approach to organic synthesis. To gain insight into the mechanism of this oxidation process, NMR spectroscopic analysis and kinetic study are used for the mechanistic investigation of this environmentally friendly oxidation process.

Synergistic Catalysis: Highly Enantioselective Cascade Reaction for the Synthesis of Dihydroacridines.

The first stereoselective synthesis of dihydroacridines through synergistic catalysis, achieving the final target compounds with good to excellent yields and good to excellent enantioselectivities and diastereoselectivities, is reported. The synergistic approach consists in the activation of substituted quinolines with a Lewis acid catalyst that react in a cascade fashion with activated enals in the iminium form. Mechanistic calculations support a consecutive Michael-aldol reaction, followed by dehydration.

New development in the enantioselective synthesis of spiro compounds.

The enantioselective synthesis of spirocycles has long been pursued by organic chemists. Despite their unique 3D properties and presence in several natural products, the difficulty in their enantioselective synthesis makes them underrepresented in pharmaceutical libraries. Since the first pioneering reports of the enantioselective construction of spirosilanes by Tamao et al., significant effort has been devoted towards the development of new promising asymmetric methodologies. Remarkably, with the advent of organocatalysis, particularly over six years, the reported methodologies for the synthesis of spirocycles have increased exponentially. The aim of this review is to summarize the latest trends and developments in the enantioselective synthesis of spirocompounds during these last six years.

Preparation of Chiral Contiguous Epoxyaziridines and Their Regioselective Ring-Opening for Drug Syntheses.

Synthetically valuable chiral (aziridin-2-yl)oxirane-3-carbaldehydes bearing three consecutive functional groups including aziridine, epoxide, and aldehyde were prepared from the stereoselective epoxidation of (aziridin-2-yl)acrylaldehydes with H2 O2 using organocatalyst (2R)- or (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as organocatalyst. The regioselective ring opening of aziridines and epoxides enabled us to achieve the highly efficient asymmetric synthesis of the antibiotic edeine D fragment 3-hydroxy-4,5-diaminopenatanoic acid, an intermediate for the formal synthesis of non-proteinogenic amino acid (-)-galantinic acid, and for potent antifungal agent (+)-preussin, and the medicinally important framework 3-hydroxy-2-hydroxymethylpyrrolidine.

Birch Reduction of Aromatic Compounds by Inorganic Electride [Ca2N]+•e- in an Alcoholic Solvent: An Analogue of Solvated Electrons.

Birch reduction of aromatic systems by solvated electrons in alkali metal-ammonia solutions is widely recognized as a key reaction that functionalizes highly stable π-conjugated organic systems. In spite of recent advances in Birch reduction with regard to reducing agent and reaction conditions, there remains an ongoing challenge to develop a simple and efficient Birch reaction under mild conditions. Here, we demonstrate that the inorganic electride [Ca2N]+•e- promotes the Birch reduction of polycyclic aromatic hydrocarbons (PAHs) and naphthalene under alcoholic solvent in the vicinity of room temperature as a solid-type analogy to solvated electrons in alkali metal ammonia solutions. The anionic electrons from electride [Ca2N]+•e- are transferred to PAHs and naphthalene via alcoholysis in a polar cosolvent medium. It is noteworthy that a high conversion yield to the hydrogenated products is ascribed to the extremely high electron transfer efficiency of 98%. This simple protocol utilizing an inorganic electride offers a direct and practical strategy for the reduction of aromatic compounds and provides an outstanding reducing agent for synthetic chemistry.

A metal-free and mild approach to 1,3,4-oxadiazol-2(3H)-ones via oxidative C-C bond cleavage using molecular oxygen.

A mild metal-free approach to 1,3,4-oxadiazol-2(3H)-ones via 1,3,4-oxadiazin-5(6H)-ones is described. This novel transformation, promoted by the electron-withdrawing p-substituents on the phenyl group at the α-carbonyl position, features a tandem reaction consisting of oxidative hydroxylation and C-C bond cleavage using molecular oxygen. The method utilizes K2CO3 in CH3CN without any oxidants, transition metals, or additives, enabling the tunable synthesis of 1,3,4-oxadiazin-5(6H)-ones, 1,3,4-oxadiazol-2(3H)-ones, and α-ketoamides under mild aerobic conditions.

Mixed Monosilyl Acetals and Catalyst-Dependent Chemoselective Mukaiyama Aldol Reactions.

We report a direct, simple, and straightforward approach for the construction of a mixed monosilyl acetal as a new and synthetically valuable functional group by mixing an aldehyde, sodium tert-butoxide, and trimethylsilyl azide. We also demonstrate a catalyst-dependent chemoselective reaction between mixed monosilyl acetals and silyl ketene acetals through Mukaiyama aldol reactions to give different structures of O-protected ß-hydroxy esters in excellent yields with high chemoselectivities. This study provided the existence of an oxonium ion intermediate and of its kinetically controlled reaction with the pre-equilibrated silyl enol ether obtained from (E)- and (Z)-isomerization.

