Ionic nucleophilic catalysis of chiral ammonium betaines for highly stereoselective aldol reaction from oxindole-derived vinylic carbonates

A new strategy for developing stereoselective bond-forming reactions is introduced; it takes advantage of the ionic nucleophilic catalysis of chiral ammonium betaines to utilize vinylic esters simultaneously as the enolate precursor and the acylating agent for coupling with electrophiles. Its synthetic utility is clearly demonstrated by the realization of a highly diastereo- and enantioselective aldol reaction from oxindole-derived vinylic carbonates.     

Activation of chlorine and fluorine by a phenylazo group towards nucleophilic aromatic substitution. Regioselective preparation of polysubstituted anilines

A phenylazo group was used for selective activation of ortho fluorine and chlorine atoms towards nucleophilic aromatic substitution with the propanethiolate anion. This enabled a regioselective synthesis of three substituted 4-alkoxyanilines. The regioselectivity of substitution was confirmed by comparison of experimental NMR chemical shifts with empirically predicted values. The observed reactivity of the substrates is discussed in the context of the substituent effect.     

Regioselective nucleophilic substitution reaction of meso-hexakis(pentafluorophenyl) substituted [26]hexaphyrin

Reaction of various alkoxides led to the selective replacement of the p-fluorine substituents of meso-hexakis(pentafluorophenyl) substituted [26]hexaphyrin. Reaction with isopropyl amine gave meso-hexakis(4-isopropylamino-2,3,5,6-tetrafluorophenyl) substituted [28]hexaphyrin.     

Vicarious nucleophilic substitution of hydrogen versus vinylic substitution of halogen in the reactions of carbanions of halomethyl aryl sulfones with dialkyl halofumarates and halomaleates

Reaction of halomethyl aryl sulfone carbanions with dialkyl halofumarates and halomaleates results in nucleophilic substitution of hydrogen and/or of the halogen. The reaction with halofumarates proceeds via addition of the carbanions to the vinylic carbon atom connected with hydrogen, followed by base promoted β-elimination of hydrogen halide in which the halogen originates from the carbanion moiety or from the alkene. In the case of halomaleates the reaction proceeds via an elimination-addition sequence.     

Rare example of nucleophilic substitution at vinylic carbon with inversion: mechanism of methyleneaziridine formation by sodium amide induced ring closure revisited

Intramolecular nucleophilic substitution of the C-Br bond of (E)- and (Z)-2-bromobut-2-enylamines by the pendant nitrogen atom leads to 2-ethyleneaziridines by way of stereochemical inversion at the vinylic carbon atom. The stereochemistry of the products is unambiguously established by X-ray crystallography performed on two derivatives. These cyclizations represent some of the first examples of substitution with inversion in unactivated vinylic substrates. In conjunction with additional deuterium-labeling experiments, the accepted mechanism for this reaction is shown to be flawed.     

Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine

Optimized synthesis and purification of erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine hydrochloride) were studied. Highly polar piperazine was used in a nucleophilic substitution reaction with the chlorinated intermediate byproduct N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. As a result, N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was completely transformed to N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The polarity of N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was changed, and its molecule was enlarged. It was easy to remove this larger, more polar, compound by recrystallization. Highly pure erlotinib hydrochloride was obtained with low impurity content (<1 %). The purity of erlotinib hydrochloride was >99.9 %.     

Control of the regioselectivity of sulfonamidyl radical cyclization by vinylic halogen substitution

The radical cyclization reactions of unsaturated sulfonamides were investigated. The photolysis of N-(4-halo-4-pentenyl)sulfonamides (X=I, Br, or Cl) with (diacetoxyiodo)benzene (DIB) and iodine at room temperature afforded exclusively the corresponding piperidines in 73-98% yield via 6-endo radical cyclization. On the other hand, the reactions of N-(5-halo-4-pentenyl)sulfonamides with DIB/I2 led to the only formation of the pyrrolidine products in 84-99% yield via 5-exo radical cyclization. The vinylic halogen substitution not only successfully inhibits the competing ionic iodocyclization process to allow the radical cyclization to proceed smoothly but also shows a remarkable effect in controlling the regioselectivity of cyclization.     

