Secondary benzylation using benzyl alcohols catalyzed by lanthanoid, scandium, and hafnium triflate

The combination of a secondary benzyl alcohol and a metal triflate (e.g., La, Yb, Sc, and Hf triflate) in nitromethane was a highly effective secondary-benzylation system. Secondary benzylation of carbon (aromatic compounds, olefins, an enol acetate), nitrogen (amide derivatives), and oxygen (alcohols) nucleophiles was carried out with a secondary benzyl alcohol and 0.01-1 mol % of a metal triflate in the presence of water. Secondary benzyl alcohols and nucleophiles bearing acid-sensitive functional groups (e.g., tert-butyldimethylsilyloxy and acetoxy groups and methyl and benzyl esters) could be used for alkylation. Hf(OTf)4 was the most active catalyst for this alkylation, and trifluoromethanesulfonic acid (triflic acid, TfOH) was also a good catalyst. The catalytic activity of metal triflates and TfOH increased in the order La(OTf)3 < Yb(OTf)3 < TfOH < Sc(OTf)3 < Hf(OTf)4. A mechanistic study was also performed. The reaction of 1-phenylethanol (4a) in the presence of Sc(OTf)3 in nitromethane gave an equilibrium mixture of 4a and bis(1-phenylethyl) ether (54). Addition of a carbon nucleophile to the equilibrium mixture gave alkylated product in high yield.     

Benzylic triflates prepared in‐situ: novel initiators for mono‐, bi‐ and trifunctional living poly(THF)s

Mono‐, bis‐, and tris(trifluoromethanesulfonate ester)s ((triflate ester)s) were prepared by the reaction of benzyl alcohol ( 1 ), 1,4‐bis(hydroxymethyl)benzene ( 2 ) and 1,3,5‐tris(hydroxymethyl)benzene ( 3 ) with trifluoromethanesulfonic anhydride in the presence of 2,6‐di‐tert‐butylpyridine. These benzylic triflate esters were applied in‐situ for the living polymerization of tetrahydrofuran (THF). The subsequent end‐capping reaction with a suitable nucleophile proceeded quantitatively to produce mono, bi‐ and, in particular, novel trifunctional telechelic poly(THF)s, respectively.     

Imidazolium ionic liquids as solvents for cerium(IV)-mediated oxidation reactions

Use of imidazolium ionic liquids as solvents for organic transformations with tetravalent cerium salts as oxidizing agents was evaluated. Good solubility was found for ammonium hexanitratocerate(IV) (ceric ammonium nitrate, CAN) and cerium(IV) triflate in 1-alkyl-3-methylimidazolium triflate ionic liquids. Oxidation of benzyl alcohol to benzaldehyde in 1-ethyl-3-methylimidazolium triflate was studied by in-situ FTIR spectroscopy and 13C NMR spectroscopy on carbon-13-labeled benzyl alcohol. Careful control of the reaction conditions is necessary because ammonium hexanitratocerate(IV) dissolved in an ionic liquid can transform benzyl alcohol not only into benzaldehyde but also into benzyl nitrate or benzoic acid. The selectivity of the reaction of cerium(IV) triflate with benzyl alcohol in dry ionic liquids depends on the degree of hydration of cerium(IV) triflate: anhydrous cerium(IV) triflate transforms benzyl alcohol into dibenzyl ether, whereas hydrated cerium(IV) triflate affords benzaldehyde as the main reaction product. Reactions of ammonium hexanitratocerate(IV) with organic substrates other than benzyl alcohol have been explored. 1,4-Hydroquinone is quantitatively transformed into 1,4-quinone. Anisole and naphthalene are nitrated. For the cerium-mediated oxidation reactions in ionic liquids, high reaction temperatures are an advantage because under these conditions smaller amounts of byproducts are formed.     

A highly selective Bi(OTf)3 mediated fragmentation-contraction of δ-ortholactones. A facile route to functionalized γ-lactones

A very selective method for the formation of γ-lactones from pyranyl ortholactones has been developed which occurs via a fragmentation-acetate migration-ring contraction process. The reaction is very functional group tolerant, providing functionalized γ-lactones as a single isomeric product following the ring contraction. Mechanistic studies indicate the reaction is mediated by triflic acid liberated from Bi(OTf)₃ in a slow and controlled manner providing excellent chemo and regioselectivity. We propose the triflic acid acts as both a proton and a nucleophile source with triflate anion mediating the fragmentation process.     

