Methyl-aryl ketones, aldol reactions

Hydroxy ketones can be synthesized via the pyrrolidine sulfonamide- and prolinamide-catalyzed direct aldol reaction of methyl-aryl ketones with aromatic aldehydes [51]. Modest enantioselectivities were obtained for all donors and acceptors studied. Yields are strongly affected by the nature of the substrates (Chart 3.2). These ketones react also with acetals and hemiacetals of ttichloro- or trifluoroacetaldehyde in the presence of prohne-derived tetrazol to provide the desired aldols [28c, 52]. 

If the ketone is blocked on one side so that it cannot enolize—in other words it has no a protons on that side—only one aldol reaction is possible. Ketones of this type migitt bear a tertiary alkyl or an aryl substituent, f- Butyl methyl ketone (3,3-dimethylbutan-2-one), for example, gives aldol reactions with various bases in 60-70% yield. Enolization cannot occur towards the t- butyl group and must occur towards the methyl group instead. 

Aldol reactions. Chalcones are formed by exposing aryl methyl ketones to SiCl in ethanol. With Hg(OAc)j as catalyst trimethylsilyl enol ethers are converted by SiCl to trichlorosilyl derivatives at room temperature which are useful donors in aldol reactions. 

The dinuclear zinc complex (7.61) developed by Trost and coworkers functions as an alternate bifunctional catalyst that is highly effective in the direct aldol reaction of aliphatic aldehydes with aryl methyl ketones and has also been used... 

Retrosynthetically, spiroketal precursor 8 would be accessed via a diaster-eoselective aldol reaction between chiral aldehyde 9 and a-chiral (3-arylated methyl ketone 10 (Scheme 3). Aldehyde 9 would be readily accessible from commercially available ethyl (S)-hydroxybutyrate, while methyl ketone 10 would be constmcted by the Suzuki cross-coupling of trifluoroboratoamide 11 and rotationally symmetric aryl halides 12/13. The use of Br or I in place of Cl in halides 12/13 was intended to increase the reactivity of 12/13 toward oxidative insertion and overcome the steric hindrance imparted by the ortho-disubstituted aromatic framework. The required functionalization of the aromatic ring to install the phthalide motif was envisioned to be possible via iridium-catalyzed CH-borylation either before or after formation of the spiroketal core. Our group already had experience with this remarkable transformation in the context of naphthalene chemistry. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

Other sulfur-proline derivatives have been prepared and screened as catalysts in the intramolecular aldol reaction. Remarkably, sulfonamide 83a (10 mol%. Fig. 4.9) was an efQcient catalyst for the aldol reaction between aryl methyl ketones... 

On the other hand, Trost used zinc in his bimetallic catalyst. One zinc atom is believed to form the metal enolate, whereas the other acts as a Lewis acid for carbonyl activation. Aldol reactions between branched aldehydes and methyl ketones perform in good yields and excellent selectivities (Scheme 2.117). Besides aryl methyl ketones, simple acetone or methyl vinyl ketone could be used as well [28]. These extensions make this protocol a truly universal method for convergent natural product synthesis. 

Cinchona-based primary amine catalysis in the asymmetric functionalization of carbonyl compounds has been reviewed and their modularly designed thioamide 0 derivatives have been applied successfully to direct cross-aldol reactions between aldehydes and ketones, reactions of activated carbonyl compounds (isatins) with acetylphosphonate as the enol precursor, and C( 1) functionalization of 1,3-dicarbonyl compounds by aldehydes and ketones. Cross-aldol addition to C(3) of isatins by the methyl group of 4-aryl-tra 5 -cf, -unsaturated methyl ketones has also been promoted... 

The aryl aldehyde (10 mmol) and the methyl ketone (10 mmol) are stirred at room temperature with aqueous NaOH (0.02 M, 100 ml) and CTMA-Br (50 mg, 1.37 mmol). When the reaction is complete, as shown by TLC analysis, the mixture is extracted with E20 n-C6H14 (1 1, 3 x 35 ml). The dried (MgS04) extracts are evaporated to yield the aldol condensation product [e.g. from MeCOPh 74% with PhCHO 78%, 4-MeOC6H4CHO 95%, 4-ClC6H4CHO 90%, 4-Me2NC6H4CHO. PhCHO and Me2CO produce (PhCH=CH)2CO (89%)]. 

Oxamborolidenes. There are noteworthy advances in the design, synthesis, and study of amino acid-derived oxazaborolidene complexes as catalysts for the Mukaiyama aldol addition. Corey has documented the use of complex 1 prepared from A-tosyl (S)-tryptophan in enantioselective Mukaiyama aldol addition reactions [5]. The addition of aryl or alkyl methyl ketones 2a-b proceeded with aromatic as well as aliphatic aldehydes, giving adducts in 56-100% yields and up to 93% ee (Scheme 8B2.1, Table 8B2.1). The use of 1-trimethylsilyloxycyclopentene 3 as well as dienolsilane 4 has been examined. Thus, for example, the cyclopentanone adduct with benzaldehyde 5 (R = Ph) was isolated as a 94 6 mixture of diastereomers favoring the syn diastereomer, which was formed with 92% ee, Dienolate adducts 6 were isolated with up to 82% ee it is important that these were shown to afford the corresponding dihydropyrones upon treatment with trifuoroacetic acid. Thus this process not only allows access to aldol addition adducts, but also the products of hetero Diels-Alder cycloaddition reactions. 

Shibasaki has examined catalysis of a complex, prepared in situ from PdCl2, AgOTf, (R)-or (S)-BINAP, 4 A molecular sieves, and H20, in the aldol addition reaction of enolsilanes by (Eq. 8B2.5) [13]. Under these conditions, aryl methyl ketone-derived trimethylsilyl enolates add to benzaldehyde and hydrocinnamaldehyde, affording adducts with up to 73% ee. 

In this example, 2-methyl-l,3-cyclopentanedione (a /3-diketone) is i to generate the enolate ion required for Michael reaction, and an aryl-s stituted ,6-unsaturated ketone is used as the acceptor. Base-cataJj Michael reaction between the two partners yields an intermediate ketone, which then cydizes in an intramolecular aldol condensation to giti a Robinson annulation product. Several further transformations required to complete the synthesis of estrone. 

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