Influence of hydrogen bonding in the activation of nucleophiles: PhSH-(catalytic) KF in N-methyl-2-pyrrolidone as an efficient protocol for selective cleavage of alkyl/aryl esters and aryl alkyl ethers under nonhydrolytic and neutral conditions

The nucleophilicity of arenethiols can be augmented via hydrogen bonding with "naked" halide anion. The activity of the halide anions follow the order F(-) > Cl(-) approximately Br(-) approximately I(-) and is dependent on the countercation (Bu(4)N approximately Cs approximately K > Na > Li). The solvent plays an important role in nucleophilic activation as well as regeneration of the effective nucleophile (e.g. ArS(-)) and those with high dielectric constant, high molecular polarizability, high donor number (DN), and low acceptor number (AN) are the most effective. Selective deprotection of alkyl/aryl esters and aryl alkyl ethers can be achieved under nonhydrolytic and neutral conditions by the treatment with thiophenol in 1-methyl-2-pyrrolidone (NMP) in the presence of a catalytic amount of KF. Aryl esters are selectively deprotected in the presence of alkyl esters and alkyl methyl ethers during intramolecular competitions.     

Demand-based thiolate anion generation under virtually neutral conditions: influence of steric and electronic factors on chemo- and regioselective cleavage of aryl alkyl ethers

Thiolate anions have been generated in a "demand-based" fashion under virtually neutral conditions for chemoselective deprotection of aryl alkyl ethers. Solvents play the critical role in making the reaction effective and should have high values of epsilon (>30), molecular polarizabilities (>10), and DN (>27) and low values of AN (<14). However, it is the combined effect of all of these physical properties that make a particular solvent effective. The reaction rates of cleavage of various aryl alkyl ethers are dependent on the steric crowding around the O-alkyl carbon and follow the order propargyl approximately allyl approximately benzyl > methyl > ethyl. Electron-withdrawing substituents increase the rate of ether cleavage reaction. The influence of the steric and electronic factors have been successfully exploited for selective deprotection of aryl alkyl ethers during inter- and intramolecular competitions.     

Tertiary-butoxycarbonyl (Boc) – A strategic group for N-protection/deprotection in the synthesis of various natural/unnatural N-unprotected aminoacid cyanomethyl esters

A number of cyanomethyl esters of natural/unnatural aminoacids with un-protected amino functionality were synthesized because of their synthetic and medicinal importance. Critical N-Boc deprotection methods in the presence of labile (hydrolytic sensitivity) cyanomethyl functionality were screened thoroughly and it was found that readily available 4M HCl in 1,4-dioxane solution (2–4 equiv); acetonitrile, 0?°C, 2–4?h was a suitable condition. This condition was generalized and successfully applied to a variety of alkyl, alkynyl, aryl, heteroaryl, benzyl, azido, spiro amino acid cyanomethylesters irrespective of the nature of the amine (primary or secondary) and the distance between the amine and ester group to achieve final deprotected amino esters with high yield, and purity compared to other commonly known N-protecting groups (Cbz, Fmoc, Ac, Bn, Bz etc.). It was also demonstrated that N-Boc protected aminoacid cyanomethylesters are stable enough to carry out further functionalization compared to N-unprotected counterparts.     

Novel C-C bond cleavage under mild, neutral conditions: conversion of electron-deficient aryl alkyl ketones to aryl carboxylic esters

A novel, unique way to cleave the carbon-carbon bond in aryl alkyl ketones under mild, neutral conditions is described. Treatment of aryl alkyl ketones in a refluxing mixture of N,N-dimethylformamide dimethyl acetal and methanol for 16 h provided aryl carboxylic esters. The scope and limitations of the reaction are discussed. Useful yields of the reaction can be obtained with electron-deficient aryl groups, and the yields are higher when the alkyl group is larger than a methyl group. Studies toward elucidation of the reaction mechanism led to a proposed mechanism that is consistent with all the observations.     

An efficient FeCl3‐promoted O‐alkyl cleavage of esters to carboxylic acids

A reliable and practical procedure for FeCl₃‐promoted ester cleavage has been developed. Lewis acids including TiCl₄, ZnO and FeCl₃ etc. were investigated as promoters for O‐alkyl cleavage of carboxylic acid ester. Under optimal reaction conditions, FeCl₃ (1.5 equiv.) was found to possess the highest activity and efficiently enhanced dealkylation of aryl esters, alkyl esters and aromatic heterocyclic esters to give their corresponding carboxylic acids in 54–98% yield, the method provides a complementary access to dealkylation of ester under neutral condition. Copyright © 2011 John Wiley & Sons, Ltd.     

