Phase aldol reaction

Polar polyoxyethylene-polyoxypropylene (POEPOP) resin, deriva-tized with a 4-hydroxymethyl phenoxy linker, was used as a solid support for lanthanide triflate-catalyzed Mukaiyama-type solid-phase aldol reactions.282 The use of an aqueous solvent was found to be crucial. The reactions on an N-terminal peptide aldehyde substrate proceeded in very high yields. 

Scheme 7.2. Double diastereodifferentiation in solid-phase aldol reactions toward spiroketal synthesis.

Formaldehyde condenses with itself in an aldol-type reaction to yield lower hydroxy aldehydes, hydroxy ketones, and other hydroxy compounds the reaction is autocatalytic and is favored by alkaline conditions. Condensation with various compounds gives methylol (—CH2OH) and methylene (=CH2) derivatives. The former are usually produced under alkaline or neutral conditions, the latter under acidic conditions or in the vapor phase. In the presence of alkahes, aldehydes and ketones containing a-hydrogen atoms undergo aldol reactions with formaldehyde to form mono- and polymethylol derivatives. Acetaldehyde and 4 moles of formaldehyde give pentaerythritol (PE) ... 

Class (2) reactions are performed in the presence of dilute to concentrated aqueous sodium hydroxide, powdered potassium hydroxide, or, at elevated temperatures, soHd potassium carbonate, depending on the acidity of the substrate. Alkylations are possible in the presence of concentrated NaOH and a PT catalyst for substrates with conventional pX values up to - 23. This includes many C—H acidic compounds such as fiuorene, phenylacetylene, simple ketones, phenylacetonittile. Furthermore, alkylations of N—H, O—H, S—H, and P—H bonds, and ambident anions are weU known. Other basic phase-transfer reactions are hydrolyses, saponifications, isomerizations, H/D exchange, Michael-type additions, aldol, Darzens, and similar... 

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.237 The presence of surfactants led mainly to the dehydration reactions. The most common solvents for aldol reactions are ethanol, aqueous ethanol, and water.238 The two-phase system, aqueous sodium hydroxide-ether, has been found to be excellent for the condensation reactions of reactive aliphatic aldehydes.239... 

In the present Ln(OTf)3-catalyzed aldol reactions in aqueous media, the amount of water strongly influences the yields of the aldol adducts. The effects of the amount of water on the yields in the model reaction of benzaldehyde with the silyl enol ether 2 in the presence of 10 mol% Yb(OTf)3 in THF were investigated (Eq. 2). The best yields are obtained when the amount of water present in THF is in the range 10-20 %. When the amount of water is increased, the yield begins to decrease The reaction system becomes a two phase one when the... 

Asymmetric Phase Transfer Catalysis Aldol Reactions... 

The first promising asymmetric aldol reactions through phase transfer mode will be the coupling of silyl enol ethers with aldehydes utilizing chiral non-racemic quaternary ammonium fluorides,1371 a chiral version of tetra-n-butylammonium fluoride (TBAF). Various ammonium and phosphonium catalysts were tried138391 in the reaction of the silyl enol ether 41 of 2-methyl-l-tetralone with benzaldehyde, and the best result was obtained by use of the ammonium fluoride 7 (R=H, X=F) derived from cinchonine,1371 as shown in Scheme 14. 

Subsequent ion exchange of the metal cation with the quaternary ammonium ion catalyst provides a lipophilic ion pair (step 2), which either reacts with the requisite alkyl electrophile at the interface (step 3) or is partitioned into the electrophile-containing organic phase, whereupon alkylation occurs and the catalyst is reconstituted. Enantioselective PTC has found apphcation in a vast number of chemical transformations, including alkylations, conjugate additions, aldol reactions, oxidations, reductions, and C-X bond formations." ... 

In contrast to these vapour-phase reactions, it has been reported that ketones and aqueous ammonia (or ammonium acetate) in an autoclave give less complex mixtures of pyridines. Crotonaldehyde gives 5-ethyl-2-methylpyridine (570) in up to 59% yield, methyl vinyl ketone gives 2,3,4-trimethylpyridine (571) rather than 2,3,6-trimethylpyridine 1,3,3-trimethoxybutane has been used in place of methyl vinyl ketone (49JA2629). In some cases reverse aldol reactions occur (for example with benzalacetophenone) giving unwanted products. A similar reverse aldol is responsible for the production of triarylpyridines (572) when benzalacetophenones are treated with formamide and ammonium formate (73JA4891). 

Enantioselective aldol reactions also can be used to create arrays of stereogenic centers. Two elegant ot-amino anion approaches have recently been published. Fujie Tanaka and Carlos F. Barbas III of the Scripps Institute, La Jolla, have shown (Org. Lett. 2004,6,3541) that L-proline catalyzes the addition of the aldehyde 6 to other aldehydes with high enantio- and diastereocontroJ. Keiji Maruoka of Kyoto University has developed (J. Am. Chem. Soc. 2004,126,9685) a chiral phase transfer catalyst that mediates the addition of the ester 9 to aldehydes, again with high enantio- and diastcrcocontrol. 

The diacetone alcohol reaction is a catalytic liquid-phase aldol condensation. The subsequent reactions involve dehydration, hydrogenation, and esterification. 

Aldol condensations were originally carried out in the liquid phase and catalysed homogeneously by acids or bases this way of operation is still predominant. Solid-catalysed aldol reactions can also be performed in the liquid phase (in trickle or submerged beds of catalyst), but in many cases vapour phase systems are preferred the factors determining the choice are the boiling points and the stability of the reactants at elevated temperatures. At higher temperatures, the formation of a, j3-unsaturated aldehydes or ketones [reactions (B) and (C)] is preferred to aldol (ketol) formation [reaction (A)]. A side reaction, which may become important in some cases, is the self-condensation of the more reactive carbonyl compound if a mixed condensation of two different aldehydes or ketones is occurring. The Cannizzaro reaction of some aldehydes or polymerisation to polyols or other resin-like products can also accompany the main reaction. 

As with homogeneous aldol reactions, simple power-type rate equations have been frequently used to describe the kinetics of solid-catalysed condensations. For several liquid phase reactions, second-order kinetics was established, viz. 

Detailed analysis of the rate and equilibrium constants determined for both phases of intramolecular aldol condensation reactions (13 —>15, 16—>18, and 19—>21) in terns of Marcus theory, has established that the intrinsic barriers for die intramolecular reactions are the same as those determined previously for the intermolecular counterparts.31 Consequently, rate constants for intramolecular aldol reactions are predictable from the energetics of the reactions and the effective molarity can be calculated. An associated discussion of Baldwin s rales suggests that they are a consequence of the need to achieve a conformation from which reaction can take place... 

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