Synthesis of Fully Substituted Difluoromethylpyrazoles by Cyclization of Difluoroacetohydrazonoyl Bromides with 2-Acylacetonitriles or Malononitrile.

A concise and efficient method for the construction of fully substituted difluoromethylpyrazoles is achieved by a cyclization reaction between difluoroacetohydrazonoyl bromides and 2-acylacetonitrile or malononitrile. The method features advantages such as mild reaction conditions, broad substrate scope, good product yields, and high regioselectivity.

[3 + 2] Cycloaddition Reaction of Vinylsulfonium Salts with Hydrazonoyl Halides: Synthesis of Pyrazoles.

An efficient [3 + 2] cycloaddition reaction between in situ generated nitrile imines from hydrazonoyl halides and vinylsulfonium salts is developed. The nitrile imines are demonstrated to be a new class of reaction partner for vinylsulfonium salts to conduct the [3 + 2] cycloaddition reaction. The process provides a concise and efficient method for the construction of pyrazole derivatives under mild reaction conditions with broad substrate scope, good product yields, and high regioselectivity.

Synthesis of difluoromethylated spiropyrazolones via [3 + 2] cycloaddition of difluoroacetohydrazonoyl bromides with alkylidene pyrazolones.

An effective [3 + 2] cycloaddition reaction of difluoromethyl or trifluoromethyl hydrazonoyl bromides with alkylidene pyrazolones was disclosed. This method provides an efficient approach for accessing a variety of highly functionalized fluoroalkyl spiropyrazolones in good yields. This protocol also features some advantages such as easily available and stable substrates, simple operation procedures, and atom and step economy. The formation of (cis)- and (trans)-products was discussed.

Tandem Addition/Cyclization/Halogenation Reaction of Difluoromethylated N-Acylhydrazones with Allyltrimethylsilanes.

As novel difluoromethyl building blocks, difluoromethylated N-acylhydrazones react with allyltrimethylsilanes and the halogen source via a tandem addition/cyclization/halogenation strategy, which produces various difluoromethylpyrazoline compounds in good yields. The method features mild reaction conditions, broad substrate scopes, and a transition metal-free process with easy operation. It also proves that difluoromethylated N-acylhydrazones are useful difluoromethyl building blocks for the construction of difluoromethylated nitrogen heterocycles.

The cyclization/rearrangement of α-hydroxy ketones with trifluoromethyl N-acylhydrazones to synthesize multi-substituted trifluoromethyloxazolines.

A highly efficient and metal-free [3+2] cyclization/rearrangement reaction toward the synthesis of multisubstituted trifluoromethyloxazolines from α-hydroxyketones and trifluoromethyl N-acylhydrazones has been developed. The unprecedented rearrangement of the amide fragment under acidic conditions after cleavage of the N-N bond of acylhydrazones has opened up new avenues for the development of reactions involving trifluoromethyl N-acylhydrazones. DFT calculations show that the mechanism involves multiple proton transfer processes.

Visible-Light-Induced Four-Component Ritter-Type Reaction: Access to ß-Trifluoromethyl Imides.

A visible-light-induced four-component Ritter-type reaction was developed for the synthesis of ß-trifluoromethyl imides from CF3Br, alkenes, carboxylic acids, and nitriles. This protocol features mild reaction conditions, a broad substrate scope, and excellent functional group compatibility. Furthermore, this method has been proven to be suitable for the late-stage diversification of drug molecules. A mechanism involving a Ritter-type reaction and Mumm rearrangement was proposed on the basis of the control experiments.

Visible Light Promotes Cascade Trifluoromethylation/Cyclization, Leading to Trifluoromethylated Polycyclic Quinazolinones, Benzimidazoles and Indoles.

