Van Leusen Reaction Research Articles

Broadening the Scope of van Leusen Reaction: Investigation of Benzofuro[2,3‐d]imidazole Formation

AbstractThe van Leusen reaction utilizes p‐toluenesulfonylmethyl isocyanide as a versatile synthon for constructing nitrogen‐containing heterocycles, such as oxazoles, imidazoles, thiazoles, and pyrroles. In this study, the van Leusen imidazole reaction, employed for synthesizing potential Hsp90 inhibitors, yielded unexpected side products containing novel condensed tricycles, specifically 3a,8b‐dihydro‐1H‐benzofuro[2,3‐d]imidazoles. The mechanism behind the formation of this unprecedented fragment was further analyzed through quantum mechanical calculations and experimental investigations of the reaction outcome under different reaction conditions and with various substituents. Additionally, the stabilities of the products were evaluated.

Synthesis, In Silico Study, and In Vitro Antifungal Activity of New 5-(1,3-Diphenyl-1H-Pyrazol-4-yl)-4-Tosyl-4,5-Dihydrooxazoles.

The increase in multi-drug resistant Candida strains has caused a sharp rise in life-threatening fungal infections in immunosuppressed patients, including those with SARS-CoV-2. Novel antifungal drugs are needed to combat multi-drug-resistant yeasts. This study aimed to synthesize a new series of 2-oxazolines and evaluate the ligands in vitro for the inhibition of six Candida species and in silico for affinity to the CYP51 enzymes (obtained with molecular modeling and protein homology) of the same species. The 5-(1,3-diphenyl-1H-pyrazol-4-yl)-4-tosyl-4,5-dihydrooxazoles 6a-j were synthesized using the Van Leusen reaction between 1,3-diphenyl-4-formylpyrazoles 4a-j and TosMIC 5 in the presence of K2CO3 or KOH without heating, resulting in short reaction times, high compound purity, and high yields. The docking studies revealed good affinity for the active site of the CYP51 enzymes of the Candida species in the following order: 6a-j > 4a-j > fluconazole (the reference drug). The in vitro testing of the compounds against the Candida species showed lower MIC values for 6a-j than 4a-j, and for 4a-j than fluconazole, thus correlating well with the in silico findings. According to growth rescue assays, 6a-j and 4a-j (like fluconazole) inhibit ergosterol synthesis. The in silico toxicity assessment evidenced the safety of compounds 6a-j, which merit further research as possible antifungal drugs.

Synthesis of Polycyclic Imidazoles via α-C-H/N-H Annulation of Alicyclic Amines.

Secondary alicyclic amines are converted to their corresponding ring-fused imidazoles in a simple procedure consisting of oxidative imine formation followed by a van Leusen reaction. Amines with an existing α-substituent undergo regioselective ring-fusion at the α'-position. This method was utilized in a synthesis of fadrozole.

Trioxazolo[23]metacyclophane: synthesis, structural analysis, and optical properties.

The synthesis and characterization of the conjugated macrocycle trioxazolo[23]metacyclophane, C27H15N3O3 (M), is reported. The macrocycle was synthesized in three steps by the multicomponent van Leusen reaction and consists of meta-linked phenylenes connected through positions 4 and 5 of an oxazole heterocyclic ring. The molecular structure was investigated by NMR spectroscopy, mass spectrometry, gel permeation chromatography (GPC), and single-crystal X-ray crystallography. X-ray diffraction (XRD) analysis shows that M possesses a twisted saddle-like shape and interacts with nearby molecules by various π-π interactions. Absorption and emission spectroscopy and density functional theory (DFT) calculations were further used to study the electronic properties of M.

One-Pot, Three-Component Cascade Synthesis of New Imidazoles by Van Leusen Reaction from 2-Functionally Substituted 2-Alkenals, Amines, and p-Tosylmethylisocyanide

The reactivity of 2-alkoxy- and 2-alkylthiosubstituted 3-aryl(hetaryl)-2-propenals in a three-component reaction with primary amines and p-toluenesulfonylmethyl isocyanide (TosMIC) to afford the functionalized 1,3-imidazoles in good yields (36–69%) has been studied.

