Synthesis of α‐Trifluoromethylated Ketones from Vinyl Triflates in the Absence of External Trifluoromethyl Sources

A novel method for the conversion of vinyl triflates into α‐trifluoromethylated ketones in the absence of external trifluoromethyl sources is described. This process accomplishes an efficient migration of the trifluoromethyl group of the triflate to the α‐position in the ketone through a radical process. The reaction proceeds by the addition of a trifluoromethyl radical to the vinyl triflate and subsequent fragmentation of the trifluoromethane sulfonyl radical. Based on this reaction, a one‐pot two‐step procedure for the trifluoromethylation of ketones was developed. The method presented herein also allows the transfer of perfluoroalkyl groups from vinyl perfluoroalkanesulfonates, which are readily accessible from alkynes and perfluoroalkanesulfonic acids.     

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.     

A Photochemical Organocatalytic Strategy for the α‐Alkylation of Ketones by using Radicals

Reported herein is a visible‐light‐mediated radical approach to the α‐alkylation of ketones. This method exploits the ability of a nucleophilic organocatalyst to generate radicals upon S_N2‐based activation of alkyl halides and blue light irradiation. The resulting open‐shell intermediates are then intercepted by weakly nucleophilic silyl enol ethers, which would be unable to directly attack the alkyl halides through a traditional two‐electron path. The mild reaction conditions allowed functionalization of the α position of ketones with functional groups that are not compatible with classical anionic strategies. In addition, the redox‐neutral nature of this process makes it compatible with a cinchona‐based primary amine catalyst, which was used to develop a rare example of enantioselective organocatalytic radical α‐alkylation of ketones.     

PPh3⋅HBr‐DMSO Mediated Expedient Synthesis of γ‐Substituted β,γ‐Unsaturated α‐Ketomethylthioesters and α‐Bromo Enals: Application to the Synthesis of 2‐Methylsulfanyl‐3(2 H)‐furanones

An efficient chemoselective general procedure for the synthesis of γ‐substituted β,γ‐unsaturated α‐ketomethylthioesters from α,β‐unsaturated ketones has been achieved through an unprecedented PPh₃?HBr‐DMSO mediated oxidative bromination and Kornblum oxidation sequence. The newly developed reagent system serves admirably for the synthesis of α‐bromoenals from enals. Furthermore, AuCl₃‐catalyzed efficient access to 3(2H)‐furanones from the above intermediates under extremely mild conditions are described.     

An Unexpected α‐Oxidation of Cyclic Ketones with 1,4‐Benzoquinone by Enol Catalysis

The first direct and asymmetric α‐aryloxylation of cyclic ketones via enol catalysis has been achieved using quinones as the reaction partners. Catalytic amounts of a phosphoric acid promote the exclusive formation of α,α‐disubstituted ketones from the corresponding α‐substituted ketones in good yields and enantioselectivities (up to 96.5:3.5 er). Preliminary mechanistic experiments suggest that this reaction proceeds via a proton‐coupled electron transfer (PCET) followed by radical recombination.     

Oxidative Difunctionalization of Alkenyl MIDA Boronates: A Versatile Platform for Halogenated and Trifluoromethylated α‐Boryl Ketones

The synthesis of halogenated and trifluoromethylated α‐boryl ketones via a one‐pot oxidative difunctionalization of alkenyl MIDA boronates is reported. These novel densely functionalized organoborons bearing synthetically and functionally valuable carbonyl, halogen/CF₃ and boronate moieties within the same molecule are synthetically challenging for the chemist, but have great synthetic potential, as demonstrated by their applications in a straightforward synthesis of borylated furans. The generality of this reaction was extensively investigated. This reaction is attractive since the starting materials, alkenyl MIDA boronates, are easily accessible.     

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.     

Rhodium‐catalyzed Asymmetric Hydrogenation of α‐Dehydroamino Ketones: A General Approach to Chiral α‐amino Ketones

Rhodium/DuanPhos‐catalyzed asymmetric hydrogenation of aliphatic α‐dehydroamino ketones has been achieved and afforded chiral α‐amino ketones in high yields and excellent enantioselectives (up to 99 % ee), which could be reduced further to chiral β‐amino alcohols by LiAlH(tBuO)₃ with good yields_. This protocol provides a readily accessible route for the synthesis of chiral α‐amino ketones and chiral β‐amino alcohols.     

Gas‐Phase Generation and Decomposition of a Sulfinylnitrene into the Iminyl Radical OSN

The dipolar oxathiazyne‐like sulfinylnitrene RS(O)N, a highly reactive α‐oxo nitrene, has been rarely investigated. Upon flash vacuum pyrolysis of sulfinyl azide CF₃S(O)N₃ at 350 °C, an elusive sulfinylnitrene CF₃S(O)N was generated in the gas phase in its singlet ground state and was characterized by matrix‐isolation IR spectroscopy. Further fragmentation of CF₃S(O)N at 600 °C produced CF₃ and a novel iminyl radical OSN, an SO₂ analogue, which were unambiguously identified by IR spectroscopy. Consistent with the experimental observations, DFT calculations clearly support a stepwise decomposition mechanism of CF₃S(O)N₃.     

