Stereoselective Nucleophilic Fluoromethylation of Aryl Ketones: Dynamic Kinetic Resolution of Chiral α‐Fluoro Carbanions

Although many methods are available for the synthesis of optically enriched monofluoromethyl secondary alcohols, synthesizing optically enriched monofluoromethyl tertiary alcohols remains a challenge. An efficient and easy‐to‐handle nucleophilic fluoromethylation protocol was developed. The current monofluoromethylation showed much higher facial selectivity than the corresponding difluoromethylation and proceeded via a different type of transition state. Excellent stereoselective control at the fluorinated carbon chiral center was found, an effect believed to be facilitated by the dynamic kinetic resolution of the chiral α‐fluoro carbanions.     

Reversing Polarity: Carbonyl α‐Aminations with Nitrogen Nucleophiles

The synthesis of α‐amino carbonyl compounds is an important challenge in synthesis en route to biologically essential structures. While classical approaches involve the use of enol or enolate chemistries in combination with an electrophilic source of nitrogen, those strategies usually necessitate further transformations to reach the desired targets. In recent years, a new approach arose involving the direct use of nucleophilic sources of nitrogen along with an oxidant. This approach advantageously leads, in one‐pot, to the biologically relevant α‐amino compound without requiring further transformation. This review highlights the recent advances in the emerging field of oxidative α‐amination reactions using nucleophilic sources of nitrogen.     

Heterocycles from α‐Aminonitriles

Owing to their various modes of reactivity, α‐aminonitriles represent versatile building blocks for the construction of a wide range of nitrogen heterocycles. The present Concept article focuses on synthetic methodologies using their bifunctional nature which is the basis of their reactivity as α‐amino carbanions and as iminium ions. Reactions exclusively taking place on either the amine or on the nitrile moiety will not be considered.     

Transition‐Metal‐Free Formal Sonogashira Coupling and α‐Carbonyl Arylation Reactions

Transition‐metal‐free formal Sonogashira coupling and α‐carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S_NAr) of β‐carbonyl sulfones to electron‐deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or α‐aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two‐step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and α‐carbonyl arylated products from a range of electron‐deficient aryl fluorides with a variety of functional groups and aryl‐, heteroaryl‐, alkyl‐, and alkoxy‐substituted sulfone nucleophiles. These transition‐metal‐free reactions complement the metal‐catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.     

Synergistic Relay Reactions To Achieve Redox‐Neutral α‐Alkylations of Olefinic Alcohols with Ruthenium(II) Catalysis

Herein, we report a ruthenium‐catalyzed redox‐neutral α‐alkylation of unsaturated alcohols based on a synergistic relay process involving olefin isomerization (chain walking) and umpolung hydrazone addition, which takes advantage of the interaction between the two rather inefficient individual reaction steps to enable an efficient overall process. This transformation shows the compatibility of hydrazone‐type “carbanions” and active protons in a one‐pot reaction, and at the same time achieves the first Grignard‐type nucleophilic addition using olefinic alcohols as latent carbonyl groups, providing a higher yield of the corresponding secondary alcohol than the classical hydrazone addition to aldehydes does. A broad scope of unsaturated alcohols and hydrazones, including some complex structures, can be successfully employed in this reaction, which shows the versatility of this approach and its suitability as an alternative, efficient means for the generation of secondary and tertiary alcohols.     

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.     

The synthesis and reactions of β-substituted ethyl sulfates

The synthesis of β-substituted ethyl sulfates and their reactions with nucleophilic reagents has been studied. Amines, phenolates, carboxylates, amine oxides, carbanions, and thiophenolates reacted with ethylene sulfate in high yield, with short reaction times, and at low temperatures, to form β-substituted ethyl sulfates. The β-substituted ethyl sulfates were easily hydrolyzed and in some cases were converted into polymeric material.     

Azines and Azoloazines,Part 1: Reactions of Triazolo[3,4‐a]phthalazine and Its Derivatives with Carbanions

Triazolo[3,4‐a]phthalazine as well as their chloro and nitro derivatives were subjected to the reactions with the carbanions typical for the vicarious nucleophilic substitution (VNS) of hydrogen. The reactions were strongly dependent on the substituents present on the triazolo[3,4‐a]phthalazine ring and resulted not only in the substitution of hydrogen but also in exchange of chlorine atom and pyridazine ring scission; the latter process dominated for the unsubstituted triazolophthalazine. Two of the products showed promising stimulating activity towards the central nervous system with no significant toxic effects.     

Dual Functionalization of α‐Monoboryl Carbanions through Deoxygenative Enolization with Carboxylic Acids

A dual functionalization of 1,1‐diborylalkanes through deoxygenative enolization with carboxylic acids was developed. 1,1‐Diborylalkanes were activated by MeLi to generate α‐monoboryl carbanions. In situ IR spectroscopy indicated an interaction between carboxylic acid and 1,1‐diborylalkane before addition of the activation reagent. Release of the active α‐monoboryl carbanion from the masked form was necessary for its reaction with carboxylate to afford enolate species. Electrophilic trapping of enolate species with various electrophiles achieved dual functionalization of 1,1‐diborylalkanes to afford a variety of α‐mono, di‐, and tri‐substituted ketones.     

