Benzaldehyde, condensation with thiazolium

Upon treating certain (but not all) aromatic aldehydes or glyoxals (a-keto aldehydes) with cyanide ion (CN ), benzoins (a-hydroxy-ketones or acyloins) are produced in a reaction called the benzoin condensation. The reverse process is called the retro-benzoin condensation, and it is frequently used for the preparation of ketones. The condensation involves the addition of one molecule of aldehyde to the C=0 group of another. One of the aldehydes serves as the donor and the other serves as the acceptor. Some aldehydes can only be donors (e.g. p-dimethylaminobenzaldehyde) or acceptors, so they are not able to self-condense, while other aldehydes (benzaldehyde) can perform both functions and are capable of self-condensation. Certain thiazolium salts can also catalyze the reaction in the presence of a mild base. This version of the benzoin condensation is more synthetically useful than the original procedure because it works with enolizable and non-enolizable aldehydes and asymmetric catalysts may be used. Aliphatic aldehydes can also be used and mixtures of aliphatic and aromatic aldehydes give mixed benzoins. Recently, it was also shown that thiazolium-ion based organic ionic liquids (Oils) promote the benzoin condensation in the presence of small amounts of triethylamine. The stereoselective synthesis of benzoins has been achieved using chiral thiazolium salts as catalysts. 

Active carbonyl compounds such as benzaldehyde attack the electron-rich double bond in DTDAFs to give a dipolar adduct, which immediately undergoes dissociation with formation of two molecules of 146 (64BSF2857 67LA155).Tlie existence of by-products such as benzoin led to the synthetic application of thiazolium salts in the acyloin condensation. For example, replacement of the classic cyanide ion by 3-benzyl-4-methyl-5(/3-hydroxyethyl) thiazolium salts allowed the benzoin-type condensation to take place in nonaqueous solvents (76AGE639) (Scheme 57). 

Thiazolium ion based ionic liquids (OIL) have been used to promote the benzoin condensation of benzaldehyde. 4- And 5-methylthiazoles are readily alkylated with n-butyl bromide to give the corresponding bromide salt. Anion exchange with sodium tetrafluoroborate gave the tetrafluoroborate salt 53 as a stable yellow orange oil. When activated with a small quantity of triethylamine (5 mol%) the oil promotes the coupling of benzaldehyde to benzoin <99TL1621>. 

When, in 1832, Wohler and Liebig first discovered the cyanide-catalyzed coupling of benzaldehyde that became known as the benzoin condensation , they laid the foundations for a wide field of growing organic chemistry [1]. In 1903, Lapworth proposed a mechanistical model with an intermediate carbanion formed in a hydrogen cyanide addition to the benzaldehyde substrate and subsequent deprotonation [2]. In the intermediate active aldehyde , the former carbonyl carbon atom exhibits an inverted, nucleophilic reactivity, which exemplifies the Umpo-lung concept of Seebach [3]. In 1943, Ukai et al. reported that thiazolium salts also surprisingly catalyze the benzoin condensation [4], an observation which attracted even more attention when Mizuhara et al. found, in 1954, that the thiazolium unit of the coenzyme thiamine (vitamin Bi) (1, Fig. 9.1) is essential for its activity in enzyme biocatalysis [5]. Subsequently, the biochemistry of thiamine-dependent enzymes has been extensively studied, and this has resulted in widespread applications of the enzymes as synthetic tools [6]. 

When the thiazolium unit was attached to the larger y-cyclodextrin in 6, with eight glucose units in the ring, benzoin condensation of two benzaldehydes was indeed well... 

The diastereomerically pure thiazolium salt 509 which bears a 2-/i t7-butylphenyl substituent at the nitrogen atom was converted into a mixture of 510 and its atropisomer 510 (dr = 75 25) upon treatment with base (Scheme 128). The stereogenic center in the intermediate carbene favors one rotamer 510. Upon reaction with benzaldehyde, it accounts in a similar fashion for the formation of the major enol diastereoisomer 511 over 511, which, in turn, leads to the major enantiomer 512 rather than 512 observed in the benzoin condensation catalyzed by 509. The concept of axial chirality was proven to be viable for an efficient chirality transfer. Replacement of the isopropyl group at C-4 by the bulkier 2-phenyl-2-propyl substituent using 8-phenylmenthone is likely thought to increase the ee <2004EJ02025>. 

Figure 2.10 Thiazolium salts catalyse the benzoin condensation, and with an extra rate when they are linked to y-cyclodextrin, which can bind two benzaldehydes into its large cavity...

Davis and Forrester have studied the benzoin condensation promoted with a small ( 5 mol %) quantity of triethylamine and thiazolium salts (160). The reaction was accomplished when the thiazolium based organic ionic liquid (OIL) was stirred under nitrogen as a clearly heterogeneous mixture with a toluene solution of benzaldehyde. The reaction gave about 80% conversion to benzoin (163) (scheme-40) (Davis Forrester 1999). 

The pioneering work of Sheehan showed as early as 1966 that the use of the chiral thiazolium precatalyst (+)-7 imparted low but measurable enantioselectivity in the conversion of benzaldehyde to benzoin. Since this report, many groups have developed chiral carbene catalysts that effect asymmetric benzoin condensation reactions. The best catalyst identified to date with respect to enantioselectivity is the triazolium pre-catalyst 8 reported... 

---