Mikiko Sodeoka

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.

Catalytic Enantioselective Aldol-type Reaction of β-Ketosters with Acetals†

Optically active β-oxycarbonyl compounds are useful intermediates in synthetic organic chemistry, and great efforts have been devoted to the development of catalytic asymmetric aldol reactions. Excellent methods have been developed with chiral Lewis acids and chiral secondary amines, in which ketones and their silyl derivatives react with aldehydes in a highly enantioselective manner. In contrast, readily enolizable 1,3-dicarbonyl compounds, such as β-keto esters and malonates have rarely been used as nucleophiles, probably because of insufficient nucleophilicity of the metal enolates of such compounds, although a plausible alternative explanation is that the products are unstable and readily undergo retro-aldol reaction (Scheme 1). Because of these general difficulties, there are only a few examples of the synthesis of optically active β-oxymalonates using π-allyl Pd chemistry, aldol reaction, and oxy-Michael reaction. As for catalytic aldol reactions of 1,3-dicarbonyl compounds, we recently reported a catalytic asymmetric hydroxymethylation of β-keto esters using paraformaldehyde as a C1 unit. However, reactions with less reactive aldehydes were difficult (vide infra), and we found no precedents in the literature. Previously, we showed that chiral Pd enolates were formed by the reaction of chiral Pd-bisphosphine complexes 1 with β-keto esters, being accompanied with the formation of a protic acid (Scheme 1). We envisaged that this proton might activate O,O-acetals to give an oxonium intermediate, so that aldol-type reactions with β-keto esters would proceed smoothly. Since the product is O-protected, we expected that the undesired retro-aldol reaction would be suppressed. The use of O,O-acetals as a synthetic equivalent of aldehydes has been extensively investigated in Lewis acid-mediated or catalyzed aldol-type reactions with silyl enolates. A general principle of these reactions is that chiral induction is hard to achieve, since the chiral Lewis acid interacts only weakly with the prochiral electrophile (Scheme 2). To our knowledge, no asymmetric version of such reactions has been reported. Here, we disclose the first example of a catalytic asymmetric aldol-type reaction of O,O-acetals using chiral Pd and Pt complexes, in which the chiral metal enolates of prochiral β-keto esters are the key intermediates.

Pd-II-catalyzed asymmetric addition reactions of 1,3-dicarbonyl compounds: Mannich-type reactions with N-Boc Imines and three-component aminomethylation

This paper describes catalytic asymmetric Mannich-type reactions of beta-ketoesters and malonates using chiral palladium complexes. Although readily enolizable, carbonyl compounds are attractive substrates, the use of such compounds as nucleophiles in Mannich-type reactions has not been extensively investigated. In the presence of chiral Pd aqua complexes (2.5 mol %), beta-ketoesters reacted with various N-Boc imines (Boc=tert-butoxycarbonyl) to afford the desired beta-aminocarbonyl compounds in good yield with high to excellent stereoselectivity (up to 96:4 d.r., 95-99 % ee in most cases). In these reactions, construction of highly crowded vicinal quaternary and tertiary carbon centers was achieved in one step. A chiral Pd enolate is considered to be the key intermediate. To elucidate the stereoselectivity observed in the reaction, possible transition-state models are discussed, taking into account steric and stereoelectronic effects. Furthermore, this catalytic system was applied to the Mannich-type reaction of malonates with N-Boc imine as well as one-pot classical aminomethylation of beta-ketoesters using benzylamine salt and formalin. The reactions proceeded smoothly, and the corresponding Mannich products were obtained in high yield with moderate to good enantioselectivity.

CHAPTER 7:Asymmetric Cross-Dehydrogenative-Coupling Reactions

Asymmetric cross-dehydrogenative-coupling (CDC) reactions provide a means of constructing carbon–carbon bonds directly from two different C–H bonds in an enantioselective manner. These reactions are expected to be extremely useful in terms of cost- and step-economy, since no pre-functionalization of substrates is required. Coupled with in situ oxidative activation of substrates using molecular oxygen, tert-butyl peroxide, hydrogen peroxide, benzoquinone, or 2,3-dichloro-5,6-dicyanobenzoquinone as the oxidant, the use of appropriate chiral catalysts should allow the production of optically active and highly functionalized molecules in a single step. Since asymmetric CDC reactions must be performed under oxidative conditions, the keys to success include the use of chiral catalysts that are robust under such conditions and appropriate oxidants depending on the nature of the substrates. Following the rapid progress in non-asymmetric CDC reactions, development of asymmetric versions has attracted increasing attention, and high levels of asymmetric induction have become feasible in some cases. This chapter will focus on: (1) reactions of α-C–H bonds of nitrogen-containing compounds; (2) reactions of benzylic C–H bonds; (3) functionalization via oxidation of enamine and Breslow intermediates; (4) naphthol coupling reactions; and (5) coupling reactions of arenes with olefins (Fujiwara–Moritani reactions).