Benzoin condensation mechanisms

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... 

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. 

The nse of NHCs to catalyse the benzoin condensation of aldehydes was first reported by Ugai in 1943 [38], with the now generally accepted mechanism for this transformation first proposed by Breslow in 1958 [39],... 

Chemists were using cyanide ion for the synthesis of 1,2-D systems even before the concept of "reactivity inversion" was formally established. Thus, in the classical benzoin condensation, the cyanide-induced coupling of two aromatic aldehydes takes place according to the following mechanism [7] (Scheme 5.6) ... 

Lapworth, A. J. J. Chem. Soc. 1903, 83, 995. Arthur Lapworth (1872—1941) was bom in Scotland. He was one of the great figures in the development of the modem view of the mechanism of organic reactions. Lapworth investigated the Benzoin condensation at the Chemical Department, The Goldsmiths Institute, New Cross, UK. 

Propose a mechanism for the benzoin condensation, which is specifically catalyzed by cyanide ... 

The benzoin condensation catalyzed by N-heterocyclic carbenes has been investigated intensively. First investigations date back to 1832 when Wohler and Liebig discovered the cyanide-catalyzed coupling of benzaldehyde to benzoin (Wohler and Liebig 1832). In 1903 Lapworth postulated a mechanism for this reaction in which an intermediate car-banion is formed by hydrogen cyanide addition to benzaldehyde fol-... 

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

Figure 6.1 The mechanism of the benzoin condensation according to Breslow [i,41...

Rather than direct reaction with an aldehyde or ketone, the bisulfite addition product is often treated with cyanide. The addition is nucleophilic and the actual nucleophile is CN, so the reaction rate is increased by the addition of base. " " This was demonstrated by Lap worth in 1903, and consequently this was one of the first organic mechanisms to be known. This method is especially useful for aromatic aldehydes, since it avoids competition from the benzoin condensation. If desired, it is possible to hydrolyze the cyanohydrin in situ to the corresponding a-hydroxy acid. This reaction is important in the Kiliani-Fischer method of extending the carbon chain of a sugar. 

In the benzoin condensation, both aromatic and heterocyclic aldehydes are transformed into a-hydroxy ketones of the general formula ArCHOHCOAr, often called benzoins. This class of compounds is frequently encountered in natural products, hence the benzoin and related reactions have received much at-tention. The reaction employs a cyanide ion as the catalyst and the mechanism, proposed by Lapworth, involves formation of carbanions stabilized by the nitrile group (Scheme 1). 

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... 

The mechanism of the benzoin condensation, as depicted in Scheme 1, suggested that anions derived from a protected aldehyde cyanohydrin should function as nucleophilic acylating reagents. The use of protected cyanohydrins as carbanion equivalents has been studied by Stork and by Hunig and has found wide applicability in chemical synthesis. Such species may serve as either acyl anion equivalents or homoenolate anions. ... 

The generally accepted mechanism of the thiazolium salt-catalyzed benzoin condensation was first proposed by R. Breslow. ... 

Lopez-Celahorra, F., Castells, J., Domingo, L., Marti, J., Bofill, J. M. Use of 3,3 -polymethylene-bridged thiazolium salts plus bases as catalysts of the benzoin condensation and its mechanistic implications proposal of a new mechanism in aprotic conditions. Heterocycles 1994, 37, 1579-1597. 

Lopez-Calahorrra, F., Castells, J. Reaction mechanism of the benzoin condensation catalyzed by a thiazolium salt plus base or by a bis(thiazolidin-2-ylidene). Afinidad 1993, 50,461-466. 

Problem 2.3. An aldol reaction is one of the key steps in the benzoin condensation, which requires a catalytic amount of CN to proceed. Draw a reasonable mechanism. 

When the reaction is specifically catalyzed by cyanide ion it is usually referred to as the benzoin condensation.40 Any mechanism for the transformation should be in accordance with these facts ... 

