Hiromichi Egami

Trifluoromethylation of Alkenes with Concomitant Introduction of Additional Functional Groups

The trifluoromethyl group is found in many synthetic bioactive compounds, and the difunctionalization of a C=C bond, as a powerful strategy for the construction of compounds with various functional groups, has been intensively investigated. Therefore, the difunctionalizing trifluoromethylation of alkenes has attracted growing interest because of the potential of the products as building blocks for bioactive molecules. In this review, we focus on recent advances in the trifluoromethylation of alkenes with concomitant introduction of additional functional groups.

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.

Copper-Catalyzed Trifluoromethylation of Allylsilanes†

The trifluoromethyl group is of interest in the pharmaceutical and agrochemical fields because it is lipophilic, hydrophobic, and metabolically stable; thus, great efforts have been made to develop reactions to introduce this group into organic molecules. The formation of Csp2 CF3 bonds is now a well-developed field of study. On the other hand, Csp3 CF3 bond formation is still generally achieved only through carbonyl groups, by one of a variety of protocols. New synthetic methods are still needed for the construction of Csp3 CF3 bonds in a wider range of molecular contexts. In 2010, we reported the trifluoromethylation of indole derivatives using Cu and Togni s reagent 2 (1-trifluoromethyl-1,2-benziodoxol-3-(1H)-one) in MeOH (Scheme 1 a). As an extension of that work, we next focused on C=C bond trifluoromethylation. Groups led by Buchwald, Liu, and Wang have recently reported the trifluoromethylation of unactivated olefins with a copper (I) salt and either Togni s reagent 2 or Umemoto s reagent 2’ (Scheme 1b). Although these reactions can provide structures bearing a trifluoromethyl group at the allylic position, the reported substrates are mostly limited to monosubstituted terminal olefins. We also independently investigated the trifluoromethylation of unactivated olefins, but when we applied our original Cu/2/MeOH system to the trifluoromethylation of unactivated olefins, we also found the substrate scope to be limited. To overcome this problem, we focused on allylsilanes as substrates, anticipating that they would be more nucleophilic than unactivated olefins. Herein, we disclose the trifluoromethylation of allylsilanes to afford either gem-disubstituted terminal olefins or vinylsilanes bearing a trifluoromethyl group in the allylic position (Scheme 1c). We initially examined the reaction of (2-phenylallyl)trimethylsilane 1 a with CuOAc and Togni s reagent 2 in MeOH. The desired trifluoromethylation product was obtained in low yield along with the recovery of 65 % of the starting material (Table 1, entry 1). Other copper (I) salts were examined in order to increase the effectiveness of this reaction. The use of [Cu(CH3CN)4]PF6 or CuCl gave slightly better results, but the yield was still low (entries 2 and 3). However, CuI was found to afford the desired product 3a in Scheme 1. Cu-catalyzed trifluoromethylation. CuTc = Copper(I)-thiophene2-carboxylate, DMAc= N,N-dimethylacetamide, OTf= trifluoromethanesulfonate.

Iron-catalyzed asymmetric aerobic oxidation: oxidative coupling of 2-naphthols.

Fe(salan) complexes were found to be efficient catalysts for the asymmetric aerobic oxidative coupling of 2-naphthol derivatives. This reaction can be carried out in air at 60 degrees C with high enantioselectivity up to 97% ee. This is the first report for asymmetric aerobic oxidation using molecular oxygen in air in the absence of additives.

Enantioenriched Synthesis of C1-Symmetric BINOLs: Iron-Catalyzed Cross-Coupling of 2-Naphthols and Some Mechanistic Insight

Highly enantioselective aerobic oxidative cross-coupling of 2-naphthols with broad substrate scope was achieved using an iron(salan) complex as the catalyst. Enantiomeric excesses of the products ranged from 87 to 95%. The scope of the cross-coupling reaction was found to be different from that of the homocoupling reaction under the same reaction conditions.

Trifluoromethylation reactions for the synthesis of β-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 β-trifluoromethylamine derivatives (see scheme).

Iron-catalyzed trifluoromethylation with concomitant C–C bond formation via 1,2-migration of an aryl group

Iron-catalyzed trifluoromethylation with concomitant 1,2-migration of an aryl group starting from diaryl allyl alcohol was achieved under mild conditions. This reaction system affords α-substituted-β-trifluoromethyl carbonyl compounds in high efficiency. In the case of substrates bearing different aryl groups, selective migration was observed.

Oxidation Catalysis of Nb(salan) Complexes: Asymmetric Epoxidation of Allylic Alcohols Using Aqueous Hydrogen Peroxide as an Oxidant

Several optically active Nb(salan) complexes were synthesized, and their oxidation catalysis was examined. A dimeric mu-oxo Nb(salan) complex that was prepared from Nb(OiPr)(5) and a salan ligand was found to catalyze the asymmetric epoxidation of allylic alcohols using a urea-hydrogen peroxide adduct as an oxidant with good enantioselectivity. However, subsequent studies of the time course of this epoxidation and of the relationship between the ee of the ligand and the ee of the product indicated that the mu-oxo dimer dissociates into a monomeric species prior to epoxidation. Moreover, monomeric Nb(salan) complexes prepared in situ from Nb(OiPr)(5) and salan ligands followed by water treatment were found to catalyze the epoxidation of allylic alcohols better using aqueous hydrogen peroxide in CHCl(3)/brine or toluene/brine solution with high enantioselectivity ranging from 83 to 95% ee, except for the reaction of cinnamyl alcohol that showed a moderate ee of 74%. This is the first example of the highly enantioselective epoxidation of allylic alcohols using aqueous hydrogen peroxide as an oxidant.

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.

Enantioselective Bromocyclization of Allylic Amides Catalyzed by BINAP Derivatives

A highly enantioselective bromocyclization of allylic amides with N-bromosuccinimide (NBS) was developed with DTBM-BINAP as a catalyst, affording chiral oxazolines with a tetrasubstituted carbon center in high yield with up to 99% ee. By utilizing the bromo substituent as a handle, the obtained compounds were converted to synthetically useful chiral building blocks.