Reduction, acid chlorides carboxylic acids

Reductions. Aldehydes, ketones, acid chlorides, carboxylic acids, and N-Boc amino acids are reduced to the corresponding alcohols, generally in excellent yields. The reduction of a,P-epoxy ketones gives alcohols without affecting the heterocycle. ... 

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

The synthesis of a triptan with a chiral side chain begins by reduction of the carboxylic acid in chiral 4-nitrophenylalanine (15-1). The two-step procedure involves conversion of the acid to its ester by the acid chloride by successive reaction with thionyl chloride and then methanol. Treatment of the ester with sodium borohy-dride then afford the alanilol (15-2). Reaction of this last intermediate with phosgene closes the ring to afford the oxazolidone (15-3) the nitro group is then reduced to the aniline (15-4). The newly obtained amine is then converted to the hydrazine (15-5). Reaction of this product with the acetal from 3-chloropropionaldehyde followed by treatment of the hydrazone with acid affords the indole (15-6). The terminal halogen on the side chain is then replaced by an amine by successive displacement by means of sodium azide followed by catalytic reduction of the azide. The newly formed amine is then methylated by reductive alkylation with formaldehyde in the presence of sodium cyanoborohydride to afford zolmitriptan (15-7) [15]. 

The reduction of nitriles, carboxylic acids and carboxylic acid chlorides (Expts 5.80 and 5.81). 

THE REDUCTION OF NITRILES. CARBOXYLIC ACIDS AND CARBOXYLIC ACID CHLORIDES... 

Cellulose can be modified with organostannane chlorides, such as dibutyl or triphenyl derivatives [91,92], or with organotin halides in the presence of bisethylenediamine copper(II) hydroxide [93]. Epoxy-activated cellulose was prepared by reacting cellulose acetate fibers with sodium methoxide, followed by reacting it with epichlorohydrin in DMSO. This epoxy-activated cellulose has proved to be a useful intermediate to react with substances containing active hydrogen, such as amine, amino acid, or carboxylic acids [94], as shown in Fig. 3. Epoxidized cellulose has also been converted to a thiol derivative via reduction of a thiosulfate intermediate [95], and sulfoethylcellu-[ose has been obtained from sodium chloroethanesulfonate [96]. Cellulose... 

Methyl groups by reduction of aromatic carboxylic acids with trichbrosilane-tri-n-propylamine.2 In a hood well vented to permit open atmospheric transfer of trichloro-silane and to remove hydrogen chloride off gas produced, a 300-ml. three-necked. 

Chromous chloride Carboxylic acids from lactones Selective reduction... 

Scheme 9.109. A cartoon representation of the reduction of a carboxylic acid (L = OH), an ester (L = OR ), and an acid chloride (L = Cl) of 2-phenylethanoic acid (2-phenylacetic acid, a-phenylacetic acid, C6H5CH2CO2H) to the corresponding alcohol, 2-phenylethanol (C6H5CH2CH2OH) with lithium aluminum hydride (LiAlH4) in ether [(CH3CH2)20] solution.

Kedrowski and Dougherty developed a one-pot, four-step room temperature protocol for the synthesis of allylphosphonates (6) from acyl chlorides/carboxylic acids (5) via a Wolff-Kishner-type reductive deoxygenation (Scheme 3). This method offers a low-temperature alternative to the Arbuzov reaction that works well for a variety of aliphatic acids and shows a functional group tolerance similar to that of other hydrazone-forming reactions. The investigators also proposed a mechanism for this transformation (Scheme 4). 

Scheme 3 Synthesis of alkylphosphonates from acyl chlorides/carboxylic acids via a Wolff-Kishner-type reductive deoxygenation.

The most apparent chemical property of carboxylic acids their acidity has already been examined m earlier sections of this chapter Three reactions of carboxylic acids—con version to acyl chlorides reduction and esterification—have been encountered m pre vious chapters and are reviewed m Table 19 5 Acid catalyzed esterification of carboxylic acids IS one of the fundamental reactions of organic chemistry and this portion of the chapter begins with an examination of the mechanism by which it occurs Later m Sec tions 19 16 and 19 17 two new reactions of carboxylic acids that are of synthetic value will be described... 

Isoquinoline can be reduced quantitatively over platinum in acidic media to a mixture of i j -decahydroisoquinoline [2744-08-3] and /n j -decahydroisoquinoline [2744-09-4] (32). Hydrogenation with platinum oxide in strong acid, but under mild conditions, selectively reduces the benzene ring and leads to a 90% yield of 5,6,7,8-tetrahydroisoquinoline [36556-06-6] (32,33). Sodium hydride, in dipolar aprotic solvents like hexamethylphosphoric triamide, reduces isoquinoline in quantitative yield to the sodium adduct [81045-34-3] (25) (152). The adduct reacts with acid chlorides or anhydrides to give N-acyl derivatives which are converted to 4-substituted 1,2-dihydroisoquinolines. Sodium borohydride and carboxylic acids combine to provide a one-step reduction—alkylation (35). Sodium cyanoborohydride reduces isoquinoline under similar conditions without N-alkylation to give... 

