N‐Heterocyclic Carbene Catalyzed Enantioselective α‐Fluorination of Aliphatic Aldehydes and α‐Chloro Aldehydes: Synthesis of α‐Fluoro Esters,Amides, and Thioesters

The asymmetric fluorination of azolium enolates that are generated from readily available simple aliphatic aldehydes or α‐chloro aldehydes and N‐heterocyclic carbenes (NHCs) is described. The process significantly expands the synthetic utility of NHC‐catalyzed fluorination and provides facile access to a wide range of α‐fluoro esters, amides, and thioesters with excellent enantioselectivity. Pyrazole was identified as an excellent acyl transfer reagent for catalytic amide formation.     

Oxidative Enantioselective α‐Fluorination of Aliphatic Aldehydes Enabled by N‐Heterocyclic Carbene Catalysis

Described is the first study on oxidative enantioselective α‐fluorination of simple aliphatic aldehydes enabled by N‐heterocyclic carbene catalysis. N‐fluorobis(phenyl)sulfonimide serves as a an oxidant and as an “F” source. The C? F bond formation occurs directly at the α position of simple aliphatic aldehydes, thus overcoming nontrivial challenges, such as competitive difluorination and nonfluorination, and proceeds with high to excellent enantioselectivities.     

The Catalytic Asymmetric α‐Benzylation of Aldehydes

The first aminocatalyzed α‐alkylation of α‐branched aldehydes with benzyl bromides as alkylating agents has been developed. Using a sterically demanding proline derived catalyst, racemic α‐branched aldehydes are reacted with alkylating agents in a DYKAT process to give the corresponding α‐alkylated aldehydes with quaternary stereogenic centers in good yields and high enantioselectivities.     

Nickel‐Catalyzed α‐Allylation of Aldehydes and Tandem Aldol Condensation/Allylation Reaction with Allylic Alcohols

An additive‐free nickel‐catalyzed α‐allylation of aldehydes with allyl alcohol is reported. The reaction is promoted by 1 mol % of in situ formed nickel complex in methanol, and water is the sole by‐product of the reaction. The experimental conditions allow the conversion of various α‐branched aldehydes and α,β‐unsaturated aldehydes as nucleophiles. The same catalyst and reaction conditions enabled a tandem aldol condensation of aldehyde/α‐allylation reaction.     

Umpolung Strategy for α‐Functionalization of Aldehydes for the Addition of Thiols and other Nucleophiles

Nucleophile–nucleophile coupling is a challenging transformation in organic chemistry. Herein we present a novel umpolung strategy for α‐functionalization of aldehydes with nucleophiles. The strategy uses organocatalytic enamine activation and quinone‐promoted oxidation to access O‐bound quinol‐intermediates that undergo nucleophilic substitution reactions. These quinol‐intermediates react with different classes of nucleophiles. The focus is on an unprecedented organocatalytic oxidative α‐thiolation of aldehydes. The reaction scope is demonstrated for a broad range of thiols and extended to chemoselective bioconjugation, and applicable to a large variety of aldehydes. This strategy can also encompass organocatalytic enantioselective coupling of α‐branched aldehydes with thiols forming quaternary thioethers. Studies indicate a stereoselective formation of the intermediate followed by a stereospecific nucleophilic substitution reaction at a quaternary stereocenter, with inversion of configuration.     

Enantio‐ and Site‐Selective α‐Fluorination of N‐Acyl 3,5‐Dimethylpyrazoles Catalyzed by Chiral π–CuII Complexes

Catalytic enantioselective α‐fluorination reactions of carbonyl compounds are among the most powerful and efficient synthetic methods for constructing optically active α‐fluorinated carbonyl compounds. Nevertheless, α‐fluorination of α‐nonbranched carboxylic acid derivatives is still a big challenge because of relatively high pK_a values of their α‐hydrogen atoms and difficulty of subsequent synthetic transformation without epimerization. Herein we show that chiral copper(II) complexes of 3‐(2‐naphthyl)‐l ‐alanine‐derived amides are highly effective catalysts for the enantio‐ and site‐selective α‐fluorination of N‐(α‐arylacetyl) and N‐(α‐alkylacetyl) 3,5‐dimethylpyrazoles. The substrate scope of the transformation is very broad (25 examples including a quaternary α‐fluorinated α‐amino acid derivative). α‐Fluorinated products were converted into the corresponding esters, secondary amides, tertiary amides, ketones, and alcohols with almost no epimerization in high yield.     

Efficient Synthesis of β‐Hydroxy‐α‐Amino Acid Derivatives via Direct Catalytic Asymmetric Aldol Reaction of α‐Isothiocyanato Imide with Aldehydes

An easily available and efficient chiral N,N′‐dioxide–nickel(II) complex catalyst has been developed for the direct catalytic asymmetric aldol reaction of α‐isothiocyanato imide with aldehydes which produces the products in morderate to high yields (up to 98 %) with excellent diastereo‐ (up to >99:1 d.r.) and enantioselectivities (up to >99 % ee). A variety of aromatic, heteroaromatic, α,β‐unsaturated, and aliphatic aldehydes were found to be suitable substrates in the presence of 2.5 mol % L ‐proline‐derived N,N′‐dioxide L5 –nickel(II) complex. This process was air‐tolerant and easily manipulated with available reagents. Based on experimental investigations, a possible transition state has been proposed to explain the origin of reactivity and asymmetric inductivity.     

