N-Trifluoromethyl Hydrazines,Indoles and Their Derivatives

Reported herein is the first efficient strategy to synthesize a broad range of unsymmetrical N-CF₃ hydrazines, which served as platform to unlock numerous currently inaccessible derivatives, such as tri- and tetra-substituted N-CF₃ hydrazines, hydrazones, sulfonyl hydrazines, and valuable N-CF₃ indoles. These compounds proved to be remarkably robust, being compatible with acids, bases, and a wide range of synthetic manipulations. The feasibility of RN(CF₃)-NH₂ to function as a directing group in C−H functionalization is also showcased.     

Models for the Carbonyl–ene Cyclization Reaction: Open and Closed Transition States

Different cyclization products are formed with different Lewis acids in the ene cyclization of 5-hexenals (see scheme on the right; a: methylaluminum bisphenoxide, b: Me₂AlCl, c: Sc(OSO₂CF₃)₃). This is not surprising, but it is gratifying that these result can be rationalized with an internally consistent model.     

Concise access to enantiopure (S)- and (R)-α-trifluoromethyl pyroglutamic acids from ethyl trifluoropyruvate-based chiral CF3-oxazolidines (Fox)

A straightforward synthesis of enantiopure (S)- and (R)-α-Tfm-pyroglutamic acid is reported. The strategy is based on the use of a chiral CF₃-hydroxymorpholinone intermediate conveniently obtained from ethyl trifluoropyruvate-based chiral CF₃-oxazolidines (Fox). The key step is an oxidative cyclization followed by a reductive cleavage of the (R)-phenylglycinol chiral auxiliary.     

Azoltrifluormethylschwefeldifluoride

Azoltrifluoromethylsulfurdifluorides From CF₃SF₃ and the silylated azoles N‐trimethylsilylpyrazole, N‐trimethylsilylimidazole, and 1‐trimethylsilyl‐1,2,4‐triazole the corresponding azole trifluoromethyl sulfurdifluorides Az–SF₂–CF₃ were prepared in 30–40% yield (Az = pyrazole, imidazole, 1,2,4‐triazole). The X‐ray structure of the pyrazole derivative was determined.     

A one-pot tandem oxidation-reduction protocol for the synthesis of cyclic ethers from their diols

A novel and an efficient one-pot cyclization method for the preparation of cyclic ethers from their diols via a tandem oxidation-reduction protocol using a cocktail of MnO₂/Et₃SiH/CF₃COOH is reported.     

Cu/Pd Synergistic Dual Catalysis: Asymmetric α‐Allylation of an α‐CF3 Amide

Despite the burgeoning demand for fluorine‐containing chemical entities, the construction of CF₃‐containing stereogenic centers has remained elusive. Herein, we report the strategic merger of Cu^I/base‐catalyzed enolization of an α‐CF₃ amide and Pd⁰‐catalyzed allylic alkylation in an enantioselective manner to deliver chiral building blocks bearing a stereogenic carbon center connected to a CF₃, an amide carbonyl, and a manipulable allylic group. The phosphine complexes of Cu^I and Pd⁰ engage in distinct catalytic roles without ligand scrambling to render the dual catalysis operative to achieve asymmetric α‐allylation of the amide. The stereoselective cyclization of the obtained α‐CF₃‐γ,δ‐unsaturated amides to give tetrahydropyran and γ‐lactone‐fused cyclopropane skeletons highlights the synthetic utility of the present catalytic method as a new entry to non‐racemic CF₃‐containing compounds.     

Iron-Catalyzed Trifluoromethylation of Indole-Tethered Alkene Enables Synthesis of CF3-Containing Spiroindolenines and Tetrahydrocarbazoles

An iron-catalyzed trifluoromethylation of indole-tethered alkene with Togni's reagent to construct CF₃-containing spiro[indole-3,3′-pyrrolidine] and tetrahydrocarbazole derivatives under mild and convenient conditions has been disclosed. Mechanistic studies indicate that the reaction proceed through a CF₃ radical addition to the alkene, followed by sequential dearomatizing spiocyclization of the indole and oxidation to afford the spiro[indole-3,3′-pyrrolidine] derivatives. Meanwhile, when the substituent at the C2 position of the indole is hydrogen, the CF₃-containing tetrahydrocarbazole is obtained through trifluoromethylation of alkene and cyclization of indole.     