Transition state differences in hydrolysis reactions of alkyl versus aryl phosphate monoester monoanions

Although aryl phosphates have been the subject of numerous experimental studies, far less data bearing on the mechanism and transition states for alkyl phosphate reactions have been presented. Except for esters with very good leaving groups such as 2,4-dinitrophenol, the monoanion of phosphate esters is more reactive than the dianion. Several mechanisms have been proposed for the hydrolysis of the monoanion species. (18)O kinetic isotope effects in the nonbridging oxygen atoms and in the P-O(R) ester bond, and solvent deuterium isotope effects, have been measured for the hydrolysis of m-nitrobenzyl phosphate. The results rule out a proposed mechanism in which the phosphoryl group deprotonates water and then undergoes attack by hydroxide. The results are most consistent with a preequilibrium proton transfer from the phosphoryl group to the ester oxygen atom, followed by rate-limiting P-O bond fission, as originally proposed by Kirby and co-workers in 1967. The transition state for m-nitrobenzyl phosphate (leaving group pK(a) 14.9) exhibits much less P-O bond fission than the reaction of the more labile p-nitrophenyl phosphate (leaving group pK(a) = 7.14). This seemingly anti-Hammond behavior results from weakening of the P-O(R) ester bond resulting from protonation, an effect which calculations have shown is much more pronounced for aryl phosphates than for alkyl ones.     

dM-Dim for carboxylic acid protection

The 1,3-dithian-2-yl-methyl (Dim) and its analogous groups including dimethyl-Dim (dM-Dim) can provide a new dimension of orthogonality for carboxylic acid protection. They can be deprotected under nearly neutral oxidative conditions. In this paper, the protection of carboxylic acid with dM-Dim, deprotection of dM-Dim ester with sodium periodate, stability of dM-Dim protected carboxylic acid under acidic and basic conditions, and selective deprotection of dM-Dim protected carboxylic acids in the presence of tertiary butyl and methyl esters are presented.     

Efficient halogen-lithium exchange reactions to functionalize poly(alkyl aryl ether) dendrimers

Poly(alkyl aryl ether) dendrimers were functionalized with bromophenyl groups at their peripheries, so as to have 3, 6, 12, and 24 groups in the zero, first, second, and third generation dendrimers, respectively. The new bromophenyl functionalized dendrimers were assessed for their reactivities in C-heteroatom and C-C bond forming reactions. For this purpose, the bromophenyl functionalized dendrimers were converted quantitatively to their polylithiated derivatives, using n-BuLi in benzene. The polylithiated dendrimers were reacted either with D₂O or with CO₂, so as to afford the corresponding deuterated and carboxylic acid functionalized dendrimers, respectively. The carboxylic acid functionalized dendrimers were modified further to the methyl esters during their characterization.     

Synthesis of poly(alkyl aryl ether) dendrimers

Poly(alkyl aryl ether) dendrimers of up to four generations composed of a phloroglucinol core, branching components, and pentamethylene spacers are synthesized by a divergent growth methodology. A repetitive synthetic sequence of phenolic O-alkylation and O-benzyl deprotection reactions are adopted for the synthesis of these dendrimers. The peripheries of the dendrimers contain 6, 12, 24, and 48 phenolic hydroxyl groups, either in the protected or unprotected form, for the first, second, third, and fourth generations, respectively. Because of the presence of hydrophilic exterior and relatively hydrophobic interior regions, alkaline aqueous solutions of these dendrimers are able to solubilize an otherwise insoluble pyrene molecule and these supramolecular complexes precipitate upon neutralization of the aqueous solutions.     

Carbonylation of aryl chlorides with oxygen nucleophiles at atmospheric pressure. Preparation of phenyl esters as acyl transfer agents and the direct preparation of alkyl esters and carboxylic acids

A mild, functional group tolerant method of the preparation of phenyl esters from aryl chlorides via palladium-catalyzed carbonylation is described using atmospheric pressure of carbon monoxide. Phenyl esters are shown to be useful acylating agents, delivering libraries of carbonyl derivatives, including alkyl, allyl and thioesters, under very mild conditions. Direct preparation of alkyl esters and carboxylic acids is also demonstrated, providing the first method for the preparation of methyl and ethyl esters from aryl chlorides without pressured reactors.     