Chemoselective Hydrodehalogenation of Organic Halides Utilizing Two-Dimensional Anionic Electrons of Inorganic Electride [Ca2N]+·e.

Halogenated organic compounds are important anthropogenic chemicals widely used in chemical industry, biology, and pharmacology; however, the persistence and inertness of organic halides cause human health problems and considerable environmental pollution. Thus, the elimination or replacement of halogen atoms with organic halides has been considered a central task in synthetic chemistry. In dehalogenation reactions, the consecutive single-electron transfer from reducing agents generates the radical and corresponding carbanion and thus removes the halogen atom as the leaving group. Herein, we report a new strategy for an efficient chemoselective hydrodehalogenation through the formation of stable carbanion intermediates, which are simply achieved by using highly mobile two-dimensional electrons of inorganic electride [Ca2N]+·e- with effective electron transfer ability. The consecutive single-electron transfer from inorganic electride [Ca2N]+·e- stabilized free carbanions, which is a key step in achieving the selective reaction. Furthermore, a determinant more important than leaving group ability is the stability control of free carbanions according to the s character determined by the backbone structure. We anticipate that this approach may provide new insight into selective chemical formation, including hydrodehalogenation.

Organocatalytic regiospecific synthesis of 1H-indene-2-carbaldehyde derivatives: suppression of cycloolefin isomerisation by employing sterically demanding catalysts.

The regiospecific synthesis of 1H-indene-2-carbaldehyde derivatives was achieved through transition-metal-free, reductive cyclisation of ortho-formyl trans-cinnamaldehydes with Hantzsch ester in the presence of an aminocatalyst. In particular, cycloolefin isomerisation of the resulting products could be inhibited efficiently by the introduction of a sterically demanding stereo-defined aminocatalyst.

Acetaldehyde: A Small Organic Molecule with Big Impact on Organocatalytic Reactions.

Stereocontrolled formation of carbon-carbon and carbon-heteroatom bonds through asymmetric organocatalysis is a formidable challenge for modern synthetic chemistry. Among the most significant contributions to this field are the transformations involving the use of acetaldehyde or α-heteroatom-substituted acetaldehydes for constructing valuable synthons (e.g., amino acid derivatives and hydroxycarbonyl). In this Minireview, versatile (enantioselective) organocatalytic transformations are discussed.

Enantioselective Organocatalytic Cyclopropanation of Enals Using Benzyl Chlorides.

Herein, we describe the first enantioselective cyclopropanation of enals using benzyl chlorides as bifunctional (nucleophilic and electrophilic) reagents. The reaction is simply catalyzed by chiral secondary amines to afford the formyl cyclopropane derivatives in good yields with moderate to excellent stereoselectivities.

Chemoselective and repetitive intermolecular cross-acyloin condensation reactions between a variety of aromatic and aliphatic aldehydes using a robust N-heterocyclic carbene catalyst.

We found that chemoselectivity of the crossed acyloin product is controlled by the adjustment of the aromatic aldehyde/aliphatic aldehyde ratio. Moreover, we observed the persistent catalytic activity of the homogeneous NHC catalyst in a solution due to NHC catalyst robustness.

Proline-catalysed Mannich reactions of acetaldehyde.

Small organic molecules recently emerged as a third class of broadly useful asymmetric catalysts that direct reactions to yield predominantly one chiral product, complementing enzymes and metal complexes. For instance, the amino acid proline and its derivatives are useful for the catalytic activation of carbonyl compounds via nucleophilic enamine intermediates. Several important carbon-carbon bond-forming reactions, including the Mannich reaction, have been developed using this approach, all of which are useful for making chiral, biologically relevant compounds. Remarkably, despite attempts, the simplest of all nucleophiles, acetaldehyde, could not be used in this way. Here we show that acetaldehyde is a powerful nucleophile in asymmetric, proline-catalysed Mannich reactions with N-tert-butoxycarbonyl (N-Boc)-imines, yielding beta-amino aldehydes with extremely high enantioselectivities-desirable products as drug intermediates and in the synthesis of other biologically active molecules. Although acetaldehyde has been used as a nucleophile in reactions with biological catalysts such as aldolases and thiamine-dependent enzymes, and has also been employed indirectly, its use as an inexpensive and versatile two-carbon nucleophile in asymmetric, small-molecule catalysis will find many practical applications.

Organocatalytic asymmetric synthesis of ß(3)-amino acid derivatives.