The Use of 5-Hydroxymethylfurfural towards Fine Chemicals: Synthesis and Direct Arylation of 5-HMF-Based Oxazoles

Abstract5-Hydroxymethylfurfural (5-HMF) is a renewable platform chemical used as a source for obtaining diverse fine chemicals. In this letter, we report the synthesis of 5-HMF-based oxazole compounds. While 5-HMF could be easily converted into the oxazole derivative through the Van Leusen reaction, the direct arylation step needed to access the final compounds was problematic at first. After optimization, a palladium-catalyzed procedure has been developed and used for the synthesis of a series of 33 derivatives. This article reports an extension of the late-stage CH arylation reaction as an application to the oxazole platform derived from biosourced 5-HMF. The challenges in the preparation of the derivatives containing some electron-withdrawing substituents were overcome by the use of a palladium-free method.

Isonitrile-Based Multicomponent Synthesis of β-Amino Boronic Acids as β-Lactamase Inhibitors.

The application of various isonitrile-based multicomponent reactions to protected (2-oxoethyl)boronic acid (as the carbonyl component) is described. The Ugi reaction, both in the four components and in the four centers–three components versions, and the van Leusen reaction, proved effective at providing small libraries of MIDA-protected β-aminoboronic acids. The corresponding free β-aminoboronic acids, quantitatively recovered through basic mild deprotection, were found to be quite stable and were fully characterized, including by 11B-NMR spectroscopy. Single-crystal X-ray diffraction analysis, applied both to a MIDA-protected and a free β-aminoboronic acid derivative, provided evidence for different conformations in the solid-state. Finally, the antimicrobial activities of selected compounds were evaluated by measuring their minimal inhibitory concentration (MIC) values, and the binding mode of the most promising derivative on OXA-23 class D β-lactamase was predicted by a molecular modeling study.

Recent Advances in the Synthesis of Oxazole-Based Molecules via van Leusen Oxazole Synthesis.

Oxazole compounds, including one nitrogen atom and one oxygen atom in a five-membered heterocyclic ring, are present in various biological activities. Due to binding with a widespread spectrum of receptors and enzymes easily in biological systems through various non-covalent interactions, oxazole-based molecules are becoming a kind of significant heterocyclic nucleus, which have received attention from researchers globally, leading them to synthesize diverse oxazole derivatives. The van Leusen reaction, based on tosylmethylisocyanides (TosMICs), is one of the most appropriate strategies to prepare oxazole-based medicinal compounds. In this review, we summarize the recent advances of the synthesis of oxazole-containing molecules utilizing the van Leusen oxazole synthesis from 1972, aiming to look for potential oxazole-based medicinal compounds, which are valuable information for drug discovery and synthesis.

Synthesis of Imidazole-Based Medicinal Molecules Utilizing the van Leusen Imidazole Synthesis.

Imidazole and its derivatives are one of the most vital and universal heterocycles in medicinal chemistry. Owing to their special structural features, these compounds exhibit a widespread spectrum of significant pharmacological or biological activities, and are widely researched and applied by pharmaceutical companies for drug discovery. The van Leusen reaction based on tosylmethylisocyanides (TosMICs) is one of the most appropriate strategies to synthetize imidazole-based medicinal molecules, which has been increasingly developed on account of its advantages. In this review, we summarize the recent developments of the chemical synthesis and bioactivity of imidazole-containing medicinal small molecules, utilizing the van Leusen imidazole synthesis from 1977.

Charge Transport in Sequence-Defined Conjugated Oligomers

A major challenge in synthetic polymers lies in understanding how primary monomer sequence affects materials properties. In this work, we show that charge transport in single molecule junctions of conjugated oligomers critically depends on the primary sequence of monomers. A series of sequence-defined oligomers ranging from two to seven units was synthesized by an iterative approach based on the van Leusen reaction, providing conjugated oligomers with backbones consisting of para-linked phenylenes connected to oxazole, imidazole, or nitro-substituted pyrrole. The charge transport properties of these materials were characterized using a scanning tunneling microscope-break junction (STM-BJ) technique, thereby enabling direct measurement of molecular conductance for sequence-defined dimers, trimers, pentamers, and a heptamer. Our results show that oligomers with specific monomer sequences exhibit unexpected and distinct charge transport pathways that enhance molecular conductance more than 10-fold. A systematic analysis using monomer substitution patterns established that sequence-defined pentamers containing imidazole or pyrrole groups in specific locations provide molecular attachment points on the backbone to the gold electrodes, thereby giving rise to multiple conductance pathways. These findings reveal the subtle but important role of molecular structure including steric hindrance and directionality of heterocycles in determining charge transport in these molecular junctions. This work brings new understanding for designing molecular electronic components.

