Stereospecificity and stereoselectivity in electrophilic substitution reactions of non-alpha-heterosubstituted organolithiums and stannanes: a rotationally restricted amide as an internal stereochemical marker.

The complete stereochemical course of a tin-lithium exchange/electrophilic quench sequence has been unambiguously determined by stereochemical characterization (using X-ray crystallography or NOE studies) at every step. Pairs of diastereoisomeric stannanes of known stereochemistry bearing atropisomeric amide substituents undergo tin-lithium exchange with alkyllithiums to give diastereoisomeric benzylic organolithiums whose stereochemistry can be assigned by NMR. For one atropisomer of the stannanes, the tin-lithium exchange is fully stereospecific and proceeds with retention of stereochemistry. The other atropisomer undergoes nonstereospecific tin-lithium exchange: the first reported example of a lack of stereospecificity in electrophilic substitution of tin for lithium. One of the diastereoisomeric atropisomeric organolithiums produced by the tin-lithium exchange is deuterated and alkylated with retention but stannylated with inversion of stereochemistry. The other is alkylated nonstereospecifically but stannylated with retention.     

A DFT computational study on electrophilic substitutions upon alpha-oxy-substituted benzylorganolithium compounds: lithium catalysis is the hidden piece of the puzzle

A detailed DFT (B3LYP/6-31+G*) study upon alpha-oxybenzylorganolithium compounds such as alpha-carbamoyloxybenzyllithium 1 has revealed two relevant issues concerning the outcome of electrophilic substitutions (1) lithium salts catalyze these reactions, and (2) some pi lithium complexes can provide an extra position to which electrophiles can anchor and thus drive invertive (at the carbanionic carbon) processes. Calculations have shown that carboxylation, alkylation, and acylation should take place with inversion at the original C-Li bond.     

The stereochemistry of thiane oxidation : Participation of neighboring groups

Thianes not containing 4-OH or 4-CO groups are oxidized by wet bromine predominantly to equatorial thiane 1-oxides. The reaction is assumed to proceed by way of an equatorial electrophilic attack by hypobromous acid at the S atom. An electronic interpretation is given of the steric course of electrophilic reactions at the S atom in thianes. With thianes containing 4-OH or 4-CO groups, oxidation to thiane 1-oxides by wet bromine or by t-butyl hypochlorite resulted in a reversal of the usual stereospecificities of these reagents. A two step process involving participation by the 4-substituents is given to account for the different steric course of the reactions in these cases.     

Synthetic Applications of the beta-Lithiation of beta-Aryl Secondary Amides: Diastereoselective and Enantioselective Substitutions

The sequence of beta-lithiation and electrophilic substitution of beta-aryl secondary amides is reported. The lithiations occur regioselectively at the beta-position, and the resulting lithiated intermediates can be reacted with a wide range of electrophiles to give substituted products. Reactions of beta-lithiated amides bearing an alpha-substituent provide substituted products with high diastereoselectivity. Electrophilic substitutions of beta-lithiated N-methylamides in the presence of the chiral diamine (-)-sparteine provide highly enantioenriched products. The methodology is used to synthesize enantioenriched beta-aryl beta-substituted amides, acids, and lactones.     

Synthesis of Functionalized Ketones from Acid Chlorides and Organolithiums by Extremely Fast Micromixing

Synthesis of ketones containing various functional groups from acid chlorides bearing electrophilic functional groups and functionalized organolithiums was achieved using a flow microreactor system. Extremely fast mixing is important for high chemoselectivity.     

The stereochemistry of the reactions of organo transition metal complexes

The stereochemistry of homogeneously catalysed hydrogenation, carbonylation and decarbonylation is discussed, as well as the stereochemistry of nucleophilic and electrophilic addition to co-ordinated alkynes and dienes. Examples are presented of formation and lysis of carbon-transition metal bonds together with data relating to the steric course of these processes.     

