One-pot synthesis of tertiary alkyl fluorides from methyl oxalates by radical deoxyfluorination under photoredox catalysis

Tertiary alkyl fluorides have been prepared from methyl oxalates derived from tertiary alcohols by a sequential one-pot hydrolysis/photoredox catalyzed radical deoxyfluorination sequence. The reaction operates under mild conditions and tolerates a wide range of functional groups. This method provides an alternative approach to ionic deoxyfluorination transformations for the incorporation of Carbone–Fluorine quaternary centers into organic molecules.     

Mild Copper‐Catalyzed Fluorination of Alkyl Triflates with Potassium Fluoride

A chemoselective catalytic fluorination of alkyl triflates is described using potassium fluoride as a fluoride source. Excellent yields of the desired alkyl fluorides are obtained after one hour at 45 °C using 2 mol % of the copper catalyst. With 10 mol % of the catalyst, full conversion can be achieved in less than 10 minutes at 45 °C, and thus makes this procedure potentially suited for the preparation of ¹⁸F‐labeled PET probes. As a result of the mild reaction conditions, only the substitution products are observed with no evidence of common side reactions, such as elimination. Reported is a preliminary study of the reaction scope, which demonstrates that the fluorination can be performed in the presence of a wide range of functional groups. Evidence suggests an unusual role of the [IPrCuOTf] catalyst as a phase‐transfer catalyst and points to [IPrCuF] as the active fluorinating reagent (IPr=1,3‐bis(2,6‐diisopropylphenyl)imidazol‐2‐ylidene).     

Deoxyfluorination with CuF2: Enabled by Using a Lewis Base Activating Group

Deoxyfluorination is a primary method for the formation of C−F bonds. Bespoke reagents are commonly used because of issues associated with the low reactivity of metal fluorides. Reported here is the development of a simple strategy for deoxyfluorination, using first-row transition-metal fluorides, and it overcomes these limitations. Using CuF₂ as an exemplar, activation of an O-alkylisourea adduct, formed in situ, allows effective nucleophilic fluoride transfer to a range of primary and secondary alcohols. Spectroscopic investigations have been used to probe the origin of the enhanced reactivity of CuF₂. The utility of the process in enabling ¹⁸F-radiolabeling is also presented.     

Tertiary-Amine-Initiated Synthesis of Acyl Fluorides from Carboxylic Acids and CF3SO2OCF3

A convenient method for deoxyfluorination of aromatic and aliphatic carboxylic acids with CF₃SO₂OCF₃ in the presence of a suitable base at room temperature has been developed. The reaction allows a straightforward access to a variety of acyl fluorides and proves that CF₃SO₂OCF₃ is an effective deoxyfluorination reagent for carboxylic acids. The method features simplicity, expeditiousness, high efficiency, ease of handling, good functional group tolerance, a wide range of substrates, excellent yields of products, compatibility of many amine initiators, use of environmentally friendly reagents, and effortless removal of byproducts. This reaction represents the first utilization of trifluoromethyl trifluoromethanesulfonate as a fluorination reagent.     

Deoxyfluorination with CuF2: Enabled by Using a Lewis Base Activating Group

Deoxyfluorination is a primary method for the formation of C?F bonds. Bespoke reagents are commonly used because of issues associated with the low reactivity of metal fluorides. Reported here is the development of a simple strategy for deoxyfluorination, using first‐row transition‐metal fluorides, and it overcomes these limitations. Using CuF₂ as an exemplar, activation of an O‐alkylisourea adduct, formed in situ, allows effective nucleophilic fluoride transfer to a range of primary and secondary alcohols. Spectroscopic investigations have been used to probe the origin of the enhanced reactivity of CuF₂. The utility of the process in enabling ¹⁸F‐radiolabeling is also presented.     

Light-Mediated Formal Radical Deoxyfluorination of Tertiary Alcohols through Selective Single-Electron Oxidation with TEDA2+.