Cu-Catalyzed Oxidative-Reaction of Tosylmethylisocyanide and Benzyl Alcohols: Efficient Synthesis of 4-(tert-butylperoxy)-5-aryloxazol-2(3H)-ones and 5-Aryloxazol-2(5H)-ones

Herein, a novel copper-catalyzed reaction of tosylmethylisocyanide (TosMIC) with benzyl alcohols has been developed using tert-butyl hydroperoxide (TBHP) for the first time. The reaction involves the in-situ oxidation of benzyl alcohol to corresponding benzaldehyde, followed by sequential formal [3+2] cycloaddition/radical addition/ring oxidation reactions, and provides an efficient method for the construction of 4-(tert-butylperoxy)-5-aryloxazol-2(3H)-ones from readily available starting materials. Replacement of TBHP with H2O2 led to the production of 5-aryloxazol-2(5H)-ones in good yields. Tandem oxidative Van Leusen reaction: efficient three-component approach for the synthesis of 4-(tert-butylperoxy)-5-aryloxazol-2(3H)-ones and 5-phenyloxazol-2(5H)-one for the first time.

Aryl Azides as Forgotten Electrophiles in the Van Leusen Reaction: A Multicomponent Transformation Affording 4-Tosyl-1-arylimidazoles.

Considering aryl azides as electrophilic partners for the TosMIC mediated Van Leusen reaction, a novel multicomponent synthesis of 4-tosyl-1-arylimidazoles is reported. In this transformation, two molecules of TosMIC participate in the reaction mechanism in two different ways, with the second molecule undergoing a novel type of fragmentation resulting in the incorporation of a C-H into the final product.

Computationally Driven Structure Optimization, Synthesis, and Biological Evaluation of Imidazole-Based Proprotein Convertase Subtilisin/Kexin 9 (PCSK9) Inhibitors.

Proprotein convertase subtilisin/kexin 9 (PCSK9) is responsible for the degradation of the hepatic low-density lipoprotein receptor (LDLR), which in turn regulates the circulating low-density lipoprotein cholesterol (LDL-C) level. For this reason, the PCSK9 inhibition, by small molecules or peptides, is a validated therapeutic approach for fighting hypercholesterolemia and cardiovascular diseases. In this field, we have recently reported an imidazole-based peptidomimetic that has shown PCSK9 inhibitory activity in the micromolar range. Here, by applying advanced computational techniques, the binding mechanism of that imidazole peptidomimetic was predicted. Then, among a small set of poly-imidazole analogs, compounds showing the highest theoretical affinity were suitably synthesized, relying on a van Leusen reaction based multicomponent strategy. One compound (named RIm13) displayed a PCSK9 inhibitory activity 10-fold lower than the template compound, and, remarkably, at a concentration of 1 μM, it successfully prevented the LDLR degradation mediated by PCSK9 on HepG2 cells. As well as increasing the LDL uptake at the same concentration, RIm13 represents currently one of the most potent small molecules targeting the PCSK9/LDLR protein-protein interaction.

Synthesis of Nanostructured Organosilicon Luminophores Based on Phenyloxazoles

A series of nanostructured organosilicon luminophores (NOLs) composed of a central 1,4-bis(5-phenyl-1,3-oxazol-2-yl)benzene (POPOP) acceptor chromophore and various peripheral p-terphenyl and 2,5-diphenyl-1,3-oxazole donor fragments have been synthesized for the first time using van Leusen reaction and direct palladium-catalyzed C-arylation of oxazole ring. Due to different functionalities of the silicon branching centers, NOLs with different donor-acceptor ratios have been obtained. The synthesized structures are expected to possess good optical characteristics for use in photonics and optoelectronics.

The base-free van Leusen reaction of cyclic imines on water: synthesis of N-fused imidazo 6,11-dihydro β-carboline derivatives.

