Carboxylic acid esters ethers, reduction

Sodium tetrahgdridboratelboron fluoride Ethers from carboxylic acid esters by reduction... 

Fig. 17.62. Two-step reduction of carboxylic acid esters to ethers. In the first step, a reduction via hydride transfer occurs and leads to a tetrahedral intermediate that is stable enough to be acylated to the (alpha))-acetoxyether A. The second step involves a so-called "ionic reduction"...

A reduction with triethylsilane, which is a pure SN1 reaction, is familiar from Figure 17.62, namely as the second step of a two-step reduction of a carboxylic acid ester to a simple ether via an oc-acetoxyether. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Reduction of carboxylic acids and esters, aldehydes, and nitriles, and the hydro-boration of alkenes with diborane in non-ethereal solvents is highly effective (Table 11.8), but reduction of nitro groups or cleavage of arena-halogen bonds does not occur [1]. However, in spite of the potential advantages, very little use appears to have been made of the procedure. 

Types of compounds are arranged according to the following system hydrocarbons and basic heterocycles hydroxy compounds and their ethers mercapto compounds, sulfides, disulfides, sulfoxides and sulfones, sulfenic, sulfinic and sulfonic acids and their derivatives amines, hydroxylamines, hydrazines, hydrazo and azo compounds carbonyl compounds and their functional derivatives carboxylic acids and their functional derivatives and organometallics. In each chapter, halogen, nitroso, nitro, diazo and azido compounds follow the parent compounds as their substitution derivatives. More detail is indicated in the table of contents. In polyfunctional derivatives reduction of a particular function is mentioned in the place of the highest functionality. Reduction of acrylic acid, for example, is described in the chapter on acids rather than functionalized ethylene, and reduction of ethyl acetoacetate is discussed in the chapter on esters rather than in the chapter on ketones. 

A carboxylic acid group may be introduced into the 2-position of dibenzofuran by Friedel-Crafts reaction with 2,2-dichloro-l,3-benzodioxole (catechol dichloromethylene ether) and hydrolysis of the resultant ester. Similarly, reaction with methylphenylcarbamoyl chloride produces the 2-(N-methyl-yV-phenylcarboxamide) or the 2,8-disubstituted derivative under more stringent conditions. Controlled reduction of these amides with lithium aluminum hydride supplies the corresponding aldehydes. ... 

The most common procedure is ozonolysis at -78 °C (P.S. Bailey, 1978) in methanol or methylene chloride in the presence of dimethyl sulfide or pyridine, which reduce the intermediate ozonides to aldehydes. Unsubstituted cydohexene derivatives give 1,6-dialdehydes, enol ethers or esters yield carboxylic acid derivatives. Oxygen-substituted C—C bonds in cyclohexene derivatives, which may also be obtained by Birch reduction of alkoxyarenes (see p. 103f.), are often more rapidly oxidized than non-substituted bonds (E.J. Corey, 1968 D G. Stork, 1968 A,B). Catechol derivatives may also be directly cleaved to afford conjugated hexa-dienedioic acid derivatives (R.B. Woodward, 1963). Highly regioselective cleavage of the more electron-rich double bond is achieved in the ozonization of dienes (W. KnOll, 1975). 

We also found that ester functionality was compatible with this reduction sequence. Thus, treatment of the ester-lactone 81 with sodium borohydride and boron trifluoride etherate provided the tetrahydropyran 123 in 55% purified yield. Upon reaction with sodium hydroxide, 81 underwent simple ester hydrolysis to furnish the carboxylic acid 127 (see Table 3). 

Functional Group Transformation Alcohols can be prepared by nucleophilic substitution of alkyl halides, hydrolysis of esters, reduction of carboxylic acids or esters, reduction of aldehydes or ketones, electrophilic addition of alkenes, hydroboration of alkenes, or substitution of ethers. 

Reductions in methanol-containing solvents Primary amides can be reduced selectively in the presence of carboxylic acid salts or of secondary amides by LiBHj in diglyme-CH,OH. Esters and epoxides are reduced selectively in the presence of nitro, chloro, or amide groups by LiBHj in ether containing some CH,OH. 

Figure 26.2. Synthesis of an Ether Phospholipid. Steps in the synthesis include (1) acylation of dihydroxyacetone phosphate by acyl CoA, (2) exchange of an alcohol for the carboxylic acid, (3) reduction by NADPH, (4) acylation by a second acyl CoA, (5) hydrolysis of the phosphate ester, and (6) transfer of a phosphocholine moiety.

Aromatic carboxylic acids have been reduced using HSiCl3 and tertiary amines, Generally, this reaction leads to deoxygenation and the formation of (trichlorosilylmethyl)arenes. However, this reaction was found to produce ether (3) on the reduction of diacid (2 Scheme 3). Reduction by HSiCh is selective for aromatic carboxylic acids in the presence of esters. A representative reduction using HSiCls is also given in Scheme 3. 

Alkylation of potassium enolates is not always fruitful, and so counterion exchange with lithium bromide prior to addition of the electrophile has been recommended. Reduction of aromatic esters instead of acids provides a number of potential advantages. The esters tend to be more soluble than carboxylate salts, hydrogenolysis of 2-alkoxy substituents does not appear to present the s me problem, and the products are more stable. This can be important when enol ether functions are generated, allowing the necessarily acidic work-up procedures for carboxylic acids to be avoided. Indeed, the hydrolysis of enol ether functions may be very slow in aqueous acid and is best achieved through catalysis by mercury(II) nitrate. ... 

Many other examples of chemoselective enone reduction in the presence of other reducible functionalities have been reported. For instance, the C—S bonds of many sulfides and thioketals are readily cleaved by dissolving metals. " Yet, there are examples of conjugate reduction of enones in the presence of a thioalkyl ether group." " Selective enone reduction in the presence of a reducible nitrile group was illustrated with another steroidal enone. While carboxylic acids, because of salt formation, are not reduced by dissolving metals, esters" and amides are easily reduced to saturated alcohols and aldehydes or alcohols, respectively. However, metal-ammonia reduction of enones is faster than that of either esters or amides. This allows selective enone reduction in the presence of esters"" and amides - -" using short reaction times and limited amounts of lithium in ammonia. 

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