Since the comprehensive studies of Nord et al. in the 1940s, [1] the catalytic aldol-Tishchenko reaction has received much attention as a means to couple unactivated carbonyl compounds. [2] Only more recently have stoichiometric [3] and catalytic stereoselective reactions [4] become the focus of development. Mechanistic studies on stereoselective aldol-Tishchenko reactions suggest that the reaction occurs by the mechanism depicted in Scheme 1. [3a,d,e, 4a] After generation of H O R R 1 R 2 O O M R 2 R O OM R R 1 OM R 2 O O R 1 R 2 H OM R 1 H R 2 R R 2 CHO R 2 O OM R 2 O R 1 R R R 1 O R 2 O OH R 1 R A O R 2 R 2 CHO Scheme 1. Cycle for catalytic aldol-Tishchenko reactions.the enolate, a reversible aldolization step is thought to precede a rate-determining reduction via transition state A. [5] The major product stereoisomer is derived from the stereoisomer of structure A wherein all substituents at the sixmembered ring occupy equatorial positions. Despite the fact that stereocontrol in the aldol-Tishchenko reaction appears to result from a highly organized metal-centered transition state, this reaction has not been subject to enantioselective catalysis under the influence of chiral ancillary ligands. In this report, we describe the first catalytic enantioselective version of this process. [6] We recently reported that simple metal alkoxides can catalyze a diastereoselective hetero aldol-Tishchenko reac-tion thereby offering access to propionate equivalents directly from simple carbonyl compounds. [7] Expecting that de novo design of chiral metal alkoxide catalysts would be treacherous due to the inherent difficulty in predicting coordination numbers and aggregation states of metal alkoxides, we have used an arrayed catalyst evaluation [8] protocol to discover promising catalyst candidates. Initial studies with 96 independent complexes revealed the complex of Y 5 O(OiPr) 13 [9] and salen (1 a) [10] as an effective catalyst for the enantioselective aldol-Tishchenko reaction. [11] We now examined the effect of ligand structure on this reaction [Eq. (1)]. As seen in Table 1, the aldol-Tishchenko adduct is obtained with ligand 1 a in 44 % overall yield and in a 78:22 enantiomer ratio. The reaction provides two regioisomeric esters 2 in similar enantiopurity suggesting a nonselective intramolecular acyl migration after formation of the aldol-Tishchenko adduct. Bulky substituents ortho to the salen oxygen atom (R 1 ) are necessary for reactivity and selectivity, whereas the presence of para substituents (R 2 ) is not essential for asymmetric induction. Also of note is that the diphenylethylene-derived ligand 1 e displays greater enantioselection than the corresponding diaminocyclohexane-derived ligand 1 a. With some of the structural requirements for effective ligands exposed, we prepared salen 1 f containing both a bulky ortho adamantyl unit and the diphenyl backbone. The use of 1 f in the aldol-Tishchenko reaction (1) results in 70 % yield and an 87:13 ratio of enantiomers, the highest selectivity of all ligands e...
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This paper reports the utility of simple metal alkoxides for the catalytic, stereoselective hetero-aldol−Tishchenko reaction (eq 1). Choice of metal alkoxide is crucial to achieving high efficiency and stereoselectivity. Whereas NaO-t-Bu is an effective catalyst, delivering one product in 68% yield and 99:1 stereoselection, Sm(O-i-Pr)3 is less effective and delivers the same product in 42% yield with 4:1 stereoselection.
Unmodified carbonyl compounds are converted in an enantioselective aldol‐Tishchenko reaction directly into the chiral adduct by using catalytic amounts of a chiral base prepared in situ [Eq. (1)]. The catalyst was developed through the combination of arrayed catalyst evaluation and informed ligand design. Ad=adamantyl.
