Preparation and Reactivity Study of a Versatile Trifluoromethylthiolating Agent: S-Trifluoromethyl Trifluoromethanesulfonothioate (TTST).

A novel, air and thermally stable, yet highly reactive trifluoromethylthiolating reagent, CF3 SO2 SCF3 (1), was prepared easily in one step from commercially inexpensive CF3 SO2 Na and Tf2 O. 1 is a highly versatile and atom-efficient reagent that can generate one equivalent of CF3 S+ , two equivalents of CF3 S- , or a combination of CF3 S⋅/CF3 ⋅ species. Many high-yielding CF3 S reactions of C, O, S, and N-nucleophiles were achieved, including the simple-step preparations of many reported CF3 S reagents. 1 delivered a hitherto hard-to-synthesize ArOSCF3 that was followed by a novel CF3 SII -rearrangement. Through Cu or TDAE/Ph3 P combinations, 1 generated two equivalents of CF3 S anion species, and the photo-catalyzed reactions of alkenes with 1 provided CF3 /CF3 S-containing products in high atom-efficiency.

Synthesis and applications of S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (Umemoto reagent IV).

A new, powerful, and easy-to-handle electrophilic trifluoromethylating agent, S-(trifluoromethyl)-2,8-bis(trifluoromethoxy)dibenzothiophenium triflate (Umemoto reagent IV), was developed. Due to the extraordinary electronic effect of trifluoromethoxy group, Umemoto reagent IV was easily synthesized by a one-pot method from readily available 3,3'-bis(trifluoromethoxy)biphenyl. It was shown that Umemoto reagent IV was more powerful than Umemoto reagent II and could trifluoromethylate many kinds of nucleophilic substrates more effectively. In addition, Umemoto reagent IV was successfully utilized for the preparation of trifluoromethyl nonaflate, a useful trifluoromethoxylating agent. The direct conversion of 2,8-bis(trifluoromethoxy)dibenzothiophene to Umemoto reagent IV with triflic anhydride was achieved, albeit in low yield.

Self-Sustaining Fluorination of Active Methylene Compounds and High-Yielding Fluorination of Highly Basic Aryl and Alkenyl Lithium Species with a Sterically Hindered N-Fluorosulfonamide Reagent.

Fluorination of carbanions is pivotal for the synthesis of fluorinated compounds, but the current N-F fluorinating agents have significant drawbacks due to many reactive locations that surround the reactive N-F site. By developing a sterically hindered N-fluorosulfonamide reagent, namely N-fluoro-N-(tert-butyl)-tert-butanesulfonamide (NFBB), we discovered a conceptually novel base-catalyzed, self-sustaining fluorination of active methylene compounds and achieved the high-yielding fluorination of the hitherto difficult highly basic (hetero)aryl and alkenyl lithium species. In the former, the mild and high yield fluorination of active methylene compounds exhibited wide functional group tolerance and its novel catalytic fluorination-deprotonation cycle mechanism was demonstrated by deuterium-tracing experiments. In the latter, NFBB reacted with a variety of highly basic (hetero)aryl and alkenyl lithium species to provide the desired fluoro (hetero)arenes and alkenes in unprecedented high or quantitative yields.

Broadly Applicable Ion Pair-Assisted Nucleophilic Substitution of sp3-Carbon Electrophiles with Alkynyltrifluoroborates.

Alkynyltrifluoroborate nucleophiles react smoothly with a wide range of sp3-carbon electrophiles, including propargyl methanesulfonates and unactivated alkyl triflates, to give Sonogashira-type products, via a novel ion pair-assisted nucleophilic substitution mechanism. An ion pair-organic complex, investigated using computational chemistry and in situ NMR experiments, may play a crucial role in this reaction.

Gold (I/III)-Catalyzed Trifluoromethylthiolation and Trifluoromethylselenolation of Organohalides.

The first C-SCF3 /SeCF3 cross-coupling reactions using gold redox catalysis [(MeDalphos)AuCl], AgSCF3 or Me4 NSeCF3 , and organohalides as substrates are reported. The new methodology enables a one-stop shop synthesis of aryl/alkenyl/alkynyl trifluoromethylthio- and selenoethers with a broad substrate scope (>60 examples with up to 97 % isolated yield). The method is scalable, and its robustness is evidenced by the late-stage functionalization of various bioactive molecules, which makes this reaction an attractive alternative in the synthesis of trifluoromethylthio- and selenoethers for pharmaceutical and agrochemical research and development.

Unbalanced-Ion-Pair-Catalyzed Nucleophilic Fluorination Using Potassium Fluoride.

An unbalanced ion pair promoter (e.g., tetrabutylammonium sulfate), consisting of a bulky and charge-delocalized cation and a small and charge-localized anion, greatly accelerates nucleophilic fluorinations using easy handling KF. We also successfully converted an inexpensive and commercially available ion-exchange resin to the polymer-supported ion pair promoter (A26-SO42-), which could be reused after filtration. Moreover, A26-SO42- can be used in continuous flow conditions. In our conditions, water is well-tolerated.