Chemo‐ and Enantioselective Oxidative α‐Azidation of Carbonyl Compounds

We report high‐performance I⁺/H₂O₂ catalysis for the oxidative or decarboxylative oxidative α‐azidation of carbonyl compounds by using sodium azide under biphasic neutral phase‐transfer conditions. To induce higher reactivity especially for the α‐azidation of 1,3‐dicarbonyl compounds, we designed a structurally compact isoindoline‐derived quaternary ammonium iodide catalyst bearing electron‐withdrawing groups. The nonproductive decomposition pathways of I⁺/H₂O₂ catalysis could be suppressed by the use of a catalytic amount of a radical‐trapping agent. This oxidative coupling tolerates a variety of functional groups and could be readily applied to the late‐stage α‐azidation of structurally diverse complex molecules. Moreover, we achieved the enantioselective α‐azidation of 1,3‐dicarbonyl compounds as the first successful example of enantioselective intermolecular oxidative coupling with a chiral hypoiodite catalyst.     

Addition of Electrophilic Radicals to 2‐Benzyloxyglycals: Synthesis and Functionalization of Fluorinated α‐C‐Glycosides and Derivatives

A new method for the synthesis of fluorinated α‐C‐glycosides is described. The reactions between highly electrophilic radicals (fluorinated or unfluorinated) and a 2‐benzyloxyglucal or galactal provide 2‐keto‐D ‐arabino‐ or 2‐keto‐D ‐lyxo‐hexopyranosides through an addition/fragmentation process. Sodium borohydride mediated or Meerwein–Ponndorf–Verley (MPV) reduction of these compounds provides α‐C‐glycosides that feature appropriate anchoring groups for further synthetic elaboration. The presence of CF₂CO₂iPr or CF₂Br groups at the pseudo‐anomeric position allows efficient reduction/olefination or Br/Li‐exchange/nucleophilic‐addition sequences. These transformations open the way for the synthesis of fluorinated C‐glycosidic analogues of glycoconjugates.     

Chemical transformation of bis((perfluoroalkyl)sulfonyl)methanes and 1,1,3,3‐tetraoxopolyfluoro‐1,3‐dithiaycloalkanes

Halogenation of the potassium or silver salts of bis((trifluoromethyl)sulfonyl)methane(CF₃SO₂)₂CH₂ and its cyclo analogues (CF₂)_nSO₂‐CH₂SO₂CF₂ with N‐fluoro‐bis((trifluoromethyl)sul‐fonyl)imine (CF₃SO₂)₂NF, chlorine or bromine gave good yields of the corresponding α‐halo disulfones (CF₃SO₂)₂CHX and (CF₂)_nSO₂CHXSO₂CF₂ (X: F, Cl, Br; n = 1,2). Some chemical transformations of these fluorinated α‐halo‐disulfones are described. © 1999 John Wiley & Sons, Inc. Heteroatom Chem 10: 147–151, 1999     

Protecting‐Group‐Free Enantioselective Synthesis of (−)‐Pallavicinin and (+)‐Neopallavicinin

The first enantioselective synthesis of (?)‐pallavicinin and (+)‐neopallavicinin has been achieved in 15 steps. The described synthesis avoids protecting‐group manipulations by synthesis designs predicated on highly chemo‐ and stereoselective transformations. Highlights of the synthesis include a palladium‐catalyzed enantioselective decarboxylative allylation to form the chiral all‐carbon quaternary stereocenter, a palladium‐catalyzed oxidative cyclization to assemble the [3.2.1]‐bicyclic moiety, and an unprecedented LiBHEt₃‐induced fragmentation/protonation of an α‐hydroxy epoxide to form the α‐furan ketone with the desired configuration.     

Pd‐Catalyzed Carbonylative α‐Arylation of Aryl Bromides: Scope and Mechanistic Studies

Reaction conditions for the three‐component synthesis of aryl 1,3‐diketones are reported applying the palladium‐catalyzed carbonylative α‐arylation of ketones with aryl bromides. The optimal conditions were found by using a catalytic system derived from [Pd(dba)₂] (dba=dibenzylideneacetone) as the palladium source and 1,3‐bis(diphenylphosphino)propane (DPPP) as the bidentate ligand. These transformations were run in the two‐chamber reactor, COware, applying only 1.5 equivalents of carbon monoxide generated from the CO‐releasing compound, 9‐methylfluorene‐9‐carbonyl chloride (COgen). The methodology proved adaptable to a wide variety of aryl and heteroaryl bromides leading to a diverse range of aryl 1,3‐diketones. A mechanistic investigation of this transformation relying on ³¹P and ¹³C NMR spectroscopy was undertaken to determine the possible catalytic pathway. Our results revealed that the combination of [Pd(dba)₂] and DPPP was only reactive towards 4‐bromoanisole in the presence of the sodium enolate of propiophenone suggesting that a [Pd(dppp)(enolate)] anion was initially generated before the oxidative‐addition step. Subsequent CO insertion into an [Pd(Ar)(dppp)(enolate)] species provided the 1,3‐diketone. These results indicate that a catalytic cycle, different from the classical carbonylation mechanism proposed by Heck, is operating. To investigate the effect of the dba ligand, the Pd⁰ precursor, [Pd(η³‐1‐PhC₃H₄)(η⁵‐C₅H₅)], was examined. In the presence of DPPP, and in contrast to [Pd(dba)₂], its oxidative addition with 4‐bromoanisole occurred smoothly providing the [PdBr(Ar)(dppp)] complex. After treatment with CO, the acyl complex [Pd(CO)Br(Ar)(dppp)] was generated, however, its treatment with the sodium enolate led exclusively to the acylated enol in high yield. Nevertheless, the carbonylative α‐arylation of 4‐bromoanisole with either catalytic or stoichiometric [Pd(η³‐1‐PhC₃H₄)(η⁵‐C₅H₅)] over a short reaction time, led to the 1,3‐diketone product. Because none of the acylated enol was detected, this implied that a similar mechanistic pathway is operating as that observed for the same transformation with [Pd(dba)₂] as the Pd source.     

