O-alkylation Reaction Research Articles

Secondary N-nitrosocarbamate anions: Structure and alkylation reactions. A DFT study

The current article reports theoretical studies (DFT: B3LYP/6-31+G(d)) on the structure and alkylation reactions of the anions of some secondary N-nitrosocarbamates, a class of ambident nucleophiles whose chemistry has been little explored. Several anions ( 1– 4), with an increasing size of the carbamate alkyl (aryl) group were investigated, in an attempt to establish the influence of the size of that group on the thermal stability and regioselectivity of alkylation of the title anions. The conclusion is that thermal stability and the mode of reaction are affected significantly only in the presence of very large and branched carbamate groups. The thermal decomposition studies at the B3LYP/6-31+G(d) level of theory yield quantitative results that are in very good or excellent agreement with experimental data. A detailed study of N- vs. O-alkylation reactions was conducted, in an attempt to reveal the nature and origin of regioselectivity. Several factors seem to play prominent role: (1) charge distribution within the N-nitrosocarbamate anion; (2) exothermicity of alkylation; (3) size of electrophile and (4) size of the carbamate alkyl (aryl) group. Computational results on the alkylation reactions of N-nitrosocarbamate anions are compared to results for alkylation of the acetone enolate ion, the outcome for the latter being in sharp contrast to earlier, lower-level calculations. In addition, alkylation studies were conducted on the Z-isomers of the title anions and the results indicate that they undergo O-alkylation with significantly lower barriers compared to the E-isomers. However, Z-isomers are 5–6 kcal/mol less stable thermodynamically and application of the Curtin–Hammett principle leads to the conclusion that O-alkylation occurs almost exclusively on the E-isomers.

O-Alkylation of a lignite humic acid by phase-transfer catalysis

A mild phase-transfer catalytic reaction has been conducted to O-alkylate the acidic functions of a lignite humic acid (HA), using tetrabutylammonium hydroxide as the phase-transfer catalyst. The HA acidic functional groups were made to react, in tetrahydrofuran, by nucleophilic substitution with several alkyl halides-methyl iodide, and ethyl, propyl, and butyl, and benzyl bromide. The occurrence of the O-alkylation reaction was assessed by elemental analysis and 1H NMR, CPMAS 13C NMR, and FTIR spectroscopy. Bonding of alkyl groups increased the carbon and hydrogen content and the H/C ratios of all the humic reaction products. Increased nitrogen in the reaction products suggested incomplete removal of the phase-transfer catalyst after purification of the alkylated HA. 1H NMR and CPMAS 13C NMR spectra of alkylated products provided evidence of the successful occurrence of the alkylation reactions. Infrared spectra confirmed the NMR results, revealing the characteristic absorption of newly formed alkyl and aryl ethers and esters in the alkylated products and C-H stretching in the aromatic ring of the benzylated derivative. These findings indicate that humic matter can be successfully alkylated with several different alkylating groups by catalysed phase-transfer reaction. This O-alkylation reaction has the advantage of being mild, versatile, and high-yielding compared with traditional methylation reactions applied to HA. The possibility of introducing different alkyl groups into the HA by a mild phase-transfer reaction may become useful by enabling improved fractionation of humic supramolecular associations and further understanding of the molecular nature of humic substances.

Regioselectivity in the Addition of Vinylmagnesium Bromide to Heteroarylic Ketones: C‐versus O‐Alkylation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Microwave‐Assisted O‐Alkylation of Carboxylic Acids in Dry Media: Expeditious Synthesis of 2‐Oxo‐2‐arylethyl Carboxylates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Analysis of Phase-Transfer-Catalyzed O-Alkylation Reaction Using Fractional Factorial Design Method

ABSTRACT The reactions of alcohols and alkyl halides to synthesize di-ether compounds under phase-transfer catalysis conditions were carried out in an alkaline solution/organic solvent two-phase medium. Accordingly, the concentrations of alkyl halide, di-ether compound, active intermediate (QOR), and hydration number of active intermediate (QOR) were measured during these reactions. The fractional factorial design (FFD) method was first employed to study the effects of single factors and the effects of their interactions on the PTC reaction. The following reaction conditions (or factors) were investigated in the present FFD analysis: amount of alkaline salt, temperature, amount of water, amount of catalyst, volume of organic solvent, and agitation speed. A polynomial model and an analysis of variance table (ANOVA) were developed to connect the reaction conditions and the conversion from statistical results. Plots of the partition coefficient of alcohol between organic and aqueous phase, the concentration of active intermediate (QOR), and the hydration number of active intermediate (QOR) were used to elucidate the reasons for interactions between factors.

