Efficient and stereoselective synthesis of beta-trifluoromethyl alpha,beta-unsaturated esters via iron(III) porphyrin-catalyzed olefination of ketones

beta-Trifluoromethyl alpha,beta-unsaturated esters were efficiently prepared by reactions of fluorine-containing ketones with diazo compounds via metalloporphyrin-catalyzed olefination in the presence of triphenylphosphine. The commercially available Fe(III)(TPP)Cl (TPP: tetraphenylporphyrin) is effective for catalyzing the olefination of a variety of trifluoromethyl ketones with different diazoacetate esters under mild conditions. The reactions proceeded with high yields (up to 95% isolated yield) and high stereoselectivity (up to 99% (E)-selectivity).     

3,5-bis(trifluoromethyl)phenyl sulfones in the direct Julia-Kocienski olefination

3,5-bis(trifluoromethyl)phenyl (BTFP) sulfones 7 have been employed in the Julia-Kocienski olefination reaction with carbonyl compounds. Sulfones 7 are readily prepared in high yields (64-97%) from commercially available 3,5-bis(trifluoromethyl)thiophenol through an alkylation/oxidation two-step sequence. The stability of metalated BTFP sulfones has been studied and compared with heteroaryl benzothiazol-2-yl (BT), 1-phenyl-1H-tetrazol-5-yl (PT), and 1-tert-butyl-1H-tetrazol-5-yl (TBT) sulfones 9-11 under different reaction conditions. The Julia-Kocienski olefination between alkyl BTFP sulfones 7 and a wide variety of aldehydes affords the corresponding 1,2-disubstituted alkenes and dienes in good yields and stereoselectivities. This one-pot protocol can be performed using KOH at room temperature or the phosphazene bases P2-Et and P4-t-Bu at -78 degrees C or rt and has been successfully used in a high-yielding and stereoselective synthesis of various methoxylated stilbenes such as trimethylated resveratrol. These new reaction conditions for the Julia-Kocienski olefination reaction have been also studied with BT, PT, and TBT sulfones, giving poorer results. Methylenation of aliphatic and aromatic aldehydes, ketones, and 1,2-dicarbonyl compounds is carried out through the modified Julia olefination using BTFP methyl sulfone 7d to give terminal alkenes and dienes. Mechanistic studies of the olefination reaction between benzyl BTFP sulfone 7a and aromatic aldehydes performed by KOH-induced Smiles rearrangement of stereodefined syn- and anti-beta-hydroxyalkyl BTFP sulfones indicate that the stereocontrol of the reaction is determined in the elimination step.     

Catalytic enantioselective alkenylation and phenylation of trifluoromethyl ketones

Catalytic enantioselective alkenylation and phenylation of trifluoromethyl ketones are described. High enantioselectivity (up to 84% ee) was produced in an alkenylation of aryl trifluoromethyl ketones using a CuF-DTBM-SEGPHOS complex as the catalyst (5-10 mol %) and alkenylsilanes as the nucleophile. This is the first example of catalytic enantioselective alkenylation of trifluoromethyl ketones. The products are versatile chiral building blocks, which contain a trifluoromethyl-substituted tertiary alcohol moiety.     

Solvent free synthesis of trifluoromethyl tertiary alcohols by cross Aldol reaction

Exceedingly fast preparation of trifluoromethyl tertiary alcohols has been accomplished from methyl ketones and trifluoromethyl ketones under solvent free conditions by cross Aldol reaction. The reaction was achieved in the presence of common inorganic base by grinding method at ambient temperature to give β-trifluoromethyl-β-hydroxyl ketones in high yields (up to 95%).     

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.     

Access to Trifluoromethylketones from Alkyl Bromides and Trifluoroacetic Anhydride by Photocatalysis

Aliphatic trifluoromethyl ketones are a type of unique fluorine-containing subunit which play a significant role in altering the physical and biological properties of molecules. Catalytic methods to provide direct access to aliphatic trifluoromethyl ketones are highly desirable yet remain underdeveloped, partially owing to the high reactivity and instability of trifluoroacetyl radical. Herein, we report a photocatalytic synthesis of trifluoromethyl ketones from alkyl bromides with trifluoroacetic anhydride. The reaction features dual visible-light and halogen-atom-transfer catalysis, followed by an enabling radical-radical cross-coupling of an alkyl radical with a stabilized trifluoromethyl radical. The reaction provides straightforward access to aliphatic trifluoromethyl ketones from readily available and cost-effective alkyl halides and trifluoroacetic anhydride (TFAA).     

