Trisubstituted Oxazoles Research Articles

Three-Component Photochemical Construction of Trisubstituted Oxazoles

Three-Component Photochemical Construction of Trisubstituted Oxazoles

Photochemical three-component assembly of tri-substituted oxazoles through a carbenic phosphorus-nitrile hybrid ylide formation/trapping cascade.

Construction of complex molecular skeletons with ubiquitous chemical feedstocks in a single transformation is highly appealing in organic synthesis. We report a novel visible-light-induced three-component reaction for the construction of complex 2,4,5-trisubstituted oxazoles, which are valuable in medicinal chemistry, from simple and readily available iodonium-phosphonium hybrid ylides, carboxylic acids, and nitriles. This reaction features a carbenic phosphorus-nitrile hybrid ylide formation/trapping cascade, in which a photo-generated α-phosphonium carbene acts as a sequence trigger. This catalyst- and additive-free transformation exhibits high efficiency and broad substrate scope for synthesizing diverse oxazoles.

Copper-Catalyzed Benzylic sp3 C–H Oxidative Annulation of Ketones and Amines

Key words trisubstituted oxazoles - sp3 C–H oxidative annulation - aerobic oxidation - copper catalysis

Development of Catalytic Isocyanation via Precise Reactivity Control of Ambident Reagent

Isonitrile (R-NC) is a regioisomer of the corresponding nitrile (R-CN), whose C-terminus has carbene like property. Isonitriles have been deeply investigated from the viewpoint of their use. In contrast to the usability, the synthesis of isonitriles themselves are not sufficiently studied. In this manuscript, we describe our findings on catalytic nucleophilic isocyanation using cyanide with precise control of the ambident reactivity. We successfully demonstrated Pd-catalyzed allylic isocyanation. A wide variety of allylic isonitriles were obtained by this method, in high yield with good linear selectivity. Allylic nitriles were not observed at all, which were the possible side products in the reaction. Even though the reaction is the Pd-catalyzed allylic substitution, no π-allyl Pd(II) intermediate is involved in the catalytic cycle. Pd salt, such as Pd(OAc)2 and Pd(CN)2, was just the precursor of catalytic active species. It was reversibly converted into the ate complex, (Me3Si)[Pd-(CN)3], with excess amount of trimethylsilyl cyanide (Me3SiCN). The ate complex plays dual roles: 1) The Me3Si group activates phosphate leaving group on the allylation electrophile. 2) The [Pd(CN)3]- part reacts as the nucleophile with its N-terminus because the strong interaction between Pd center and C-terminus of cyanide suppresses the C-nucleophilicity. Benzylic isocyanation was successfully catalyzed by Ag2O. Both primary and secondary benzylic isonitriles were obtained in high yield. Pd-catalyzed synthesis of α-aryl-α-isocyanoacetamide derivative was also demonstrated. This catalytic procedure was appropriate to the sequential transformation into the trisubstituted oxazole without isolation of the isonitrile intermediate. Mechanistic investigations revealed that the nucleophilic isocyanation proceeded through a SN1-type substitution predominantly.

Visible‐Light Induced Oxidative Annulation of Enamides to 2,4,5‐Trisubstituted Oxazole Skeletons

AbstractA novel approach to various trisubstituted oxazoles (28 examples, up to 88% yield) has been developed via 9H‐thioxanthen‐9‐one (TX) mediated oxidative annulation of N‐acetyl enamide under visible light irradiation in the presence of BF3 ⋅ Et2O (2.0 equiv) and 40 mol% of PhNO2. This metal‐free procedure features high atom and step economy, green and mild conditions and broad substrate scope.

Synthesis of 2,4,5-trisubstituted oxazoles from 1,2-diketones and amines by using an electrochemical method

An efficient electrochemical synthesis of trisubstituted oxazoles from readily available 1,2-diketones and amines is described. With KI as the electrocatalyst, t-BuOK as the base and MeOH as the electrolytic solvent, the electrochemical synthesis could be smoothly performed in an undivided cell to afford 2,4,5-trisubstituted oxazoles in good yields at room temperature.

