A thiourea‐Brønsted base bifunctional catalyst allowed the enantioselective 1,6‐aza‐Michael addition of isoxazolin‐5‐ones to p‐quinone methides to give isoxazolin‐5‐ones having a chiral diarylmethyl ...moiety attached to the N atom with fair to good yields and enantiomeric excesses. To the best of our knowledge this reaction represents the first example of enantioselective N‐alkylation of isoxazolin‐5‐ones as well as the first example of enantioselective 1,6‐aza‐Michael reaction involving p‐quinone methides.
A bifunctional organocatalyst allowed the enantioselective 1,6‐aza‐Michael addition of isoxazolin‐5‐ones to p‐quinone methides to give isoxazolin‐5‐ones having a chiral diarylmethyl moiety attached to the N atom with fair to good yields and enantiomeric excesses.
Enantioenriched spirocyclic compounds bearing three contiguous stereocenters and high functionalization were obtained through a formal 3+2 cycloaddition reaction catalyzed by a cooperative system. ...The spiro compounds were synthesized from 4‐arylideneisoxazol‐5‐ones and isocyanoacetate esters using a bifunctional squaramide/Brønsted base organocatalyst derived from a Cinchona alkaloid and silver oxide as Lewis acid. This method afforded two out of the four possible diastereomers with good yields and high enantiomeric excess for both diastereomers.
The spirocyclic motif is present in natural products, chiral ligands, and compounds of pharmacological interest. Isothiocyanates as well as isocyanides bearing electron‐withdrawing groups in the ...α‐position can be deprotonated and react as formal dipoles on account of the presence of a nucleophilic carbanion and an electrophilic atom in the isothiocyanate or isocyanide functional groups. In the last years a number of procedures involving the formal 3+2 cycloaddition reaction of isothiocyanates or isocyanides with cyclic compounds bearing electrophilic exocyclic double bonds have been developed for the enantioselective synthesis of aza‐spirocyclic compounds. Among them, organocatalysis has played a predominant role in the development of asymmetric versions for these reactions. The synthesis of spirooxindoles by using this methodology has received especial attention, although other spirocyclic scaffolds are available depending on the structure of the dipolarophiles and the formal isothiocyanate and isocyanide dipoles.
Formal 3+2 cycloaddition reactions of compounds bearing exocyclic unsaturated functional groups and isothiocyanate or isocyanide derivatives as formal 1,3‐dipoles provide spirooxindoles and other aza‐spirocyclic compounds. This review surveys the latest developments of these reactions under asymmetric organocatalysis.
Five‐membered heterocycles bearing an exocyclic double bond have been successfully used as substrates in asymmetric addition and cycloaddition reactions. Ylidene‐heterocycles are attractive ...substrates due to their high functionalization and the presence of an electrophilic conjugated exocyclic double bound that can participate in nucleophilic addition reactions as well as cycloaddition reactions, which may be triggered by the formation of aromatic intermediates or products in many cases. During the last decades, catalytic methodologies have been developed using ylidene‐heterocycles as substrates in order to synthesize useful optically active heterocyclic derivatives. 4‐Ylidene‐pyrazol‐5‐ones, isoxazolin‐5‐ones, 2,3‐dioxopyrrolidines, rhodanines, oxazolidindiones, Erlenmeyer‐Ploch azlactones and 5‐ylidene‐thiazolones have been successfully used as substrates in asymmetric reactions. This review collects the powerful research in asymmetric addition and cycloaddition reactions where ylidene‐five‐membered heterocycles have been used.
An enantioselective organocatalytic addition of sodium bisulfite to (E)‐nitroalkenes has been developed by using a chiral bifunctional organocatalyst. The present methodology provides a variety of ...chiral β‐nitroethanesulfonic acid compounds (17 examples) with excellent results: up to 99 % yield and excellent enantioselectivity (up to 96 % ee). The reaction tolerates (hetero)aryl and alkyl substituents on the β‐nitroalkenes, and β,β‐disubstituted nitroalkenes.
