Selective fluorination of adamantanes by an electrochemical method

Selective fluorination of adamantanes was achieved by the electrochemical fluorination method, using Et 3N-5HF as electrolyte and a fluorine source. Mono-, di-, tri-, and tetrafluoroadamantanes were selectively prepared from adamantanes by controlling the oxidation potential, and the fluorine atoms were introduced selectively at the tertiary carbons. Adamantanes that have functional groups such as ester, cyano, and acetoxymethyl were also fluorinated selectively.     

Synthesis of perfluorochemicals for use as blood substitutes,part II: electrochemical fluorination of partly fluorinated compounds

Electrochemical fluorination of 2-methoxy-1,1,1-trifluoro-2-(F-methyl) octane gave the corresponding perfluorinated ether in 27% yield, along with cyclic by-products in 9%. A mixture of partly fluorinated tertiary amines, consisting of 1-dipropylamino-F-1-propene and 1-dipropylamino-2-hydryl-F-propane, did not afford a superior yield of tri(F-propyl)amine compared to the unfluorinated tripropylamine. 1-Diethylamino-2-(F-methyl)-F-1-pentene was fluorinated to give the corresponding F-tertiary amine in fairly good yields, together with 1-di(F-ethyl)amino-2-hydryl-2-(F-methyl)-F-pentane and their fragmented products. The study indicates that blocking of the α-carbon atom of an ether with F-methyl groups seems to reduce fragmentation, resulting in good yields of an unrearranged product. However, partial fluorination of a tertiary amine prior to electrochemical fluorination rather allows high yields of undesired by-products, as far as our experiments were concerned.     

Iron(II)‐Catalyzed Site‐Selective Functionalization of Unactivated C(sp3)−H Bonds Guided by Alkoxyl Radicals

An alkoxyl radical guided strategy for site‐selective functionalization of unactivated methylene and methine C?H bonds enabled by an Fe^II‐catalyzed redox process is described. The mild, expeditious, and modular protocol allows efficient remote aliphatic fluorination, chlorination, amination, and alkynylation of structurally and electronically varied primary, secondary, and tertiary hydroperoxides with excellent functional‐group tolerance. The application for one‐pot 1,4‐hydroxyl functionalization of non‐oxygenated alkane substrates initiated by aerobic C?H oxygenation is also demonstrated.     

Interaction between Divalent Copper Fluoride and Carboxamide Group Enabling Stereoretentive Fluorination of Tertiary Alkyl Halides

Herein, we report a copper-catalyzed stereospecific fluorination involving CsF and α-bromocarboxamides as tertiary alkyl sources that, unlike traditional stereospecific routes involving stereoinversive S_N2 reactions, proceeds with retention of stereochemistry. The developed stereospecific Cu-catalyzed reaction is among the most efficient methods for synthesizing fluorinated molecules that possess highly congested stereogenic carbon centers. Mechanistic studies revealed that the combined reactivity of CuF₂ and Cs salt is essential for completing the catalytic cycle. Our catalytic system underwent fluorination exclusively with tertiary alkyl bromides and did not react with primary alkyl bromides, indicating that this stereospecific fluorination methodology is suitable for synthesizing fluorinated building blocks possessing stereo-defined F-containing tertiary carbon stereogenic center.     

Selective Radical Fluorination of Tertiary Alkyl Halides at Room Temperature

Direct fluorination of tertiary alkyl bromides and iodides with Selectfluor is described. The halogen‐exchange fluorination proceeds efficiently in acetonitrile at room temperature under metal‐free conditions and exhibits a wide range of functional group compatibility. Furthermore, the reactions are highly selective in that alkyl chlorides and primary and secondary alkyl bromides remain intact. A radical mechanism is proposed for this selective fluorination.     

Ring-opening fluorination of bicyclic azaarenes

We have discovered a ring-opening fluorination of bicyclic azaarenes. Upon treatment of bicyclic azaarenes such as pyrazolo[1,5-a]pyridines with electrophilic fluorinating agents, fluorination of the aromatic ring is followed by a ring-opening reaction. Although this overall transformation can be classified as an electrophilic fluorination of an aromatic ring, it is a novel type of fluorination that results in construction of tertiary carbon–fluorine bonds. The present protocol can be applied to a range of bicyclic azaarenes, tolerating azines and a variety of functional groups. Additionally, mechanistic studies and enantioselective fluorination have been examined.

A ring-opening fluorination of bicyclic azaarenes was developed. Although this overall transformation can be classified as an electrophilic fluorination of aromatics, it is a novel type of fluorination that results in construction of tert-C–F bonds.     

