Acetones direct aldol reaction

The values of x = 0.5 and = 1 for the kinetic orders in acetone [1] and aldehyde [2] are not trae kinetic orders for this reaction. Rather, these values represent the power-law compromise for a catalytic reaction with a more complex catalytic rate law that corresponds to the proposed steady-state catalytic cycle shown in Scheme 50.3. In the generally accepted mechanism for the intermolecular direct aldol reaction, proline reacts with the ketone substrate to form an enamine, which then attacks the aldehyde substrate." A reaction exhibiting saturation kinetics in [1] and rate-limiting addition of [2] can show apparent power law kinetics with both x and y exhibiting orders between zero and one. 

Aminocatalysis is a biomimetic strategy used by enzymes such as class I aldolases. Application of aminocatalysis in an asymmetric aldol reaction was reported in the early 1970s. Proline (19) efficiently promoted an intramolecular direct aldol reaction to afford Wieland-Miescher ketone in 93% ee [17,18]. More than 25 years later, in 2000, List, Barbas, and co-workers reported that proline (19) is also effective for intermolecular direct aldol reactions of acetone (le) and various aldehydes 3. Notably, the reaction proceeded smoothly in anhydrous DMSO at an ambient temperature to afford aldol adducts in good yield and in modest to excellent enantioselectivity (up to >99% ee, Scheme 9) [19-22]. The chemical yields and selectivity of proline catalysis are comparable to the best metallic catalysts, although high catalyst loading (30 mol %) is required. Proline (19)... 

Important extensions of proline catalysis in direct aldol reactions were also reported. Pioneering work by List and co-workers demonstrated that hydroxy-acetone (24) effectively serves as a donor substrate to afford anfi-l,2-diol 25 with excellent enantioselectivity (Scheme 11) [24]. The method represents the first catalytic asymmetric synthesis of anf/-l,2-diols and complements the asymmetric dihydroxylation developed by Sharpless and other researchers (described in Chap. 20). Barbas utilized proline to catalyze asymmetric self-aldoli-zation of acetaldehyde [25]. Jorgensen reported the cross aldol reaction of aldehydes and activated ketones like diethyl ketomalonate, in which the aldehyde... 

Hartree-Fock and density functional theory (DFT) calculations have been used to probe the enantioselectivity of the direct aldol reaction of acetone and 2,2-dimethyl-propanal, catalysed by (S)-proline, in DMSO solution.107... 

Several reports deal with aqueous media. Acid-base catalysis by pure water has been explored, using DFT, for the model aldol reaction of acetone and acetaldehyde.125 A Hammett correlation of nornicotine analogues (28) - a series of meta- and para-substituted 2-arylpyrrolidines - as catalysts of an aqueous aldol reaction shows p = 1.14.126 Also, direct aldol reactions have been carried out in water enantioselectively, using protonated chiral prolinamide organocatalysts.127... 

Epothilone A (2) is a natural product that exhibits taxoterelike anticancer activity. A new synthesis of the ketoacid 6, a common C1-C6 fragment used in the total synthesis of epothilone A, was accomplished by directed aldol reaction of acetone with the aldehyde 34 (Scheme 2.3c). The aldol reaction of acetone with the aldehyde 3 in the presence of D-proline proceeded smoothly to furnish the expected aldol product (4) in 75% yield and with greater than 99% ee. Intramolecular aldol reaction of the hydroxy ketone 4 in the presence of pyrrolidine gave the cyclohexenone 5 in good yield. Protection of the alcohol as a TBS ether followed by oxidation of the alkene then produced the desired ketoacid (6). 

By using of a modified proline, L-prolinamide 47 (which is known to be a more reactive catalyst than L-proline in cross-aldol reactions [80]), the enantioselectivity of the direct aldol reactions in ionic liquid [bmim][BF4] was remarkably increased as compared with the reaction carried out in acetone (69% ee) (Scheme 7.26) [81]. However, the reusability of the recovered 47 when immobilized in the ionic liquid layer was somewhat inferior to that of the L-proline catalyst this effect could be ascribed to the increased solubility of the organocatalyst 47 in the extracting organic solvents (not provided in the literature), leading to an increased leaching of the catalyst. 

Table 7.13 Direct aldol reaction between benzaldehyde and acetone with different L-proline catalyst forms.

