A Cu-BOX catalysed enantioselective Mukaiyama-aldol reaction with difluorinated silyl enol ethers and acylpyridine N-oxides.

A Cu(II)/BOX complex catalyses the enantioselective addition of difluorinated silyl enol ethers to acylpyridine N-oxides. The reaction provides difluorinated chiral tertiary alcohols of great interest in medicinal chemistry. These compounds are obtained in moderate to excellent yields and with high enantioselectivities. The stereochemical outcome of the reaction has been explained by DFT calculations.

Radical Addition of Dihydroquinoxalin-2-ones to Trifluoromethyl Ketones under Visible-Light Photoredox Catalysis.

A visible-light photocatalytic radical addition reaction of dihydroquinoxalin-2-ones to trifluoromethyl ketones has been established using Ru(bpy)3Cl2 as photocatalyst, acetonitrile as solvent, and HP Single Blue LED as the source of light. The reaction provides a straightforward approach to the synthesis of dihydroquinoxalin-2-ones bearing a trifluoromethyl-substituted tertiary alcohol moiety in moderate to good yields under mild conditions.

Catalytic Diastereo- and Enantioselective Synthesis of Tertiary Trifluoromethyl Carbinols through a Vinylogous Aldol Reaction of Alkylidenepyrazolones with Trifluoromethyl Ketones.

A diastereo- and enantioselective organocatalytic aldol reaction between alkylidenepyrazolones and trifluoromethyl ketones leading to chiral tertiary alcohols bearing a trifluoromethyl group is presented. The methodology is based on the use of a bifunctional organocatalyst in order to activate the γ-hydrogen atoms of the alkylidenepyrazolone nucleophile and the carbonyl group of the trifluoromethylarylketone providing highly functionalized trifluoromethyl alcohols with moderate yields, excellent diastereoselectivity, and moderate to good enantioselectivity. Experiments monitoring the conversion by 1H NMR and the enantiomeric excess by HPLC with the reaction time showed that full conversion of the starting materials is not achieved and that the enantiomeric excess decreases upon extended times, probably due to the reversibility of the reaction.

Organocatalytic enantioselective Mannich reaction of isoxazol-5(4H)-ones to isatin-derived ketimines.

An efficient organocatalytic asymmetric Mannich reaction between isoxazol-5(4H)-ones and isatin-derived ketimines has been developed. A bifunctional squaramide/Brønsted base organocatalyst catalyzed the enantioselective Mannich addition to afford chiral 3-aminooxindoles bearing a tetrasubstituted stereocenter at C3 decorated with an isoxazole moiety in good yields and with excellent enantioselectivities. Additionally, several synthetic transformations were described showing the versatility of the prepared compounds.

Catalytic Enantioselective Cyclopropylalkynylation of Aldimines Generated In Situ from α-Amido Sulfones.

A convenient procedure of synthesis of N-carbamoyl-protected propargylic amines substituted with a cyclopropyl group from α-amido sulfones and cyclopropylacetylene is described. The reaction is catalyzed by a chiral BINOL-type zinc complex and provides the corresponding products in good yields and enantioselectivities.

Visible-light-accelerated amination of quinoxalin-2-ones and benzo[1,4]oxazin-2-ones with dialkyl azodicarboxylates under metal and photocatalyst-free conditions.

A direct sp3 C-H amination of cyclic amines (dihydroquinoxalinones and dihydrobenzoxazinones) with dialkyl azo dicarboxylates accelerated by visible-light irradiation under metal and photocatalyst-free conditions is described. This protocol features very mild reaction conditions for the synthesis of aminal quinoxaline and benzoxazine derivatives with good to high yields (up to 99%). These aminal derivatives respresent versatile building blocks for the divergent synthesis of quinoxalin-2-one derivatives.

Enantioselective Friedel-Crafts reaction of hydroxyarenes with nitroenynes to access chiral heterocycles via sequential catalysis.

Naphthols, hydroxyindoles and an activated phenol are reacted with differently substituted (E)-nitrobut-1-en-3-ynes using the commercially available Rawal's chiral squaramide. The corresponding ß-nitroalkynes were obtained with good yields and excellent enantioselectivities. Moreover, dihydronaphthofurans can be accessed via silver catalysed cyclization in a tandem one-pot procedure, with high preservation of the optical purity.

Enantioselective Synthesis of 5-Trifluoromethyl-2-oxazolines under Dual Silver/Organocatalysis.

