Carboxylic acid derivatives, sodium borohydride

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. 

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

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... 

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... 

Carboxylic acids can also be used as a source of the C-4 atom, and the reaction of a diphenylurea derivative 835 with carboxylic acids in polyphosphoric acid (PPA), followed by treatment of the intermediates 836 with sodium borohydride has been used as a source of 3,4-dihydro-2-quinazolinones 837 <2006H(68)1443>. 

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. 

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... 

Carboxylic acids and acid derivatives are not reduced by the milder reducing agent such as sodium borohydride (NaBH). This reagent can, therefore, be used to reduce aldehydes and ketones without affecting any carboxylic acids or acid derivatives which might be present. 

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. ... 

Amination can be achieved by reductive amination of carboxyl groups using sodium cyano-borohydride [124]. By this method, 2-amino-2-deoxy functionalized amylose and cellulose have been produced. Reductive amination can also be applied to the synthesis of other amino derivatives of various oxidized polysaccharides such us xanthan [125] or alginic acid and galactomannans [126]. 

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... 

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