Thiazolium carbenes

Two general classes of N-heterocyclic carbenes were investigated including the thiazolium and imidazolium carbenes (Scheme 5 f. The thiazolium carbenes were formed in situ from their respective salts with 5 equivalents of triethylamine, 11. The ROP of lactide was accomplished in CH2CI2 under mild conditions (2-4 days at 25 °C) producing polymers of controlled molecular weight and narrow polydispersity with -85%... 

Chiefly in an hydrophobic medium, a base can extract the proton on position 2 leading to a reactive intermediate (able to give subsequent condensation) that could be an ylid (35, 36) or a carbene (37), though no dimer has ever been isolated as is the case with benzothiazolium (32, 38). Two mechanisms have been proposed for explaining the particular reactivity of thiazolium ... 

Carbene structure, of thiazolium salts in basic medium, 31.34 Carbocation, in thiazolium salts, 32 Carbocyanines. see Trimethine thiazolo-cyanines... 

The pentagon stabilization has been found in a biochemical phenomenon [80], The hydrogen on the thiazolium ring 9 (Scheme 7) is easily ionized to afford the corresponding carbene 10, a key catalyst in enzymatic reactions for which thiamine (vitamin B-1,11) pyrophosphate is the cofactor. The pentagon stability is expected to contribute to this unusual deprotonation. A lone pair generated on the carbon atom in 10 can similarly delocalize through the vicinal C-N and C-S a bonds in a cyclic manner. 

Addition of acyl anions generated from acylsilanes to a,(3-unsaturated ketones using N-heterocyclic carbenes (NHCs) derived from thiazolium salts as catalyst produced 1,4-diketones, which cyclized to form the corresponding furans in good yields under an acidic condition <06JOC5715>. 

It is noteworthy that both types of reactions can also be applied to prepare (carbene)gold(m) compounds A-alkyl-thiazolium salts react with HAuG14 or NaAuCl4, followed by the addition of base, to give (thiazol-2-ylidene)gold(m)... 

One Au-C bond in bis(thiazol-2-ylidene)gold cations is cleaved in the reaction with elemental iodine to give the corresponding (carbene)AuI complex and a 2-iodo-thiazolium salt, while chlorine and bromine oxidize the gold center to the gold(m) state.267... 

Equilibrium studies. Acidities of thiazolium cations, such as 213, cannot be measured in basic aqueous solution because the hydroxyl adduct ( pseudobase ) 216 of the thiazolium cation is formed rapidly and is subject to base-catalyzed ring opening (Scheme 36).151 In DMSO, formation of the carbene dimer 217 from 213 and 214 is a complicating factor.8 If indicator anion (In") was added to a solution of 213, a very rapid drop in absorbance was followed by a somewhat... 

Evaluation of kinetic data. Rate constants were determined for 2-H exchange from 3-R-4-methylthiazolium ions, catalyzed by D2O (pseudo first order) and DO- (second order).154 The observed rate constants for the pD-independent exchange reaction were corrected for the solvent isotope effect ( h2o/ d2o = 2.6), and the reverse protonation of the carbene by H30+ was assumed to be diffusion-controlled (k = 2 x 1010 M-1 s-1). A similar analysis was performed for the exchange catalysed by DO-. The results agreed nicely, giving pAfa = 18.9 for 213 and p/sfa = 18.0 for thiamine.154 The thiazolium ion 213 seems to be less acidic in water154 than in DMSO152 (Ap/fa = 2.4). Aside from the... 

In addition to the compounds listed above, a number of triazolium [36], thiazolium [37], and benzimidazolin-2-thione [32] derivatives as well as five-membered heterocycles with only one nitrogen atom [38, 39] or two phosphorus atoms [40] within the heterocycle, all of which are suitable for the generation of heterocyclic carbenes, have been described. 

In order to vary the electronic situation at the carbene carbon atom a number of carbo- and heterocycle-annulated imidazolin-2-ylidenes like the benzobis(imida-zolin-2-ylidenes) [58-60] and the singly or doubly pyrido-annulated A -heterocyclic carbenes [61-63] have been prepared and studied. Additional carbenes derived from a five-membered heterocycle like triazolin-5-ylidenes 10 [36], which reveals properties similar to the imidazolin-2-ylidenes 5 and thiazolin-2-ylidene 11 [37] exhibiting characteristic properties comparable to the saturated imidazolidin-2ylidenes 7 have also been prepared. Bertrand reported the 1,2,4-triazolium dication 12 [64]. Although all attempts to isolate the free dicarbene species from this dication have failed so far, silver complexes [65] as well as homo- and heterobimetallic iridium and rhodium complexes of the triazolin-3,5-diylidene have been prepared [66]. The 1,2,4-triazolium salts and the thiazolium salts have been used successfully as precatalysts for inter- [67] and intramolecular benzoin condensations [68]. 

While the reductive elimination is a major pathway for the deactivation of catalytically active NHC complexes [127, 128], it can also be utilized for selective transformations. Cavell et al. [135] described an interesting combination of oxidative addition and reductive elimination for the preparation of C2-alkylated imida-zohum salts. The in situ generated nickel catalyst [Ni(PPh3)2] oxidatively added the C2-H bond of an imidazolium salt to form a Ni hydrido complex. This complex reacts under alkene insertion into the Ni-H bond followed by reductive elimination of the 2-alkylimidazolium salt 39 (Fig. 14). Treatment of N-alkenyl functionalized azolium salts with [NiL2] (L = carbene or phosphine) resulted in the formation of five- and six-membered ring-fused azolium (type 40) and thiazolium salts [136, 137]. 

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]. 

Since mechanistic studies modeling the Stetter reaction have not yet been reported, the proposed mechanism is based on that elucidated by Breslow for the thiazolium catalyzed benzoin reaction (Scheme 9). The carbene, formed in situ by deprotonation... 

Almost 20 years after the initial report of the Stetter reaction, Ciganek reported an intramolecular variant of the Stetter reaction in 1995 with thiazolium precatalyst 74 providing chromanone 73 in 86% yield (Scheme 10) [64]. This intramolecular substrate 72 has become the benchmark for testing the efficiency of new catalysts. Enders and co-workers illnstrated the first asymmetric variant of the intramolecnlar Stetter reaction in 1996 utilizing chiral triazolinylidene pre-catalyst 14 [65]. Despite moderate selectivity, the implementation of a chiral triazolinylidene carbene in the Stetter reaction laid the fonndation for future work. 

Hydrogen atoms in azolium ions can be removed easily as protons (e.g. 300— 302) exchange with deuterium occurs in heavy water. The intermediate zwitterion (e.g. 301) can also be written as a carbene. The pKa values of thiazolium ions range from 16 to 20 (87CRV863, 88B5044). 

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... 

I have been pursuing enzyme mimics, artificial enzymes that perform biomimetic chemistry, since starting my independent career in 1956. In the first work [52-59] my co-workers and I studied models for the function of thiamine pyrophosphate 1 as a coenzyme in enzymes such as carboxylase. We discovered the mechanism by which it acts, by forming an anion 2 that we also described as a stabilized carbene, one of its resonance forms. We examined the related anions from imidazolium cations and oxazolium cations, which produce anions 3 and 4 that can also be described as nucleophilic carbenes. We were able to explain the structure-activity relationships in this series, and the reasons why the thiazolium ring is best suited to act as a biological... 

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]. 

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. 

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