Chemoselectivity carboxylic acid reductions

Access to the corresponding enantiopure hydroxy esters 133 and 134 of smaller fragments 2 with R =Me employed a highly stereoselective (ds>95%) Evans aldol reaction of allenic aldehydes 113 and rac-114 with boron enolate 124 followed by silylation to arrive at the y-trimethylsilyloxy allene substrates 125 and 126, respectively, for the crucial oxymercuration/methoxycarbonylation process (Scheme 19). Again, this operation provided the desired tetrahydrofurans 127 and 128 with excellent diastereoselectivity (dr=95 5). Chemoselective hydrolytic cleavage of the chiral auxiliary, chemoselective carboxylic acid reduction, and subsequent diastereoselective chelation-controlled enoate reduction (133 dr of crude product=80 20, 134 dr of crude product=84 16) eventually provided the pure stereoisomers 133 and 134 after preparative HPLC. 

The reactivity of boranes is dominated by the desire to accept an electron pair into the empty p-orbital. Therefore boranes reduce electron-rich carbonyl groups fastest. In the context of carboxylic acid reduction a triacylborate 35 is formed first. Compared to, for example, ketones, esters are less electrophilic because of conjugation between the carbonyl group and the lone pair of the sp -hybridized oxygen atom. However, in the case of boron esters such as 35, the oxygen next to the boron has to share its lone pair between the carbonyl group and the empty p-orbital of the boron. This fact makes them considerably more reactive than normal esters and allows the chemoselective reduction of carboxylic acids in the presence of esters or acyl chlorides. 

N,N-dimethylchloromethylenammonium chloride is a highly chemoselective agent for carboxylic acid reduction. It selectively activate the carboxylic acid and is known to tolerate active functionalities such as ketone as well as the moderate ester, olefin, nitrile and halide moeties. 

The carboxylic acid 150 (Scheme 10.15) was prepared from commercial (-)-carvone (68) via a chemoselective reduction of the terminal olefin using tris... 

Step 2 Chemoselective reduction of a carboxylic acid in the presence of an... 

By conducting the reaction in a flow reactor, where the heat of reaction can be rapidly dissipated, the authors were able to maintain a reaction temperature of 90 °C as a result of adding the nitrating mixture continuously. Coupled with a residence time of 35 min, the authors were able to attain a throughput of 5.5 gh 1 with an overall yield of 73% 219. In addition to the dramatic reduction in residence time (10h-35min) and the increased process safety, the continuous flow methodology afforded a facile route to the chemoselective synthesis of 2-methyl-4-nitro-5-propyl-2H-pyrazole-3-carboxylic acid 219. 

Fig. 6.43. Chemoselective reduction of carboxylic acid chloride to furnish an aldehyde the keto group of the substrate is compatible with these reaction conditions, too.

Fig. 6.34. Chemoselective reduction of free carboxylic acids to aldehydes. Intermediate B yields, upon hydrolysis, initially an aldehyde hydrate, which dehydrates to the aldehyde spontaneously (mechanism Section 7.2.1).

Borane is a highly chemoselective reagent for the reduction of carboxylic acids in the presence of other reducible functional groups such as esters, and even ketones. 

Selective reduction of—COOH to —CH2OH.2 Chemoselective reduction of carboxylic acids is possible by in situ conversion to the carboxymethyleneiminium salt by reaction with the Vilsmeier reagent (DMF and oxalyl chloride). This salt is then reduced with NaBH4 (2 equiv.) to the alcohol (equation I). Various functional groups are tolerated bromo, cyano, ester, and C=C (even when conjugated to COOH). 

Although Smh is more chemoselective than traditional dissolving metal reagents, it does react with sulfoxides, epoxides, the conjugated double bonds of unsaturated ketones, aldehydes and esters, alkyl bromides, iodides and p-toluenesulfonates. It does not, however, reduce carboxylic acids, esters, phosphine oxides or alkyl chlorides. In common with most dissolving metal systems, ketones with an a-hetero substituent suffer loss of the substituent rather than reduction of the carbonyl group. ... 

Alane (AIH3) and its derivatives have also been utilized in the reduction of carboxylic acids to primary alcohols. It rapidly reduces aldehydes, ketones, acid chlorides, lactones, esters, carboxylic acids and salts, tertiary amides, nitriles and epoxides. In contrast, nitro compounds and alkenes are slow to react. AIH3 is particularly useful for the chemoselective reduction of carboxylic acids containing halogen or nitro substituents, to produce the corresponding primary alcohols. DIBAL-H reduces aliphatic or aromatic carboxylic acids to produce either aldehydes (-75 °C) or primary alcohols (25 C) Aminoalu-minum hydrides are less reactive reagents and are superior for aldehyde synthesis. ... 

Many other examples of chemoselective enone reduction in the presence of other reducible functionalities have been reported. For instance, the C—S bonds of many sulfides and thioketals are readily cleaved by dissolving metals. " Yet, there are examples of conjugate reduction of enones in the presence of a thioalkyl ether group." " Selective enone reduction in the presence of a reducible nitrile group was illustrated with another steroidal enone. While carboxylic acids, because of salt formation, are not reduced by dissolving metals, esters" and amides are easily reduced to saturated alcohols and aldehydes or alcohols, respectively. However, metal-ammonia reduction of enones is faster than that of either esters or amides. This allows selective enone reduction in the presence of esters"" and amides - -" using short reaction times and limited amounts of lithium in ammonia. 

Sodium borohydride reduction offers a significant advantage in synthetic applications. The method allows the reductive removal of halides selectively without affecting other functional groups, such as ester, carboxylic acid, nitrile and sulfone. A typical chemoselective dehalogenation is illustrated in Scheme 19. ... 

Lithium tri-t-butoxyaluminum hydride readily reduces aldehydes and ketones to the corresponding alcohols and reduces acid chlorides to aldehydes. Epoxides, esters, carboxylic acids, tert-amides, and nitriles are not, or only slowly, reduced. Thus, the reagent may be used for chemoselective reductions. ... 

A new method for the transformation of —CO2H to —H has been attained by formation of the selenol ester from carboxylic acid, followed by its reduction. Owing to high chemoselectivity and mild reaction conditions, this method is often utilized for the synthesis of natural products (equation 21). ... 

Borane is typically used as a THF (BHs-THF) or dimethylsulfide complex (BH3 SMe2). Although the reactivity of the two complexes is similar, the boron dimethylsulfide species is more stable over longer periods of time. Borane will chemoselectively reduce a carboxylic acid in the presence of an ester or nitrile. Reviews (a) Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis, Wiley-VCH New York, 1997, 2" edition, (b) Brown, H. C. ... 

Carboxylic acids, esters, amides, nitriles, nitro groups and most aromatic nuclei are not reduced under ionic hydrogenation conditions (133). An organosiloxane, polymethylhydrosiloxane [9004-73-3] (PMHS), is most economically favored for large-scale reductions. Polymethylhydrosiloxane is a versatile low cost hydride transfer reagent having a hydride equivalent weight of 60. Reactions are catalyzed by Pd or dibutyltinoxide. The choice of reaction conditions leads to chemoselective reduction, eg, allyl reductions in the presence of ketones and aldehydes (134—136). Esters are reduced to... 

Reduction of the intermediate generated from a carboxylic acid and DMFCl provides aldehydes with Lithium Tri-tert-butoxy-aluminum Hydride, and alcohols with Sodium Borohydride both in high yield and chemoselectivity. 

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