The effect of element substitution on high-temperature thermoelectric properties of Ca3Co2O6 compounds

Polycrystalline Ca₃Co_1.8M_0.2O₆ (M=Mn, Fe, Co, Ni, Cu) and Ca_2.7Na_0.3Co₂O₆ were synthesized by solid-state reaction to evaluate the effect of substitution on the thermoelectric properties of Ca₃Co₂O₆. Substitution by Mn, Cu and Na appears to increase carrier density, given that electrical resistivity (ρ) and the Seebeck coefficient (S) were simultaneously reduced. Conversely, Fe substitution seems to reduce carrier density, resulting in a simultaneous increase in S and ρ. Cu and Na substitution resulted in a significant decrease in ρ due to enhancement of grain size and grain boundary connectivity, which could have a strong impact on ρ. Not only the intrinsic substitution effect on the electronic state but also this modification of the microstructure plays an important role in improvement of the thermoelectric power factor, particularly in the case of the Na-substituted sample.     

A new mechanism of nucleophilic vinylic substitution and unexpected products in the reaction of chlorotrifluoroethylene with [Re(CO)5]Na and [CpFe(CO)2]K

The mechanism of chloride substitution in CF₂CFCl with [Re(CO)₅]⁻ and [CpFe(CO)₂]⁻ anions is investigated experimentally and theoretically. The substitution reaction begins with the nucleophile addition to CF₂CFCl producing the carbenoid anion [MCF₂CFCl]⁻ (A) (M = Re(CO)₅, CpFe(CO)₂). This is shown by trapping the intermediate A with electrophiles - proton donor (t-BuOH) to give MCF₂CFClH or with CF₂CFRe(CO)₅ to give acylmetallate III, and by the formation of the substitution products CF₂CFM from the anion A, generated by the deprotonation of MCF₂CFClH with t-BuOK. 1,2-Shift of metal carbonyl group concerted with the α-elimination of chloride anion is proposed as the transformation pathway of carbenoid A into CF₂CFM. A competing process of carbene insertion into Fe-CO bond is proposed to explain the formation of (XI). The feasibility of these two pathways is confirmed by DFT (B3LYP/SDD and 6-31G^∗) calculations of the carbenes [MCF₂CF:] and carbenoid anions [MCF₂CFCl]⁻. Transition states (TS) for 1,2-shift (+3.2 kcal/mol) and for nucleophilic addition at CO ligand (+5.4 kcal/mol) are located for [(CO)₅ReCF₂CFCl]⁻, but only one TS corresponding to carbene insertion into Fe-CO bond (+2.1 kcal/mol) is located for [(CO)₂CpFeCF₂CFCl]⁻. The formation of other newly observed products, F(CO)CHFRe(CO)₅ (V) and Cp(CO)₂FeCCFeCp(CO)₂ (VIII) is also discussed.     

Synthesis of highly substituted 1,3-dienes and 1,3,5-trienes by the palladium-catalyzed coupling of vinylic halides,internal alkynes,and organoboranes

[reaction: see text] Highly substituted 1,3-dienes and trienes have been prepared in good to excellent yields by the palladium-catalyzed coupling of vinylic halides, internal alkynes, and organoboranes.     

Investigation of the reaction order for nucleophilic substitution of dialkyl methylphosphonates by alkoxides

The rate of nucleophilic substitution at the phosphorus centre of dialkyl methylphosphonates by methoxide and ethoxide has been studied to investigate the possible involvement of hexacoordinated phosphorus species in this reaction. For alkoxide concentrations less than ca. 1.5 M the rate increases with the square of alkoxide concentration. However, consideration of the activity of the alkoxides, represented by an appropriate acidity function, reveals that only one equivalent of alkoxide is involved in the rate-determining step. Thus, there is no requirement to invoke the intermediacy of a hexacoordinated species in the reaction pathway. © John Wiley & Sons, Inc.     

Preparation of fully substituted anilines for the synthesis of functionalized indoles

A wide range of highly functionalized indoles were prepared by the successive magnesiation of readily available o-alkynyl protected anilines using TMPMgCl.LiCl or LDA, followed by a KH-mediated cyclization reaction.     

Fast production of highly concentrated reactive [F] fluoride for aliphatic and aromatic nucleophilic radiolabelling

The use of a polymeric solid support loaded with a long alkyl chain quaternary ammonium allows the rapid and efficient recovery of cyclotron produced [¹⁸F]F⁻ from [¹⁸O]water to a low water content organic solution compatible with fast nucleophilic labelling of most precursors for PET radiopharmaceuticals in high yield.     

