The Role of Hydrogen Bonds in Baeyer−Villiger Reactions

Various Baeyer−Villiger (B−V) oxidation reactions were examined by density functional theory calculations. Proton movements in transition states (TSs) of the two key steps, the nucleophilic addition of a peroxyacid molecule to a ketone (TS1) and the migration−cleavage of O−O (TS3), were discussed. A new TS of a hydrogen-bond rearrangement in the Criegee intermediate (TS2) was found. The hydrogen-bond directionality requires a trimer of the peroxyacid molecules at the nucleophilic addition of a peroxyacid molecule to a ketone TS (TS1). At the migration−cleavage of O−O TS (TS3), also three peroxyacid molecules are needed. Elementary processes of the B−V reaction were determined by the use of the (acetone and (H−CO−OOH)n, n = 3) system. The geometries of the nucleophilic addition of a peroxyacid molecule to a ketone TS (TS1) and the migration−cleavage of O−O TS (TS3) in the trimer (n = 3) participating are nearly insensitive to the substituent on the peroxyacid. The directionality is satisfied in those geometries. The migration−cleavage of O−O TS (TS3) was found to be rate-determining in reactions, [Me2CO + (H−CO−OOH)3], [Me2CO + (F3C−CO−OOH)3], and [Me2CO + (MCPBA)3]. In contrast, the nucleophilic addition of a peroxyacid molecule to a ketone (TS1) is rate-determining in the reaction, [Ph(Me)CO + (H−CO−OOH)3]

A Computational Study on Addition of Grignard Reagents to Carbonyl Compounds

The mechanism of stereoselective addition of Grignard reagents to carbonyl compounds has been investigated using B3LYP density functional theory calculations. The study of the reaction of methylmagnesium chloride and formaldehyde in dimethyl ether revealed a new reaction path involving carbonyl compound coordination to magnesium atoms in a dimeric Grignard reagent. The structure of the transition state for the addition step shows that an interaction between a vicinal-magnesium bonding alkyl group and CO causes the C−C bond formation. The simplified mechanism shown by this model is in accord with the aggregation nature of Grignard reagents and their high reactivities toward carbonyl compounds. Concerted and four-centered formation of strong O−Mg and C−C bonds was suggested as a polar mechanism. When the alkyl group is bulky, C−C bond formation is blocked and the Mg−O bond formation takes precedence. A diradical is formed with the odd spins localized on the alkyl group and carbonyl moiety. Diradical formation and its recombination were suggested to be a single electron transfer (SET) process. The criteria for the concerted polar and stepwise SET processes were discussed in terms of precursor geometries and relative energies

Catalytic Enantioselective Friedel−Crafts/Michael Addition Reactions of Indoles to Ethenetricarboxylates

The Friedel−Crafts reaction is an important reaction for the formation of new C−C bonds. Recently, catalytic enantioselective Friedel−Crafts reaction of alkylidene malonates has been reported. However, the substituents in alkylidene malonates are limited. To explore new substituents such as carboxyl and carbonyl groups, catalytic enantioselective Friedel−Crafts reactions of reactive ethenetricarboxylates and acyl-substituted methylenemalonates 1 were investigated. The reaction of 1 with indoles in the presence of catalytic amounts of chiral bisoxazoline copper(II) complex (10%) in THF at room temperature gave alkylated products in high yields and up to 95% ee. The enantioselectivity can be explained by the secondary orbital interaction on approach of indole to the less hindered side of the 1−Cu(II)−ligand complex

Catalytic Enantioselective Friedel−Crafts/Michael Addition Reactions of Indoles to Ethenetricarboxylates

The Friedel−Crafts reaction is an important reaction for the formation of new C−C bonds. Recently, catalytic enantioselective Friedel−Crafts reaction of alkylidene malonates has been reported. However, the substituents in alkylidene malonates are limited. To explore new substituents such as carboxyl and carbonyl groups, catalytic enantioselective Friedel−Crafts reactions of reactive ethenetricarboxylates and acyl-substituted methylenemalonates 1 were investigated. The reaction of 1 with indoles in the presence of catalytic amounts of chiral bisoxazoline copper(II) complex (10%) in THF at room temperature gave alkylated products in high yields and up to 95% ee. The enantioselectivity can be explained by the secondary orbital interaction on approach of indole to the less hindered side of the 1−Cu(II)−ligand complex

TiCl₄-Promoted Cyclization Reactions of Aminoacetals and Ethenetricarboxylates Leading to Nitrogen-Containing Heterocycles

Lewis acid-catalyzed cyclization of aminoacetals 2 and triethyl ethenetricarboxylate (1a) has been examined. The reaction of 3-aminopropionaldehyde diethyl acetal (2a) and 1a in the presence of 1 equiv of TiCl4 at room temperature gave 4-ethoxypiperidine-2,3,3-tricarboxylate 3a in 92% yield with a 2,4-diastereomer ratio of 1:1. The reaction in the presence of 3 equiv of TiCl4 gave 2,4-trans-piperidine derivative 3a in 86% yield predominantly. The reaction of aminoacetaldehyde diethyl/dimethyl acetals 2c,d and 1a with 3 equiv of TiCl4 gave 2,4-trans-4-pyrrolidine-2,3,3-tricarboxylates 5a,b predominantly

