Acetone aldol reactions

The first aldol needs no control only acetone can enolise and the aldehyde 85 is more electrophilic than acetone. Aldol reaction under equilibrating conditions gives 84 in good yield and the alkene can be reduced catalytically. The ketone 82 also contains an acidic phenol so that must be protected before the next aldol and a silyl group is the answer 86. 

The secondary amine of the AEP group is responsible for the supported enamine formation with acetone (aldol reaction), the deprotonation of nitromethane (Henry reaction) and the generation of a potential nucleophile from trimethylsilyl cyanide through hypervalent silicate formation (cyanosilylation reaction). Therefore, the presence of both AEP and UDP groups in close proximity can cooperatively activate the electrophile (through hydrogen bond) and the nucleophile by enamine formation, thus enhancing the reaction rate. 

Furthermore, extending the boundaries of this method, the a-amination reaction was combined with an acetone aldol reaction." " The resulting one-pot reaction furnished p-amino alcohols 28 in good enantioselectivities for the anti-diastereomer. Both stereoisomers were obtained in close-to equal amounts (Scheme 5.18). 

A highly stereoselective proline-catalyzed acetone aldol reaction has recently been used in the synthesis of sugar derivatives such as 141 (Scheme 4.28) [124]. 

This cleavage is a retro aldol reaction It is the reverse of the process by which d fruc tose 1 6 diphosphate would be formed by aldol addition of the enolate of dihydroxy acetone phosphate to d glyceraldehyde 3 phosphate The enzyme aldolase catalyzes both the aldol addition of the two components and m glycolysis the retro aldol cleavage of D fructose 1 6 diphosphate... 

Some unsaturated ketones derived from acetone can undergo base- or acid-catalyzed exothermic thermal decomposition at temperatures under 200°C. Experiments conducted under adiabatic conditions (2) indicate that mesityl oxide decomposes at 96°C in the presence of 5 wt % of aqueous sodium hydroxide (20%), and that phorone undergoes decomposition at 180°C in the presence of 1000 ppm iron. The decomposition products from these reactions are endothermic hydrolysis and cleavage back to acetone, and exothermic aldol reactions to heavy residues. 

Problem 23.2 Using curved arrows to indicate the electron flow in each step, show how the base-catalyzed reverse aldol reaction of 4-hydroxy-4-methyi-2-pentanone takes place to yield 2 equivalents of acetone. 

The a-alkoxy iron-acyl complex 5 may be deprotonated to generate the lithium enolate 6, which undergoes a highly diastereoselective aldol reaction with acetone to generate the adduct 7 as the major product. Deprotonation of acetone by 6 is believed to be a competing reaction 30% of the starting complex 5 is found in the product mixture48 40. 

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. 

It is often said that the property of acidity is manifest only in the presence of a base, and NMR studies of probe molecules became common following studies of amines by Ellis [4] and Maciel [5, 6] and phosphines by Lunsford [7] in the early to mid 80s. More recently, the maturation of variable temperature MAS NMR has permitted the study of reactive probe molecules which are revealing not only in themselves but also in the intermediates and products that they form on the solid acid. We carried out detailed studies of aldol reactions in zeolites beginning with the early 1993 report of the synthesis of crotonaldehyde from acetaldehyde in HZSM-5 [8] and continuing through investigations of acetone, cyclopentanone [9] and propanal [10], The formation of mesityl oxide 1, from dimerization and dehydration of... 

Another approach involved encapsulation of a bulky guanidine, N,N,N-tricyclohexyl-guanidine, in the super-cages of hydrophobic zeolite Y (Sercheli et ai, 1997). The resulting ship-in-a-bottle guanidine catalysed the aldol reaction of benzaldehyde with acetone to give 4-phenyl-4-hydroxybutan-2-one. 

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. 

Table 50.1 shows two sets of conditions for carrying out the prohne-mediated aldol reaction in Scheme 1, employing the same catalyst concentration but different initial concentrations of the two reactants chosen such that the value of the excess, [e], is the same in the two experiments. Note that more conventionally reported parameters - for example, the number of equivalents of acetone and the catalyst mol% - are not the same for the two experiments. 

