Benzoin condensation catalysts

One may find many publications in the literature on the theoretical aspects of thiazolium quaternary salts, because of the biological importance of thiamine and their use as catalysts for benzoin condensation. 

The cyanide ion plays an important role in this reaction, for it has three functions in addition to being a good nucleophile, its electron-withdrawing effect allows for the formation of the carbanion species by proton transfer, and it is a good leaving group. These features make the cyanide ion a specific catalyst for the benzoin condensation. 

Acyloins (a-hydroxy ketones) are formed enzymatically by a mechanism similar to the classical benzoin condensation. The enzymes that can catalyze reactions of this type arc thiamine dependent. In this sense, the cofactor thiamine pyrophosphate may be regarded as a natural- equivalent of the cyanide catalyst needed for the umpolung step in benzoin condensations. Thus, a suitable carbonyl compound (a -synthon) reacts with thiamine pyrophosphate to form an enzyme-substrate complex that subsequently cleaves to the corresponding a-carbanion (d1-synthon). The latter adds to a carbonyl group resulting in an a-hydroxy ketone after elimination of thiamine pyrophosphate. Stereoselectivity of the addition step (i.e., addition to the Stand Re-face of the carbonyl group, respectively) is achieved by adjustment of a preferred active center conformation. A detailed discussion of the mechanisms involved in thiamine-dependent enzymes, as well as a comparison of the structural similarities, is found in references 1 -4. 

The mechanism of the cyanide- and thioazolium ion-catalyzed conjugate addition reactions is considered to be analogous to the Lapworth mechanism for the cyanide-catalyzed benzoin condensation. Thus the cyano-stabilized carbanion resulting from deprotonation of the cyanohydrin of the aldehyde is presumed to be the actual Michael donor. After conjugate addition to the activated olefin, cyanide is eliminated to form the product and regenerate the catalyst. 

Scheme 12.20 Triazolium pre-catalysts for the asymmetric benzoin condensation...

Tetra-n-butylammonium cyanide is a better catalyst for benzoin condensation reactions than is sodium cyanide, and >70% yields are obtained under mild conditions [63, 64] tetra-ethylammonium cyanide is less effective. Polymer-supported ammonium catalysts have also been used to promote the benzoin reaction and, although yields are only moderate (40-60%), the convenience of removal of the catalyst is an advantage. Use of chiral ammonium groups produces an enantiomeric excess of chiral products from the condensation of benzaldehyde, but furfural tends to produce a racemate [65]. 

Chiral bicyclic 1,2,4-triazolium salts, in which a defined face of the heterocycle is hindered, catalyse the benzoin condensation with up to 80% ee, and with the opposite chirality to the corresponding thiazole catalysts. Conformationally restricted chiral bicyclic thiazolium salts have been similarly investigated. " ... 

Dicarbonyl derivatives from aldehydes and a,P-unsaturated ketones. The thi-azolium catalyst serves as a safe surrogate for CN. Also known as the Mi-chael-Stetter reaction. Cf. Benzoin condensation. 

Examples of nonasymmetric organocatalysts that were introduced in the 1950s include analogs of thiamine reported by Breslow in 1957 as an alternative to cyanide as a catalyst for the benzoin condensation [8]. Asymmetric versions of these thiazolium catalysts were used in organocatalytic benzoin condensations by Sheehan and Hunneman in 1966 [9]. In another important development, in 1969 the nucleophilic catalyst 4-(dimethylamino)pyridine (DMAP), which is now widely used for difficult esterifications, was reported by Steglich [10]. 

The thiazolium salt 3-benzyl-5-(2-hydroxyethyl)-4-methyl-l,3-thiazolium chloride is an excellent catalyst for the addition of unsaturated aliphatic aldehydes to vinylketones (79CB84). The presence of a base such as sodium acetate or triethylamine is required, for the thiazolium salt must first be transformed into the ylide structure (615), which then exerts a catalytic effect resembling that of cyanide ion in the benzoin condensation (Scheme 137). Yields of 1,4-diketones (616) produced in this process were generally good. The use of thiazolium salts for other related reactions has been reviewed (76AG(E)639). 

Benzamido-cinnamic acid, 20, 38, 353 Benzofuran polymerization, 181 Benzoin condensation, 326 Benzomorphans, 37 Benzycinchoninium bromide, 334 Benzycinchoninium chloride, 334, 338 Bifiinctional catalysts, 328 Bifiinctional ketones, enantioselectivity, 66 BINAP allylation, 194 allylic alcohols, 46 axial chirality, 18 complex catalysts, 47 cyclic substrates, 115, 117 double hydrogenation, 72 Heck reaction, 191 hydrogen incorporation, 51 hydrogen shift, 100 hydrogenation, 18, 28, 57, 309 hydrosilylation, 126 inclusion complexes, oxides, 97 ligands, 19, 105 molecular structure, 50, 115 mono- and bis-complexes, 106 NMR spectra, 105 olefin isomerization, 96... 