Enantioselective Formal α‐Methylation and α‐Benzylation of Aldehydes by Means of Photo‐organocatalysis

Detailed herein is the photochemical organocatalytic enantioselective α‐alkylation of aldehydes with (phenylsulfonyl)alkyl iodides. The chemistry relies on the direct photoexcitation of enamines to trigger the formation of reactive carbon‐centered radicals from iodosulfones, while the ground‐state chiral enamines provide effective stereochemical control over the radical trapping process. The phenylsulfonyl moiety, acting as a redox auxiliary group, facilitates the generation of radicals. In addition, it can eventually be removed under mild reducing conditions to reveal methyl and benzyl groups.     

Amidation of Aldehydes and Alcohols through α‐Iminonitriles and a Sequential Oxidative Three‐Component Strecker Reaction/Thio‐Michael Addition/Alumina‐Promoted Hydrolysis Process to Access β‐Mercaptoamides from Aldehydes,Amines, and Thiols

Mild and general alumina‐promoted hydrolysis conditions for converting α‐iminonitriles into carboxamides have been developed. In combination with the oxidative three‐component Strecker reaction, the one‐pot direct amidation of aldehydes and alcohols is reported. Subsequently, an Yb(OTf)₃‐catalyzed Michael addition of thiols to α,β‐unsaturated α‐iminonitriles is reported for the synthesis of β‐mercapto‐α‐iminonitriles. The successful integration of an oxidative Strecker reaction, thio‐Michael addition, and neutral‐alumina‐promoted hydrolysis of β‐mercapto‐α‐iminonitriles into a three‐component one‐pot process allowed us to develop the direct conversion of amines, aldehydes, and thiols into β‐mercaptoamides. All of these procedures were applicable to aromatic and aliphatic amines and aldehydes.     

Direct α‐Vinylidenation of Aldehydes and Subsequent Cascade: Gold and Amine Catalysts Work Synergistically

Carbonyl‐substituted allenes are highly important synthetic intermediates for a number of heterocycles and strained‐ring systems. However, chemistry of allenyl aldehydes has not been explored as extensively as their ketone, ester, or amide analogues because of a lack of general synthetic methods. Described herein is the first direct α‐vinylidenation of aldehydes and an α‐vinylidenation/γ‐functionalization cascade to access tri‐ and tetrasubstituted allenyl aldehydes using a combination of a gold catalyst and an secondary amine. The reactive enamine intermediate of an aldehyde reacts with the gold‐activated hypervalent silylethynyl benziodoxolone to selectively generate the corresponding trisubstituted allenyl aldehyde. The allenyl aldehyde can further react with another equivalent of the alkynylation reagent or other electrophiles to afford tetrasubstituted allenes bearing an aldehyde group, an acetylene, and a halogen functionality. This method enables rapid access to polysubstituted furans from aldehydes.     

Synthesis of Functionalized α‐Vinyl Aldehydes from Enaminones

An efficient Rh^II‐catalyzed synthesis of functionalized α‐vinyl aldehydes with high E/Z stereoselectivity was developed. The reaction mediates the cyclopropanation of enaminones with vinyl carbenoids that are generated from cyclopropenes in situ to give the aminocyclopropane intermediates. Selective C?C bond cleavage of the cyclopropane intermediates leads to formation of α‐vinyl aldehyde derivatives with high E/Z selectivity. This method proceeds at room temperature under very mild reaction conditions and works with a broad substrate scope.     

N‐Heterocyclic Carbene Catalyzed Oxidative Coupling of Alkenes/ α‐Bromoacetophenones with Aldehydes: A Facile Entry to α,β‐Epoxy Ketones

A novel, N‐heterocyclic carbene (NHC) catalyzed direct oxidative coupling of styrenes with aldehydes has been described for the synthesis of α,β‐epoxy ketones in good yields. This unprecedented regioselective oxidative coupling employs NBS/DBU/DMSO (DBU=1,8‐diazabicyclo [5.4. 0] undec‐7‐ene, DMSO=dimethylsulfoxide, NBS=N‐bromosuccinimide) as an oxidative system at ambient conditions. Additionally, first NHC‐catalyzed Darzens reaction of α‐bromoketones and aldehydes under mild reaction conditions has also been described. Interestingly, mechanistic studies have revealed the preferred reactivity of NHC with alkene/α‐bromoketone rather than aldehydes, thus proceeding via the ketodeoxy Breslow intermediate.     

