Propiophenone aldol reactions

J0rgensen and co-workers (230) reported the aldol reaction between enolsilanes and ketomalonate esters. Catalyst 269c proved to be nearly nonselective in these reactions. Optimal conditions involve the use of < /-269d in Et20 at -78°C. The reactions are quite sluggish under these conditions. Benzosubarone-derived enol-silane affords the aldol adduct in 93% ee, Eq. 200, while propiophenone enolsilane provides the aldol product in 90% ee under identical conditions, Eq. 201. Other nucleophiles are less selective. No model was advanced to account for the observed enantioselectivities. 

Zinc bisenolate 136 (Figure 11) is prepared by the transmetallation of propiophenone lithium enolate with 0.5 equivalents of ZnBr2 136 reacts with aldehydes, both aliphatic and aromatic, in a domino aldol reaction which mimics the action of aldolases167. The first aldol reaction between 136 and the aldehyde produces zinc aldolate 137, which then undergoes a second intramolecular aldol addition to adduct 138. Spontaneous hemiacetalization affords 139, where all large substituents occupy equatorial positions168. 

Draw the structural formulae of the products from the aldol reaction of acetaldehyde and propiophenone and determine the configuration of the chirality centres. Assume that on the addition of base propiophenone attacks the acetaldehyde. 

In the crossed aldol reaction between acetaldehyde and propiophenone, two chirality centres are created and consequently, four stereoisomers will be produced. Compounds A and B are enantiomers of each other and can be described with the stereo descriptor u. Similarly, C and D are enantiomers and are /-configured. Since both starting materials are achiral, without the use of a chiral base or chiral auxiliary, racemates will be produced. Likewise the choice of base, the addition of a Lewis acid and the reaction conditions used to form the enolate can control which diastereomer is preferentially formed. If the Z enolate is formed, the u product is the preferred product, whilst the E enolate yields predominately the / product. 

Mukaiyama aldol reactions of various silyl enol ethers or ketene silyl acetals with aldehydes or other electrophiles proceed smoothly in the presence of 2 mol % B(CgF5)3 [151a,c]. The following characteristic features should be noted (i) the products can be isolated as j8-trimethylsilyloxy ketones when crude adducts are worked-up without exposure to acid (ii) this reaction can be conducted in aqueous media, so that the reaction of the silyl enol ether derived from propiophenone with a commercial aqueous solution of formaldehyde does not present any problems (iii) the rate of an aldol reaction is markedly increased by use of an anhydrous solution of B(C6Fs)3 in toluene under an argon atmosphere and (iv) silyl enol ethers can be reacted with chloromethyl methyl ether or trimethylorthoformate hydroxymethyl, methoxy-methyl, or dimethoxymethyl Cl groups can be introduced at the position a to the carbonyl group. These aldol-type reactions do not proceed when triphenylborane is used (Eq. 92). 

Kobayashi et al. discovered that Yb(OTf)3 and other lanthanide triflates (l,ri(() lf)(, Ln=La, Pr, Nd, Sm, Eu, Gd, Dy, Ho, and Er) are excellent catalysts of hydroxymefhylation of propiophenone TMS enolate with aqueous formaldehyde solution at room temperature (Scheme 10.22) [70, 71]. The Yb(OTf) j-catalyzed hydroxymefhylation of a variety of SEE, including sterically hindered compounds, proceeds regiospecifically in high yield. In addition, almost 100% of Yb(OHf). is quite easily recovered from fhe aqueous layer and can be reused. Yb(OTf)3 also has high catalytic activity in fhe aqueous aldol reaction of other aldehydes. Interestingly, the catalytic activity is rather low in the absence of water. In aqueous media water would coordinate to ytterbium to form active ytterbium cations. 

We recently disclosed that salts of alkali and alkaline earth metals effectively promote fhe aldol reaction of DMS enolates (Scheme 10.34) [101]. For example, fhe CaCl2-catalyzed reaction of propiophenone DMS enolate with aldehydes proceeds smoothly in DMF at 30 °C with high reaction efficiency. In the metal salt-catalyzed aldol reaction fhe counter anion of fhe metal salt plays a crucial role in rate acceleration. The activity of metal salt increases with increasing intrinsic nucleophilicity of fhe counter anion TfO metal salts work as Lewis bases to activate DMS enolates. To our surprise, the... 