A bifunctional thiourea catalyzes the enantioselective addition of sodium bisulfite to nitroalkenes to give chiral β‐nitrosulfonic acids with good yields and enantiomeric excesses. The sulfonic acids can be converted into the corresponding esters by treatment with trimethyl orthoacetate.
In this paper, we present an unprecedented and general umpolung protocol that allows the functionalization of silyl enol ethers and of 1,3‐dicarbonyl compounds with a large range of heteroatom ...nucleophiles, including carboxylic acids, alcohols, primary and secondary amines, azide, thiols, and also anionic carbamates derived from CO2. The scope of the reaction also extends to carbon‐based nucleophiles. The reaction relies on the use of 1‐bromo‐3,3‐dimethyl‐1,3‐dihydro‐1λ3d1,2iodaoxole, which provides a key α‐brominated carbonyl intermediate. The reaction mechanism has been studied experimentally and by DFT, and we propose formation of an unusual enolonium intermediate with a halogen‐bonded bromide.
A useful strategy: Herein, we report an umpolung strategy mediated by a hypervalent iodine(III) reagent for the functionalization of enol derivatives with different heteronucleophiles including carboxylic acids, thiols, alcohols, primary and secondary amines, azides and carbamates generated from CO2. Relevant examples for the derivatization of natural products and pharmaceutical compounds are also presented. The mechanism of the reaction was investigated by DFT calculations and experimental studies.
In this communication, a straighforward asymmetric synthesis of spiro‐indoline‐pyrazolone compounds is described. This methodology consists in a formal 4+1 cycloaddition reaction of ...4‐bromopyrazolones and aza‐ortho‐quinone methides generated in situ catalyzed by a bisquinine‐derived squaramide in CHCl3 under basic conditions. A variety of chiral spirocyclic compounds bearing a pyrazolone and an indoline moieties were obtained in moderate to good yields (up to 68 %) and moderate to excellent enantioselectivities (up to 93 % ee).
We have used experimental studies and DFT calculations to investigate the IrIII‐catalyzed isomerization of allylic alcohols into carbonyl compounds, and the regiospecific isomerization–chlorination ...of allylic alcohols into α‐chlorinated carbonyl compounds. The mechanism involves a hydride elimination followed by a migratory insertion step that may take place at Cβ but also at Cα with a small energy‐barrier difference of 1.8 kcal mol−1. After a protonation step, calculations show that the final tautomerization can take place both at the Ir center and outside the catalytic cycle. For the isomerization–chlorination reaction, calculations show that the chlorination step takes place outside the cycle with an energy barrier much lower than that for the tautomerization to yield the saturated ketone. All the energies in the proposed mechanism are plausible, and the cycle accounts for the experimental observations.
Experimental and DFT calculations have been used to understand the mechanism of the IrIII‐catalyzed isomerization of allylic alcohols into carbonyl compounds, and the regiospecific isomerization–chlorination of allylic alcohols into α‐chlorinated carbonyl compounds. The results presented, point to the importance of using an experimental–computational approach to comprehend the mechanisms of complex reactions (see scheme).
The first method to access unsymmetrical aliphatic acyloins is presented. The method relies on a fast 1,3‐hydride shift mediated by an IrIII complex in allylic alcohols followed by oxidation with ...TEMPO+. The direct conversion of allylic alcohols into acyloins is achieved in a one‐pot procedure. Further functionalization of the Cα′ of the α‐amino‐oxylated ketone products gives access to highly functionalized unsymmetrical aliphatic ketones, which further highlights the utility of this transformation.
Selective oxidation: A selective method to synthesize unsymmetrical acyloins as single constitutional isomers is presented. From allylic alcohols, a fast iridium‐catalyzed 1,3‐hydride followed by an oxidation affords α‐hydroxy carbonyls with outstanding selectivity.
An efficient method for the synthesis of α‐iodoketones from allylic alcohols and elemental iodine is reported. We show in this paper that the isomerization of allylic alcohols catalyzed by ...iridium(III) complexes can be combined with an aerobic oxidative iodination protocol, resulting in a straightforward method for the synthesis of a wide range of α‐iodoketones as single constitutional isomers and in high yields under mild reaction conditions.
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