Synthesis of Bicyclo[4.n.1]alkanones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of cyclobutanones and four-membered enol ethers by using a rearrangement reaction of enol triflates

A new synthetic method of cyclobutanone derivatives and four-membered enol ethers via an intramolecular cyclization of a ketone enolate was developed. The cyclization precursors, enol triflates having a silyloxy group at the β′-position, were synthesized from the corresponding β-hydroxy ketones, which were prepared via an aldol reaction of a cycloalkanone and an aldehyde. Under the influence of TBAF, the enol triflates afforded a cyclobutanone or a four-membered enol ether through rearrangement of the trifluoromethanesulfonyl group followed by an intramolecular C- or O-alkylation reaction.

Regioselectivity in the Addition of Vinylmagnesium Bromide to Heteroarylic Ketones: C- versusO-Alkylation

The reactivity of heteroarylic ketones toward vinylmagnesium bromide (2) and the regiochemistry of the addition were investigated. The reactivity drastically increases when the carbonyl is conjugated with at least one aza group and the regiochemistry of the addition of the vinyl Grignard reagent depends on the carbonyl compound: in the series of di(heteroazolyl) ketones the O-alkylation product was observed as unique with di(1,3-benzothiazol-2-yl) ketone, and in different relative ratios with respect to the classic C-alkylation product with di(1,3-thiazol-2-yl) ketone, (1,3-benzothiazol-2-yl) (1,3-thiazol-2-yl) ketone, and di(1,3-benzoxazol-2-yl) ketone, whereas di(N-methylbenzimidazol-2-yl) ketone gave the exclusive formation of the carbinol. This behavior can be explained by the intervention of the delocalization power of the heterocyclic ring and this was confirmed by the results obtained from the reaction between vinylmagnesium bromide and a series of mixed (1,3-benzothiazol-2-yl) (para-substituted phenyl) ketones, that showed a relative O-/C-alkylation ratio dependent on the nature and on the electronic effect of the substituent on the phenyl ring. The results are in agreement with the existence of intermediate species bearing a negative charge on the benzylic carbonyl carbon atom, and make the O-alkylation reaction between vinyl Grignard reagents and carbonyl compounds no longer a rare case, since it was observed with a number of heterocyclic carbonyl compounds, such as (1,3-benzothiazol-2-yl) aryl ketones and di(heteroaryl) ketones of the pentatomic 1,3-heteroazolic series.

Synthesis of bicyclo[4.n.1]alkanones.

Cyclic beta-keto ester monoanions react with 1,4-dihalobutenes to give C-alkylated products which subsequently undergo a stereoselective SN2' O-alkylation reaction to yield functionalized enol ethers. When the starting material was ethyl cyclopentanone carboxylate, the C-alkylated product, treated with a base, directly afforded the functionalized bicyclo[4.2.1]nonanone. The enol ethers were submitted to a flash vacuum thermolysis (FVT) reaction to readily afford functionalized bicyclo[4.n.1]alkanones (n = 3, 4). This reaction sequence was applied to the synthesis of a functionalized tricyclo[7.4.1.0(1,5)]tetradecanone, which represents an analogue to the tricyclic core of ingenol.