The synthesis of tertiary alkyl fluorides through a formal radical deoxyfluorination process is described herein. This light-mediated, catalyst-free methodology is fast and broadly applicable allowing for the preparation of C−F bonds from (hetero)benzylic, propargylic, and non-activated tertiary alcohol derivatives. Preliminary mechanistic studies support that the key step of the reaction is the single-electron oxidation of cesium oxalates—which are readily available from the corresponding tertiary alcohols—with in situ generated TEDA^2+. (TEDA: N-(chloromethyl)triethylenediamine), a radical cation derived from Selectfluor®.     

Transition metal catalysis and nucleophilic fluorination

Transition metal catalyzed transformations using fluorinating reagents have been developed extensively for the preparation of synthetically valuable fluorinated targets. This is a topic of critical importance to facilitate laboratory and industrial chemical synthesis of fluorine containing pharmaceuticals and agrochemicals. Translation to (18)F-radiochemistry is also emerging as a vibrant research field because functional imaging based on Positron Emission Tomography (PET) is increasingly used for both diagnosis and pharmaceutical development. This review summarizes how fluoride sources have been used for the catalytic nucleophilic fluorination of various substrates inclusive of aryl triflates, alkynes, allylic halides, allylic esters, allylic trichloroacetimidates, benzylic halides, tertiary alkyl halides and epoxides. Until recently, progress in this field of research has been slow in part because of the challenges associated with the dual reactivity profile of fluoride (nucleophile or base). Despite these difficulties, some remarkable breakthroughs have emerged. This includes the demonstration that Pd(0)/Pd(II)-catalyzed nucleophilic fluorination to access fluoroarenes from aryl triflates is feasible, and the first examples of Tsuji-Trost allylic alkylation with fluoride using either allyl chlorides or allyl precursors bearing O-leaving groups. More recently, allylic fluorides were also made accessible under iridium catalysis. Another reaction, which has been greatly improved based on careful mechanistic work, is the catalytic asymmetric hydrofluorination of meso epoxides. Notably, each individual transition metal catalyzed nucleophilic fluorination reported to date employs a different F-reagent, an observation indicating that this area of research will benefit from a larger pool of nucleophilic fluoride sources. In this context, a striking recent development is the successful design, synthesis and applications of a fluoride-derived electrophilic late stage fluorination reagent. This new class of reagents could greatly benefit preclinical and clinical PET imaging.     

Direct Dehydroxytrifluoromethylthiolation of Alcohols Using Silver(I) Trifluoromethanethiolate and Tetra‐n‐butylammonium Iodide

An unprecedented reaction for the direct trifluoromethylthiolation and fluorination of alkyl alcohols using AgSCF₃ and nBu₄NI has been developed. The trifluoromethylthiolated compounds and alkyl fluorides were selectively formed by changing the ratio of AgSCF₃/nBu₄NI. This protocol is tolerant of different functional groups and might be applicable to late‐stage trifluoromethylthiolation of alcohols.     

Silver-catalyzed decarboxylative fluorination of aliphatic carboxylic acids in aqueous solution

Although fluorinated compounds have found widespread applications in the chemical and materials industries, general and site-specific C(sp(3))-F bond formations are still a challenging task. We report here that with the catalysis of AgNO(3), various aliphatic carboxylic acids undergo efficient decarboxylative fluorination with SELECTFLUOR(?) reagent in aqueous solution, leading to the synthesis of the corresponding alkyl fluorides in satisfactory yields under mild conditions. This radical fluorination method is not only efficient and general but also chemoselective and functional-group-compatible, thus making it highly practical in the synthesis of fluorinated molecules. A mechanism involvinig Ag(III)-mediated single electron transfer followed by fluorine atom transfer is proposed for this catalytic fluorodecarboxylation.     

