Carboxylic acid derivatives partial reduction

A third method of aldehyde synthesis is one that we ll mention here just briefly and then return to in Section 21.6. Certain carboxylic acid derivatives can be partially reduced to yield aldehydes. The partial reduction of an ester by dhsobutylaluminum hydride (DIBAH), for instance, is an important laboratory-scale method of aldehyde synthesis, and mechanistically related processes also occur in biological pathways. The reaction is normally carried out at —78 °C (dry-ice temperature) in toluene solution. 

The aldehyde intermediate can be isolated if 1 equivalent of diisobutvl-aluminum hydride (D1BAH) is used as the reducing agent instead of LiAlH4. The reaction has to be carried out at -78 °C to avoid further reduction to the alcohol. Such partial reductions of carboxylic acid derivatives to aldehydes also occur in numerous biological pathways, although the substrate is either a thioester or acyl phosphate rather than an ester. 

One of the more difficult partial reductions to accomplish is the conversion of a carboxylic acid derivative to an aldehyde without over-reduction to the alcohol. Aldehydes are inherently more reactive than acids or esters so the challenge is to stop the reduction at the aldehyde stage. Several approaches have been used to achieve this objective. One is to replace some of the hydrogens in a group III hydride with more bulky groups, thus modifying reactivity by steric factors. Lithium tr i - / - b u to x y a I u m i n u m hydride is an example of this approach.42 Sodium tri-t-butoxyaluminum hydride can also be used to reduce acyl chlorides to aldehydes without over-reduction to the alcohol.43 The excellent solubility of sodium bis(2-methoxyethoxy)aluminum hydride makes it a useful reagent for selective... 

It is possible to reduce a few other carbonyl compounds using catalytic hydrogenation, but not all. Partial reduction is also possible. Carboxylic acid derivatives are an obvious choice, but carboxylic acids themselves, as well as esters, are difficult to reduce by catalytic hydrogenation. Likewise, amides are very difficult to reduce, but acid chlorides are an exception. Acid chlorides are converted to alcohols via catalytic hydrogenation with an excess of hydrogen gas. However, it is also possible to reduce an acid chloride to an aldehyde with the proper catalyst and control of the number of molar equivalents of hydrogen gas. 

On the other hand, following the same sequences from the differently protected serine-derived nitrone 168, through the formation of hydroxylamines 169, C2 epimers of carboxylic acid and aldehydes are obtained, i.e., (2S,3R)-170 and (2S,3R)-171. Moreover, the syn adducts 164 were exclusively obtained in the addition of Grignard reagents to the nitrone 163, whereas the same reactions on nitrone 168 occurred with a partial loss of diastereoselectivity [80]. Q, j6-Diamino acids (2R,3S)- and (2R,3R)-167 can also be prepared from the a-amino hydroxylamines 164 and 169 by reduction, deprotection and oxidation steps. The diastereoselective addition of acetylide anion to N,N-dibenzyl L-serine phenyhmine has been also described [81]. 

A wide-ranging investigation of quinuclidine derivatives was started in 1953 by M. V. Rubtsov who in collaboration with M. I. Dorokhova devised a simple method for preparation of quinuclidine-2-carboxylic acid [62]. The synthesis is basically condensation of y-picoline with mezoxalic esters followed by reduction of the unsaturated diester (IX) to a piperidine compound (X) and cyclization of the bromoderivative thereof (XI) to 2,2-diethoxycarbonylquinuclidine (XII). Hydrolysis and partial decarboxylation of compound XII yield quinuclidine-2-carboxylic acid (XIII), a key substance in the synthesis of the various 2-sub-... 

Substituted aromatic acids provide a route to other cyclohexyl derivatives. An example is the catalytic hydrogenation of the benzene ring in 7.107 to give 4-amino-methyl-1-cyclohexene carboxylic acid, 7.108. Partial reduction of abenzene ring... 

Reduction of nitro derivatives of 2-hydroxy-4-oxo-pyrido[l, 2-a] pyrimidine-3-carboxylates 119 (R = N02, R1 = H R = H, R = N02) could be carried out by zinc and acetic acid to yield the appropriate unsaturated amino derivative (92AJC1825). Catalytic reduction at 1 atm gave only partially reduced products. 

---