Development of an Efficient and Straightforward Methodology Toward the Synthesis of Molecularly Diverse 2,6‐Disubstituted 3,4‐Dihydropyrimidin‐4(3H)‐ones.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Development of an Efficient and Straightforward Methodology Toward the Synthesis of Molecularly Diverse 2,6-Disubstituted 3,4-Dihydropyrimidin-4(3H)-ones

A simple and efficient methodology toward the synthesis of highly molecularly diverse 2,6-disubstituted 3,4-dihydropyrimidin-4(3H)-ones of type 3 has been developed. The methodology is based on a selective O-alkylation reaction with i-PrOH under Mitsunobu conditions followed by a nucleophilic heteroaromatic ipso-substitution of sulfones 20 and subsequent acidic hydrolysis of the isopropoxy group.

Selective O-Alkylation Reaction of Hydroquinone with Methanol over Cs Ion-Exchanged Zeolites

O-alkylation reaction of hydroquinone with excess methanol was performed by using alkali metal ion-exchanged zeolite catalysts in a slurry type reactor to substitute the solid zeolite catalysts for the homogeneous liquid phase catalysts. This was also done to produce selectively mono-alkylated 4-methoxyphenol, a valuable intermediate for the perfume, flavor, food and photo industries. The effects of the basicity of various zeolites and reaction conditions such as temperature, reaction time and the amount of catalyst on the catalytic activity and selectivity were tested to maximize the yield of 4-methoxyphenol. Thus far, 84% selectivity at 95% conversion of hydroquinone was obtained at the optimum reaction conditions (240 ‡C, reaction with 0.6 g catalyst for 16 h), which was thought to result from the strong basic property and shape selectivity of the Cs ion-exchanged NaX zeolite.

Domino Michael–O-alkylation reaction: one-pot synthesis of 2,4-diacylhydrofuran derivatives and its application to antitumor naphthofuran synthesis

The reaction of enolates of 1,3-dicarbonyl compounds with α-halo-α,β-unsaturated carbonyl compounds affords 2,4-diacyldihydrofuran derivatives in the presence of DBU in THF. Chemical manganese dioxide oxidation of the hydrofurans leads to 2,4-diacylfuran derivatives. Application of the protocol enables short-step syntheses of antitumor naphthofuran natural products.

Effect of Etherifying Species on O-Alkylation of Phenethyl Alcohol to Perfumery Alkyl Ethers

The ethers like phenethyl methyl ether (PEME), phenethyl ethyl ether (PEEE), phenethyl isopropyl ether (PEIPE) and phenethyl isoamyl ether (PEIAE) are major components in the perfume and flavour industries. The O-alkylation reaction of phenethyl alcohol (PEA) with alkanols like methanol, ethanol, isopropanol, isoamyl alcohol, in the presence of Dodecatungstophospheric acid, a heteropoly acid supported on K-10 (montmorillonite) catalyst, to the selective formation of PEME, PEEE, PEIPE, PEIAE, respectively, were studied. The initial rate of reaction of phenethyl alcohol with different alkanols was found to be independent of the concentration of the alkanol for an initial phenethyl alcohol concentration of 1.465 × 10−3 gmol cm−3. The reaction up to 90 minutes on stream, was also independent of the concentration of alkanols, despite the fact that different initial concentrations of alkanols were chosen. It is interesting to note that, the Arrhenius plots of ln(rate) versus l / T for all alkanols are represented by a single line with slope which is almost equal, to give activation energy values of 6.1, 6.6, 6.1 and 6.1kcalgmol−1 for methanol, ethanol, isopropanol and isoamyl alcohol, respectively. According to the Eiley–Rideal type of mechanism, the rate of phenethyl alcohol reaction is controlled by its chemisorption on the active sites in the absence of any intraparticle resistances.

Synthesis of Calix[4]arene Derivatives with Alkyl Guanidinium or Chiral Bicyclic Guanidinium

A series of p-tetra-tert-butyl calix[4]arene derivatives with alkyl guanidinium or chiral bicyclic guanidinium functionalities were synthesized as the receptors of organic anions. Mono- and di-alkyl guanidinium derivatives were prepared by the reaction of 5,11,17,23-tetra-tert-butyl-25,27-(2-aminoethoxy)-26,28-dihydroxy calix[4]arene (1) with methyl isothiourea sulphate. While mono- and di-chiral bicyclic guanidinium derivatives were all obtained via an O-alkylation reaction of p-tetra-tert-butyl calix[4]arene with chloromethyl chiral bicyclic guanidinium (6 or 7) in the presence of anhydrous K2CO3 in acetonitrile, good yields were only observed for mono-substituted derivatives.