A kinetic and thermodynamic study of the glycosidic bond cleavage in deoxyuridine

Density functional theory was used to study the thermodynamics and kinetics for the glycosidic bond cleavage in deoxyuridine. Two reaction pathways were characterized for the unimolecular decomposition in vacuo. However, these processes are associated with large reaction barriers and highly endothermic reaction energies, which is in agreement with experiments that suggest a (water) nucleophile is required for the nonenzymatic glycosidic bond cleavage. Two (S(N)1 and S(N)2) reaction pathways were characterized for direct hydrolysis of the glycosidic bond by a single water molecule; however, both pathways also involve very large barriers. Activation of the water nucleophile via partial proton abstraction steadily decreases the barrier and leads to a more exothermic reaction energy as the proton affinity of the molecule interacting with water increases. Indeed, our data suggests that the barrier heights and reaction energies range from that for hydrolysis by water to that for hydrolysis by the hydroxyl anion, which represents the extreme of (full) water activation (deprotonation). Hydrogen bonds between small molecules (hydrogen fluoride, water, or ammonia) and the nucleobase were found to further decrease the barrier and overall reaction energy but not to the extent that the same hydrogen-bonding interactions increase the acidity of the nucleobase. Our results suggest that the nature of the nucleophile plays a more important role in reducing the barrier to glycosidic bond cleavage than the nature of the small molecule bound, and models with more than one hydrogen fluoride molecule interacting with the nucleobase provide further support for this conclusion. Our results lead to a greater fundamental understanding of the effects of the nucleophile, activation of the nucleophile, and interactions with the nucleobase for this important biological reaction.     

Nucleophilic substitution reaction of benzyl benzenesulfonates with anilines in MeOH-MeCN mixtures-I : Effects of substituent and solvent on the transition-state structure

Kinetic studies on nucleophilic substitution reaction of benzyl tosylates with anilines are reported. The reaction was found to proceed via a dissociative S_N2 mechanism with less than 50 % bond formation and extensive bond breaking at the transition state. It was found that positive charge development at the benzylic carbon is substantial and para-substituent effect on the substrate is predominantly of resonance type. Bond formation is shown to be favored by a better nucleophile, by an electron withdrawing group on the substrate and by the more polar(higher MeCN content) solvent. The substrate, nucleophile and solvent were found to follow the RSP.     

Mechanisms of nucleophilic reactions of carbonyl compounds in the gas phase and in a solution

The effect of substituents on nucleophilic addition at the C=O bond, which occurs by the mechanism of intramolecular proton transfer, has been studied by the quantum-chemical MNDO/H method. The effect of nucleophiles and substituents at the carbonyl C atom in the gas phase is opposite to that in solution. Strengthening of the bond between the nucleophile and the carbonyl compound as the result of the transfer of electron density to the carbonyl C atom results in the stabilization of the tetrahedral bipolar adduct. In the formation of an adduct with a strong nucleophile the geometry of the transition state (TS) is closer to that of the reaction product, whereas in the case of a weak nucleophile it is similar to that of the initial reagents. Attack by a weak nucleophile and electron-donating groups at the carbonyl C atom favor the situation in which the reaction system achieves a TS earlier and proton transfer occurs with a low activation barrier.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 227–230, February, 1994.     

一种多取代硝基环丙烷的开环反应研究

以一种多取代硝基环丙烷为底物,研究其在不同条件下的开环反应.以苄胺为亲核试剂时,底物发生开环生成烯胺化合物,对此反应机理进行了分析.研究了底物的还原开环反应：1）在Pd/C的催化氢化下,底物发生开环并消除硝基,得到烷基取代丙二酸二甲酯衍生物;2）在浓盐酸存在下用锌粉还原底物,得到五元环内酰胺.     

Catalytic Mechanism of the Arylsulfatase Promiscuous Enzyme from Pseudomonas Aeruginosa

To elucidate the working mechanism of the “broad substrate specificity” by the Pseudomonas aeruginosa aryl sulfatase (PAS) enzyme, we present here a full quantum chemical study performed at the density functional level. This enzyme is able to catalyze the hydrolysis of the original p‐nitrophenyl‐sulfate (PNPS) substrate and the promiscuous p‐nitrophenyl‐phosphate (PNPP) one with comparable reaction kinetics. Based on the obtained results, a multistep mechanism including activation of the nucleophile, the nucleophilic attack, and the cleavage of the S? O (P? O) bond is proposed. Regarding the phosphate monoester, the results indicate that only some steps of the promiscuous reaction are identical to those in the native process. Differences concern mainly the last step in which the His115 residue acts as a general base to accept the proton by the O atom of the FGly51 in the PNPS, whereas in PNPP, the Asp317 protonated residue works as a general acid to deliver a proton by a water molecule to the oxygen atom of the C? O bond. The shapes of the relative potential‐ energy surface (PES) are similar in the two examined cases but the rate‐determining step is different (nucleophile attack vs. nucleophile activation). The influence of the dispersion contributions on the investigated reactions was also taken into account.     

