Efficient Procedure for Preparing Salicyl Alcohols

A new convenient procedure was developed for selective ortho-hydroxymethylation of phenols by reaction of paraformaldehyde with a mixture of phenol and orthoboric acid. The method is general for phenols containing no strong electron-withdrawing substituents; it allows preparation of o-hydroxybenzyl alcohols of high purity in a high yield.     

A simple Lewis acid induced reaction of phenols with electrophiles: Synthesis of functionalized 4H-chromenes and ortho-benzylphenols

Abstract

Lewis acid ZnCl₂ promoted cyclization protocol to 4H-chromenes is accomplished, using readily available phenols and acetophenones as starting materials. Interestingly, the process is feasible under the solvent free environment. Synthesis of a variety of 4H-chromenes have been accomplished using this strategy. In addition, this concept is extended to the synthesis of ortho-benzylphenols by treating phenols either with styrenes or secondary benzylic alcohols.     

p-Toluenesulfonic acid catalyzed regiospecific nitration of phenols with metal nitrates

Highly regiospecific mononitration of phenols and substituted phenols is accomplished employing a metal nitrate and a catalytic amount of p-toluenesulfonic acid in acetone. An exclusive ortho-selectivity was observed with excellent yields. A variety of metal nitrates were used to obtain o-nitrophenols exclusively in good to excellent yields. The use of p-toluenesulfonic acid is key for the selectivity observed.     

Rhodium-HMPT-catalyzed direct ortho arylation of phenols with aryl bromides

Direct ortho arylation of phenols with aryl bromides catalyzed by a rhodium complex and hexamethylphosphorous triamide (HMPT) have been developed. A plausible reaction mechanism involving in situ generation of arylphosphites from phenols and HMPT, phosphorus-directed ortho metalation, and transesterification of the arylated arylphosphites with the substrate phenols is proposed.     

Regiospecific oxidation of polycyclic aromatic phenols to quinones by hypervalent iodine reagents

The hypervalent iodine reagents o-iodoxybenzoic acid (IBX) and bis(trifluoro-acetoxy)iodobenzene (BTI) are shown to be general reagents for regio-controlled oxidation of polycyclic aromatic phenols (PAPs) to specific isomers (ortho, para, or remote) of polycyclic aromatic quinones (PAQs). The oxidations of a series of PAPs with IBX take place under mild conditions to furnish the corresponding ortho-PAQs. In contrast, oxidations of the same series of PAPs with BTI exhibit variable regiospecificity, affording para-PAQs where structurally feasible and ortho-PAQs or remote PAQ isomers in other cases. The structures of the specific PAQ isomers formed are predictable on the basis of the inherent regioselectivities of the hypervalent iodine reagents in combination with the structural requirements of the phenol precursors. IBX and BTI are recommended as the preferred reagents for regio-controlled oxidation of PAPs to PAQs.     

Base-promoted nucleophilic fluoroarenes substitution of CF bonds

With the use of KOH/DMSO as the superbase medium, the nucleophilic fluoroarene substitution for CF bonds is presented. The transformation proceeds smoothly with the use of fluoroarenes bearing not only electron-withdrawing group, but also electron-donating group and a variety of nucleophiles such as alcohols, phenols, amines, amides and nitrogen-heterocyclic compounds. The double nucleophilic substitution using ortho-difluoroarenes and nucleophiles bearing ortho-dinucleophilic groups results in the formation of 2,3-dihydro-1,4-benzodioxins, dibenzo[b,e][1,4]dioxins and 10H-phenoxazines in moderate to good yields.     

Mitsunobu reactions of aliphatic alcohols and bulky phenols

Alkylation of hydrazinedicarboxylate (a Mitsunobu by-product) is not a notable problem in common Mitsunobu alkyl aryl etherification reactions. Good yields can be obtained with a wide range of solvents. However, this side reaction can cause yield reduction for the reactions of sterically hindered phenols and primary alcohols. To suppress the side reaction, solvent effect was investigated. It was found that hydrazinedicarboxylate is about five times less soluble in diethyl ether than in THF, and the yields are improved for ortho-substituted phenols of a wide range of steric hindrance using diethyl ether as the solvent instead of THF which is the more commonly used for Mitsunobu reactions.     

