Géraldine Masson

Chiral Brønsted Acid-Catalyzed Enantioselective Three-Component Povarov Reaction

The three-component Povarov reaction of aldehydes (2), anilines (3), and benzyl N-vinylcarbamate 4 in the presence of 0.1 equiv of chiral phosphoric acid 5 afforded cis-2,4-disubstituted tetrahydroquinolines (1) in good yields and excellent enantiomeric excesses. The shortest synthesis of torcetrapib reported to date, which features this key three-component reaction, is documented.

Chiral Phosphoric Acid-Catalyzed Enantioselective Three-Component Povarov Reaction Using Enecarbamates as Dienophiles: Highly Diastereo- and Enantioselective Synthesis of Substituted 4-Aminotetrahydroquinolines

A chiral phosphoric acid (5)-catalyzed three-component Povarov reaction of aldehydes 2, anilines 3, and enecarbamates 4 afforded cis-4-amino-2-aryl(alkyl)-1,2,3,4-tetrahydroquinolines 1 in high yields with excellent diastereoselectivities (>95%) and almost complete enantioselectivities (up to >99% ee). The reaction was applicable to a wide range of anilines bearing electron-donating (OMe) and electron-withdrawing groups (e.g., Cl, CF(3), NO(2)) and allowed, for the first time, aliphatic aldehydes to be employed in the enantioselective Povarov reaction. With β-substituted acyclic enecarbamates, 2,3,4-trisubstituted 1,2,3,4-tetrahydroquinolines with three contiguous stereogenic centers were produced in excellent diastereo- and enantioselectivities (87 to >99% ee). A detailed study of the active catalytic species allowed us to reduce the catalyst loading from 10% to 0.5% with no deterioration of enantiomeric excess. In addition, mechanistic studies allowed us to conclude unequivocally that the Povarov reaction involving enecarbamate as dienophile proceeded via a stepwise mechanism. The key role of the free NH function of the enecarbamate in the success of this transformation was demonstrated. NMR experiments indicating the catalyst-substrate interaction as well as a linear correlation between catalyst and product ees were also documented.

Photoredox-Induced Three-Component Oxy-, Amino-, and Carbotrifluoromethylation of Enecarbamates

A photoredox-catalzyed trifluoromethylation of enecarbamates process is reported. This pathway uses Tognis reagent as the CF3 source and follows a radical/cationic pathway. Under the optimized conditions using [Ru(bpy)3(PF6)2] as the photocatalyst, a wide range of substituted enecarbamates can readily be difunctionalized by means of various O, N, and C nucleophiles.

Highly enantioselective electrophilic α-bromination of enecarbamates: chiral phosphoric acid and calcium phosphate salt catalysts.

Metal-free chiral phosphoric acids and chiral calcium phosphates both catalyze highly enantio- and diastereoselective electrophilic α-bromination of enecarbamates to provide an atom-economical synthesis of enantioenriched vicinal haloamines. Either enantiomer can be formed in good yield with excellent diastereo- and enantioselectivity simply by switching the catalyst from a phosphoric acid to its calcium salt.

Brønsted Acid Catalyzed Enantioselective Three-Component Reaction Involving the α Addition of Isocyanides to Imines†

That a chiral phosphoric acid is able to catalyze the three-component reaction of aldehydes, anilines, and alpha -isocyanoacetamides, leading to 2-(1-aminoalkyl)-5-aminooxazoles in excellent yields and moderate to good enantioselectivities, was reported. [on SciFinder (R)]

Photoredox-Induced Three-Component Azido- and Aminotrifluoromethylation of Alkenes

We report herein a photoredox-catalyzed azidotrifluoromethylation of alkenes. Under the optimized conditions using [Ru(bpy)3(PF6)2] as the photocatalyst and Umemotos reagent as the CF3 source, a wide range of substituted styrenes as well as various activated and nonactivated alkenes can readily be difunctionalized, affording β-trifluoromethylated azides or amines in good yields.

Chiral Brønsted Acid-Catalyzed Enantioselective Multicomponent Mannich Reaction: Synthesis of anti-1,3-Diamines Using Enecarbamates as Nucleophiles

Reaction of aldehydes 2, anilines 3, and enecarbamates 4 in dichloromethane in the presence of EtOH and a catalytic amount of chiral phosphoric acid 5 afforded the Mannich adducts which were in situ reduced to anti-1,2-disubstituted 1,3-diamines 1 in excellent diastereoselectivity and enantioselectivity.

