Aldol reactions mechanistic studies

Aldol reactions of silyl enolates are promoted by a catalytic amount of transition metals through transmetallation generating transition metal enolates. In 1995, Shibasaki and Sodeoka reported an enantioselective aldol reaction of enol silyl ethers to aldehydes using a Pd-BINAP complex in wet DMF. Later, this finding was extended to a catalytic enantioselective Mannich-type reaction to a-imino esters by Sodeoka s group [Eq. (13.21)]. Detailed mechanistic studies revealed that the binuclear p-hydroxo complex 34 is the active catalyst, and the reaction proceeds through a palladium enolate. The transmetallation step would be facilitated by the hydroxo ligand transfer onto the silicon atom of enol silyl ethers ... 

The undefined mechanism of the aldol-type Mukaiyama and Sakurai allylation reactions arose the discussion and interest in mechanistic studies [143-145]. The proposed mechanism was proved to proceed through the catalytic activation of the aldehyde and its interaction with the silyl ketene acetal or allylsilane producing the intermediate. From that point the investigation is complicated with two possible pathways that lead either to the release of TMS triflate salt and its electrophihc attack on the trityl group in the intermediate or to the intramolecular transfer of the TMS group to the aldolate position resulting in the evolution of the trityl catalyst and the formation of the product (Scheme 51). On this divergence, series of experimental and spectroscopic studies were conducted. 

Arnett and coworkers later examined the reaction of lithium pinacolone enoiate with substituted benzaldehydes in THE at 25 °C. The determination of the heat of reaction indicated that the Hammett p value for the process is 331. Although the aldol reaction was instantaneous in THF at 25 °C, the reaction with o- or p-methylbenzaldehyde could be followed using a rapid injection NMR method in methylcyclohexane solvent at —80 °C. Application of Eberson s criterion based on the Marcus equation, which relates the free energy of ET determined electrochemically and the free energy of activation determined by kinetics, revealed that the barriers for the ET mechanism should be unacceptably high. They concluded that the reaction proceeds via the polar mechanism . Consistent with the polar mechanism, cyclizable probe experiments were negative . The mechanistic discrepancy between the reactions of benzaldehyde and benzophenone was later solved by carbon kinetic isotope effect study vide infraf. ... 

Mechanistic studies of the Erlenmeyer reaction suggest that the reaction proceeds through initial rapid and reversible formation of the saturated oxazolone followed by an aldol condensation of the latter with the carbonyl compound and subsequent dehydration. ... 

It is interesting that aldol-type condensation of tosylmethyl isocyanide (16) with aldehydes is catalyzed by the silver catalyst more stereoselectively than that catalyzed by the gold catalyst under the standard reaction conditions (Scheme 8B1.9) [26], Elucidation of the mechanistic differences between the gold and silver catalysts in the asymmetric aldol reaction of 16 needs further study. Oxazoline 17 can be converted to optically active a-alkyl-p-(A-methyl-amino)ethanols. 

The mechanism A very detailed mechanistic study of this phosphoramide-catalyzed asymmetric aldol reaction was conducted by the Denmark group (see also Section 6.2.1.2) [59, 60], Mechanistically, the chiral phosphoramide base seems to coordinate temporarily with the silicon atom of the trichlorosilyl enolates, in contrast with previously used chiral Lewis acids, e.g. oxazaborolidines, which interact with the aldehyde. It has been suggested that the hexacoordinate silicate species of type I is involved in stereoselection (Scheme 6.15). Thus, this cationic, diphosphoramide silyl enolate complex reacts through a chair-like transition structure. 

List B (2004) Enamine catalysis is a powerful strategy for the catalytic generation and use of carbanion equivalents. Acc Chem Res 37 548-557 List B, Hoang L, Martin HJ (2004) New mechanistic studies on the proline-catalyzed aldol reaction. Proc Natl Acad Sci USA 101 5839-5842... 

The mixed Tishchenko reaction involves the reaction of the aldol prodnct 113 from one aldehyde with another aldehyde having no a-hydrogens to yield an ester The products were proposed to be formed through an aldol step (equation 33), followed by addition of another aldehyde (equation 34) and an intramolecular hydride transfer (equation 35). However, several aspects of this mechanism need to be clarified. As part of the continuing mechanistic studies carried out by Streitwieser and coworkers on reactions of alkali enolates ", it was found that the aldol-Tishchenko reaction between certain lithium eno-lates and benzaldehyde proceeded cleanly in thf at room temperature". Reaction of the lithium enolate of isobutyrophenone (Liibp) with 1 equiv of benzaldehyde in thf at — 65 °C affords a convenient route to the normal aldol product 113 (R = R" = Ph, R = Me). At room temperature, however, the only product observed after acid workup was the diol-monoester 116, apparently derived from the corresponding lithium ester alcoholate (115, R = R" = Ph, R = Me), which was quantitatively transformed into 116 after quenching. As found in other systems", only the anti diol-monoester diastereomer was formed. 

Murahashi and Naota studied the reaction mechanism of cyclopentadienyl ruthenium enolate complex-catalyzed aldol and Michael addition reactions [80-82]. This mechanistic study revealed that the cone angle of the tertiary phosphine ligands largely affects the stability of C- and N-bound complexes [80, 82], Thus, ligation of bulky phosphine ligand would favor the N -bound complexes [80]... 