Electrophilic Reactivities of 1,2‐Diaza‐1,3‐dienes

The kinetics of the reactions of 1,2‐diaza‐1,3‐dienes 1 with acceptor‐substituted carbanions 2 have been studied at 20 °C. The reactions follow a second‐order rate law, and can be described by the linear free energy relationship log k(20 °C)=s(N+E) [Eq. (1)]. With Equation (1) and the known nucleophile‐specific parameters N and s for the carbanions, the electrophilicity parameters E of the 1,2‐diaza‐1,3‐dienes 1 were determined. With E parameters in the range of ?13.3 to ?15.4, the electrophilic reactivities of 1 a–d are comparable to those of benzylidenemalononitriles, 2‐benzylideneindan‐1,3‐diones, and benzylidenebarbituric acids. The experimental second‐order rate constants for the reactions of 1 a – d with amines 3 and triarylphosphines 4 agreed with those calculated from E, N, and s, indicating the applicability of the linear free energy relationship [Eq. (1)] for predicting potential nucleophilic reaction partners of 1,2‐diaza‐1,3‐dienes 1 . Enamines 5 react up to 10² to 10³ times faster with compounds 1 than predicted by Equation (1), indicating a change of mechanism, which becomes obvious in the reactions of 1 with enol ethers.     

Sterically Demanding Oxidative Amidation of α‐Substituted Malononitriles with Amines Using O2

An efficient amidation method between readily available 1,1‐dicyanoalkanes and either chiral or nonchiral amines was realized simply with molecular oxygen and a carbonate base. This oxidative protocol can be applied to both sterically and electronically challenging substrates in a highly chemoselective, practical, and rapid manner. The use of cyclopropyl and thioether substrates support the radical formation of α‐peroxy malononitrile species, which can cyclize to dioxiranes that can monooxygenate malononitrile α‐carbanions to afford activated acyl cyanides capable of reacting with amine nucleophiles.     

Regioselective Insertion of o‐Carborynes into the α‐CH Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C? H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C? H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Regioselective Insertion of o‐Carborynes into the α‐C?H Bond of Tertiary Amines: Synthesis of α‐Carboranylated Amines

o‐Carboryne can undergo α‐C H bond insertion with tertiary amines, thus affording α‐carboranylated amines in very good regioselectivity and isolated yields. In this process, the nucleophilic addition of tertiary amines to the multiple bond of o‐carboryne generates a zwitterionic intermediate. An intramolecular proton transfer, followed by a nucleophilic attack leads to the formation of the final product. Thus, regioselectivity is highly dependent upon the acidity of α‐C H proton of tertiary amines. This approach serves as an efficient methodology for the preparation of a series of 1‐aminoalkyl‐o‐carboranes.     

Control over the Chemoselectivity of Pd‐Catalyzed Cyclization Reactions of (2‐Iodoanilino)carbonyl Compounds

The factors that control the chemoselectivity of palladium‐catalyzed cyclization reactions of (2‐iodoanilino)carbonyl compounds have been explored by an extensive experimental computational (DFT) study. It was found that the selectivity of the process, that is, the formation of fused six‐ versus five‐membered rings, can be controlled by the proper selection of the initial reactant, reaction conditions, and additives. Thus, esters or amides produce ketones by a nucleophilic addition process, whereas the addition of PhO^? ions leads to the formation of indolines by an α‐arylation reaction. In contrast, the corresponding ketone reactants yield a mixture of both reaction products, the ratio of which depends on the base used, in the presence of phenol. The outcome of the processes can be explained by the formation of a common four‐membered palladacycle intermediate from which the competitive nucleophilic addition and α‐arylation reactions occur. The remarkable effect of phenol in the process, which makes the α‐arylation reaction easier, favored the formation of enol complexes, which are stabilized by an intramolecular hydrogen bond between the hydroxy group of the enol moiety and the oxygen atom of the phenoxy ligand. Moreover, the chemoselectivy of the process can be also controlled by the addition of bidendate ligands that lead to the almost exclusive formation of indoles at expenses of the corresponding alcohols.     

Nucleophilic reactivities of carbanions in water: the unique behavior of the malodinitrile anion

