Double nucleophilic N-alkylation of α-oxime-esters with Grignard reagents

Double nucleophilic N-alkylation of α-oxime-esters, affording N,N-dialkyl-α-amino acids is herein described. Grignard reagents accomplished double N-alkylations via umpolung and various N,N-dialkylated α-amino acids were successfully synthesized in 15 min. Both electron-withdrawing sulfonyl groups and electron-donating silyl and methyl groups on oximes were available. Alkylmagnesium species and (E)-configuration of α-oxime-ester were essential to this cascade reaction.     

Reactions of cyclic α-methoxy nitrones with nucleophilic reagents

Reactions of cyclic -methoxy nitrones, which are derivatives of imidazole or dihydroimidazole N-oxides, with amines, KOH, or KSH result in the replacement of the MeO group to form cyclic -amino nitrones, hydroxamic acids, or thiohydroxamic acids, respectively. Analogous reactions occur with C-nucleophiles.     

Synthesis of β-aminovinylphosphonates by organocatalytic nucleophilic displacement of acetate with amines

The synthesis of diethyl β-aminovinylphosphonates 2 from acetoxy phosphonate 1 is described. The reaction entails an organocatalyzed substitution of the acetoxy group by primary or secondary amines. The use of a catalytic amount of DABCO is necessary if the amine is not nucleophilic enough, otherwise a strong nucleophilic amine can react without organocatalyst. The reaction led to a series of functionalized title compounds in good to excellent yields.     

Dual Brønsted acid/nucleophilic activation of carbonylimidazole derivatives

Carbonylimidazole derivatives have been found to be highly active acylation reagents for esterification and amidation in the presence of pyridinium salts. These reactions are thought to involve both Br?nsted acid and nucleophilic catalysis. This mode of activation has been applied to the synthesis of difficult to access oxazolidinones, as well as esters and amides. Finally, the use of pyridinium salts has been shown to accelerate the esterification of carboxylic acids with imidazole carbamates.     

An allylic nucleophilic substitution reaction of 1α-hydroxyvitamin D derivatives

The first transformation of the 5,6- trans-vitamin D conjugated triene system into that of isovitamin D occurring under nucleophilic conditions is observed in the reaction of 5 with n-butyl-lithium to give 6.     

Vicarious nucleophilic substitution of α-hydrogen of BODIPY and its extension to direct ethenylation

Direct, oxidizer-free substitution of the 3-hydrogen of BODIPY derivatives has been established through a vicarious nucleophilic substitution procedure. This methodology has been combined with a reversible Michael addition on nitrostyrenes to provide a novel, highly efficient entry to the valuable 3-styrylated BODIPY dyes.     

A one-pot synthesis of α-formyl-α-allylacetates via nucleophilic catalysis

A step-economical one-pot nucleophilic catalysis/thermal Claisen-rearrangement protocol for the direct synthesis of α-formyl-α-allylacetates from allylic alcohols and activated alkynes has been developed. The product α-formyl-α-allylacetates were further reacted in situ to give either protected enol ethers or β-hydroxy-4-pentenoates.     

Asymmetric nucleophilic monofluorobenzylation of carbonyl compounds: synthesis of enantiopure vic-fluorohydrins and α-fluorobenzylketones

Asymmetric nucleophilic monofluoroalkylation of a broad range of aldehydes with an α-fluoro-γ-sulfinylbenzyl carbanion takes place with complete control of the facial selectivity at the carbanion and good to high anti-diastereoselectivity to give easily separable mixtures of two optically pure 1,2-fluorohydrin derivatives (up to 24:1 anti/syn). Separation and removal of the p-tolylsulfinyl group with tBuLi provides enantiomerically pure anti-1,2-disubstituted-1,2-fluorohydrins, whereas α-fluorobenzylketones can be obtained by desulfinylation of the mixture followed by pyridinium chlorochromate oxidation (one-pot process).     

