Benzoin condensation carbonyls

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. 

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. 

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]. 

The dithiane anion 1.9 also reacts with acyl halides, ketones and aldehydes to give the corresponding dioxygenated compounds. Schemes 1.4 and 1.5 show the reaction of dithiane anions 1.11 and 1.12 with ketones. The most common example of umpolung reactivity of a carbonyl group is the benzoin condensation (Scheme 1.6). 

Condensation of Carbonyl Compounds (Acyloin and Benzoin Condensations )... 

Treatment of a-phenylquinazolin-4-ylmethanols 4 with potassium cyanide in dimethylform-amide results in C—C bond cleavage to give quinazolines 5 and ketones 6. This reaction proceeds through a retro-benzoin condensation in which the N3 —C4 double bond of quinazolines behaves like a carbonyl group. 

A Michael-type addition has been used to insert suitable Michael acceptors (47 R = CN, COMe, C02Me/Et) between the carbonyls of benzils (48), to give a range of 1,4-diketones (49). The reaction is catalysed by cyanide (typically as B114NCN), and the aryl rings can bear substituents such as chloro or methoxy. Reminiscent of the Benzoin condensation, the reaction proceeds through an O-aroylmandelonitrile anion (50). The reaction has also been extended to C—O rather than C—C insertion benzaldehyde inserts into benzil under the same conditions to give an a-aroyloxy-ketone (51). 

Studies on thiamine (vitamin Bi) catalyzed formation of acyloins from aliphatic aldehydes and on thiamine or thiamine diphosphate catalyzed decarboxylation of pyruvate have established the mechanism for the catalytic activity of 1,3-thiazolium salts in carbonyl condensation reactions. In the presence of bases, quaternary thiazolium salts are transformed into the ylide structure (2), the ylide being able to exert a cat ytic effect resembling that of the cyanide ion in the benzoin condensation (Scheme 2). Like cyanide, the zwitterion (2), formed by the reaction of thiazolium salts with base, is nucleophilic and reacts at the carbonyl group of aldehy s. The resultant intermediate can undergo base-catalyzed proton... 

In the benzoin condensation, one molecule of aldehyde serves as an electrophile. If a carbanion is generated from protected cyanohydrins, a-aminonitriles or dithioacetals, it can react with electrophiles such as alkyl halides, strongly activated aryl halides or alkyl tosylates to form ketones. Amongst other electrophiles which are attacked by the above carbanions are heterocyclic A -oxides, carbonyl compounds, a,p-unsaturated carbonyl compounds, a,3-unsaturated nitriles, acyl halides, Mannich bases, epoxides and chlorotiimethyl derivatives of silicon, germanium and tin. 

The benzoin condensation has recently been recognized as belonging to the general class of reactions that involve masked acyl anions as intermediates. For example, an aldehyde is converted into an addition product RCH(OX)Y, which renders the C—H acidic. Then under basic conditions, a masked acyl anion (see 1) can be formed and may react with an electrophilic component E. Decomposition of the product RCE(OX)Y should regenerate the carbonyl group with formation of RC(0)E. Intermediates such as (1) are us in the conversion of aldehydes into a-hydroxy ketones, a-diketones and 1,4-dicarbonyl compounds, proving to be a powerful strategy in the development of new synthetic methods. ... 

In addition to these reactions in which the carbanions are supplied from carbonyl compounds, we will discuss in this chapter Grignard reactions, the benzilic acid rearrangement, the benzoin condensation, and the Kolbe synthesis of hydroxy aromatic acids. These reactions illustrate the addition of other kinds of carbanions to carbonyl groups. The benzilic acid rearrangement is an example of the intramolecular addition of a group with its pair of electrons to a carbonyl carbon atom. 

One of the aspects of polymer-supported reactions (see Section 4) is the ability to separate reactive centres from each other. The extent to which a benzoin condensation reaction occurs on a crosslinked polymer was examined [45]. The starting material, a polymeric benzaldehyde, was prepared by incorporation of vinyl benzaldehyde into a resin using either divinylbenzene or tetraethyleneglycol diacrylate as a crosslinker. The product was examined using CP/MAS. The spectra showed two important peaks at 86.2, 126.0 and 166.0 ppm. These were attributed to the a-hydroxy carbon, the proton-ated aromatic carbons and the carbonyl carbon of the a-hydroxy ketone. This demonstrated that in the polymer the benzoin condensation reaction had occurred to a significant extent. 

From two conjugated carbonyl compounds the cross-benzoin condensation initiated by a chiral azolecarbene (199) sets up a sequence of oxy-Cope rearrangement, aldol reaction and decarboxylation/ ... 

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