Ester with LiAlH

Carboxylic esters have been reduced to aldehydes with DIBALH at -70°C, with di-aminoaluminum hydrides,1224 with LiAlH E NH,1226 and with NaAlH4 at -65 to -45°C, and (for phenolic esters) with LiAlH(0-/-Bu)3 at (fC.1227 Aldehydes have also been prepared by reducing ethyl thiol esters RCOSEt with Et3SiH and a Pd-C catalyst.1228... 

Problem 21.20 Show the products you would obtain by reduction of the following esters with LiAlH. ... 

The hydrogenolyaia of cyclopropane rings (C—C bond cleavage) has been described on p, 105. In syntheses of complex molecules reductive cleavage of alcohols, epoxides, and enol ethers of 5-keto esters are the most important examples, and some selectivity rules will be given. Primary alcohols are converted into tosylates much faster than secondary alcohols. The tosylate group is substituted by hydrogen upon treatment with LiAlH (W. Zorbach, 1961). Epoxides are also easily opened by LiAlH. The hydride ion attacks the less hindered carbon atom of the epoxide (H.B. Henhest, 1956). The reduction of sterically hindered enol ethers of 9-keto esters with lithium in ammonia leads to the a,/S-unsaturated ester and subsequently to the saturated ester in reasonable yields (R.M. Coates, 1970). Tributyltin hydride reduces halides to hydrocarbons stereoselectively in a free-radical chain reaction (L.W. Menapace, 1964) and reacts only slowly with C 0 and C—C double bonds (W.T. Brady, 1970 H.G. Kuivila, 1968). 

Primary and secondary amines also react with epoxides (or in situ produced episulfides )r aziridines)to /J-hydroxyamines (or /J-mercaptoamines or 1,2-diamines). The Michael type iddition of amines to activated C—C double bonds is also a useful synthetic reaction. Rnally unines react readily with. carbonyl compounds to form imines and enamines and with carbo-tylic acid chlorides or esters to give amides which can be reduced to amines with LiAlH (p. Ilf.). All these reactions are often applied in synthesis to produce polycyclic alkaloids with itrogen bridgeheads (J.W. Huffman, 1967) G. Stork, 1963 S.S. Klioze, 1975). 

Ketone 5 was converted to acetal 27 with ethylene glycol (Scheme 9), and 27 was reduced with LiAlH The diol 28 was then boiled in concentrated aqueous HC1 to provide the tricyclic lactone 29 in ca. 60% yield. The selectivity of the LiAltLi for the esters over the CN group was noteworthy. Another nice feature of this step was the lactonization, which served to differentiate the two CH2OH groups in 28. 

The chemistry of acid anhydrides is similar to that of acid chlorides. Although anhydrides react more slowly than acid chlorides, the kinds of reactions the two groups undergo are the same. Thus, acid anhydrides react with water to form acids, with alcohols to form esters, with amines to form amides, and with LiAlH.i to form primary alcohols (Figure 21.7, p. 864). 

Reduction Conversion of Esters into Alcohols (RCO3R —> RCH2OH) Esters are easily reduced by treatment with LiAlH to yield primary alcohols (Section 17.5). 

All diamino alcohols (2a-g) were derived from N-Z-(S)-proline via the intermediate N-[(N-benzyloxycarbonyl)prolyl]proline methyl ester (4). The diamino alcohol 2a WHS obtained by the reduction of 4 with LiAlH, and 2b-e were obtained by the reaction of 4 with the corresponding Grignard reagents. Diamino alcohols 2f-g and triamino alcohol 5 were obtained by the following sequence of reactions ... 

Reaction of conjugated carbonyls with LiAlH(Ot-Bu)3 gives primarily 1,2-reduction, as in the quantitative reduction of 78 to 79 in Marshall s synthesis of globulol. goth sulfonate esters such as the mesylate group in 78, and halides are resistant to reduction with LiAlH(Of Bu)3. 

Quantitative Distribution of Adducts as a Function of Dienophile Stereochemistry. For accurate quantitation of the isomer distribution in the products of cycloaddition to each of the dienophiles 5—8, the entire mixtures of the four stereoisomeric products in each instance were first subjected to sequential Q-deacetylation and periodate oxidation to afford a mixture of two aldehydo esters 29 and 30, which upon reduction with LiAlH afforded trans-2-norbornene-5,6-dimethanol as an unequal mixture of the two enantiomers (only the 5S,6g enantiomer is shown). NMR analysis of the mixture of 29 and 30 showed distinctive resonances for the CH3O and CHO groups in exo and endo orientations, permitting accurate determination of the endo/exo ratio of the products in the mixture. The observed specific rotation of the diol, in comparison with that (+23 ) determined for the enantiomerically pure 5S,6S diol 26 (and its enantiomer), provided a quantitative measure of the si.re diastereofacial selectivity. 