Efficient visible-light-induced radical cascade trifluoromethylation/cyclization of inactivated alkenes with CF3Br, which is a nonhygroscopic, noncorrosive, cheap and industrially abundant chemical, was developed in this work, producing trifluoromethyl polycyclic quinazolinones, benzimidazoles and indoles under mild reaction conditions. The method features wide functional group compatibility and a broad substrate scope, offering a facile strategy to pharmaceutically produce valuable CF3-containing polycyclic aza-heterocycles.

Photoinduced Trifluoromethylation with CF3Br as a Trifluoromethyl Source: Synthesis of α-CF3-Substituted Ketones.

An efficient and novel photoinduced trifluoromethylation employing CF3Br as a trifluoromethyl source is described. With commercially accessible fac-Ir(III)(ppy)3 as the catalyst, radical trifluoromethylation between O-silyl enol ether and CF3Br occurs successfully. This method provides various α-CF3-substituted ketones with a broad substrate scope in good yields under mild reaction conditions.

Synthesis of 3-Trifluoromethyl-1,2,4-triazolines and 1,2,4-Triazoles via Tandem Addition/Cyclization of Trifluoromethyl N-Acylhydrazones with Cyanamide.

A tandem addition/cyclization reaction between trifluoromethyl N-acylhydrazones and cyanamide is described, which provides a novel and efficient process for the synthesis of polysubstituted 3-trifluoromethyl-1,2,4-triazolines and their derivatives. The method has the advantages of mild reaction conditions, a broad substrate scope, good product yields, and atom economy.

Synthesis of Difluoromethylated Pyrazoles by the [3 + 2] Cycloaddition Reaction of Difluoroacetohydrazonoyl Bromides.

As novel and efficient difluoromethyl building blocks, difluoroacetohydrazonoyl bromides have been synthesized for the first time. The synthetic utility of this reagent for the construction of difluoromethyl organic compounds is demonstrated by their effective regioselective [3 + 2] cycloaddition reactions with ynones, alkynoates, and ynamides. The reactions provide a novel and efficient protocol to access difluoromethyl-substituted pyrazoles in good to excellent yields.

Synthesis of CF3-Substituted 1,6-Dihydropyridazines by Copper-Promoted Cascade Oxidation/Cyclization of Trifluoromethylated Homoallylic N-Acylhydrazines.

A highly efficient strategy for the construction of CF3-substituted 1,6-dihydropyridazines has been developed by cascade oxidation/cyclization of trifluoromethylated N-acylhydrazines. The produced 1,6-dihydropyridazines could be easily transformed to 3-trifluoromethyl pyridazine derivatives. Some of the 1,6-dihydropyridazines exhibited aggregation-induced emission (AIE). DFT calculations were conducted to explain the mechanism.

Diastereoselective synthesis of spiro-cyclopropanyl-cyclohexadienones via direct sulfide-catalyzed [2 + 1] annulation of para-quinone methides with bromides.

An efficient sulfide-catalyzed [2 + 1] annulation of para-quinone methides (p-QMs) with diverse bromides has been achieved. This catalytic strategy provides an efficient and straightforward protocol for accessing a variety of spiro-cyclopropanyl-cyclohexadienone compounds in good to excellent yields (64% to 96% yields) with outstanding diastereoselectivities (>20 : 1 dr), displaying good functional group tolerance as well as gram-scale capacity.

Visible-light-promoted acyl radical cascade reaction for accessing acylated isoquinoline-1,3(2H,4H)-dione derivatives.

A visible-light-promoted decarboxylative acyl radical acylation/cyclization cascade reaction of N-methacryloylbenzamides for accessing acylated isoquinoline-1,3(2H,4H)-dione derivatives was described. In this report, α-keto acids were used for generating acyl radicals and inducing radical acylations. This protocol features mild reaction conditions, operational practicality and a broad substrate scope.

Synthesis of Polysubstituted Trifluoromethylpyridines from Trifluoromethyl-α,ß-ynones.

