In this reaction, easily removable tetramethylpyrazine and trimethylsilyl halides were generated as byproducts. The focus is on synthetically useful procedures and the work is organized according to the type of carbonyl compound subjected to the trifluoromethylation reaction. Ketones and aldehydes notably via their enol ether and enamine derivatives enable electro philic trifluoromethylation at the. Polyfluoroalkylation of carbonyl compounds by polyfluoroalkyl anions generated from polyfluorocarboxamides natshumi wakita and shoji hara graduate school of engineering, hokkaido university, sapporo 0608628, japan email. Isolated yields of alcohols are related to the initial carbonyl compound. Trifluoromethylation synthetic reagents tokyo chemical. Trifluoromethylation an overview sciencedirect topics. In 1989, prakash and olah first reported activation of tmscf 3 by fluoride to perform nucleophilic trifluoromethylation of carbonyl compounds. Both enolizable and nonenolizable aldehydes and alphaketo.
The use of organic catalysis acrh 2 enables the direct trifluoromethylation of carbonyl compounds by atom transfer radical addition reactions with broad substrate scopes under mild conditions. Us5008425a us07337,186 us33718689a us5008425a us 5008425 a us5008425 a us 5008425a us 33718689 a us33718689 a us 33718689a us 5008425 a us5008425 a us 5008425a authority us united states prior art keywords mg mmol cyclohexadien trifluoromethyl mixture prior art date 19880404 legal status the legal status is an assumption and is not a legal conclusion. Trifluoromethylation of carbonyl compounds ethyl corporation. World scientific series in 20th century chemistry across conventional lines, pp. In the presence of 10 mol% of mgcl 2, a variety of carbonyl substrates such as aliphaticaromatic aldehydes, acycliccyclic ketones and esters could be trifluoromethylated in dmf, giving the corresponding.
Trifluoromethylation of carbonyl groups in aromatic poly. To demonstrate the synthetic utility of this micro. A process which comprises reacting in the presence of a catalyst and under substantially anhydrous conditions trifluoromethyltriethylsilane and a carbonyl compound other than a quinone such that the carbonyl compound is perfluoromethylated. Apr 16, 1991 not all carbonyl compounds will react in accordance with the process of this invention. Application of fluoroform in trifluoromethylation and di. Carbonyl compounds carbonyl group a compound containing a carbonyl group is often referred to as a carbonyl compound.
However, the suitability of any given carbonyl compound can be readily determined by the simple expedient of running an experiment of the type referred to in the examples hereinafter. Articles selective fluoroalkylations with fluorinated sulfones. These are the accepted, unedited articles published online and citable. For example, the present transformation provides an improved route to fluorinated compound 14, a tebufenpyrad analogue with acaricidal activity scheme 3. Request pdf trifluoromethylation of nonenolizable carbonyl compounds with a stable piperazino hemiaminal of trifluoroacetaldehyde a new stable hemiaminal of fluoral 1 can easily be obtained. Here we report the first flow trifluoromethylation of carbonyl compounds and its utility for drug synthesis of efavirenz and hsd016. This active species shows nucleophilicity and reacts with carbonyl compounds to proceed with the trifluoromethylation. Fluorideinduced trifluoromethylation of carbonyl compounds with trifluoromethyltrimethylsilane. A novel nheterocyclic carbene nhc catalyzed trifluoromethylation reaction of carbonyl compounds was discovered. Cf3 reagents shimeng wanga, jiabin hana, chengpan zhanga, huali qina, jichang xiaob, aschool of chemistry, chemical engineering and life science, wuhan university of technology, 205 luoshi road, wuhan 430070, china. Macmillan merck center for catalysis at princeton university, princeton, new jersey 08544 received june 29, 2009. Nucleophilic trifluoromethylation of carbonyl compounds and disulfides with trifluoromethane and.
Click on the title to browse this list of accepted articles. Electrophilic trifluoromethylation of carbonyl compounds and their. The use of 2,3,5,6tetramethyl1,4bistrimethylsilyl1,4dihydropyrazine achieves a saltfree stereoselective synthesis of silyl enol ethers from. In the same year, stahly described similar reactions for the synthesis of trifluoromethylated phenols and anilines. A mild, operationally simple approach to the synthesis of atrifluoromethyl carbonyl compounds phong v. A barbier procedure, under moderate pressure, was used for the trifluoromethylation of various carbonyl compounds, starting from trifluoromethyl bromide and zinc in pyridine. This method also allows the first microflow transformation of nsulfinylimines into trifluoromethyl amines with excellent diastereoselectivity. Nheterocyclic carbene catalyzed trifluoromethylation of. Cf3so2x x na, cl as reagents for trifluoromethylation. In 1991, langlois and coworkers reported the first trifluoromethylation of aromatic compounds with sodium trifluoromethanesulfinate under oxidative conditions. The reaction was found to be applicable to the nucleophilic trifluoromethylation of a broad spectrum of carbonyl compounds with satisfactory yields in general. Electrophilic trifluoromethylation of carbonyl compounds. Us5008425a trifluoromethylation of carbonyl compounds.