Methylquinazolin-4(3//)-one was obtained in over 62% yield by reacting the phosphorane (25) with sodium hydride in methyl cyanide. The phos-phorane was readily formed from anthranilamide and prop-2-ynyltriphenyl-phosphonium bromide. When anthranilamide was fused with benzoin and a trace of acid at 150°C, it gave 2-phenylquinazolin-4(3H)-one together with o-iV-(a-benzoyl benzyl)aminobenzamide. The latter was cyclized, with ethyl orthoformate, to l-(a-benzoylbenzyl)quinazolin-4-one. If anthranilamide and benzoin were boiled in benzene with azeotropic removal of water, then the Schiff base (26) was formed. This gave 2-phenylquinazolin-4(3Jf/)-one and benzoic acid on heating alone at 150°C or with ethyl orthoformate. The mechanism of this reaction is not clear unless a retro-benzoin condensation and oxidation are occurring. 

The benzoin condensation of benzaldehyde in the presence of the cyanide ion in aqueous solution is believed to have the following mechanism ... 

The C-2-exchange of azolium salts via an ylide mechanism was discussed in Section 24.1.2.1. Thiamin pyrophosphate acts as a coenzyme in several biochemical processes and in these, its mode of action depends on the intermediacy of a 2-deprotonated species (32.2.4). In the laboratory, thiazolium salts (3-benzyl-5-(2-hydroxyethyl)-4-methylthiazolium chloride is commercially available) will act as catalysts for the benzoin condensation, and in contrast to cyanide, the classical catalyst, allow such reactions to proceed with alkanals, as opposed to araldehydes the key steps in thiazolium ion catalysis for the synthesis of 2-hydroxy-ketones are shown below and depend on the formation and nucleophilic reactivity of the C-2-ylide. Such catalysis provides acyl-anion equivalents. 

The following reaction is known as the benzoin condensation. The reaction will not take place if sodium hydroxide is used instead of sodium cyanide. Propose a mechanism for the reaction. 

As with all reactive intermediates it is important that they are not too stabilised to prevent facile further reaction. The thiazolium ylide is a potent carbon nucleophile but also a good leaving group. This is reminiscent of cyanide ion in the benzoin condensation and, in fact, the chemical logic of that reaction mechanism is similar to the thiamine-catalysed decarboxylations of a-keto acids (Scheme 2). 

More recently, concave NHC have been investigated as nucleophilic catalysts. The catalytic potential of NHC is well known since Breslow elucidated the mechanism of thiamine dependent enzymes. With aldehydes, NHC may catalyse the benzoin condensation in the same way, a cyanide ion can. But when additional substrates are added, the nature of the NHC becomes important.Thus, in a mixture of aldehydes and enals, two competing pathways may be catalysed and either so called Stetter products (for instance 1,4-diones) or y-lactones can be formed (Figure 7.25). Using one particular concave NHC,... 

A -Alkylated thiazolium and benzothiazolium salts also experience base-promoted deprotonation at the 2-position to form ylides. Such compounds, often referred to as TV-heterocyclic carbene (NHC), are nucleophilic catalysts in benzoin condensation. In 1943, Ugai and co-workers reported that thiazolium salts catalyze self-condensation of benzaldehyde to generate benzoin via an umpoulong process. Breslow at Columbia University in 1958 proposed thiazolium ylide as the actual catalyst for this transformation. In this mechanism, the catalytically active species was represented as a thiazolium zwitterion, the resonance structure of an NHC, and the reaction was postulated to ensue via the enaminol or the Breslow intermediate. ... 

This reaction is very closely related to the Baylis-Hillman Reaction, and is also related to Stetter Reaction and Benzoin Condensation in mechanism. 

The mechanism operating in A-heterocyclic carbene-mediated reactions was proposed initially by Breslow in 1958 for the thiazolium salt-catalyzed benzoin condensation (Scheme 6.1). This proposal involves the formation of a carbene as the catalytically active species by deprotonation of the thiazolium cation, which subsequently adds to one molecule of the aldehyde, generating a nucleophilic intermediate known as the Breslow intermediate. Next, this... 

---