Stereoselective Synthesis of Polysubstituted Alkenes through a Phosphine‐Mediated Three‐Component System of Aldehydes, α‐Halo Carbonyl Compounds,and Terminal Alkenes

Geometrical control : PPh₃ and methyl acrylate (or acrylamide) are able to mediate the one‐pot Wittig reaction of aldehydes with α‐halo carbonyl compounds for the synthesis of 1,2‐disubstituted and trisubstituted alkenes in an excellent stereoselective fashion. Furthermore, the first one‐pot, three‐component reaction of aldehydes, α‐halo acetates, and terminal alkenes has been developed in the presence of PPh₃ to produce trisubstituted alkenes with excellent E selectivity (see scheme).

     

Ligand‐Controlled Regiodivergent Palladium‐Catalyzed Decarboxylative Allylation Reaction to Access α,α‐Difluoroketones

α,α‐Difluoroketones possess unique physicochemical properties that are useful for developing therapeutics and probes for chemical biology. To access the α‐allyl‐α,α‐difluoroketone substructure, complementary palladium‐catalyzed decarboxylative allylation reactions were developed to provide linear and branched α‐allyl‐α,α‐difluoroketones. For these orthogonal processes, the fluorination pattern of the substrate enabled the ligands to dictate the regioselectivity of the transformations.     

Catalytic Enantioselective α‐Fluorination of 2‐Acyl Imidazoles via Iridium Complexes

The first highly enantioselective α‐fluorination of 2‐acyl imidazoles utilizing iridium catalysis has been accomplished. This transformation features mild conditions and a remarkably broad substrate scope, providing an efficient and highly enantioselective approach to obtain a wide range of fluorine‐containing 2‐acyl imidazoles which are found in a variety of bioactive compounds and prodrugs. A large scale synthesis has also been tested to demonstrate the potential utility of this fluorination method.     

Umpolung Reactions of α‐Imino Esters: Useful Methods for the Preparation of α‐Amino Acid Frameworks

This paper summarizes our recent efforts toward the development of tandem reactions utilizing umpolung reactions of α‐imino esters. A highly diastereoselective tandem N‐alkylation–Mannich reaction of α‐imino esters was developed. A tandem N‐alkylation–addition reaction of α‐imino esters derived from ethyl glyoxylate with various aldehydes proceeded to give 1,2‐amino alcohols. The same reaction also proceeded efficiently using a novel flow system comprising two connected microreactors. Novel syntheses of α‐quaternary alkynyl amino esters and allenoates were developed through the use of umpolung N‐addition to β,γ‐alkynyl α‐imino esters, followed by regioselective acylation. In addition, a highly regioselective tandem N‐alkylation–vinylogous aldol reaction of β,γ‐alkenyl α‐imino esters was discovered. N‐Alkylation of α‐iminophosphonates followed by a Horner–Wadsworth–Emmons reaction with aldehydes occurred to afford enamines, which can be used in a four‐component coupling reaction with methyl vinyl ketone. α‐N‐Acyloxyimino esters served as highly efficient substrates for the N,N,C‐trialkylation reaction to introduce various nucleophiles at the imino nitrogen and carbon atoms.     

Organocatalyzed Cyclopropanation of α‐Substituted α,β‐Unsaturated Aldehydes: Enantioselective Synthesis of Cyclopropanes Bearing a Chiral Quaternary Center

An enantioselective cyclopropanation of α‐substituted α,β‐unsaturated aldehydes with bromomalonate has been successfully developed through a domino Michael/α‐alkylation strategy. The method allows the efficient formation of cyclopropanes bearing a quaternary carbon stereocenter at the α‐position of the aldehydes by using iminium/enamine catalysis and gives a nice extension on the organocatalytic cyclopropanation of bromomalonate and α,β‐unsaturated aldehydes previously reported by other groups. Very good yields (up to 81 %) and enantioselectivities (up to 97 % ee) have been obtained. The optically active cyclopropane derivatives are of high synthetic interest as useful targets for further elaboration into more complex structures.     

Synthesis of α‐alkenyl‐β‐hydroxy adducts by α‐addition of unprotected 4‐bromocrotonic acid and amides with aldehydes and ketones by chromium(II)‐mediated reactions

The regioselective and diastereoselective chromium(II)‐mediated reactions of 4‐bromocrotonic acid or amides with aldehydes and ketones can proceed without the need to protect protic sites to generate the respective α‐alkenyl‐β‐hydroxy adducts, i.e. formally the addition of the α‐anion of a carboxylic acid or amide to an oxo‐compound is featured. Copyright © 2016 John Wiley & Sons, Ltd.     

A Novel Organocatalytic Asymmetric Transfer Hydrogenation of α,β‐Unsaturated Aldehydes

α,β‐Unsaturated aldehydes reacted with diimide (diazene) in the presence of optically active ammonium salt 1 as a catalyst to give the corresponding saturated aldehydes in excellent yields and up to 98 : 2 er. Attractive features of the asymmetric transfer hydrogenation are its high yields, and chemo‐, and enantioselectivities.