Aldol reactions with aromatic aldehydes

Most of the examples in this chapter have been of molecules without selectivity. They have indeed all been self condensations. We hope this has established the basic disconnections and the chemistry but we must now turn to examples where selectivity is needed. So the ketone 46 was made to study aldol reactions with aromatic aldehydes.13 They found that, in acid or base, the enone 52 was the main product with the best yield from HCI in EtOH. The product 52 was isolated as its HCI salt. In this case it is easy to see that only the ketone can enolise, that the aldehyde is more electrophilic than the ketone and that the geometrical isomer shown is the more stable. Such considerations are the substance of the next chapter. 

A representative set of such structures (7.80-7.86) is shown, all of which result in the formation of aldol adducts with high ee. Replacement of the carboxylic acid moiety with a bioisosteric tetrazole results in a catalyst (7.80) that is both more reactive than L-proline (7.66) and more readily soluble in organic solvents such as THF.38a.b jji a similar vein, acyl sulfonamides such as (7.81) give good enantios-electivities in the aldol reaction with aromatic aldehydes in organic solvents such as dichloromethane and acetone. 3 The addition of stoichiometric amounts of water increases the activity of tetrazole (7.80) further and this allows the use of aldehydes such as chloral monohydrate (7.87) and formaldehyde, which have an affinity for water and are generally poor substrates for the catalytic asymmetric aldol reaction. 38 = Catalysts (7.82)38 (7.33) 3Sd ijpophilic substiments,... 

Recently, kinetic and specdoscopic studies gave a mechanistic explanation of the role of water in the aldol reaction with aromatic aldehydes. While the addition of water increases the catalyst concentration by suppression the formation of parasitic species such as the oxazolidinone, decreases the relative concentration of key minimum intermediates by Le Chatelier s principle, shifting the equilibrium towards proline (1). The net effect on the reaction rate of these opposing roles would differ when different substrates are used in the reaction, with the intrinsic rate per active catalysts species within the cycle being suppressed by the added water in the aldol reaction of acetone with aromatic aldehydes [37]. 

In the presence of (la), aryl cyclopropyl ketones react with aromatic aldehydes to afford a,p-unsaturated ketones (66) [103a]. The proposed mechanism includes a ring-opening reaction of (la)-activated cyclopropyl ketones by nucleophilic attack of ambient H2O and subsequent aldol reaction with aromatic aldehydes. When a-ketoesters are used instead of aldehydes, 5,6-dihydropyran-2-ones (67) are formed by the pathway including the transesterification between the intermediate (68) and a-ketoesters (Scheme 9.39) [103b]. 

Dendritic molecules with a single triethylene amine core surrounded by hyperbranched polyether sectors catalyze the nitro-aldol reaction between aromatic aldehydes and nitroalkanes (Eq. 3.5).15 The activity of the catalysts decreases when the generation number increases. No significant changes in stereo-control are observed on passing from lower- to higher-generation dendrimers. 

In general, the product ratio of a mixed aldol condensation will depend upon the individual reaction rates. Most ketones show a pattern similar to butanone in reactions with aromatic aldehydes. Base catalysis favors reaction at a methyl position over a methylene group, whereas acid catalysis gives the opposite preference. 

Vankar and co-workers709 have shown that Nafion-H can catalyze the hetero Diels-Alder reaction between the Danisefsky diene 164 and aromatic imines to form 2,3-dihydro-y-pyridones (Scheme 5.69). The reaction with aromatic aldehydes, however, yields only the Mukaiyama aldol condensation products. 

Not only does acetone undergo a highly enantioselective aldol reaction, but hydroxy acetone exhibits excellent stereoselectivity to produce the anti-aldol products 75 (Scheme 2.3d). For example, L-proline catalyzed the aldol reaction between hydroxy acetone and cyclohexanecarbaldehyde to furnish the anti -diol in 60% yield with a greater than 20 1 diastereomeric ratio. The enantiofacial selectivity of the anti-isomer was higher than >99%. Diastereoselectivities are very high with a-substituted aldehydes, whereas low selectivities are recorded in reactions with aromatic aldehydes and with a-unsubstituted aliphatic aldehydes. It is noteworthy that the levels of enantiofacial selectivity for the anti -aldol products... 

There is also another similar case in which 5-oxohexanal was employed as functionalized Michael donor undergoing Michael addition/intramolecular aldol reaction with aromatic enals (Scheme 7.3), which also ended up with a final dehydration step leading to the formation of functionalized cyclohexenes. Under the optimized reaction conditions, the final compounds were obtained in moderate yields but with excellent enantioselect vities and as single diaster-eoisomers. It should be pointed out that, from the mechanistic point of view, a dual activation of the 5-oxohexanal via enamine formation) and the a,p-unsaturated aldehyde via iminium ion formation) might operate in this case in the catalytic cycle, although no mechanistic proposal was provided by the authors. 

