Carbonyl intramolecular aldol reactions

Nitro groups can be added to organic molecules through an aldol reaction between the anion of a nitroalkane and an aldehyde or ketone carbonyl. Intramolecular aldol reactions can be used to create five- or six-membered rings from dicarbonyl compounds (either aldehydes or ketones), which form in preference to smaller or larger rings that may be possible. 

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). 

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. 

Synthesis of the common intermediate C (4), and its further conversion to 2 and 3 is illustrated in Scheme 7-3. Two racemic compounds, ( )-7 and ( + )-10, are prepared from readily available starting materials 5 and 8, respectively (Scheme 7-2). Coupling of 7 and 10 gives a mixture of diastereomers 11. An intramolecular aldol reaction of 11 catalyzed by D-proline yields diastereomers 12 and 13 in equal molar ratios (about 36% ee for each diastereomer). Compound 12, the desired ketone, is converted to 14, which is further purified by crystallization to give the compound in the desired stereochemistry in sterically pure form. Reduction of the ketone carbonyl group and subsequent methoxy... 

We should also consider occasions when there are two carbonyl groups in the same molecule. We then have the possibility of an intramolecular aldol reaction, and this offers a convenient way of... 

The strategy of the sequence is a Michael addition to an a,/3-unsaturated ketone followed by an intramolecular aldol reaction. Treatment of a ketone enolate with a Michael acceptor gives a diketone intermediate which is poised to produce a six-membered ring if an enolate is produced and it intramolecularly adds to the carbonyl group. 

In 2002, Skrydstrup reported the diastereoselective construction of functionalised prolines using a Sml2-mediated aldol cyclisation.162 Treatment of p-lactam-derived a-benzoyloxy esters, such as 155, with Sml2 led to the generation of a Sm(III) enolate 156, aldol cyclisation and addition of the resultant samarium alkoxide to the (3-lactam carbonyl. The efficient sequential reaction gave proline derivatives, such as 157, with high diastereoselectivity and in good yield (Scheme 5.103).162 This example illustrates how the presence of a protic cosolvent does not necessarily interfere with the intramolecular aldol reaction and can in fact be crucial to the success of the cyclisation. 

The precise nature of the carbonyl groups determines what happens next. If R is a leaving group (OR, Cl, etc.), the tetrahedral intermediate collapses to form a ketone and the product is a 1,3-di-ketone. The synthesis of dimedone (later in this chapter) is an example of this process where an alkoxy group is the leaving group. Alternatively, if R is an alkyl or aryl group, loss of R is not an option and the cyclization is an intramolecular aldol reaction, Dehydration produces an a,P-unsaturated ketone, which is a stable final product. 

Phenols add intramolecularly to Michael acceptors. " Under acidic conditions, a one-pot sequence starts with initial electrophilic acetylation of the activated aromatic ring and is followed by cyclization." With an appropriate leaving group in the /f-position (OMe. or other amines such as in the unsaturated carbonyl compound (e.g., 4) is formed. Other approaches to pyroncs include the self-condensation of protected //-hydroxy acrylates,intramolecular aldol reactions followed by condensation,thermal cycli-zations of unsaturated ()-chloro esters,and an iodo-cyclization-elimination sequence w th Michael acceptors.Oxymercuration of an unsaturated alcohol is an alternative cyclization approach to tetrahydropyrans. 

The mechanism of intramolecular aldol reactions is similar to that of inter-molecular reactions. The only difference is that both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule. One complication, however, is that intramolecular aldol reactions might lead to a mixture of products, depending on which eiiolate ion is formed. For example, 2,5-hexanedione might yield either the five-membered-ring product 3-methyl-2-cyclopentenone or the three-membered-ring product (2-methyl-cyclopropenyl)ethanone (Figure 23.4). In practice, though, only the cycio-pentenone is formed. 

The Robinson annulation is a ring-forming reaction that combines a Michael reaction with an intramolecular aldol reaction. Like the other reactions in Chapter 24, it involves enolates and it forms carbon-carbon bonds. The two starting materials for a Robinson annulation are an a,P-unsaturated carbonyl compound and an enolate. 