Synthesis of alkyl or aryl pyridazinyl ethers

This paper presents the synthesis of some alkyl or aryl pyridazinyl ethers from 2‐alkyl‐4‐halo‐5‐hydroxy‐and 2‐alkyl‐4,5‐dichloropyridazin‐3(2H)‐ones or 3,6‐dichloropyridazine. Reaction of 2‐alkyl‐4‐halo‐5‐hydroxypyridazin‐3(2H)‐ones 1 with 1,2‐dibromoethane or 1,3‐dibromopropane gave the corresponding monopyridazin‐5‐yl ethers 2 and α,ω‐[di(pyridazin‐5‐oxy)]alkanes 3 . Treatment of 4 with 4‐substituted‐phenol afforded 5‐(4‐substituted‐phenoxy)‐2‐(4‐substituted‐phenoxymethyl) derivatives 5 . Reaction of 2‐alkyl‐4,5‐dichloro derivatives 7 with 1 gave the corresponding di(pyridazin‐5‐yl) ethers 8 in good yields. Compound 10 was reacted with catechol to give monopyridazin‐3‐yl ether 11 and/or di(pyridazin‐3‐yl) ether 12 . Also we described the results for the reaction of 2‐alkyl‐4‐chloro‐5‐(4‐substituted‐phenoxy)pyridazin‐3(2H)‐ones with nucleophiles.     

Conformational analysis of alkyl aryl ethers and alkyl aryl sulphides by photoelectron spectroscopy

Photoelectron spectroscopy shows that in t-butoxybenzenes, but not in methoxy-, ethoxy- or isopropoxybenzenes, there is a loss of p-π orbital overlap. A similar effect is observed in 2,6-dimethylalkoxybenzenes. In alkyl aryl sulphides two conformers predominate, the one with maximum p-π overlap and the other with reduced overlap. The importance of the less conjugated conformer increases monotonously through the series hydrogen, methyl, ethyl, isopropyl and t-butyl in alkyl phenyl sulphides.     

Iodoarene-mediated one-pot preparation of 2,5-disubstituted and 2,4,5-trisubstituted oxazoles from alkyl aryl ketones with oxone in nitriles

The reaction of alkyl aryl ketones with Oxone^® and trifluoromethanesulfonic acid in the presence of iodoarene in acetonitrile, propionitrile, butyronitrile, and isobutyronitrile, provided directly the corresponding 2,5-disubstituted and 2,4,5-trisubstituted oxazoles, respectively, in moderate yields. Here, reactive aryliodonium I(III) species is formed in situ by the reaction of iodoarene with Oxone^® and trifluoromethanesulfonic acid, and the formed aryliodonium I(III) species reacts with alkyl aryl ketone to generate β-keto iodonium species. Then, β-keto iodonium species reacts with nitrile to produce the corresponding oxazole. In principle, iodoarene works as a catalyst. However, 1 equiv of iodoarene is required because 1 equiv of reactive aryliodonium I(III) species must be formed before the reaction with alkyl aryl ketone.     

LAH aryl alkyl ether cleavage of BINOL derivatives

Herein we report the cleaving of aryl alkyl ethers on BINOL derivatives, using the common reducing agent LAH. The cleavage of the alkyl oxygen bond is observed when the BINOL derivative is treated with LAH, in refluxing dioxane, for 60 h. The resulting BINOL derivative can then be re-alkylated using a standard Williamson ether synthesis. The same procedure was tested on 6-hydroxy-2-naphthoic acid derivatives and cleavage was not observed, thus suggesting a chelating mechanism for the BINOL ether cleavage.     

Practical one-pot preparation of ketones from aryl and alkyl bromides with aldehydes and DIH via Grignard reagents

Various diaryl ketones, alkyl aryl ketones, and dialkyl ketones were efficiently prepared in good yields by the reactions of the Grignard reagents derived from aryl or alkyl bromides, followed by the reactions with aromatic or aliphatic aldehydes and the subsequent treatment with 1,3-diiodo-5,5-dimethylhydantoin and K₂CO₃, in a one-pot method. The same treatment of aromatic bromides bearing electron-withdrawing groups, such as ester, nitrile, ketone, and nitro groups with i-PrMgCl·LiCl or PhMgCl instead of Mg, also provided the corresponding diaryl and alkyl aryl ketones in good yields. The above methods are simple and practical transition-metal-free methods for the preparation of various diaryl ketones and alkyl aryl ketones bearing electron-rich aromatic groups and electron-deficient aromatic groups, as well as dialkyl ketones.     

A facile method for the stereoselective Horner-Wadsworth-Emmons reaction of aryl alkyl ketones

Excellent Z or E selectivity was observed in the Horner-Wadsworth-Emmons (HWE) reactions of methyl bis(2,2,2-trifluoroethyl)phosphonoacetate or ethyl 2-fluoro-2-diethylphosphonoacetate with aryl alkyl ketones bearing substituents on an aromatic moiety employing Sn(OSO2CF3)2 in the presence of N-ethylpiperidine.     

