AgF‐Mediated Fluorinative Cross‐Coupling of Two Olefins: Facile Access to α‐CF3 Alkenes and β‐CF3 Ketones

A AgF‐mediated fluorination with a concomitant cross‐coupling between a gem‐difluoroolefin and a non‐fluorinated olefin is reported. This highly efficient method provides facile access to both α‐CF₃ alkenes and β‐CF₃ ketones, which otherwise remain challenging to be directly prepared. The application of this method is further demonstrated by the synthesis of bioactive isoxazoline derivatives. This approach represents a conceptually novel route to trifluoromethylated compounds that combines the in situ generation of the CF₃ moiety and a C? H functionalization in a single reaction system.     

From C1 to C3: Copper‐Catalyzed gem‐Bis(trifluoromethyl)olefination of α‐Diazo Esters with TMSCF3

A Cu‐catalyzed gem‐bis(trifluoromethyl)olefination of α‐diazo esters, using TMSCF₃ as the only fluorocarbon source, has been developed and provides an exquisite method to access gem‐bis(trifluoromethyl)alkenes. This unprecedented olefination process involves a carbene migratory insertion into “CuCF₃” to generate the α‐CF₃‐substituted organocopper species, which then undergoes β‐fluoride elimination and two consecutive addition‐elimination processes to give the desired products. The key to this efficient one‐pot C₁‐to‐C₃ synthetic protocol lies in the controllable double (over single and triple) trifluoromethylations of the gem‐difluoroalkene intermediates.     

Nickel‐Catalyzed Mizoroki–Heck‐ versus Michael‐Type Addition of Organoboronic Acids to α,β‐Unsaturated Alkenes through Fine‐Tuning of Ligands

Various arylboronic acids reacted with activated alkenes in the presence of [Ni(dppe)Br₂], ZnCl₂, and H₂O in CH₃CN at 80 °C to give the corresponding Mizoroki–Heck‐type addition products in good to excellent yields. Furthermore, 1 equivalent of the hydrogenation product of the activated alkene was also produced. By tuning the ligands of the nickel complexes and the reaction conditions, Michael‐type addition was achieved in a very selective manner. Thus, various p‐ and o‐substituted arylboronic acids or alkenylboronic acid reacted smoothly with activated alkenes in CH₃CN at 80 °C for 12 h catalyzed by Ni(acac)₂, P(o‐anisyl)₃, and K₂CO₃ to give the corresponding Michael‐type addition products in excellent yields. However, for m‐substituted arylboronic acids, the yields of Michael‐type addition products are very low. The cause of this unusual meta‐substitution effect is not clear. By altering the solvent or phosphine ligand, the product yields for m‐substituted arylboronic acids were greatly improved. In contrast to previous results in the literature, the present catalytic reactions required water for Mizoroki–Heck‐type products and dry reaction conditions for Michael‐type addition products. Possible mechanistic pathways for both addition reactions are proposed.     

A Regioselective Synthesis of Benzopinacolones through Aerobic Dehydrogenative α‐Arylation of the Tertiary sp3 CH Bond of 1,1‐Diphenylketones with Aromatic and Heteroaromatic Compounds

A regioselective synthesis of symmetrical and unsymmetrical benzopinacolones through aerobic dehydrogenative α‐arylation at the tertiary sp³ C?H bond of substituted 1,1‐diphenylketones with aromatic and heteroaromatic compounds, in the presence of K₂S₂O₈ in CF₃COOH at room temperature, is described. The reaction is proposed to go via a carbocation intermediate, which could be generated directly from cleavage of the sp³ C?H bond of 1,1‐diphenylketone. Subsequent α‐arylation was achieved at the methene sp³ carbon atom of the substituted ketone. A variety of substituted aromatic and heteroaromatic compounds were compatible with this reaction. In addition, benzopinacolones were converted into sterically hindered, tetrasubstituted alkenes and polycyclic aromatic compounds.     

Synthesis of Three‐, Five‐, and Six‐Membered Heterocycles Derived from New β‐Amino‐α‐(trifluoromethyl) Alcohols

Nucleophilic trifluoromethylation of α‐imino ketones 2 , derived from arylglyoxal, with Ruppert–Prakash reagent (CF₃SiMe₃) offers a convenient access to the corresponding O‐silylated β‐imino‐α‐(trifluoromethyl) alcohols. In a ‘one‐pot’ procedure, by treatment with NaBH₄, these products smoothly undergo reduction and desilylation yielding the expected β‐amino‐α‐(trifluoromethyl) alcohols 4 . The latter were used as starting materials for the synthesis of diverse trifluoromethylated heterocycles, including aziridines 5 , 1,3‐oxazolidines 8 , 1,3‐oxazolidin‐2‐ones 9 , 1,3,2‐oxazaphospholidine 2‐oxides 10 , 1,2,3‐oxathiazolidine 2‐oxides 11 , and morpholine‐2,3‐diones 12 . An optically active 5‐(trifluoromethyl)‐substituted 1,3‐oxazolidin‐2‐one 9g was also obtained.     

