Nickel‐Catalyzed Umpolung Arylation of Ambiphilic α‐Bromoalkyl Boronic Esters

A nickel‐catalyzed reductive arylation of ambiphilic α‐bromoalkyl boronic esters with aryl halides is described. This platform provides an unrecognized opportunity to promote the catalytic umpolung reactivity of ambiphilic reagents with aryl halides, thus unlocking a new cross‐coupling strategy that complements existing methods for the preparation of densely functionalized alkyl‐substituted organometallic reagents from simple and readily accessible precursors.     

配体参与的有机金属化合物对亚胺的不对称加成反应

手性胺类化合物是一类重要的有机化合物,在生物化学及药物合成中有广泛应用.有机金属化合物对亚胺的不对称加成反应是合成手性胺类化合物的重要方法之一.本文对近年来外加配体参与的有机金属化合物对亚胺的不对称加成反应,特别是催化合成手性胺类化合物的研究进展作一概述.     

Unlocking Hydrogenation for C-C Bond Formation: A Brief Overview of Enantioselective Methods

Hydrogenation of π-unsaturated reactants in the presence of carbonyl compounds or imines promotes reductive C-C coupling, providing a byproduct-free alternative to stoichiometric organometallic reagents in an ever-increasing range of C=X (X = O, NR) additions. Under transfer hydrogenation conditions, hydrogen exchange between alcohols and π-unsaturated reactants triggers generation of electrophile-nucleophile pairs, enabling carbonyl addition directly from the alcohol oxidation level, bypassing discrete alcohol oxidation and generation of stoichiometric byproducts.     

Reductive Cross‐Coupling Reactions between Two Electrophiles

Reductive cross‐electrophile coupling reactions have recently been developed to a versatile and sustainable synthetic tool for selective C?C bond formation. The employment of cheap and abundant electrophiles avoids the pre‐formation and handling of organometallic reagents. In situ reductive coupling is effected in the presence of a transition‐metal catalyst (Ni, Co, Pd, Fe) and a suitable metallic reductant (Mn, Zn, Mg). This Concept article assesses the current state of the art and summarizes recent protocols with various combinations of alkyl, alkenyl, allyl, and aryl reagents and highlights key mechanistic studies.     

Reductive Catalytic Difluorocarbene Transfer via Palladium Catalysis

A palladium-catalyzed reductive difluorocarbene transfer reaction that tames difluorocarbene to couple with two electrophiles has been developed, representing a new mode of difluorocarbene transfer reaction. The approach uses low-cost and bulk industrial chemical chlorodifluoromethane (ClCF₂H) as the difluorocarbene precursor. It produces a variety of difluoromethylated (hetero)arenes from widely available aryl halides/triflates and proton sources, featuring high functional group tolerance and synthetic convenience without preparing organometallic reagents. Experimental mechanistic studies reveal that an unexpected Pd^0/II catalytic cycle is involved in this reductive reaction, wherein the oxidative addition of palladium(0) difluorocarbene ([Pd⁰(L_n)]=CF₂) with aryl electrophile to generate the key intermediate aryldifluoromethylpalladium [ArCF₂Pd(L_n)X], followed by reaction with hydroquinone, is responsible for the reductive difluorocarbene transfer.     

Preparation of stereodefined homoallylic amines from the reductive cross-coupling of allylic alcohols with imines

Regio-, diastereo-, and enantioselective coupling reactions between imines and allylic alcohols have been developed. These coupling reactions deliver complex homoallylic amine products through a convergent C-C bond forming process that does not proceed through intermediate allylic organometallic reagents. In general, convergent coupling, by exposure of an allylic alkoxide to a preformed Ti-imine complex, occurs with allylic transposition in a predictable and stereocontrolled manner. While simple diastereoselection in these reactions is high, delivering anti-products with ≥20:1 selectivity, the organometallic transformation described is compatible with a diverse range of functionality and substrates (including aliphatic and aromatic imines, allylic silanes, trisubstituted alkenes, vinyl- and aryl halides, trifluoromethyl groups, thioethers, and aromatic heterocycles). Alkene geometry of the products is a complex function of the allylic alcohol structure and is consistent with a mechanistic proposal based on syn-carbometalation followed by syn-elimination by way of a boat-like transition state geometry. Single asymmetric coupling reactions provide a means to translate the stereochemical information of the allylic alcohol to the homoallylic amine or to control diastereoselection in the coupling reactions of achiral allylic alcohols with chiral imines. Double asymmetric coupling reactions are also described that afford a unique means to control stereoselection in these complex convergent coupling processes. Finally, empirical models are proposed that are consistent with the observed stereochemical course of these coupling reactions en route to chiral homoallylic amines possessing di- or trisubstituted alkenes and anti- or syn- relative stereochemistry at the allylic and homoallylic positions.     