The first catalytic asymmetric tandem Michael-aldol reactions were also achieved by the Al-Li-binol complex (ALB), which was prepared from LiAlH4 and binol. The ALB catalysts gave the Michael adducts in up to 99% ee (Eq. (12.2)) [12J. Mechanistic and calculation studies on ALB revealed that ALB is a heterobimetallic complex which acts as a multifunctional catalyst. 

A number of structural and mechanistic studies of related nucleophilic addition processes deserve close scrutiny since they provide relevant parallels that are useful in the analysis of the Mukaiyama aldol addition reaction [43, 44]. 

In contrast to the mechanism discussed in the previous section, catalytic, enantioselective aldol addition processes have been described which proceed through an intermediate aldolate that undergoes subsequent intermolecular silylation. Denmark has discussed this possibility in a study of the triarylmethyl-cation-catalyzed Mukaiyama aldol reaction (Scheme 10) [73]. The results of exploratory experiments suggested that it would be possible to develop a competent catalytic, enantioselective Lewis-acid mediated process even when strongly Lewis acidic silyl species are generated transiently in the reaction mixture. A system of this type is viable only if the rate of silylation of the metal aldolate is faster than the rate of the competing silyl-catalyzed aldol addition reaction (ksj>> ksi-aidoi Scheme 10). A report by Chen on the enantioselective aldol addition reaction catalyzed by optically active triaryl cations provides support for the mechanistic conclusions of the Denmark study [74]. 

Mechanistic studies have discounted the possibility that cycloadduct 70 arises from a tandem Michael-aldolization pathway [ 140]. Stereospecificity is observed using fumaronitrile trans double bond) or maleonitrile cis double bond) as di-enophiles, indicating either a concerted reaction or a rapid second step (aldol) relative to internal bond rotation. Upon treatment with triethylamine in methanol, ring opening to the formal Michael adduct, a thermodynamic sink, is observed this Michael adduct was not formed in the enantioselective catalytic reaction. Further, the Michael adduct was not converted to cycloadduct 70 upon treatment with quinidine in chloroform in fact, access to 70 from the Michael product could be achieved only under fairly special conditions. 

The reactions of imines with ester enolates provide a route to (3-lactams. Because of the importance of this class of antibiotics, much study has been devoted to this type of reaction [116a, 316a]. Recently published theoretical treatments [1283, 1284] suggest a mechanistic pathway different from that of the aldol reaction... 

Huyghues-Despoints, A. and Yaylayan, V.A. Retro-aldol and redox reactions of Amadori compounds Mechanistic studies with variously labelled D-[13C] glucose, J. Agric. Food Chem., 44, 672, 1996. 

Detailed mechanistic studies of this reaction have been undertaken hy several teams. Michael addition of the simplest enolisahle aldehyde, acetaldehyde, poses a significant challenge due to high auto-aldol reactivity of acetaldehyde. List and coworkers used prolinol silyl ether eatalysts to promote enantioselective Michael addition of acetaldehyde to nitroalkenes.The key to successful accomplishment of this transformation was slow addition of acetaldehyde via a syringe pump. 

I 6 Mechanistic Studies of Solid Acids and Base-Catalyzed Clean Technologies Table 6.1 Tandem deprotection-aldol reaction with acids and bases."... 

In carbonyl condensation reactions the enolate or enol of one carbonyl compound reacts with the carbonyl group of another to join the two reactants. As part of the process, a new molecule that is derived from them condenses (forms). Often this molecule is that of an alcohol or water. The main types of condensation reactions we shall study are the Claisen condensation and the aldol condensation. Aldol condensations are preceded mechanistically by aldol additions, which we shall also study. The name aldol derives from the fact that aldehyde and alcohol functional groups are present in the products of many aldol reactions. 

Recently, kinetic and specdoscopic studies gave a mechanistic explanation of the role of water in the aldol reaction with aromatic aldehydes. While the addition of water increases the catalyst concentration by suppression the formation of parasitic species such as the oxazolidinone, decreases the relative concentration of key minimum intermediates by Le Chatelier s principle, shifting the equilibrium towards proline (1). The net effect on the reaction rate of these opposing roles would differ when different substrates are used in the reaction, with the intrinsic rate per active catalysts species within the cycle being suppressed by the added water in the aldol reaction of acetone with aromatic aldehydes [37]. 

As stated above, the studies of Wieland and Miescher, as well as Woodward, on the intramolecular aldol reaction of diketones and dialdehydes were encouraged by this previous work. Wieland, Miescher, and Woodward studied the application of the intramolecular aldol reaction, catalyzed by secondary amine salts, to the synthesis of steroids and believed that their aldolizations proceed via enamine intermediates [ 10]. This was corroborated by the mechanistic studies carried out by Spencer in 1965 [11]. Based on these works, Hajos and Parrish (1974) andEder, Sauer, and Wiechert... 

Another important fact was reported in the 1980s Agami and co-workers studied the application of proline in an enolendo aldolization reaction. Their mechanistic studies showed nonlinear and dilution effects that suggested the involvement of two molecules of proline in the transition state (Scheme 1.6) [18]. 

---