Development of N-F fluorinating agents and their fluorinations: Historical perspective.

This review deals with the historical development of all N-F fluorinating agents developed so far. The unique properties of fluorine make fluorinated organic compounds attractive in many research areas and therefore fluorinating agents are important. N-F agents have proven useful by virtue of their easy handling. This reagent class includes many types of N-F compounds: perfluoro-N-fluoropiperidine, N-fluoro-2-pyridone, N-fluoro-N-alkylarenesulfonamides, N-fluoropyridinium salts and derivatives, N-fluoroquinuclidium salts, N-fluoro-trifluoromethanesulfonimide, N-fluoro-sultams, N-fluoro-benzothiazole dioxides, N-fluoro-lactams, N-fluoro-o-benzenedisulfonimide, N-fluoro-benzenesulfonimide, 1-alkyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane salts, N-fluoropyridinium-2-sulfonate derivatives, 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane salts, N-fluorodinitroimidazole, N-fluoro-trichloro-1,3,5-triazinium salt, N-F ethano-Tröger's base derivatives, N-fluoro-methanesulfonimide, N-fluoro-N-arylarenesulfonamides, bisN-F salts such as N,N'-difluorobipyridinium salts and N,N'-difluoro-1,4-diazoniabicyclo[2.2.2]octane salts, and their many derivatives and analogs, including chiral N-F reagents such as optically active N-fluoro-sultam derivatives, N-fluoro-alkaloid derivatives, DABCO-based N-F derivatives, and N-F binaphthyldisulfonimides. The synthesis and reactions of these reagents are described chronologically and the review also discusses the relative fluorination power of each reagent and their mechanisms chronicling developments from a historical perspective.

Aromatic Ketone-Catalyzed Photochemical Synthesis of Imidazo-isoquinolinone Derivatives.

We have developed an efficient photocatalytic decarboxylative radical addition/cyclization strategy to synthesize imidazo-isoquinolinone derivatives using inexpensive aromatic ketone photocatalysts. This method not only tolerates a wide range of functional groups but also works well for both alkyl and aryl radicals.

Practical Synthesis of α-Trifluoromethylated Pyridines Based on Regioselective Cobalt-Catalyzed [2+2+2] Cycloaddition using Trifluoromethylated Diynes with Nitriles.

Regioselective cobalt-catalyzed [2+2+2] cycloaddition using fluorine-containing diynes with nitriles was described. Cycloaddition of fluorinated diynes with nitriles under the influence of CoCl2(phen), zinc bromide, and zinc dust in dichloroethane at 80°C for 3 h took place smoothly, exclusively affording the corresponding α-fluoroalkylated pyridines in excellent yields. In addition, dinitriles as substrate were also found to be suitable for this reaction, giving the corresponding fluoroalkylated bipyridine derivatives in excellent yields.

Cobalt-Catalyzed Aerobic Oxidative Cleavage of Alkyl Aldehydes: Synthesis of Ketones, Esters, Amides, and α-Ketoamides.

A widely applicable approach was developed to synthesize ketones, esters, amides via the oxidative C-C bond cleavage of readily available alkyl aldehydes. Green and abundant molecular oxygen (O2 ) was used as the oxidant, and base metals (cobalt and copper) were used as the catalysts. This strategy can be extended to the one-pot synthesis of ketones from primary alcohols and α-ketoamides from aldehydes.

Trifluoromethyl Nonaflate: A Practical Trifluoromethoxylating Reagent and its Application to the Regio- and Stereoselective Synthesis of Trifluoromethoxylated Alkenes.

The trifluoromethoxy group has elicited much interest among drug and agrochemical discovery teams because of its unique properties. We developed trifluoromethyl nonafluorobutanesulfonate (nonaflate), TFNf, an easy-to-handle, bench-stable, reactive, and scalable trifluoromethoxylating reagent. TFNf is easily and safely prepared in a simple process in large scale and the nonaflyl part of TFNf can easily be recovered as nonaflyl fluoride after usage and recycled. The synthetic potency of TFNf was showcased with the underexplored synthesis of various trifluoromethoxylated alkenes, through a high regio- and stereoselective hydro(halo)trifluoromethoxylation of alkyne derivatives such as haloalkynes, alkynyl esters, and alkynyl sulfones. The synthetic merits of TFNf were further underscored with a high-yielding and smooth nucleophilic trifluoromethoxylation of alkyl triflates/bromides and primary/secondary alcohols.

Cobalt-Catalyzed C-H Activation/Annulation of Benzamides with Fluorine-Containing Alkynes: A Route to 3- and 4-Fluoroalkylated Isoquinolinones.

