Reactions of aldehydes

A more eflicient and general synthetic procedure is the Masamune reaction of aldehydes with boron enolates of chiral a-silyloxy ketones. A double asymmetric induction generates two new chiral centres with enantioselectivities > 99%. It is again explained by a chair-like six-centre transition state. The repulsive interactions of the bulky cyclohexyl group with the vinylic hydrogen and the boron ligands dictate the approach of the enolate to the aldehyde (S. Masamune, 1981 A). The fi-hydroxy-x-methyl ketones obtained are pure threo products (threo = threose- or threonine-like Fischer formula also termed syn" = planar zig-zag chain with substituents on one side), and the reaction has successfully been applied to macrolide syntheses (S. Masamune, 1981 B). Optically pure threo (= syn") 8-hydroxy-a-methyl carboxylic acids are obtained by desilylation and periodate oxidation (S. Masamune, 1981 A). Chiral 0-((S)-trans-2,5-dimethyl-l-borolanyl) ketene thioketals giving pure erythro (= anti ) diastereomers have also been developed by S. Masamune (1986). 

Table 17 2 summarizes the reactions of aldehydes and ketones that you ve seen m ear her chapters All are valuable tools to the synthetic chemist Carbonyl groups provide access to hydrocarbons by Clemmensen or Wolff-Kishner reduction (Section 12 8) to alcohols by reduction (Section 15 2) or by reaction with Grignard or organolithmm reagents (Sections 14 6 and 14 7)... 

Summary of Reactions of Aldehydes and Ketones Discussed in Earlier Chapters... 

With this as background let us now examine how the principles of nucleophilic addition apply to the characteristic reactions of aldehydes and ketones We 11 begin with the addition of hydrogen cyanide... 

Many of the most interesting and useful reactions of aldehydes and ketones involve trans formation of the initial product of nucleophilic addition to some other substance under the reaction conditions An example is the reaction of aldehydes with alcohols under con ditions of acid catalysis The expected product of nucleophilic addition of the alcohol to the carbonyl group is called a hemiacetal The product actually isolated however cor responds to reaction of one mole of the aldehyde with two moles of alcohol to give gem mal diethers known as acetals... 

The characteristic reactions of aldehydes and ketones involve nude ophihc addition to the carbonyl group and are summarized m Table 17 5 Reagents of the type HY react according to the general equation... 

Reactions of Aldehydes and Ketones That Involve Enol or Enolate Ion Intermediates... 

Aldehydes. Alkyleneamines react exothermically with ahphatic aldehydes. The products depend on stoichiometry, reaction conditions, and stmcture of the alkyleneamine. Reactions of aldehydes with ethyleneamines like EDA or DETA give mono- and disubstituted imidazohdines via cyclization of the intermediate Schiff base (20). 

Scheme 8.2. Addition-Elimination Reactions of Aldehydes and Ketones...

Knoevenagel reaction is the synthesis of a, p-unsaturated acids by reaction of aldehydes and compounds with active methylene groups in the presence of an organic base... 

A fluorine-hydrogen migration is typical for the reactions of aldehydes branched at the carbon atom a to the formyl group. Comparable amounts of 1,1 -difluoroalkanes and 1,2-difluoroalkanes together with bis(l -fluoroalkyl) ethers are obtained [169] (equation 84). 

Sections The characteristic reactions of aldehydes and ketones involve nticle-... 

Other than nucleophilic addition to the carbonyl group, the most important reactions of aldehydes and ketones involve replacing an a hydrogen. A par ticularly well studied exfflnple is halogenation of aldehydes and ketones. 

A class of nitrogen-containing compounds that was omitted from the section just discussed includes imines and their- derivatives. Irnines are formed by the reaction of aldehydes and ketones with ammonia. Imines can be reduced to primary amines by catalytic hydrogenation. 

Additional evidence that a dynamic equilibrium exists between an enamine, N-hemiacetal, and aminal has been presented by Marchese (41). It should be noted that no acid catalysts were used in the reactions of aldehydes and amines discussed thus far. The piperidino enamine of 2-ethylhexanal (0.125 mole), morpholine (0.375 mole), and p-toluene-sulfonic acid (1.25 x 10 mole) diluted with benzene to 500 ml were refluxed for 5 hr. At the end of this time the enamine mixture was analyzed by vapor-phase chromatography, which revealed that exchange of the amino residue had occurred in a ratio of eight morpholine to one piperidine. Marchese proposed a scheme [Eqs. (4), (5) and (6)] to account for these... 

The initial investigation of the reaction of aldehydes and ketones with complex secondary amine salts was that of Lamchen et al. (11). A few salts had been observed before by Zincke and Wiirker (24), but the reaction was not examined in detail. Lamchen et al. prepared a number of compounds that were presumed to be iminium salts. The amine salts were halostannates, halobismuthates, haloantimonates, and hexahaloplatinates. Among the reported products were N-ethylidenepiperidinium (13) and N-cinnamili-denetetrahydroisoquinolinium (14) salts. 