Tandem molecular rearrangement in the alkylation of phenol with camphene

The alkylation of phenol with camphene in the presence of boron trifluoride in glacial acetic acid was accompanied by tandem molecular rearrangement with formation of a mixture of ortho- and para-substituted phenols having 1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yl and 5,5,6-trimethylbicyclo[2.2.1]hept-exo-2-yl substituents. The same products were obtained by rearrangement of 1,7,7-trimethylbicyclo[2.2.1]hept-exo-2-yloxybenzene under analogous conditions. Similar reactions performed in the presence of aluminum phenoxide as catalyst resulted in predominant formation of the corresponding ortho-substituted phenols.     

Zirconium-catalyzed Nagata reaction for the synthesis of 2-aryl-1,3,2-aryldioxaborins via a mild three-component condensation of phenols, aldehydes, and boronic acid

An efficient ZrCl₄-catalyzed ortho-hydroxyalkylation of phenols with aldehydes promoted by 3,5-bis(trifluoromethyl)phenyl boronic acid, leading to the formation of 2-aryl-1,3,2-aryldioxaborins, was investigated and optimized. The reaction afforded the desired aryldioxaborins in good to excellent yields under mild conditions at room temperature. The electron-deficient boronic acid promoter was essential. Electron-rich phenols react faster, and both alkyl and aryl aldehydes are suitable substrates. The resulting aryldioxaborins can be further elaborated to produce substituted saligenols, 2-ethoxy chromans, and 2-substituted phenols.     

Organic-base-catalyzed synthesis of phthalides via highly regioselective intramolecular cyclization reaction

The organic-base-catalyzed 5-exo intramolecular cyclization reaction of o-alkynylbenzoic acid produces the corresponding phthalide regioselectively in good to excellent yields. The method provides a practical access to the phthalides, an important class of biologically active molecules.     

Dipole moments and structure of <Emphasis Type="Italic">ortho</Emphasis>-diphenyl(diethyl)phosphinoyl-substituted benzyl alcohols,phenols, and their derivatives

The method of dipole moments and DFT B3LYP/6-31G* quantum-chemical calculations were used to study the structures of ortho-substituted aryl-and arylmethyldiphenyl(diethyl)phosphine oxides. It was established that methyl ethers of phosphorus-containing benzyl alcohols and phenols exist as equilibrium mixtures of several conformers with prevalence of forms with the weakest steric interactions. Preferred conformers of o-[(diethylphosphinoyl)methyl]benzyl alcohol and i-[(diphenylphosphinoyl)methyl]phenol contain an intramolecular hydrogen bond between the hydroxyl hydrogen atom and phosphinoyl oxygen atom.     

Acid-mediated domino reaction of ortho-carbonylated alkynyl-substituted arylaldehydes with phenols: Rapid access to fused indeno[2,1-c]chromen-7-one derivatives

Acid-mediated domino reaction of ortho-carbonylated alkynyl-substituted arylaldehydes with phenols is described. The implement of this reaction can provide directly a variety of tetracyclic indeno[2,1-c]chromen-7-one products in good yields. The mechanism was proposed to be a domino indanone ring formation/ortho-alkylation of phenols/dehydrated cyclization for the formation of polycyclic skeleton. In addition, several interesting dimeric products containing a pentacyclic scaffold were also afforded stereoselectively albeit in moderate yields. The present transformations feature the use of simple acid catalyst, short reaction time and good substrate scope.     

Radical Arylation of Phenols,Phenyl Ethers,and Furans

Radical arylations of para‐substituted phenols and phenyl ethers proceeded with good regioselectivity at the ortho position with respect to the hydroxy or alkoxy group. The reactions were conducted with arenediazonium salts as the aryl radical source, titanium(III) chloride as the reductant, and diluted hydrochloric acid as the solvent. Substituted biaryls were obtained from hydroxy‐ and alkoxy‐substituted benzylamines, phenethylamines, and aromatic amino acids. The methodology described offers a fast, efficient, and cost‐effective new access to diversely functionalized biphenyl alcohols and ethers. Free phenolic hydroxy groups, aromatic and aliphatic amines, as well as amino acid substructures, are well tolerated. Two examples for the applicability of the methodology are the partial synthesis of a β‐secretase inhibitor and the synthesis of a calcium‐channel modulator.     

