crossed aldol condensation examples

In addition, COFGT (1995) <1995COFGT(3)53> described both intramolecular aldol reactions where, for example, 1,6- or 1,7-dialdehyde systems react with regioselectivity through control of the reaction conditions or by use of enamines, and intermolecular aldol reactions, where control of regiochemistry is achieved by use of enamines, enol ethers, α-lithioimines, or α-lithiohydrazones. This C–C bond-forming strategy could facilitate challenging molecule synthesis in chemical, biological, and medicinal research. In another example, taken from the synthesis of siphonarin B by Patterson et al.112 aldehyde 89 was condensed with ketone 90 in the presence of Sn(OTf)2 to give a 92% yield of 91. A directed-aldol addition reaction mediated by aluminum tris(2,6-diphenylphenoxide) has recently been reported <1998JA813>, where regioselective reaction of conjugated carbonyl substrates with aldehydes proceeds upon precomplexation of the reactants with the bulky aluminum reagent (Equation (23)). 1.5.B, 6.6.Bsecs. Foster, in Comprehensive Organic Functional Group Transformations II, 2005. From: Comprehensive Organic Synthesis, 1991, Robert J. Ouellette, J. David Rawn, in Organic Chemistry Study Guide, 2015. Whereas aldol condensation is a classic C–C bond-forming transformation, it requires other chemical promoters, such as strong base and reactive acidic catalysts. This route is of particular interest as aldehydes having acid- or base-sensitive substituents can undergo aldol reactions to give alkenals in reasonable yields. This means treating an ester with a mild base will result in a dimerization reaction. Note: An 'active' methylene group flanked by two electron withdrawing groups (e.g., carbonyls) has much more acidic alpha hydrogens and can be readily deprotonated by alkoxide bases. Chiral bases can be used for enantioselective aldol condensation reactions. In a synthesis of the immunosuppressant FR901483 by Fukuyama and co-workers,114 keto-aldehyde 145 was treated with camphorsulfonic acid in refluxing benzene, and subsequent protonation of the aldehyde led to the protonated intermediate in the presence of the enol form of the ketone (see 146). Note: Crossed Claisen condensations are possible, but a mixture of many products often results. Other studies of the Reformatsky reaction in refluxing benzene with ketone substrates are readily explained in terms of equilibrated zinc aldolates, although direct evidence for equilibration was not obtained. The course of the intramolecular aldol condensation can be influenced by steric and conformational factors, as well as the rate of competing cyclization reactions. 9.5.A.vi.) The aldol condensation, where an aldehydic enol or enolate is reacted with a second carbonyl group, followed by dehydration of the β-hydroxyaldehyde intermediate so formed, is one of the most widely used approaches to α,β-unsaturated aldehydes. Michael B. Smith, in Organic Synthesis (Third Edition), 2010. Note: The result after alkylation of a double activated enolate can itself be deprotonated again to yield another double activated enolate. Synergistic gold-iron catalytic system toward C–C bond construction, Successful example of vinyl gold addition toward carbonyl compounds, Fe(acac)3 as a new dynamic l-ligand suppresses the protodeauration of vinyl gold, A practical macrocyclization protocol without extended dilution (0.2 M). The reaction of 2-methylpentan-3-one with sodium ethoxide, under thermodynamic control conditions, generates two different enolate anions. Fig. Mackie, C.E. The aldol addition product can be dehydrated via two mechanisms; a strong base like potassium t-butoxide, potassium hydroxide or sodium hydride in an enolate mechanism, or in an acid-catalyzed enolmechanism. In dichloromethane at ambient temperature, a 62% yield of aldolate 154 was obtained after a reaction time of 43 h. The other product of this reaction was acetone, which was readily removed. In general, the hydrolysis step provides the aldolate, but sometimes elimination of water (dehydration) accompanies the hydrolysis to yield a conjugated ketone [1,3-diphenylprop-2-en-1-one, otherwise known as (E)-chalcone]. Nonetheless, the reaction continues to a stable product because the subsequent step has a much more favorable equilibrium constant. At equilibrium, this enolate anion can react with either benzaldehyde or with another molecule of acetophenone, which is the