Thiazolium salts, deprotonation

Tire deprotonation of thiazolium salts (see Section II) under argon at room temperature allowed the characterization of nonfused DTDAF of types 52 and 53 by cyclic voltammetry. Their very good donor properties were confirmed by two quasi-reversible peaks of equal intensity (93CC601). It is noteworthy that upon a second scan the first oxidation peak was shifted from -0.03 to -0.04 V. Upon further scans the voltam-mogram remains unchanged. Tliis interesting feature has been observed previously with TTF analogs. It was demonstrated that the neutral form... 

Breslow and co-workers elucidated the currently accepted mechanism of the benzoin reaction in 1958 using thiamin 8. The mechanism is closely related to Lapworth s mechanism for cyanide anion catalyzed benzoin reaction (Scheme 2) [28, 29], The carbene, formed in situ by deprotonation of the corresponding thiazolium salt, undergoes nucleophilic addition to the aldehyde. A subsequent proton transfer generates a nucleophilic acyl anion equivalent known as the Breslow intermediate IX. Subsequent attack of the acyl anion equivalent into another molecule of aldehyde generates a new carbon - carbon bond XI. A proton transfer forms tetrahedral intermediate XII, allowing for collapse to produce the a-hydroxy ketone accompanied by liberation of the active catalyst. As with the cyanide catalyzed benzoin reaction, the thiazolylidene catalyzed benzoin reaction is reversible [30]. 

In the thiazolium cation the proton in the 2-position is acidic and its removal gives rise to the ylide/carbene 227. This nucleophilic carbene 227 can add, e.g., to an aldehyde to produce the cationic primary addition product 228. The latter, again via C-deprotonation, affords the enamine-like structure 229. Nucleophilic addition of 229 to either an aldehyde or a Michael-acceptor affords compound(s) 230. The catalytic cycle is completed by deprotonation and elimination of the carbene 227. Strictly speaking, the thiazolium salts (and the 1,2,4-triazolium salts discussed below) are thus not the actual catalysts but pre-catalysts that provide the catalytically active nucleophilic carbenes under the reaction conditions used. This mechanism of action of thiamine was first formulated by Breslow [234] and applies to the benzoin and Stetter-reactions catalyzed by thiazolium salts [235-237] and to those... 

Addition of the cyanide ion to create a cyanohydrin effects an umpolung of the normal carbonyl charge affinity, and the electrophilic aldehyde carbon becomes nucleophilic after deprotonation A thiazolium salt may also be used as the catalyst in this reaction. 

The thiazolium salts may be converted into ylides by deprotonation. These ylides are comparable to the cyanide adducts in their ability to catalyze the Stetter Reaction effectively. 

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 most common way to prepare N-heterocyclic carbenes is the deprotonation of the corresponding azolium salts, like imidazolium, triazolium, tetrazolium, pyrazolium, benzimidazolium, oxazolium or thiazolium salts or their partly saturated pendants, with the help of suitable bases. The pJCa value of imidazolium and benzimidazolium salts was determined to be between 21 and 24, which puts them right in between the neutral carbonyl carbon acids acetone and ethyl acetate [41,42], Arguably, imidazolium-based carbenes have proven to be especially versatile and useful and their synthesis should be discussed in more detail. The synthesis of imidazolium salts has been developed over many decades and numerous powerful methods exist [43]. 

Anhydro bases resulting from the proton abstraction by a base at an activated a -methyl group of a quaternary salt (see Section 4.19.2.3.3(iv)(a)) are active C-nucleophiles. These attack the C-2 position of a thiazolium salt affording adducts whose further reaction may lead to thiacyanines. Scheme 28 summarizes the successive steps in the reaction resulting from the addition of sodium ethoxide to a fairly concentrated ethanolic solution of 2,3-dimethylbenzothiazolylium salt (45) (c =0.1 moll-1). The initially formed anhydro base (46) cannot be isolated, it reacts as a nucleophile with a second molecule of benzothiazoly-lium salt yielding an adduct (47) which is deprotonated by ethoxide anion affording the dimeric anhydro base (48) whose reactivity will be discussed later (see Section 4.19.2.3.3.i). Monocyclic thiazolylium salts react similarly. 