Novel organic molecules derived from L-proline and amines or amino alcohols, were found to catalyse the asymmetric direct aldol reaction with high efficiency. Notably those containing L-proline amide moiety and terminal hydroxyl group could catalyse direct asymmetric aldol reactions of aldehydes in neat acetone with excellent results[1]. Catalyst (1), prepared from L-proline and (IS, 2Y)-diphcnyl-2-aminoethanol, exhibits high enantioselectivities of up to 93% ee for aromatic aldehydes and up to >99% ee for aliphatic aldehydes. 

A number of methods have been developed to bring about the directed aldol reaction between two different carbonyl compounds to give a mixed-aldol product. Most of them proceed from the preformed enolate or silyl enol ether of one of the components. With enolates, a number of metal counterions have been used and the best results have been obtained with lithium or boron enolates, although zinc or transition-metal enolates have found widespread use. For example, the aldol reaction of acetone with acetaldehyde under basic aqueous conditions is inefficient... 

Hartikka and Arvidsson demonstrated the high catalytic efficiency of catalyst 5a for the direct aldol reaction of acetone with various aldehydes. In the organocatalysed direct asymmetric aldol reaction, acetone reacted with aromatic and aliphatic aldehydes, resulting in formation of p-hydro) ketones with good yields and moderate to high enantiomeric excesses (Scheme 9.9). ... 

A simple preparation of benzoimidazole derived pyrrolidine 5k was developed by Landais, Vincent and coworkers. The direct aldol reaction of acetone with 4-nitrobenzaldehyde catalysed by the 5k (5 mol%) TFA (2 mol%) combination, afforded an aldol product in 87% yield and with 82% enantiomeric excess. A transition state was proposed to explain the stereochemical outcome of the reaction (Scheme 9.10). 

In 2006 Gu and coworkers proposed the use of 4,4 -disubstituted-prolines as highly enantioselective catalysts for the direct aldol reaction. The 1-methylnaphthyl 4,4 -disubstituted catalyst 30 was applied successfully for the reaction of acetone with some selected aromatic and aliphatic aldehydes (Scheme 11.26). ... 

SCHEME 3.7. The direct aldol reaction of benzaldehyde (2b) with acetone catalyzed by prolinamides. 

TABLE 3.3. Synthesis of Linear Products in the Direct Aldol Reaction of an a-Heterosuhstituted Acetone... 

Diketones are active enough to perform as electrophiles in the direct aldol reaction not only with acetone, but also with cyclopentanone and cyclohexanone... 

Other chiral zinc based Lewis acid, such as zinc(II) complex with pybox, showed good stability in aqueous media and gave syn-adducts in moderate to excellent catalytic activity and enantioselectivity for asymmetric Mukaiyama aldol reactions (113,114). A simple combination of Lewis acidic zinc salt (Zn(OTf)2) and organocatalyst is also shown to be effective catalysts for the direct aldol reaction of acetone and aldehydes in the presence of water (115). 

Mixed aldol reactions between different aldehydes or ketones are usually plagued by formation of a mixture of products, because each component can function as a CH-acidic and carbonyl-active compound. Whereas the directed aldol reaction [14-16] is a rather general solution to this problem, the traditional aldol addition of non-identical carbonyl compounds is only successful when applied within the framework of a limited substitution pattern. Thus, a fruitful combination in mixed aldol reactions is that of an aldehyde with an enolizable ketone. Obviously, the aldehyde, having higher carbonyl reactivity, reacts as the electrophilic component, whereas the ketone, with comparatively lower carbonyl reactivity, serves as the CH-acidic counterpart. Because the self-aldolization of ketones is endothermic, this type of side reaction does not occur to a significant extent, so the product of the mixed aldol condensation is obtained in fair yield, as illustrated by the formation of ketone 6 from citral 5 and acetone, a key step in the synthesis of j5-ionone (Eq. (7)) [17]. 

Asymmetric direct aldol reaction is a practical process to synthesize p-hydroxy-carbonyl compounds [28]. The phebox-Rh acetate complex 5- Pr serves also as an excellent catalyst for asymmetric direct aldol reaction of cyclic ketones with benzaldehyde derivatives (Scheme 24) [29]. For example, Scheme 24 shows that the reaction of cyclohexanone with 4-nitrobenzaldehyde using 5 mol% of 5- Pr and AgOTf gave the corresponding anri-p-hydroxyketone 36 preferentially in 79% yield with 87 % ee for the anti-isomer. The coupling reaction of cyclopentanone and acetone afforded p-hydroxyketones 37 and 38, respectively, with up to 91% ee. 