Acyloin condensations. Formaldehyde in the presence of 1 undergoes selfcondensation to form dihydroxyacetone (a triose) in high yield rather than the expected glycolaldehyde.1 Surprisingly, the condensation of formaldehyde and another aldehyde catalyzed by 1 in the presence of N(C2H5)3 results almost exclusively in a l-hydroxy-2-one, RCOCH2OH. Sodium cyanide, a known catalyst for benzoin condensations, is not effective for the condensation of formaldehyde and benzal-dehyde in the presence of N(C2H5)3.2... 

Benzoin condensation.1 The benzoates of cyanohydrins of aromatic aldehydes undergo benzoin condensation with an aromatic aldehyde in 50% NaOH/C6H6 in the presence of a phase-transfer catalyst, benzyltriethylammonium chloride. Theoretically two symmetrical and two unsymmetrical benzoins are possible, but in practice only one unsymmetrical benzoin is formed, that in which the carbonyl group is adjacent to the benzene ring substituted by the more electron-donating group. 

It should, however, be pointed out that - where applicable - product composition can be significantly different. For example, whereas thiazolium catalysts afford exclusively dihydroxyacetone with formaldehyde as substrate, the triazolium systems afford glycolic aldehyde (plus glyceraldehyde and C4 and C5 sugars as secondary products) [246], Catalyst-dependent differences in the relative rates of the partial reactions within the catalytic cycle (Scheme 6.105) most probably account for this phenomenon. A subsequent study by Enders et al. on chiral triazolium salts identified the derivative 233 as a first catalyst for the asymmetric benzoin condensation that affords substantial enantiomeric excesses (up to 86%) with satisfactory chemical yields (Table 6.3) [247]. 

The thiazolium and, particularly, triazolium catalysts discussed above have been developed to the extent that they perform remarkably well in the asymmetric benzoin condensation of aromatic aldehydes. Triazolium catalysts are also very effective in the (non-stereoselective) condensation of aliphatic aldehydes [250]. It seems, however, that no catalyst is yet available that enables condensation of aliphatic aldehydes with synthetically useful enantioselectivity. The best ee yet obtained are in the range 20-25%, e.g. in the dimerization of the straight-chain C2-C7 aldehydes [251]. 

In the benzoin condensation, a new stereogenic center is formed, as the product is an a-hydroxy ketone. Consequently, many chemists aspired to develop heterazolium-catalyzed asymmetric benzoin condensations and, later, other nucleophilic acylation reactions [9]. For example, Sheehan et al. presented the first asymmetric benzoin condensation in 1966, with the chiral thiazolium salt 7 (Fig. 9.2) as catalyst precursor [10]. 

Unfortunately, the chiral bicyclic triazolium salt that had been found to be an excellent catalyst for the enantioselective intermolecular benzoin condensation proved to be ineffective in the intramolecular reaction. In searching for alternative catalysts, we synthesized the novel triazolium salts 19 and 20, starting from easily accessible enantiopure polycyclic y-lactams (Schemes 9.4 and 9.5) that finally delivered good results in the enantioselective intramolecular cross-benzoin condensation [35]. 

The promising results of triazolium salt catalysis inspired our research group to synthesize a variety of chiral triazolium salts for the asymmetric benzoin condensation (Enders et al. 1996b Enders and Breuer 1999 Teles et al. 1999). Extensive investigations have shown that the enantiomeric excesses and catalytic activities are highly dependent on the substitution pattern of the triazolium system. The most active catalyst (S, S)-97, which is readily available from an intermediate of the industrial chloramphenicol synthesis, provided benzoin (857) in its (R)-configuration with 75% ee and a good yield of 66%. Remarkably, only... 

Further contributions to the research on the asymmetric benzoin condensation were made by Leeper et al. using novel chiral, bicyclic thia-zolium salts, which led to enantiomeric excesses up to 21% and yields up to 50% (Knight and Leeper 1997). Another thiazolium catalyst containing a norbonane backbone gave benzoin in quantitative yields with an enantiomeric excess of 26% (Gerhards and Leeper 1997). In 1998, Leeper et al. reported novel chiral, bicyclic triazolium salts that produced aromatic acyloins with varying enantioselectivities (20%—83% ee) (Knight and Leeper 1998). 

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