Site‐Selective Approach to β‐Fluorination: Photocatalyzed Ring Opening of Cyclopropanols

To expand upon the recent pioneering reports of catalyzed sp³ C?H fluorination methods, the next rational step is to focus on directing “radical‐based fluorination” more effectively. One potential solution entails selective C?C bond activation as a prelude to selective fluorination. Herein, we report the tandem photocatalyzed ring‐opening/fluorination reactions of cyclopropanols by 1,2,4,5‐tetracyanobenzene (TCB) and Selectfluor to afford a process tantamount to site‐selective β‐fluorination of carbonyl‐containing compounds. This new approach provides a synthetically mild and operationally simple route to otherwise difficult‐to‐prepare β‐fluorinated products in good yields and with good‐to‐excellent regioselectivity. Remarkably, substrates that contain other usually reactive (e.g., benzylic) sites undergo ring‐opening fluorination preferably. The versatility of this method to give cyclic β‐fluorides from tertiary cyclopropanols and γ‐fluoro alcohols is also highlighted.     

Fluorine transfer to alkyl radicals

The development of new synthetic technologies for the selective fluorination of organic compounds has increased with the escalating importance of fluorine-containing pharmaceuticals. Traditional methods potentially applicable to drug synthesis rely on the use of ionic forms of fluorine (F(-) or F(+)). Radical methods, while potentially attractive as a complementary approach, are hindered by a paucity of safe sources of atomic fluorine (F(?)). A new approach to alkyl fluorination has been developed that utilizes the reagent N-fluorobenzenesulfonimide as a fluorine transfer agent to alkyl radicals. This approach is successful for a broad range of alkyl radicals, including primary, secondary, tertiary, benzylic, and heteroatom-stabilized radicals. Furthermore, calculations reveal that fluorine-containing ionic reagents are likely candidates for further expansion of this approach to polar reaction media. The use of these reagents in alkyl radical fluorination has the potential to enable powerful new transformations that otherwise would take multiple synthetic steps.     

Catalytic Nucleophilic Fluorination of Secondary and Tertiary Propargylic Electrophiles with a Copper–N‐Heterocyclic Carbene Complex

A catalytic method for the nucleophilic fluorination of propargylic electrophiles is described. Our protocol involves the use of a Cu(NHC) complex as the catalyst and is suitable for the preparation of secondary and tertiary propargylic fluorides without the formation of isomeric fluoroallenes. Preliminary mechanistic investigations suggest that fluorination proceeds via copper acetylides and that cationic species are involved.     

Predictable site-selective radical fluorination of tertiary ethers

In this communication,we disclose the first example of metal-free and site-selective radical fluorination of readily available tertiary alkyl ethers,enabled by synergistic photocatalysis and organocatalysis.This catalytic combination allows for exclusive fluorination of tertiary C–O bonds under mild conditions even in the presence of competing reaction sites.The excellent functional group tolerance affords valuable access to sterically hindered alkyl fluorides through late-stage modification of complex molecules.The successful use of tertiary alkyl ethers in radical fluorination enhances the structural diversity of aliphatic fluorides that can be derived from naturally abundant alcohols.     

Electrochemical fluorination of toluene and benzotrifluoride in the presence of triallylamine

Electrochemical fluorination of benzotrifluoride in the presence of triallylamine as depolarizer was studied. The possibility of preparing perfluoromethylcyclohexane and its isomers with high current efficiency and substance yield in combination with perfluorinated tertiary amines was examined.     

Sequence-Dependent Stereodivergent Allylic Alkylation/Fluorination of Acyclic Ketones

The stereodivergent iridium-catalyzed allylic alkylation and fluorination of acyclic ketones is described. α-Pyridyl-α-fluoroketones with vicinal tertiary and quaternary stereocenters were obtained in moderate to excellent yields and stereoselectivities. Distinct from known stereodivergent synthesis, for which two different chiral catalysts are required in general, herein we report a sequence-dependent stereodivergent synthesis. With only a single chiral Ir catalyst, all four possible stereoisomers of the products were prepared from the same starting materials by simply adjusting the sequence of asymmetric allylic alkylation and fluorination and varying the absolute configuration of the Ir catalyst.     

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.     

