Aldol dimerizations

In the six-membered series the alkaloids of Punica gr ana turn, isopelletier-ine and methylisopelletierine, have been obtained by treatment of enamines with acetoacetic acid. Isopelletierine (194, R = H) was prepared also by Schopf et al. from d -piperideine (309-311). The reversibility of aldol dimerization (124,131) of enamines has been established by the synthesis of methylisopelletierine (194, R = Me) from dimethyltetrahydroanabasine, accomplished by Lukes and Kovaf (101) (Scheme 19). 

Enone (37) is mesityl oxide, the aldol dimer of acetone (p T 150), In this synthesis, the Nef hydrolysis... 

We believe that the primary reason of deactivation is the formation of irreversibly adsorbed species and oxygen poisoning occurs when the blocking of active sites reaches a critical level. By-products can be formed during the oxidation reaction. A frequently observed side-reaction is the aldol-dimerization of the carbonyl compound and a further oxidation of the product. The process is catalyzed by bases, including the basic functional groups of a carbon support (25). 

Closely related to the Robinson annelation is the sequence of conjugate addition and acylation used to make dimedone 83. Either disconnection of the 1,5-dicarbonyl compound 84 is good but we prefer 84a as the enone 85 is the aldol dimer of acetone (chapter 19) and is readily available. 

A simple but surprising example of using an available starting material is the synthesis of 1,7-difunctionalised heptan-4-ones 86 and 88, each having two 1,4-diX relationships.13 The dihaloketone 86 was made from the aldol dimer 85 of butyrolactone 75, as described in chapter 19, where compound 85 was compound 26. The two 1,4-diX relationships in 86 can be seen in the intermediate 85 which has lost CO2 on its way to 86. 

A modification of this system was also used in intramolecular MBH reactions (also called as aldol cycloisomerization) [71, 74]. In this reaction, optically active pipecolinic acid 61 was found to be a better co-catalyst than proline, and allowed ee-values of up to 80% to be obtained, without a peptide catalyst. The inter-molecular aldol dimerization, which is an important competing side-reaction of the basic amine-mediated intramolecular MBH reaction, was efficiently suppressed in a THF H20 (3 1) mixture at room temperature, allowing the formation of six-membered carbocycles (Scheme 5.14). The enantioselectivity of the reaction could be improved via a kinetic resolution quench by adding acetic anhydride as an acylating agent to the reaction mixture and a peptide-based asymmetric catalyst such as 64 that mediates a subsequent asymmetric acylation reaction. The non-acylated product 65 was recovered in 50% isolated yield with ee >98%. 

Fig. S. Kipping s 1894 identification of the aldol dimer 7 as an intermediate in the cyclotrimerization of 1-indanone.

Fig. 8. a-Tetralone (38) gives the /l,y-unsaturated aldol dimer, which does not continue on to form the cyclic trimer. 

To be useful, of course, a hypothesis must have predictive value. Can one predict in advance whether the aldol dimer from a particular ketone will be a,y -unsaturated or / , >-unsaturated ... 

We have performed single-point energy calculations, using density functional theory with AMI optimized geometries (pBP/DN //AMl) [31], on many of the ketones discussed above that are known to give tris-annulated benzenes by the aldol trimerization reaction (1, 5, 8,10, 22, 24, 26, and 28). In agreement with our hypothesis, the a,y -unsaturated aldol dimer is calculated to be more stable than the //,y-unsa turated isomer in every case, sometimes by as much as 10 kcal mol-1 or more. In those cases in which the a,y -unsaturated aldol dimer can adopt either an E- or a Z-configuration, the more stable of the two was used for the comparison. 

In an attempt to derive some predictive power from this hypothesis, we have demonstrated how cases that are destined to fail at the second step can be identified in advance by relatively straightforward energy calculations on the isomeric aldol dimers. The number of examples is still limited, so one must use this hypothesis with caution, but we have so far found no exceptions. 

When a-alkoxyaldehyde substrates were subjected to organocatalytic conditions, a highly enantioselective aldol dimerization reaction occurred6 (Scheme 2.3f). Substrates bearing relatively electron-rich alkoxy groups provide dimers... 