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.     

Asymmetric Catalysis with CO2: The Direct α‐Allylation of Ketones

Quaternary stereocenters are found in numerous bioactive molecules. The Tsuji–Trost reaction has proven to be a powerful C?C bond forming process, and, at least in principle, should be well suited to access quaternary stereocenters via the α‐allylation of ketones. However, while indirect approaches are known, the direct, catalytic asymmetric α‐allylation of branched ketones has been elusive until today. By combining “enol catalysis” with the use of CO₂ as a formal catalyst for asymmetric catalysis, we have now developed a solution to this problem: we report a direct, highly enantioselective and highly atom‐economic Tsuji–Trost allylation of branched ketones with allylic alcohol. Our reaction delivers products bearing quaternary stereocenters with high enantioselectivity and water as the sole by‐product. We expect our methodology to be of utility in asymmetric catalysis and inspire the design of other highly atom‐economic transformations.     

Efficient Cu‐catalyzed Atom Transfer Radical Addition Reactions of Fluoroalkylsulfonyl Chlorides with Electron‐deficient Alkenes Induced by Visible Light

Fluoroalkylsulfonyl chlorides, R_fSO₂Cl, in which R_f=CF₃, C₄F₉, CF₂H, CH₂F, and CH₂CF₃, are used as a source of fluorinated radicals to add fluoroalkyl groups to electron‐deficient, unsaturated carbonyl compounds. Photochemical conditions, using Cu mediation, are used to produce the respective α‐chloro‐β‐fluoroalkylcarbonyl products in excellent yields through an atom transfer radical addition (ATRA) process. Facile nucleophilic replacement of the α‐chloro substituent is shown to lead to further diverse functionalization of the products.     

Photoredox‐Coupled F‐Nucleophilic Addition: Allylation of gem‐Difluoroalkenes

A novel strategy for the expedient construction of CF₃‐embeded tertiary/quarternary carbon centers was developed by taking advantage of photoredox catalysis. Thanks to a key step of single‐electron oxidation, electron‐rich gem‐difluoroalkenes, which otherwise are essentially reluctant towards F‐nucleoplilic addition, now readily participate in this fluoroallylation reaction. Furthermore, this strategy provides an elegant example for the generation, as well as functionalization, of α‐CF₃‐substituted benzylic radical intermediates using cheap and readily available starting materials.     

Ethylene/α‐olefin copolymerization with bis(β‐enaminoketonato) titanium complexes activated with modified methylaluminoxane

Copolymerizations of ethylene with α‐olefins (i.e., 1‐hexene, 1‐octene, allylbenzene, and 4‐phenyl‐1‐butene) using the bis(β‐enaminoketonato) titanium complexes [(Ph)NC(R₂)CHC(R₁)O]₂TiCl₂ ( 1a : R₁ = CF₃, R₂ = CH₃; 1b : R₁ = Ph, R₂ = CF₃; and 1c : R₁ = t‐Bu, R₂ = CF₃), activated with modified methylaluminoxane as a cocatalyst, have been investigated. The catalyst activity, comonomer incorporation, and molecular weight, and molecular weight distribution of the polymers produced can be controlled over a wide range by the variation of the catalyst structure, α‐olefin, and reaction parameters such as the comonomer feed concentration. The substituents R₁ and R₂ of the ligands affect considerably both the catalyst activity and comonomer incorporation. Precatalyst 1a exhibits high catalytic activity and produces high‐molecular‐weight copolymers with high α‐olefin insertion. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 6323–6330, 2005     

α‐Aminoxy‐Acid‐Auxiliary‐Enabled Intermolecular Radical γ‐C(sp3)−H Functionalization of Ketones

A method for site‐specific intermolecular γ‐C(sp³)?H functionalization of ketones has been developed using an α‐aminoxy acid auxiliary applying photoredox catalysis. Regioselective activation of an inert C?H bond is achieved by 1,5‐hydrogen atom abstraction by an oxidatively generated iminyl radical. Tertiary and secondary C‐radicals thus formed at the γ‐position of the imine functionality undergo radical conjugate addition to various Michael acceptors to provide, after reduction and imine hydrolysis, the corresponding γ‐functionalized ketones.