Photoredox‐Initiated α‐Alkylation of Imines through a Three‐Component Radical/Cationic Reaction

The a-alkylation of imines is a valuable carbon–carbon bond-forming strategy, which is still an underdeveloped area despite the synthetic potential of its a-branched imine products. The direct C H bond functionalization of imines with alkyl halides has proven challenging, owing to competing side reactions, such as Mannich condensation, Nalkylation, and hydrolysis. The indirect approach, based on the intermolecular nucleophilic alkylation reaction of enamine or enamide derivatives, was not found to be more efficient. Moreover, the only corresponding products reported were a-alkylated carbonyl compounds. To the best of our knowledge, there is no efficient method for the preparation of a-alkylated imines. Herein, we disclose a novel a-alkylation reaction of imines, which can be achieved by photoredox-mediated direct intermolecular C H functionalization of enamide derivatives, involving a radical/cationic domino process. Recently, Friestad et al. reported an interesting tinmediated, non-reductive radical alkylation of tertiary enamides, forming two-carbon-elongated homologues by oxidation and proton transfer through N-amido radical intermediates. Based on this, we envisaged that the same radical/ cationic process in the presence of a nucleophile might provide an expedient synthesis of a-alkylated imines. The principle of this multicomponent domino process is depicted in Scheme 1. After radical reduction of alkyl halide 2, the resulting alkyl radical 5 reacts with enamide 1 to produce aamidoalkyl radical 6. The oxidative radical-polar crossover reaction then furnishes an N-acyliminium cation 7, which can be trapped by a suitable nucleophile. Alcohol 3 was the nucleophile of choice to generate b-alkylated a-amido ether 4, which is a stable precursor of a-alkylated imines 14f] and can be found in a number of biologically important natural products. To initiate this radical/cationic domino process, a free-radical redox initiator, which was compatible with the nucleophile, was selected. As visible-light photoredox catalysis has emerged as an efficient tool to promote single-electron-transfer (SET) redox transformations since the success of MacMillan et al., Yoon et al., Stephenson et al. , and others, environmentally friendly photoredox catalysts were chosen. Initial studies focused on examining the reaction of (E)benzyl prop-1-enylcarbamate (1 a), diethyl bromomalonate (2 a), and ethanol (3 a) in the presence of Et3N (2 equiv), [Ru ACHTUNGTRENNUNG(bpy)3]Cl2 (8, 1.5 mol %, bpy= bypyridine), and light from a 25 W compact fluorescent lamp. As described in Table 1, we were able to obtain the desired three-component adduct 4 a as a 3:2 mixture of diastereomers, although the reaction was not clean. To optimize the reaction, different photoredox catalysts, alcohols, and solvents were screened. To our delight, a change from Ru-containing photocatalyst 8 to [IrACHTUNGTRENNUNG(ppy)2ACHTUNGTRENNUNG(dtbbpy)]PF6 (9, dtbbpy =4,4’-di-tertbutyl-2,2’-dipyridyl) gave the product in higher yield (79 %, Table 1, entry 1 vs. 2). The change in the nature of the base (DIPEA =N,N-diisopropylethylamine instead of Et3N) lowered the yield (entry 3). The reaction proceeds in various solvents, except DMF. Dichloromethane was found to be the solvent of choice regarding both the yield and the reaction rate to give product 4 a in almost quantitative yield within 3 h (entry 7). A reduced reaction time to less than 1 h was observed under the same conditions, but in sunlight (entry 7 vs. 8). Additional alcohols, namely MeOH and iPrOH, were also found to be suitable nucleophiles, albeit slightly lower in yield, to give the corresponding b-alkylated a-carbamido ethers 4 b and 4 c, respectively (entries 11 and 12). After having identified the optimal conditions of the three-component radical/cationic process, the scope of the enamide substrates 1 was investigated (Table 2). We were pleased to find that the reaction conditions developed were applicable to a range of enamides to provide good to excellent yields of a-alkylated imine adducts 4 in short reaction [a] T. Courant, Dr. G. Masson Centre de Recherche de Gif Institut de Chimie des Substances Naturelles CNRS Avenue de la Terrasse, 91198 Gif-sur-Yvette Cedex (France) Fax: (+33) 1-6907-7247 E-mail : masson@icsn.cnrs-gif.fr Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201103062. Scheme 1. Rational design for a three-component radical/cationic reaction of enamide 1, alkyl halide 2 and alcohol 3.

Catalytic Asymmetric Passerini-Type Reaction: Chiral Aluminum−Organophosphate-Catalyzed Enantioselective α-Addition of Isocyanides to Aldehydes

A chiral Lewis acid catalyst was prepared by mixing 2 equiv of chiral binol-derived organophosphoric acid and 1 equiv of Et(2)AlCl. In the presence of a catalytic amount of [4j](2)Al(III)Cl complex (0.05 equiv), reaction between alpha-isocyanoacetamides (2) and aldehydes (3) afforded the corresponding 5-aminooxazoles (1) in good yields and enantioselectivities. Complex [4j](2)Al(III)Cl isolated as a white solid displayed similar reactivity as that prepared in situ.

Cinchona Alkaloid Amide Catalyzed Enantioselective Formal [2+2] Cycloadditions of Allenoates and Imines: Synthesis of 2,4-Disubstituted Azetidines†

Mix and go. The quinidine-amide (1)-catalyzed [2+2] cycloaddition between N-sulfonylimines (2) and alkyl 2,3-butadienoate (3) afforded the (R)-azetidines 4 in excellent yields and enantioselectivities. The (S)-enantiomer was obtained when a quinine-amide catalyst, the pseudoenantiomer of (1) was used.