Cu(II)-catalyzed synthesis of 2,4,5-trisubstituted oxazoles

A copper catalyzed simple and efficient protocol for the synthesis of 2,4,5-trisubstituted oxazoles has been developed from the direct coupling of α-diazoketones with aryl or alkyl nitriles. The reaction proceeds through the formation of nitrilium ion by the nucleophic addition of nitrile onto diazo functionality followed by an intramolecular trapping of nitrilium ion by keto group. Both aryl, and alkyl nitriles underwent smooth cyclocondensation with diazo compounds to afford the trisubstituted oxazoles in excellent yields.

Tf2O-Mediated Direct Synthesis of 4-Sulfenylated Oxazoles from β-Keto Sulfoxides and Nitriles.

A general and efficient method for the synthesis of 4-sulfenylated oxazoles is described. Trisubstituted oxazoles are obtained in good to excellent yields from β-keto sulfoxides and nitriles. The mechanistic study suggests that the reaction proceeds via the nucleophilic addition of nitriles to the in situ formed α-carbonyl cation followed by intramolecular cyclization.

Cover Feature: Electrochemical Synthesis of Trisubstituted Oxazoles and Imines from β‐Diketones and Amines (ChemElectroChem 15/2022)

The Cover Feature shows electrochemical synthesis of trisubstituted oxazoles from β-diketones and amines, like the high energy meet-up between a Chinese dragon and a tiger typically described in Chinese folklore. More information can be found in the Research Article by Y. Wang, X.-J. Zhao et al.

Electrochemical Synthesis of Trisubstituted Oxazoles and Imines from β‐Diketones and Amines

AbstractAn electrochemical oxidation reaction was developed for the synthesis of trisubstituted oxazoles and imines. The use of external oxidant and transition‐metal catalyst was avoided in the methodology. Various trisubstituted oxazoles and imines were obtained in moderate to excellent yields. The mechanism studies propose the electrochemical reaction involves a radical process.

Synthesis of Trisubstituted Oxazoles via Aryne Induced [2,3] Sigmatropic Rearrangement-Annulation Cascade.

A transition-metal-free, [2,3] sigmatropic rearrangement-annulation cascade of 2-substituted thio/amino acetonitriles with arynes allowing the synthesis of 2,4,5-trisubstituted oxazoles under mild conditions has been demonstrated. The key sulfur/nitrogen ylides were generated by the initial S/N arylation followed by proton transfer, which was followed by the selective [2,3] sigmatropic rearrangement involving the -CN moiety and a subsequent annulation to afford the desired products in reasonable yields.

Access to 5-fluoroalkylated trisubstituted oxazoles via copper-catalyzed cyclization of α-fluoroalkyl-α-diazoketones with amides.

A novel copper-catalyzed cyclization of α-fluoroalkyl-α-diazoketones with (thio)amides has been developed. This mechanistically distinct protocol provides a robust and straightforward approach to construct 5-fluoroalkylated trisubstituted oxazoles and thiazoles with high efficiency and excellent functional group compatibility. Experimental studies suggest a mechanism involving imidate ligand migratory insertion of a copper carbenoid as the key step.

Palladium-Catalyzed Nucleophilic Isocyanation for the Synthesis of α-Aryl-α-Isocyanoacetoamide Derivatives

Abstract α-Aryl-α-isocyanoacetoamide derivatives were synthesized through palladium-catalyzed nucleophilic isocyanation. Diethylphosphates derived from N,N-disubstituted mandelamide derivatives reacted with trimethylsilyl cyanide in the presence of a catalytic amount of Pd(OAC)2 to afford the titled isonitriles (13 examples) in moderate to high yield. The silyl cyanopalladate complex formed in situ was a proposed catalyst, which behaved as a Lewis acid promoting elimination of the phosphate group and also the N-nucleophilic cyanide reagent. The isocyanation was applied to a gram-scale reaction with 0.2 mol% of the catalyst. The obtained isocyanoacetoamide was employable for the further transformation into the trisubstituted oxazole without any purification procedure. DFT calculation suggested that the neighboring group effect of the carbonyl moiety in the substrate amide group assisted the elimination of phosphate and stabilized the carbocation intermediate. A plausible reaction mechanism of the isocyanation is also described.

Iron-Catalyzed Cycloaddition of Amides and 2,3-Diaryl-2H-azirines To Access Oxazoles via C-N Bond Cleavage.

