Ligand-Controlled Copper-Catalyzed Halo-Halodifluoromethylation of Alkenes and Alkynes Using Fluorinated Carboxylic Anhydrides.

Polyhalogenated molecules are often found as bioactive compounds in nature and are used as synthetic building blocks. Fluoroalkyl compounds hold promise for the development of novel pharmaceuticals and agrochemicals, as the introduction of fluoroalkyl groups is known to improve lipophilicity, membrane permeability, and metabolic stability. Three-component 1,2-halo-halodifluoromethylation reactions of alkenes are useful for their synthesis. However, general methods enabling the introduction of halodifluoromethyl (CF2X) and halogen (X') groups in the desired combination of X and X' are lacking. To address this gap, for the first time, we report a three-component halo-halodifluoromethylation of alkenes and alkynes using combinations of commercially available fluorinated carboxylic anhydrides ((CF2XCO)2O, X = Cl and Br) and alkali metal halides (X' = Cl and Br). In situ prepared fluorinated diacyl peroxides were identified as important intermediates, and the use of appropriate bipyridyl-based ligands and a copper catalyst was essential for achieving high product selectivity. The synthetic utility of the polyhalogenated products was demonstrated by exploiting differences in the reactivities of their C-X and C-X' bonds to achieve selective derivatization. Finally, the reaction mechanism and ligand effect were investigated using experimental and theoretical methods to provide important insights for the further development of catalytic reactions.

Understanding and Controlling Fluorinated Diacyl Peroxides and Fluoroalkyl Radicals in Alkene Fluoroalkylations.

The demand for practical methods for the synthesis of novel fluoroalkyl molecules is increasing owing to their diverse applications. Our group has achieved efficient difunctionalizing fluoroalkylations of alkenes using fluorinated carboxylic anhydrides as user-friendly fluoroalkyl sources. Fluorinated diacyl peroxide, prepared in situ from carboxylic anhydrides, enables the development of novel reactions when used as a radical fluoroalkylating reagent. In this account, we aim to provide an in-depth understanding of the structure, bonding, and reactivity of fluorinated diacyl peroxides and radicals as well as their control in fluoroalkylation reactions. In the first part of this account, the physical properties and reactivity of diacyl peroxides and fluoroalkyl radicals are described. In the subsequent part, we categorize the reactions into copper-catalyzed and metal-free methods utilizing the oxidizing properties of fluorinated diacyl peroxides. We also outline examples and mechanisms.

Color-scalable flow cytometry with Raman tags.

Flow cytometry is an indispensable tool in biology and medicine for counting and analyzing cells in large heterogeneous populations. It identifies multiple characteristics of every single cell, typically via fluorescent probes that specifically bind to target molecules on the cell surface or within the cell. However, flow cytometry has a critical limitation: the color barrier. The number of chemical traits that can be simultaneously resolved is typically limited to several due to the spectral overlap between fluorescence signals from different fluorescent probes. Here, we present color-scalable flow cytometry based on coherent Raman flow cytometry with Raman tags to break the color barrier. This is made possible by combining a broadband Fourier-transform coherent anti-Stokes Raman scattering (FT-CARS) flow cytometer, resonance-enhanced cyanine-based Raman tags, and Raman-active dots (Rdots). Specifically, we synthesized 20 cyanine-based Raman tags whose Raman spectra are linearly independent in the fingerprint region (400 to 1,600 cm-1). For highly sensitive detection, we produced Rdots composed of 12 different Raman tags in polymer nanoparticles whose detection limit was as low as 12 nM for a short FT-CARS signal integration time of 420 µs. We performed multiplex flow cytometry of MCF-7 breast cancer cells stained by 12 different Rdots with a high classification accuracy of 98%. Moreover, we demonstrated a large-scale time-course analysis of endocytosis via the multiplex Raman flow cytometer. Our method can theoretically achieve flow cytometry of live cells with >140 colors based on a single excitation laser and a single detector without increasing instrument size, cost, or complexity.

Recent Advances on the Halo- and Cyano-Trifluoromethylation of Alkenes and Alkynes.