Catalytic effect of supramolecular system based on cationic surfactant and monopodands in nucleophilic substitution of phosphorus esters

The data are presented on the synthesis of podands with terminal quinoxaline fragments of rings and their influence on both the micellization properties of cetyltrimethylammonium bromide in a water—DMF solution and kinetics of basic hydrolysis of O-p-nitrophenyl O-ethyl chloromethylphosphonate and O-p-nitrophenyl O-hexyl chloromethylphosphonate in the absence and presence of surfactants. The mechanism of the podand effect on the reaction rate depends on the structures of phosphonate and podand. 1,8-Bis(3-ethyl-1,2-dihydro-2-oxoquinoxalin-1-yl)-3,6-dioxaoctane inhibits the basic hydrolysis of the substrates to 3—4 times. In a micellar solution of the surfactant, an approximately 20-fold acceleration of the reaction rate constant is observed. The observed rate constant decreases when podand is added to a micellar solution. The catalytic effect of the polycomponent system is due to concentrating of the reactants. The micellar microenvironment can exert both positive and negative effects on the reactivity of phosphonates.     

Synthesis of substituted quinolines by the electrophilic cyclization of n-(2-alkynyl)anilines

A wide variety of substituted quinolines are readily synthesized under mild reaction conditions by the 6-endo-dig electrophilic cyclization of N-(2-alkynyl)anilines by ICl, I₂, Br₂, PhSeBr, and p-O₂NC₆H₄SCl. The reaction affords 3-halogen-, selenium- and sulfur-containing quinolines in moderate to good yields in the presence of various functional groups. Analogous quinolines bearing a hydrogen in the 3-position have been synthesized by the Hg(OTf)₂-catalyzed ring closure of these same alkynylanilines.     

Organocatalysis of nucleophilic substitution reactions by the combined effects of two promoters fused in a molecule: oligoethylene glycol substituted imidazolium salts

Oligoethylene glycol substituted imidazolium salts were synthesized as promoters for a range of S_N2 reactions, and their efficiency was examined. These tailor-made organic promoters enhanced the nucleophilicity of alkali metal salts significantly through the combined effects of two promoters (oligoethylene glycols and imidazolium salts) in a single molecule. The effects of the oligoethylene glycol side chain length, ionic liquid anions, nucleophiles, and substrates were investigated systematically. [hexaEGmim][OMs] and [dihexaEGim][OMs] showed the highest efficiency for S_N2 reactions using alkali metal salts. The role of the terminal hydroxyl groups of the oligoethylene glycol moiety was assessed by examining the relative S_N2 yields of chlorination and bromination. The results showed that the hydrogen bonding strength of the hydroxyl groups with the nucleophile is very important. The mechanism for the excellent promotion of S_N2 reactions by oligoEGILs was examined by quantum chemical calculations. The results showed that the oxygen atoms in the oligoethylene glycol portion and the ionic liquid anion act on the counter cation K⁺ or Na⁺ as a Lewis base, to enhance the reactivity of the metal salts significantly.     

A CNDO/2 investigation of the CH3/CF3 substitution effect

The variation of the A-C bond lengths with substitution of methyl by perfluoromethyl in molecules of the kind A(CH₃ )_n is investigated using the CNDO/2 method. Calculations were performed with A as fluorine, oxygen, nitrogen, sulphur and phosphorous and n = 1, 2 or 3. The variation of the A-C bond length can be explained qualitatively by combining two effects, (1) changes in the covalent bond order and (2) changes in the ionic bond strength. While the covalent bond order decreases in all cases, the extent of the decrease depending largely on the electronegativity of A, the ionic bond order increases for fluorine, oxygen, nitrogen and sulphur and decreases in the case of phosphorous. The variations in the ionic bond strength are found to depend on the electronegativity of A as well as on the number of substituted methyl groups.     

Combined QM/MM study of the mechanism and kinetic isotope effect of the nucleophilic substitution reaction in haloalkane dehalogenase

Combined QM/MM molecular dynamics simulations have been carried out for the dehalogenation reaction of the nucleophilic displacement of dichloroethane catalyzed by haloalkane dehalogenase. The computed chlorine kinetic isotope effects and free energies of activation in the wild-type and the Phe172Trp mutant enzyme are found to be consistent with experiment. In comparison with the uncatalyzed model reaction in water, the enzyme lowers the activation barrier by about 16 kcal/mol. The enormous enzymatic action was attributed to a combination of contributions from a change in the solvation effect and transition state stabilization. The unique features of tryptophan's ability to interact favorably with hydrophobic substrates and to form hydrogen bonds to the leaving group chloride ion at the transition state enable both factors to make significant contributions to the barrier lowering mechanism in the enzyme. This is in contrast to the reference reaction in water, in which hydrogen bonding interactions are weakened at the transition state because of dispersed charge distribution at the transition state relative to that in the reactant and product states.