ß(3)-Amino acid derivatives are an essential resource for pharmaceutical production, medicinal chemistry, and biochemistry. In this article, recent developments in versatile organocatalysis, i.e., Brønsted acid catalysis, Brønsted base catalysis, Lewis acid catalysis, Lewis base catalysis, and phase-transfer catalysis, for the asymmetric synthesis of ß(3)-amino acid derivatives will be presented.

Transition-Metal-Free Unusual Oxidative Cleavage of Homoallylic Alcohol and Its Application in the Upcycling of Terpene to Value-Added Chemicals.

A NaOtBu-O2 -mediated oxidative dehomologation of homoallylic alcohols into structurally different carboxylic acids through direct oxidative cleavage of either the C(sp2 )-C(sp2 ) or C(sp3 )-C(sp3 ) bond utilizing enolate chemistry was demonstrated. Furthermore, under transition-metal-free conditions, this protocol has been applied to convert terpene as biomass feedstock into value-added chemicals.

Preparation of Contiguous Bisaziridines for Regioselective Ring-Opening Reactions.

Aziridines, a class of reactive organic molecules containing a three-membered ring, are important synthons for the synthesis of a large variety of functionalized nitrogen-containing target compounds through the regiocontrolled ring-opening of C-substituted aziridines. Despite the tremendous progress in aziridine synthesis over the past decade, accessing contiguous bisaziridines efficiently remains difficult. Therefore, we were interested in synthesizing contiguous bisaziridines bearing an electronically diverse set of N-substituents beyond the single aziridine backbone for regioselective ring-opening reactions with diverse nucleophiles. In this study, chiral contiguous bisaziridines were prepared by organocatalytic asymmetric aziridination of chiral (E)-3-((S)-1-((R)-1-phenylethyl)aziridin-2-yl)acrylaldehyde with N-Ts-O-tosyl or N-Boc-O-tosyl hydroxylamine as the nitrogen source in the presence of (2S)-[diphenyl(trimethylsilyloxy)methyl]pyrrolidine as a chiral organocatalyst. Also demonstrated here are representative examples of regioselective ring-opening reactions of contiguous bisaziridines with a variety of nucleophiles such as sulfur, nitrogen, carbon, and oxygen, and the application of contiguous bisaziridines to the synthesis of multi-substituted chiral pyrrolidines by Pd-catalyzed hydrogenation.

N-heterocyclic carbene-catalysed intermolecular Stetter reactions of acetaldehyde.

A facile method for the intermolecular Stetter reaction of various Michael acceptors with acetaldehyde as a biomimetic acylanion source was realized using N-heterocyclic carbene catalysis. This catalytic system has also been applied to the enantioselective Stetter reaction and resulted in moderate to good enantioselectivities for the corresponding Stetter products.

Copper-Catalyzed Asymmetric Synthesis of Borylated cis-Disubstituted Indolines.

A copper-catalyzed, intramolecular borylative cyclization of vinyl arenes with imines is reported, which affords enantio-enriched indolines as a single diastereomer under mild conditions. A benzylcopper species is generated by Cu-Bpin addition to the alkene, which then acts as a nucleophile for intramolecular imine addition. The reaction is applicable to various vinyl arenes with an imine moiety at the ortho-position, including heterocycles, for formation of borylated indolines in good yields and ee values up to 90 %.

Impact of Carboxyl Groups in Graphene Oxide on Chemoselective Alcohol Oxidation with Ultra-Low Carbocatalyst Loading.

A highly efficient and simple chemoselective aerobic oxidation of primary alcohols to either aldehydes or carboxylic acids in the presence of nitric acid was developed, utilising 5 wt% graphene oxide as a carbocatalyst under ambient reaction conditions. Carboxylic acid functional groups on graphene oxides played a vital role in carbocatalyst activity, greatly influencing both the reactivity and selectivity. We also applied this protocol to a variant of the Knoevenagel condensation for primary alcohols and malonates with a secondary amine co-catalyst via cooperative catalysis.

Asymmetric Synthesis of α-Fluoro-ß-Amino-oxindoles with Tetrasubstituted C-F Stereogenic Centers via Cooperative Cation-Binding Catalysis.

Biologically relevant chiral 3,3-disubstituted oxindole products containing a ß-fluoroamine unit are obtained in high yields and with excellent stereoselectivity (up to 99% ee, dr >20:1 for syn) through the organocatalytic direct Mannich reaction of 3-fluoro-oxindoles as fluoroenolate precursors and α-amidosulfones as the bench-stable precursors of sensitive imines by using a chiral oligoethylene glycol and KF as a cation-binding catalyst and base, respectively. This protocol can be easily scaled without compromising the asymmetric induction. Furthermore, this protocol was also successfully extended to generate tetrasubstituted C-Cl and C-Br stereogenic centers.