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.     

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‐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.     

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.     

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.     

Synthesis of Functionalized Indoles with a Trifluoromethyl‐Substituted Stereogenic Tertiary Carbon Atom Through an Enantioselective Friedel–Crafts Alkylation with β‐Trifluoromethyl‐α,β‐enones

Chiral complexes of BINOL‐based ligands with zirconium tert‐butoxide catalyze the Friedel–Crafts alkylation reaction of indoles with β‐trifluoromethyl‐α,β‐unsaturated ketones to give functionalized indoles with an asymmetric tertiary carbon center attached to a trifluoromethyl group. The reaction can be applied to a large number of substituted α‐trifluoromethyl enones and substituted indoles. The expected products were obtained with good yields and ees of up to 99 %.     

Direct aldol condensation reaction of ethyl diazoacetate with trifluoromethyl ketones

An efficient and direct aldol-type condensation of ethyl diazoacetate with trifluoromethyl ketones was developed in the presence of dialkyl zinc. A series of trifluoromethylated products were obtained in good to excellent yields (60-95%). A preliminary extension to a catalytic enantioselective aldol reaction of ethyl diazoacetate to trifluoromethyl ketones (up to 72% ee) is also described.     

Synthesis of trifluoromethyl alcohols from tert-butoxy-β-(trifluoromethyl)styrenes and trifluoromethylbenzyl ketones under the conditions of the Leuckart-Wallach reaction

A novel pathway towards trifluoromethylalcohols by an unexpected reaction of tert-butoxy-β-(trifluoromethyl)styrenes or corresponding trifluoromethylbenzyl ketones under the conditions of the Leuckart-Wallach reaction was elaborated.     

Trifluoromethyl ketones from enolizable carboxylic acids via enediolate trifluoroacetylation/decarboxylation

Primary and secondary (enolizable) carboxylic acids were converted in a single step to trifluoromethyl ketones. Treatment of the acid with 2.2 equiv of LDA generated an enediolate that was trifluoroacetylated with EtO(2)CCF(3). Quenching the reaction mixture with aqueous HCl resulted in rapid decarboxylation and provided the trifluoromethyl ketone product in good yield. The process may be performed at -20 degrees C with a slight reduction in yield. The reaction was extended to the preparation of pentafluoroethyl and chlorodifluoromethyl ketones.     

Silver salts and DBU cooperatively catalyzed domino reaction of propargylic alcohols with trifluoromethyl ketones: direct method to trifluoromethyl‐substituted 5‐alkylidene‐1,3‐dioxolane derivatives

A general and efficient synthesis of trifluoromethyl‐substituted 5‐alkylidene‐1,3‐dioxolanes using AgNO₃ and DBU cooperatively catalyzed domino reaction of propargylic alcohols and trifluoromethyl ketones is described. The reaction tolerates a broad range of functional groups, and the desired products are obtained in good to excellent yields (62–99%) with acceptable diastereoselectivities. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis of some trifluoromethyl substituted 1‐methylpyrazoles

The major products from the reaction of β‐alkoxyvinyl trifluoromethyl ketones 1a‐c with methylhydrazine ( 2 ) in absolute ethanol are the 3‐(trifluoromethyl)‐substituted‐1‐methylpyrazoles 3a‐3c with lesser amounts of the 5‐(trifluoromethyl)‐substituted products 4a‐4c and 5a‐5c. Carrying out the reaction in non‐polar, aprotic solvents can further enhance the regioselectivity favoring the 3‐ (trifluoromethyl) ‐substituted isomers.     

