Aldol reactions of acetone

An analogous reaction has been carried out using malononitrile and different products derived by a Cross-Aldol reaction of acetone (Scheme 32). The cyclic furanimide 91 was then reacted under microwave irradiation in the presence of NaOEt with a second molecule of malononitrile to give the furanone 92 [66]. The NLO chromophore 93 was prepared using this procedure. 

Antibodies produced by this procedure were screened for their ability to react with the hapten to form the vinylogous amide 6, which has a convenient UV chromophore near 318nm, clear of the main protein absorption. Two antibodies selected in this way catalysed the expected aldol reaction of acetone with aldehyde 7 by way of the enamine 8 (Scheme 3) the remainder did not. These two effective aldolase mimics have been studied in some detail, and a crystal structure is available for (a Fab fragment of) one of them.126,281... 

Munson and Haw (151) reported the first in situ NMR study of acetaldehyde in a zeolite. Figure 27 shows 13C spectra of this species reacting on HZSM-5 in the presence of water to form crotonaldehyde with high selectivity (an example of aldol condensation). We later reported a very detailed study of the aldol reactions of acetone and cyclopentanone on various zeolites (Scheme 4) (147). Dimerization of acetone followed by dehydration gives mesityl oxide (31), and the I3C isotropic shifts of this conjugated ketone are strongly dependent on state of protonation. Farcasiu and Ghen-ciu (152,153) have reported extensive measurements of the 13C shifts of 31... 

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)... 

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... 

Table 2.2 Aldol reactions of acetone and aldehydes catalyzed by proline amide 4 [9].

For the (S)-proline-catalyzed aldol reaction of acetone and 4-nitrobenzaldehyde in DM SO, involvement of a single molecule of (S)-proline in the C-C bond-... 

In the (S)-proline-catalyzed aldol reactions, the addition of a small amount of water did not affect the stereoselectivities [6]. However, a large amount of water often resulted in products with low enantiomeric excess water molecules interrupt the hydrogen bonds and ionic interactions critical for the transition states that lead to the high stereocontrol. For example, in the (S)-proline-catalyzed aldol reaction of acetone and 4-nitrobenzaldehyde in DMSO, the addition of 10% (v/v) water to the reaction mixture reduced the ee-value from 76% (no water) to 30% [6]. Note that the addition of a small amount of water into (S)-proline-catalyzed reactions often accelerates the reaction rate, and the addition of water should be investigated when optimizing these reactions [61]. 

Whereas the (S)-proline- and 13-catalyzed Mannich reactions afforded (2S,3S)-syn-products and (2S,3R)-anh-products, respectively, as shown in Scheme 2.15, with high diastereo- and enantioselectivities, the (S)-pipecolic acid (14)-catalyzed reaction afforded (2S,3S)-syn- and (2S,3.R)-anh-products with moderate diastereo-selectivities but high enantioselectivities for both the syn- and anti-products [74] (Scheme 2.16). This was explained by computational analyses indicating that (S)-pipecolic acid uses both the s-trans and s-cis conformations of the enamine similarly (the energy differences 0.2 kcal mol-1 for pipecolic acid versus 1.0 lccal mol-1 for proline) in the C-C bond-forming transition state [74]. Note that (S)-pipecolic acid was not a catalyst for the aldol reaction of acetone and... 

Although typical equilibrium constants for formation of a tertiary aldol prohibit direct forward aldol synthesis (0.002 M 1 for the aldol reaction of acetone with acetophenone) (Guthrie and Wang, 1992), the retro-aldol reaction is greatly favored (a 1 mM solution of the resulting tertiary aldol is converted almost completely to acetone and acetophenone at equilibrium) (List et al., 1999). 

An approach has recently been made in which asymmetric aldol reactions are performed without the need for preformed metal enolates.1 In 2000, List and co-workers reported that the cyclic amino acid L-proline is an effective catalyst for the asymmetric aldol reaction of acetone with a variety of aromatic and aliphatic aldehydes2 (Scheme 2.3a). When L-proline was mixed with acetone... 

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). 

Houk has further explored conformational factors that may play a role in determining selectivity. The proline ring can be puckered in two orientations, up 57 or down 58. Consideration of the four TSs with the up orientation and the four with the down orientation for the aldol reaction of acetone with p-nitrobenzaldehyde is necessary. The up TSs predict an ee that is too low, while the down TSs predict an... 

