Aldehydes from carboxylic acid derivative

A common procedure in C-C-bond formation is the aldol addition of enolates derived from carboxylic acid derivatives with aldehydes to provide the anion of the [5-hydroxy carboxylic acid derivative. If one starts with an activated acid derivative, the formation of a [Mac lone can follow. This procedure has been used by the group of Taylor [137] for the first synthesis of the l-oxo-2-oxa-5-azaspiro[3.4]octane framework. Schick and coworkers have utilized the method for their assembly of key intermediates for the preparation of enzyme inhibitors of the tetrahydrolipstatin and tetrahydroesterastin type [138]. Romo and coworkers used a Mukaiyama aldol/lac-tonization sequence as a concise and direct route to 3-lactones of type 2-253, starting from different aldehydes 2-251 and readily available thiopyridylsilylketenes 2-252 (Scheme 2.60) [139]. 

The a-hydrogens of carboxylic acid derivatives show enhanced acidity, as do those of aldehydes and ketones, and for the same reasons, that the carbonyl group stabilizes the conjugate base. Thus, we can generate enolate anions from carboxylic acid derivatives and use these as nucleophiles in much the same way as we have already seen with enolate anions from aldehydes and ketones. 

Until about 1950, reduction of carboxylic acids and their derivatives to aldehydes was not straightforward, and even one of the best methods, the Rosenmund hydrogenation of acid chlorides, required very careful control of both the reaction conditions and preparation of catalyst. The advent of aluminum and boron hydrides and their ready commercial availability transformeKl the situation to such an extent that the formation of aldehydes from carboxylic acids, acid chlorides, esters, amides, nitriles and similar groups in the presence of other reducible functional groups has become a relatively easy operation on both small and large scale. 

One possible retrosynthetic strategy for an alcohol TM is to simply convert the hydroxyl group to another functional group from which the hydroxyl can be derived, leaving the carbon chain intact. The possible starting materials include alkyl halides, alkenes and carbonyl-containing compounds (ketone, aldehyde, and carboxylic acid derivative). 

The signal for an aldehyde hydrogen typically appears between 8 9.5 and 8 10.1 in a H-NMR spectrum. Because almost nothing else absorbs in this region, it is very useful for identification. Hydrogens on an a-carbon (carbon directly adjacent to carbonyl) of an aldehyde or a ketone appear around 8 2.2 to 2.6. The carbonyl carbons of aldehydes and ketones have characteristic positions in the C-NMR between 8 180 and 8 215 (and can be distinguished from carboxylic acid derivatives, which absorb at a higher field). 

The chemistry of carboxylic acid derivatives is different from the chemistry of ketones and aldehydes, because carboxylic acid derivatives possess a built-in leaving group, which allows the carbonyl group to re-form after being attacked ... 

We recall that an aldol condensation occurs by attack of a carbanion derived from an aldehyde or ketone on the carbonyl carbon atom of a second molecule of an aldehyde or ketone. The product is a (3-hydroxy carbonyl compound, or an a,P-unsaturated carbonyl dehydration product. Aldol-type condensations also occur when the carbanion is derived from carboxylic acid derivatives. 

The chemistry of the carbonyl group is probably the single most important aspect of organic chemical reactivity Classes of compounds that contain the carbonyl group include many derived from carboxylic acids (acyl chlorides acid anhydrides esters and amides) as well as the two related classes discussed m this chapter aldehydes and ketones... 

In addition to those methods already discussed, ketones can also be prepared from certain carboxylic acid derivatives, just as aldehydes can. Among the most useful reactions of this type is that between an acid chloride and a Gilman diorganocopper reagent such as we saw in Section 10.8. We ll discuss this subject in more detail in Section 21.4. 

Figure 19.14 Carboxylic acid derivatives have an electronegative substituent Y = -Br, —Cl, -OR, -NR2 that can be expelled as a leaving group from the tetrahedral intermediate formed by nucleophilic addition. Aldehydes and ketones have no such leaving group and thus do not usually undergo this reaction.

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

More recent developments in the field of the Pirkle-type CSPs are the mixed r-donor/ r-acceptor phases such as the Whelk-Of and the Whelk-02 phases.The Whelk-Of is useful for the separation of underiva-tized enantiomers from a number of families, including amides, epoxides, esters, ureas, carbamates, ethers, aziridines, phosphonates, aldehydes, ketones, carboxylic acids, alcohols and non-steroidal anti-inflammatory drugs.It has been used for the separation of warfarin, aryl-amides,aryl-epoxides and aryl-sulphoxides. The phase has broader applicability than the original Pirkle phases. The broad versatility observed on this phase compares with the polysaccharide-derived CSPs... 

The initial reaction is effectively the same as with an aldehyde or ketone, in that hydride is transferred from the reducing agent, and that the tetrahedral anionic intermediate then complexes with the Lewis acid aluminium hydride. However, the typical reactivity of the carboxylic acid derivatives arises because of the presence of a leaving group. 

An enolate anion generated from a carboxylic acid derivative may be used in the same sorts of nucleophilic reactions that we have seen with aldehyde and ketone systems. It should be noted, however, that the base used to generate the enolate anion must be chosen carefully. If sodium hydroxide were used, then hydrolysis of the carboxylic derivative to the acid (see Section 7.9.2) would compete with enolate anion formation. However, the problem is avoided by using the same base, e.g. ethoxide, as is present in the ester... 

Nucleophilic addition of an enolate anion from a carboxylic acid derivative onto an aldehyde or ketone is simply an aldol-type reaction (see Section 10.3). 

Now this is exactly the same situation we encountered when we compared the reactivity of aldehydes and ketones with that of carboxylic acid derivatives (see Section 7.8). The net result here is acylation of the nucleophile, and in the case of acylation of enolate anions, the reaction is termed a Claisen reaction. It is important not to consider aldol and Claisen reactions separately, but to appreciate that the initial addition is the same, and differences in products merely result from the absence or presence... 

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