Kobayashi et al. recently developed the Pb(OTf)2-crown ether 56 complex as an efficient chiral catalyst of asymmetric aldol reactions in aqueous media (Scheme 10.51) [146]. This catalyst system achieves good to high yields and high levels of diastereo- (syn-selective) and enantioselectivity in the aldol reaction of a variety of aldehydes with propiophenone TMS enolate. The hole size of 56 is essential because 57 and 58 show no chiral induction. The unique structure of the Pb(OTf)2-56 complex as a chiral catalyst has been revealed by X-ray diffraction. 

In fact, Sc(DS)3 worked very efQciently in the aldol reaction of benzaldehyde with the silyl enol ether derived from propiophenone in water, whereas the reaction proceeded sluggishly when Sc(OTf)3 was the catalyst (Scheme 15.3). ... 

The aldol reactions of titanium enolates generated in situ were reported by Harrison [27] to give excellent yield and selectivity for syn aldol products, as shown in Table 2.10. However, methyl ketones tended to eliminate under the reaction conditions and provided a,/i-unsaturated ketones. Reactions with propiophenone and benzaldehyde provided excellent yields of aldolates, with syn aldols being the major product (95 5 ratio). The stereochemical outcome was rationalized by Zimmerman-Traxler transition state model 67. 

Enol stannanes of cyclohexanone and propiophenone have been indicated to take part in r/treo-selective aldol reactions with benzaldehyde at low temperatures e.g. —78 °C), but to be erythro-seAsciiwe at higher temperatures ca 45 °C). Two complementary methods have been described for stereoselection in aldol-type reactions. Whilst a-mercurio-ketones show eryr/wo-selection in their reactions with aldehydes in the presence of boron trifluoride diethyl etherate, pre-formed lithium enolates and aldehydes, in the presence of simple trialkyl-boranes, lead to mixtures that are rich in the more stable threo-d do product. Aldol-type products arise from 1,3-alkyl migrations of alk-l-enyl alkyl acetals and ketals, in a reaction that is catalysed by boron trifluoride diethyl etherate (Scheme 52). Diastereoselection is possible, since (.E)-alkenyl acetals give the... 

The utility of aqueous [ C2]acetaldehyde is illustrated by its Homer-Wadsworth-Emmons olefmation with diethyl (cyanomethyl)phosphonate under phase transfer conditions to give [3,4- C2]crotonitrile (16) in 83% radiochemical yield. Subsequent Michael addition of a-aminonitrile 17 produced the masked y-ketoacid derivative IS (Figure 8.6), which served as a key intermediate in the synthesis of [ " C2]C1930 (19). For the TiCLi-promoted aldol reaction with the propiophenone derivative 20, however, the use of anhydrous [ 2] acetaldehyde was essential. The reaction proceeded with excellent stereoselectivity, providing exclusively the racemic syn-diastereomers 21. Subsequent... 

In contrast to the -enolates derived from cyclic ketones, addition of propiophenone trichlorosilyl enolate (Z)-21 to aldehydes requires longer reaction times and higher loadings of catalyst. Although the yields of the aldol products remain high, both the diastereo- and enantioselectivities are attenuated as compared to their E counterparts (eq 9, Table 8). 

Preparation of Monomers. Methyl vinyl ketone (MVK) was obtained from Pfizer Chemical Division, New York, and distilled to remove the inhibitor. Methyl isopropenyl ketone (MIPK) was prepared by the aldol condensation of methyl ethyl ketone and formaldehyde, according to the method of Landau and Irany 0. The major impurity in this monomer is ethyl vinyl ketone (5. The monomer was redistilled before use. 3 Ethyl 3 buten 2 one (EB) was prepared by the aldol condensation of methyl propyl ketone and formaldehyde. Ethyl vinyl ketone (EVK) was prepared by a Grignard synthesis of the alcohol, followed by oxidation to the ketone. t-Butyl vinyl ketone (tBVK) was prepared from pinacolone and formaldehyde by the method of Cologne (9). Phenyl vinyl ketone (PVK) was prepared fay the dehydrochlorlnatlon of 0 cbloro propiophenone (Eastman Kodak). Phenyl isopropenyl ketone (PPK) was prepared by the Mannich reaction using propiophenone, formaldehyde and dimethylamine HCl. 