Sunoj also predicted the enantioselectivity offered by a series of bicyclic proline analogs in the aldol reaction of acetone with p-nitrobenzaldehyde. The two best performing catalysts are 59 and 60 both are predicted to give an ee greater than 90 percent, which exceeds the selectivity afforded by proline itself. The TS geometries all display the Houk-List characteristics. 

The immobilized catalyst (SiO2-[bmim]BF4-L-prohne, 70) displayed higher enantioselectivity (64% ee) with acceptable activity (51% yield) than the homogeneous conditions (60% ee, 62% yield) in the aldol reaction of acetone and benzaldehyde [71b]. Additionally, this system was even more efficient than the PEG-prohne-... 

Of the inorganic supports, best results were reported for a mesoporous MCM-41 [337]. Support on ionic-liquid phases has been studied by different groups with variable results [338, 339], Of the non-conventional organic polymers, non-covalent immobilization on poly(diallyldimethylammonium) is notable [340], Catalysts 133 (15 mol.%) promoted the aldol reaction of acetone and benzaldehydes to afford the corresponding (i-hydroxyketones in 50-98% yields and 62-72% ee, which are clearly lower than those reported for other polymer-supported systems. Recycling of the catalysts was possible at least six times without loss of efficiency. More recently, proline has been attached to one DNA strand while an aldehyde was tethered to a complementary DNA sequence and made to react with a non-tethered ketone [341], To date, the work has focused more on conceptual development than on the analysis of its practical applications in organic synthesis. 

The use of L-proline as an aldolase mimic has produced extraordinary results in cross-aldol reactions of acetone and aldehydes and of dissimilar aldehydes, giving p-hydroxyketones with ee s > 80%. From limited results it appears that L-proline is as active or more active than the catalysts mentioned above (below ambient temperatures, with good yields in <24 h), and exhibits consider-... 

The diastereoselectivity of the Baylis-Hillman reaction was investigated by attaching chiral auxiliaries to a,-unsaturated ketones [216]. The use of the 4-isopropyloxazoladinone chiral auxiliary in [EMIM][OTf] gave rise to very low di-astereomer ratios (45 55) (Scheme 5.2-88). The authors also describe a proline -catalyzed aldol reaction of acetone, butanone, hydroxyacetone and chloroacetone with a chiral imine and obtain up to 9 1 diastereomer ratios. 

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... 

Scheme 5.4 A mmetric Aldol reaction of acetone and isobutyraldehyde.

The scope of this chapter does not allow nor attempt a comprehensive account of all developed processes to date. A detailed summary, in particular of aldol, Mannich, or ot-functionalisation reactions, can be found in excellent reviews written on the topic." Barbas and List reported an asymmetric, direct, intermolecular aldol reaction of acetones and aldehydes (Scheme 5.4), presumably via enamine formation of proline and acetone. As compared to its metal-catalysed alternatives, no preformation of the respective enolate is required, a mode of action that mimics metal-free aldolase enzymes. ... 

Catalyst 15n is able to promote asymmetric cross-aldol reactions of acetone with activated ketones, to generate a quaternary carbon stereogenic centre bearing an OH function, whereas catalysts 15b-d are very active in the reaction of acetone and p-nitrobenzaldehyde in a series of solvents and catalyst loadings. Ley and coworkers reported the synthesis of the parent members of the sulfonamide family - proline methyl sulfonamide... 

Ellman and coworkers have shown that chiral sulfinate 14 can catalyse asymmetric aldol reactions of acetone, whereas proline itself gave poor results. However, more active and selective catalysts are prolinamides with general structure 16 containing two or more stereocentres in the molecule, and based on ot-alkylbenzylamines ISa," chiral (3-amino alcohols (16b-d, 16e-f, axially chiral amino hydroxyl-2,2 -binaphtyl amide 16i, ... 

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). 

Scheme 9.9 Direct asymmetric aldol reaction of acetone with aldehydes.

Recently, Bazito with coworkers have reported that a 4-TBSO-proline 29-catalysed asymmetric aldol reaction of acetone with 4-nitrobenzaldehyde can run in supercritical (sc) CO2 or sc-COj/IL green solvent systems with a poor yield and low enantiomeric excesses. The moderate catalytic performance of 29 in SC-CO2 may be attributed to the known capability of primaiy and secondary amines to generate carbamic acid salts with CO2, which hamper the catalytic process. 

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