Cs2CO3-catalyzed alkylation of indoles with trifluoromethyl ketones

A Cs₂CO₃-catalyzed alkylation reaction of indoles with trifluoromethyl ketones was presented. Both alicyclic and aromatic trifluoromethyl ketones as well as various substituted indoles are compatible with the methodology. Good to excellent yields of the corresponding trifluoromethyl substituted tertiary alcohols 2,2,2-tritrifluoro-1-(1H-indol-3-yl)-ethan-1-ols were acquired as the sole products.     

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.     

Novel efficient synthesis of β-fluoro-β-(trifluoromethyl)styrenes

CF₃CFBr₂ was employed in catalytic olefination reactions of aromatic aldehydes. In situ prepared hydrazones of aldehydes were transformed to β-fluoro-β-(trifluoromethyl)styrenes by reaction with CF₃CFBr₂ under CuCl catalysis. Based on this reaction, a novel stereoselective approach towards β-fluoro-β-(trifluoromethyl)styrenes was elaborated. Nucleophilic vinylic substitution of fluorine by secondary amines, thiolates and alkoxides in β-fluoro-β-(trifluoromethyl)styrenes was also tested.     

Condensations of aryl trifluoromethyl ketones with arenes in acidic media

The chemistry of trifluoromethyl ketones has been studied. The work examines the condensation reactions of trifluoromethyl ketones with arenes in the superacid, including both synthetic and mechanistic aspects.     

Two classes of enzymes of opposite stereochemistry in an organism: one for fluorinated and another for nonfluorinated substrates

Reduction of methyl ketones by dried cells of Geotrichum candidum (APG4) afforded (S)-alcohols in excellent enantiomeric excess (ee), whereas the reduction of trifluoromethyl ketones gave the corresponding alcohols of the opposite configuration also in excellent ee. The replacement of the methyl moiety with a trifluoromethyl group alters both the bulkiness and the electronic properties, the effect of which on the stereoselectivity was examined. No inversion in stereochemistry was observed in the reduction of hindered ketones such as isopropyl ketone, while the stereoselectivity was inverted in the reduction of ketones with electron-withdrawing atoms such as chlorine. The mechanism for the inversion in stereochemistry was investigated by enzymatic studies. Several enzymes with different stereoselectivities were isolated; one of them catalyzed the reduction of methyl ketones, and another with the opposite stereoselectivity catalyzed the reduction of trifluoromethyl ketones. Furthermore, both APG4 and the isolated enzyme were applied to the reduction of fluorinated ketones on a preparative scale, which resulted in the synthesis of chiral fluorinated alcohols with excellent ee.     

Stereoselective olefination of unfunctionalized ketones via ynolates

Ynolates react with ketones at room temperature to afford alpha,beta,beta-trisubstituted acrylates (tetrasubstituted olefins) with 2:1-8:1 geometrical selectivities. This can be regarded as a new olefination reaction of ketones giving tetrasubstituted olefins in good yield, even in the case of sterically hindered substrates. The reaction mechanism involves cycloaddition of ynolates with a carbonyl group and subsequent thermal electrocyclic ring-opening of the resulting beta-lactone enolates. The stereoselectivity is determined in the ring-opening, which is regulated by torquoselectivity. In this paper, we describe the scope and limitations of olefination of ketones via ynolates and discuss the stereocontrol mechanism.     

Hetero-Diels-Alder reaction of photochemically generated α-hydroxy-o-quinodimethanes with trifluoromethyl ketones

Hetero-Diels-Alder reaction of α-hydroxy-o-quinodimethanes photochemically generated from o-tolualdehydes with trifluoromethyl ketones gave a mixture of hemiacetals and hydroxyaldehydes in fairly good yields. Their subsequent oxidation with PCC provided 1-isochromanones as formal oxidative [4+2] cycloaddition products. In contrast, similar reaction of aromatic ketones such as o-methylbenzophenone, 1-indanone, and α-tetralone gave exclusively the corresponding ketones having (trifluoromethyl)methylol groups at the o-position.     