The key in each part is to convert the carboxylic acid to an amide and then to reduce the amide with LiAlH. The amide can be prepared by treating the carboxylic acid with SOCI2 to give the acid chloride (Section 17.8) and then treating the acid chloride with an amine (Section 18.6A). Alternatively the carboxylic acid can be converted to an ethyl ester by Fischer esterification, and the ester can then be treated with an amine to give the amide. Solution (a) uses the acid chloride route, and solution (b) uses the ester route. 

Prepare methyl ester (a) by Fischer esterification of phenylacetic acid with methanol. Then treat this ester with ammonia to prepare amide (b). Alternatively, treat phenylacetic acid with thionyl chloride (Section 17.8) to give an acid chloride. Then treat this acid chloride with ammonia to give amide (b). Reduction of the amide (b) by LiAlH gives the primary amine (c). Similar reduction of either phenylacetic acid or ester (a) gives alcohol (d). 

Yields of primary and secondary alcohols are generally excellent, but esters such as methyl benzoate were not reduced. Results of typical examples are listed in Table I. Both 2 and 3 predominantly afforded 2-cyclohexenol as the 1,2 reduction product from 2-cyclohexenone. Chemoselectivity in the reduction was also demonstrated by the competitive reduction of a mixture of pentanal and cyclohexanone. The ratios of primary and secondary alcohols were 75/25 for 2 at 0 °C and 79/21 for 3 at room temperature. These values are fairly larger than the corresponding one (63/37) from a mixture of butanal and methyl ethyl ketone reduced by LiAlH at 25 but smaller than those from a mixture of hexanal and cyclohexanone with LiAlH(0-f-Bu)3 at 0 °C (87/13) and LiAlH(OCEt3)3 at 0 °C (94/6).10... 

The bicyclization commences with the hydroformylation of an appropriate N-substituted allyl amide, producing the linear aldehyde as the main product. The compound undergoes spontaneous intramolecular cyclization. The final product of this domino reaction is formed by the reaction with the solvent (AcOH). Subsequent oxidation of the acylic keto group to the corresponding ester and reduction with LiAlH produced the targeted racemic natural compound with 33% overall yield over four steps. 

The individual methyl esters were reduced with LiAlH, at 0 C and gave the corresponding aldehyde hydrates, which were dehydrated in the usual way. This route is the preferred method for the preparation of FDBA. (Eqn. 7)... 

It is sometimes necessary to reduce a functionalized site to a CH or CH group. Starting from the acid level of oxidation, this is usually done in two stages. For example, an ester may be reduced to an alcohol with LiAlH, the alcohol converted to a tosylate, and then reduced again to a CH group. Ketones and aldehydes can be reduced completely via the tosylhydrazone using catecholborane followed by decomposition of the hydroboration intermediate as in Equation 6.71 [116]. 

The conversion of carboxylic acid derivatives (halides, esters and lactones, tertiary amides and lactams, nitriles) into aldehydes can be achieved with bulky aluminum hydrides (e.g. DIBAL = diisobutylaluminum hydride, lithium trialkoxyalanates). Simple addition of three equivalents of an alcohol to LiAlH, in THF solution produces those deactivated and selective reagents, e.g. lithium triisopropoxyalanate, LiAlH(OPr )j (J. Malek, 1972). 

Commercially, pure ozonides generally are not isolated or handled because of the explosive nature of lower molecular weight species. Ozonides can be hydrolyzed or reduced (eg, by Zn/CH COOH) to aldehydes and/or ketones. Hydrolysis of the cycHc bisperoxide (8) gives similar products. Catalytic (Pt/excess H2) or hydride (eg, LiAlH reduction of (7) provides alcohols. Oxidation (O2, H2O2, peracids) leads to ketones and/or carboxyUc acids. Ozonides also can be catalyticaHy converted to amines by NH and H2. Reaction with an alcohol and anhydrous HCl gives carboxyUc esters. 

Reduction with Metals and Metal Hydrides. Practically any ester can be reduced by Na—C2H OH, Li or Na—NH, LiAlH, LiBH, or NaBH to give alcohols in excellent yield (35,36). Carbon-carbon double bonds are usually preserved using these reducing reagents. 

Expecting that the introduction of 1,2-dimethyl substituents to ( )-cycIoalkenes should increase non-bonding interaction across the ring, Marshall and coworkers 29) prepared (—)-( )-l,2-dimethylcyclodecene (27a) and showed that this compound is optically quite stable. In their synthetic approach to 27a, they started from the p-keto ester 24 which was converted into (+)-25 through a sequence of reactions involving condensation with 3-buten-2-one, LiAlH reduction, and resolution via the camphor-... 

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