New Catalytic Approaches towards the Enantioselective Halogenation of Alkenes

The addition of electrophilic reagents to the carbon–carbon double bond is one of the most fundamental reactions in organic chemistry. Halogen electrophiles constitute probably the most important class of electrophiles and have been widely used to induce electrophilic addition reactions to alkenes like halolactonizations or dihalogenations. Despite their long history and high importance, catalytic, asymmetric variants of these reactions have been underdeveloped until very recently. During the last two years this has changed and many novel approaches have been reported. This review aims to cover these new developments through discussing the common themes as well as the suggested mechanistic scenarios.     

Palladium-catalyzed electrophilic allylation reactions via bis(allyl)palladium complexes and related intermediates

The synthetic scope of the allyl-palladium chemistry can be extended to involve electrophilic reagents. The greatest challenge in these reactions is the catalytic generation of an allyl-palladium intermediate incorporating a nucleophilic allyl moiety. A vast majority of the published reactions that involve palladium-catalyzed allylation of electrophiles proceed via bis(allyl)palladium intermediates. The eta(1)-moiety of the bis(allyl)palladium intermediates reacts with electrophiles, including aldehydes, imines, or Michael acceptors. Recently, catalytic electrophilic allylations via mono-allylpalladium complexes were also presented by employment of so-called "pincer complex" catalysts.     

N,N'-diarylureas: a new family of atropisomers exhibiting highly diastereoselective reactivity

2,6-disubstituted N-aryl ureas rotate slowly about their Ar-N bonds and can exist as separable atropisomers. They also react remarkably diastereoselectively, with the urea axis controlling new stereogenic centers with high fidelity in a variety of nucleophilic and electrophilic addition reactions. The sense of diastereoselectivity in lateral lithiation-electrophilic quench reactions is electrophile-dependent and appears to be the result of stereospecific reaction with one of two interconvertible diastereoisomeric organolithiums.     

Extremely Fast Gas/Liquid Reactions in Flow Microreactors: Carboxylation of Short‐Lived Organolithiums

Carboxylation of short‐lived organolithiums bearing electrophilic functional groups such as nitro, cyano, and alkoxycarbonyl groups with CO₂ to give carboxylic acids and active esters was accomplished in a flow microreactor system. The successful reactions indicate that gas/liquid mass transfer and the subsequent chemical reaction with CO₂ are extremely fast.     

Regiodivergent C−H Acylation of Arenes by Switching from Ionic- to Radical-Type Chemistry Using NHC Catalysis

The Friedel–Crafts acylation reaction, which belongs to the class of electrophilic aromatic substitutions is a highly valuable and versatile reaction in synthesis. Regioselectivity is predictable and determined by electronic as well as steric factors of the (hetero)arene substrate. Herein, a radical approach for the acylation of arenes and heteroarenes is presented. C−H acylation is achieved through mild cooperative photoredox/NHC radical catalysis with the cross-coupling of an arene radical cation with an NHC-bound ketyl radical as a key step. As compared to the classical Friedel–Crafts acylation, a regiodivergent outcome is observed upon switching from the ionic to the radical mode. In these divergent reactions, aroyl fluorides act as the acylation reagents in both the ionic as well as the radical process.     

Dicationic intermediates involving protonated amides: dual modes of reactivity including the acylation of arenes

In the Br?nsted superacid CF(3)SO(3)H (triflic acid), amides are able to form reactive, dicationic electrophiles. It is shown that these dicationic intermediates participate in two distinctly different types of electrophilic reactions. The protonated amide increases the reactivity of an adjacent electrophilic group, and the protonated amide group itself shows enhanced reactivity arising from an adjacent cationic charge. In the latter case, several types of amides are even capable of reacting with benzene by Friedel-Crafts acylation. [reaction--see text]     

Dearomatizing cyclization of arylsulfonylalkoxymethyl lithiums: a route to the podophyllotoxin skeleton

[reaction: see text] The phenylsulfonyl group promotes the dearomatizing cyclization of tethered organolithiums onto aromatic rings. With an ether tether, the cyclizations create a new tetrahydrofuran ring, and both cyclization and subsequent electrophilic quenches proceed with high levels of diastereoselectivity. The sulfonyl group can be removed from the cyclized products oxidatively or reductively. The dearomatizing cyclization of a naphthyl sulfone was used in the synthesis of a close structural analogue of podophyllotoxin.     

