LiAlH4, reaction with carboxylic acids

It should finally be pointed out that trimethylsilyl ethers can also be transformed directly into other functionalities. Oxidation with NBS leads to ketones and aldehydes, treatment with LiAlH4/AlCl3 results in deoxygenation of the alcohol,reaction with carboxylic acid anhydrides in the presence of 6F3 OEt2 prepuces esters and on treatment with PhsP Bra acid bromides are formed directly from TMSesters. 59... 

Alternatively, borane in tetrahydrofuran (BH/THF) is a useful reagent for reducing carboxylic acids to primary alcohols. Reaction of an acid with BH3/THF occurs rapidly at room temperature, and the procedure is often preferred to reduction with LiAlH because of its relative ease, safety, and specificity. Borane reacts with carboxylic acids faster than with any other functional group, thereby allowing selective transformations such as that shown below on p-nitrophenylacetic acid. If the reduction of p-nitrophenyl-acetic acid were done with LiAlH4, both nitro and carboxyl groups would be reduced. 

The epimeric 2-hydroxymethyl-5,6-exo-trimethylenenorbomanes on reaction with sulphuric acid in pentane yield 4-homoisotwistane (811). Seychellene, which possesses the homoisotwistane skeleton, on conversion to its unstable epoxide, which was stored in the presence of light and air before reduction with LiAlH4, was transformed into the abnormal oxidation product norseychelanol (812) a scheme based on dioxetan formation was proposed. Bromination or Koch-Haaf carboxylation of (811) produces the appropriate 3-substituted derivative, indicating that C-3 in (811) is at least as reactive as the 1-position in adamantane, while the 1- and 8-positions in (811) are unreactive. The 3-bromo-derivative (813) is solvolytically more reactive than 1-bromoadamantane, and reaction with sodamide in boiling toluene yielded the anti-Bredt olefin (815) which could be isolated in 52% yield (815) exhibited typical... 

Reactions of carboxylic acids can be grouped into the four categories indicated in Figure 15.2. Of the four, we ve already discussed the acidic behavior of carboxylic acids in Sections 15.2 and 15.3, and we mentioned reduction by reaction of the acid with LiAlH4 in Section 13.3. The remaining two categories are examples of fundamental carbonyl-group reaction mechanisms— nucleophilic acyl substitution and a substitution—that will he discussed in detail in Chapters 16 and 17. 

Reactions of carboxylic acids (Section 15.6) Reduction with LiAlH4 to give alcohols... 

An anti-selective diastereoselective aldol reaction [14] has been performed by using enantiomerically pure carboxylic esters derived from (-) or (+) norephedrine 30 [15], This method is applicable to a wide range of aldehydes with high selectivity (both syn/anti and diastereoselectivity of anti isomer). It is proposed that ( ) boron enolates 31 are formed by this procedure and aldol reaction proceeds via the six-membered transition state (Eq. (14)). The aldol products 32 are converted to the corresponding alcohols (LiAlH4 THF) or carboxylic acids (LiOH, THF-H2O) without loss of stereochemical integrity. 

Alcohols are among the most versatile of all organic compounds. They occur widely in nature, are important industrial 7, and have an unusually rich chemistry. The most widely used methods of alcohol synthesis start with carbonyl compounds. Aldehydes, ketones, esters, and carboxylic acids are reduced by reaction with LiAlH4. Aldehydes, esters, and carboxylic acids yield primary alcohols (RCH2OH) on reduction ketones yield secondary alcohols (R2CHOH). 

Carboxyl redution. A sample of pennethylated PI (5 mg) was carboxyl-reduced by a modification of the method described by Lindberg and Lbnngren [9], as follows. The methylated fraction was solubilized and added a mixture of LiAlH4 (25 mg) in THF (5 mL) at 20 °C for 4 h. and refluxed during 1 h. The excess of reagent was destroyed with ethyl acetate (5-6 drops) and water (10 drops) and the pH of the mixture adjusted to neutrality with acetic acid. The insoluble residue was removed by centrifugation. The reduced fi action was precipitated with EtOH. The reaction was monitored by l.r. specroscopy. Hydrolysis products were analysed by GC-MS as methyl alditol acetates... 

LiAlH4 usually reduces open-chain anhydrides to give 2 moles of alcohol, With cyclic anhydrides the reaction with LiAIH4 can be controlled to give either diols or lactones572 (see 9-41). NaBH4 in THF, with dropwise addition of methanol, reduces open-chain anhydrides to one mole of primary alcohol and one mole of carboxylic acid.573 OS VI, 482. 

Piperidine 141 was synthesized from the Barton-McCombie reaction <75JCSP11574> of 142 which gave the expected amido-ester (96 %) as a 3 2-mixture of diastereomers. The mixture was hydrolyzed to the corresponding carboxylic acid which, upon thermal decarboxylation, gave the desired /V-bcnzyl lactam (85% overall yield) as a single diastereomer whose structure was unequivocally established by a single-crystal X-ray analysis. Reduction of the lactam with LiAlH4 (81%) followed by debenzylation via... 

The methyl ester of lO-methylphenothiazine-4-carboxylic acid was converted into the 4-hydroxymethyl derivative on reaction with LiAlH4 the product was identical to that obtained on metalation... 

The ideas for delocalization of nitrogen lone pair electron density into an aromatic or heteroaromatic system were pursued through reduction of acylated pyrazoles and imidazoles to aldehydes in high yield. 3,5-Dimethyl-A -acylpyrazoles are easy to prepare and afford 77-96% yields of aldehydes with LiAlH4 in diethyl ether at 0 Further examples of this reaction have appeared.Although these later publications commented unfavorably on the ability of LiAlH4 to reduce acyl imidazoles to aldehydes (low yields), other workers have demonstrated that yields of 60-80% could be attained at temperatures of -20 to 4-20 °C in diethyl ether.It was considered that the earlier failure may have been caused by the presence of impurities in the acyl imidazoles. The latter are easy to prepare from the parent carboxylic acid and A jV -carbonyldiimidazole. 

Reduction Conversion of Amides Into Amines (RCONHj —> RCH2NH2) Like other carboxylic acid derivatives, amides can be reduced by LiAlH4. The product of the reduction, however, is an amine rather than an alcohol. The net effect of an amide reduction reaction is thus to convert the amide carbonyl group into a methylene group (C=0 —> CH2). This kind of reaction is specific for amides and does not occur with other carboxyl acid derivatives. 

An alternate route to fluoroolefins relies upon the ease of reduction of difluoroolefins(18). Reduction of 114 with sodium bis(2-methoxyethoxy)aluminum hydride (Scheme 35) afforded the fluoroolefins 115 and 116 considerably enriched with the (E)-isomer 116. In a complementary reaction, reduction of the allylic alcohol 117 with LiAlH4 afforded selectively the (Z)-isomer 118. The difluoromethacrylic acid (121) was prepared in similar manner from 120 (Scheme 36) (53 for related examples see references 75 and 76). Under more forcing conditions, further reduction afforded 3-fluoromethacrylic acid 122. Of more general use is the reaction of 120 with Grignard reagents whereupon the 1,4-addition elimination mechanism offers an entry into a-difluoromethylene substituted aliphatic and aromatic carboxylic acids 123. Ester enolates (125) have been shown to add to trifluoropropene (124) forming the difluoroolefins (126) (Scheme 37) (54). 

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