A novel and efficient iron-catalyzed cycloaddition reaction using readily available 2,3-diaryl-2H-azirines and primary amides is reported. A wide range of trisubstituted oxazoles could be achieved in good yields with good functional group compatibility. In this transformation, two C-N bonds were cleaed and new C-N and C-O bonds were formed.

Development of a Continuous Flow Photoisomerization Reaction Converting Isoxazoles into Diverse Oxazole Products.

A continuous flow process is presented, which directly converts isoxazoles into their oxazole counterparts via a photochemical transposition reaction. This results in the first reported exploitation of this transformation to establish its scope and synthetic utility. A series of various di- and trisubstituted oxazole products bearing different appendages including different heterocyclic moieties were realized through this rapid and mild flow process. Furthermore, the robustness of this approach was demonstrated by generating gram quantities of selected products while also providing insights into likely intermediates.

Copper-Catalyzed Three-Component Domino Cyclization for the Synthesis of 4-Aryl-5-(arythio)-2-(trifluoromethyl)oxazoles.

A copper-catalyzed oxidative cyclization of oxime, arylthiol, and trifluoroacetic anhydride for the construction of trisubstituted oxazoles has been developed. This transformation combines N-O bond cleavage, C-H functionalization, and intramolecular annulation, providing a practical protocol for the introduction of a trifluoromethyl (-CF3) group at oxazole rings.

A Highly Efficient Heterogeneous Copper-Catalyzed Oxidative Cyclization of Benzylamines and 1,3-Dicarbonyl Compounds To Give Trisubstituted Oxazoles

The heterogeneous copper-catalyzed cascade oxidative cyclization between benzylamines and 1,3-dicarbonyl compounds was achieved by using the 3-(2-aminoethylamino)propyl-functionalized MCM-41-immobilized copper(II) complex [MCM-41-2N-Cu(OAc)2] as catalyst and t-BuOOH (TBHP) as oxidant, with iodine as additive, under mild conditions, yielding a wide variety of 2,4,5-trisubstituted oxazoles in mostly good to excellent yields. This heterogeneous copper catalyst can be facilely prepared via a simple two-step procedure from readily available and inexpensive reagents and exhibits a slightly higher activity than Cu(OAc)2. MCM-41-2N-Cu(OAc)2 is also easy to recover and can be recycled up to eight times with almost consistent activity. The reaction is the first example of heterogeneous copper-catalyzed intermolecular cyclization for the construction of polysubstituted oxazoles.

Synthesis of 2,4,5-Trisubstituted Oxazoles via Pd-Catalyzed C-H Addition to Nitriles/Cyclization Sequences.

A practical and flexible intermolecular protocol for the diverse synthesis of trisubstituted oxazole derivatives via a Pd-catalyzed direct C-H addition of electronic-rich heteroarenes to O-acyl cyanohydrins bearing an α-hydrogen/cyclization sequence is described. A wide range of trisubstituted oxazoles can be prepared from readily available starting materials in good to high yields with high efficiency under redox neutral reaction conditions.

Macrocyclic Core of Salarin C: Synthesis and Oxidation.

The synthesis of the macrocyclic core of the cytotoxic natural product salarin C from the sponge Fascaplysinopsis sp. is described, with the two epoxides being replaced by alkene moieties. In the key step, ring-closing metathesis exclusively afforded the ( E)-product. NOESY-based conformational analysis of the macrolactone showed that the oxazole ring and its unsaturated side chains are located in a common plane. Mimicking the conversion of salarin C to salarin A, the trisubstituted oxazole unit embedded in the 17-membered ring underwent photooxidation on treatment with singlet oxygen, affording macrocyclic trisacylamines.

Copper-Catalyzed Oxygenation Approach to Oxazoles from Amines, Alkynes, and Molecular Oxygen.

A novel and efficient oxygenation approach to trisubstituted oxazoles via a copper-catalyzed aerobic oxidative dehydrogenative annulation of amines, alkynes, and O2 has been developed. This transformation combines dioxygen activation and oxidative C-H bond functionalization and provides a practical protocol for the preparation of oxazole derivatives, which are privileged units found in various bioactive compounds or other natural products. 18O-labeling experiments were conducted to reveal that oxygenation was involved in this chemistry.