Deoxyfluorination of alcohols using N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine

Deoxyfluorination of alcohols was carried out using N,N-diethyl-α,α-difluoro-(m-methylbenzyl)amine (DFMBA). Primary alcohols were effectively converted to fluorides under microwave irradiation or conventional heating. Deoxyfluorination of an anomeric hydroxy group in sugars by DFMBA proceeded at below room temperature and glycosyl fluorides could be obtained in good yields. The deoxyfluorination reaction chemoselectively proceeded and various protecting groups on the sugar can survive under the reaction conditions.     

Deoxyfluorination of phenols

An operationally simple ipso fluorination of phenols with a new deoxyfluorination reagent is presented.     

Facile nucleophilic fluorination reactions using tert-alcohols as a reaction medium: significantly enhanced reactivity of alkali metal fluorides and improved selectivity

Although protic solvents are generally not preferred for nucleophilic displacement reactions because of their partial positive charge and hydrogen-bonding capacity that solvate the nucleophile and reduce its reactivity, we recently reported a remarkably beneficial effect of using tertiary alcohols as a reaction media for nucleophilic fluorination with alkali metal fluorides, as well as fluorine-18 radiolabeling with [18F]fluoride ion for the preparation of PET radiopharmaceuticals. In this work, we investigate further the influence of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluorides by studying various interactions among tert-alcohols, the alkali metal fluoride (CsF), and the sulfonyloxy substrate. Factors such as hydrogen bonding between CsF and the tert-alcohol solvent, the formation of a tert-alcohol solvated fluoride, and hydrogen bonding between the sulfonate leaving group and the tert-alcohol appear to contribute to the dramatic increase in the rate of the nucleophilic fluorination reaction in the absence of any kind of catalyst. We found that fluorination of 1-(2-mesyloxyethyl)naphthalene (5) and N-5-bromopentanoyl-3,4-dimethoxyaniline (8) with Bu(4)N(+)F(-) in a tert-alcohol afforded the corresponding fluoro products in much higher yield than obtained by the conventional methods using dipolar aprotic solvents. The protic medium also suppresses formation of byproducts, such as alkenes, ethers, and cyclic adducts.     

1,1,3,3,3-Pentafluoropropene secondary amine adducts new selective fluorinating agents

Addition of secondary amine SA (dimethylamine DMA, diethylamine DEA, pyrrolidine Pyr, piperidine Pip, morpholine Mor) to pentafluoropropene PFP gives rise to generation of mixtures of two products (1-dialkylamine-1,3,3,3-tetrafluoropropene and N,N-dialkyl-1,1,3,3,3-pentafluoropropylamine) in different ratios. Those reaction mixtures, however, were found to be efficient fluorinating agents replacing hydroxyl groups in alcohols into fluorine. In general, they react with alcohols yielding corresponding fluorides, equimolar amounts of appropriate 3,3,3-trifluoropropionamide and hydrogen fluoride. Aliphatic primary alcohols including octanol and benzylic alcohol yield only alkyl fluorides. The secondary and tertiary alcohols, beside the desired fluorides, give usually considerably amount of alkenes.     

氟烷磺酰氟和全乙酰基保护的吡喃型半缩醛单糖的氟代反应

考察了5-氢-3-氧杂-1,1,2,2,4,4,5,5-八氟戊烷磺酰氟(HCF2CF2OCF2CF2SO2F)和全乙酰基保护的吡喃型半缩醛单糖在有机碱存在下的氟代反应.实验结果表明,氟烷基磺酰氟试剂HCF2CF2OCF2CF2SO2F能够诱导全乙酰基保护的吡喃型半缩醛单糖发生氟代反应而生成相应的氟代糖苷,得率44%～94%.该方法具有反应条件温和和后处理简便等优点,可作为一种有效的方法用于氟代糖苷的制备中.     