self-condensation. The reaction conditions used for the aldol condensation of 3-pentanone described above are rather harsh, and this is a disadvantage if elimination of water from the aldol product occurs, or if self-condensation occurs under these equilibrating conditions. For the time being, we will assume that the reaction produces close to a 1:1 mixture of the two products. There are countless synthetic examples of the aldol condensation. Cyclization occurs if the α carbon atom and the second carbonyl carbon atom can bond to form a five- or six-membered ring. (Note that removal of the proton directly attached to the aldehyde carbonyl carbon does not give a resonance-stabilized anion, and there are no hydrogens on the carbon α to the aldehyde carbonyl.). This protocol can also be applied to macrocyclization without extended dilution. Whereas aldol condensation is a classic C–C bond-forming transformation, it requires other chemical promoters, such as strong base and reactive acidic catalysts. This enolate can condense with either unenolized 3-pentanone (to produce 133) or with unenolized cyclopentanone (to produce 135). Note that heating is usually required to induce dehydration unless there is a conjugating substituent. We have seen, in the halogenation of aldehydes and ketones, that enolates are quite good nucleophiles: This reaction shows that the ɑ position of a carbonyl compound is a potential nucleophilic site. An attempted mixed-aldol condensation of butan-2-one and 2-methylpentan-3-one should therefore produce eight different aldolate products. Under the acidic conditions of the workup, that double bond moved into conjugation to give the final product 167. Therefore, there are two possible aldol products, 3-hydroxy-1,3-diphenylbutan-1-one and 3-hydroxy-1,3-diphenylpropan-1-one. Under these conditions, cyclopentanone reacts to yield enolate anion 79. This enolate could condense with a second molecule of dione to give an aldolate product, but intramolecular attack of the second carbonyl group is much faster and leads to the cyclic aldolate product 156, which gives 157 upon hydrolysis. Pure MgO was the most active catalyst whereas Al2O3 showed the lowest activity. If selectivity can be controlled, the main advantage is the construction of a relatively complex carbon skeleton from simple precursors. Aldolisation crois e L'aldolisation crois e (en anglais : mixed (crossed) aldol condensation) met en jeu deux compos s carbonyl s (ald hyde ou c tone) diff rents. In presence of a catalytic amount of TiCl4,115 2-butanone was condensed with benzaldehyde in toluene to give an 83% yield of the aldolate product. One of the, shown above, is when one of the carbonyls does not have ɑ hydrogens and, therefore cannot be deprotonated to serve as a nucleophile. Depending on the nature of the … When reacted with an aldehyde with no α-hydrogens (benzaldehyde), two aldol products are formed (138 and 139) if there is no self-condensation of 43. If acetophenone reacted with benzaldehyde in the presence of sodium ethoxide (in ethanol), the initial product was alkoxide 124. Even if one aldolate is produced with some selectivity, the problems of poor yields and isolation of the desired product remain. When an aromatic aldehyde is condensed with an enolate of an aliphatic aldehyde or ketone to yield the α-,β-unsaturated compound, the reaction is called the Claisen-Schmidt reaction.103d,105 Note that the aldol condensation can be done using high-intensity ultrasound,106 where good yields of aldol products were isolated that normally yield significant elimination under conditions that did not use sonication. Díez, ... J.I. The Aldol condensation and Knoevenagel condensation (eqn. and the resultant enolate anion reacts with benzaldehyde. And this particular reaction will occur even at room temperate because the product is a fully conjugated system involving the aromatic ring. If 2-methylpentan-3-one were to react with sodium ethoxide under thermodynamic conditions in the presence of an unsymmetrical ketone (e.g., butan-2-one), both the kinetic and thermodynamic enolate anions of both ketones can be formed. The intramolecular aldol condensation of a ketone with a second unsaturated ketone is a useful annelation procedure, and occurs under both acid <70CC52, 70TL4069, 71TL3803, 89CB1653> and base catalysis <54BSF780, 79JA5070> (Equation (132)) <90JOC3>.

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