The first enantioselective formal [3 + 2] cycloaddition between α-isocyanoesters and trifluoromethylketones to give 5-trifluoromethyl-2-oxazolines bearing two contiguous stereogenic centers, one of them being a quaternary stereocenter substituted with a CF3 group, has been developed. The reaction is based upon a multicatalytic approach that combines a bifunctional Brønsted base-squaramide organocatalyst and Ag+ as Lewis acid. The reaction could be achieved with a range of aryl and heteroaryl trifluoromethyl ketones, and the resulting oxazolines were obtained with good to excellent diastereo- and enantioselectivity.

Organocatalytic enantioselective aminoalkylation of pyrazol-3-ones with aldimines generated in situ from α-amido sulfones.

Herein, an efficient asymmetric aminoalkylation of pyrazolones with α-amido sulfones catalyzed by a quinine-derived squaramide in dichloromethane/aqueous media has been established. A variety of chiral amines were obtained with high yields (up to 98%) and excellent enantioselectivities (up to 99% ee). The corresponding products are transformed into optically active acetylated pyrazoles after treatment with Ac2O/Et3N, because of the instability of some adducts. The reaction tolerates a wide range of α-amido sulfones and different pyrazolones.

Enantioselective Synthesis of 2-Amino-1,1-diarylalkanes Bearing a Carbocyclic Ring Substituted Indole through Asymmetric Catalytic Reaction of Hydroxyindoles with Nitroalkenes.

An asymmetric catalytic reaction of hydroxyindoles with nitroalkenes leading to the Friedel-Crafts alkylation in the carbocyclic ring of indole is presented. The method is based on the activating/directing effects of the hydroxy group situated in the carbocyclic ring of the indole providing nitroalkylated indoles functionalizated at the C-4, C-5, and C-7 positions with high yield, regio-, and enantioselectivity. The optically enriched nitroalkanes were transformed efficiently in optically enriched 2-amino-1,1-diarylalkanes bearing a carbocyclic ring substituted indole.

Catalytic Asymmetric Formal [3+2] Cycloaddition of 2-Isocyanatomalonate Esters and Unsaturated Imines: Synthesis of Highly Substituted Chiral γ-Lactams.

Unlike their isocyano and isothiocyanato analogues, isocyanato esters remain almost unexplored as formal 1,3-dipoles in asymmetric catalytic reactions. The first asymmetric formal [3+2] cycloaddition involving isocyanato esters and electrophilic alkenes is reported. Diisopropyl 2-isocyanatomalonate reacts with α,ß-unsaturated N-(o-anisidyl) imines in the presence of a Mg(OTf)2 -BOX complex to give highly substituted chiral pyrrolidinones featuring a conjugate exocyclic double bond with excellent yields and enantiomeric excesses up to 99 %. Several transformations of the resulting heterocycles, including the synthesis of a pyroglutamic acid derivative, have been carried out.

Copper-catalysed enantioselective Michael addition of malonic esters to ß-trifluoromethyl-α,ß-unsaturated imines.

Copper triflate-BOX complexes catalyse the enantioselective conjugate addition of methyl malonate to ß-trifluoromethyl-α,ß-unsaturated imines to give the corresponding enamines bearing a trifluoromethylated stereogenic centre with good yields, and diastereo- and enantioselectivities. The usefulness of the method has been shown with the synthesis of optically active ß-trifluoromethyl δ-amino esters and optically active trifluoromethyl piperidones.

Catalytic Enantioselective Conjugate Alkynylation of α,ß-Unsaturated 1,1,1-Trifluoromethyl Ketones with Terminal Alkynes.

The first catalytic enantioselective conjugate alkynylation of α,ß-unsaturated 1,1,1-trifluoromethyl ketones has been carried out. Terminal alkynes and 1,3-diynes were treated with trifluoromethyl ketones in the presence of a low catalytic load of a Cu(I) -MeOBIPHEP complex (2.5 mol %) and triethylamine (10 mol %) to give the corresponding trifluoromethyl ketones bearing a propargylic stereogenic center at the ß position with good yields and excellent enantiomeric excesses in most of the cases. No 1,2-addition products were formed under the reaction conditions. The procedure showed broad substrate scope for alkyne, diyne, and enone. A rationale for the observed stereochemistry has been provided. Finally, the potential application of the reaction products in the synthesis of chiral tetrahydrofurans bearing a trifluoromethylated quaternary stereocenter has been devised.

Catalytic Enantioselective Aza-Reformatsky Reaction with Cyclic Imines.