The mechanism of the Robinson annulation consists of two parts a Michael addition to the a,p-unsaturated carbonyl compound to form a 1,5-dicarbonyl compound, followed by an intramolecular aldol reaction to form the six-membered ring. The mechanism is written out in two parts (Mechanisms 24.7 and 24.8) for Reaction [2] between methyl vinyl ketone and 2-methyl-1,3-cyclohexanedione. 

The mechanism of these intramolecular aldol reactions is similan that of inlermolecular reactions. The only difference is that both the nu philic carbonyl anion donor and the electrophilic carbonyl acceptor are in the same molecule. 

Methylation of 13-oxobaccatin III with methyl iodide and sodium hydride led to an interesting series of rearranged products. The initial product 6.3.6 is presumably formed by a homoretroaldol type of reaction initiated by methylation of the C-13 carbonyl group. Continued treatment with methyl iodide and base gave rise to an intramolecular aldol reaction, leading to the tetracyclic product 6.3.7 and two less methylated intermediates (226). 

When both carbonyl groups are in the same molecule, aldol reaction results in the formation of a ring. These intramolecular aldol reactions are particularly useful for the formation of five- and six-membered rings. 

In comparison to samarium and ytterbium salts, there were few examples for cerium, praseodymium, and other the rare earth metals catalyzed aldol reaction (214,215). In 2000s, Samarium salts, especially Sml2, have been used in versatile aldol reactions, for example, direct aldol of aldehydes and substituted oxi-ranyl ketones (216), nitro aldol reaction (217,218), intramolecular aldol reaction (219), and other aldol reaction of special carbonyl compounds (220-222). However, catalytic asymmetric samarium-catalytic aldol reaction was not reported so far. In the asymmetric version of the aldol reaction, ytterbium exhibited promising enantioinduction. In the first example of the asymmetric ytterbium-catalyzed aldol reaction, moderate levels of enantioselectivities were achieved (Scheme 56) (223). Subsequently, Mlynarski and co-workers improved enatioinduction ability of the ytterbium-catalyzed aldol reaction by using catalytic amount of Yb(OTf)3... 

The intermolecular coupling of homoallyl alcohols with o-bromoacetophenone (181) or o-bromostyryl ketones 183 gave dihydro-182 and tetrahydronaphthalene derivatives 184 in a sequence of the Heck and aldol or the Heck and Michael reactions (Scheme 8.43 and Scheme 8.44) [350]. After addition of the initially formed arylpalladium species to the homoallyl alcohols, ehmination/isomerization yield carbonyl compounds that, under the reaction conditions, undergo intramolecular aldol reactions or Michael additions. 

One possible reaction for 60 is an intramolecular condensation with the other carbonyl (see Chapter 22, Section 22.6, for reactions of this type), but that would lead to a four-membered ring product, 61. The activation barrier to form this strained ring is high, so this reaction is slow (see Chapter 8, Section 8.5.3). The reaction conditions favor thermodynamic control (protic solvent, hydroxide, heat see Chapter 22, Section 22.4.2), which means that enolate anion 60 is in equilibrium with the neutral diketone. Further reaction with hydroxide generates the kinetic enolate anion 62 as part of the equilibrium mixture. If 62 attacks the carbonyl in an intramolecular aldol reaction (Chapter 22, Section 22.6), a six-membered ring is formed (63) in a rapid and highly favorable process. 

The Robinson annulation involves two reactions occurring in tandem a Michael reaction followed by an aldol condensation (loss of water is normally expected in this reaction so the aldol product is typically dehydrated to give an a,P-unsaturated cyclohexenone product). The reaction of an enolate as a nucleophile attacking the beta carbon of methyl vinyl ketone as the electrophile (a Michael reaction) forms the first carbon-carbon bond in the Robinson annulation and results in a 1,5-dicarbonyl product. The methyl group from MVK serves as the nucleophile for the second part of the reaction when it finds a carbonyl electrophile six atoms away to undergo an intramolecular aldol reaction. After dehydration, an a,P-unsaturated cyclohexenone product is formed. Ultimately, two new carbon-carbon bonds are formed within the cyclohexenone moiety. 

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