The group of Moutevelis-Minakakis reported in 2014 the preparation and application of a series of tripeptides containing proline, phenylalanine and tert-butyl esters of different amino acids (see 36, Scheme 13.22c) for the asymmetric aldol reaction of aromatic aldehydes and various substituted ketones in both aqueous and organic medium. The authors assume in the proposed transition-state model, besides the well-known enamine activation, a stabilisation of the aldehyde via hydrogen-bond interactions of the two amide protons of the tripeptide with the carbonyl group of the aldehyde. The desired adducts were isolated in good to excellent yields and with very good diastereoselectivities and enantioselectivities. ... 

Recently, 4-substituted prochiral cyclohexanones (10 equiv.) have been efficiently desymmetrized by their reaction with aromatic aldehydes catalyzed by (5)-prohne (1, 20 mol%) in the presence of 3,5-dimethylphenyl 3,5-bisfluoromethylphenyl thiourea as co-catalyst (20 mol%) in toluene at 25°C [53], affording the corresponding aldol products in good yields (68-87%), diastereoselectivities up to 78% de and in high enantioselectivities (94-99% ee). 

The o. o -disubshtuted thioglycolate amide was successfully Incorporated in highly diastereoselecUve aldol reaction with aromatic and aunsaturated aldehydes through transmetallation of the enolates with dicyclohexylboron bromide (eq 4). ... 

Scheme 8.3 Aldol reaction of aromatic aldehydes with methyl vinyl ketone in the presence of a preformed nickel catalyst derived from the sparteine ligand.

In a complementary study, the use of Ai-benzyl-2(/ )-methoxy-(-F)-10-bornylamide as chiral lithium amide in the addition to a,p-unsaturated esters, followed by an aldol reaction with aromatic and aliphatic aldehydes, gave products similar to 62 with diastereoselectivities up to 78% [66]. 

Later on, a fluorous organocatalyst 27 with a perfluorooctyl propanoxyl group on the aromatic ring was prepared from i-tyrosine by the same group (Scheme 7.26) [41]. It efficiently catalyzed the direct aldol reaction of aromatic aldehydes with cyclohexanone. In accordance with previous results, catalyst 27 showed higher efficiency than its non-fluorinated analog which is probably because the fluorous tag created a hydrophobic reaction field in brine. The catalyst 27 was easily recovered with FSG extraction and reused without further purification. 

The a-ionization of 7-methylpteridines can also be utilized in aldol-type condensation reactions. 7-Methyl-pterin and -lumazine and 2,4-diaminopteridine condense readily in aqueous base with aromatic aldehydes to afford 7-alkylidenepteridines (77JOC2951). A Claisen condensation requires the protection of the acidic hydrogens of the amide bonds. 

The lithium cnolate generated by deprotonation of 2-/m-butyl-6-methyl-l,3-dioxan-4-onc, readily available from polyhydroxybutyric acid (PHB), predominantly affords the diastereo-mers 7 when reacted with aldehydes. The diastereomeric ratios of aldol adducts 7/8, produced by reactions with aliphatic aldehydes, range from 87.5 12.5 to >99 1. Pure diastereoiners7are obtained by recrystallization in 25-74% yield116-118. Only marginal diastereoselectivities with respect to the carbinol center are obtained with aromatic aldehydes111-119. Benzoylation of the dioxanones 7, followed by reduction with lithium aluminum hydride, affords enan-tiomerically and diastereomerically pure triols 9 in >85% yield 11. ... 

Chiral imines derived from 1-phenylethanone and (I. Sj-exo-l, 7,7-trimethyIbicyclo-[2.2.1]heptan-2-amine [(S)-isobornylamine], (.S>1-phenylethanamine or (R)-l-(1-naphthyl) ethanamine are transformed into the corresponding (vinylamino)dichloroboranes (e.g., 3) by treatment with trichloroborane and triethylamine in dichloromethane. Reaction of the chiral boron azaenolates with aromatic aldehydes at 25 "C, and subsequent acidic hydrolysis, furnishes aldol adducts with enantiomeric excesses in the range of 2.5 to 47.7%. Significantly lower asymmetric inductions are obtained from additions of the corresponding lithium and magnesium azaenolates. Best results arc achieved using (.S )-isobornylamine as the chiral auxiliary 3. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

Feringa s group has demonstrated that cyclopentene-3,5-dione monoacetals as 2-47 can also be successfully applied as substrates in an asymmetric three-component domino Michael/aldol reaction with dialkyl zinc reagents 2-48 and aromatic aldehydes 2-49 [17]. In the presence of 2 mol% of the in-sitw-generated enantiomeri-cally pure catalyst Cu(OTf)2/phosphoramidite 2-54, the cyclopentanone derivatives 2-51 were formed nearly exclusively in good yields and with high ee-values (Scheme 2.11). 

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