Construction of imidazoles has been demonstrated on water under base-free conditions. The reaction of dihydro β-carboline imines and p-toluenesulfonylmethyl isocyanides furnished the corresponding substituted N-fused imidazo 6,11-dihydro β-carboline derivatives in very good yields under ambient conditions. The use of deuterium oxide (D2O) as a solvent enabled the incorporation of deuterium isotopes in the imidazole ring.

New efficient synthesis of 1H-imidazo-[4,5-c]quinolines by a sequential Van Leusen/Staudinger/aza-Wittig/carbodiimide-mediated cyclization

A new efficient synthesis of multisubstituted 1H-imidazo-[4,5-c]quinoline derivatives via sequential van Leusen/Staudinger/aza-Wittig/carbodiimide-mediated cyclization was developed. Azides 4, obtained from Van Leusen reaction of 2-azidobenzaldehyde 1, amine 2 and TosMIC (tosylmethyl isocyanide) 3, reacted with triphenyl phosphine to produce iminophosphorane 5. A tandem aza-Wittig reaction of iminophosphorane 5 with isocyanate generated 1H-imidazo-[4,5-c]quinoline 7 through carbodiimide intermediate 6 in moderate to good yield.

Improvement of the Van Leusen reaction in the presence of β-cyclodextrin: a green and efficient synthesis of oxazoles in water

Abstract An efficient approach for the synthesis of oxazoles through the Van Leusen reaction in the presence of β-cyclodextrin is described. In aqueous medium using β-cyclodextrin as a supramolecular catalyst, tosylmethyl isocyanide was deprotonated by triethylamine and subsequently underwent an addition/cyclization reaction with aldehydes to produce corresponding oxazoles in excellent yields. This protocol improves the Van Leusen reaction with the use of catalytic amounts of base at low temperature in green media.

Experimental and theoretical investigation of new furan and thiophene derivatives containing oxazole, isoxazole, or isothiazole subunits

Herein, we present joint experimental and theoretical studies on newly designed thiophene- or furan-based oxazole, isoxazole, and isothiazole derivatives. Our synthetic approach towards the preparation of target compounds is based on Van Leusen reaction. By following this reaction, oxazoles (1 and 2) containing the pertinent heterocyclic systems were obtained from the reaction of suitable furan or thiophene derivatives with tosylmethyl isocyanide (TOSMIC). Hereby, three ring systems of furan or thiophene, linked to the oxazole rings at their 2- and 5-positions (3 and 4), were also successfully synthesized for the first time. Reaction of the starting materials containing acetyl groups in their 2-position with dimethyl acetal and following the treatment by hydroxylamine hydrochloride, desired isoxazole derivatives (5 and 6), were obtained. Additionally, isothiazole derivatives (7 and 8) were prepared by following the similar approach to the isoxazole synthesis. Whole of these cyclization reactions occurred with good to excellent yields. Structural analyses of the synthesized compounds were performed by appropriate spectroscopic methods (UV-vis, FT-IR, LC-MS, 1H-NMR, 13C-NMR, and elemental analysis). We also carried out theoretical studies for identifying the structure-activity relationship and determining chemical properties of the studied molecules. For this purpose, we obtained information about structural properties (bond lengths, bond angles, dihedral angles, and dipole moments), band gap energies, and spectroscopic characteristics (UV-vis, FT-IR, 1H-NMR, and 13C-NMR) of the target compounds.

ChemInform Abstract: A One‐Pot Tandem Approach for the Synthesis of 5‐(Het)aryloxazoles from Substituted (Het)aryl Methyl Alcohols and Benzyl Bromides.

AbstractThe title oxazoles are prepared from (het)aryl methyl alcohols or benzyl bromides by a new modified van Leusen reaction under basic conditions.

Synthesis of 2H-pyrrolo[3,4-C]quinoline via an Aldol/Van Leusen/Staudinger/aza-Wittig sequence

ABSTRACTAn aldol/van Leusen/Staudinger/aza-Wittig reaction for the preparation of the derivatives of 2H-pyrrolo[3,4-c]quinolines from 2-azidobenzaldehyde, acetyl compounds, and tosylmethyl isocyanide was developed. The process involves an aldol condensation of 2-azidobenzaldehyde with acetyl compound in base, a van Leusen reaction to form the key pyrrole intermediates, and then a Staudinger and intramolecular aza-Wittig reaction occurred with the addition of triphenylphosphine to complete the formation of pyrrolo[3,4-c]quinoline ring in high yields.