Trifluoromethylation of various aldehydes and ketones with trifluoromethyltrimethylsilane in the presence of a catalytic amount of a lewis base such as lithium acetate proceeded smoothly to affor. Trifluoromethylation of carbonyl compounds with sodium. Nucleophilic trifluoromethylation of carbonyl compounds and disulfides with trifluoromethane and siliconcontaining bases. Ketones and aldehydes notably via their enol ether and enamine derivatives enable electrophilic trifluoromethylation at the.
Moreover, the trifluoromethylzinc reagent can also be employed as a difluorocarbene source for gemdifluoroolefination of carbonyl compounds as well as gemdifluorocyclization of alkenes or alkynes. The alcohols are obtained with good yields from aldehydes. Improving the reactivity of anionoid trifluoromethyl species in glymes. Trifluoromethylation of nonenolizable carbonyl compounds. The final edited and typeset version of record will appear in the future. Direct nucleophilic trifluoromethylation of carbonyl compounds by. A feasible nucleophilic trifluoromethylating protocol has been developed using trifluoroacetaldehyde hydrate as an atom economical trifluoromethyl source. A feasible nucleophilic trifluoromethylating protocol has been developed using trifluoroacetaldehyde hydrate as an atomeconomical trifluoromethyl source. Direct nucleophilic trifluoromethylation of carbonyl. Fluoroform cf3h, a largevolume byproduct of the manufacture of teflon, refrigerants, polyvinylidene fluoride pvdf, fireextinguishing agents, and foams, is a potent and stable greenhouse gas that has found little practical use despite the growing importance of trifluoromethyl cf3 functionality in more structurally elaborate pharmaceuticals, agrochemicals, and materials. Trifluoromethylationinitiatedremote crosscoupling of. Apr 05, 20 a feasible nucleophilic trifluoromethylating protocol has been developed using trifluoroacetaldehyde hydrate as an atom economical trifluoromethyl source.
Ketones and aldehydes notably via their enol ether and enamine derivatives enable electrophi. This operationally simple and robust protocol successfully converts a variety of chloro carbonyl compounds into the corresponding chlorofluoroalkylcarbonyl products. Trifluoromethylation and pentafluoroethylation of terpenoid. After protonating the carbonyl oxygen, we move on to the step with a yellow star near it. N,ndialkylhydrazones were widely used in organic chemistry, including using as synthetic equivalents of carbonyl compounds, as precursors to substituted hydrazines or primary amines. This method also allows the first microflow transformation of nsulfinylimines into trifluoromethyl. The scope was quite narrow with electronrich aromatics and mixtures of regioisomers were often obtained. Jul 31, 2018 a simple protocol to overcome the problematic trifluoromethylation of carbonyl compounds by the potent greenhouse gas hfc23, fluoroform with a potassium base is described.
A new alkoxideinduced nucleophilic trifluoromethylation of a variety of carbonyl compounds has been developed by beier et al. A process of claim 9 wherein the carbonyl compound is an aldehyde or ketone. With ketones the organozinc species are formed preferentially to the alcohols, but the addition of. Lithium acetatecatalyzed trifluoromethylation of carbonyl. Survey of reactions and mechanisms course notes chemistry 14d images and sample reactions taken from the chemistry 14d thinkbook for fall 2004, and. A microflow nucleophilic trifluoromethylation of carbonyl compounds using gaseous fluoroform was developed. Fluorideinduced trifluoromethylation of carbonyl compounds.
In organic chemistry, a carbonyl group is a functional group composed of a carbon atom doublebonded to an oxygen atom. Direct trifluoromethylation of arenes and heteroarenes. Dft calculations have been performed to provide mechanistic insight into the. A simple protocol to overcome the problematic trifluoromethylation of carbonyl compounds by the potent greenhouse gas hfc23, fluoroform with a potassium base is described. The ruppertprakash reagent is the most powerful and welldocumented reagent for trifluoromethylation. Dec 07, 2000 direct nucleophilic trifluoromethylation of carbonyl compounds by potent greenhouse gas, fluoroform. This material is available free of charge via the internet at pdf. Indeed, molecular mechanics calculations on model compounds suggest that, of the two enantiomeric pairs, the rssr diastereomeric pair is some 10% lower in energy than its ssrr counterpart, a value that is compatible with the observed difference in intensity between the corresponding 1h nmr resonances. Despite its versatility, no general method exists for its use in a flow system.
