Thiazolium-catalyzed reactions

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a receptor is a valuable synthetic tool leading to the synthesis of highly funtionalized products. Acyl anion receptors include Michael acceptor (Stetter reaction), aromatic aldehyde (benzoin reaction), ketone, nitroalkene, aziridine, activated imine. Recently, nucleophilic addition of acyl anions to unactivated imines has been explored 07CC852 . Treatment of aryl aldehydes with imines 146 in the presence of triazolium salt 147 (20 mol%) and triethylamine (20 mol%) provides the a-amino ketones 148 in good yields. However, this methodology does not work for 4-pyridylaldehyde and tert-buty laldehyde. 

The phosphine-thiazole ligand 149 has been shown to promote asymmetric intermolecular Heck coupling of 2,3-dihydrofuran with aryl triflates 07ASC2595 . Microwave irradiation of a mixture of 2,3-dihydrofuran (6 equiv.), aryl triflates (1 equiv.) and DIPEA (3 equiv.) in THF in the presence of Pd2(dba)3 (3 mol%) and the ligand 149 (6 mol%) at 120 °C provides 2-aryl-2,5-dihydrofurans 150 in high enantioselectivity. Other phosphine-thiazole ligands have also been evaluated, and ligand 149 proves to be the best in terms of enantioselectivity. 

---

Despite these detailed studies and the suggestion that an NHC might be involved in this chemistry, researchers did not generally adopt the NHC nomenclature when discussing thiazolium-catalyzed reactions. This stems in large part from the belief, prior to Arduengo s demonstration that related... 

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... 

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... 

The mechanism for the bond cleavages indicated in figure 10.1b was clarified by Ronald Breslow. In one of the earliest applications of nuclear magnetic resonance to biochemical mechanisms, he demonstrated that the proton bonded to C-2 in the thiazolium ring is readily exchangeable with the protons of H20 and deuterons of D20 in a base-catalyzed reaction... 

This procedure is representative of a new general method for the preparation of noncyclic acyloins by thiazolium-catalyzed dimerization of aldehydes in the presence of weak bases (Table I).5 The advantages of this method over the classical reductive coupling of esters5 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 furoln 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.5 Benzoins have usually been prepared by cyanide-catalyzed condensation of aromatic and heterocyclic aldehydes.8,9 10 Unsymmetrlcal acylolns may be obtained by thiazolium-catalyzed cross-condensation of two different aldehydes.11 The thiazolium ion-catalyzed cycllzation of 1,5-dialdehydes to cyclic acylolns has been reported.18... 

In the early 1970s Stetter and co-workers succeeded in transferring the concept of the thiazolium catalyzed nucleophilic acylation to the substrate class of Michael acceptors (Stetter 1976 Stetter and Schreck-enberg 1973). Since then, the catalytic 1,4-addition of aldehydes 6 to an acceptor bearing an activated double bond 131 carries his name. The Stetter reaction enables a new catalytic pathway for the synthesis of 1,4-bifunctional molecules 132, such as 1,4-diketones, 4-ketoesters and 4-ketonitriles (Stetter and Kuhlmann 1991 for a short review, see Christmann 2005). The reaction can be catalyzed by a broad range of thiazolium salts. Stetter and co-workers found the benzyl-substituted thiazolium salt 86a to give the best results for the addition of aliphatic aldehydes, whereas 86b and 86c were chosen for the addition of aromatic aldehydes. Any one of these three was found to be suitable for additions with heterocyclic aldehydes. Salt 86d was utilized with a, )-unsaturated esters (Fig. 15). 

Mattson AE, Bharadwaj AR, Scheldt KA (2004) The thiazolium-catalyzed Sila-Stetter reaction conjugate addition of acylsilanes to unsaturated esters and ketones. J Am Chem Soc 126 2314-2315... 

Mattson AE, Bharadwaj AR, Zuhl AM, Scheldt KA (2006a) Thiazolium-catalyzed additions of acylsilanes a general strategy for acyl anion addition reactions. J Org Chem 71 5715-5724... 

