Synthesis of N-Aryl-4-trifluoromethylthiazol-2-amines via Insertion/Annulation of Trifluoromethylimidoyl Sulfoxonium Ylides with Sodium Thiocyanate.

An efficient p-TsOH-mediated insertion of sodium thiocyanate into trifluoromethylimidoyl sulfoxonium ylides has been reported, affording annulated N-aryl-4-trifluoromethylthiazol-2-amines in 42-84% yields in a one-pot manner. This protocol encompasses a variety of trifluoromethylimidoyl sulfoxonium ylides with thiocyanate serving as the source of the "S-C═N" moiety of the thiazole ring. The versatile transformations of the resulting pharmacologically important N-aryl-4-trifluoromethylthiazol-2-amines were also demonstrated.

Lithium Bromide-Promoted Formal C(sp3)-H Bond Insertion Reactions of ß-Carbonyl Esters with Sulfoxonium Ylides to Synthesize 1,4-Dicarbonyl Compounds.

A LiBr-promoted formal C(sp3)-H bond insertion reaction between ß-carbonyl esters and sulfoxonium ylides is established. This practical reaction has a wide range of substrate scope for both ß-carbonyl esters and sulfoxonium ylides to give a variety of 1,4-dicarbonyl compounds with 43-94% yields. The reaction features transition-metal-free reaction conditions and exclusive C-alkylation chemselectivity. The use of bench-stable sulfoxonium ylides overcomes previous methods that require transition metal as catalysts and unstable diazo compounds or toxic haloketones as alkylation reagents.

Recent advances in the synthesis of trifluoromethyl-containing heterocyclic compounds via trifluoromethyl building blocks.

Trifluoromethylated heterocyclic compounds have played an increasingly significant role in pharmaceuticals, agrochemicals, and materials. This is because the introduction of trifluoromethyl could enhance the lipophilicity, metabolic stability, and pharmacokinetic properties of heterocyclic drug molecules. Therefore, the synthesis of trifluoromethylated heterocyclics has become a major subject of research. The construction of trifluoromethylated heterocyclics via the annulation of trifluoromethyl building blocks with suitable partners has been proved to be a powerful strategy. In this review, we systematically summarize and discuss recent advances in the preparation of trifluoromethyl-containing heterocyclics via trifluoromethyl building block strategies over the period from 2019 to the present.

Solvent-Controlled Enantiodivergent Construction of P(V)-Stereogenic Molecules via Palladium-Catalyzed Annulation of Prochiral N-Aryl Phosphonamides with Aromatic Iodides.

In this work, we describe an efficient and modular method for enantiodivergent accessing P(V)-stereogenic molecules by utilizing the catalytic atroposelective Catellani-type C-H arylation/desymmetric intramolecular N-arylation cascade reaction. The enantioselectivity of this protocol was proved to be tuned by the polarity of the solvent, thus providing a wide range of both chiral P(V)-stereogenic enantiomers in moderate to good yields with good to excellent enantiomeric excesses. Noteworthy is that the strategy developed herein represents an unprecedented example of solvent-dictated inversion of the enantioselectivity of P(V)-stereogenic compounds.

Palladium-Catalyzed Multicomponent Assembly of (Z)-Alkenylborons via Carbopalladation/Boronation/Retro-Diels-Alder Cascade Reaction.

A palladium-catalyzed multicomponent cascade reaction of aryl iodides, oxanorbornadiene, and diborns to access (Z)-alkenylborons is reported. This transformation proceeds through the sequential carbopalladation/boronation/retro-Diels-Alder domino reaction. The oxanorbornadiene used in this reaction serves as an acetylene surrogate, which is generated via a retro-Diels-Alder reaction. Such a stereoselective and scalable approach has a wide range of functional group tolerance and good substrate universality.

Transition-Metal-, Additive-, and Solvent-Free [3 + 3] Annulation of RCF2-Imidoyl Sulfoxonium Ylides with Cyclopropenones to Give Multifunctionalized CF3-Pyridones.

An efficient and practical strategy was developed to synthesize 1,3,4-triaryl-6-trifluoromethylpyridones from CF3-imidoyl sulfoxonium ylides and cyclopropenones in good to excellent yields. This stepwise [3 + 3] annulation reaction was carried out under transition-metal-, additive-, and solvent-free conditions, generating 1 equiv of dimethyl sulfoxide as byproduct and tolerating a series of functional groups.