The C-H activation/annulation reaction of various benzamides with fluoroalkylated alkynes in the presence of a Co(acac)2·2H2O catalyst proceeded very smoothly to give the corresponding 3- and 4-fluoroalkylated isoquinolinones in excellent yields with approximately 70% regioselectivities. These regioisomers could be successfully separated and obtained in pure form. Major or minor regioisomers were determined as 4- or 3-fluoroalkylated isoquinolinones, respectively, based on X-ray crystallographic analyses.

Optimization of Catalysts and Conditions in Gold(I) Catalysis-Counterion and Additive Effects.

Gold catalysis has proven to be an important breakthrough for organic synthesis. The tunable nature of gold catalysts, the unique properties of gold, and the mild reaction conditions required in many gold-catalyzed reactions have all contributed substantially to this metal's popularity in catalysis. However, gold-catalyzed reactions still suffer from limitations such as low turnover numbers (TON). Optimization of the catalysts and reaction conditions may significantly improve the efficiency of gold-catalyzed reactions. In this review, we will present leading examples of counterion or additive-regulated gold catalysis from a mechanistic perspective. We will pay special attention to the physical properties of counterion/additive, such as gold affinity and hydrogen bond basicity, and discuss their effects on the reactivity of gold catalysts.

Transition-State Expansion: A Quantitative Model for Counterion Effects in Ionic Reactions.

Ionic reactions are the most common reactions used in chemical synthesis. In relatively low dielectric constant solvents (e.g., dichloromethane, toluene), ions usually exist as ion pairs. Despite the importance of counterions, a quantitative description of how the paired 'counterion' affects the reaction kinetic is still elusive. We introduce a general and quantitative model, namely transition-state expansion (TSE), that describes how the size of a counterion affects the transition-state structure and the kinetics of an ionic reaction. This model could rationalize the counterion effects in nucleophilic substitutions and gold-catalyzed enyne cycloisomerizations.

Revisiting the role of acids and hydrogen bond acceptors in enamine formation.

A systematic investigation into the effects of acids and hydrogen bond acceptors on the reaction rates and equilibria of enamine formation is reported. Acids can accelerate the reaction but do not change the reaction equilibria. In comparison, hydrogen bond acceptors facilitate the enamine formation via their strong hydrogen bonding interaction with the water generated in the reaction.

Regio- and Stereoselective Synthesis of 1,2-Dihaloalkenes Using In-Situ-Generated ICl, IBr, BrCl, I2, and Br2.

We describe a catalyst-free 1,2-trans-dihalogenation of alkynes with an unprecedented substrate scope and exclusive regio- and stereoselectivity. This versatile dihalogenation system-a combination of NX1S electrophile and alkali metal halide (MX2) in acetic acid-is applicable for diverse categories of alkynes (electron-rich or poor alkynes, internal and terminal alkynes, or heteroatoms such as O-, N-, S-substituted alkynes). The hydrogen bonding donor solvent acetic acid is essential for the in-situ generation of X1X2 electrophile, including ICl, IBr, BrCl, I2, and Br2.

Base-Promoted Radical Azofluoromethylation of Unactivated Alkenes.

The base-induced reaction of aryl diazonium salts with commercially available CF3SO2Na/CF2HSO2Na allows for the generation of the corresponding diazene radicals along with fluoromethyl radicals. The addition of fluoromethyl radicals to alkenes with subsequent diazene trapping provides the azofluoromethylation products in good to excellent yields. This metal-free method under mild reaction conditions has broad functional group compatibility and is applicable in the late-stage modification of various natural products and bioactive molecules.

Photoredox-Catalyzed Synthesis of Alkylaryldiazenes: Formal Deformylative C-N Bond Formation with Alkyl Radicals.

Diazenes are valuable compounds that have found broad applicability because of their optical and biological properties. We report the synthesis of alkylaryldiazenes via formal, photoredox-catalyzed, deformylative C-N bond formation. The procedure employs dihydropyridines for the generation of alkyl radicals, which are then trapped by diazonium salts and reduced to the corresponding diazenes. Control experiments were performed to confirm the involvement of radicals in the mechanism. The reaction can be carried out at room temperature and employs readily available reagents; the mild conditions allowed the use of highly functionalized substrates. There was no observed tautomerization of the diazenes to the corresponding arylhydrazones.

HCl•DMPU-Assisted One-pot and Metal-free Conversion of Aldehydes to Nitriles.

We report an efficient HCl•DMPU assisted one-pot conversion of aldehydes into nitriles. The use of HCl•DMPU as both an acidic source as well as a non-nucleophilic base constitutes an environmentally mild alternative for the preparation of nitriles. Our protocol proceeds smoothly without the use of toxic reagents and metal catalysts. Diverse functionalized aromatic, aliphatic and allylic aldehydes incorporating various functional groups were successfully converted to nitriles in excellent to quantitative yields. This protocol is characterized by a broad substrate scope, mild reaction conditions, and high scalability.