Aza-Nazarov cyclization cascades

Benzamides with tethered acetal groups undergo reactions in CF₃SO₃H to give ring-fused isoindolinones by a cyclization cascade. The reaction initially forms an N-acyliminium ion which then gives the isoindolinone by the aza-Nazarov reaction. An unusual variant also cyclizes at the allylic position.     

Cu/Pd Synergistic Dual Catalysis: Asymmetric α-Allylation of an α-CF3 Amide

Despite the burgeoning demand for fluorine-containing chemical entities, the construction of CF₃-containing stereogenic centers has remained elusive. Herein, we report the strategic merger of Cu^I/base-catalyzed enolization of an α-CF₃ amide and Pd⁰-catalyzed allylic alkylation in an enantioselective manner to deliver chiral building blocks bearing a stereogenic carbon center connected to a CF₃, an amide carbonyl, and a manipulable allylic group. The phosphine complexes of Cu^I and Pd⁰ engage in distinct catalytic roles without ligand scrambling to render the dual catalysis operative to achieve asymmetric α-allylation of the amide. The stereoselective cyclization of the obtained α-CF₃-γ,δ-unsaturated amides to give tetrahydropyran and γ-lactone-fused cyclopropane skeletons highlights the synthetic utility of the present catalytic method as a new entry to non-racemic CF₃-containing compounds.     

Triflic acid promoted synthesis of polycyclic aromatic compounds

The triflic acid (CF₃SO₃H) promoted cyclizations of 2-styrylbiaryls are found to be useful for the synthesis of polycyclic aromatic compounds, including functionalized derivatives of polycyclic aromatic compounds and heterocyclic systems. The reaction involves cationic cyclization followed by an elimination of benzene from the intermediate product.     

New catalyst for the synthesis of 2-Phenyl-1,2,3-triazole

A new catalyst was developed for the synthesis of 2-phenyl-1,2,3-triazole: copper triflate Cu(OSO₂CF₃)₂. The process of cyclization of glyoxal phenylosazone in the presence of Cu(OSO₂CF₃)₂ was optimized that made it possible to increase the yield of the target product to 82%.     

Synthesis of polyfluorinated 4-phenyl-3,4-dihydroquinolin-2-ones and quinolin-2-ones via superacidic activation of N-(polyfluorophenyl)cinnamamides

The cyclization reactions of a series of polyfluorocinnamanilides in triflic acid (CF₃SO₃H) yield 4-phenyl-3,4-dihydroquinolin-2-ones, which include a polyfluorinated benzene moiety as a part of the quinoline scaffold. These compounds undergo dehydrophenylation in the presence of AlCl₃ to give the corresponding polyfluoroquinolin-2-ones which are converted into polyfluorinated 2-chloroquinolines on treatment with POCl₃. A mechanism for the cyclization reaction presuming the intermediacy of a superelectrophilic O,C-diprotonated form of the starting material is suggested.     

Synthesis of 4,5-disubstituted-3-trihalomethylisothiazoles

Herein, we describe the synthesis of 4,5-disubstituted-3-trihalomethylisothiazoles from trihaloacetonitriles and 2-cyanothioacetamides or 2-ethoxycarbonylthioacetamides. The reactivity of the necessary trihaloacetonitriles has a significant impact on the observed reaction pathways. Reactions with CF₃CN require an oxidant to mediate cyclization, while CCl₃CN functions as both the reactant and oxidant.     

CF3SO2Na as a Bifunctional Reagent: Electrochemical Trifluoromethylation of Alkenes Accompanied by SO2 Insertion to Access Trifluoromethylated Cyclic N‐Sulfonylimines

An unprecedented electrochemical trifluoromethylation/SO₂ insertion/cyclization process has been achieved in an undivided cell in an atom‐economic fashion. The protocol relies on tandem cyclization of N‐cyanamide alkenes by using Langlois’ reagent as a source of both CF₃ and SO₂ under direct anodically oxidative conditions, in which two C?C bonds, two C?X bonds (N?S and S?C), and two rings were formed in a single operation. This transformation enabled efficient construction of various trifluoromethylated cyclic N‐sulfonylimines from readily accessible materials.     

