Carboxylic acid derivatives reductions, sodium borohydride

The reaction of derivatives of 2-ethylamino-8-ethyl-7-pteridinone carboxylic acid (155) with sodium borohydride gave the corresponding 4,8-dihydropteridine153 (156). The original assignment of the 5,8-dihydro-structure153 was revised on the basis of NMR studies of the reduction products.154... 

Reduction with concomitant A, Af -dialkylation is achieved by the action of potassium borohydride in the presense of carboxylic acids. Similarly, reduction of quinoxalines with sodium borohydride or sodium cyanoborohydride in the presence of benzyl chloroformate gives A -benzyloxycarbonyl- or /V,jV -bis(benzyloxycarbonyl)tetrahydro derivatives. ... 

There have been two major approaches towards achieving selective reduction of carboxylic acid derivatives to aldehydes (or derivatives) by hydrides. Firstly, hydride reagents themselves have been modified as, for example, sodium borohydride and sodium cyanoborohydride. Sometimes these modifications have led to finely tuned reducing agents, as with the dimethyl sulfide adduct of thexylbromoborane (see later). Secondly, the type of carboxylic acid derivative has been modified for the optimum yield of aldehyde. For example, amides have been made from an assortment of amines in efforts to maximize yields of aldehyde. Best yields of aldehydes are obtained usually by a combination of modified hydride reagent with a modified carboxylic acid derivative. 

Hydroxymethylpyrazines may be prepared by reduction of carboxylic acid derivatives. Thus reduction of 2-amino-3-methoxycarbonylpyrazine with lithium aluminum hydride in tetrahydrofuran gave 2-amino-3-hydroxymethylpyrazine (1074, 1075) the imide from 23-dicarboxypyrazine (20) with sodium borohydride in tetrahydrofuran gave 2-carbamoyl-3-hydroxymethylpyrazine (21), and the methylcarbamoyl analogue was prepared similarly (1076). 

Various 7-carboxylic acid derivatives of bicyclo[4.1.0]heptane and -ene were reduced using a two-step procedure starting with generation of anhydride derivatives which were not isolated, but reduced directly with sodium borohydride - for example reduction of... 

Amides such as A/ AT-dimethylcyclohexanecarboxamide (23 see Chapter 20, Section 20.7) are also carboxylic acid derivatives. Sodium borohydride does not reduce an amide. Lithium aluminum hydride reacts with 23, but the product is an amine rather than an alcohol—specifically, l-(iV, Ar-dimeth-ylaminomethyl)cyclohexane, 24. Amine 24 is isolated in 88% yield. Although the mechanism will not be discussed here in a formal manner, delivery of hydride to the acyl carbon of the C=0 is followed by formation of an imine (C=N) that is further reduced to the amine. Nitriles such as octanenitrile (25) also react with LiAlH4 in one experiment, reduction of 25 gave amine 26 (1-aminopentane) in 92% isolated yield. This reduction also proceeds by delivery of hydride to the carbon of the nitrile, generating an imine that is further reduced to the amine. In general, NaBH4 does not reduce amides or nitriles. 

Carbonyl Group Reduction. The flow of new methods for reduction of acid derivatives and aldehydes or ketones to alcohols continues unabated. The Report last year (4,134) featured the sodium borohydride reduction of carboxylic acid derivatives, originally thought to be 2-thiazoline-2-thiol esters (14), to give alcohols in good yields. Full details of the method have now appeared (Scheme 8), and it seems that the acid derivatives are in fact the 3-acyl thiazolidine-2-thiones (IS) dissappearance of their yellow colour is an easy way to monitor the reduction. Carboxylic acids or their chlorides can also be reduced to primary alcohols in good yields at room temperature using a titanium tetrachloride-sodium borohydride combination. ... 

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... 

The methyl substituent of 2-methyl-4,8-dihydrobenzo[l,2- 5,4-. ]dithiophene-4,8-dione 118 undergoes a number of synthetic transformations (Scheme 8), and is therefore a key intermediate for the preparation of a range of anthraquinone derivatives <1999BMC1025>. Thus, oxidation of 118 with chromium trioxide in acetic anhydride at low temperatures affords the diacetate intermediate 119 which is hydrolyzed with dilute sulfuric acid to yield the aldehyde 120. Direct oxidation of 118 to the carboxylic acid 121 proceeded in very low yield however, it can be produced efficiently by oxidation of aldehyde 120 using silver nitrate in dioxane. Reduction of aldehyde 120 with sodium borohydride in methanol gives a 90% yield of 2-hydroxymethyl derivative 122 which reacts with acetyl chloride or thionyl chloride to produce the 2-acetoxymethyl- and 2-chloromethyl-4,8-dihydrobenzo[l,2-A5,4-3 ]-dithiophene-4,8-diones 123 and 124, respectively. 

