Ketones self-addition

Reactions with Aldehydes and Ketones. The base-catalyzed self-addition of acetaldehyde leads to formation of the dimer, acetaldol [107-89-1/, which can be hydrogenated to form 1,3-butanediol [107-88-0] or dehydrated to form crotonaldehyde [4170-30-3]. Crotonaldehyde can also be made directiy by the vapor-phase condensation of acetaldehyde over a catalyst (53). 

An important variation on the Claisen condensation is to use a ketone as the anionic reagent. This often works well because ketones usually are more acidic than simple esters and the base-induced self-condensation of ketones (aldol addition) is thermodynamically unfavorable (Section 17-3C). A typical example is the condensation of cyclohexanone with diethyl ethanedioate (diethyl oxalate) ... 

Directed aldol condensation. Aldol condensation between an aldehyde and a ketone usually is not successful because self-addition of the aldehyde is the preferred reaction. Wittig and Reiff,1 however, showed that, if the aldehyde is first converted into a Schiff base (cyclohexylamine was used) and then metalated with lithium di-isopropylamide (chosen for obvious stcric reasons), aldol condensation can be achieved, usually in good yield.2 In the case of ketones, this route is superior to olefination via a phosphorylide. 

Previously, it was not possible to control the aldoi condensation so that aldehydes would combine with the carbonyl groups of ketones with their a—CH-groups. For example, acetaldehyde does not react with benzophenone under the usual base catalyzed conditions to give adduct VIII because the aldehyde undergoes a much more rapid self addition to acetaldol IX. 

Reactions between ketone donors and aldehyde acceptors strrMigly depend on the nature of the aldehyde. While a-disubstimted aldehydes normally react easily, unbranched ones often undergo self-addition reactions. List et al. reported one of the first examples of a direct aldol addition of ketones to a-unbranched aldehydes en route to a natural product in 2001 (44). The operationally simple reaction between 13 and 19 in the presence of catalytic amounts of (5)-12 furnished the enantiomerically enriched p-hydroxy-ketone 20 in moderate yield. The reduced yield can be rationalized by the concomitant formation of the crmdensation product 21, which is one of the limiting factors in such reactions (besides the self reaction of a-unbranched aldehydes). Intermediate 20 can then be further converted to the bark beetle pheromone (5)-ipsenol (22) in two more steps (Scheme 6). 

The experiment presented in this section is an example of a mixed-or crossed-aldol condensation. This term describes cases in which two different carbonyl compounds are the reactants. Such reactions are synthetically practical under certain circumstances, selectively producing a single major condensation product. For example, a ketone may preferentially condense with an aldehyde rather than undergoing self-addition with another molecule of itself (Scheme 18.3). This is because the carbonyl carbon atom of ketones is sterically and electronically not as susceptible to nucleophilic attack as is that of aldehydes. The aldehydic partner in such a reaction generally has no a-hydrogen atoms, so that it is unable to undergo an aldol reaction. 

The aldol reaction enjoys a longstanding history in synthetic organic chemistry for the facile formation of carbon-carbon bonds. The discovery of the aldol condensation is associated with the Russian composer and chemist Borodin, who reported the reaction of valeraldehyde with the extrusion of water in 1869 [1, 22]. The term aldol reaction was coined by Wurt2 in 1872 in the description of the self-addition product of acetaldehyde (Equation 1) [23]. This terminology was later applied to the analogous reactions of ketones, the first known example of which, namely that of acetone, was discovered in 1838 [24]. 

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

The situation is similar for other ketones Special procedures for aldol addition and self condensation of ketones have been developed but are rarely used... 

Synthesis of pyrazole 3 by the Medicinal Chemistry route was straightforward from N-Boc isonipecotic acid (45), so we utilized the route after some optimizations, as summarized in Table 2.4. The key 1,3-diketone intermediate 48 was prepared from 45 without issues. A minor problem in the original route was the exothermic nature of the Claisen condensation between methyl ketone 47 and methyl phenylacetate. Slow addition of l.lequiv of methyl phenylacetate to a mixture of 47, 0.2equiv of MeOH, and 2.5equiv of NaH in THF at room temperature solved this exothermic issue and reduced the amount of self-condensation of... 

An ab initio MO calculation by Jorgensen revealed enhanced hydrogen bonding of a water molecule to the transition states for the Diels-Alder reactions of cyclopentadiene with methyl vinyl ketone and acrylonitrile, which indicates that the observed rate accelerations for Diels-Alder reactions in aqueous solution arise from the hydrogenbonding effect in addition to a relatively constant hydrophobic term.7,76 Ab initio calculation using a self-consistent reaction field continuum model shows that electronic and nuclear polarization effects in solution are crucial to explain the stereoselectivity of nonsymmetrical... 

We Have studied data for one molecular association set, the self association of dlalkyl ketones, using the XB equation with the addition of a term in the number of C atoms (no) as a measure of polarizability. Thus,... 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

On addition of S04 to the triple bond in the lO-member cycloalkyne 24 and cyclo-aUcynone 27, a nonchain, and anionic, self-terminating radical cyclization cascade is induced. In the former reaction (equation 22) the bicyclic ketones 25 and 26 are formed, and in the latter reaction (equation 23) the a,/3-epoxy ketones 28 and 29 are formed in good yields. Because of the difficulty of oxidizing isolated triple bonds, 804 does not react as an electron-transfer reagent in these reactions but acts as a donor of atomic oxygen. 

In this proper sense, aldol condensation includes reactions producing j3-hydroxyaldehydes or j3-hydroxyketones by self-condensation or mixed condensation of aldehydes and ketones these reactions are, in fact, additions of a C—H bond activated by the carbonyl to the C=0 bond of the other molecule, viz. 

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