Chemoselective glycosylation of carboxylic acid with glycosyl ortho-hexynylbenzoates as donors

The gold(I)-catalyzed glycosylation of acid alcohols with glycosyl ortho-hexynylbenzoates in the presence of BF₃·Et₂O and DBU provided the corresponding ester glycosides chemoselectively in high yield; while with DTBP as an additive instead, orthoester formation with the alcohol was effected selectively.     

Gold-catalyzed substitution reaction with ortho-alkynylbenzoic acid alkyl ester as an efficient alkylating agent

ortho-Alkynylbenzoic acid alkyl esters behave as alkylating agents in combination with gold catalysts. The reaction with alcohols occurs smoothly in the presence of catalytic amounts of Ph₃PAuCl and AgOTf under mild conditions to produce the corresponding ether products in high yields. The protocol is also useful for Friedel-Crafts alkylation and N-alkylation of sulfonamides. The reaction likely proceeds through the gold-induced in situ construction of leaving groups and subsequent nucleophilic attack of nucleophiles, such as alcohols, aromatic compounds, and sulfonamides.     

Steric and electronic effects on the oxidation of ortho-substituted benzhydrols by chromic acid

A study has been made of the oxidation of a number of substituted benzhydrols by chromic acid in aqueous acetic acid. The reaction rate constants are linearly proportional to the K_R+ values of the alcohols. ortho-Substitution increases the rate of reaction and reduces the magnitude of the primary kinetic isotope effect. The major result of steric crowding appears to be an increase in the energy of the reactants, while the main electronic effect of substituents is to stabilize or destabilize the transition state.     

Synthesis of Chiral Pyridylphenols for the Enantioselective Addition of Diethylzinc to Aldehydes

Chiral 8‐substituted 2‐(8,10,10‐trimethyl‐6‐aza‐tricyclo[7.1.1.0^2,7]undeca‐2(7),3,5‐trien‐5‐yl)‐phenols were prepared from a high enantiopurity (>97% ee) of (1R)‐(+)‐α‐pinene, and assessed in the enantioselective addition of diethylzinc to substituted benzaldehydes, giving the (S)‐alcohols with enantiomeric excess ranging from 33% to 89%. Interestingly, in all cases, except for those of ortho‐chlorobenzaldehyde, ortho‐ and para‐methoxybenzaldehydes, the ee was >71%. The plot of the Hammett substitution constants vs. enantiomeric excess of the diethylzinc addition to either the ortho‐ or para‐substituted benzaldehydes shows a linear correlation.     

Use of 13C isotope shifts to assign carbon atoms α and β (and para) to a hydroxy group in alkyl substituted phenols and alcohols

Doublets can be observed for carbons α and β to the hydroxyl in aliphatic alcohols containing equimolar amounts of OH and OD dissolved in (CH₃)₂SO containing CaSO₄ desiccant. Isotopic doublets are also observed for the ipso and ortho carbons in alkyl substituted phenols. Para isotopic doublets are observable in para-substituted phenols containing a large 2-substituent. The isotope shift is positive (low field) for the para carbon, opposite to the negative shifts usually observed.     

Synthesis of coumarins by ring-closing metathesis using Grubbs’ catalyst

A novel generally applicable synthesis of coumarins from phenolic substrates utilizing ring-closing metathesis is described. This sequence involves O-allylation of phenols followed by ortho-Claisen rearrangement, subsequent based-induced isomerization affording 2-(1-propenyl)phenols, acylation with acryloyl chloride, and finally ring-closing metathesis (RCM) with Grubbs’ second generation catalyst.     

Monoligated Pd(0)-catalyzed intramolecular ortho- and para-arylation of phenols for the synthesis of aporphine alkaloids. Synthesis of (−)-lirinine

An intramolecular palladium(0)-mediated ortho-arylation of phenols applied to the synthesis of various substituted aporphines is reported. Most significantly, the efficiency of the transformation was enhanced by the use of monoligated Pd(0) complexes. This methodology was extended to para-arylation of phenols and employed in the synthesis of the aporphine alkaloid (?)-lirinine.