Incorporation of fluorine into organic molecules is a well-established strategy in the design of advanced materials, agrochemicals, and pharmaceuticals. Among numerous modern synthetic approaches, functionalization of unsaturated bonds with simultaneous addition of trifluoromethyl group along with other substituents is currently one of the most attractive methods undergoing wide-ranging development. In this review article, we discuss the most significant contributions made in this area during the last decade (2012-2021). The reactions reviewed in this work include chloro-, bromo-, iodo-, fluoro- and cyano-trifluoromethylation of alkenes and alkynes.

1,2-Bis-perfluoroalkylations of alkenes and alkynes with perfluorocarboxylic anhydrides via the formation of perfluoroalkylcopper intermediates.

A novel, Cu-mediated protocol toward the 1,2-bis-perfluoroalkyaltion of alkenes/alkynes was developed. The method proceeded with perfluorocarboxylic anhydrides as inexpensive and readily available perfluoroalkyl sources. Diacyl peroxide was generated in situ from the perfluorocarboxylic anhydrides and H2O2. The key step in this reaction is the formation of a stable perfluoroalkylcopper intermediate that is achieved with the aid of a bipyridyl ligand. Subsequent reaction of the intermediate with perfluoroalkyl-containing alkyl or vinyl radicals affords the desired products.

Recent advances in reactions using diacyl peroxides as sources of O- and C-functional groups.

Diacyl peroxides, (RCO2)2, are readily available and widely used reagents for organic synthesis, because they can serve as electrophiles, oxidants, and radical sources. Recently, they have been used extensively as sources of O- and C-functional groups, in contrast to their classical applications as radical initiators. These novel reaction modes have greatly expanded the synthetic utility of diacyl peroxides by making it possible to simultaneously utilize plural functionalities of diacyl peroxides in unprecedented ways, with or without the aid of transition-metal catalysts. Here, we review recent advances in reactions utilizing diacyl peroxides as O- and C-sources, with examples illustrating how the reactivity of diacyl peroxides in organic reactions can be controlled.

Metal-free alkene oxy- and amino-perfluoroalkylations via carbocation formation by using perfluoro acid anhydrides: unique reactivity between styrenes and perfluoro diacyl peroxides.

We present a strategy for metal-free, alkene difunctionalization-type, oxy- and amino-perfluoroalkylations, using perfluoro acid anhydrides as practical and user-friendly perfluoroalkyl sources. This method provides efficient access to oxy-perfluoroalkylation products via carbocation formation due to the unique reactivity between styrenes and bis(perfluoroacyl) peroxides generated in situ from perfluoro acid anhydrides. This reaction is also applicable to metal-free intramolecular amino-perfluoroalkylation of styrenes bearing a pendant amino group. Synthetic utility of the oxy-trifluoromethylation products was confirmed by demonstrating derivatization via hydrolysis, elimination, and acid-catalyzed substitution with carbon nucleophiles. The mechanism of the carbocation formation was investigated experimentally and theoretically.

Reactivity and properties of bis(chlorodifluoroacetyl) peroxide generated in situ from chlorodifluoroacetic anhydride for chlorodifluoromethylation reactions.

We developed a practical chlorodifluoromethylation reaction mediated by diacyl peroxide generated in situ from chlorodifluoroacetic anhydride. Allylic and amino-chlorodifluoromethylations of alkenes proceeded well with the combination of this reagent, Cu(ii) catalyst and a pyridine additive. Carbo- and aromatic chlorodifluoromethylations proceeded under metal-free conditions.

N-Heterocycle-Forming Amino/Carboperfluoroalkylations of Aminoalkenes by Using Perfluoro Acid Anhydrides: Mechanistic Studies and Applications Directed Toward Perfluoroalkylated Compound Libraries.

