Aldol condensation Lewis acids

Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with aldehydes proceeds via "open" transition state to give anti aldols starting from either E- or Z- enolates. 

A regioselective aldol condensation described by Biichi succeeds for sterical reasons (G. Biichi, 1968). If one treats the diaidehyde given below with acid, both possible enols are probably formed in a reversible reaaion. Only compound A, however, is found as a product, since in B the interaction between the enol and ester groups which are in the same plane hinders the cyclization. BOchi used acid catalysis instead of the usual base catalysis. This is often advisable, when sterical hindrance may be important. It works, because the addition of a proton or a Lewis acid to a carbonyl oxygen acidifies the neighbouring CH-bonds. 

In an intramolecular aldol condensation of a diketone many products are conceivable, since four different ends can be made. Five- and six-membered rings, however, wUl be formed preferentially. Kinetic or thermodynamic control or different acid-base catalysts may also induce selectivity. In the Lewis acid-catalyzed aldol condensation given below, the more substituted enol is formed preferentially (E.J. Corey, 1963 B, 1965B). 

Ketene acetals prepared from fluorinated esters by trimethylsilylation undergo Lewis acid-promoted aldol condensations giving satisfactory yields but low diastereoselectivity [27] (equation 22). 

Scheme 7.5 gives some examples of the Reformatsky reaction. Zinc enolates prepared from a-haloketones can be used as nucleophiles in mixed aldol condensations (see Section 2.1.3). Entry 7 is an example. This type of reaction can be conducted in the presence of the Lewis acid diethylaluminum chloride, in which case addition occurs at -20° C.171... 

Annual Volume 71 contains 30 checked and edited experimental procedures that illustrate important new synthetic methods or describe the preparation of particularly useful chemicals. This compilation begins with procedures exemplifying three important methods for preparing enantiomerically pure substances by asymmetric catalysis. The preparation of (R)-(-)-METHYL 3-HYDROXYBUTANOATE details the convenient preparation of a BINAP-ruthenium catalyst that is broadly useful for the asymmetric reduction of p-ketoesters. Catalysis of the carbonyl ene reaction by a chiral Lewis acid, in this case a binapthol-derived titanium catalyst, is illustrated in the preparation of METHYL (2R)-2-HYDROXY-4-PHENYL-4-PENTENOATE. The enantiomerically pure diamines, (1 R,2R)-(+)- AND (1S,2S)-(-)-1,2-DIPHENYL-1,2-ETHYLENEDIAMINE, are useful for a variety of asymmetric transformations hydrogenations, Michael additions, osmylations, epoxidations, allylations, aldol condensations and Diels-Alder reactions. Promotion of the Diels-Alder reaction with a diaminoalane derived from the (S,S)-diamine is demonstrated in the synthesis of (1S,endo)-3-(BICYCLO[2.2.1]HEPT-5-EN-2-YLCARBONYL)-2-OXAZOLIDINONE. 

Silyloxy)alkenes were first reported by Mukaiyama as the requisite latent enolate equivalent to react with aldehydes in the presence of Lewis acid activators. This process is now referred to as the Mukaiyama aldol reaction (Scheme 3-12). In the presence of Lewis acid, anti-aldol condensation products can be obtained in most cases via the reaction of aldehydes and silyl ketene acetals generated from propionates under kinetic control. 

A stereoselective tandem iodination and aldol-type condensation has been described for the reaction of methyl propiolate and carbonyl compounds in the presence of a stoichiometric amount of tetra-n-butylammonium iodide and zirconium chloride to yield Z-3-iodo-2-(l-hydroxyalkyl)propenoates, as the major products [48]. No reaction occurs in the absence of the Lewis acid. There does not appear to be any control on the chirality of the hydroxyl centre. 

TABLE 9.7. Lewis Acid Mediated Aldol Condensations of Boron Enolate 100b... 

The iridium-catalyzed addition of water could be applied to the reaction of a,03-diynes. Thus, 1,7-octadiyne 125 was converted to l-(2-methylcyclopent-l-enyl)ethanone 127 (Equation 10.32). The formation of 127 was explained by assuming intramolecular aldol condensation of the resulting 2,7-octadione by Lewis acid. 

Lewis acid-catalyzed aldol condensation of aldehyde and silyl enol ether. 

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... 

Scheme 7.41). It seems to be reasonable to presume that the isomerization of propargylic alcohol to cinnamaldehyde proceeds via an intramolecular nucleophilic attack of coordinated water on an electropositive a-carbon of the allenylidene ligand (Scheme 7.42). Then, dicationicdiruthenium complexes work as Lewis acids to promote the aldol condensation between cinnamaldehyde and acetone. Thus, the dual catalytic activity of dicationic chalcogenolate-bridged diruthenium complexes is essential to promote the present novel reaction between propargylic alcohols and acetone. 