Protolytic defluorination of trifluoromethyl-substituted arenes

A series of trifluoromethyl-substituted arenes were studied in their reactions with Br?nsted superacids. The products from these reactions suggest the formation of reactive electrophiles, such as carbocations, acylium cations or equivalent electrophilic species. As such, Friedel-Crafts-type reactions occur between these species and arene nucleophiles. NMR studies were done, and the results suggest the formation of an acyl group from the trifluoromethyl groups in the superacid.     

Comparison between experimental and theoretical scales of electrophilicity in benzhydryl cations

The theoretical electrophilicity pattern of a series of benzhydryl cations as described in terms of a model based on global reactivity indexes is compared with an experimental scale recently proposed by Mayr et al. [J. Am. Chem. Soc. 2001, 123, 9500]. A good correlation between both theoretical and experimental quantities is found. The effect of chemical substitution on the electrophilic power of these charged electrophiles may also be assessed as local responses at the active site, in terms of a global contribution described by changes in global electrophilicity with reference to the dianisylcarbenium ion, and a local contribution described by the variations in electrophilic Fukui function at that site.     

A computational approach towards predicting π-facial selectivity in sterically unbiased olefins: an evaluation of the relative importance of electrostatic and orbital effects

Computational studies are presented to show that electrostatic interactions significantly impact the stereochemical outcome in electrophilic addition to a number of sterically unbiased alkenes. Transition states have been located for the reaction of different electrophiles with all the sterically unbiased alkenes studied here and the calculations effectively include interactions involving the σ and σ^∗ orbitals of the newly formed bond. Electrostatic interaction between the substrates and electrophiles was modelled by removing the electrophiles from the transition state geometry and placing the calculated charge at a distance from a selected atom as observed in TS structures. Electrostatic interactions between the electrophiles and the substrate seem to effectively determine the face selectivities in the systems studied and our model calculations indicate that it may not be important to invoke Cieplak type orbital interactions to rationalize the observed face selectivities. The face selectivities predicted for these alkenes and electrophiles with DFT B3LYP/6-31G^∗ and ab initio MP2/6-31G^∗ levels are generally in good agreement.     

Indole Derivatives. 142. Some Properties of [4-(2-Indolyl)phenyl]phenylmethane and 1-[4-(2-Indolyl)phenyl]-2-phenylethane

The reactions of 2-arylindoles with strong electrophiles take place with significant resin formation. It was shown that electrophilic substitution is directed into the indole ring and into the side chain. 1,7-Migration of the substituent is observed in the investigated systems.     

Electronic effects on the stereochemistry of attack on trigonal atoms in six membered rings

The steric course of attack on a trigonal atom in a six-membered ring is attributed to electronic effects due to the interaction of the p-orbital of the trigonal atom with the symmetric σ orbital of the β CC bonds. This interaction leads to a different electron density on the two faces of the plane containing the trigonal atom. Nucleophilic attack involves preferential axial approach, but electrophilic attack involves preferential equatorial approach to the ring, in the absence of steric effects. Polarization by the reagent makes the σ-p interaction stronger. These principles are used to explain addition to trigonal carbon, sulfur, and pyramidal nitrogen.     

Lithiation and Electrophilic Substitution of Dimethyl Triazones

The lithiation and electrophilic substitution of dimethyl triazones is described. Directed lithiation or tin-lithium exchange of dimethyl triazones afforded the corresponding dipole stabilized nucleophiles that were trapped with various electrophiles. Keto-triazone derivatives accessed by acylation of such nucleophiles were readily converted into the corresponding imidazolone heterocycles.     

Copper activation of boronic acids: factors affecting reactivity

The generation of nucleophiles from the combination of aryl boronic acids and catalytic amounts of copper salt allows a reactivity distinct from other organometallic species, such as organolithiums or Grignard reagents. Here we examine how the electronic and steric properties of the boronic acid affect the formation of active nucleophiles and their subsequent reactivity with iminium‐type compounds, showing that electron‐rich substrates display reduced reactivity. Copyright © 2014 John Wiley & Sons, Ltd.