From reduction of carboxylic acids and acyl derivatives Sodium borohydride, 278 Sodium cyanoborohydride-Tin(II) chloride, 280... 

Dihydro-1,4-benzothiazines are generally more reactive, and direct N-alkylation has been reported, but this reaction is not always straightforward.21 Funke et al. could not alkylate 2-phenyldihydro-l,4-benzothiazine with co-chloramines, even under forcing conditions.90 However, later work showed that this reaction was possible in toluene solution,37 and other workers have also reported direct alkylations.143 The l,4-benzothiazin-3-ones are, however, more easily alkylated, and reduction of the N-alkyl derivatives of these compounds, usually with lithium aluminum hydride, affords the corresponding N-alkyldihydro-1,4-benzothiazines.52,56 70 90,154 These products can also be prepared in one step from the corresponding 1,4-benzothiazines, e.g., Ill - 112, presumably via intermediate dihydro-1,4-benzothiazines, by sodium borohydride in the presence of a carboxylic acid. Boron derivatives, such as Na[(RCOO)3BH] and Na[(RCOO)4B] are suggested as the species responsible for N—C bond formation.155... 

Phosphorus-containing compounds provide useful substrates for ozonolysis reactions as well and can provide several products depending on the reaction workup. Several biological uses exist for -amino-a-hydroxy phosphonic acid derivatives and they can be readily prepared by ozonolysis of Al-(ethoxycarbonyl)-/3-amino-Q -methylene phosphonic esters after reductive workup with sodium borohydride (eq 54). When the reaction mixture is treated with sodium hydroxide in MeOH, an anomalous ozonolysis reaction occurs and cleavage of the methylene as well as the carbon-phosphorus bond occurs to yield (V-(ethoxycarbonyl)-a-amino methyl carboxylic esters. 

Reduction of ketones with sodium borohydride in the presence of a carboxylic acid and 1,2 5,6-di-0-cyclohexylidene-a -D-glucofuranose gave 35-50% enantiomeric enhancement values.Another group has reported a similar reaction with the corresponding di-O-isopropylidene-glucose derivative and prochiral aromatic ketones. Optical yields of up to 64% were claimed. The chiral reagents appear to be sodium acyloxyborohydrides, which complex with the carbohydrate before reduction takes place. 

Synthesis of Esters and Aldehydes. Monoalkylation of methylthiomethyl p-tolyl sulfone (MT-sulfone) with an alkyl halide is achieved by the action of a phase-transfer catalyst (PTC) in toluene-50% aq NaOH. sodium hydride and butyl-lithium also generate a carbanion of MT-sulfone. Arylmethyl derivatives of MT-sulfone are prepared by sodium borohydride reduction of the Knoevenagel condensation products with aromatic aldehydes. The monoalkylated products are converted into the corresponding methyl esters (eq 1). This functionalization can be utilized for synthesizing a-alkoxy carboxylic esters (eq 2) and Q -amino acids (eq 3). ... 

Carboxylic acids, their esters, and amides are usually resistant to sodium borohydride reduction, whereas carboxylic acid chlorides may be reduced in inert solvents to give alcohols. Where this proves unsatisfactory a new alternative procedure for acid chloride reduction in ether solution involves sodium borohydride adsorbed on alumina. Other recently published borohydride reductions of acid derivatives to primary alcohols include those of the 1-succinimidyl esters (8)" and the N-nitroso-amides (9). 2-Methoxyethoxymethyl (MEM) esters have the possibility of co-ordinating the metal cation of complex hydrides at the MEM group, and hence of activating the carbonyl group towards reduction by intramolecular hydride delivery. The selective reduction of the less hindered ester group in the bis-MEM ester (10) to give (11) illustrates this idea. 

Effective and selective reductions of carboxylic acids and their derivatives by eight categories of sodium borohydride reduction systems have been reviewed. The recent progress in establishing reaction mechanism and optimum conditions, as well as the reduction capacity and scope of application of the reduction systems has been discussed. i ... 

A -Protected amino acids and peptides are rapidly converted to the corresponding amino alcohols in high yields with complete retention of optical purity via reduction of the mixed anhydride by cold Sodium Borohydride in THE with dropwise addition of methanol (eq 16). The disulfide bridges of cystine, the methyl and benzyl esters of w-carboxyl-protected glutamic and aspartic acids of peptides, and Ai-Cbz and IV-Boc protection are compatible with the methodology. The anhydrides derived from ethyl chloroformate are superior to isobutyl and benzyl carbonates both in terms of yield and retention of optical purity. 

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