Tishchenko reactions

The Tishchenko reaction is a dimerization of aldehydes to the corresponding esters, which is classically carried out in homogeneous media using aluminum 

Yields in the Tishchenko Reaction of Furfural on Alkaline Earth Metal Oxides in a Batch Reactor (178) 

Catalyst Catalyst pretreatment temperature (K) Surface area (m /g) Reaction temp (K) Time (h) Yield (%) 

Reaction conditions amount of furfural, 10 mmol mass of catalysts, 100 mg. 

The results obtained with the Tishchenko reaction of furfural using alkaline earth metal oxides as base catalysts are presented in Table III. Because the strength of basic sites increases in the order MgO CaO SrO BaO, and the order of their acid strengths is the reverse 73), it was concluded that CaO and SrO— which have moderate acid and base sites in comparison with MgO and BaO—are appropriate 

The mechanism of the Tishchenko reaction was extensively studied and there were three different mechanisms proposed. The most commonly accepted mechanism is depicted below. According to this proposal, first the aluminum alkoxide coordinates to the aldehyde. This is followed by the attack of a second molecule of aldehyde. Subsequent hydride shift leads to the regeneration of the catalyst and formation of the product. 

Sarains A-C are a family of alkaloids isolated from marine sponges. J.K. Cha and co-workers accomplished the synthesis of the western macrocyclic ring of sarain To establish the C3 quaternary stereocenter, they treated the aldehyde substrate with formaldehyde in the presence of sodium carbonate. The aldehyde substrate underwent an aldol reaction followed by a Tishchenko reaction to provide the formate ester of the 1,3-diol product. This ester was hydrolyzed in situ under the reaction conditions and the 1,3-diol was isolated. 

Schreiber and co-workers accomplished the total synthesis of (-)-rapamycin. In their approach, they utilized an Evans-Tishchenko reaction of C22-C42 fragment and Boc pipecolinal. The reaction provided the product with excellent yield and as a 20 1 mixture of the anti and syn diastereomers. 

Rhizoxin D, a natural product possessing potent antitumor and antifungal activity, was synthesized by J.W. Leahy and co-workers. To establish the C17 stereocenter, they utilized the Evans-Tishchenko reaction. To this end, the 3-hydroxyketone substrate was reacted with p-nitrobenzaldehyde in the presence of catalytic Smb. The reaction yielded the monoester of the anti 1,3-diol as a single product. 

The scalable total synthesis of the cytotoxic natural product (+)-FR182877 was accomplished in the laboratory of E.J. Sorensen.The key steps of the synthetis were an intramolecular Tsuji-Trost allylation to prepare the 19-membered macrocyclic pentaene followed by a double transannular DIels-Alder cycloadditlon to obtain the desired pentacyclic structure. The allylic carbonate was exposed to 10 mol% of the Pd-catalyst under high dilution conditions in THF. The new bond between Cl and Cl 9 was formed with complete diastereoselectivity and in good yield, although the configuration at Cl 9 was not determined. 

Hybrid materials [Ln N(SiMe3)2 3] AS-380.7oo with yttrium (12c) and samarium metal centers (12d) (Table 12.3) have been studied for the transformation of benz-aldehyde (Sj) (Table 12.10), displaying a lower conversion than the molecular homologs Ln[N(SiMe3)2]3 [89% (Y), 67% (Sm)j [117]. 

Esters from the corresponding aldehydes and Al(OEt)3, which serves as a homogeneous catalyst. 

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Esters. The monoisobutyrate ester of 2,2,4-trimethyl-1,3-pentanediol is prepared from isobutyraldehyde ia a Tishchenko reaction (58,59). Diesters, such as trimethylpentane dipelargonate (2,2,4-trimethylpentane 1,3-dinonanoate), are prepared by the reaction of 2 mol of the monocarboxyhc acid with 1 mol of the glycol at 150—200°C (60,61). The lower aUphatic carboxyHc acid diesters of trimethylpentanediol undergo pyrolysis to the corresponding ester of 2,2,4-trimethyl-3-penten-l-ol (62). These unsaturated esters reportedly can be epoxidized by peroxyacetic acid (63). 

Manufacture. Hydroxypivalyl hydroxypivalate may be produced by the esterification of hydroxypivaUc acid with neopentyl glycol or by the intermolecular oxidation—reduction (Tishchenko reaction) of hydroxypivaldehyde using an aluminum alkoxide catalyst (100,101). 

Upon treatment with aluminum ethoxide, the aldehyde is converted to cinnamyl cinnamate [122-69-0] (Tishchenko reaction), a valuable perfumery ingredient. 