CF3SO2Na as a Bifunctional Reagent: Electrochemical Trifluoromethylation of Alkenes Accompanied by SO2 Insertion to Access Trifluoromethylated Cyclic N-Sulfonylimines

An unprecedented electrochemical trifluoromethylation/SO₂ insertion/cyclization process has been achieved in an undivided cell in an atom-economic fashion. The protocol relies on tandem cyclization of N-cyanamide alkenes by using Langlois’ reagent as a source of both CF₃ and SO₂ under direct anodically oxidative conditions, in which two C−C bonds, two C−X bonds (N−S and S−C), and two rings were formed in a single operation. This transformation enabled efficient construction of various trifluoromethylated cyclic N-sulfonylimines from readily accessible materials.     

Synthesis of 2-substituted-7-azaindoles from 2-amino-3-picolin

An easy route to the synthesis of 2-substituted-7-azaindole derivatives has been developed. The carbinol intermediate dissolved in DMF undergoes cyclization upon treatment with sodium hydride, trifluoroacetic anhydride, and trifluoroacetic acid at 120 °C in a straightforward and one-pot step. An alternative methodology using (CF₃SO₂)₂O in acetonitrile in basic media followed by the addition of CF₃COOH affords the expected 2-substituted azaindole in best yields.     

Superacid-promoted synthesis of indolizidine derivatives

A series of amido-acetals were reacted with the Brønsted superacid, CF₃SO₃H, to provides indolizidine derives by a cyclization cascade. A mechanism is proposed involving formation of a vinylogous enol which undergoes a 6π-electrocyclization reaction with an adjacent N-acyl iminium ion group. With aryl substituents, there is a strong tendency for the N-acyl iminium ion group to undergo Friedel-Crafts type cyclizations with the aryl group. The synthetic methodology was used to prepare the alkaloid natural product, ipalbidine.     

Visible-light-induced dearomative spirocyclization of N-benzylacrylamides toward perfluorinated azaspirocyclic cyclohexadienones

A feasible approach to 2-azaspirocyclic cyclohexadienones via visible-light-induced perfluoroalkylation cyclization of N-benzylacrylamides was reported. Using R_f-X (X = I or Br) as the R_f radical source, the reaction underwent a cascade radical addition/dearomative cyclization process by Ir photocatalyst, leading to various 2-azaspiro[4.5]deca-6,9-diene-3,8-diones bearing perfluorinated groups including CF₃, n-C₃F₇, n-C₄F₉, n-C₆F₁₃, n-C₈F₁₇, n-C₁₀F₂₁, CH₂CF₂ and CF₂CO₂Et.     

Synthesis and x-ray crystal structure of a tripeptidic cyclol

Properties, spectral data and X-ray crystallographic analysis of a tetracyclic tripeptidic aza-cyclol, obtained by cyclization of CF₃COOH·Pro-Phe-Pro-CNp in aqueous medium, are reported.     

S‐((Phenylsulfonyl)difluoromethyl)thiophenium Salts: Carbon‐Selective Electrophilic Difluoromethylation of β‐Ketoesters, β‐Diketones,and Dicyanoalkylidenes

S‐((Phenylsulfonyl)difluoromethyl)thiophenium salts were designed and prepared by a triflic acid catalyzed intramolecular cyclization of ortho‐ethynyl aryldifluoromethyl sulfanes. The thiophenium salts were found to be efficient as electrophilic difluoromehtylating reagents for introduction of a CF₂H group to sp³‐hybridized carbon nucleophiles such as of β‐ketoesters and dicyanoalkylidenes. The (phenylsulfonyl)difluoromethyl group can be readily transformed into CF₂H under mild reaction conditions. Enantioselective electrophilic difluoromethylation was also achieved in the presence of bis(cinchona) alkaloids.