Phenolic esters reduction

EC oxidation is commonly employed in the analysis of some basic drugs, especially morphine and related opioids (Chapter 6, Section 1). Even if a compound is not amenable to EC oxidation, its metabolites may be. Phase I metabolism of aromatic xenobiotics often proceeds with aromatic hydroxylation. Hydrolysis of phenolic esters, reduction of diazo double bonds to primary amines and other reactions also occur. EC detection is not widely used to measure acidic or neutral compounds, such as salicylate or paracetamol after overdosage, since these compounds, although easily oxidised, are normally present at relatively high concentrations and UV detection is adequate. However, EC methods may be useful in measuring the plasma concentrations of these compounds attained after a single oral dose. ... 

Reduction of phenols, phenolic ethers, or phenolic esters... 

Reduction of Phenols and Phenolic Esters and Ethers175 Hydro-de-hydroxylation or Dehydroxylation, etc. 

Reduction of nitro compounds 1-30 Rearrangement of phenolic esters... 

Fig (14) Olefin (107) has been converted to cyclic ether (114) by standard reactions. Its transformation to enone (115) is accomplished by annelation with methyl vinyl ketone and heating the resulting diketone with sodium hydride in dimethoxyethane. The ketoester (116) is subjected to Grignard reaction with methyllithium, aromatization and methylation to obtain the cyclic ether (117). Its transformation to phenolic ester (119) has been achieved by reduction, oxidation and esterification and deoxygenation. 

The reduction of phenols and phenolic esters and ethers is discussed in Chapter 19 (see 19-38 and 19-35). The reaction ArX ArH is treated in Chapter 11 (reaction 11-39), although, depending on reagent and conditions, it can be nucleophilic or free-radical substitution, as well as electrophilic. 

Esters. Reductive carbonylation in the presence of an alcohol or phenol leads to an ester. Substrates include organoiodonium salts and allylic alcohols. p,y-Unsaturated thioesters can be generated by the method or from allenes. Note that y-lactones are formed when allylic alcohols are carbonylated without additives. ... 

Reduction of quinone propionic esters or amides 129 bearing three Me groups in the so-called trialkyl lock positions (< -, 0-, P-positions) or hydrolysis of the corresponding phenolic esters 130 has been shown to undergo spontaneous lactonization with the release of alcohol or amine, respectively (Scheme 22).73-75 Several amides... 

Estradiol and estrone are metabolized to an array of oxidized products, one of which consists of the 16a-hydroxy derivative 30-4. One approach to preparing that compound starts by reaction of estrone with isopropyhdene acetate, to afford the acetate of the enolic form of the ketone and also the ester of the phenol at position 3 (30-1) (Scheme 3.30). Treatment of that product with perbenzoic acid leads to the a-oxirane 30-2, formed from approach of the reagent from the less hindered backside. Acetolysis of that intermediate gives 16a-acetoxyestrone (30-3). Reaction of that product with lithium aluminum hydride leads to reduction of the 17-carbonyl and also the phenolic ester to give the trans-Aio 16a-hydroxy- 17(3-estradiol (30-4). The same product is obtained on reducing 30-2 directly also with lithium aluminum hydride. 

The preparation of 76 began with phenol 65. A key TiCLj-mediated coupling with isatin 67 afforded a tertiary alcohol, which was reduced to form 78 via the chloride. Ester reduction followed by p-TsOH-catalyzed reaction with 2,2-dimethoxypropane afforded acetonide 79. Oxindole silylation and an aldol reaction with HCHO provided an equimolar mixture of both CIO stereoisomers 80. A two-step protection followed by 9-BBN reduction of the lactam gave fragment 76 in good yield (Scheme 13). 

As shown, under the reducing ligation conditions, 0—>S acyl transfer occurred at the o-disulfide phenolic ester as previously described (see above), to provide the thioester, which underwent transthioesteriflcation with the thiol-containing glyco-peptide (upon in situ reduction of the auxiliary disulfide bond) the transient intermediate underwent an S N acyl transfer to generate the thermodynamically favored amide bond of the doubly glycosylated peptide adduct. The auxiliary was subsequently removed through sequential methylation of the fi-ee thiol to prevent the reverse acid-mediated N S acyl shift, followed by TFA treatment. 