Nucleophilic Fluoroalkylation of α,β‐Unsaturated Carbonyl Compounds with α‐Fluorinated Sulfones: Investigation of the Reversibility of 1,2‐Additions and the Formation of 1,4‐Adducts

A detailed investigation of the reactions of PhSO₂CF₂H and PhSO₂CH₂F with (E)‐chalcone (=(E)‐1,3‐diphenylprop‐2‐en‐1‐one) at low temperatures revealed that these two reactions were kinetically controlled, and the ratios of 1,2‐ vs. 1,4‐adducts, which did not change much over time at these temperatures, reflect the relative rates of the two reaction pathways. The controlled experiments of converting the PhSO₂CF₂‐ and PhSO₂CHF‐substituted 1,2‐adducts to 1,4‐adducts showed that these isomerizations are not favored due to the low stability and hard‐soft nature of PhSO₂CF and PhSO₂CHF^? anions. Moreover, taking advantage of the remarkable stability and softness of (PhSO₂)₂CF^? anion, an efficient thermodynamically controlled isomerization of (PhSO₂)₂CF‐substituted 1,2‐adduct to 1,4‐adduct was achieved for the first time.     

Copper(I)‐Catalyzed Asymmetric [3+2]‐Cycloaddition of α‐Substituted Iminoesters with α‐Trifluoromethyl α,β‐Unsaturated Esters

Reported herein is an example of highly regio‐, diastereo‐ and enantioselective Cu(I)‐catalyzed intermolecular [3+2] cycloaddition reaction of α‐substituted iminoesters with α‐trifluoromethyl α,β‐unsaturated esters. This novel strategy provided a facile access to pyrrolidines with two skipped (aza)quaternary stereocenters including a CF₃ all‐carbon quaternary stereocenter. A broad substrate scope was observed and high yields (up to 94%) with excellent diastereoselectivity (up to >20 : 1 d.r.) and enantioselectivity (up to 98% ee) were obtained.     

Copper‐Catalyzed Intermolecular Trifluoromethylazidation of Alkenes: Convenient Access to CF3‐Containing Alkyl Azides

A novel copper‐catalyzed intermolecular trifluoromethylazidation of alkenes has been developed under mild reaction conditions. A variety of CF₃‐containing organoazides were directly synthesized from a wide range of olefins, including activated and unactivated alkenes, and the resulting products can be easily transformed into the corresponding CF₃‐containing amine derivatives.     

Electropolymerizable IrIII Complexes with β‐Ketoiminate Ancillary Ligands

A series of electropolymerizable cyclometallated Ir^III complexes were synthesized and their electrochemical and photophysical properties studied. The triphenylamine electropolymerizable fragment was introduced by using triphenylamine‐2‐phenylpyridine and, respectively, triphenylamine‐benzothiazole as cyclometalated ligands. The coordination sphere was completed by two differently substituted β‐ketoiminate ligands deriving from the condensation of acetylacetone or hexafluoroacetylacetone with para‐bromoaniline. The influence of the ‐CH₃/‐CF₃ substitution to the electrochemical and photophysical properties was investigated. Both complexes with CH₃ substituted β‐ketoiminate were emissive in solution and in solid state. Highly stable films were electrodeposited onto ITO coated glass substrates. Their emission was quenched by electron trapping within the polymeric network as proven by electrochemical studies. The ‐CF₃ substitution of the β‐ketoiminate leads instead to the quenching of the emission and inhibits electropolymerization.     

Benzylamine as Hydrogen Transfer Agent: Cobalt‐Catalyzed Chemoselective C=C Bond Reduction of β‐Trifluoromethylated α,β‐Unsaturated Ketones via 1,5‐Hydrogen Transfer

An efficient cobalt‐catalyzed chemoselective reduction of β‐CF₃‐α,β‐unsaturated ketones using benzylamine as hydrogen transfer agent involving intramolecular 1,5‐hydrogen transfer is reported. The reaction proceeded smoothly with a relatively wide range of substrates including those bearing aromatic heterocycles such as a furyl ring system in high yields (74–92 %). This provides an efficient method for the synthesis of β‐CF₃ saturated ketones in one‐pot. This methodology was also applied to the selective C=C reduction of other enone substrates bearing no β‐CF₃‐substituent, of which β‐substituted or β,β‐disubstituted enones are tolerated, giving the desired products in good yields (72–75 %). Mechanistic studies indicate that the reaction involves 1,5‐hydrogen transfer.     

