Recent Advances in the Synthesis and Transformation of Carbamoyl Fluorides, Fluoroformates, and Their Analogues.

Carbamoyl fluorides, fluoroformates, and their analogues are a class of important compounds and have been evidenced as versatile building blocks for the preparation of useful molecules in organic chemistry. While major achievements were made in the synthesis of carbamoyl fluorides, fluoroformates, and their analogues in the last half of 20th century, an increasing number of reports have focused on using O/S/Se=CF2 species or their equivalents as the fluorocarbonylation reagents for the direct construction of these compounds from the parent heteroatom-nucleophiles in recent years. This review mainly summarizes the advances in the synthesis and typical application of carbamoyl fluorides, fluoroformates, and their analogues by the halide exchanges and fluorocarbonylation reactions since 1980.

Photoinduced Copper-Promoted Decarboxylative Trifluoromethylselenolation of Aromatic Carboxylic Acids with [Me4N][SeCF3].

Visible-light-induced decarboxylative trifluoromethylselenolation of (hetero)aromatic carboxylic acids with [Me4N][SeCF3], oxidant, and catalysts afforded a variety of (hetero)aryl trifluoromethyl selenoethers in good yields. The reaction might involve a radical process, which generated (hetero)aryl radicals from the stable (hetero)aromatic carboxylic acids via oxidative decarboxylation with NFSI as the oxidant, [di-tBu-Mes-Acr-Ph][BF4] as the photocatalyst, and 1,1'-biphenyl as the cocatalyst. Both catalysts had a decisive influence on the reaction. The trifluoromethylselenolation was further promoted by the copper salts probably via Cu-mediated cross-coupling of the sensitive SeCF3 species with the in situ formed (hetero)aryl radicals. Advantages of the method include visible light irradiation, mild reaction conditions at ambient temperature, good functional group tolerance, no pre-functionalization/activation of the starting carboxylic acids, and applicability to drug molecules. This protocol is promising and synthetically useful, which overcame the limitations of the known trifluoromethylselenolation methods and represented the first decarboxylative trifluoromethylselenolation of (hetero)aromatic carboxylic acids.

Divergent dehydroxyfluorination and carbonation of alcohols with trifluoromethyl trifluoromethanesulfonate.

Preparation of alkyl fluorides and carbonates via divergent dehydroxyfluorination and carbonation of alcohols with trifluoromethyl trifluoromethanesulfonate (CF3SO2OCF3) is described. The reactions performed with BTMG in THF provided alkyl fluorides in good yields, whereas those of two different alcohols with Et3N in DCM formed asymmetric carbonates in moderate to excellent yields. CF3SO2OCF3 was demonstrated to be either a "F" or a "CO" reagent in the reactions by changing the base, allowing the selective construction of alkyl fluorides and carbonates from the corresponding alcohols with high efficiency. Notably, the fluorine-containing asymmetric carbonates that are difficult to synthesize by other methods were comprehensively prepared by this method, which would have great application potential in both academic and industrial fields.

Trifluoromethylselenolation and N-acylation of indoles with [Me4N][SeCF3].

An efficient method for oxidative trifluoromethylselenolation/N-acylation of indoles with excess [Me4N][SeCF3] in the presence of acyl peroxides and their derivatives is described. The reaction is easy to handle, proceeds smoothly at room temperature under metal-free conditions, and shows advantages such as good functional group tolerance, excellent regioselectivity, and compatibility of a number of substrates, producing 1-acyl and 3-trifluoromethylselanyl substituted indoles in good yields. Acyl peroxides and peroxycarboxylic acid behave as both oxidants and acyl sources in the transformation. This one-pot procedure provides a convenient access to a new class of indole derivatives, representing the first trifluoromethylselanyl bifunctionalization of indoles with the nucleophilic [Me4N][SeCF3] reagent.

Tertiary-Amine-Initiated Synthesis of Acyl Fluorides from Carboxylic Acids and CF3 SO2 OCF3.