Palladium‐Catalyzed Fluorination of Cyclic Vinyl Triflates: Effect of TESCF3 as an Additive

A method for the palladium‐catalyzed fluorination of cyclic vinyl triflates has been developed. As with several previous palladium‐catalyzed fluorination reactions using fluoride salts, controlling the regioselectivity presented a challenge in developing a practical synthetic procedure. The addition of triethyl(trifluoromethyl)silane (TESCF₃) was found to effectively address this problem and resulted in drastically improved regioselectivities in this palladium‐catalyzed fluorination reaction. This discovery, along with the use of a new biarylphosphine ligand, allowed for the development of an efficient and highly regioselective protocol for the fluorination of vinyl triflates. This method is compatible with a range of sensitive functional groups and provides access to five‐, six‐, and seven‐membered cyclic vinyl fluorides.     

Stereospecific Electrophilic Fluorination of Alkylcarbastannatrane Reagents

We report the use of isolable primary and secondary alkylcarbastannatrane nucleophiles in site‐specific fluorination reactions. These reactions occur without the need for transition metal catalysis or in situ activation of the nucleophile. In the absence of the carbastannatrane backbone, alkyltin nucleophiles exhibit no activity towards fluorination. When enantioenriched alkylcarbastannatranes are employed, fluorination occurs predominately via a stereoinvertive mechanism to generate highly enantioenriched alkyl fluoride compounds. These conditions can also be extended to stereospecific chlorination, bromination, and iodination reactions.     

Ionic liquids as media for nucleophilic fluorination

The use of Room Temperature Ionic Liquids (RTILs) for a variety of halogen exchange (Halex) fluorination processes using alkali metal fluorides is assessed. Whilst fluorination of a range of halogenated substrates is possible in good yield, the utility of RTILs as reusable, inert media for such reactions is limited by the gradual decomposition of the RTIL in the presence of highly basic fluoride ion.     

Solvent-free fluorination of partially-chlorinated heterocyclics: Synthesis of 2,6-difluoropyridine from 2,6-dichloropyridine

Previous studies on the solvent-free fluorination of partially-chlorinated heterocyclics such as 2-chloropyridine, 2,3,4,6- and 2,3,5,6-tetrachloropyridine, and 2,4,6-trichloropyrimidine with alkali metal fluorides or hifluorides revealed an inconsistent product pattern: degradation, partial or complete halogen exchange could occur. The present study concerned application of the solvent-free halogen exchange technique (potassium fluoride) to 2,6-dichloropyridine (I). The latter, as well as its fluorination products, exhibited good stability at 400° to provide an 80% yield of 2,6-difluoropyridine (III). Moderation of fluorination conditions also permitted isolation of the precursor, 2-chloro-6-fluoropyridine (II), a new compound. The above solvent-free process to III is superior to the previously-reported halogen-exchange route in dimethyl sulfone solvent on the basis of yield, reaction time and number of processing steps.     

Photoredox Activation of SF6 for Fluorination

We report the first practical use of SF₆ as a fluorinating reagent in organic synthesis. Photoredox catalysis enables the in situ conversion of SF₆, an inert gas, into an active fluorinating species by using visible light. Under these conditions, deoxyfluorination of allylic alcohols is effected with high chemoselectivity and is tolerant of a wide range of functional groups. Application of the methodology in a continuous‐flow setup achieves comparable yields to those obtained with a batch setup, while providing drastically increased material throughput of valuable allylic fluoride products.     

Cocatalysis in phase-transfer catalyzed fluorination of alkyl halides and sulfonates

Phase-transfer catalyzed (PTC) fluorination of alkyl halides and sulfonates with solid KF proceeds efficiently when cocatalyst triphenyltin fluoride is used. The cocatalytic action of the tin compound consists in continuous formation of difluorotriphenylstannate anion that as the tetraalkyloammonium salt enter the solution where it reacts with alkyl halides to produce alkyl fluorides. The cocatalytic system was used to synthesis of 1,1-difluoroalkanes in two steps from aldehydes. A new kind of PTC was elaborated in which Ph₃SnF acts as phase transfer catalyst via continuous formation of potassium salts of diflurotriphenylstannate anions soluble in dipolar aprotic solvents. A new, simple and general method of synthesis of tetraalkylammonium and potassium salts of difluorotriorgano-tin, silicon and germanium anions is reported.