Aldol aromatic ketones

The product is a P-hydroxy aldehyde (called an aldol) or ketone, which in some cases is dehydrated during the course of the reaction. Even if the dehydration is not spontaneous, it can usually be done easily, since the new double bond is in conjugation with the C=0 bond so that this is a method of preparing a,P-unsaturated aldehydes and ketones as well as P-hydroxy aldehydes and ketones. The entire reaction is an equilibrium (including the dehydration step), and a,P-unsaturated and P-hydroxy aldehydes and ketones can be cleaved by treatment with OH (the retrograde aldol reaction). There is evidence that an SET mechanism can intervene when the substrate is an aromatic ketone. ... 

A straightforward method for aldolizing unsymmetrical ketones on the more hindered side involves the use of catalytic titanium(lV) chloride in toluene at room temperature. For examples using acyclic and cyclic ketones, and linear, branched, and aromatic aldehydes, the regioselectivity varied from 7 1 to >99 1, while the symanti ratios were moderate to good, and yields were in the range 62-91%. In contrast to other methods, base is not required, and the ketone can be used as is (i.e. the silyl enol ether is not required). 

Iwasawa and Mukaiyama have previously reported the first example of forming highly optically active aldols from aromatic ketones and various aldehydes, again via divalent tin enolates employing chiral diamines derived from (S)-proline as ligands 172>. 

On the other hand, rare-earth trifluoromethanesulfonates (rare earth triflate, RE(OTf)3) have been found to work efficiently as Lewis acids even in aqueous media or in the presence of amines [4], A catalytic amount of RE(OTf)3 enables several synthetically useful reactions, for example aldol, Michael, allylation, Mannich, Diels-Alder reactions, etc., to proceed. It has also been demonstrated that a small amount of RE(OTf)3 is enough to complete the reactions and that RE(OTf)3 can easily be recovered from the reaction mixture and can be reused. A key to accomplishing the catalytic processes was assumed to be the equilibrium between Lewis acids and Lewis bases, for example water, carbonyl compounds, and amines, etc. A similar equilibrium was expected between Lewis adds and aromatic ketones, and, thus, RE(OTf)3-catalyzed Friedel-Crafts acylation was investigated [5]. 

It is equally noteworthy that both aliphatic and aromatic ketones undergo the aldol trimerization reaction. 

Regio- and stereoselective aldol condensations. The cnol boronates of ketones, obtained by reaction with 1 and diisopropylcthyluminc (1 equiv.), react with both aliphatic and aromatic ketones at —78° to — 15° to form (i-hydroxy ketones with high, yvn-dia-stereoselectivity, ... 

In the aldol reaction,the a carbon of one aldehyde or ketone molecule adds to the carbonyl carbon of another. Although acid-catalyzed aldol reactions are known,the most common form of the reaction uses a base. There is evidence that an SET mechanism can intervene when the substrate is an aromatic ketone. " Although hydroxide was commonly used in early versions of this reaction, stronger bases, such as alkoxides (RO ) or amides (R2N ), are also common. Amine bases have been used. Hydroxide ion is not a strong enough base to convert substantially all of an aldehyde or ketone molecule to the corresponding enolate ion, that is., the equilibrium lies well to the left, for both aldehydes and... 

Hindered phenolates have low nucleophilicity and in aprotic solvent may act usefully as EGBs. 2,6-Di-t-butyl-/ -cresol = 16.8) was reduced directly with concomitant hydrogen evolution to give, ex situ, the corresponding tetraethylammonium phenolate [59,60], which was clearly capable of deprotonating aromatic ketones and in the presence of aromatic aldehydes promoted aldol reaction to a, /3-unsaturated ketones which underwent Michael addition. The initial proton transfer from the aromatic ketone ] K = 24.7) is thermodynamically very unfavorable. Even so, aldol reaction took place within a matter of hours upon addition of an aromatic ketone together with an aromatic aldehyde leading to or, /3-unsaturated ketones which subsequently underwent Michael addition with a sec-... 

Table 14. Enantioselective Cross-Aldol Reaction between Aromatic Ketones and Various Aldehydes...

Jacques and coworkers examined the Reformatsky reaction of a series of a-alkyl-substituted bromo esters. In refluxing benzene, the zinc aldolates derived from aromatic ketones, but not from aromatic... 

Trichlorotitanium enolates are formed in variable yield from trimethylsilyl enol ethers and an equivalent of TiCU in dichloromethane at 20-35 C. These highly Lewis acidic preformed enolates then undergo aldol reactions at -70 C to give moderate levels of syn selectivity, as in equation (13). Trichlorotitanium enolates have also been used by Reetz et al. in their studies on diastereofacially selective aldol additions to a-alkoxy aldehydes.Trichlorotitanium enolates are formed in situ in the aldol reaction of aromatic ketones and aldehydes using TiCU and EtsN. ... 

These favourable results can probably be traced back to the stable chelates formed by the lithium salts of the aldol adducts. In the hydrolysis product the nitrogen of the aldimine group is linked through an intramolecular hydrogen bond bridge, as was established by the IR spectrum. Since the aldimine adduct could finally be converted by treatment with acid in a nearly quantitative yield to 3-phenylcinnamaldehyde, the preparative problem of subjecting aromatic ketones to the directed aldol condensation was solved. 