Highly functionalized organomagnesium reagents prepared through halogen-metal exchange

Organomagnesium reagents occupy a central position in synthetic organic and organometallic chemistry. Recently, the halogen-magnesium exchange has considerably extended the range of functionalized Grignard reagents available for synthetic purposes. Functional groups such as esters, nitriles, iodides, imines, or even nitro groups can be present in a wide range of aromatic and heterocyclic organomagnesium reagents. Also various highly functionalized alkenyl magnesium species can be prepared. These recent developments as well as new applications of organomagnesium reagents in cross-coupling reactions and amination reactions will be covered in this Review.     

Catalytic Reactions of Titanium Alkoxides with Grignard Reagents and Imines: A Mechanistic Study

The reactivity of Grignard reagents towards imines in the presence of catalytic and stoichiometric amounts of titanium alkoxides is reported. Alkylation, reduction, and coupling of imines take place. Whereas reductive coupling is the major reaction in stoichiometric reactions, alkylation is favored in catalytic reactions. Mechanistic studies clearly indicate that intermediates involved in the two reactions are different. Catalytic reactions involve a metal–alkyl complex. This has been confirmed by reactions of deuterium‐labeled substrates and different alkylating agents. Under the stoichiometric conditions, however, titanium olefin complexes are formed through reductive elimination, probably through a multinuclear intermediate.     

Electronic and steric control in regioselective addition reactions of organolithium reagents with enaldimines

A reaction mode of imines derived from naphthalene-1-carbaldehyde and acyclic alpha,beta-unsaturated aldehydes with organolitium reagents was dependent on the characteristic nature of a substituent on the imine nitrogen atom. An imine having an electron-withdrawing aryl group on the nitrogen atom behaves as a 1,2-directing imine toward organolithium reagents. In contrast, an imine bearing an alkyl or a bulky aryl group favors 1,4-addition of organolithium reagents. Electronic and steric tuning of a substituent on the imine nitrogen atom for a reaction mode was rationalized on the basis of molecular orbital calculations.     

Synthesis and applications of masked oxo-sulfinamides in asymmetric synthesis

This short perspective reports on the synthesis and applications of a class of chiral amino carbonyl compounds, masked oxo-sulfinamides where the amine is protected with an N-sulfinyl moiety and the carbonyl group is protected as the ketal or 1,3-dithiane. These polyfunctionalized chiral building blocks are prepared by addition of organometallic reagents to masked oxo-sulfinimines (N-sulfinyl imines) or the addition of oxo-organometallic reagents and lithio-1,3-dithianes to sulfinimines. Because unmasking of the amino and carbonyl groups results in cyclic imines, these chiral building blocks are particularly useful for the asymmetric synthesis of functionalized nitrogen heterocycles, including prolines, pipecolic acids, pyrrolidines, homotropinones, tropinones, and tropane alkaloids such as cocaine and C-1 cocaine analogues.     

Highly efficient route to o-Allylbiaryls via palladium-catalyzed three-component coupling of benzynes, allylic halides, and aryl organometallic reagents

[reaction: see text] o-Allylbiaryl derivatives have been prepared in good to excellent yields by the palladium-catalyzed three-component reaction of allyl halides, benzynes, and aryl organometallic reagents.     

Highly Selective Addition of a Broad Spectrum of Trimethylsilane Pro‐nucleophiles to N‐tert‐Butanesulfinyl Imines

Addition of organotrimethylsilane reagents to chiral N‐tert‐butanesulfinyl imines can be achieved in good yields and with excellent diastereoselectivities by employing TMSO^?/Bu₄N⁺ as a Lewis base activator in THF. A variety of aliphatic, aromatic, heteroaromatic and organometallic chiral imines were utilised as electrophiles for the synthesis of enantioenriched N‐tert‐butanesulfinyl amides. Remarkably, the same sets of reaction conditions could be used with a highly diverse range of bench‐stable organotrimethylsilane reagents, which highlights the generality and robustness of this methodology.     

Direct Addition of Grignard Reagents to Aliphatic Carboxylic Acids Enabled by Bulky turbo-Organomagnesium Anilides

The synthesis of ketones through addition of organometallic reagents to aliphatic carboxylic acids is a straightforward strategy that is limited to organolithium reagents. More desirable Grignard reagents can be activated and controlled with a bulky aniline-derived turbo-Hauser base. This operationally simple procedure allows the straightforward preparation of a variety of aliphatic and perfluoroalkyl ketones alike from functionalized alkyl, aryl and heteroaryl Grignard reagents.     