Hydrazine and its derivatives find considerable use in the synthesis of biologically active materials, dyestuff intermediates and other organic derivatives. Reactions of aldehydes to form hydrazides (RCH=NNH2) and azines (RCH=NN=CHR) are well known in organic chemistry, as is the use of hydrazine and its derivatives in the synthesis of heterocyclic compounds. 

Stereoselective epoxidation can be realized through either substrate-controlled (e.g. 35 —> 36) or reagent-controlled approaches. A classic example is the epoxidation of 4-t-butylcyclohexanone. When sulfonium ylide 2 was utilized, the more reactive ylide irreversibly attacked the carbonyl from the axial direction to offer predominantly epoxide 37. When the less reactive sulfoxonium ylide 1 was used, the nucleophilic addition to the carbonyl was reversible, giving rise to the thermodynamically more stable, equatorially coupled betaine, which subsequently eliminated to deliver epoxide 38. Thus, stereoselective epoxidation was achieved from different mechanistic pathways taken by different sulfur ylides. In another case, reaction of aldehyde 38 with sulfonium ylide 2 only gave moderate stereoselectivity (41 40 = 1.5/1), whereas employment of sulfoxonium ylide 1 led to a ratio of 41 40 = 13/1. The best stereoselectivity was accomplished using aminosulfoxonium ylide 25, leading to a ratio of 41 40 = 30/1. For ketone 42, a complete reversal of stereochemistry was observed when it was treated with sulfoxonium ylide 1 and sulfonium ylide 2, respectively. ... 

An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

The development of the key intermediate, 5-(2-methoxy-4-nitrophenyl)oxazole (25), in the preparation of the hepatitis C drug candidate, VX-497, utilizes a van Leusen reaction of aldehyde 24 with TosMIC. ... 

Workers at Lilly prepared the oxazole-containing partial ergot alkaloid, 27, a 5-HTl A agonist, through van Leusen reaction of aldehyde 26. ... 

In another example reaction of aldehyde 22 and amine 23 gave imine 24 which cyclised under strongly acidic conditions to yield the corresponding isoquinoline 25 in good yields It is interesting that the aldehyde portion 22 is not benzaldehyde derived. 

The [ 2 + 4]-cycloaddition reaction of aldehydes and ketones with 1,3-dienes is a well-established synthetic procedure for the preparation of dihydropyrans which are attractive substrates for the synthesis of carbohydrates and other natural products [2]. Carbonyl compounds are usually of limited reactivity in cycloaddition reactions with dienes, because only electron-deficient carbonyl groups, as in glyoxy-lates, chloral, ketomalonate, 1,2,3-triketones, and related compounds, react with dienes which have electron-donating groups. The use of Lewis acids as catalysts for cycloaddition reactions of carbonyl compounds has, however, led to a new era for this class of reactions in synthetic organic chemistry. In particular, the application of chiral Lewis acid catalysts has provided new opportunities for enantioselec-tive cycloadditions of carbonyl compounds. 

Yamamoto et al. were probably the first to report that chiral aluminum(III) catalysts are effective in the cycloaddition reactions of aldehydes [11]. The use of chiral BINOL-AlMe complexes (R)-S was found to be highly effective in the cycloaddition reaction of a variety of aldehydes with activated Danishefsky-type dienes. The reaction of benzaldehyde la with Danishefsky s diene 2a and traws-l-methoxy-2-methyl-3-(trimethylsilyloxy)-l,3-pentadiene 2b affords cis dihydropyrones, cis-3, as the major product in high yield with up to 97% ee (Scheme 4.6). The choice of the bulky triarylsilyl moiety in catalyst (J )-8b is crucial for high yield and the en-antioselectivity of the reaction in contrast with this the catalysts derived from AlMe3 and (J )-3,3 -disubstituted binaphthol (substituent = H, Me, Ph) were effective in stoichiometric amounts only and were less satisfactory with regard to reactivity and enantioselectivity. 

Chiral boron(III) Lewis acid catalysts have also been used for enantioselective cycloaddition reactions of carbonyl compounds [17]. The chiral acyloxylborane catalysts 9a-9d, which are also efficient catalysts for asymmetric Diels-Alder reactions [17, 18], can also catalyze highly enantioselective cycloaddition reactions of aldehydes with activated dienes. The arylboron catalysts 9b-9c which are air- and moisture-stable have been shown by Yamamoto et al. to induce excellent chiral induction in the cycloaddition reaction between, e.g., benzaldehyde and Danishefsky s dienes such as 2b with up to 95% yield and 97% ee of the cycloaddition product CIS-3b (Scheme 4.9) [17]. 

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