Lewis-Acid Catalyzed. Recently, various Lewis acids have been examined as catalyst for the aldol reaction. In the presence of complexes of zinc with aminoesters or aminoalcohols, the dehydration can be avoided and the aldol addition becomes essentially quantitative (Eq. 8.97).245 A microporous coordination polymer obtained by treating anthracene- is (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral pH.246 The La network is stable against hydrolysis and maintains microporosity and reversible substrate binding that mimicked an enzyme. Zn complexes of proline, lysine, and arginine were found to be efficient catalysts for the aldol addition of p-nitrobenzaldehyde and acetone in an aqueous medium to give quantitative yields and the enantiomeric excesses were up to 56% with 5 mol% of the catalysts at room temperature.247... 

As shown in Scheme 53, L-proline-catalyzed asymmetric aldol reaction between 3-methylbutanal and acetone was used by List for the synthesis of (S)-34 [79]. 

As predicted, l,2,3,4-13C-labeled acetone dicarboxylate (15) provided an intact three-carbon chain into lycopodine. It also helped to explain why two molecules of pelletierine (12) were not incorporated (Scheme 6.3) [12]. As before, lysine (6) is converted to piperideine (8) via a decarboxylation. Then a Mannich reaction of labeled 15 with 8 provides pelletierine 12. The other half of the molecule to be incorporated must be pelletierine-like (12-CC>2Na), still containing one of the carboxylates. An aldol reaction of the two pelletierine fragments and a series of transformations leads to phlegmarine 9. Oxidation of 9 involving imine formation between N-C5, isomerization to the enamine and then cyclization onto an imine (at N-C13), provides lycopodine 10. Phlegmarine 9 and lycopodine 10 are proposed as... 

In the MPVO reaction, several side-reactions can occur (Scheme 20.23). For example, an aldol reaction can occur between two molecules of acetone, which then leads to the formation of diacetone alcohol. The latter acts as a good ligand for the metal of the MPVO catalyst, rendering it inactive. Moreover, the aldol product may subsequently eliminate water, which hydrolyzes the catalyst. The aldol reaction can be suppressed by adding zeolite NaA [84, 92]. 

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... 

Rate and equilibrium constants have been determined for the aldol condensation of a, a ,a -trifluoroacetophenone (34) and acetone, and the subsequent dehydration of the ketol (35) to the cis- and fraw -isomeric enones (36a) and (36b)." Hydration of the acetophenone, and the hydrate acting as an acid, were allowed for. Both steps of the aldol reaction had previously been subjected to Marcus analyses," and a prediction that the rate constant for the aldol addition step would be 10" times faster than that for acetophenone itself is borne out. The isomeric enones are found to equilibrate in base more rapidly than they hydrate back to the ketol, consistent with interconversion via the enolate of the ketol (37), which loses hydroxide faster than it can protonate at carbon. 

For the mixed aldol reaction to be of value in synthetic work, it is necessary to restrict the number of combinations. This can be accomplished as follows. First, if one of the materials has no a-hydrogens, then it cannot produce an enoiate anion, and so cannot function as the nucleophile. Second, in aldehyde plus ketone combinations, the aldehyde is going to be a better electrophile, so reacts preferentially in this role. A simple example of this approach is the reaction of benzaldehyde with acetone under basic conditions. Such reactions are synthetically important as a means of increasing chemical complexity by forming new carbon-carbon bonds. 

Warfarin was initially developed as a rodenticide, and has been widely employed for many years as the first-choice agent, particularly for destruction of rats. After consumption of warfarin-treated bait, rats die from internal haemorrhage. Warfarin is synthesized from 4-hydroxycoumarin by a Michael reaction on benzalacetone, again exploiting the nucleophilicity of the hydroxypyrone. Benzalacetone is the product from an aldol reaction between benzaldehyde and acetone (see Section 10.3). 

The first reaction involves a ketone reaction with an aldehyde under basic conditions, so enolate anion chemistry is likely. This is a mixed aldol reaction the acetone has acidic a-hydrogens to form an enolate anion, and the aldehyde is the more reactive electrophile. The reaction is then driven by the ability of the intermediate alcohol to dehydrate to a conjugated ketone. 