Addition of nucleophilic reagents to α,β-unsaturated sulfones in presence of Triton B

Summary Triton B is a good catalyst for the addition of nucleophilic reagents at the double bonds of , ß-unsaturated sulfones of various structures.     

Versatile synthesis of α, β-acetylenic ketones by oxidative nucleophilic addition of vanadium acetylides

Treatment of aldehydes with vanadium acetylides generated from equimolar amounts of vanadium trichloride and acetylenic Grignard or lithium compounds gave α,β-acetylenic ketones via oxidative nucleophilic addition.     

Trimethylsilyl chloride promoted synthesis of α-branched amines by nucleophilic addition of organozinc halides to nitrones

A general procedure for the nucleophilic addition of organozinc halides with nitrones in the presence of trimethylsilyl chloride has been developed. Trimethylsilyl chloride was found to be both an indispensable reaction promoter and a ready hydroxylamine protective agent in these reactions. The produced O-(trimethylsilyl)hydroxylamines can be easily reduced into corresponding amines just by a zinc-copper couple in saturated aqueous NH(4)Cl solution.     

Noncovalent organocatalysis: a powerful tool for the nucleophilic epoxidation of α-ylideneoxindoles

A novel asymmetric nucleophilic epoxidation for α-ylideneoxindole esters has been successfully devised, resulting in enantioenriched spiro compounds with two new contiguous stereocenters. The employed (S)-α,α-diphenylprolinol functions as a bifunctional catalyst, creating a complex H-bond network in conjunction with a substrate and an oxidant.     

Vicarious nucleophilic substitution of hydrogen in aldehydes and Knoevenagel reaction of iminium salts with α-halocarbanions

Iminium salts derived from aromatic aldehydes react with -chlorocarbanions via two different pathways: reaction with secondary carbanion of halomethyl sulfones proceeds as the Knoevenagel condensation, while tertiary -chlorocarbanions gave products of vicarious nucleophilic substitution of hydrogen in parent aldehydes.     

Reaction of Β-oxonitrones — Imidazoline and pyrroline derivatives — With nucleophilic reagents

The reaction of -oxonitrones — imidazoline derivatives — with hydroxylamine, phenylhydrazine, and semicarbazide takes place at the carbonyl group with retention of the nitrone group. Stable nitroxyl radicals — spiroimidazoisoxazole derivatives — are formed in the oxidation of -hydroximinonitrones. The recyclization of the -oxonitrones, which takes place in an acidic medium, as well as by the action of hydrazine and thiosemicarbazide, leads, respectively, to pyrroline and pyrazole derivatives.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 912–919, July, 1991.     

Surfactant-type Brønsted acid catalyzed dehydrative nucleophilic substitutions of alcohols in water

A protocol for the dehydrative nucleophilic substitution of benzyl alcohols with a variety of carbon- and heteroatom-centered nucleophiles using dodecylbenzenesulfonic acid (DBSA) as a surfactant-type Br?nsted acid catalyst in water has been developed. The reaction system can be applied to the stereoselective C-glycosylation of 1-hydroxy sugars in water. [reaction: see text].     

Hyperaromatic stabilization of arenium ions: a remarkable cis stereoselectivity of nucleophilic trapping of β-hydroxyarenium ions by water