This work describes a practical and efficient method for synthesizing a diverse array of perfluoroalkylated amines, including N-heterocycles, to afford perfluoroalkylated chemical libraries as potential sources of drug candidates, agrochemicals, and probe molecules for chemical-biology research. Perfluoro acid anhydrides, which are commonly used in organic synthesis, were employed as a perfluoroalkyl source for intramolecular amino- and carbo-perfluoroalkylations of aminoalkenes, affording perfluoroalkylated N-heterocycles, including: aziridines, pyrrolidines, benzothiazinane dioxides, indolines, and hydroisoquinolinones. Diacyl peroxides were generated in situ from the perfluoro acid anhydrides with urea·H2O2, and allowed to react with aminoalkenes in the presence of copper catalyst to control the product selectivity between amino- and carbo-perfluoroalkylations. To illustrate the synthetic utility of bench-stable trifluoromethylated aziridine, which was prepared on a gram scale, we used it to synthesize a wide variety of trifluoromethylated amines including complex molecules, such as trifluoromethylated tetrahydroharmine and spiroindolone. A mechanistic study of the role of the copper catalyst in the aminotrifluoromethylation of allylamine suggested that Cu(I) accelerates CF3 radical formation via decomposition of diacyl peroxide, which appears to be the turnover-limiting step, while Cu(II) controls the product selectivity.

Synthesis of Aryl C-Glycosides via Iron-Catalyzed Cross Coupling of Halosugars: Stereoselective Anomeric Arylation of Glycosyl Radicals.

We have developed a novel diastereoselective iron-catalyzed cross-coupling reaction of various glycosyl halides with aryl metal reagents for the efficient synthesis of aryl C-glycosides, which are of significant pharmaceutical interest due to their biological activities and resistance toward metabolic degradation. A variety of aryl, heteroaryl, and vinyl metal reagents can be cross-coupled with glycosyl halides in high yields in the presence of a well-defined iron complex, composed of iron(II) chloride and a bulky bisphosphine ligand, TMS-SciOPP. The chemoselective nature of the reaction allows the use of synthetically versatile acetyl-protected glycosyl donors and the incorporation of various functional groups on the aryl moieties, producing a diverse array of aryl C-glycosides, including Canagliflozin, an inhibitor of sodium-glucose cotransporter 2 (SGLT2), and a prevailing diabetes drug. The cross-coupling reaction proceeds via generation and stereoselective trapping of glycosyl radical intermediates, representing a rare example of highly stereoselective carbon-carbon bond formation based on iron catalysis. Radical probe experiments using 3,4,6-tri-O-acetyl-2-O-allyl-α-d-glucopyranosyl bromide (8) and 6-bromo-1-hexene (10) confirm the generation and intermediacy of the corresponding glycosyl radicals. Density functional theory (DFT) calculations reveal that the observed anomeric diastereoselectivity is attributable to the relative stability of the conformers of glycosyl radical intermediates. The present cross-coupling reaction demonstrates the potential of iron-catalyzed stereo- and chemoselective carbon-carbon bond formation in the synthesis of bioactive compounds of certain structural complexity.

Perfluoroalkylation of Unactivated Alkenes with Acid Anhydrides as the Perfluoroalkyl Source.

An efficient perfluoroalkylation of unactivated alkenes with perfluoro acid anhydrides was developed. Copper salts play a crucial role as a catalyst to achieve allylic perfluoroalkylation with the in situ generated bis(perfluoroacyl) peroxides. Furthermore, carboperfluoroalkylation of alkene bearing an aromatic ring at an appropriate position on the carbon side chain was found to proceed under metal-free conditions to afford carbocycles or heterocycles bearing a perfluoroalkyl group. This method, which makes use of readily available perfluoroalkyl sources, offers a convenient and powerful tool for introducing a perfluoroalkyl group onto an sp(3) carbon to construct synthetically useful skeletons.

Product Control in Alkene Trifluoromethylation: Hydrotrifluoromethylation, Vinylic Trifluoromethylation, and Iodotrifluoromethylation using Togni Reagent.

Hydrotrifluoromethylation, vinylic trifluoromethylation, and iodotrifluoromethylation of simple alkenes have been achieved by using Togni reagent in the absence of any transition metal catalyst. These reactions were readily controllable by selection of appropriate salts and solvents. The addition of K2CO3 afforded the hydrotrifluoromethylation product, with DMF acting not only as a solvent, but also as the hydrogen source. In contrast, the use of tetra-n-butylammonium iodide (TBAI) in 1,4-dioxane resulted in vinylic trifluoromethylation, while the use of KI afforded the iodotrifluoromethylation product. The vinylic trifluoromethylation product was obtained by treatment of the iodotrifluoromethylation product with ammonium 2-iodobenzoate, indicating that it was formed through an elimination reaction of the in-situ-generated iodotrifluoromethylation product, and the solubility of the resulting 2-iodobenzoate salt plays a key role in the product switching. A radical-clock experiment showed that these reactions proceed via radical intermediates.