Derivatization of prostaglandins and related compounds to (methoxime) alkyl ester alkyl ether derivatives for gas chromatographic analysis

Rapid and convenient methods are described for the exhaustive derivatization of carbonyl, carboxyl and hydroxyl groups of prostaglandins and related compounds to methoxime, alkyl ester and alkyl ether compounds respectively. Optimal reaction conditions were established for each group. The reactions were carried out in polar aprotic solvents. Alkyl ester alkyl ether derivatives were obtained quantitatively and rapidly in one step with n-alkyl (C1-C4) halides in the presence of sodium hydroxide. Methyl ester methyl ether derivatives have the highest volatility, but propyl ester propyl ether derivatives improved the separation of complex mixtures. The carbonyl group sometimes induced side-products, so the carbonyl group was converted into methoxime. Methoximation was achieved quantitatively by using methoxylamine in the presence of hydrochloric acid or sodium hydroxide, followed by alkylation in same reaction medium. Methoximation gave syn- and anti-isomers, which were separated chromatographically, decreasing the resolution for complex samples.     

alpha,beta-Unsaturated and cyclopropyl acyl radicals, and their ketene alkyl radical equivalents. Ring synthesis and tandem cyclisation reactions

Treatment of the alpha,beta-unsaturated selenyl esters 12 and 14 with Bu(3)SnH-AIBN produces the corresponding 2-cyclohexenones 13 and 15 respectively via presumed alpha-ketene alkyl radical intermediates, viz. 10. By contrast, the 2,7-diene esters 34 and 39 undergo tandem radical cyclisations producing diquinanes, e.g.(76%), and the corresponding allene-substituted alpha,beta-unsaturated selenyl ester 48 gives the cyclooctadienone 56 on treatment with Bu(3)SnH-AIBN in refluxing benzene. The selenyl ester 19 derived from chrysanthemic acid produces a mixture of the gamma,delta-unsaturated aldehyde 22 and the corresponding dimer 25a on treatment with Bu(3)SnH-AIBN. Furthermore, in the presence of methanol the only product from this reaction was the bis(methyl ester) dimer 25b, thereby lending further credence to the involvement of ketene alkyl radical intermediates in these reactions, and in the aforementioned reactions involving 2,6- and 2,7-diene selenyl esters. Treatment of the cyclopropane selenyl esters and , containing keto- and oxy-group functionality in their side-chains, with Bu(3)SnH-AIBN led to excellent syntheses of the enol lactone 66 (76%) and the trans-fused bicyclo[6.1.0]nonane 67 (80-95%) respectively.     

An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N′-di-Boc-substituted thiourea with alkyl and aryl amines under mild conditions

An efficient method for the synthesis of disubstituted thioureas via the reaction of N,N′-di-Boc-substituted thiourea 5 with alkyl and aryl amines under mild conditions has been developed. In the presence of NaH as a base, trifluoroacetic anhydride (TFAA) reacted with 5 providing intermediate 6, which then reacted with amines giving thioureas 7 in excellent yields. This reaction conditions tolerated other functional groups such as amide, ester, enol ether and hydroxyl groups.     

Palladium-catalyzed cascade reaction of alpha,beta-unsaturated sulfones with aryl iodides

Unlike traditionally used acyclic 1,2-disubstituted alkenes, the reaction of alpha,beta-unsaturated phenyl sulfones with aryl iodides under Heck reaction conditions (Pd(OAc)(2) as catalyst, Ag(2)CO(3) as base in DMF at 120 (0)C) takes place mainly by a cascade process, involving one unit of the alkene and three units of the aryl iodide, to afford a substituted 9-phenylsulfonyl-9,10-dihydrophenanthrene. The dominant formation of this 3:1 coupling product, instead of the Heck trisubstituted olefin, shows that aromatic C-H bond activation processes can compete with the usually fast syn beta-hydrogen elimination step in the Heck arylation of an acyclic olefin. The structural scope of this palladium-catalyzed cascade arylation of alpha,beta-unsaturated sulfones has proved to be wide with regard to substitution at the beta-position (alkyl, aryl, or alkenyl substitution), substitution at the sulfone unit (alkyl or phenyl sulfones), and configuration at the CdoublebondC bond (trans or cis). Moreover, although less favored than in the case of the arylation of alpha,beta-unsaturated sulfones, similarly substituted 9,10-dihydrophenanthrenes have also been obtained in the case of alpha,beta-unsaturated phosphine oxides and alpha,beta-unsaturated phosphonate esters. A Pd(0)-Pd(II)-Pd(IV) mechanistic pathway involving the successive formation of highly electrophilic sigma-alkylpalladium intermediates and palladacycles is proposed for this multicomponent arylation.