A novel and efficient method for synthesis of polysubstituted trifluoromethylpyridine derivatives by the Bohlmann-Rahtz heteroannulation reaction is described, which use trifluoromethyl-α,ß-ynones as trifluoromethyl building blocks to react with ß-enamino esters or ß-enamino ketones in the presence of ZnBr2 to form the trifluoromethylpyridine derivatives in good yields. The protocol has the advantages of readily available starting materials, mild reaction conditions, and high atom economy.

Visible-light induced decarboxylative alkylation of quinoxalin-2(1H)-ones at the C3-position.

A simple and efficient method for the visible light induced direct carbon alkylation of quinoxalin-2(1H)-ones at the C3 position is described. This protocol employs cheap and readily available phenyliodine(iii) dicarboxylates as the alkylation reagents to conduct decarboxylative radical coupling reaction with quinoxalin-2(1H)-ones. The process exhibits excellent compatibility to functional groups and provides a convenient and selective access to various 3-alkylquinoxalin-2(1H)-ones in good yields.

Tin Powder-Promoted Cascade Condensation/Allylation/Lactamization: Synthesis of Isoindolinones and Pyrazoloisoindol-8-ones.

An efficient tin powder-promoted cascade condensation/allylation/lactamization of 2-formylbenzoic acids, hydrazides, and allyl bromides was developed for the synthesis of isoindolinones in good to excellent yields under mild conditions without any other additives or catalysts. Further manipulation of isoindolinones by iodocyclization process afforded the tricyclic tetrahydro-8 H-pyrazolo[5,1- a]isoindol-8-one derivatives, which could be converted into more complicated tetracyclic tetrahydro-4 H-azirino[1',2':2,3]pyrazolo[5,1- a]isoindol-4-ones.

[3 + 2] Cycloaddition of para-Quinone Methides with Nitrile Imines: Approach to Spiro-pyrazoline-cyclohexadienones.

[3 + 2] cycloaddition of para-quinone methides with nitrile imines under mild conditions has been achieved. The corresponding spiro-pyrazoline-cyclohexadienone products were constructed in good to excellent yields (up to 97% yield) with high regioselectivity. This straightforward protocol exhibits good functional group tolerance and scalability and provides the spiro-pyrazoline-cyclohexadienones.

N-Arylations of trifluoromethylated N-acylhydrazones with diaryliodonium salts as arylation reagents.

A novel and efficient N-arylation of trifluoromethylated N-acylhydrazones is described by using diaryliodonium salts as arylation reagents in the presence of copper salts. A wide variety of N-aryl acylhydrazones are obtained with good to excellent yields under mild reaction conditions.

Synthesis of Trifluoroethyl Pyrazolines via Trichloroisocyanuric Acid Promoted Cascade Cyclization/Trifluoromethylation of ß,γ-Unsaturated Hydrazones.

A novel and efficient protocol for the construction of trifluoroethyl pyrazolines has been developed by cascade cyclization/trifluoromethylation reaction of ß,γ-unsaturated hydrazones. This strategy uses cheap and commercially available trichloroisocyanuric acid as promoter and TMSCF3 as the trifluoromethylating reagent, which make the trifluoromethylating process much cheaper. A wide range of substrates can be applied in this process to afford the trifluoroethyl pyrazolines in good yield.

Cascade Oxidation/Halogenoaminocyclization Reaction of Trifluoromethylated Homoallylic N-Acylhydrazines: Metal-free Synthesis of CF3-Substituted Pyrazolines.

An efficient and practical cascade oxidation/halogenoaminocyclization of trifluoromethylated homoallylic N-acylhydrazines is developed. The protocol enables an efficient access to various biologically interesting CF3-containing pyrazoline compounds from readily accessible trifluoromethylated homoallylic N-acylhydrazines in good to excellent yields under mild conditions without any other additives or catalysts. The produced pyrazoline compounds can be further manipulated to other more complicated derivatives through transformation of residual halogen atom.