Transition metal-catalyzed three-component coupling of allenes and the related allylation reactions

The feature article surveys the transition metal-catalyzed three-component coupling of allenes and the related allylation reactions. Most of the reactions shown in the article mechanistically proceed via oxidative addition of organic electrophiles to metals, followed by carbometallation of allene and then transmetalation by main group metals or reagents and organometallic reagents. These reactions provide an efficient route for the synthesis of various substituted allyl and vinyl metal reagents and complex organic molecules in highly regio-, stereo- and chemoselective manner in one pot. The metal reagents or pi-allyl-metal intermediates obtained from the reaction are utilized for the allylation of aldehydes, ketones and imines, producing various homoallylic alcohols and amines in a highly regio- and stereoselective manner.     

σ‐Noninnocence: Masked Phenyl‐Cation Transfer at Formal NiIV

Reductive elimination is an elementary organometallic reaction step involving a formal oxidation state change of ?2 at a transition‐metal center. For a series of formal high‐valent Ni^IV complexes, aryl–CF₃ bond‐forming reductive elimination was reported to occur readily (Bour et al. J. Am. Chem. Soc. 2015 , 137, 8034–8037). We report a computational analysis of this reaction and find that, unexpectedly, the formal Ni^IV centers are better described as approaching a +II oxidation state, originating from highly covalent metal–ligand bonds, a phenomenon attributable to σ‐noninnocence. A direct consequence is that the elimination of aryl–CF₃ products occurs in an essentially redox‐neutral fashion, as opposed to a reductive elimination. This is supported by an electron flow analysis which shows that an anionic CF₃ group is transferred to an electrophilic aryl group. The uncovered role of σ‐noninnocence in metal–ligand bonding, and of an essentially redox‐neutral elimination as an elementary organometallic reaction step, may constitute concepts of broad relevance to organometallic chemistry.     

Adventures in sulfur-nitrogen chemistry

This account reviews our efforts over the past 37 years to understand the chemistry of a select group of sulfur-nitrogen compounds including sulfinimines (N-sulfinyl imines) and N-sulfonyloxaziridines. Our early exploration of the thermal properties of sulfenamides, a class of sulfur-nitrogen compounds about which little was known, resulted in a new procedure, the silver-assisted method, for the construction of sulfenimines (N-sulfenyl imines). Selective oxidations of these compounds resulted in the production of N-sulfinyl imines (sulfinimines) and N-sulfonyloxaziridines. N-Sulfonyloxaziridines turned out to be a new class of aprotic neutral oxidizing reagents. Enantiomerically pure examples afford high ee values in the oxidation of enolates to alpha-hydroxy carbonyl compounds and in the oxidation of sulfides and selenides to sulfoxides and selenoxides. Additions of organometallic reagents to enantiomerically pure sulfinimines provide the best and most versatile method for the asymmetric construction of the carbon-nitrogen stereocenters found in many biologically active compounds. Sulfinimine-derived chiral building blocks provide efficient access to many classes of nitrogen heterocycles including aziridines, 2H-azirines, pyrrolidines, and piperidines.     

Highly stereoselective addition of organometallic reagents to N-tert-butanesulfinyl imines derived from 3- and 4-substituted cyclohexanones

Addition of alkyl or aryl Grignard reagents to N-sulfinyl imines derived from 3- and 4-substituted cyclohexanones proceeds with good yields and with excellent diasteroselectivity. The selectivity of the reaction is controlled by the ring substituent rather than the sulfinyl group stereochemistry, and therefore racemic tert-butanesulfinamide can be employed.     

CoI-Catalyzed Barbier Reactions of Aromatic Halides with Aromatic Aldehydes and Imines

The reductive Barbier coupling of aromatic halides and electrophiles has been achieved using a CoBr₂/1,10-phenanthroline catalytic system and over stoichiometric amounts of zinc. The reaction displayed a broad scope of substrates, including (hetero)aryl chlorides as pro-nucleophiles and aldehydes or imines as electrophiles, leading to diarylmethanols and diarylmethylamines in moderate to excellent yields, respectively.     

Organocerium reagents from iodine activated cerium metal and organic iodides: Their reactions with carbonyl compounds

Cerium metal activated by a trace of iodine reacted smoothly with alkyl, allyl, and aryl iodides to give the corresponding organocerium reagents. The reaction of the organocerium reagents thus prepared in situ with carbonyl compounds gave not only Grignard-type adducts but also reduction and reductive coupling products.     

Three component coupling of alpha-iminoesters via umpolung addition of organometals: synthesis of alpha,alpha-disubstituted alpha-amino acids

The synthesis of alpha,alpha-disubstituted alpha-amino acids by means of a three component coupling is reported. The coupling occurs through umpolung addition of organometallic reagents to the nitrogen of alpha-iminoesters. The resulting enolate intermediates subsequently react with electrophiles (aldehydes, imines, alpha,beta-unsaturated nitro, alkyl halides, acyl cyanides) to form a quaternary center. Tethering of the electrophile and nucleophile components provides cyclic alpha,alpha-disubstituted alpha-amino acid derivatives.