Regioselective Synthesis of 2,4-Diaryl-6-trifluoromethylated Pyridines through Copper-Catalyzed Cyclization of CF3-Ynones and Vinyl Azides.

A novel copper-catalyzed cyclization of readily available vinyl azides with CF3-ynones is steadily achieved under mild conditions to furnish the versatile 2,4-diaryl-6-trifluoromethylated pyridine products, which are of great interest in medicinal chemistry. The generation of the vinyl iminophosphorane intermediates from vinyl azides through the Staudinger-Meyer reaction ensures the subsequent 1,4-addition process with CF3-ynones in this transformation.

Base-Promoted Stereoselective Hydrogenation of Ynamides with Sulfonyl Hydrazide to Give Z-Enamides.

A base-mediated semihydrogenation of ynamides using p-toluenesulfonyl hydrazide as an inexpensive and easy-to-handle hydrogen donor is reported. This transition-metal-free protocol avoids overhydrogenation and reduction of other functional groups, generating the thermodynamically unfavorable Z-enamides exclusively.

Modular and Stereoselective Synthesis of C-Aryl Glycosides via Catellani Reaction.

In this work, we describe a Catellani-type C-H glycosylation to provide rapid access to various highly decorated α-C-(hetero)aryl glycosides in a modular and stereoselective manner (>90 examples). The termination step is flexible, which is demonstrated by ipso-Heck reaction, hydrogenation, Suzuki coupling, and Sonogashira coupling. Application of this methodology has been showcased by preparing glycoside-pharmacophore conjugates and a dapagliflozin analogue. Notably, the technology developed herein represents an unprecedented example of Catellani-type alkylation involving an SN1 pathway.

Ruthenium(II)-Catalyzed Construction of Isocoumarins via Dual C-H/C-C Activation of Sulfoxonium Ylides.

A ruthenium(II)-catalyzed annulation between two molecules of sulfoxonium ylides is achieved, generating a variety of substituted isocoumarins in reasonable yields. This strategy features dual C-H/C-C activation in one pot and has a wide substrate scope and good functional group tolerance.

Palladium-Catalyzed Chemoselective Synthesis of 2-Aminocinnamyl Esters via Sequential Amination and Olefination of Aryl Iodides.

We report a highly chemoselective palladium-catalyzed Catellani-type amination of aryl iodides terminated by the Heck reaction using allylic esters as terminating reagents. 2-Aminocinnamyl esters were formed exclusively via ß-H elimination rather than ß-OAc elimination without the assistance of a silver salt. This protocol represents a useful extension of Catellani-type transformations.

Catalytic Enantioselective [2+2] Cycloaddition of α-Halo Acroleins: Construction of Cyclobutanes Containing Two Tetrasubstituted Stereocenters.

A catalytic enantioselective formal [2+2] cycloaddition between α-halo acroleins and electronically diverse arylalkenes is described. In the presence of (S)-oxazaborolidinium cation as the catalyst, densely functionalized cyclobutanes containing two vicinal tetrasubstituted stereocenters were produced in high yields and high diastereoselectivities with excellent enantioselectivities. Mechanistic studies revealed that the cis isomer could be transformed into the trans isomer via an enantiocontrolled process. A gram-scale reaction of this catalytic method was used to demonstrate its synthetic potential.

Palladium-Catalyzed ortho-C-H Methylation of Benzoic Acids.

A palladium-catalyzed methylation of C-H bonds of benzoic acids with di-tert-butyl peroxide as the methylating reagent under an external oxidant and ligand-free conditions has been achieved. The reaction is found to be directed by a weakly coordinating carboxyl group, offering a facile route for the synthesis of highly functionalized ortho-methyl benzoic acids.

Palladium-Catalyzed Catellani-Type Bis-silylation and Bis-germanylation of Aryl Iodides and Norbornenes.

A palladium-catalyzed three-component reaction of aryl iodides, norbornenes, and hexamethyldisilane/hexamethyldigermane has been developed for the assembly of highly functionalized disilanes/digermanes. The potential synthetic utility of this methodology was highlighted by the late-stage manipulations of natural products and the iterative C-H bis-silylation for the synthesis of highly decorated arenes.