A convenient method for deoxyfluorination of aromatic and aliphatic carboxylic acids with CF3 SO2 OCF3 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 CF3 SO2 OCF3 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.

Oxidative trifluoromethylselenolation of 1,3-dicarbonyls with [Me4N][SeCF3].

Reactions of 1,3-ketoesters, -diesters, -diketones, and -ketoamides with [Me4N][SeCF3] in the presence of an appropriate oxidant provided a series of 2-trifluoromethylselenolated 1,3-dicarbonyls in moderate to good yields. The trifluoromethylselenolation featured simplicity, mildness, high efficiency, transition-metal-free conditions, and compatibility of various oxidants, and represented the first oxidative trifluoromethylselenolation of 1,3-dicarbonyl compounds with [Me4N][SeCF3]. This protocol was also applicable to the oxidative trifluoromethylthiolation of 1,3-dicarbonyls with [Me4N][SCF3]/NCS, and oxidative trifluoromethylchalcogenation with nucleophilic XCF3 (X = O, S, and Se) reagents were compared. The results demonstrated that these nucleophilic XCF3 salts showed different reaction profiles towards 1,3-dicarbonyls under oxidation conditions.

Markovnikov-Type Hydrotrifluoromethylchalcogenation of Unactivated Terminal Alkenes with [Me4N][XCF3] (X = S, Se) and TfOH.

The first Markovnikov-type hydrotrifluoromethylselenolation of unactivated terminal alkenes with the readily accessible [Me4N][SeCF3] reagent and the superacid TfOH is reported. The reaction proceeded at room temperature under catalyst- and additive-free conditions to give the branched trifluoromethylselenolated products in good yields. This protocol is also applicable to the Markovnikov-type hydrotrifluoromethylthiolation of unactivated terminal alkenes using [Me4N][SCF3]/TfOH, but not to the hydrotrifluoromethoxylation with CsOCF3/TfOH under the same conditions. The successful hydrotrifluoromethylselenolation and hydrotrifluoromethylthiolation showed simplicity and high regioselectivity, taming the sensitive -XCF3 (X = Se, S) anions with TfOH, and offered a convenient method for the straightforward synthesis of branched trifluoromethyl selenoethers and thioethers from unactivated alkenes.

Concise and Additive-Free Click Reactions between Amines and CF3 SO3 CF3.

Trifluoromethyl trifluoromethanesulfonate has proved to be an excellent reservoir of difluorophosgene and a promising click ligation for amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under metal- and additive-free conditions. The reactions are rapid, efficient, selective, and versatile, and can be performed in benign solvents, giving products in excellent yields with minimal efforts for purification. The characteristics of the reactions meet the requirements of a click reaction. The use of trifluoromethyl trifluoromethanesulfonate as a click reagent is advantageous over other "CO" sources (e.g., TsOCF3 , PhCO2 CF3 , CsOCF3 , AgOCF3 , and triphosgene) because this reagent is readily accessible; easy to scale up; and highly reactive, even under metal- and additive-free conditions. It is anticipated that CF3 SO3 CF3 will be increasingly as important as SO2 F2 as a click agent in future drug design and development.

Cu-Mediated arylselenylation of aryl halides with trifluoromethyl aryl selenonium ylides.

An unprecedented arylselenylation of aryl halides with trifluoromethyl aryl selenonium ylides in the presence of copper is described. The reaction proceeded at 100-140 °C under ligand- and additive-free conditions for 3-20 h to form a variety of unsymmetrical diaryl selenides in good to high yields. Arylselenylation is easy to operate, has good functional group tolerance, and demonstrates the different reaction profiles of trifluoromethyl aryl selenonium ylides from the homologous trifluoromethyl aryl sulfonium ylides.

Transition-Metal-Free N-Arylation of Amines by Triarylsulfonium Triflates.