Formation of α‐SF5‐Enolate Enables Preparation of 3‐SF5‐Quinolin‐2‐ones, 3‐SF5‐Quinolines,and 3‐SF5‐Pyridin‐2‐ones: Evaluation of their Physicochemical Properties

This study describes, for the first time, the generation of a SF₅‐substituted ester enolate from benzyl SF₅‐acetate under soft enolization conditions, which in turn participates in aldol addition reactions in high yield. The reaction was applied in the synthesis of 3‐SF₅‐quinolin‐2‐ones, 3‐SF₅‐quinolines, and 3‐SF₅‐pyridin‐2‐ones, none of which have previously been reported. To provide guidelines for their use in drug discovery, the physicochemical properties of these building blocks were determined and compared with those of their CF₃‐ and t‐Bu‐analogues.     

Formation of α‐SF5‐Enolate Enables Preparation of 3‐SF5‐Quinolin‐2‐ones, 3‐SF5‐Quinolines,and 3‐SF5‐Pyridin‐2‐ones: Evaluation of their Physicochemical Properties

This study describes, for the first time, the generation of a SF₅‐substituted ester enolate from benzyl SF₅‐acetate under soft enolization conditions, which in turn participates in aldol addition reactions in high yield. The reaction was applied in the synthesis of 3‐SF₅‐quinolin‐2‐ones, 3‐SF₅‐quinolines, and 3‐SF₅‐pyridin‐2‐ones, none of which have previously been reported. To provide guidelines for their use in drug discovery, the physicochemical properties of these building blocks were determined and compared with those of their CF₃‐ and t‐Bu‐analogues.     

Transfer Hydrocyanation of α‐ and α,β‐Substituted Styrenes Catalyzed by Boron Lewis Acids

A straightforward gram‐scale preparation of cyclohexa‐1,4‐diene‐based hydrogen cyanide (HCN) surrogates is reported. These are bench‐stable but formally release HCN and rearomatize when treated with Lewis acids. For BCl₃, the formation of the isocyanide adduct [(CN)BCl₃]^? and the corresponding Wheland complex was verified by mass spectrometry. In the presence of 1,1‐di‐ and trisubstituted alkenes, transfer of HCN from the surrogate to the C?C double bond occurs, affording highly substituted nitriles with Markovnikov selectivity. The success of this transfer hydrocyanation depends on the Lewis acid employed; catalytic amounts of BCl₃ and (C₆F₅)₂BCl are shown to be effective while B(C₆F₅)₃ and BF₃?OEt₂ are not.     

Oxydifluoromethylation of Alkenes by Photoredox Catalysis: Simple Synthesis of CF2H‐Containing Alcohols

We have developed a novel and simple protocol for the direct incorporation of a difluoromethyl (CF₂H) group into alkenes by visible‐light‐driven photoredox catalysis. The use of fac‐[Ir(ppy)₃] (ppy=2‐pyridylphenyl) photocatalyst and shelf‐stable Hu's reagent, N‐tosyl‐S‐difluoromethyl‐S‐phenylsulfoximine, as a CF₂H source is the key to success. The well‐designed photoredox system achieves synthesis of not only β‐CF₂H‐substituted alcohols but also ethers and an ester from alkenes through solvolytic processes. The present method allows a single‐step and regioselective formation of C(sp³)–CF₂H and C(sp³)?O bonds from C=C moiety in alkenes, such as hydroxydifluoromethylation, regardless of terminal or internal alkenes. Moreover, this methodology tolerates a variety of functional groups.     

Microwave‐Assisted Synthesis of β‐Lactams and Cyclo‐β‐dipeptides

Different cyclo‐β‐dipeptides were prepared from corresponding N‐substituted β‐alanine derivatives under mild conditions using PhPOCl₂ as activating agent in benzene and Et₃N as base. To evaluate β³‐substituent influence, the amino acids 7 – 26 were synthesized, and a β‐lactam formation reaction was carried out instead of cyclo‐β‐dipeptide formation. The crystal structures of three derivatives of cyclo‐β‐peptides and one β‐lactam are presented.     

Synthesis of Some Novel Phenyl Substituted Oxothiazolidin- 1’’,3’’,4’’-thiadiazolo-[3’,4’-b]thiazoline of 3β-Substituted Cholestane

Three title compounds 4a—4c have been synthesized by the cyclodehydration of 1’-benzylidine-4’-(3β-substituted-5α-cholestane-6-yl)thiosemicarbazones 2a—2c with thioglycolic acid followed by the treatment with cold conc. H2SO4 in dioxane. The compounds 2a—2c were prepared by condensation of 3β-substituted-5α-cholestan- 6-one-thiosemicarbazones 1a—1c with benzaldehyde. These thiosemicarbazones 1a—1c were obtained by the reaction of corresponding 3β-substituted-5α-cholestan-6-ones with thiosemicarbazide in the presence of few drops of conc. HCl in methanol. The structures of the products have been established on the basis of their elemental, analytical and spectral data.     