Aug 01, 2014 the proposed efficiency, functional group compatibility, and operational simplicity of the trifluoromethylation of aldehydes and ketones should provide rapid access to important target compounds. Coupling of carbonyl compounds to form carbonheteroatomcarbon bonds. Using trifluoromethyltrimethylsilane tmscf 3 as the trifluoromethylating agent, mgcl 2catalyzed trifluoromethylation of carbonyl compounds proceeded readily at room temperature. Electrophilic trifluoromethylation of carbonyl compounds and.
Direct trifluoromethylation of csp 2h with a electrophilic trifluoromethylation reagent tognis reagent. The electroreduction of cf 3 br in dmf containing aldehydes or ketones, using a sacrificial zinc anode, affords the corresponding trifluoromethyl alcohols together with the unreactive organozinc species cf 3 znbr and cf 3 2 zn. Nucleophilic trifluoromethylation, ketones, aldehydes, esters, imines. International audiencerecent advances in electrophilic trifluoromethylation reactions of carbonyl compounds and their usual surrogates are highlighted with particular focus on coppercatalysed or mediated ccf3 bond forming reactions. Nucleophilic trifluoromethylation of carbonyl compounds and. Trifluoromethylation of aldehydes and ketones with sodium trifluoroacetate. Trifluoromethylation of carbonyl compounds bentham science. An overview of reductive trifluoromethylation reactions using. This is the attack of the alcohol on the carbonyl carbon.
Trifluoromethylation of aldehydes, ketones, chalcones, and nsulfinylimines a gasliquidphase microflow nucleophilic trifluoromethylation of carbonyl compounds using gaseous fluoroform is developed. Recent advances in electrophilic trifluoromethylation reactions of carbonyl compounds and their usual surrogates are highlighted with particular focus on coppercatalysed or mediated ccf3 bond forming reactions. Jun 01, 2005 read trifluoromethylation of carbonyl compounds with sodium trifluoroacetate, journal of fluorine chemistry on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Request pdf trifluoromethylation of carbonyl compounds with sodium trifluoroacetate in the presence of copperi iodide as catalyst, a variety of carbonyl. Trifluoromethyl carbinol synthesis organic chemistry portal. Read trifluoromethylation and pentafluoroethylation of terpenoid carbonyl compounds used in perfumery, journal of fluorine chemistry on deepdyve, the largest online rental service for scholarly research with thousands of academic publications available at your fingertips. Trifluoromethylation of aldehydes via photoredox organocatalysis. They are three classes of carbonyl compounds so named because they all contain the co group or carbonyl group figure. Tbdcatalyzed trifluoromethylation of carbonyl compounds. Trifluoroacetaldehyde hydrate as a trifluoromethyl source.
Thiswas achieved using an electrogenerated base 25, 26 or a strong base to deprotonate cf 3hwithsubsequent trapping of cf 3 trifluoromethyl anion by dimethylformamide dmf to. Mgcl2catalyzed trifluoromethylation of carbonyl compounds. In recent years, a series of nucleophilic trifluoromethylation reactions has been established. A mild, operationally simple approach to the synthesis of. Emphasis was given to the description of the trifluoromethylating agents, their activation mode, their reaction with carbonyl compounds, as well as applications in organic synthesis.
Macmillan the unique physical and chemical advantages conferred by the c f bond have led to the broad exploitation of this motif throughout the pharmaceutical,1 materials,2 and. Application of fluoroform in trifluoromethylation and. Nucleophilic trifluoromethylation of carbonyl compounds. Trifluoromethylation of carbonyl compounds with sodium trifluoroacetate. Course objectives at the end of this course you should be able to. Recent advances in electrophilic trifluoromethylation reactions of carbonyl compounds and their usual surrogates are highlighted with particular focus on coppercatalysed or mediated ccf3 bond. This crosscoupling is triggered by radical trifluoromethylation of alkenes, thereby achieving highly selectiveremote difunctionalization of alkenes and aposition of the carbonyl group for facile access to trifluoromethyl ahalo and acyanocarbonyl compounds.
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