Copper‐Catalysed Decarboxylative Trifluoromethylation of β‐Ketoacids

An efficient method for Cu‐catalyzed decarboxylative trifluoromethylation of β ‐ketoacids to achieve α ‐trifluoromethyl ketones was developed. A wide variety of synthetically useful α ‐trifluoromethyl ketones were obtained in modest to good yields under mild reaction conditions. The present method also exhibits good functional‐group compatibility.     

Catalytic Enantioselective Conjugate Alkynylation of α,β‐Unsaturated 1,1,1‐Trifluoromethyl Ketones with Terminal Alkynes

The first catalytic enantioselective conjugate alkynylation of α,β‐unsaturated 1,1,1‐trifluoromethyl ketones has been carried out. Terminal alkynes and 1,3‐diynes were treated with trifluoromethyl ketones in the presence of a low catalytic load of a Cu^I‐MeOBIPHEP complex (2.5 mol %) and triethylamine (10 mol %) to give the corresponding trifluoromethyl ketones bearing a propargylic stereogenic center at the β position with good yields and excellent enantiomeric excesses in most of the cases. No 1,2‐addition products were formed under the reaction conditions. The procedure showed broad substrate scope for alkyne, diyne, and enone. A rationale for the observed stereochemistry has been provided. Finally, the potential application of the reaction products in the synthesis of chiral tetrahydrofurans bearing a trifluoromethylated quaternary stereocenter has been devised.     

A novel, short and efficient synthesis of divinyl ethers

An efficient one-step synthesis of divinyl ethers from aldehydes and ketones using Wittig olefination is described.     

Fluoroalkyl alpha,beta-unsaturated imines. Valuable synthetic intermediates from primary fluorinated enamine phosphonates

[reaction: see text] A simple method for the preparation of fluoroalkyl allylamines or alpha,beta-unsaturated ketones by an olefination reaction of primary enamine phosphonates and aldehydes, followed by selective reduction with hydrides or hydrolysis, is reported. Fluorinated beta-amino nitriles are also obtained by an olefination reaction of primary enamine phosphonates with aldehydes and subsequent addition of metalated acetonitrile.     

Copper‐Mediated Trifluoroacetylation of Arenediazonium Salts with Ethyl Trifluoropyruvate

A copper‐mediated trifluoroacetylation of various arenediazonium salts with ethyl trifluoropyruvate is reported. The reaction proceeded smoothly under mild conditions at room temperature giving trifluoromethyl aryl ketones in moderate to good yields. A variety of functional groups, including methoxy, hydroxy, ester, ketone, trifluoromethyl, and halide groups, were well tolerated. A possible reaction mechanism involving an aryl radical intermediate was proposed and supported by experimental evidence. This reaction provides a new route to trifluoromethyl aryl ketones, notable synthetic targets, from the corresponding anilines.     

Combining Photoredox‐Catalyzed Trifluoromethylation and Oxidation with DMSO: Facile Synthesis of α‐Trifluoromethylated Ketones from Aromatic Alkenes

Trifluoromethylated ketones are useful building blocks for organic compounds with a trifluoromethyl group. A new and facile synthesis of ketones with a trifluoromethyl substituent in the α‐position proceeds through a one‐pot photoredox‐catalyzed trifluoromethylation–oxidation sequence of aromatic alkenes. Dimethyl sulfoxide (DMSO) serves as a key and mild oxidant under these photocatalytic conditions. Furthermore, an iridium photocatalyst, fac[Ir(ppy)₃] (ppy=2‐phenylpyridine), turned out to be crucial for the present photoredox process.     

A newly-designed PE-supported arsine for efficient and practical catalytic Wittig olefination

A newly designed PE-supported arsine has been developed as an excellent catalyst for catalytic Wittig-type olefination. Simple ketones, in particular inactive ketones prove to be suitable substrates for the first time. This reaction provides an easy access to di-, tri-, and tetra-substituted olefins in high yield.