Reactions of the carboxyl group include salt and acid chloride formation, esterification, pyrolysis, reduction, and amide, nitrile, and amine formation. Salt formation occurs when the carboxyUc acid reacts with an alkaline substance (22)... 

Claisen ester condensation, 6, 279 Thiazolecarboxylic acid chlorides reactions, 6, 279-280 Thiazolecarboxylic acid hydrazides synthesis, 6, 280 Thiazolecarboxylic acids acidity, 6, 279 decarboxylation, 6, 279 reactions, S, 92 6, 274 Thiazole-2-carboxylic acids decarboxylation, S, 92 Thiazole-4-carboxylic acids stability, S, 92 Thiazole-5-carboxylic acids decarboxylation, S, 92 Thiazole-4,5-dicarboxylic acid, 2-amino-diethyl ester reduction, 6, 279 Thiazole-4,5-dicarboxylic acids diethyl ester saponification, 6, 279 Thiazolediones diazo coupling, 5, 59 Thiazoles, 6, 235-331 ab initio calculations, 6, 236 acidity, S, 49 acylation, 6, 256 alkylation, S, 58, 73 6, 253, 256 analytical uses, 6, 328 antifogging agents... 

Benzanthrone has been prepared by three general methods, the first of which is generally regarded as the best (i) by heating a reduction product of anthraquinone with sulfuric acid and glycerol,1 or with a derivative of glycerol, or with acrolein. The anthraquinone is usually reduced in sulfuric acid solution, just prior to the reaction, by means of aniline sulfate, iron, , or copper. It has also been prepared (2) by the action of aluminum or ferric chloride on phenyl-a-naphthyl ketone, and (3) from i-phenylnaphthalene-2-carboxylic acid. ... 

The Rosenmund reduction is usually applied for the conversion of a carboxylic acid into the corresponding aldehyde via the acyl chloride. Alternatively a carboxylic acid may be reduced with lithium aluminum hydride to the alcohol, which in turn may then be oxidized to the aldehyde. Both routes require the preparation of an intermediate product and each route may have its advantages over the other, depending on substrate structure. 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

The complex thioamide lolrestat (8) is an inhibitor of aldose reductase. This enzyme catalyzes the reduction of glucose to sorbitol. The enzyme is not very active, but in diabetic individuals where blood glucose levels can. spike to quite high levels in tissues where insulin is not required for glucose uptake (nerve, kidney, retina and lens) sorbitol is formed by the action of aldose reductase and contributes to diabetic complications very prominent among which are eye problems (diabetic retinopathy). Tolrestat is intended for oral administration to prevent this. One of its syntheses proceeds by conversion of 6-methoxy-5-(trifluoroniethyl)naphthalene-l-carboxyl-ic acid (6) to its acid chloride followed by carboxamide formation (7) with methyl N-methyl sarcosinate. Reaction of amide 7 with phosphorous pentasulfide produces the methyl ester thioamide which, on treatment with KOH, hydrolyzes to tolrestat (8) 2[. 

Anhydrides are reduced with relative ease. McAlees and McCrindle 20) established the following increasing order of difficulty for various carbonyls acid chlorides > aldehydes, ketones > anhydrides > esters > carboxylic acids > amides. Reduction may proceed by 1,2-addilion of hydrogen or by cleavage of an oxygen-carbonyl bond. If 1,2-addition to the carbonyl occurs, as in the presence of strong protic acids over palladium, 1,1-diesters are formed by acylation 26). 

Acid halides are among the most reactive of carboxylic acid derivatives and can be converted into many other kinds of compounds by nucleophilic acyl substitution mechanisms. The halogen can be replaced by -OH to yield an acid, by —OCOR to yield an anhydride, by -OR to yield an ester, or by -NH2 to yield an amide. In addition, the reduction of an acid halide yields a primary alcohol, and reaction with a Grignard reagent yields a tertiary alcohol. Although the reactions we ll be discussing in this section are illustrated only for acid chlorides, similar processes take place with other acid halides. 

Conversion of Acid Chlorides into Alcohols Reduction Acid chlorides are reduced by LiAJH4 to yield primary alcohols. The reaction is of little practical value, however, because the parent carboxylic acids are generally more readily available and can themselves be reduced by L1AIH4 to yield alcohols. Reduction occurs via a typical nucleophilic acyl substitution mechanism in which a hydride ion (H -) adds to the carbonyl group, yielding a tetrahedral intermediate that expels Cl-. The net effect is a substitution of -Cl by -H to yield an aldehyde, which is then immediately reduced by UAIH4 in a second step to yield the primary alcohol. 

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