Sequence‐Dependent Stereodivergent Allylic Alkylation/Fluorination of Acyclic Ketones

The stereodivergent iridium‐catalyzed allylic alkylation and fluorination of acyclic ketones is described. α‐Pyridyl‐α‐fluoroketones with vicinal tertiary and quaternary stereocenters were obtained in moderate to excellent yields and stereoselectivities. Distinct from known stereodivergent synthesis, for which two different chiral catalysts are required in general, herein we report a sequence‐dependent stereodivergent synthesis. With only a single chiral Ir catalyst, all four possible stereoisomers of the products were prepared from the same starting materials by simply adjusting the sequence of asymmetric allylic alkylation and fluorination and varying the absolute configuration of the Ir catalyst.     

Electrolytic partial fluorination of organic compounds: 89: Regioselective anodic fluorination of tetrazolyl sulfides

Anodic fluorination of five-membered nitrogen-containing heterocyclic sulfides like tetrazolyl sulfides was comparatively studied. The anodic fluorination of tetrazolyl sulfides having α-electron-withdrawing groups was successfully carried out to provide α-monofluorinated tetrazolyl derivatives in moderate yields. This is in sharp contrast to the low efficient anodic fluorination of triazolyl sulfides. Thus, it was found that the efficiency of anodic fluorination is greatly affected by the basicity of the heterocyclic groups of the starting heterocyclic sulfides.     

Site‐Selective Tertiary Alkyl–Fluorine Bond Formation from α‐Bromoamides Using a Copper/CsF Catalyst System

A copper‐catalyzed site‐selective fluorination of α‐bromoamides possessing multiple reaction sites, such as primary and secondary alkyl?Br bonds, using inexpensive CsF is reported. Tertiary alkyl?F bonds, which are very difficult to synthesize, can be formed by this fluorination reaction with the aid of an amide group. Control experiments revealed that in situ generated CuF₂ is a key fluorinating reagent that reacts with the tertiary alkyl radicals generated by the reaction between an α‐bromocarbonyl compound and a copper(I) salt.     

Nickel‐Catalyzed Alkyl–Alkyl Cross‐Couplings of Fluorinated Secondary Electrophiles: A General Approach to the Synthesis of Compounds having a Perfluoroalkyl Substituent

Fluorinated organic molecules are of interest in fields ranging from medicinal chemistry to polymer science. Described herein is a mild, convenient, and versatile method for the synthesis of compounds bearing a perfluoroalkyl group attached to a tertiary carbon atom by using an alkyl–alkyl cross‐coupling. A nickel catalyst derived from NiCl₂?glyme and a pybox ligand achieves the coupling of a wide range of fluorinated alkyl halides with alkylzinc reagents at room temperature. A broad array of functional groups is compatible with the reaction conditions, and highly selective couplings can be achieved on the basis of differing levels of fluorination. A mechanistic investigation has established that the presence of 2,2,6,6‐tetramethyl‐1‐piperidinyloxy (TEMPO) inhibits cross‐coupling under these conditions and that a TEMPO–electrophile adduct can be isolated.     

Photoinduced Remote Functionalization of Amides and Amines Using Electrophilic Nitrogen Radicals

The selective functionalization of C(sp³)?H bonds at distal positions to functional groups is a challenging task in synthetic chemistry. Reported here is a photoinduced radical cascade strategy for the divergent functionalization of amides and protected amines. The process is based on the oxidative generation of electrophilic amidyl radicals and their subsequent transposition by 1,5‐H‐atom transfer, resulting in remote fluorination, chlorination and, for the first time, thioetherification, cyanation, and alkynylation. The process is tolerant of most common functional groups and delivers useful building blocks that can be further elaborated. The utility of this strategy is demonstrated through the late‐stage functionalization of amino acids and a dipeptide.     

Synthesis of alpha-fluorosulfonamides by electrophilic fluorination

Alpha-fluorosulfonamides were prepared by electrophilic fluorination of tertiary sulfonamides using N-fluorobenzenesulfonimide as fluorinating agent and utilizing the dimethoxybenzyl group (DMB) as a new sulfonamide protecting group. Removal of the DMB group with TFA/CH(2)Cl(2) gave primary and secondary alpha-fluorosulfonamides.     

The fluorination of 2-methylpropane over cobalt trifluoride

2-Methylpropane has been fluorinated over cobalt trifluoride at 140-200°C to give a mixture of at least 30 components, of which 22 have been identified with some certainty and five, more tentatively; this represents well over 95% of the reaction mixture. About 95% of the identified products were polyfluoro(2-methylpropanes); the rest were polyfluorobutanes. The fluorination was not completely random; there was a clear preference (by some 10 times greater than chance) for compounds in which the tertiary hydrogen had been replaced by fluorine. A scheme for the fluorination pathway is proposed. Attempts to dehydrofluorinate 1 ,3 -pentafluoro-2-fluoromethylpropane failed.