Intramolecular aldol reactions

The aldol reaction Crossed aldol reactions Directed aldol reactions Intramolecular aldol reactions... 

While the order of silyl transfer or cleavage is inconsequential to bond formation, it is one of the more important and hotly debated aspects of the mechanism owing to its importance in the development of catalytic enantioselective variants of the Mukaiyama aldol reaction. Intramolecular silyl transfer, as shown in the formation of 10, would regenerate the chiral,... 

Protonated pyridazine is attacked by nucleophilic acyl radicals at positions 4 and 5 to give 4,5-diacylpyridazines. When acyl radicals with a hydrogen atom at the a-position to the carbonyl group are used, the diacylpyridazines are mainly converted into cyclo-penta[ f]pyridazines by intramolecular aldol reactions (Scheme 43). 

The mechanism of the Feist-Benary reaction involves an aldol reaction followed by an intramolecular 0-alkylation and dehydration to yield the furan product. In the example below, ethyl acetoacetate (9) is deprotonated by the base (B) to yield anion 10 this carbanion reacts with chloroacetaldehyde (8) to furnish aldol adduct 11. Protonation of the alkoxide anion followed by deprotonation of the [i-dicarbonyl in 12 leads to... 

Mechanistically, the reaction of diketosulfides and glyoxal likely proceeds via an initial aldol reaction to provide 22. A second intramolecular aldol reaction and the elimination of two equivalents of water produce the thiophene 23. The timing of the elimination reactions and the ring-closing, carbonyl condensation reaction is not completely understood. However, 2,5-disubstituted thiophenes 23 are available in good yields via this process. 

The next step is an intramolecular aldol reaction leading to closure of a six-membered ring. Subsequent dehydration yields the bicyclic enone 4 ... 

Figure 23.4 Intramolecular aldol reaction of 2,5-hexanedione yields 3-methyl-2-cyclopentenone rather than the alternative cyclopropene.

The selectivity observed in the intramolecular aldol reaction of 2,5-hexanedione is due to the fact that all steps in the mechanism are reversible, so an... 

The Robinson annulation is a two-step process that combines a Michael reaction with an intramolecular aldol reaction. It takes place between a nucleophilic donor, such as a /3-keto ester, an enamine, or a /3-diketone, and an a,/3-unsaturated ketone acceptor, such as 3-buten-2-one. The product is a substituted 2-cyclohexenone. 

The aldol reaction is a carbonyl condensation that occurs between two aldehyde or ketone molecules. Aldol reactions are reversible, leading first to a /3-hydroxy aldehyde or ketone and then to an cr,/6-unsaturated product. Mixed aldol condensations between two different aldehydes or ketones generally give a mixture of all four possible products. A mixed reaction can be successful, however, if one of the two partners is an unusually good donor (ethyl aceto-acetate, for instance) or if it can act only as an acceptor (formaldehyde and benzaldehyde, for instance). Intramolecular aldol condensations of 1,4- and 1,5-diketones are also successful and provide a good way to make five-and six-inembered rings. 

The following molecule was formed by an intramolecular aldol reaction. What dicarbonyl precursor was used for its preparation ... 

The Stork enamine reaction and the intramolecular aldol reaction can be carried out in sequence to allow the synthesis of cyclohexenones. For example, reaction of the pyrrolidine enamine of cyclohexanone with 3-buten-2-one. followed by enamine hydrolysis and base treatment, yields the product indicated. Write each step, and show the mechanism of each. 

The following reaction involves an intramolecular Michael reaction followed by an intramolecular aldol reaction. Write both steps., and show their mechanisms. 

Robinson annulation reaction (Section 23.12) A synthesis of cyclohexenones by sequential Michael reaction and intramolecular aldol reaction. 

Initiation step (radical), 140 Insulin, structure of, 1035 Integration (NMR), 459 Intermediate, See Reaction intermediate lntoxilyzer test, 637 Intramolecular aldol reaction,... 

In the Thorpe reaction, the a carbon of one nitrile molecule is added to the CN carbon of another, so this reaction is analogous to the aldol reaction (16-38). The C=NH bond is, of course, hydrolyzable (16-2), so p-keto nitriles can be prepared in this manner. The Thorpe reaction can be done intramolecularly, in which case it is... 

A DFT study found a corresponding TS to be the lowest energy.167 This study also points to the importance of the solvent, DMSO, in stabilizing the charge buildup that occurs. A further computational study analyzed the stereoselectivity of the proline-catalyzed aldol addition reactions of cyclohexanone with acetaldehyde, isobu-tyraldehyde, and benzaldehyde on the basis of a similar TS.168 Another study, which explored the role of proline in intramolecular aldol reactions, is discussed in the next section.169... 

The aldol reaction can be applied to dicarbonyl compounds in which the two groups are favorably disposed for intramolecular reaction. Kinetic studies on cyclization of 5-oxohexanal, 2,5-hexanedione, and 2,6-heptanedione indicate that formation of five-membered rings is thermodynamically somewhat more favorable than formation of six-membered rings, but that the latter is several thousand times faster.170 A catalytic amount of acid or base is frequently satisfactory for formation of five- and six-membered rings, but with more complex structures, the techniques required for directed aldol condensations are used. 

A particularly important example of the intramolecular aldol reaction is the Robinson annulation, a procedure that constructs a new six-membered ring from a ketone.171 The reaction sequence starts with conjugate addition of the enolate to methyl... 

Scheme 2.10. Intramolecular Aldol and Mukaiyama Aldol Reactions... 

The key cyclization in Step B-2 was followed by a sequence of steps that effected a ring expansion via a carbene addition and cyclopropyl halide solvolysis. The products of Steps E and F are interesting in that the tricyclic structures are largely converted to tetracyclic derivatives by intramolecular aldol reactions. The extraneous bond was broken in Step G. First a diol was formed by NaBH4 reduction and this was converted via the lithium alkoxide to a monomesylate. The resulting (3-hydroxy mesylate is capable of a concerted fragmentation, which occurred on treatment with potassium f-butoxide. 

Aldol addition and related reactions of enolates and enolate equivalents are the subject of the first part of Chapter 2. These reactions provide powerful methods for controlling the stereochemistry in reactions that form hydroxyl- and methyl-substituted structures, such as those found in many antibiotics. We will see how the choice of the nucleophile, the other reagents (such as Lewis acids), and adjustment of reaction conditions can be used to control stereochemistry. We discuss the role of open, cyclic, and chelated transition structures in determining stereochemistry, and will also see how chiral auxiliaries and chiral catalysts can control the enantiose-lectivity of these reactions. Intramolecular aldol reactions, including the Robinson annulation are discussed. Other reactions included in Chapter 2 include Mannich, carbon acylation, and olefination reactions. The reactivity of other carbon nucleophiles including phosphonium ylides, phosphonate carbanions, sulfone anions, sulfonium ylides, and sulfoxonium ylides are also considered. 

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