A catalytic highly enantioselective aza-Reformatsky reaction with cyclic aldimines and ketimines for the synthesis of chiral ß-amino esters with good yields and excellent enantioselectivities is reported. A readily available diaryl prolinol is used as a chiral ligand, ZnMe2 as a zinc source and ethyl iodoacetate as reagent in the presence of air atmosphere. The reaction with cyclic ketimines generates a quaternary stereocenter with excellent levels of enantioselectivity. Furthermore, five-membered N-sulfonyl ketimines were used as electrophiles with good enantiomeric excesses, under the optimized reaction conditions. Moreover, several chemical transformations were performed with the chiral ß-amino esters.

Enantioselective alkynylation of benzo[e][1,2,3]-oxathiazine 2,2-dioxides catalysed by (R)-VAPOL-Zn complexes: synthesis of chiral propargylic cyclic sulfamidates.

(R)-VAPOL-Zn(II) complexes catalysed the enantioselective addition of terminal alkynes to cyclic benzoxathiazine 2,2-dioxides, providing the corresponding chiral propargylic sulfamidates with high yields (up to 93%) and good enantiomeric excesses (up to 87%).

Organocatalytic asymmetric addition of naphthols and electron-rich phenols to isatin-derived ketimines: highly enantioselective construction of tetrasubstituted stereocenters.

A quinine-derived thiourea organocatalyst promoted the highly enantioselective addition of naphthols and activated phenols to ketimines derived from isatins. The reaction afforded chiral 3-amino-2-oxindoles with a quaternary stereocenter in high yields (up to 99%) with excellent enantioselectivity (up to 99% ee). To the best of our knowledge, this transformation is the first highly enantioselective addition of naphthols to ketimines.

Highly enantioselective copper(I)-catalyzed conjugate addition of terminal alkynes to 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones: new ester/amide surrogates in asymmetric catalysis.

A highly enantioselective copper-catalyzed conjugate alkynylation of monoactivated enones, namely 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones, is described. The reaction products are obtained with good yields and excellent enantioselectivities (from 92 to 99% ee). The ß-alkynylated difluoro(phenylsulfonyl) ketones can be converted into the corresponding ß-alkynylated difluoro- and trifluoromethyl ketones, esters and amides. This is the first example on the use of 1,1-difluoro-1-(phenylsulfonyl)-3-en-2-ones as substrates in an enantioselective reaction, which have been shown to be new ester/amide surrogates.

Asymmetric conjugate addition of malonate esters to α,ß-unsaturated N-sulfonyl imines: an expeditious route to chiral δ-aminoesters and piperidones.

The asymmetric conjugate addition of malonate esters to α,ß-unsaturated N-sulfonyl imines is catalyzed by PyBOX/La(OTf)3 complexes in the presence of 4 ŠMS. The reaction gives the corresponding E enamines bearing a stereogenic center at the allylic position with good yields and enantiomeric ratios up to 97:3. This reaction provides a synthetic entry to chiral δ-aminoesters and piperidones.

Synthesis of densely functionalised 5-halogen-1,3-oxazin-2-ones by halogen-mediated regioselective cyclisation of N-Cbz-protected propargylic amines: a combined experimental and theoretical study.

A very efficient synthesis of 5-halogen-1,3-oxazin-2-ones has been accomplished by the halocyclisation reaction of chiral nonracemic N-carbobenzyloxy (N-Cbz)-protected propargylic amines by using I2, Br2 and Cl2 as electrophile sources. The nature of the halogen influences the reaction time and yield. However, in all cases the reaction is totally regioselective taking place through a 6-endo-dig process regardless of the nature of the halogen and of the substituents in the starting material. To rationalise the experimental results, theoretical studies at the B3LYP/6-311G* level have been performed.

Synthesis of α,α-Diaryl-α-amino Acid Precursors by Reaction of Isocyanoacetate Esters with o-Quinone Diimides.

A novel procedure for the synthesis of α,α-diaryl-α-amino acid derivatives has been developed. Silver oxide catalyzes the conjugate addition of α-aryl isocyanoacetates to o-quinone diimide, affording the corresponding α,α-diarylisocyano esters in excellent yields and regioselectivities in short reaction times. Acid hydrolysis of the isocyano group provides the corresponding amino acids bearing a diarylated tetrasubstituted carbon atom. The reaction is also amenable to the synthesis of α-alkyl-α-arylisocyano esters, while the reaction with 3-hydroxy o-quinone diimides provides 4H-benzo[e][1,3]oxazines via a conjugate addition/cyclization process.