Since the comprehensive studies of Nord et al. in the 1940s, [1] the catalytic aldol-Tishchenko reaction has received much attention as a means to couple unactivated carbonyl compounds. [2] Only more recently have stoichiometric [3] and catalytic stereoselective reactions [4] become the focus of development. Mechanistic studies on stereoselective aldol-Tishchenko reactions suggest that the reaction occurs by the mechanism depicted in Scheme 1. [3a,d,e, 4a] After generation of H O R R 1 R 2 O O M R 2 R O OM R R 1 OM R 2 O O R 1 R 2 H OM R 1 H R 2 R R 2 CHO R 2 O OM R 2 O R 1 R R R 1 O R 2 O OH R 1 R A O R 2 R 2 CHO Scheme 1. Cycle for catalytic aldol-Tishchenko reactions.the enolate, a reversible aldolization step is thought to precede a rate-determining reduction via transition state A. [5] The major product stereoisomer is derived from the stereoisomer of structure A wherein all substituents at the sixmembered ring occupy equatorial positions. Despite the fact that stereocontrol in the aldol-Tishchenko reaction appears to result from a highly organized metal-centered transition state, this reaction has not been subject to enantioselective catalysis under the influence of chiral ancillary ligands. In this report, we describe the first catalytic enantioselective version of this process. [6] We recently reported that simple metal alkoxides can catalyze a diastereoselective hetero aldol-Tishchenko reac-tion thereby offering access to propionate equivalents directly from simple carbonyl compounds. [7] Expecting that de novo design of chiral metal alkoxide catalysts would be treacherous due to the inherent difficulty in predicting coordination numbers and aggregation states of metal alkoxides, we have used an arrayed catalyst evaluation [8] protocol to discover promising catalyst candidates. Initial studies with 96 independent complexes revealed the complex of Y 5 O(OiPr) 13 [9] and salen (1 a) [10] as an effective catalyst for the enantioselective aldol-Tishchenko reaction. [11] We now examined the effect of ligand structure on this reaction [Eq. (1)]. As seen in Table 1, the aldol-Tishchenko adduct is obtained with ligand 1 a in 44 % overall yield and in a 78:22 enantiomer ratio. The reaction provides two regioisomeric esters 2 in similar enantiopurity suggesting a nonselective intramolecular acyl migration after formation of the aldol-Tishchenko adduct. Bulky substituents ortho to the salen oxygen atom (R 1 ) are necessary for reactivity and selectivity, whereas the presence of para substituents (R 2 ) is not essential for asymmetric induction. Also of note is that the diphenylethylene-derived ligand 1 e displays greater enantioselection than the corresponding diaminocyclohexane-derived ligand 1 a. With some of the structural requirements for effective ligands exposed, we prepared salen 1 f containing both a bulky ortho adamantyl unit and the diphenyl backbone. The use of 1 f in the aldol-Tishchenko reaction (1) results in 70 % yield and an 87:13 ratio of enantiomers, the highest selectivity of all ligands e...
For Abstract see ChemInform Abstract in Full Text.
In this experiment, organic chemistry students perform reactions between three naphthyl acetate derivatives and the diazonium salt Fast-Red TR, under basic conditions. The three naphthyl acetate derivatives used in this study are 2-naphthyl acetate (1a), 6-bromo-2-naphthyl acetate (1b) and 1,6-dibromo-2-naphthyl acetate (1c). The two-step, one-pot reactions (ester hydrolysis followed by reaction with Fast Red TR) are screened for the formation of an orange–red diazo dye both visually and by UV–vis spectroscopy. Students discover that the hydrolysis and electrophilic aromatic substitution is the fastest with ester 1a and the slowest with ester 1c. This allows students to conclude that electrophilic aromatic substitution, rather than ester hydrolysis, is rate-limiting. This experiment is performed over a two-week period: during the first week students synthesize and purify compounds 1b and 1c, which are easily characterized through 1H NMR and IR spectroscopies. The ester hydrolysis and diazotization visual and UV–vis studies are performed during the second week of the experiment.
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