TiCl₄-Promoted Cyclization Reactions of Aminoacetals and Ethenetricarboxylates Leading to Nitrogen-Containing Heterocycles

Lewis acid-catalyzed cyclization of aminoacetals 2 and triethyl ethenetricarboxylate (1a) has been examined. The reaction of 3-aminopropionaldehyde diethyl acetal (2a) and 1a in the presence of 1 equiv of TiCl4 at room temperature gave 4-ethoxypiperidine-2,3,3-tricarboxylate 3a in 92% yield with a 2,4-diastereomer ratio of 1:1. The reaction in the presence of 3 equiv of TiCl4 gave 2,4-trans-piperidine derivative 3a in 86% yield predominantly. The reaction of aminoacetaldehyde diethyl/dimethyl acetals 2c,d and 1a with 3 equiv of TiCl4 gave 2,4-trans-4-pyrrolidine-2,3,3-tricarboxylates 5a,b predominantly

Zn(OTf)₂-Catalyzed Reactions of Ethenetricarboxylates with 2-Aminobenzaldehydes Leading to Tetrahydroquinoline Derivatives

Quinolines are an important class of compounds, and the development of new efficient synthetic strategies for the construction of quinolines is of considerable interest. Zinc triflate catalyzed cyclization of ethenetricarboxylate derivatives with 2-aminobenzaldehydes has been examined. The reaction of ethenetricarboxylate with 2-aminobenzaldehydes in the presence of zinc triflate (0.2 equiv) at 80 °C in ClCH2CH2Cl gave bridged tetrahydroquinoline derivatives in 15−95% yield. On the other hand, the reaction at room temperature in CH2Cl2 gave hydroxy tetrahydroquinoline derivatives in 38−90% yield. Heating the hydroxy tetrahydroquinolines with zinc triflate (0.2 equiv) at 80 °C in ClCH2CH2Cl led to the bridged tetrahydroquinoline derivatives in 75−96% yield. Thermal reaction of the bridged tetrahydroquinolines (180 °C) gave indole derivatives regioselectively

How Is the Oxidation Related to the Tautomerization in Vitamin B9?

The relationship between the lactim–lactam tautomerization and the free-radical scavenging reaction in vitamin B9 [folic acid (FA)] was investigated by density functional theory calculations. 6-Methylpterin was also adopted for the detailed analyses of various reaction paths. For pterin, the transition state of the tautomerization with two water molecules (n = 2) was calculated to be of the lowest activation energy. The proton-transfer circuit of n = 2 is retained (not broken) even with the addition of outer water molecules, n = 2 + 2, 2 + 4, 2 + 8, and 2 + 14. At the oxidation of the system composed of 6-methylpterin + (H2O)2 + HO•, the radical character of HO• is directly transmitted to the pterin ring along with the C–O → H → O → H → O → H → OH proton transfer. The patterns of the electron transfer (pterin ring → OX•) and the concomitant proton transfer via the water dimer were commonly obtained for the oxidant (OX•) = HO•, Cl3C–O2•, N3•, or SO4–•. The hydrogen atom transfer mechanism was ruled out. Two conformations of the puckered form with the −C­(O)–OH···N intramolecular hydrogen bonds of FA were found to have the stability similar to that of the linear conformer. Both the tautomerization and the oxidation were calculated to occur competitively in the three conformers

A FMO-Controlled Reaction Path in the Benzil−Benzilic Acid Rearrangement

Reaction paths for the title rearrangement along with its methyl analogue were investigated by density functional theory calculations. The reaction model is R−CO−CO−R + OH-(H2O)4 → R2C(OH)−COO- + (H2O)4 (R = Me and Ph), where the water tetramer is employed both for solvation to OH- and for the proton relay along hydrogen bonds. The reaction is composed of OH- addition, C−C rotation, carbanion [1,2] migration, and proton relay toward the product anions. The rate-determining step was calculated to be the carbanion migration. Apparently, carbanion [1,2] migration is unlikely relative to the carbonium ion one. However, LUMOs of the 1,2-diketones have large and nodeless lobes at the reaction center, the C(1)−C(2) bond. The specific LUMO character is reflected both in the [2+1]-like one-center nucleophilic addition and in the carbanion [1,2] shift. The proton relay involved in the isomerization from the oxo intermediate to the carboxylate was calculated to take place via the water tetramer

Chiral Synthesis of Cyclopropanes. Stereoselective [2 + 1] Cycloaddition Reactions of 1-Seleno-2-silylethenes with Di-(−)-menthyl Ethene-1,1-dicarboxylates

Reaction of 1-seleno-2-silylethenes 1 with the chiral electrophiles 2, 3, and 4 derived from (−)-menthol, in the presence of zinc halides gave the cyclopropane products 5, 6, and 7, respectively, with high diastereoselectivity. The absolute configuration of 5a, prepared by the reaction of 1-(phenylseleno)-2-(trimethylsilyl)ethene (1a) and di-(−)-menthyl methylenemalonate (2), was determined to be 2S by conversion to the known chiral compound 11. The proposed mechanism, involving fixation of the (−)-menthyl group to the CC plane by the Lewis acid in the addition step, is consistent with the experimental observations. A selenium-participating secondary orbital interaction in the synclinal addition path was elucidated by ab initio calculations and explained the observed diasteroselectivity