Phenols ester synthesis

Phenolic esters (1) of aliphatic and aromatic carboxylic acids, when treated with a Lewis acid as catalyst, do undergo a rearrangement reaction to yield ortho- and para-acylphenols 2 and 4 respectively. This Fries rearrangement reaction is an important method for the synthesis of hydroxyaryl ketones. 

For a method of hydrolyzing phenolic esters in the presence of other esters, see Blay, G. Cardona, L. Garcia, B. Pedro, J.R. Synthesis, 1989, 438. 

The second step, nucleophilic attack of an alcohol or phenol on the activated carboxylic acid RCOIm (carboxylic acid imidazolide), is usually slow (several hours), but it can be accelerated by heating[7] or by adding a base[8] [9] such as NaH, NaNH2, imidazole sodium (ImNa), NaOR, triethylamine, diazabicyclononene (DBN), diazabicycloimdecene (DBU), or /7-dimethylaminopyridine to the reaction mixture (see Tables 3—1 and 3—2). This causes the alcohol to become more nucleophilic. Sodium alcoholate applied in catalytic amounts accelerates the ester synthesis to such an extent that even at room temperature esterification is complete after a short time, usually within a few minutes.[7H9] This catalysis is a result of the fact that alcoholate reacts with the imidazolide very rapidly, forming the ester and imidazole sodium. 

A photochemical approach to the synthesis of precocenes /, II, and III, interesting as juvenile hormome inhibitors [177,178], has been deviced starting from the phenolic esters of 3-methylcrotonic acid. This is shown in Scheme 61 for the synthesis of precocene I (235) [179] and in Scheme 62 for the synthesis of precocenes II (238) and III (239) [180]. The rate of the cyclization process leading to chromanones, like 234 or 237, has been found to depend on the stereochemistry of the double bond. Thus, ring closure is more rapid for the trans than for the cis isomer, although no clear-cut trend can be established [181],... 

Phenolic ketones may be prepared by the Hoesch acylation reaction, which may be regarded as an extension of the Gattermann aldehyde synthesis (Section 6.10.1, p. 990). The procedure involves reaction of a nitrile with a phenol (or phenolic ether) in the presence of zinc chloride and hydrogen chloride best results are usually obtained with polyhydric phenols or their ethers, as for example in the preparation of phloroacetophenone (Expt 6.125). The formation of phenolic ketones by means of the Fries rearrangement of phenolic esters with aluminium chloride is discussed on p. 976. 

In Fig. (12) keto ester (94) was selected as starting material. It was converted to the formyl derivative (95) which yielded a,P-unsaturated aldehyde (96) by treatment with DDQ. Michael addition of the sodium enolate of tert-butyl- isovalerylacetate to aldehyde (96) afforded the adduct (97) as a mixture of C-ll diastereomers. By fractional crystallization one of the adducts could be separated but for the synthetic purpose the mixture was not separated. Treatment of the adduct (97) with p-toluenesulfonic acid in glacial acetic acid caused t-butyl ester cleavage, decarboxylation and cyclodehydration leading the formation of tricyclic enedione (98) in 80% yield. This approach was previously utilized by Meyer in the synthesis of nimbiol [29], Treatment of (98) with pyridinium bromide perbromide, followed by hydrogenolysis with palladium and carbon caused aromatization of (98) leading the formation of the phenolic ester (99). 

In spite of the essential difficulties mentioned above concerning the direct substitution of a particular hydrogen atom of multi phenylated benzenes giving rise to a well defined phenol or phenol ester, much work has been done29). Its emphasis, however, has been on mechanism rather than on synthesis. In this account we will only discuss some of the more promising synthetic routes of arylated phenols. An interesting example may be that of 2,4,6-triphenylphenol via direct hydroxylation or acyloxylation of 1,3,5-triphenylbenzene. 

