Dimerization benzoin condensation

Although the catalysis of the dimerization of aldehydes to acyloins by thiazolium ion has been known for some tlrae, the development of procedures using anhydrous solvents which give satisfactory yields of acyloins on a preparative scale was first realized in the submitters laboratories. The mechanism proposed by Breslow - for the thiazolium ion-catalyzed reactions is similar to the Lapworth mechanism for the benzoin condensation with a thiazolium ylide replacing the cyanide ion. Similar mechanisms are involved... 

Novel tetrameric 7t-conjugated oligomers are produced by an intramolecular benzoin condensation from the dimeric thiophene, followed by air oxidation to give 28 <2003SM(135)85> in low yields (Equation 84). 

Most of the reactions of aromatic aldehydes, ArCHO, are those expected of aldehydes with no a hydrogens and most of these will not be reviewed here. One reaction that usually is regarded as being characteristic of aromatic aldehydes (although, in fact, it does occur with other aldehydes having no a hydrogens), is known as the benzoin condensation. This reaction essentially is a dimerization of two aldehyde molecules through the catalytic action of sodium or potassium cyanide ... 

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 an aprotic medium, such as DM SO, a C2a-hydroxybenzylthiazolium salt is formed by nucleophilic addition55. There have appeared suggestions that in nonaqueous media, the double enamine or syn-anti symmetrical dimer formed between two thiazolium salts on addition of base is the template for benzoin condensations (Scheme 4)56. The... 

More recent evidence from our laboratory indicates that when the thiazolium salt is first converted totally to the unsymmetrical and symmetrical syn-anti dimers (13C NMR indicated the presence of both configurations), addition of benzaldehyde to this solution cannot form HBT, whereas addition of benzaldehyde to a mixture that still contains monomeric thiazolium salts indeed forms this HBT adduct57. Such experiments tend to confirm that it is the enamine rather than the double enamine (the benzaldehyde adduct of the syn-anti dimers) that participates in thiazolium salt catalyzed benzoin condensations. 

Breslow, R., Kim, R. The thiazolium catalyzed benzoin condensation with mild base does not involve a "dimer intermediate. Tetrahedron Lett. 1994, 35, 699-702. 

Ikeda, H., Horimoto, Y., Nakata, M., Ueno, A. Artificial holoenzymes for benzoin condensation using thiazolio-appended -cyclodextrin dimers. Tetrahedron Lett. 2000, 41, 6483-6487. 

Benzoin Condensation. In the presence of alkali cyanides, magne-sium,39 or amalgamated aluminum,39 aromatic aldehydes often dimerize to form a-hydroxy ketones ... 

The original work in this area was done by Dumesic et al. and involved various condensations of HMF and related molecules with acetone followed by HDO to give Ci-Ci5 alkanes (for example, 1—>17+19) (Scheme 6) [100]. Liu and co-workers recently described the benzoin condensation of HMF to give a dimer that could be submitted to HDO to give C10-C12 alkanes [101]. Sutton and co-workers likewise employed simple aldol chemistry between HMF and acetone to access C9-C15 hydrocarbons [102]. This sugar derivative to alkane chemistry has been successfully piloted by the startup company Virent [103],... 

The Benzoin Condensation. Treatment of benzenecarboxaldehyde (benzalde-hyde, CeHsCHO) and similar aldehydes with sodium cyanide (Na " CN") in ethanol (ethyl alcohol, CH3CH2OH) as solvent at reflux for brief periods results in the formation of a dimer, 2-hydroxy-l,2-diphenylethanone (benzoin) (Equation 9.49). A mechanism has been proposed (Scheme 9.60) that accounts for the following observations ... 

Figure 1.2 The mechanism of the benzoin condensation catalyzed by a thiazoiium yiide. Some have asserted that the true catalyst is the yiide dimer 6, but careful kinetic studies have excluded this possibility.

Mechanistic studies on the tail-to-tail dimerization of methyl methacrylate (317), catalysed by NHC (316), revealed noticeable differences in the kinetics, reversibility, and stability of the intermediates compared to benzoin condensation (Scheme 16). The initial addition, involving a rapid intermolecular proton transfer, generates the deoxy-Breslow intermediate (318), which has been found to be quite stable. Its addition to the second molecule of (317), followed by the final catalyst elimination, producing (320), is the rate-limiting step. ... 

Metal cyanides and heterocyclic carbenes are commonly employed catalysts for the benzoin condensation. Symmetrical acyloins can be prepared by dimerization of a wide range of aromatic and aliphatic aldehydes. Chiral heterocyclic carbene catalysts have also been developed that provide symmetrical acyloin products with high levels of enantiomeric purity. 

Milller and co-workers recently developed an enantioselective benzoin dimerization using purified enzymes from Pseudomonas. The thiamine diphosphate (ThDP) dependent enzymes benzaldehyde lyase (BAL) and benzoylformate decarboxylase (BED) were found to catalyze the reversible benzoin condensation of aromatic aldehydes. The reaction is driven in the forward direction by the poor solubility of the benzoin products in aqueous media. A wide variety of aromatic aldehydes are accepted by BAL, and products of the (/ )-configuration are produced in excellent yield and enantiomeric purity. The (S)-enantiomer of benzoin is also available in high enantiomeric purity from a BAL-catalyzed kinetic resolution of rac-benzoin. In the presence of excess acetaldehyde, BAL selectively converts (i )-benzoin into (/ )-2-hydroxy-l-phenylpropanone, while the (iS)-benzoin enantiomer is not a substrate for the enzyme. At 49% conversion, (5)-benzoin is resolved to > 99% ee. BED can produce (i )-benzoin from benzaldehyde in comparable yield and enantiomeric purity with respect to BAL, but the substrate scope appears more limited. ... 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazol ium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I). The advantages of this method over the classical reductive coupling of esters or the modern variation in which the intermediate enediolate is trapped by silylation, are the simplicity of the procedure, the inexpensive materials used, and the purity of the products obtained. For volatile aldehydes such as acetaldehyde and propionaldehyde the reaction Is conducted without solvent in a small, heated autoclave. With the exception of furoin the preparation of benzoins from aromatic aldehydes is best carried out with a different thiazolium catalyst bearing an N-methyl or N-ethyl substituent, instead of the N-benzyl group. Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.Unsymnetrical acyloins may be obtained by thiazol1um-catalyzed cross-condensation of two different aldehydes. -1 The thiazolium ion-catalyzed cyclization of 1,5-dialdehydes to cyclic acyloins has been reported. 

Another benzoin-like condensation of pyrido[2,3-/>]pyrazines is catalyzed by cyanide ion in dimethyl sulfoxide and leads to 3,3 -dimers, e.g. 14.78... 

N-Methylbenzothiazolone hydrazone hydrochloride (MBTH) is suitable for characterizing steroids such as 17-hy oxy-3,20-dioxopregn-4-en-21-al as osazones." N-Methylbenzothiazolium and naphtho[2,l-d]thiazolium salts (121) and (122) and certain dimers, e.g. (123), promote catalytically the acyloin condensation of benzaldehyde to benzoin." ... 

---