In general, these compounds were synthesized from appropriately substituted and selectively protected phenolic esters. A reaction sequence that consisted of selective deprotection, oxidation to the quinoid system, and addition of an amino acid gave vinylogous esters. Linkage to the trans-decalin building blocks with an exocyclic double bond was achieved with a Suzuki coupling of substituted arylboronic acids to the corresponding decalin-derived vinyl bromides. Reduction of... 

We have focused our attention on the solid phase synthesis of such compounds and described our results here. Alternative routes for the preparation of peptide aldehydes and side-chain protected peptide aldehydes in solid phase synthesis are described. Three new linkers that are stable tmder classical Fmoc or Boc strategies have been developed to obtain the peptide aldehyde from the solid support. One of these linkers was conceptualized on the basis of the Weinreb amide (49) and the other on the basis of phenolic esters (50). Both strategies required the reduction with hydrides of the peptide-linker-resin to release the peptidic aldehydic function. The use of these two different approaches was demonstrated by the synthesis of N-protected a-amino-aldehydes and peptide aldehydes, llie third approach used the ozonolysis reaction for the generation of the desired aldehyde. This concept requires a linker incorporating a double bond in the a-position of the asymmetric carbon of the C-terminal residue that will be cleaved by ozone to produce the carbonyl function. 

Quinic acid is also found throughout the plant kingdom, usually with shikimic acid. It occurs as the free acid in many plants and its phenolic esters are also very common. The simplest assumption for the biosynthesis of quinic acid is through the reduction of 3-dehydroquinic acid, catalyzed by quinate dehydrogenase. However, because of the rare occurrence of this enzyme, the biosynthesis of quinic acid still remains to be explained. 

The ester and catalj st are usually employed in equimoleciilar amounts. With R =CjHs (phenyl propionate), the products are o- and p-propiophenol with R = CH3 (phenyl acetate), o- and p-hydroxyacetophenone are formed. The nature of the product is influenced by the structure of the ester, by the temperature, the solvent and the amount of aluminium chloride used generally, low reaction temperatures favour the formation of p-hydroxy ketones. It is usually possible to separate the two hydroxy ketones by fractional distillation under diminished pressure through an efficient fractionating column or by steam distillation the ortho compounds, being chelated, are more volatile in steam It may be mentioned that Clemmensen reduction (compare Section IV,6) of the hj droxy ketones affords an excellent route to the substituted phenols. 

The acylpalladium complex formed from acyl halides undergoes intramolecular alkene insertion. 2,5-Hexadienoyl chloride (894) is converted into phenol in its attempted Rosenmund reduction[759]. The reaction is explained by the oxidative addition, intramolecular alkene insertion to generate 895, and / -elimination. Chloroformate will be a useful compound for the preparation of a, /3-unsaturated esters if its oxidative addition and alkene insertion are possible. An intramolecular version is known, namely homoallylic chloroformates are converted into a-methylene-7-butyrolactones in moderate yields[760]. As another example, the homoallylic chloroformamide 896 is converted into the q-methylene- -butyrolactams 897 and 898[761]. An intermolecular version of alkene insertion into acyl chlorides is known only with bridgehead acid chlorides. Adamantanecarbonyl chloride (899) reacts with acrylonitrile to give the unsaturated ketone 900[762],... 

Another synthesis of the cortisol side chain from a C17-keto-steroid is shown in Figure 20. Treatment of a C3-protected steroid 3,3-ethanedyidimercapto-androst-4-ene-ll,17-dione [112743-82-5] (144) with a tnhaloacetate, 2inc, and a Lewis acid produces (145). Addition of a phenol and potassium carbonate to (145) in refluxing butanone yields the aryl vinyl ether (146). Concomitant reduction of the C20-ester and the Cll-ketone of (146) with lithium aluminum hydride forms (147). Deprotection of the C3-thioketal, followed by treatment of (148) with y /(7-chlotopetben2oic acid, produces epoxide (149). Hydrolysis of (149) under acidic conditions yields cortisol (29) (181). 

An aiyl methane- or toluenesulfonate ester is stable to reduction with lithium aluminum hydride, to the acidic conditions used for nitration of an aromatic ring (HNO3/HOAC), and to the high temperatures (200-250°) of an Ullman reaction. Aiyl sulfonate esters, formed by reaction of a phenol with a sulfonyl chloride in pyridine or aqueous sodium hydroxide, are cleaved by warming in aqueous sodium hydroxide. ... 

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