Mattson, A. E., Bharadwaj, A. R., Scheldt, K. A. The Thiazolium-Catalyzed Sila-Stetter Reaction Conjugate Addition of Acylsilanes to Unsaturated Esters and Ketones. J. Am. Chem. Soc. 2004, 126, 2314-2315. 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the thiazolylalanine-derived catalyst 191 for asymmetric intramolecular Stetter reaction of a,P-unsaturated esters <05CC195>. However, these cyclizations proceed only in moderate enantioselectivities and yields even under optimized conditions. Thiazolium salt 191 has been used successfully for enantioselective intermolecular aldehyde-imine cross coupling reactions <05JA1654>. Treatment of tosylamides 194 with aryl aldehydes in the presence of 15 mol% of 191 and 2... 

Starting with the work of Lienhard and his coworkers there have been several contributions in the literature that indicate that the thiazolium catalyzed decarboxylation is significantly accelerated by the use of a low dielectric medium, leading to the suggestion that a major source of rate acceleration in enzymes that perform this reaction is provided by a medium effect. As estimated recently by Alvarez and coworkers , the enzyme accelerates the overall pyruvate decarboxylation reaction by a factor of 10, over and above the corresponding thiamin catalyzed rate. It was also estimated that the enzyme accelerates the decarboxylation step by a factor of 10. ... 

In general, the unsatisfactory yields obtained in the asymmetric variants of the thiazolium-catalyzed benzoin reaction are probably caused by the low inherent activity of the thiazolium salts, which is aggravated by the steric bulk accumulated in the neighborhood of the active site. 

We used triazolium salt 7 as the catalyst for the intramolecular Stetter reaction of 2-formylphenoxycrotonates 11 affording the corresponding 4-chromanones 12 [49], since these were known to be highly active substrates in the non-enan-tioselective thiazolium-catalyzed Stetter reaction [50] (Scheme 7). Apparently, the entropically favorable proximity of the reacting functionalities leads to a strong enhancement of the reactivity. 

Cyclocondensation of V-aryl-A -formylethylenediamines 5 6 with trimethylsilyl polyphosphate furnished l-aryl-l//-4,5-dihydroimidazoles 57 in good yields <04S851>. 1,2-Diaminoimidazoles 59 were obtained in good yields by reaction of l,2-diaza-l,3-butadienes 58 with cyanamide under solvent-free conditions <04SL549>. Thiazolium-catalyzed addition of the... 

The thiazolium-catalyzed addition of an aldehyde-derived acyl anion with a Michael acceptor (Stetter reaction) is a well-known synthetic tool leading to the synthesis of highly funtionalized products. Recent developments in this area include the conjugate addition of... 

The earliest research on NHC-catalyzed reactions was mainly focused on the benzoin reaction. In 1943, Ugai and co-workers reported that thiazolium salts eould catalyze the self-condensation of benzaldehyde to produce benzoin. In 1966, Sheehan and Hunneman reported the first asymmetrie variant of the benzoin eondensation employing a ehiral thiazolium salt as precatalyst (up to 83% yield, 95% ee). Since asymmetric cross-benzoin reactions... 

Abstract The discovery and development of new A-heterocyclic carbene-catalyzed reaction is described. Based on inspiration from nature, we have taken thiazolium-based approaches to umpolung reactivity and invented a suite of related reactions involving acyl anions, homoenolate, and enolate nucleophiles all generated under catalytic conditions. 

In this manuscript we disclose new synthetic methodology to prepare a member of a class of tetrasubstituted imidazole p38 inhibitors. The optimal route involves a thiazolium catalyzed cross acyloin-type condensation of a pyridinealdehyde with an iV-acylimine. The pyridinealdehyde was prepared in 3 steps and 68% yield from 2-chloro-4-cyano pyridine. The tosylamide precursor to the iV-acyl imine was prepared in two steps and 93% yield from isonipecotic acid. We have demonstrated the scope and some preliminary mechanistic studies concerning this new reaction. The resulting a-keto-amide is then cyclized with methyl ammonium acetate to provide the desired tetrasubstituted imidazole. Cbz deprotection and formation of a pharmaceutically acceptable salt completes the synthesis in 6 steps and 38% overall yield. 

In this chapter we report new methodology which allows for an efficient, practical synthesis of the p38 MAP kinase inhibitor 1.(6, 7) The key step in this synthesis is a thiazolium catalyzed cross-acyloin coupling reaction of an aldehyde with an acyl imine.((S)... 

In addition, the use of thiazolium catalyzed processes to prepare conq)ounds which are the result of an acyl anion addition reaction have shown utility in synthetic organic chemistry. The benzoin condensation (21-24) and the Stetter reaction (25-27) represent two of the most powerful exan5>les of these types of transformations (Figure 2.). 

---