FRIEDLANDER Quinoline synthesis t32 FRIES Phenol ester rearrangement 133 FRITSCH. BUTTENBERG - WIECHELL Acetylene synthesis 134... 

The total synthesis of the lichen diphenyl ether epiphorellic acid 1 was achieved in the laboratory of J.A. Elix using the Smiles rearrangement as the key step. The diaryl phenolic ester substrate was heated in dry DMSO in the presence of potassium carbonate, which brought about the rearrangement. The resulting carboxylic acid was converted to the methyl ester with diazomethane and was debenzylated under catalytic hydrogenation conditions. 

Cyanate esters (CEs) are formed in excellent yields by the reaction of the corresponding phenols with cyanogen halide [34]. The reaction scheme is shown in Scheme la. The reaction is usually carried out in solution, in the presence of a tertiary amine as the acid scavenger at very low temperatures. Since the trimer-ization reactions of cyanate esters are highly prone to catalysis by spurious impurities, the most difficult aspect of cyanate ester synthesis is their scrupulous purification. Low molar mass esters are purified by distillation or recrystallization. Polymeric cyanates are purified by repeated precipitation in non-solvents such as water, isopropanol, etc. While distillation and recrystallization lead to pure materials, the precipitation method for polymeric cyanates is not always conducive to obtaining pure materials. A recent patent application claims a purification method for polymeric cyanates based on treatment with cation and anion exchangers [35]. 

The synthesis is easier than it may seem since Friedel-Crafts acylation of phenols is best done by first making the phenolic ester and rearranging this with AICI3. In this case, the ester needed is (14) which hardly needs to be made since it is aspirin. No doubt this Saibutamol synthesis was planned with this cheap starting material in mind. 

A variety of novel procedures has been developed for the synthesis of phenolic esters in the last decade. 

The methodology of active ester synthesis, as shown in Fig. 2, is generally applicable and covers a wide range of nucleophiles, including primary, secondary and aromatic amines, primary alcohols and phenols. Thus, chemical modification d polymeric active esters (i.e. active ester synthesis) provides a single-step route for the preparation of functional polymers in general. The syntl sis of various polymer types by the active ester method is advanced in Sects. 5-7. Here, an example of a relativdy simpk fiinctional group (OH) is discussed to illustrate the versatility of the active ester method, as compared with conventional methods of polymer functionalization. 

PEG itself is useful as a phase-transfer catalyst because it is an acyclic analog of a crown ether [86]. This property of PEG and its potential as a support for a substrate were combined in a recent synthesis of monoethers of hydro-quinone and resorcinol [87]. In this chemistry (Eq. 17), a dihydroxyl PEG 4,000 (n=ca. 90) 33 was first allowed to react with an excess of oxalyl chloride. The resulting diacid chloride was then allowed to react with the hydroquinone or resorcinol to form a diester, which was easily isolated by solvent precipitation with diethyl ether. Subsequent treatment of this phenolic ester with an alkyl iodide in the presence of K2CO3 in DMF led to the PEG-bound monoether ester. In this reaction, the PEG acted both as a support and as a phase-transfer catalyst. Subsequent hydrolysis generated the monoether of the hydroquinone or resorcinol. 

This and other information show that nine Cg units from malonyl-coenzyme A and one C3 unit from propionyl-coenzyme A condense to form the linear polyketide intermediate shown below. These units are joined by acylation reactions that are the biosynthetic equivalent of the malonic ester synthesis we studied in Section 18.7. These reactions are also similar to the acylation steps we saw in fatty acid biosynthesis (Special Topic E in WileyPLUS). Once formed, the linear polyketide cyclizes by enzymatic reactions akin to intramolecular aldol additions and dehydrations (Section 19.6). These steps form the tetracyclic core of akiavinone. Phenolic hydroxyl groups in akiavinone arise by enolization of ketone carbonyl groups present after the aldol condensation steps. Several other transformations ultimately lead to daunomycin ... 

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