Aminotrifluoromethylation of olefins via cyclic amine formation: mechanistic study and application to synthesis of trifluoromethylated pyrrolidines.

We examined the mechanism of our previously reported aminotrifluoromethylation reaction, which proceeds via intramolecular cyclization of alkenylamines in the presence of the combination of copper catalyst and Togni reagent (1). Kinetic studies revealed that the initial rate of the reaction was first order with respect to Togni reagent and CuI, as well as the substrate. Changes of the (19)F NMR chemical shift of Togni reagent during the reaction suggested the existence of a dynamic equilibrium involving coordination of not only Togni reagent, but also the substrate amine and the product aziridine to copper. ESI-MS analysis provided evidence of involvement of reactive Cu(II) intermediates in the catalytic cycle. Overall, our results indicate that the reaction proceeds at the hypervalent iodine moiety of Togni reagent, which is activated by Cu(II) species acting as a Lewis acid catalyst. On the basis of these mechanistic considerations, we developed an efficient synthesis of trifluoromethylated pyrrolidine derivatives. This transformation exhibited a remarkable rate enhancement upon addition of Et3N.

Trifluoromethylation reactions for the synthesis of ß-trifluoromethylamines.

A multitalented system: N-migratory oxytrifluoromethylation and one-pot three-component reactions of allylamines as well as the aminotrifluoromethylation of alkenyl amines all proceeded efficiently in the presence of the Togni reagent (1) and CuI to afford a variety of ß-trifluoromethylamine derivatives (see scheme).

Iron-catalysed cross-coupling of halohydrins with aryl aluminium reagents: a protecting-group-free strategy attaining remarkable rate enhancement and diastereoinduction.

Non-protected halohydrins are cross-coupled with aryl aluminium reagents to produce aryl alkanols in the presence of the iron-bisphosphine catalysts. Remarkable reaction rate enhancement and diastereoinduction are realized by the in situ generated aluminium alkoxides, offering a new method for the reactivity and selectivity control of the iron-catalysed cross-coupling reaction.

The first iron-catalysed aluminium-variant Negishi coupling: critical effect of co-existing salts on the dynamic equilibrium of arylaluminium species and their reactivity.

The first example of an iron-catalysed Negishi coupling between arylaluminium reagents and alkyl halides illustrates that the co-existing salts highly influence the dynamic equilibrium of the organoaluminium species, and have a critical effect on the reactivity and selectivity of the coupling reaction.

A vacuum technique to increase anterior thickness of athletic mouthguards to achieve a full-balanced occlusion.

A full-balanced occlusion is essential for mouthguards. It has been reported that a balanced occlusion for upper and lower anterior teeth is essential for prevention of injuries occurring to the maxillary anterior teeth and alveolar bone caused by horizontal direct impact. The support of the mandibular teeth through the mouthguard is critical to prevent maxillary front tooth injury from a direct impact force. However, some vacuum mouthguard designs may not achieve a full-balanced occlusion. For example, when a player has a malocclusion, an elongated molar or premolar tooth, an open bite, a large over jet or a maxillary protrusion. An improved vacuum fabrication method is necessary to obtain full balanced occlusion in these cases as opposed to conventional vacuum type single-layer mouthguard technique.

Adhesive strength and its improvement referring to the laminated-type mouthguard.