Typical starting materials, catalysts, and products of the enamine-catalyzed aldol reaction are summarized in Scheme 17. In proline-catalyzed aldol reactions, enantioselectivities are good to excellent with selected cyclic ketones, such as cyclohexanone and 4-thianone, but generally lower with acetone. Hindered aldehyde acceptors, such as isobutyraldehyde and pivalaldehyde, afford high enantioselectivities even with acetone. In general, the reactions are anti selective, but there are aheady a number of examples of syn selective enamine aldol processes [200, 201] (Schemes 17 and 18, see below). However, syn selective aldol reactions are still rare, especially with cychc ketones. 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

The bicyclic tropane ring of cocaine of course presented serious synthetic difficulties. In one attempt to find an appropriate substitute for this structural unit, a piperidine was prepared that contained methyl groups at the point of attachment of the deleted ring. Condensation of acetone with ammonia affords the piperidone, 17. Isophorone (15) may well be an intermediate in this process conjugate addition of ammonia would then give the aminoketone, 16. Further aldol reaction followed by ammonolysis would afford the observed product. Hydrogenation of the piperidone (18) followed then by reaction with benzoyl chloride gives the ester, 19. Ethanolysis of the nitrile (20) affords alpha-eucaine (21), an effective, albeit somewhat toxic, local anesthetic. 

Aldol condensation of acetone is a well-known base-catalyzed reaction, and barium hydroxide is one of the catalysts for this reaction mentioned in textbooks. A family of barium hydroxide samples hydrated to various degress determined by the calcination temperature (473, 573, 873, and 973 K) of the starting commercial Ba(OH)2 8H2O were reported to be active as basic catalysts for acetone aldol condensation (282,286). The reaction was carried out in a batch reactor equipped with a Soxhlet extractor, where the catalyst was placed. The results show that Ba(OH)2 8H2O is less active than any of the other activated Ba(HO)2 samples, and the Ba(OH)2 calcined at 473 K was the most active and selective catalyst for formation of diacetone alcohol, achieving nearly 58% acetone conversion after 8h at 367 K in a batch reactor. When the reaction temperature was increased to 385 K, 78% acetone conversion with 92% selectivity to diacetone alcohol was obtained after 8h. The yield of diacetone alcohol was similar to that described in the literature in applications with commercial barium hydroxide, but this catalyst required longer reaction times (72-120 h) (287). No deactivation of the catalyst was observed in the process, and it could be used at least 9 times without loss of activity. 

At 673 K the product distribution over the palladium catalysts (Figure 4) was still highly selective to MIBK (> 80%) however further aldol condensation of acetone with MO to form the three intermediates, phorone, 4,4 -dimethyl hepta-2,6-dione and 2,4-dimethyl hept-2,4-dien-6-one was observed. These species were formed by aldol condensation of acetone with MO at different points in the molecule (10). All can continue to react either by subsequent aldol condensation, Michael addition, or hydrogenation as per Figure 1. There was no detectable isophorone produced, the product of internal 1,6-aldol reaction of... 

One way to achieve a higher stereoselectivity in these aldol reactions could obviously be the variation of the alkoxy group on the pyrrolidine sidechain of the chiral auxiliary. Thus, Enders and co-workers synthesized the SAMP-analogue (159). While acetone-SAMP-hydrazone leads to a (+)-[3-hydroxyketone in 47% e.e., the corres-... 

Hence, if the proline-catalyzed aldol reaction between acetone and 4-nitrobenzal-dehyde in DM SO is carried out using 5 mol% proline, decarboxylation occurs and [3 + 2] cycloaddition between the resulting ylide and benzaldehyde gives a 1,3-oxazolidinone as the maj or side product [98]. Therefore, it is important that if catalyst loadings are to be reduced, either the carboxylic acid should be unable to decarbox-ylate (e.g. Appendix 7.B, Entries 12 [97, 98], 35 [99]) or else must be replaced by an isostere [101, 102] (e.g. Appendix 7.B, Entries 7 [103, 104], 8-10 [105], 11 [106], 28 [107]). Alternatively, the relative rate of the aldol reaction can be increased in order to minimize the concentration of iminium ion in solution and remove it from equilibrium before decarboxylation can take place. 

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