A simple and efficient method for transition-metal-free N-arylation of various amines by triarylsulfonium triflates is described. Both aliphatic and aromatic amines were smoothly converted at 80 °C in the presence of tBuOK or KOH to give the corresponding mono N-arylated products in good to high yields. The molar ratios of the reactants and the choice of bases had a big effect on the reaction. When a large excess of [Ph3 S][OTf] and tBuOK were employed for primary amines under the standard conditions, the bis(N-phenyl) products were predominantly formed. This method was also applicable to the synthesis of bioactive N-phenyl amino acid derivatives. The control experiments, the deuterium labelling study, and the presence of regioisomers of N-arylated products when using 4-substituted triarylsulfonium triflates suggested that the reaction might proceed through an aryne intermediate. The present protocol demonstrated that triarylsulfonium salts are versatile arylation reagents in the construction of CAr -N bonds.

Palladium-Catalyzed Arylation of Arylboronic Acids with Yagupolskii-Umemoto Reagents.

A Pd-catalyzed Suzuki cross-coupling of arylboronic acids with Yagupolskii-Umemoto reagents was explored. In contrary to trifluoromethylations, the Pd-catalyzed reaction of R-B(OH)2 and [Ar2 SCF3 ](+) [OTf](-) provided the arylation products (R-Ar) in good to high yields. The reaction confirms that the S-Ar bonds of [Ar2 SCF3 ](+) [OTf](-) can be readily cleaved in the presence of Pd complexes. The relatively electron-poor aryl groups of asymmetric [Ar(1) Ar(2) SCF3 ](+) [OTf](-) salts are more favorably transferred compared to the electron-rich ones. This reaction represents the first report of utilization of [Ar2 SCF3 ](+) [OTf](-) as arylation reagents in organic synthesis.

A Metal-Free Diverse Synthesis of Difluoromethylthioethers and Difluorobis(arylthio)methanes from RSX (X = SR, Cl, SO2Ph) and TMSCF2H.

Construction of difluoromethylthioethers (2) and difluorobis(arylthio)methanes (3) from RSX (X = SR, Cl, SO2Ph) and TMSCF2H in the absence of transition metals has been explored. The reaction is dramatically influenced by the nature of the base and the molar ratio of the reactants. Reactions between RSX and TMSCF2H in the presence of CsF provided 2 in good yields, whereas the reaction of RSX with TMSCF2H in the presence of t-BuOK afforded 3 in good yields. These protocols allow for convenient and efficient access to both difluoromethylthioethers and difluorobis(arylthio)methanes.

Expeditious trifluoromethylthiolation and trifluoromethylselenolation of alkynyl(phenyl)iodoniums by [XCF3]- (X = S, Se) anions.

Trifluoromethylthiolation and trifluoromethylselenolation of alkynyl(phenyl)iodonium tosylates by [XCF3]- (X = S, Se) ions was accomplished in 5-10 minutes at room temperature under a N2 atmosphere and provided a variety of alkynyl trifluoromethyl sulfides and selenides in good yields. Compared to the known methods, this approach has several advantages such as short reaction times and metal- and additive-free conditions without needing excess [Me4N][XCF3] reagents. Moreover, the less efficient reactions of (phenylethynyl)benziodoxol(on)e with [Me4N][XCF3] under the standard conditions demonstrate that acyclic alkynyl(phenyl)iodoniums are more powerful alkynyl sources in the conversion. This protocol allows for a fast and convenient access to numerous alkynyl trifluoromethyl sulfides and selenides.

Pd-catalyzed divergent trifluoroethylation and arylation of arylboronic acids by aryl(2,2,2-trifluoroethyl)iodonium triflates.

Highly electrophilic aryl(2,2,2-trifluoroethyl)iodonium triflates have been used for the first time as trifluoroethyl and aryl transfer reagents in Pd-catalyzed functionalization of arylboronic acids. Electron-rich arylboronic acids reacted with aryl(2,2,2-trifluoroethyl)iodonium triflates (2a-b) in CH3CN in the presence of Pd2(dba)3 and K3PO4 at room temperature to provide trifluoroethyl arenes in up to 82% yield, while the reactions of both electron-rich and -poor arylboronic acids with 2a-b in DMF in the presence of Pd[P(t-Bu)3]2 and Cs2CO3 at 40 °C afforded arylation products in up to 99% yield. This tunable protocol allows access to trifluoroethyl arenes or biaryls in good to excellent yields under mild conditions and without the addition of extra ligands.