Intracrystalline alkylation of benzoate ions into layered double hydroxides

Several layered double hydroxides (LDHs) containing metals of different nature intercalated with benzoate anions have been synthesised in order to study the O-alkylation reaction of the interlayered species with alkyl halide in dry media conditions. In all the cases, the expected ester was obtained with good yield (>60%). The presence of anionic benzoate in the structure was prefered to obtain high selectivity and yield, in comparison with the use of sodium benzoate supported as a salt. The use of MW irradiation to promote these reactions has permitted the reaction time to be reduced considerably. The influence of water present in the LDH on the ester formation has also been investigated. Characterisation of the LDH support before and after reaction is also presented, showing the influence of the nature of the cations located in the octahedral sheets. The support can be regenerated, with no effect on the reactivity.

N- vs O-alkylation in 2(1H)-quinolinone derivatives

N- vs O-alkylation reactions of 8-benzyloxy-2(1H)-quinolinone have been investigated using both classical and phase transfer conditions. The influence of reaction solvents/conditions was found to have a dramatic effect on selectivity, with opposite trends to that observed for 2-pyridone alkylation.

Competition between C- and O-Alkylation Reactions in 5-Nitroimidazole Series: Influence of Nucleophile

Competition between C- and O-Alkylation Reactions in 5-Nitroimidazole Series: Influence of Nucleophile

An accelerated, improved synthetic route for the preparation of polyether-based dendritic fragments

An accelerated, improved synthetic strategy for the rapid construction of two different series of polyether-based dendritic fragments is described. Several modifications to the original method for the preparation of these dendritic fragements are detailed. A new branching agent, 5-(3-hydroxypropyloxy)-1,3-resorcinol 4, instead of 5-benzyloxy-1,3-resorcinol 2, is employed in this new synthetic protocol. As a result, the number of synthetic operations in each of the iterative cycle is reduced from three to two, as compared to the original procedure. Each iterative synthetic cycle involves two reactions: a bis- O-alkylation reaction of the brancher 4 with a dendritic bromide [Gn]-O(CH 2) 3Br to give a dendritic alcohol of the next generation [G(n+1)]-O(CH 2) 3OH; followed by a functional group conversion of the dendritic alcohol into the corresponding dendritic bromide [G(n+1)]-O(CH 2) 3Br of the same generation. The reaction yields of each iterative cycle are consistently higher than those of the previously reported three step cycle. Using this new protcol, the preparation of a 5th generation dendritic alcohol 15a could be realized in 10 steps and 23% overall yields from 1,3-dibromopropane.

O-alkylation of phenol derivatives over basic zeolites

Alkali metal loaded zeolite X was used to catalyze O-alkylation of phenol derivatives in the presence of excess methanol. The reactivity of zeolite in the O-alkylation increased as the basicity of ion-exchanged metals increased. The super base originated from cesium oxide particles in zeolite cavities was as equally active as the ion-exchanged cesium cation. Hence the reactivity of the Cs loaded zeolite was found to be proportional to the total amount of cesium in zeolites. In addition to mono and dialkylphenols, the phenol derivatives with hydroxy, amino, nitro and chloride group were also used as reactants to investigate the effect of acidity of reactants on the reaction. The conversion increased as the acidity of hydroxy group of reactant increased. But the strong acidity resulted in rapid deactivation of the catalyst. Except for aminophenol the reaction products were the corresponding O-alkylated products regardless of functional groups attached and for aminophenol, N-alkylated product was produced due to the strong acidity of the amino group. The high selectivity to O-alkylation reaction over base catalyst was not a function of the conversion and thought to have resulted from the suppression of the side reactions such as C-alkylation of phenol and anisole which occurred predominantly on the acidic sites.