Shintaro Kawamura

Alkene Trifluoromethylation Coupled with CC Bond Formation: Construction of Trifluoromethylated Carbocycles and Heterocycles†

The trifluoromethyl group is of great interest in pharmaceutical chemistry, agrochemistry, and materials science because of its unique properties, and great efforts have been made to develop reactions for its introduction into organic molecules. Indeed, many methods for formation of not only Csp2 CF3, but also Csp3 CF3 bonds have been developed. Nevertheless, new synthetic methods to form C CF3 bonds, especially Csp3 CF3 bonds, in a wider range of molecular contexts are still needed. Regarding trifluoromethylation of the C=C bond, a notable development has been the deprotonative trifluoromethylation of simple alkenes, a method reported in 2011 (Scheme 1a). In contrast, we recently reported the trifluoromethylation of allylsilanes using the CuI/Togni s reagent (1) system. Based on the resulting mechanistic insight, oxytrifluoromethylation of styrene derivatives was achieved under mild reaction conditions and direct synthesis of b-trifluoromethylstyrene derivatives from styrenes was demonstrated. Szab and co-workers also independently studied the oxytrifluoromethylation of multiple bonds with the CuI/1 system, and Zhu and Buchwald developed an intramolecular reaction of simple alkenes in the wake of their deprotonative trifluoromethylation. Following from our previous studies, we investigated difunctionalization-type trifluoromethylation of the C=C bond, thus focusing on the use of carbon nucleophiles. In 2012, Liu and co-workers reported the palladium/ytterbiumcatalyzed oxidative aryl trifluoromethylation of activated alkenes using a combination of TMSCF3/CsF/PhI(OAc)2. [11] Although Liu s method provided structures bearing a trifluoromethyl group, only oxindole synthesis from a,b-unsaturated amide derivatives was demonstrated. Other types of carbocycles and heterocycles, such as indane, tetralin, indoline, and tetrahydroquinoline, are also found in many bioactive compounds, and their trifluoromethylated derivatives may exhibit altered potency. It is well known that treatment of an alkene bearing allylic protons under trifluoromethylation conditions provides the deprotonative trifluoromethylation product (Scheme 1a). Difunctionalization-type trifluoromethylation of unactivated alkenes, especially those having allylic protons, is still challenging (Scheme 1b). Based on our previous mechanistic insights, 8] we considered that the acceleration of the reaction by orbital interactions between the alkene and aryl group would favor the desired trifluoromethylation reaction coupled with intramolecular C C bond formation. Herein we report the copper-catalyzed carbotrifluoromethylation of simple C=C bonds, using the Cu/1 system, as well as a unique 1,6-oxytrifluoromethylation reaction. To achieve carbotrifluoromethylation of a simple alkene bearing allylic protons, it is important to prevent competitive deprotonative trifluoromethylation of the alkene. Compound 2a was used as a test substrate for the screening of reaction conditions (Table 1). Use of [(MeCN)4Cu]PF6 in CH2Cl2 at room temperature selectively afforded the deprotonative trifluoromethylation product 4a in low yield (entry 1). The carbotrifluoromethylation product 3a was obtained in 18% yield in 1,2-dichloroethane (DCE) at 80 8C, but 4a was again the major product (entry 2). SurprisScheme 1. a) Reported electrophilic trifluoromethylation. b) Trifluoromethylation coupled with construction of carbocycles and heterocycles.

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.

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.

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.

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.

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.

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.

Regio- and stereoselective multisubstituted olefin synthesis via hydro/carboalumination of alkynes and subsequent iron-catalysed cross-coupling reaction with alkyl halides

A new synthetic route towards multisubstituted olefins, which are recurring core units in various pharmaceutical and bioactive compounds, was developed based on the direct cross coupling of alkenylaluminium reagents which were prepared in situ by the hydro- and carbometalation of alkynes, with non-activated alkyl halides in the presence of an iron catalyst. For the first time, alkenylaluminium reagents participated in an iron-catalysed cross-coupling reaction, following the activation of the aluminium reagents by a metal fluoride. The hydro- and carboalumination of alkynes and the subsequent cross-coupling reactions could be conducted in a one-pot manner and proceeded regio- and stereoselectively to give a variety of di-, tri-, and tetrasubstituted alkenes in good to excellent yields.