Biological evaluation of synthetic α,ß-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-ß aggregation.

A series of new α,ß-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aß1-42 aggregation. The effect of these compounds against amyloid ß-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aß1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037µM) inhibitory potential. Furthermore, compound 3o disassembled the Aß fibrils produced by self-induced Aß aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aß aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aß-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.

A five-coordinate nickel(II) fluoroalkyl complex as a precursor to a spectroscopically detectable Ni(III) species.

Mechanistic proposals for nickel-catalyzed coupling reactions often invoke five-coordinate alkyl- or aryl-bound Ni(II) and/or high-valent nickel(III) species, but because of their reactive nature, they have been difficult to study and fingerprint. In this work, we invoked the stabilizing properties of fluoroalkyl ligands to access such nickel species bearing ligands that are commonplace in organic coupling reactions. We show that five-coordinate Ni(II) complexes containing nickel-carbon bonds can readily be prepared given the appropriate precursor, and we also present evidence for the formation of Ni(III) species upon chemical and electrochemical oxidation of the five-coordinate complexes.

Progress in fluoroalkylation of organic compounds via sulfinatodehalogenation initiation system.

The sulfinatodehalogenation reaction represents one of the most important methodologies to incorporate fluorine into organic molecules. Using inexpensive sulfur-containing reactants such as Na(2)S(2)O(4) under mild conditions, per- and polyfluoroalkyl halides (R(F)X, X = Br, I, CCl(3)) can be transformed smoothly into the corresponding sulfinate salts. This method is also used for the perfluoroalkylation of alkenes, dienes, alkynes and aromatics. Notably, after 1998, the sulfinatodehalogenation of perfluoroalkyl chlorides (R(F)Cl) has been realized by using dimethylsulfoxide (DMSO) as a solvent instead of CH(3)CN/H(2)O in the Na(2)S(2)O(4)/NaHCO(3) initiation system. Perfluoroalkyl chlorides, ethyl chlorofluoroacetates and chlorodifluoroacetates, and even nonfluorinated compounds, such as ethyl chloro- or dichloroacetates and chloroform, were either converted into the corresponding sulfinate salts or alkylated alkenes, alkynes and aromatics (including porphyrins). The sulfinatodehalogenation reaction has remarkable advantages. With the increasing demands to utilize the unique properties of fluorine and fluorinated functional groups in medicinal, agricultural and material sciences, we believe that there will continue to be useful developments in sulfinatodehalogenation chemistry and it will be applied more widely in the future.

Copper-catalyzed trifluoromethylation of alkenes with an electrophilic trifluoromethylating reagent.

An efficient method for the copper-catalyzed trifluoromethylation of terminal alkenes with an electrophilic trifluoromethylating reagent has been developed. The reactions proceeded smoothly to give trifluoromethylated alkenes in good to excellent yields. The results provided a versatile approach for the construction of Cvinyl-CF3 bonds without using prefunctionalized substrates.

Photoinduced Trifluoromethylselenolation of Aryl Halides with [Me4N][SeCF3].

A visible-light-induced metal-free trifluoromethylselenolation of aryl iodides and bromides with [Me4N][SeCF3] is described. The reaction was conducted at ambient temperature by successfully harnessing the light-sensitive SeCF3 reagent. Mechanistically, the EDA complexes between aryl halide and the -SeCF3 anion or the base might be formed and excited by light, which subsequently undergo intracomplex SET processes to generate aryl and •SeCF3 radicals as key intermediates, allowing a convenient and green access to various aryl trifluoromethyl selenoethers.

Nickel-catalyzed synthesis of aryl trifluoromethyl sulfides at room temperature.

Inexpensive nickel-bipyridine complexes were found to be active for the trifluoromethylthiolation of aryl iodides and aryl bromides at room temperature using the convenient [NMe(4)][SCF(3)] reagent.