The manufacture of laminated-type mouthguards requires skill in fusing sheets of mouthguard materials together. Adequate adhesive strength is required to use mouthguards in a stable condition for a long time. Therefore, in this study, the exfoliation test was applied and some treating techniques and conditions that improve the adhesive strength on a laminated surface were examined. Samples were laminated with two pieces of mouthguard material (3 mm thickness) having an adhesive area of 5 x 5 mm2, and whose other end was the holding part. The experimental factors used were as follows: heating time, use of solvent, elimination and direct heating of the laminate surface, colour of materials and water sorption. The result was measured at the time of breakage of the maximum load (N) and the form of destruction was examined. At 165 s of heating time, material failure was shown at under a load exceeding 5.0 N when compared to an untreated condition. Material failure was measured when a solvent was used and during the elimination of the laminated surface at a heating time of 150 s, which is 15 s lesser than in an untreated condition. Material failure was also measured by direct heating on the bonding surface of a second sheet of material at a heating time of 135 s, which is 30 s lesser than in an untreated condition. The differences in colour of the materials influence adhesion. Clear and light coloured materials showed higher adhesion ability. One-way analysis of variance confirmed a statistically significant difference in heating time differences, usage of solvent, elimination, direct heating on bonding surface and colour (P < 0.05). The decrease of adhesive strength by water sorption at 23 degrees and 37 degrees C was not observed significantly. Maximal laminated bond strength can be obtained by minimal heating time and proper treatment with the use of solvent, elimination and direct heating on bonding surface. The differences in the colour of the materials influenced adhesion. Clear and light coloured materials showed higher adhesive ability. Water sorption did not affect the adhesive strength. Therefore, if laminated-type mouthguards were manufactured properly, it can be used for a longer time and in a good condition.

Does hard insertion and space improve shock absorption ability of mouthguard?

Mouthguards are expected to reduce sports-related orofacial injuries. Numerous studies have been conduced to improve the shock absorption ability of mouthguards using air cells, sorbothane, metal wire, or hard material insertion. Most of these were shown to be effective; however, the result of each study has not been applied to clinical use. The aim of this study was to develop mouthguards that have sufficient prevention ability and ease of clinical application with focus on a hard insertion and space. Ethylene vinyl acetate (EVA) mouthguard blank used was Drufosoft and the acrylic resin was Biolon (Dreve-Dentamid GMBH, Unna, Germany). Three types of mouthguard samples tested were constructed by means of a Dreve Drufomat (Type SO, Dreve-Dentamid) air pressure machine: the first was a conventional laminated type of EVA mouthguard material; the second was a three layer type with acrylic resin inner layer (hard-insertion); the third was the same as the second but with space that does not come into contact with tooth surfaces (hard + space). As a control, without any mouthguard condition (NOMG) was measured. A pendulum type impact testing machine with interchangeable impact object (steel ball and baseball) and dental study model (D17FE-NC.7PS, Nissin, Tokyo, Japan) with the strain gages (KFG-1-120-D171-11N30C2: Kyowa, Tokyo, Japan) applied to teeth and the accelerometer to the dentition (AS-A YG-2768 100G, Kyowa) were used to measure transmitted forces. Statistical analysis (anova, P < 0.01) showed significant differences among four conditions of NOMG and three different mouthguards in both objects and sensor. About acceleration: in a steel ball which was a harder impact object, shock absorption ability of about 40% was shown with conventional EVA and hard-insertion and about 50% with hard + space. In a baseball that was softer compared with steel ball, a decrease rate is smaller, reduction (EVA = approximately 4%, hard-insertion = approximately 12%, hard + space = approximately 25%) was admitted in the similar order. A significant difference was found with all the combinations except for between EVA and hard-insertion with steel ball (Tukey test). About distortion: both buccal and lingual, distortions had become small in order of EVA, hard-insertion, and hard + space, too. The decrease rate is larger than acceleration, EVA = approximately 47%, hard-insertion = 80% or more, and hard +space = approximately 98%, in steel ball. EVA = approximately 30%, hard-insertion = approximately 75%, and hard + space = approximately 98% in baseball. And a significant difference was found with all the combinations (Tukey test). Especially, hard + space has decreased the distortion of teeth up to several percentages. Acceleration of the maxilla and distortions of the tooth became significantly smaller when wearing any type of mouthguard, in both impact objects. But the effect of mouthguard was clearer in the distortion of the tooth and with steel ball. Considering the differences of mouthguards, the hard-insertion and the hard + space had significantly greater buffer capacity than conventional EVA. Furthermore, hard + space shows quite high shock absorption ability in the tooth distortion. Namely, hard + space has decreased the distortion of teeth up to several percentages in both impact objects.