Cis- and trans-1,2-dihydrodiol isomers of benzene undergo acid-catalyzed dehydration to form phenol. In principle the isomeric substrates react through a common β-hydroxybenzenium (cyclohexadienyl) carbocation. Notwithstanding, the isomers show a large difference in reactivity, k(cis)/k(trans) = 4500. This difference is reduced to k(cis)/k(trans) = 440 and 50 for the 1,2-dihydrodiols of naphthalene and 9,10-dihydrodiols of phenanthrene, respectively, and to 6.9 for the dihydrodiols of the nonaromatic 7,8-double bond of acenaphthylene. Because the difference in stabilities of cis- and trans-dihydrodiols should be no more than 2-3-fold, these results imply a high cis stereoselectivity for nucleophilic trapping of a β-hydroxyarenium cation by water in the reverse of the carbocation-forming reaction. This is confirmed by studies of the 10-hydroxy-9-phenanthrenium ion generated from aqueous solvolyses of the trans-9,10-bromohydrin derivative of phenanthrene and the monotrichloroacetate ester of the phenanthrene cis-9,10-dihydrodiol. The cis stereoselectivity of forward and reverse reactions is explained by the formation (in the "forward" reaction) of different conformations of carbocation from cis- and trans-dihydrodiol reactants with respectively β-C-H and β-C-OH bonds in pseudoaxial positions with respect to the charge center of the carbocation optimal for hyperconjugation. Formation of different conformations is constrained by departure of the (protonated) OH leaving group from a pseudoaxial position. The difference in stability of the carbocations is suggested to stem (a) from the greater hyperconjugative ability of a C-H than a C-OH bond and (b) from enhanced conjugation arising from the stabilizing influence of an aromatic ring in the no-bond resonance structures representing the hyperconjugation (C(6)H(6)OH(+) ? C(6)H(5)OH H(+)). This is consistent with an earlier suggestion by Mulliken and a demonstration by Schleyer that the benzenium ion is subject to hyperconjugative aromatic stabilization. It is proposed that, in analogy with the terms homoconjugation and homoaromaticity, arenium ions should be considered as "hyperaromatic".     

Synthesis of α-CN and α-CF3 N-heterocycles through tandem nucleophilic additions

Using a readily available secondary aminoalkyne as starting material, a powerful strategy was discovered to prepare precursors of biologically important unnatural cyclic aminoacids and fluorinated N-heterocycles with important ring sizes (e.g., 5-7) in a one-pot reaction using two nucleophilic additions in a tandem fashion.     

Use of the Bell–Evans–Polanyi Principle to predict regioselectivity of nucleophilic aromatic photosubstitution reactions

Regioselectivity of nucleophilic aromatic photosubstitution has been shown experimentally to depend upon activation energies of the competing transition states. Computational means of determining relative activation energies were sought, therefore, in order to predict regioselectivity. Optimization of the three triplet transition states of 2-chloro-4-nitroanisole with hydroxide ion gave energies of insufficient accuracy to predict regioselectivity. Computed enthalpy changes from the first triplet transition state to the triplet σ-complexes correlated precisely with the experimental activation energies. This exemplifies the Bell–Evans–Polanyi Principle, and it provides an accurate means of assessing regioselectivity.     

Asymmetric nucleophilic substitution of α-bromo amides via dynamic kinetic resolution for the preparation of dipeptide analogues

Asymmetric nucleophilic substitution reactions of α-bromo α-aryl acetamides derived from l-amino acids are described. The simple and practical syntheses of dipeptide analogues have been developed with dibenzylamine, TBAI and a base to provide 2a-2n and 4 in 50-98% yields with diastereomeric ratios from 74:26 to >99:1. Mechanistic investigations suggest that α-bromo acetamides are configurationally labile under the reaction condition and the primary pathway of the asymmetric induction is a dynamic kinetic resolution. The semiempirical calculations of two epimeric transition states of 1b found that (αS)-epimer is the faster reacting epimer with the formation of an intermolecular hydrogen bond that facilitates delivery of the amine nucleophile.     

First example of axial selectivity in the nucleophilic addition to (−)-menthone—addition of cyanomethyl lithium

The addition of cyanomethyl lithium to (−)-menthone at −78°C followed by 1.5 h stirring at room temperature and acidic workup produced exclusively the axial addition product, being the first example of preferred axial attack of an organometallic reagent to menthone. In the case of hydrolysis at −78°C after 0.5 h reaction time the equatorial addition product was isolated as the preferably formed isomer. The axial and equatorial cyanomethyl substituted menthol and neomenthol, respectively, were isolated in high yields.