Synthesis and reactivity of enantiomerically pure N-alkyl-2-alkenyl azetidinium salts

A synthesis of stereodefined enantiomerically pure 2-alkenyl azetidines is described using Wittig olefination as key step. The quaternary triflate ammonium salts of these heterocycles were prepared in a stereoselective way and treatment of these azetidinium salts with a base (KHMDS or PhLi) induced a regioselective Stevens rearrangement leading to a 3-alkenyl pyrrolidine. An unprecedented S_N2′ reaction involving phenyllithium as nucleophile and an ammonium as leaving group was observed in one case.     

Reactions of Nucleophiles with Reactive Intermediates in the 3,4,6‐Tri‐O‐benzyl‐d‐glucal–TfOH–n‐Bu4NI Reaction System

The unique reactive intermediate formed in the 3,4,6‐tri‐O‐benzyl‐d‐glucal–TfOH (triflic acid)–n‐Bu₄NI reaction system (in dichloromethane) reacted with nucleophiles in a regio‐ and stereoselective manner. These selectivities resulted in hitherto unknown compounds, such as benzyl 4,6‐di‐O‐benzyl‐2,3‐dideoxy‐3‐iodo‐α‐glucopyranoside, which was obtained in the presence of an iodide ion as a nucleophile. The corresponding 2‐deoxy α‐glycosides were obtained exclusively in the corresponding reaction with hydroxylic nucleophiles.     

Nucleophile-assisted racemisations of halosilanes — kinetic studies

Kinetic studies have been carried out on the nucleophile-induced racemisation of PhMeCHSiMe₂X, 2, X = triflate, Br or Cl. Thirteen nucleophiles were studied. The results are interpreted in terms of two competing mechanisms for racemisation: (a) nucleophile attack on a silane-nucleophile complex formed by displacement of the halide by the nucleophile, and (b) halide-halosilane exchange, with inversion of configuration. Solvent effects were examined, and kinetic orders in the nucleophile and in one case for the halosilane were determined. The order in added nucleophile varied between one and two, with strong nucleophiles in polar media. Anomalously high orders in nucleophile were observed in non-polar media and are ascribed to aggregation of the nucleophile. A kinetic analysis of the competing mechanisms was attempted, and was consistent with the experimental findings. In this particular series of reactions involving compounds with good leaving groups and relatively powerful nucleophiles there was no evidence for intermediates involving extracoordinate silicon.     

Synthesis of methyleneaminodipeptides via ring opening of a 2-(t-butoxycarbonylmethyl)aziridine derivative

The reactivity of 2-(t-butoxycarbonylmethyl)aziridine-1-carboxylic acid benzyl ester has been studied with various N-nucleophiles. The ring-opening reaction was always regioselective, the nucleophile attacking preferentially the less hindered carbon of the aziridine. The reaction was used to prepare a methyleneamino pseudodipeptide using the α-amine of a lysine ester.     

Photochemical Reactions of Carbohydrate Triflates

Abstract

The photochemical reactions of eight carbohydrate trifluoromethanesulfonates (triflates) have been investigated in methanol in the presence of potassium iodide. For those compounds which do not contain an aromatic chromophore, photolysis results in two types of reaction. One type produces deoxy sugars by replacement of the trifluoromethylsulfonyloxy (triflyloxy) group with a hydrogen atom. The second type of reaction generates partially protected sugars by replacement of the trifluoromethylsulfonyl (triflyl) group with a hydrogen atom. When the triflate being irradiated also has a protecting group containing an aromatic ring (i.e., benzyl, benzoyl, or p-tolylsulfonyl group), removal of the protecting group is the exclusive reaction pathway.     

Experimental and theoretical approaches to the study of the reactivity and mechanism of the substitution of phenyl 1-(2,4-dinitronaphthyl) ether with anilines derivatives

Reactions of aniline derivatives in dimethyl sulfoxide with phenyl 1-(2,4-dinitronaphthyl) ether yield aryl 1-(2,4-dinitronaphthyl) amine, which results in substitution of the phenoxy groups at the naphthyl ipso carbon atom. Rate constants were measured spectrophotometrically, and reaction proton transfer was rate limiting. The values of the rate coefficients indicate a rate-limiting proton transfer mechanism with significant substituent effects. The calculated activation parameters were of regular variation with substituents in 4- and 3-position in the aniline nucleophile, and the reaction proceeded through a common mechanism. Hammett's reaction constant showed that the reaction rate constants depend on the electron density of the nitrogen atom of aniline derivative, whereas the coefficient value obtained from the Brönsted relation indicated that the reaction was significantly associative and quite zwitterion like. Computational studies of the substitution were carried out based on density functional theory, and theoretical to the experimental agreement was achieved.     

