Electrophilic aldehydes

Penicilloic acid 5, the substrate for the projected lactamization reaction, could be derived from the suitably protected intermediate 6. Retrosynthetic disassembly of 6, in the manner illustrated, provides D-penicillamine hydrochloride (7) and tert-butyl phthalimido-malonaldehydate (8) as potential building blocks. In the synthetic direction, it is conceivable that the thiol and amino groupings in 7 could be induced to converge upon the electrophilic aldehyde carbonyl in 8 to give thiazolidine 6 after loss of a molecule of water. 

Qualitative spot tests for aldehydes, in the presence of ketones, are generally only reliable for water-soluble compounds. This problem can be overcome by the use of 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (Purpald , Aldrich Chemical Company) in the presence of Aliquat (Scheme 5.27). Under aerial oxidation, the initially formed colourless cyclic adduct changes colour through red to purple. The colourless cyclic aminal can also be formed by ketones, but only the adducts derived from the aldehydes are oxidized to the purple bicyclic aromatic system [28]. Weakly electrophilic aldehydes, e.g., 4-methoxybenzaldehyde, reacts slowly, but will give the positive coloration upon gentle heating to ca. 70°C for one or two minutes. 

Acceptor-monosubstituted diazomethanes can be further converted into other types of diazo compound. C-Acylation of diazoacetic esters generally requires very reactive acylating agents, such as acid chlorides [969,970] or bromides [971]. C-Alkylations of acyldiazomethanes are best accomplished by metallation followed by treatment with a carbon electrophile [972-977], C-alkylation can also occur without any base if sufficiently electrophilic aldehydes or ketones are used [973,978 -982] or if the alkylation proceeds intramolecularly [983]. 

Dondoni pioneered the use of 2-(trimethylsilyl)thiazole (71) as a formyl anion equivalent for the homologation of aldehydes. Extension of this reaction to ketones would be very useful, but has thus far been restricted to tritluoromethyl cases. However, it has now been widened to include several a, a -alkoxy ketones, as demonstrated in a new route to branched-chain monosaccharides. Aldehydes catalyse the reaction, although the scope is still limited electrophilic aldehydes, such as 2-fluorobenzaldehyde, promote the addition of (71) to electrophilic ketones. 

The benzoin reaction dates back to 1832 when Wohler and Liebig reported that cyanide catalyzes the formation of benzoin 6 from benzaldehyde 5, a seminal example in which the normal mode of polarity of a functional group was reversed (Eq. 1) [26], This reversal of polarity, subsequently termed Umpolung [27], effectively changes an electrophilic aldehyde into a nucleophilic acyl anion equivalent. 

For aU the chiral intermediates above mentioned (253, 257 and 258) the reaction with prochiral electrophiles (aldehydes or differently substituted ketones) gave a c 1 1 mixture of diastereomers so, as occurred in other chiral functionalized organolithium compounds, the asymmetric induction is practically non-existent. 

With tamoxifen, loss of the sulfate group cleaves the bond and yields a benzylic carbocation. In the case of diclofenac, the carbonyl carbon is reactive and can react with nucleophiles (Fig. 4.54), but the conjugate can also rearrange and yield a reactive, electrophilic aldehyde. 

Enolates are important nucleophiles which react nicely with a variety of carbonyl compounds. In this case, the nucleophilic reactivity of the enolate and the electrophilic reactivity of the carbonyl group are well matched and a wide variety of products can be made. The type of enolate (ketone, ester, etc.) and the type of carbonyl electrophile (aldehyde, ketone, ester, etc.) determine the structure of the final product. Furthermore these reactions are often named according to the two partners that are reacted and the type of product produced from them. 

This chapter will be divided into sections according to the electrophiles aldehydes and ketones, imines and iminium salts, carboxylic acid derivatives and finally a,P-unsaturated carbonyl compounds, which undergo conjugate additions. Further subdivision will be made according to the nature of the nucleophile, i.e. 0-, N-, S-, P- or C-nucleophiles. Finally, multicomponent heterocyclic syntheses will be mentioned, if they consist at least of one iron-catalyzed addition step to a carbonyl compound. 

The next steps involve attack of the deprotonated ligand upon a second equivalent of the electrophilic aldehyde. This generates an alkoxide, which undergoes an intramolecular nucleophilic attack upon the imine to give a co-ordinated oxazolidinene, 5.9 (Fig. 5-19). 

Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the normal carbonyl charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation A thiazolium salt may also be used as the catalyst in this reaction. 

An alternative strategy for preparation of monoacylated 1,2- and 1,3-diols is oxidative deavage of cyclic acetals prepared from a diol and an aliphatic or aromatic aldehyde (Scheme 10.7). For this purpose the required acetal does not need to be isolated, but can be generated in situ [25]. Acetals prepared from strongly electrophilic aldehydes, for example nitrobenzaldehydes, will, however, usually be difficult to oxidize (and to hydrolyze). 

Apart from enzymes and catalytic antibodies, chemical catalysis has been shown to be of utility for such a transformation by using either metal-containing complexes or purely organic molecules. In both cases, the catalyst plays a key role in activating both the pronucleophilic carbonyl compound and the electrophilic aldehyde it also imparts effective stereoinduction. The most representative metal-ligand complexes and organocatalysts yet reported in this context [7] are depicted in Figs. 1 and 2, respectively. 

The hydrocyanation reactions of electrophilic aldehydes, ketones and their corresponding imines gives direct access to synthetic derivatives of several important structures, including a-hydroxy carboxylic acids, / -amino alcohols and a-tertiary and a-quaternary-a-amino acids. The asymmetric hydrocyanation reaction provides access to chiral synthons, which have proven useful for the construction of many structurally complex and biologically active compounds. Catalysis of these reactions is especially attractive with respect to avoiding the cost and relative chemical inefficiency associated with the use of chiral auxiliaries. 

Mechanistically, the antibody aldolases resemble natural class I aldolase enzymes (Scheme 4.7) [52]. In the first step of a condensation reaction, the s-amino group of the catalytic lysine reacts with a ketone to form a Schiffbase. Deprotonation of this species yields a nucleophilic enamine, which condenses with electrophilic aldehydes in a second step to form a new carbon-carbon bond. Subsequent hydrolysis of the Schiffbase releases product and regenerates the active catalyst. 

These organocopper reagents (equation I) react with various electrophiles, aldehydes, acid chlorides, enones, allylic bromides, in 85-95% yield."... 

Aldehydes are so electrophilic that, even with LDA at -78°C, the rate at which the deprotonation takes place is not fast enough to outpace reactions between the forming lithium enolate and still-to-be-deproton ated aldehyde remaining in the mixture. Direct addition of the base to the carbonyl group of electrophilic aldehydes can also pose a problem, reactions which compete with aldehyde eno at formation... 

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