Conformation of Peptides Containing a Chiral α‐Ethylated α,α‐Disubstituted α‐Amino Acid: (S)‐α‐Ethylleucine (=(2S)‐2‐Amino‐2‐ethyl‐4‐methylpentanoic Acid) within Sequences of Dimethylglycine and Diethylglycine Residues

An optically active (S)‐α‐ethylleucine ((S)‐αEtLeu) as a chiral α‐ethylated α,α‐disubstituted α‐amino acid was synthesized by means of a chiral acetal auxiliary of (R,R)‐cyclohexane‐1,2‐diol. The chiral α‐ethylated α,α‐disubstituted amino acid (S)‐αEtLeu was introduced into the peptides constructed from 2‐aminoisobutyric acid (=dimethylglycine, Aib), and also into the peptide prepared from diethylglycine (Deg). The X‐ray crystallographic analysis revealed that both right‐handed (P) and left‐handed (M) 3₁₀‐helical structures exist in the solid state of CF₃CO‐(Aib)₂‐[(S)‐αEtLeu]‐(Aib)₂‐OEt ( 14 ) and CF₃CO‐[(S)‐αEtLeu]‐(Deg)₄‐OEt ( 18 ), respectively. The IR, CD, and ¹H‐NMR spectra indicated that the dominant conformation of pentapeptides 14 and CF₃CO‐[(S)‐αEtLeu]‐(Aib)₄‐OEt ( 16 ) in solution is a 3₁₀‐helical structure, and that of 18 in solution is a planar C₅ conformation. The conformation of peptides was also studied by molecular‐mechanics calculations.     

Homogeneous [RuIII(Me3tacn)Cl3]‐Catalyzed Alkene cis‐Dihydroxylation with Aqueous Hydrogen Peroxide

A simple and green method that uses [Ru(Me₃tacn)Cl₃] ( 1 ; Me₃tacn=N,N′,N′′‐trimethyl‐1,4,7‐triazacyclononane) as catalyst, aqueous H₂O₂ as the terminal oxidant, and Al₂O₃ and NaCl as additives is effective in the cis‐dihydroxylation of alkenes in aqueous tert‐butanol. Unfunctionalized alkenes, including cycloalkenes, aliphatic alkenes, and styrenes (14 examples) were selectively oxidized to their corresponding cis‐diols in good to excellent yield (70–96 %) based on substrate conversions of up to 100 %. The preparation of cis‐1,2‐cycloheptanediol (119 g, 91 % yield) and cis‐1,2‐cyclooctanediol (128 g, 92 % yield) from cycloheptene and cyclooctene, respectively, on the 1‐mol scale can be achieved by scaling up the reaction without modification. Results from Hammett correlation studies on the competitive oxidation of para‐substituted styrenes (ρ=?0.97, R=0.988) and the detection of the cycloadduct [(Me₃tacn)ClRuHO₂(C₈H₁₄)]⁺ by ESI‐MS for the 1 ‐catalyzed oxidation of cyclooctene to cis‐1,2‐cyclooctanediol are similar to those of the stoichiometric oxidation of alkenes by cis‐[(Me₃tacn)(CF₃CO₂)Ru^VIO₂]⁺ through [3+2] cycloaddition (W.‐P. Yip, W.‐Y. Yu, N. Zhu, C.‐M. Che, J. Am. Chem. Soc. 2005 , 127, 14239).     

Asymmetric Construction of Pyrrolidines Bearing a Trifluoromethylated Quaternary Stereogenic Center via CuI‐Catalyzed 1,3‐Dipolar Cycloaddition of Azomethine Ylides with β‐CF3‐β,β‐Disubstituted Nitroalkenes

A direct and convenient method has been developed for the synthesis of optically active pyrrolidines bearing a quaternary stereogenic center containing a CF₃ group at the C‐3 position of the pyrrolidine ring. The synthesis system, Cu^I/Si‐FOXAP‐catalyzed exo‐selective 1,3‐dipolar cycloaddition of azomethine ylides with β‐CF₃‐β,β‐disubstituted nitroalkenes, provides pyrrolidines with high diastereoselectivities (up to >98:2 d.r.) and excellent enantioselectivities (up to >99.9 ee) and performs well for a broad scope of substrates under mild conditions.     

Efficient Synthesis of α‐Benzylidene‐γ‐methyl‐γ‐butyrolactones

A concise synthesis of α‐benzylidene‐γ‐methyl‐γ‐butyrolactones 5a – g from substituted benzaldehydes is described. Compounds 1a – g on reaction with phosphorane 2 , provide the pentenoates 3a – g , which can be hydrolyzed to the acids 4a – g . The latter are cyclized to the corresponding butyrolactones 5a – g in excellent yields. The pentenoates 3a – g , on acid catalyzed cyclization, also provide 5a – g in very high yields.