The deprotonation rate of 1,3,4-thiadiazolium salts is about 104 times faster than for thiazolium salts. The rate equation is first order in both substrate and OD and the mechanism involves rate determining proton abstraction by OD followed by fast reaction with D20 to give the exchanged product (74AHC(16)14). 

Lithium phosphites also can catalyze the silyl benzoin reaction of acylsilanes. Its asymmetric version is successfully achieved by a lithium phosphite derived from a homochiral diol.236 Thiazolium salt 32 effectively promotes conjugate acylation of a, 3-unsaturated carbonyls with acylsilanes in the presence of DBU (Equation (61)).237,237a The active catalyst of this sila-Stetter reaction would be a carbene species generated from 32 by deprotonation. 

Initially, a solution of cinnamaldehyde and 4-chlorobenzaldehyde in tetrahydrofuran (THF) was treated with different azolium salts under basic conditions (Scheme 6). The use of thiazolium salt 4 resulted in no formation of the desired y-butyrolactone, only benzoin products were formed. In contrast, using the NHC IMes [l,3-di(2,4,6-trimethyl-phenyl)imidazol-2-ylidene generated in situ from the salt IMesHCl by deprotonation], y-butyrolactone 3a was isolated in 53% yield and a 80 20 cisltrans ratio. This different outcome might be explained by the increased steric demand of IMes compared to 4 (Scheme 7). Most likely, IMes reversibly adds to the aldehyde groups of both substrates resulting in the intermediates la and 2a. Whereas the mesityl groups shield the former aldehyde carbon in both intermediates, the conjugate position of 2a is still accessible and can add to the electrophilic aldehyde. 

Figure 6.13 Formation of a transition metal NFIC complex by deprotonation of a benzothia-zolium or thiazolium salt.

The deprotonation and addition of a base to thiazolium salts are combined to produce an acyl carbanion equivalent (an active aldehyde) [363, 364], which is known to play an essential role in catalysis of the thiamine diphosphate (ThDP) coenzyme [365, 366]. The active aldehyde in ThDP dependent enzymes has the ability to mediate an efScient electron transfer to various physiological electron acceptors, such as lipoamide in pyruvate dehydrogenase multienzyme complex [367], flavin adenine dinucleotide (FAD) in pyruvate oxidase [368] and Fc4S4 cluster in pyruvate ferredoxin oxidoreductase [369]. 

The active aldehydes are derived from the reaction of 3-benzylthiazolium salts with o-tolualdehyde in the presence of DBU (l,8-diazabicyclo[5.4.0]undec-7-ene) via deprotonation of thiazolium salts, addition of the aldehyde and deprotonation of the adduct as shown in Scheme 33 [364], The anionic form of active aldehydes in Scheme 33 is confirmed by the direct detection of the one-electron oxidized species with use of ESR [364]. From the linewidth variations of the ESR spectra of the oxidized active aldehyde radicals were determined the rate constants [(5-7) x 10 s ] and the corresponding small reorganization energies (A = 12-13... 

Dithiadiazafulvalenes 81a-c were prepared by triethylamine-catalyzed deprotonation of the thiazolium salts 82a-e in acetonitrile, which resulted in rapid precipitation of the products (Scheme 22) <2006OL2377>. 

Thiazoles can be quaternized at nitrogen by reaction with a range of alkylating agents. These salts can form an ylide by deprotonation at C-2. This thiazolium 2-ylide is markedly stable because of the ability of sulfur to stabilize an adjacent carbanion. The reaction is of considerable importance due to the occurrence of thiazolium-2-ylides as intermediates in classical biochemical (thiamine action) and chemical (Stetter reaction) processes (see Section 3.06.12). Desilylation at C-2 can lead to a thiazolium 2-ylide as well. Thus, the formation of this type of intermediate has been formulated as a key step along the reaction pathway involving a 2-trialkylsilylthiazole and C-electrophiles (Dondoni reaction, see Section 3.06.12.12). Thiazolium salts are also susceptible to be oxidized by a variety of oxidants (see Section 3.06.5.4.8). 

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. 

Heterazolium salts such as thiazolium salts (12.86) and triazohum salts " are able to catalyse the conversion of benzaldehyde (12.87) into benzoin (12.88). The mechanism involves deprotonation of the thiazolium salt to give the true catalytic species (12.89), which acts as a nucleophile towards benzaldehyde, and subsequently promotes the formation of benzoin. 

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