Asymmetric allylboration of aldehydes and ketones using 3,3'-disubstitutedbinaphthol-modified boronates

Allylboronates derived from 3,3'-disubstituted 2,2'-binaphthols react with aldehydes and ketones to give the expected allylated products with up to >99:1 er. Highest selectivities were observed for aromatic ketones. The bis(trifluoromethyl) derivative is particularly outstanding in terms of reactivity, selectivity, and robustness. [reaction: see text]     

Haloacetylated enol ethers. 9. Synthesis of 4-trifluoromethyl-2-methyl[phenyl]pyrimidines and tetrahydro derivatives

The synthesis of 4-trifluoromethyl-2-methyl[phenyl]pyrimidines and the corresponding tetrahydro derivatives from the cyclo-condensation reaction of β-alkoxyvinyl trifluoromethyl ketones 1a-d with acetamidine or benzamidine hydrochloride, is reported. For the cyclo-condensation of 1a-d with acetamidine and benzamidine hydrochloride, two methods were tested: 1 M solution of sodium hydroxide (method A) and sodium alkoxide/alcohol (method B). Depending on the structure of the β-alkoxyvinyl trifluoromethyl ketones and the reactions conditions, pyrimidines or tetrahydropyrimidines or a mixture of both compounds were obtained.     

Regioselective synthesis of β-fluoro-α,β-unsaturated ketones by the reaction of β-diketones with DFMBA

The deoxyfluorination reaction of β-diketones with N,N-diethyl-α,α-difluoro-m-methylbenzylamine (DFMBA) gave β-fluoro-α,β-unsaturated ketones in good yields. The reaction proceeded regioselectively, and only one regioisomer was obtained from the unsymmetrical 1-aryl-1,3-diketones. The reaction is applicable to diketones with a trifluoromethyl group, obtaining good yields of 3,4,4,4-tetrafluorobutenones. We used the resulting β-fluoro-α,β-unsaturated ketones for the reaction with lithium dialkyl cuprates.     

Cobalt-electrocatalytic C–H hydroxyalkylation of N-heteroarenes with trifluoromethyl ketones

Trifluoromethyl carbinols and N-heteroarenes are both prevalent in bioactive molecules. However, access to high-value pharmacophores combining these two functional groups still remains a challenge. Herein, we report an electro-chemical redox-neutral coupling for the synthesis of N-heteroaryl trifluoromethyl carbinols from readily available N-heteroarenes and trifluoromethyl ketones. The reaction starts with reversing the polarity of ketones to nucleophilic ketyl radicals through an electrocatalytic proton-coupled electron transfer (PCET), followed by radical addition to heteroarenes and rearomatization to afford tertiary alcohol products. Importantly, the merging of paired electrolysis and cobalt catalysis is crucial to this regioselective C–H hydroxyalkylation of heteroarenes, and thus avoids several known competing pathways including the spin-center shift (SCS) process. Collectively, this protocol provides straightforward access to heteroaryl trifluoromethyl carbinols, featuring ideal atom economy, excellent regioselectivity, and paired redox-neutral electrolysis.

By merging paired electrolysis and cobalt catalysis, we have developed an electrochemical redox-neutral coupling for the synthesis of N-heteroaryl trifluoromethyl carbinols from readily available N-heteroarenes and trifluoromethyl ketones.     

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.     

Catalytic ketone olefination with methyltrioxorhenium

Methyltrioxorhenium (MTO) catalyses the olefination of ketones with ethyl diazoacetate in the presence of triphenylphosphane. Unactivated ketones require the addition of 0.5 equiv of benzoic acid to achieve good yields, while trifluoromethyl ketones require no co-catalyst. The optimised system allows the olefination of aromatic, aliphatic, unsaturated, cyclic and trifluoromethyl ketones.     

Regiospecific organocatalytic asymmetric aldol reaction of methyl ketones and alpha,beta-unsaturated trifluoromethyl ketones

[structure: see text]. The aldol reaction of methyl ketones and alpha,beta-unsaturated trifluoromethyl ketones occurred under mild conditions with the combination of proline-derived N-sulfonylamide and trifluoroacetic acid as the catalyst to give the corresponding unsaturated alpha-trifluoromethyl tertiary alcohols in high yields with good enatioselectivities.