Woerpel has recently reported a tandem double asymmetric aldol/C=0 reduction sequence that diastereoselectively affords propionate stereo-triads and -pentads commonly found in polyketide-derived natural products (Scheme 8-2) [14], When the lithium enolate of propiophenone is treated with excess aldehyde, the expected aldolates 30/31 are formed however, following warming to ambient temperature a mono-protected diol 34 can be isolated. In a powerful demonstration of the method, treatment of 3-pentanone with 1.3 equiv of LDA and excess benzaldehyde yielded product in corporating five new stereocenters in 81% as an 86 5 5 3 mixture of diastereomers (Eq. (8.8)). A series of elegant experiments have shown that under the condition that the reaction is conducted, the aldol addition reaction is rapidly reversible with an irreversible intramolecular Tischenko reduction serving as the stereochemically determining step (32 34, Scheme 8-2). 

Lewis Basic Phosphoramides. In a series of elegant investigations, Denmark has documented an aldol process that utilizes trichlorosilyl enolates such as 101 and 105 in catalytic, enantioselective addition reactions (Eqs. (8.28) and (8.29)) [45]. These unusual enoxysilanes are prepared by treatment of the corresponding tribu-tylstannyl enolates with SiCl4. Trichlorosilyl enolates are sufficiently reactive to add to aldehydes at -78 °C, but their addition can be substantially accelerated by the addition of Lewis basic phosphoramides. The use of catalytic amounts of chiral phosphoramides leads to the formation of optically active products. Thus, treatment of the cyclohexanone or propiophenone-derived trichloroenolsilanes 101 and 105 with a variety of aldehydes afforded adducts displaying high levels of simple diastereoselectivity and up to 96% ee. On the basis of the stereochemical outcome of the reaction, Denmark has postulated that the reaction proceeds through an or-... 

JV-Boc protected a-amino carbonyl compounds are prepared by treatment of the lithium enolates of ketones, esters, and amides with AT-Boc 3-(4-cyanophenyl)oxaziridine (53b) <93JOC479i>. The modest yields (33-38%) are ascribed to aldol-type reactions of the enolate with the 4-cyano-benzaldehye (62) by-product (Equation (9)). In one example, the lithium enolate of propiophenone gave A-Boc-cathione (61), the pharmacologically active constituent of the leaves of khat. 

Lewis acid catalysis in micellar systems was first found in the model reaction of the silyl enol ether of propiophenone with benzaldehyde. Although the reaction proceeded sluggishly in the presence of 0.2 equiv. Yb(OTf)3 in water, remarkable enhancement of the reactivity was observed when the reaction was carried out in the presence of 0.2 equiv. Yb(OTf)3 in an aqueous solution of sodium dodecylsul-fate (SDS, 0.2 equiv., 35 mM), and the corresponding aldol adduct was obtained in a 50% yield. In the absence of the Lewis acid and in surfactant (water-promoted conditions) [11], only 20% yield of the aldol adduct was isolated after 48 h, while a 33% yield of the aldol adduct was obtained after 48 h in the absence of the Lewis acid in an aqueous solution of SDS. The amounts of the surfactant also influenced the reactivity, and the yield was improved when Sc(OTf)3 was used as a Lewis acid catalyst. Judging from the critical micelle concentration, micelles would be formed in these reactions, and it is noteworthy that the Lewis acid-catalyzed reactions proceeded smoothly in micellar systems [25]. 

In the reaction of benzaldehyde with the trimethylsilyl enol ether of cyclohexanone, both substrates were sequentially added in a solution of lOd in propionitrile at -78 °C according to Corey s procedure (24). The reaction proceeded quantitatively to give the aldol products in 78 22 synfanti ratio, and the optical yield of syn adduct was 89% ee. The reaction of butyrakiehyde with the (Z)-trimethylsilyl enol ether derived from propiophenone, however, did not proc d well. Fortunately, the reaction proceeded cleanly by adding trimethylsilyl enol ether followed by butyrakiehyde to afford only the syn aldol adduct with more than 99% ee. The syn selection observed in both reactions suggests that the reaction occurs via extended transition state assemblies. 

Catalytic quantities of chiral phosphoramides have been found to accelerate diastereoselective E syn, Z anti) aldol addition reactions of the trichlorosilyl enolates of cyclohexanone [(ii)-enolate] and propiophenone [(Z)-enolate]. ... 

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