Aldol reaction direct

1 Classical Aldol. Aldol reaction is an important reaction for creating carbon-carbon bonds. The condensation reactions of active methylene compounds such as acetophenone or cyclohexanone with aryl aldehydes under basic or acidic conditions gave good yields of aldols along with the dehydration compounds in water.The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive ahphatic aldehydes.  

The Henry (nitroaldol) reaction was reported under very mild reaction conditions, in aqueous media using a stoichiometric amount of a nitroalkane and an aldehyde, in NaOH 0.025 M and in the presence of cetyltrimethylammonium chloride (CTACl) as cationic surfactant (Eq. 8.94). ° Good to excellent yields of P-nitroalkanol are obtained. Under these conditions several functionahties are preserved, and side-reactions such as retro-aldol reaction or dehydration of 2-nitroalcohols are avoided. 

Base-catalyzed aldol reactions have been carried out intramole-cularly. The aqueous acid-catalyzed intramolecular aldol condensation of 3-oxocyclohexaneacetaldehyde proceeded diastereoselectively (Eq. 8.95).242 

Selective retro-aldol has also been reported by using aqueous HCl in THF.243 Recently, catalytic aldol reactions in aqueous media have generated great interest due to the atom-economy related to the reaction. Reaction of 2-alkyl-1,3-diketones with the aqueous formaldehyde using aqueous 6-10 M potassium carbonate as base afforded aldol reaction products, which are cleaved by the base to give vinyl ketones (Eq. 8.96).244 

2 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). A microporous coordination polymer obtained by treating anthracene-Z A (resorcinol) with La(0/Pr)3 possesses catalytic activity for ketone enolization and aldol reactions in pure water at neutral The La network is stable against hydrolysis and main- 

To anhydrous acetone (1 mL) the corresponding aldehyde (0.5 mmol) and catalyst (1) (20-30 mol%) were added and the resulting mixture was stirred at —25 °C for 12—48 hours. The reaction mixture was treated with saturated ammonium chloride solution, the layers were separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by flash column chromatography over silica gel (eluent hexane ethyl acetate = 1 3) to give the pure adducts. 

3 DIRECT CATALYTIC ASYMMETRIC MICHAEL REACTION OF a-HYDROXYKETONE PROMOTED BY Et2Zn/LINKED-BINOL COMPLEX 

Masakatsu Shibasaki, Shigeki Matsunaga and Naoya Kumagai 

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan 

The catalytic asymmetric Michael reaction is one of the most widely used synthetic methods for the asymmetric carbon-carbon bond formation.[1] Among various 

---

Table 4. Directed Aldol Reaction of Lithium Enolate of l-Fluoro-3,3-dimethylbutanone [7]...

In general the reaction of an aldehyde with a ketone is synthetically useful. Even if both reactants can form an enol, the a-carbon of the ketone usually adds to the carbonyl group of the aldehyde. The opposite case—the addition of the a-carbon of an aldehyde to the carbonyl group of a ketone—can be achieved by the directed aldol reaction The general procedure is to convert one reactant into a preformed enol derivative or a related species, prior to the intended aldol reaction. For instance, an aldehyde may be converted into an aldimine 7, which can be deprotonated by lithium diisopropylamide (EDA) and then add to the carbonyl group of a ketone ... 

By using the directed aldol reaction, unsymmetrical ketones can be made to react regioselectively. After conversion into an appropriate enol derivative (e.g. trimethylsilyl enol ether 8) the ketone reacts at the desired a-carbon. 

The Lewis acid encountered most often in this context is TiCl its broad applicability in directed aldol reactions has been reviewed by Mukaiyama (20). 

The directed aldol reaction T. Mukaiyama, Organic Reactions 28,203 (1982). 

This is known as the directed aldol reaction. Similar reactions have been performed with oc-lithiated dimethylhydrazones of aldehydes or ketones and with a-lithiated... 

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. 

Organic-Base Catalyzed. Asymmetric direct aldol reactions have received considerable attention recently (Eq. 8.98).251 Direct asymmetric catalytic aldol reactions have been successfully performed using aldehydes and unmodified ketones together with chiral cyclic secondary amines as catalysts.252 L-proline and 5,5-dimethylthiazolidinium-4-carboxylate (DMTC) were found to be the most powerful amino acid catalysts for the reaction of both acyclic and cyclic ketones as aldol donors with aromatic and aliphatic aldehydes to afford the corresponding... 

Recently, novel bifunctionalized zinc catalysts have been developed (compounds (N) and (P), Scheme 55). They have both Lewis-acid and Lewis-base centers in their complexes, and show remarkable catalytic activity in direct aldol reactions.233-236 A Zn11 chiral diamine complex effectively catalyzes Mannich-type reactions of acylhydrazones in aqueous media to afford the corresponding adducts in high yields and selectivities (Scheme 56).237 This is the first example of catalytic asymmetric Mannich-type reactions in aqueous media, and it is remarkable that this chiral Zn11 complex is stable in aqueous media. 

Besides their application in asymmetric alkylation, sultams can also be used as good chiral auxiliaries for asymmetric aldol reactions, and a / -product can be obtained with good selectivity. As can be seen in Scheme 3-14, reaction of the propionates derived from chiral auxiliary R -OH with LICA in THF affords the lithium enolates. Subsequent reaction with TBSC1 furnishes the 0-silyl ketene acetals 31, 33, and 35 with good yields.31 Upon reaction with TiCU complexes of an aldehyde, product /i-hydroxy carboxylates 32, 34, and 36 are obtained with high diastereoselectivity and good yield. Products from direct aldol reaction of the lithium enolate without conversion to the corresponding silyl ethers show no stereoselectivity.32... 

As shown in Scheme 8-49, this multifunctional catalyst can be applied in direct aldol reactions between an aldehyde R CHO and a ketone R2COCH3."... 

Marhwald reported that ligand exchange of Ti(rac-BINOLate)(Of-Bu)2 with optically active a-hydroxy acids presents an unexpected and novel approach to enantio-selective direct aldol reactions of aldehydes and ketones (Scheme 12.19). The aldol products have been isolated with a high degree of syn diastereoselectivity. High enantioselectivities have been observed when using simple optically pure a-hydroxy acids. 

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... 

The MgX2/R3N systems offer another useful synthetic interest. Recently, Evans and coworkers have demonstrated that substoichiometric amounts of magnesium halides in the presence of an amine and chlorotrimethylsilane catalyze the direct aldol reaction of A-acyloxazolidinones and A-acylthiazolidininethiones with high diastereoselectivity (equation 59). 

A directed aldol reaction requires that one partner provides a preformed enolate (or chemically equivalent reactive species) and is then added to the second carbonyl-containing molecule. 

Table 7. Products of the Directed Aldol Reaction of Lithium Gnolate of Ethyl Fiuoroacetate [/S, 19]...

Lithium salts of ketone derivatives such as imines, oximes and hydrazones have also been used for directed aldol reactions (Scheme 103).374 375 A recent example involves triple coordination of lithium in a very rigid transition state, to lead to regiospecificity in the product (Scheme 104).376... 

Asymmetric induction is another important aspect of the directed aldol reaction. The approach involves the use of a chiral aldehyde which influences the stereochemistry of the addition reaction. Reaction of a chiral phenylpropanaldehyde with a lithium enolate yields only two of the possible diastereoisomers in the ratio of 86 14 (equation 76).377... 

---