Synthesis of 2-Aminopyridines via a Base-Promoted Cascade Reaction of N-Propargylic ß-Enaminones with Formamides.

N-Substituted formamides as nucleophiles react with in situ-generated 1,4-oxazepines from N-propargylic ß-enaminones followed by spontaneous N-deformylation to deliver densely substituted 2-aminopyridines in good yields (31-88%). The formyl group is found to be a superior traceless activating group of free amines and would ultimately be removed in situ. This reaction proceeds smoothly at room temperature, in the presence of NaOH as sole additive, without protection from the atmosphere and generates H2O and sodium formate as byproducts.

Ligand-Enabled meta-Selective C-H Arylation of Nosyl-Protected Phenethylamines, Benzylamines, and 2-Aryl Anilines.

A Pd-catalyzed, meta-selective C-H arylation of nosyl-protected phenethylamines and benzylamines is disclosed using a combination of norbornene and pyridine-based ligands. Subjecting nosyl protected 2-aryl anilines to this protocol led to meta-C-H arylation at the remote aryl ring. A diverse range of aryl iodides are tolerated in this reaction, along with select heteroaryl iodides. Select aryl bromides bearing ortho-coordinating groups can also be utilized as effective coupling partners in this reaction. The use of pyridine ligands has allowed the palladium loading to be reduced to 2.5 mol %. Furthermore, a catalytic amount of 2-norbornene (20 mol %) to mediate this meta-C-H activation process is demonstrated for the first time. Utilization of a common protecting group as the directing group for meta-C-H activation of amines is an important feature of this reaction in terms of practical applications.

Transition-Metal-Free Cascade Approach toward 2-Alkoxy/2-Sulfenylpyridines and Dihydrofuro[2,3-b]pyridines by Trapping In Situ Generated 1,4-Oxazepine.

An efficient cascade reaction via trapping in situ generated active intermediate 1,4-oxazepine, formed from base-promoted 7-exo-dig cyclization reaction of N-propargyl enaminone, has been developed. Alcohols/thiols and aldehydes were used as trapping agents, providing 2-alkoxy/2-sulfenylpyridines and dihydrofuro[2,3-b]pyridines in moderate to high yields. This cascade reaction was completed within 30 min at room temperature, generating 1 equiv of H2O as the sole byproduct.

meta-C-H Arylation and Alkylation of Benzylsulfonamide Enabled by a Palladium(II)/Isoquinoline Catalyst.

Palladium(II)-catalyzed meta-C-H arylation and alkylation of benzylsulfonamide using 2-carbomethoxynorbornene (NBE-CO2 Me) as a transient mediator are realized by using a newly developed electron-deficient directing group and isoquinoline as a ligand. This protocol features broad substrate scope and excellent functional-group tolerance. The meta-substituted benyzlsulfonamides can be readily transformed into sodium sulfonates, sulfonate esters, and sulfonamides, as well as styrenes by Julia-type olefination. The unique impact of the isoquinoline ligand underscores the importance of subtle matching between ligands and the directing groups.

Access to C4-Functionalized Quinolines via Copper-Catalyzed Tandem Annulation of Alkynyl Imines with Diazo Compounds.

An efficient synthesis of C4-functionalized quinolines through copper-catalyzed tandem annulation of alkynyl imines with diazo compounds is described. This transformation involves an in situ formation of allene and intramolecular electrocyclization, which features high efficiency, mild reaction conditions, easy operation, and broad functional-group tolerance. A wide variety of C4-functionalized quinolines were provided in up to 92% yield for 33 examples.

Practical Pd(II)-Catalyzed C-H Alkylation with Epoxides: One-Step Syntheses of 3,4-Dihydroisocoumarins.

Pd(II)-catalyzed ortho-alkylation of benzoic acids with both terminal and internal epoxides affords 3,4-dihydroisocoumarins in one step. The presence of potassium countercations is crucial for this reaction. Monoprotected amino acid ligands significantly promote this reaction, enabling the development of a practical C-H alkylation reaction using 0.5 mol % Pd catalyst. The inversion of stereochemistry in the C-H alkylation step is consistent with a redox-neutral SN2 nucleophilic ring-opening process as opposed to a Pd(II)/Pd(IV) pathway.