Pinacol rearrangement driven by the release of the ring strain of a cyclobutane ring has been employed in an extremely efficient manner to form cyclopentanone derivatives. Experimentally. the Lewis acid mediated aldol condensation of benzaldehyde with l,2-bis(trimethyl-siloxy)cyclobutcne at —78 C gave the pinacol 1 in its silylated form.35,36 Subsequent treatment of this pinacol with trifluoroacetic acid at room temperature afforded 2-phenyl-cyclopentane-l,3-dione (2) in 97% yield.35,36... 

The second step in the hexose synthesis was the aldol condensation of 4 with another a-hetero aldehyde derivative S. By tuning the Lewis acid and the solvent, three of the four possible diastereomeric products could be selectively prepared. a-Amino and a-thio aldehydes worked well also, leading to 9 and 10 respectively. 

NMR has been extensively applied to carbonyl compounds in acidic zeolites and other solid acids. The unshared pairs of electrons on the oxygen can interact with either Brpnsted or Lewis sites, and aldol condensation reactions are commonly observed. Acetone was first studied on a zeolite by Bosacek and co-workers (146) followed by Haw and co-workers (147) and later by Gorte and co-workers (148). The conclusion of an earlier acetone paper of Gorte and co-workers (149) was that acetone forms a static complex on the Brdnsted site of HZSM-5 at room temperature, but this claim was later revised (150) upon the realization that molecular motion in the complex is not halted except at appreciably lower temperatures. 

A further demonstration of the Lewis acidity of Os(III) is the aldol condensation reaction of [Os(NH3)5( j1-acetone)]3+, to form the diacetone alcohol complex (67,90). The catalysis of this reaction can occur in one of two ways. Either Os(III) catalyzes the deprotonation of a methyl group of the bound acetone ligand to produce a nucleophile for attack at a second acetone ligand, or the Os(III) center polarizes the C=0 bond of... 

Enantioselective condensation of aldehydes and enol silyl ethers is promoted by addition of chiral Lewis acids. Through coordination of aldehyde oxygen to the Lewis acids containing an Al, Eu, or Rh atom (286), the prochiral substrates are endowed with high electrophilicity and chiral environments. Although the optical yields in the early works remained poor to moderate, the use of a chiral (acyloxy)borane complex as catalyst allowed the erythro-selective condensation with high enan-tioselectivity (Scheme 119) (287). This aldol-type reaction may proceed via an extended acyclic transition state rather than a six-membered pericyclic structure (288). Not only ketone enolates but ester enolates... 

Mukaiyama aldol condensation (6, 590-591).8 This reaction can be effected in the absence of a Lewis acid catalyst under high pressure (10 kbar). Surprisingly the stereoselectivity is the reverse of that of the TiCl4-catalyzed reaction (equation I). The reaction can also be effected in water with the same stereoselectivity, but the yield is low because of hydrolysis of the silyl enol ether. Yields are improved by use of water-oxolane (1 1) and by sonication.9... 

The Mukaiyama reaction is a versatile crossed-aldol reaction that uses a silyl enol ether of an aldehyde, ketone, or ester as the carbon nucleophile and an aldehyde or ketone activated by a Lewis acid as the carbon electrophile. The product is a /1-hydroxy carbonyl compound typical of an aldol condensation. The advantages to this approach are that it is carried out under acidic conditions and elimination does not usually occur. 

Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals ... 

Mukaiyama found that Lewis acids can induce silyl enol ethers to attack carbonyl compounds, producing aldol-like products.22 The reaction proceeds usually at -78 °C without selfcondensation and other Lewis acids such as TiCl4 or SnCI4 are commonly used. The requisite silyl enol ether 27 was prepared by treatment of ketone 13 with lithium hexamethyl disilazide (LiHMDS) and trapping the kinetic enolate with chlorotrimethylsilane. When the silyl enol ether 27 was mixed with aldehyde 14 in the presence of BF3-OEt2 a condensation occurred via transition state 28 to produce the product 29 with loss of chlorotrimethylsilane. The induced stereochemistry in Mukaiyama reactions using methylketones and a, -chiral aldehydes as substrates... 

Carbonyl activation and deactivation.1 Aldehydes, but not ketones, undergo aldol condensation with silyl enol ethers at —78° in the presence of dibutyltin bistriflate. In contrast, the dimethyl acetals of ketones, but not of aldehydes, can undergo this condensation (Mukaiyama reaction) with silyl enol ethers at -78° with almost complete discrimination, which is not observed with the usual Lewis-acid catalysts. Thus dibutyltin bistriflate activates aldehydes, but deactivates acetals of... 

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