Computer simulation of the chemical catalysis of DNA polymerases: discriminating between alternative nucleotide insertion mechanisms for T7 DNA polymerase

Understanding the chemical step in the catalytic reaction of DNA polymerases is essential for elucidating the molecular basis of the fidelity of DNA replication. The present work evaluates the free energy surface for the nucleotide transfer reaction of T7 polymerase by free energy perturbation/empirical valence bond (FEP/EVB) calculations. A key aspect of the enzyme simulation is a comparison of enzymatic free energy profiles with the corresponding reference reactions in water using the same computational methodology, thereby enabling a quantitative estimate for the free energy of the nucleotide insertion reaction. The reaction is driven by the FEP/EVB methodology between valence bond structures representing the reactant, pentacovalent intermediate, and the product states. This pathway corresponds to three microscopic chemical steps, deprotonation of the attacking group, a nucleophilic attack on the P(alpha) atom of the dNTP substrate, and departure of the leaving group. Three different mechanisms for the first microscopic step, the generation of the RO(-) nucleophile from the 3'-OH hydroxyl of the primer, are examined: (i) proton transfer to the bulk solvent, (ii) proton transfer to one of the ionic oxygens of the P(alpha) phosphate group, and (iii) proton transfer to the ionized Asp654 residue. The most favorable reaction mechanism in T7 pol is predicted to involve the proton transfer to Asp654. This finding sheds light on the long standing issue of the actual role of conserved aspartates. The structural preorganization that helps to catalyze the reaction is also considered and analyzed. The overall calculated mechanism consists of three subsequent steps with a similar activation free energy of about 12 kcal/mol. The similarity of the activation barriers of the three microscopic chemical steps indicates that the T7 polymerase may select against the incorrect dNTP substrate by raising any of these barriers. The relative height of these barriers comparing right and wrong dNTP substrates should therefore be a primary focus of future computational studies of the fidelity of DNA polymerases.     

Asymmetric dearomatization of the furan ring promoted by conjugate organolithium addition to (menthyloxy)(3-furyl)carbene complexes of chromium

The sequential low-temperature addition reaction of an organolithium compound and methyl triflate to (menthyloxy)(3-furyl)carbene complexes of chromium and tungsten proceeded with excellent regioselectivity (1,4-addition) and diastereoselectivity (2,3-trans disposition of the nucleophile and electrophile groups) to afford new 2,3-disubstituted (2,3-dihydro-3-furyl)carbene complexes. In addition, a high degree of diastereofacial selectivity was achieved by employing alkenyllithium compounds. After detachment of both the metal fragment and the chiral auxiliary group, trisubstituted 2,3-dihydrofuran derivatives containing a quaternary stereogenic center at the C3 position were obtained. The characterization, including X-ray crystallography, of a novel type of stable four-membered chelate (eta(2)-alkene)tetracarbonylcarbene complex of chromium is also reported.     

Die Umsetzung protonierter Alkene mit Thioäthern: Eine neue Methode zur Darstellung von Sulfoniumverbindungen

Thioethers reacted with protonated alkenes yield quantitatively alkylsulfonium salts. The rate of the reaction is dependent on the proton activity of the medium and characterized by a maximum which is determined by the protonation of the nucleophile (thioether). The reaction is following the rule of Markownikoff.     

Reversed Electron Apportionment in Mesolytic Cleavage: The Reduction of Benzyl Halides by SmI2

The paradigm that the cleavage of the radical anion of benzyl halides occurs in such a way that the negative charge ends up on the departing halide leaving behind a benzyl radical is well rooted in chemistry. By studying the kinetics of the reaction of substituted benzylbromides and chlorides with SmI₂ in THF it was found that substrates para‐substituted with electron‐withdrawing groups (CN and CO₂Me), which are capable of forming hydrogen bonds with a proton donor and coordinating to samarium cation, react in a reversed electron apportionment mode. Namely, the halide departs as a radical. This conclusion is based on the found convex Hammett plots, element effects, proton donor effects, and the effect of tosylate (OTs) as a leaving group. The latter does not tend to tolerate radical character on the oxygen atom. In the presence of a proton donor, the tolyl derivatives were the sole product, whereas in its absence, the coupling dimer was obtained by a S_N2 reaction of the benzyl anion on the neutral substrate. The data also suggest that for the para‐CN and CO₂Me derivatives in the presence of a proton donor, the first electron transfer is coupled with the proton transfer.     

A highly regioselective reaction of N-fluoropyridinium salts with stabilized sulfur,oxygen, and nitrogen nucleophiles: A convenient route to 2-substituted pyridines

2-Substituted pyridines are efficiently obtained by the reactions of N-fluoropyridinium tetrafluoroborate or triflate with anions derived from benzenethiols, phenols, azoles, cyanamide, and with azide anion. The results are consistent with a nucleophile addition at the position 2 of the N-fluoropyridinium cation as the major reaction pathway.