An important contribution to the field of direct aldol reaction was put forward by MacMillan who reported on the enantioselective direct cross aldol reaction (Scheme 2.119) [31]. Two aldehydes are brought to reaction with 10mol% prohne to produce selectively the anfi-aldol product. If different aldehydes are used, the one that contains a sterically more crowded side chain acts as the carbonyl component, whereas simple aldehydes, in most cases acetaldehyde or even acetone, act as nucleophiles. The advantage of such organocatalytic aldol reactions is the fact that aldehydes can be used, which is practically prohibited if enolates or... 

Cordova and coworkers demonstrated that simple dipeptides, particularly alanine-containing ones, were effective catalysts for the direct aldol reactions of cyclic ketones with aromatic aldehydes, and the reactions have been explored using either DMSO or water as the reaction medium [40a,b]. Tsogoeva and Wei showed that L-histidine-based dipeptides are good catalysts for the direct aldol reaction of acetone with aromatic aldehydes [41]. 

To better evaluate both methods the results of the direct aldol reaction of acetone with selected aromatic aldehydes catalyzed by prohne are presented in Figure 21.2. Although in general the Kotsuki approach offers much better yields, in the Hayashi method higher enantioselectivities (temperature effect) can be obtained. This methodology was also tested in a solvent-free aldol reaction with cyclopentanone but no improvement was noticed [23]. 

One of the simplest stractures is prolinamide 37 (Figure 24.13), which catalyzed the direct aldol reaction of acetone with 4-nitrobenzaldehyde in water in 50% ee. In the absence of water no reaction took place [59]. Further experiments were carried out using proline-thioamide 38 (Figure 24.13). Brine was found to be a suitable reaction medium for the aldol reaction of several cyclic ketones with electron-deficient aldehydes catalyzed by 38 (5mol%) and in the presence of CI2CHCOOH as additive [60]. 

A similar type of direct aldol reaction, i.e., reaction of isatin and ketone, was reported by Xiao and co-work-ers by the use of an L-proline-derived bifunctional orga-nocatalyst 99. The catalytic activity of 99 is quite high, and aldol reaction of isatin 97 with acetone proceeded at low temperature (below zero) to give the aldol adduct (5)-convolutamydine A 100 in high yield (Scheme 27.17). 

The catalysis of 24-TfOH conjugate not only reached much improved efficiency and stereoselectivity over L-proline in the typical direct aldol reactions of acetone, but enabled the first 5yn-diastereoselective aldol reactions of linear aliphatic ketones (Scheme 5.6) [17a],... 

The capability of L-proline - as a simple amino acid from the chiral pool - to act like an enzyme has been shown by List, Lemer und Barbas III [4] for one of the most important organic asymmetric transformations, namely the catalytic aldol reaction [5]. In addition, all the above-mentioned requirements have been fulfilled. In the described experiments the conversion of acetone with an aldehyde resulted in the formation of the desired aldol products in satisfying to very good yields and with enantioselectivities of up to 96% ee (Scheme 1) [4], It is noteworthy that, in a similar manner to enzymatic conversions with aldolases of type I or II, a direct asymmetric aldol reaction was achieved when using L-proline as a catalyst. Accordingly the use of enol derivatives of the ketone component is not necessary, that is, ketones (acting as donors) can be used directly without previous modification [6]. So far, most of the asymmetric catalytic aldol reactions with synthetic catalysts require the utilization of enol derivatives [5]. The first direct catalytic asymmetric aldol reaction in the presence of a chiral heterobimetallic catalyst has recently been reported by the Shibasaki group [7]. 

Scheme 4. Synthesis of (S)-ipsenol using the proline-catalyzed direct aldol addition reaction as key transformation, (a) L-Proline (10-20mol%), acetone (solvent), 3-7days, 34% (73% ee). (b) TBSCI, imidazole ...

Scheme 7. Proposed enamine mechanism of the proline-catalyzed direct aldol addition reaction of acetone [25].

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