However, even in the singularly smoothly operating directed aldol condensation with aromatic ketones, there is no such thing as perfection. In order to determine the influence of inductive and steric effects on the new process, the Schiff bases of a-substituted acetaldehydes were metallated under the standard conditions with lithium diisopropylamide, and the aldimine adducts with benzophenone were isolated. Table 1 shows the measured yields. 

You have a choice here either you first form an enol(ate) from butanone and do an aldol reaction with the aromatic ketone or you first make an imine and then form enamines from that. In either case, you would expect enol or enamine formation on the more substituted side in acid but the less substituted side in base. 

The r-BuOK-catalyzed reaction of a terminal alkyne with cyclohexanone in DMSO to give a tertiary alcohol in 91% yield (eq 47) provides a straightforward illustration of an addition to a carbonyl compound. The same type of addition takes place in the nonpolar solvent benzene but the rate is slower and the yield lower. Treatment of cyclohexanone with ethynylbenzene under the same reaction conditions yields l-(phenylethynyl)cyclohexanol in 83% yield when the reaction is carried out using 1.0 equiv of r-BuOK in the absence of solvent the yield of the tertiary alcohol is 93%. Other aliphatic and aromatic ketones give similar results. Ketones with relatively acidic a hydrogens are capable of undergoing intermolecular aldol additions in the presence of the base but, apparently, the reversibility of this reaction allows the irreversible addition of the acetyUde anion to compete favorably. ... 

Aromatic ketones bearing a-hydrogens give aldol reaction products readily, but in this case the aldol product spontaneously loses water to form the unsaturated ketone. When benzaldehyde is used in the crossed-aldol condensation the final product is the unsaturated aldehyde or ketone. Conjugation of the double bond with the aromatic ring is the reason for the spontaneous dehydration (Scheme 3.13). 

Ishihara developed a highly efficient Mukaiyama aldol reaction between ketones and trimethylsilyl enolates catalysed by sodium phenoxide-phosphine oxides (46) as simple homogeneous Lewis-base catalysts (0.5-10 mol%) (Scheme 2.29). For a variety of aromatic ketones and aldimines, aldol and Mannich-type products with an a-quaternary carbon centre were obtained in good to excellent yields. Remarkably, a retro-aldol reaction was not observed. On a scale of up to 100 mmol, benzophenone and trimethylsilyl enolate gave the product in 97% yield (34.8 g) using 0.5 mol% of catalyst. 

Scheme 19.54 Enantioselective aldol reaction of trifluoroacetaldehyde methyl hemiacetal with aromatic ketones.

Another complement to enamine catalysis is Br0nsted acid catalysis. Blanche showed that a Hg-BlNOL-derived phosphoric acid catalyzes the aldol reaction to give jy -aldols 162-165 from various ketones [175]. Gratifyingly, the method is suitable for acetophenone, fused cyclic aromatic ketones, and a,(3-unsaturated ketones, substrates that are normally challenging donors in enamine catalysis (Chart 3.22). 

The aldol reactions of the silyl enol ethers of aromatic ketones such as acetophenone with 4-bromobenzaldehyde can also be carried out in a quantitative conversion using a microflow reactor (Scheme 5.1). 

A similar, but intermolecular version of the domino hydroformylation-(aldol condensation)-hydrogenation reaction was presented by Seller and colleagues in 2014 (Scheme 5.133) [22]. NAPHOS was used as a ligand for rhodium in the hydroformylation and in the final hydrogenation step. PyrroUdine acted as the organocatalyst. A range of terminal olefins were thus converted either with acetone or aromatic ketones into saturated product ketones. 

Scheme 3 shows the flexibility of this approach in more detail. Possible electrophiles for addition to metalated intermediate 4 include iodine to give the halogenated aromatic ring 6, Weinreb amides (e.g., 9) to access the aromatic ketone 10, DMF to give aldehyde 11, or various aldehydes, e.g., 8, 12, 15, or 16, to give differently substituted benzylic alcohols, e.g., 7, 13, 14, and 17, with diverse additional functional handles for further homologation. All these products may be readily further elaborated. Possible transformations include reductions, iodolactonizations, aldol reactions, allylation, epoxidation, or direct lactonization reactions. 

A novel directed functionalization of the ortho-C-R bond of aromatic ketones (454), catalysed by Cp (MeCN)3Rh(SbF6)2, has been described. The initially generated rho-diacycle (455) adds to vinyl ketones to give Michael products (456), which undergo spontaneous aldol condensation to afford indenes (457). " ... 

Aldehydes and ketones react with primary amines to form azomethines which are usually known as Schiff bases, or sometimes, if the amine is aromatic, as anils. Stable Schiff bases are formed with aromatic aldehydes and with aliphatic and aromatic ketones, those formed from ahphatic aldehydes are often subject to aldol-type polymerization and are not suitable for group protection. The Schiff bases formed from aliphatic ketones are potentially tautomeric with the corresponding enamines, but they exist as azomethines unless there is some other structural feature present to stabilize the enamine form (section 2.1.3.2). The condensation reaction by which these derivatives are formed is acid-catalyzed and easily reversible, thus this method of oup protection is only applicable under neutral or alkaline conditions. The condensation using aromatic aldehydes or aliphatic ketones take place readily without solvent or in refluxing ethanol, those with aryl-alkyl or diaryl ketones may require catalysis or azeotropic removal of the water formed in the reaction. 

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