The kinetics of the reactions of nine carbanions 1a-i, each stabilized by two acyl, ester, or cyano groups, with benzhydrylium ions in water were investigated photometrically at 20 degrees C. Because the competing reactions of the benzhydrylium ions with water and hydroxide ions are generally slower, the second-order rate constants of the reactions of the benzhydrylium ions with the carbanions can be determined with high precision. The rate constants thus obtained can be described by the Ritchie equation, log(k/k(0)) = N(+) (eq 1), which allows us to calculate Ritchie N(+) parameters for a series of stabilized carbanions, for example, malonate, acetoacetate, malodinitrile, etc., and compare them with those of other n-nucleophiles in water (hydroxide, amines, azide, thiolates, etc.). Because the Ritchie relationship (eq 1) is a special case of the more general relationship log k = s(N + E) (eq 4), the reactivity parameters N and s for the carbanions 1a-i can also be calculated and compared with the nucleophilic reactivities of a large variety of n-, pi-, and sigma-nucleophiles, including reactivities of carbanions in dimethyl sulfoxide. While the acyl and ester substituted carbanions are approximately 3 orders of magnitude less reactive in water than in dimethyl sulfoxide, the malodinitrile anion (1i) shows almost the same reactivity in both solvents. Correlations between the nucleophilic reactivities of carbanions with the pK(a) values of the corresponding CH acids reveal that the malodinitrile anion (1i) is considerably more nucleophilic than was expected on the basis of its pK(a) value. This deviation is assigned to the exceptionally low Marcus intrinsic barriers of the reactions of the malodinitrile anion (1i).     

Stereoselective synthesis of 1,4,2‐oxazaphosphorines as precursors of chiral α‐aminophosphonic acids by intramolecular heterocyclization of β‐aldiminoalkylphosphites

The intramolecular version of nucleophilic additon of phosphites to imines was carried out for the first time taking as an example β‐aldiminoalkylphosphites, formed from chlorophosphites and β‐aldiminoalcohols [N‐(benzylidene)‐2‐aminoethanol and R‐(+)‐N‐(benzylidene)‐2‐aminobutanol‐1]. In these reactions, stereoisomeric 1,4,2‐oxazaphosphorines were obtained in good yields. R‐(+)‐N‐(benzylidene)‐2‐aminobutanol‐1 being used as a precursor, nucleophilic attack by P(III) atom on electrophilic C atom of the CN group proceeds stereospecifically with participation of only re‐face of the two possible diastereotopic faces of the imine double bond to give the epimeric at phosphorus (3R,5R)‐2‐(β‐chloroethyl)‐2‐oxo‐3‐phenyl‐5‐ethyl‐1,4,2‐oxazaphosphorines as precursors of nonracemic α‐aminophosphonic acids. © 2003 Wiley Periodicals, Inc. Heteroatom Chem 14:56–61, 2003; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.10054     

Gold(I)‐Assisted α‐Allylation of Enals and Enones with Alcohols

The intermolecular α‐allylation of enals and enones occurs by the condensation of variously substituted allenamides with allylic alcohols. Cooperative catalysis by [Au(ItBu)NTf₂] and AgNTf₂ enables the synthesis of a range of densely functionalized α‐allylated enals, enones, and acyl silanes in good yield under mild reaction conditions. DFT calculations support the role of an α‐gold(I) enal/enone as the active nucleophilic species.     

The Reaction Studies of α‐Chloroformylarylhydrazines with Thiols,Thioureas and α‐Cyclodiketones

The reactions of α‐chloroformylarylhydrazines 1 with various types of mercaptan, thiourea and α‐cyclodiketone have been studied intensively. 1‐Arylhydrazinecarbothioates 2 were obtained via thioesterization when α‐chloroformylarylhydrazines reacted with thiols. On the other hand, compounds 3 were obtained when α‐chloroformylarylhydrazines reacted with thio‐containing heterocyclic compounds, which suggested a totally different mechanism in these types of reactions. Further studies on the reaction of α‐chloroformylarylhydrazines 1 with thiourea compounds confirmed a novel cyclization and de‐cyclization mechanism, which led to give 2‐arylhydrazinecarboximidamides 5 and 1,3,4‐thiadiazolin‐5‐ones 6 . In addition, various 1,3,4‐oxadiazines 9 were obtained by reacting α‐chloroformylarylhydrazines with α‐cyclodiketones, showing ring cyclization was involved in this type of reaction.     

Trapping of Tricarbonyl(η1,η2‐homoallyl)iron and Tricarbonyl(η3‐allyl)iron Anion Intermediates with 2‐(Phenylsulfonyl)‐3‐phenyloxaziridine

The addition of reactive carbanions to (η⁴‐1,3‐diene)Fe(CO)₃ complexes at ?78 °C and 25 °C produced putative homoallyl and allyl anion complexes, respectively. Reaction of the reactive intermediates with 2‐(phenylsulfonyl)‐3‐phenyloxaziridine afforded nucleophilic substituted (η⁴‐1,3‐diene)Fe(CO)₃ complexes.     

Cyanoalkylation: Alkylnitriles in Catalytic CC Bond‐Forming Reactions

Alkylnitriles are one of the most ubiquitous nitrogen‐containing chemicals and are widely employed in reactions which result in nitrile‐group conversion into other functionalities. Nevertheless, their use as carbon pronucleophiles in carbon–carbon bond‐forming reactions has been hampered by difficulties associated mainly with the catalytic generation of active species, that is, α‐cyano carbanions or metalated nitriles. Recent investigations have addressed this challenge and have resulted in different modes of alkylnitrile activation. This review illustrates these findings, which have set the foundation for the development of practical and conceptually new catalytic, direct cyanoalkylation methodologies.