The direct conversion of ethyl alcohol to ethyl acetate is beheved to take place via acetaldehyde and its condensation to ethyl acetate (Tishchenko reaction) (28-34). 

When aldehydes are reduced, the Tishchenko reaction may be a side-reaction. It is the result of an attack of the oxygen atom of the alkoxide on the carbonyl function of the aldehyde. In particular, aldehydes lacking an a-hydrogen atom such as benzaldehyde are prone to form esters (Scheme 20.24) [108]. It has been reported that many aldehydes can be converted into Tishchenko esters at room temperature, almost quantitatively and with high turnovers, using Sml2 catalysts [109] or a bi-aluminum catalyst [8],... 

Silyltitanation of 1,3-dienes with Cp2Ti(SiMe2Ph) selectively affords 4-silylated r 3-allyl-titanocenes, which can further react with carbonyl compounds, C02, or a proton source [26]. Hydrotitanation of acyclic and cyclic 1,3-dienes functionalized at C-2 with a silyloxy group has been achieved [27]. The complexes formed undergo highly stereoselective addition with aldehydes to produce, after basic work-up, anti diastereomeric (3-hydroxy enol silanes. These compounds have proved to be versatile building blocks for stereocontrolled polypropionate synthesis. Thus, the combination of allyltitanation and Mukayiama aldol or tandem aldol-Tishchenko reactions provides a short access to five- or six-carbon polypropionate stereosequences (Scheme 13.15) [28],... 

The dimerization of aldehydes to form esters is a completely atom-efficient process known as the Tishchenko reaction, which involves no net oxidation or reduction. Suzuki, Katoh, and coworkers have used complex 77 to catalyze the Tishchenko reaction of a range of aldehydes, including dihydrocinnamaldehyde 91 and benzaldehyde 14 (Scheme 22) [81]. The same catalyst has been used for an intramolecular variant of the reaction, where keto-aldehyde 92 isomerizes to lactone 93 via an intramolecular Tishchenko reaction. The oxidized product is formed as a by-product,... 

In the aldol-Tishchenko reaction, a lithium enolate reacts with 2 mol of aldehyde, ultimately giving, via an intramolecular hydride transfer, a hydroxy ester (51) with up to three chiral centres (R, derived from rYhIO). The kinetics of the reaction of the lithium enolate of p-(phenylsulfonyl)isobutyrophenone with benzaldehyde have been measured in THF. ° A kinetic isotope effect of fee/ o = 2.0 was found, using benzaldehyde-fil. The results and proposed mechanism, with hydride transfer rate limiting, are supported by ab initio MO calculations. 

The mechanism of the aldol-Tishchenko reaction has been probed by determination of kinetics and isotope effects for formation of diol-monoester on reaction between the lithium enolate of p-(phenylsulfonyl)isobutyrophenone (LiSIBP) and two molecules of benzaldehyde. ". The results are consistent with the formation of an initial lithium aldolate (25) followed by reaction with a second aldehyde to form an acetal (26), and finally a rate-limiting intramolecular hydride transfer (Tishchenko... 

The coupling of two molecules of aldehydes into esters (Tishchenko reaction) has been used as an efficient method for the industrial preparation of dimeric esters. Although a number of systems for such reactions using transition-metal catalysts have been reported [73], there is stiU great room for improvement of the synthetic efficiency. 

A proposed mechanism for the Cp lr-catalyzed Tishchenko reaction is illustrated in Scheme 5.35. In this reaction, hydrogen transfer from the hemiacetal to aldehyde catalyzed by the Cp lr complex would be crucial. 

Scheme 12.24 (a) Tishchenko dimerization and (b) mixed Tishchenko reactions. 

The first report on organolanthanide-promoted Tishchenko reactions, that is, the transformation of aldehydes or mixed aldehydes into the corresponding esters, including a mechanistic proposal appeared in 1996 [catalyst Cp2 LnCH(SiMe3)2 with Ln = La and Nd] [233]. Two years later, lanthanide silylamide complexes Ln[N(SiMe3)2]3 were found as easily accessible and even more active catalysts (Scheme 12.24) [234, 235]. 

In mixed Tishchenko reactions using benzaldehyde combined with fural or 2,3-dimethyoxybenzaldehyde in a 1 1 ratio (Scheme 12.24/b), the Sm-supported material 17 gave a better selectivity in cross products P (53-67%) than the molecular Sm[N(SiMe3)2]3 (36-51%). Again, the changed selectivity was attributed to phenomena like spatial restriction and diffusion controlled surface confine-... 

Scheme 12.25 Tishchenko reaction of butyraldehyde catalyzed by [Sm N(SiMe3)2 3] SBA-l 5.200 (17).

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