Under more equilibrating conditions such as alkoxide bases in alcohol solution or amide bases in liquid ammonia, enolisation occurs to give the extended enolate 83 which is then alkylated in the a-position by alkyl halides. At first this seems the most difficult combination to achieve thermodynamic enolisation followed by kinetically controlled addition of an electrophile, but it is in fact a common result achieved with a variety of bases. Examples include the synthesis of pentethylcyclanone 100, an anti-tussive drug, by alkylation of the enone 103, the aldol dimer of cyclopentanone. Disconnection at the branchpoint to the available alkyl halide 102 X = Cl requires a-alkylation of the extended enolate 101 derived from the cyclopentanone aldol dimer27 103. This is easily achieved by sodium amide in toluene.28... 

Catalytic aldol dimerizations of aldehydes sometimes lead to unexpected products. An example is shown in equation (12), where the initial aldol has formed an aldoxan derivative by interacting with a third equivalent of propionaldehyde. Although the aldoxan is dissociated to 1 mol each of the aldol and aldehyde upon distillation, the reaction effectively limits the yield of the aldol addition reaction itself to 66.7%. 

Chemical deactivation by adsorbed impurities or reaction products was identified as a primary cause of catalyst deactivation [42,43,45-48,50]. Deactivation of platinum catalysts in l-methoxy-2-propanol oxidation was attributed to polymeric species formed by aldol-dimerization and detected by chromatographic... 

The higher the pH of the aqueous solution, the higher was the reaction rate, but the correlation seems to be ambiguous. The nature of the anions and cations have also some influence on the reaction rate and selectivity, and the rate of aldol dimerization of the product increases with increasing pH. 

One possibility is to add malonate to the unsaturated ketone, which is an aldol dimer of acetone and readily available. We can reduce the ketone, expecting cyclization to be spontaneous, and decarboxylate to give our target molecule. 

Reaction of a 1 2 10 mixture of hydrogen, ethylene and carbon monoxide at 90°C and 400 atm in the presence of platinum dichloride solutions of molten [(C2H5)4N][SnCla] has been reported to give a 65% combined yield of propionaldehyde and its aldol dimer, 2-methyl-2-pentenal (114). See also Section 6 for a more detailed description of these platinum catalysts dispersed in low-melting tetraalkylammonium salts of trichlorostannate(II). 

The intennolecular aldol reaction between aldehydes can be classified in two types the homo-aldol dinierization process of a single aldehyde and the CTOss-aldol process between two different aldehydes. The later is a more d anding transformation, since the two possible CTOss-aldol processes have to differentiated and the two possible homo-aldol dimerization processes must be prevented. 

Although prolinamides have shown their versatility in the aldol reaction between ketones and aldehydes, their application towards the reaction between the cross or homo-aldol reaction between aldehydes have been scarcely studied. The homo-aldol dimerization reaction between neat propionaldehyde (5, R =Me and 2, R =Et in Scheme 4.23) catalyzed by (S)-prolinamide (40, 20 mol%) in the presence of... 

The imididazolidinone 180 (10-20 mol%, Fig. 4.35) catalyzed the homo-aldol dimerization process of an aldehyde and also the cross-aldol reaction between eno-lizable aldehydes (5, source of nucleophile, 10 equiv.) and aromatic aldehydes (2, electrophile). For both cases, the yields were high (58-90%), the anti-diastereo-selectivity was moderated (60-86% de) and the enantioselectivity was excellent (91-97% ee). To prevent a hemiacetal reaction of the initial aldol product 29 with another equivalent of aldehyde, the reaction was quenched by a methanolysis process to form the corresponding dimethyl acetal [259]. 

Pyrazole (55) appears to be formed directly from the aldehyde, whereas its isomer (56) seems (as indicated by a separate experiment) to arise from initial formation of the aldol dimer Et-CM CMe-CHO. Of the other aj8-unsaturated carbonyl compounds treated with the hydrazone, only chalconegave apyrazole cinnamaldehyde and isophorone gave azines (see footnote ), whereas acrolein, crotonaldehyde, benzalacetone, mesityl oxide, or methyl vinyl ketone gave inseparable mixtures. 

Even more extensive optimization of reaction conditions was performed in the group of Aggarwal [10]. With the aim to synthesize prostaglandins, their primary goal was to obtain the intermediate bicyclic lactol 30, which allows stereoselective conjugate addition of organocuprates and derivatization of the cyclopentane scaffold. For the synthesis of the bicyclic intermediate, the researchers envisioned an asymmetric aldol dimerization of succinaldehyde (23) by means of a proline-based... 

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