Aldol addition reaction, solvent effects

Yamamoto has recently described a novel catalytic, asymmetric aldol addition reaction of enol stannanes 19 and 21 with aldehydes (Eqs. 8B2.6 and 8B2.7) [14]. The stannyl ketones are prepared solvent-free by treatment of the corresponding enol acetates with tributyltin methoxide. Although, in general, these enolates are known to exist as mixtures of C- and 0-bound tautomers, it is reported that the mixture may be utilized in the catalytic process. The complexes Yamamoto utilized in this unprecedented process are noteworthy in their novelty as catalysts for catalytic C-C bond-forming reactions. The active complex is generated upon treatment of Ag(OTf) with (R)-BINAP in THF. Under optimal conditions, 10 mol % catalyst 20 effects the addition of enol stannanes with benzaldehyde, hydrocinnamaldehyde, or cinnamaldehyde to give the adducts of acetone, rerf-butyl methyl ketone (pinacolone), and acetophenone in good yields and 41-95% ee (Table 8B2.3). 

A related Mukaiyama aldol catalyst system reported by Keck prescribes the use of a complex that is prepared in toluene from (R)- or (S)-BINOL and Ti(0 Pr)4 in the presence of 4 A molecular sieves. In work preceding the aldol addition reaction, Keck had studied this remarkable catalyst system and subsequently developed it into a practical method for enantioselective aldehyde allylation [95a, 95b, 95c, 96]. Because the performance of the Ti(IV) complex as an aldol catalyst was quite distinct from its performance as a catalyst for aldehyde allylation, a careful examination of the reaction conditions was conducted. This meticulous study describing the use of (BINOL)Ti(OiPr)2 as a catalyst for aldol additions is noteworthy since an extensive investigation of reaction parameters, such as temperature, solvent, and catalyst loading and their effect on the enantiomeric excess of the product was documented. For example, when the reaction of benzal-dehyde and tert-butyl thioacetate-derived enol silane was conducted in dichlo-romethane (10 mol % catalyst, -10 °C) the product was isolated in 45% yield and 62% ee by contrast, the use of toluene as solvent under otherwise identical conditions furnished product of higher optical purity (89% ee), albeit in 54% yield. For the reaction in toluene, increasing the amount of catalyst from 10 to 20 mol %... 

A soln. of 2-carbomethoxy-2-cyclohexenone in chloroform added during 25 min to a mixture of startg. p-ketoester and 0.47 eqs. CS2CO3 in the same solvent at room temp., 2.5 h later CS2CO3 removed, and the crude product refluxed with / -TsOH in benzene product. Y 70% (99.5% cis-cis isomer). Solvent effects and reaction mechanisms s. P. Deslongchamps, J.-F. Lavallee, Tetrahedron Letters 29, 5117-8 (1988) 14a-hydroxysteroids by sequential Michael addition-intramolecular aldol condensation s. ibid. 6033-6. 

Direct asymmetric cross-aldol reactions of ketones with aromatic aldehydes proceed in the presence of an l-proline-derived tertiary diamine and additives using water as a solvent (Scheme 26). L-Proline-derived diamines give racemic product in the absence of an acid cocatalyst. While trifluoroacetic acid (TFA) is the most effective additive for the aldol addition of cyclohexanone to 4-nitrobenzaldehyde in the presence of L-proline-derived diamine, addition of scandium triflate is also effective for the reaction with similar enantioselectivity. 

The Kotsuki group investigated the effect of high-pressure conditions on the direct proline-catalyzed aldol reaction [79a], a process which, interestingly, does not require use of DMSO as co-solvent. Use of high-pressure conditions led to suppression of the formation of undesired dehydrated by-product and enhancement of the yield. Study of the substrate range with a range of aldehydes and ketones revealed that enantioselectivity was usually comparable with that obtained from experiments at atmospheric pressure. Additionally, proline catalyzed aldol reactions in ionic liquids, preferably l-butyl-3-methylimidazolium hexafluorophosphate, have been successfully carried out [79b,c]. 

Among the fluoride ion promoted reactions which occur in dipolar non-HBD solvents are alkylations of alcohols and ketones, esterifications, Michael additions, aldol and Knoevenagel condensations as well as eliminations for a review, see reference [600]. In particular, ionic fluorides are useful in the dehydrohalogenation of haloalkanes and haloalkenes to give alkenes and alkynes (order of reactivity R4N F > K ([18]crown-6) F > Cs F K F ). For example, tetra-n-butylammonium fluoride in AjA-dimethylformamide is an effective base for the dehydrohalogenation of 2-bromo-and 2-iodobutane under mild conditions [641] cf Eq. (5-123). 

The importance of aqueous reactions is now generally recognized, and development of carbon-carbon bond-forming reactions that can be performed in aqueous media is now one of the most challenging topics in organic synthesis [59]. It has been found that Sc(OTf)3 was effective in aldol reactions of silyl enolates with aldehydes in aqueous media (water-THF Eq. 16) [4]. Reaction between aromatic and aliphatic aldehydes such as benzaldehyde and 3-phenylpropionaldehyde and silyl enolates have been performed successfully in aqueous solvents. In addition, direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enolates affords the corresponding aldol adducts in good yields. Water-sensitive silyl enolates could be used in aqueous solutions with Sc(OTf)3 as catalyst. 

For example, an effective procedure for the synthesis of LLB (where LL = lanthanum and lithium) is treatment of LaCls 7H2O with 2.7 mol equiv. BINOL dilithium salt, and NaO-t-Bu (0.3 mol equiv.) in THF at 50 °C for 50 h. Another efficient procedure for the preparation of LLB starts from La(0-/-Pr)3 [54], the exposure of which to 3 mol equiv. BINOL in THF is followed by addition of butyllithium (3 mol equiv.) at 0 C. It is worthy of note that heterobimetallic asymmetric complexes which include LLB are stable in organic solvents such as THF, CH2CI2 and toluene which contain small amounts of water, and are also insensitive to oxygen. These heterobimetallic complexes can, by choice of suitable rare earth and alkali metals, be used to promote a variety of efficient asymmetric reactions, for example nitroaldol, aldol, Michael, nitro-Mannich-type, hydrophosphonylation, hydrophosphination, protonation and Diels-Alder reactions. A catalytic asymmetric nitroaldol reaction, a direct catalytic asymmetric aldol reaction, and a catalytic asymmetric nitro-Mannich-type reaction are discussed in detail below. 

Sc(() l f) ( is an effective catalyst of the Mukaiyama aldol reaction in both aqueous and non-aqueous media (vide supra). Kobayashi et al. have reported that aqueous aldehydes as well as conventional aliphatic and aromatic aldehydes are directly and efficiently converted into aldols by the scandium catalyst [69]. In the presence of a surfactant, for example sodium dodecylsulfate (SDS) or Triton X-100, the Sc(OTf)3-catalyzed aldol reactions of SEE, KSA, and ketene silyl thioacetals can be performed successfully in water wifhout using any organic solvent (Sclieme 10.23) [72]. They also designed and prepared a new type of Lewis acid catalyst, scandium trisdodecylsulfate (STDS), for use instead of bofh Sc(OTf) and SDS [73]. The Lewis acid-surfactant combined catalyst (LASC) forms stable dispersion systems wifh organic substrates in water and accelerates fhe aldol reactions much more effectively in water fhan in organic solvents. Addition of a Bronsted acid such as HCl to fhe STDS-catalyzed system dramatically increases the reaction rate [74]. 

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