Stetter precatalysts

Rovis and co-workers have also extended the intermolecular Stetter reaction to inclnde nitroaUcenes as the electrophilic component. Fluorinated triazolinm precatalyst 155 was effective in catalysing the reaction of a variety of heteroaromatic aldehydes 153 with nitroalkenes 154 to generate P-nitroketones in excellent yields and enantioselectivities. The authors propose that stereoelectronically induced conformational effects on the catalyst skeleton are key to the high selectivities observed with flnorinated catalyst 155 (Scheme 12.33) [69],... 

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. 

First attempts of an asymmetric Stetter reaction were made 1989 in our research group with the investigation of chiral thiazolium salts such as 136 as precatalysts. The reaction of n-bu Lanai (133) with chalcone (134) in a two-phase system gave the 1,4-diketone 135 with an enanan-tiomeric excess of 39%, but a low yield of only 4% (Scheme 37) (Tiebes 1990 Enders 1993 Enders et al. 1993b). The catalytic activity of thiazolium as well as triazolium salts in the Stetter reaction persisted at a rather low level. Triazolium salts have been shown to possess a catalytic activity in the non-enantioselective Stetter reaction (Stetter and Kuhlmann 1991), but in some cases stable adducts with Michael acceptors have been observed (Enders et al. 1996a), which might be a possible reason for their failure in catalysis. 

In 1996, our research group observed an activity of triazolium salts, for example (S,. S )-97 as precatalysts in this intramolecular reaction. The stereoselective synthesis of various 4-chromanones (f )-138 via the first asymmetric intramolecular Stetter reaction was performed with enantiomeric excesses of 41%-74% and yields of 22%-73% (Scheme 38) (Enders etal. 1996c). 

With respect to the application of asymmetric carbene catalysis as a tool for enantioselective synthesis, the last decade s major success is based on substantial improvements in catalyst development. Early reports dealt with implementing chirality in thiazolium scaffolds (Sheehan and Hunneman 1966 Sheehan and Hara 1974 Dvorak and Rawal 1998), but their catalytic performance suffered from either low yields or low ee-values. In this regard, the investigation of triazole heterocycles as an alternative core structure (Enders et al. 1995) has played a crucial role to provide heterazolium precatalysts improving both asymmetric benzoin and Stetter reactions. An intramolecular Stetter reaction yielding chromanones upon cyclization of salicylaldehyde-derived substrates is commonly used as a benchmark reaction to compare catalyst efficiency (Scheme 1 Ciganek 1995 Enders et al. 1996 Kerr et al. 2002 Kerr and Rovis 2004). 

The amino-indanol-derived triazolium salt F5 was also found to be an efficient precatalyst for the intramolecular Stetter reaction of a-substituted cyclo-hexadienones (Scheme 20.17), furnishing tricyclic products 35 bearing multiple stereocentres in up to 96% yield and with >99% enantiomeric excess. ... 

The first asymmetric intermolecular Stetter reaction was developed by Enders et al. in 1989. In 2008, Enders and coworkers reported a new chiral triazolium carbene precatalyst with an N-benzyl substituent that catalysed the as3mimetric intermolecular Stetter reaction of aldehydes with chal-cones. The desired 1,4-diketones 39 were obtained in moderate to excellent yields and with moderate to good enantioselectivities (Scheme 20.19). 

Recently, the Rovis group reported the asymmetric intermolecular Stetter reactions of unactivated aliphatic aldehydes and nitrostyrenes. Using fluorinated triazolium salt II as precatalyst, both straight-chain aliphatic substitution and a-branched aldehydes worked well and provided p-nitroketones 52 in good yields and with excellent enantioselectivities (Scheme 20.25). 

In 1995, Ciganek [39] reported the thiazolium salt 31 catalyzed intramolecular Stetter reaction of aldehyde, affording corresponding 4-chromanones in up to 86% yield. In 1996, Enders et al. [40] developed the enantioselective version, using chiral triazolium salt 2 as the precatalyst. Various 4-chromanones were obtained in good yields with moderate enantiomeric excesses (Scheme 7.21). 

NHC-catalyzed organocascades allowing the creation of both a C-C and a C-X bonds are rare. The group of Rovis has recently proposed a domino Michael/Stetter reaction for the preparation of optically active benzofuranones from salicylaldehydes and dimethyl acetylenedicarboxylate (DMAD) under dual catalytic conditions (Scheme 16.45) [94]. The reaction sequence involves a Lewis base-promoted oxa-Michael addition to produce a prochiral intermediate that then undergoes an NHC-catalyzed enantiodiscriminative Stetter reaction. Remarkably, the Lewis base not only triggers the initial oxa-Michael addition, but also serves as a Brpnsted base for deprotonation of the NHC precatalyst. The reaction scope could be extended to unsymmetrical alkynes and allenes with moderate to good stereoselectivities. 

While most NHC precatalysts are known to promote the reaction between enals and nitroalkenes via the Stetter route, the novel chiral precatalyst (124) has been found to... 

Enders and co-workers were the first to report enantioselectivity in an intermolecular Stetter reaction promoted by a chiral iV-heterocyclic carbene " The chiral thiazolium precatalyst 27 effects a Stetter reaction between butanal (26) and chalcone (22) to give diketone 28 with low efficiency but measurable enantiomeric excess. 

Trost and co-workers are credited with the first intramolecular Stetter reaction in their total synthesis of hirsutic acid C. An excess of thiazolium precatalyst 34 is employed to promote the intramolecular cyclization of bicycle 33, which provides the key C2-C3 bond of the natural product in the tricyclic intermediate 35. 

In 2008, Enders and coworkers reported the first high-yielding enantioselective intermolecular Stetter reactions employing chalcones and aryUdene-malonates as acceptors and N-Bn triazolium salt 71 as precatalyst (Schemes 18.11 and 18.12) [48]. The use of an N-benzyl instead of the usual N-aryl substituent on the triazolium ring was crucial for the activity and selectivity of the catalyst. Rovis et al. subsequently disclosed a highly enantioselective Stetter reaction of alkylidene-... 

Three studies related to the archetypal Stetter reaction have been reported. An asymmetric intramolecular version has been elaborated using sahcylaldehyde derivatives (124) as substrates and chiral triazolium salts (125) as precatalysts. Good levels of efficiency and enantioselectivity (up to 86% ee) have been obtained under the optimized reaction conditions. A similar novel triazolium salt (126) promotes the asymmetric intermolecular Stetter reaction of simple acrylates, which were previously considered to be unsuitable substrates. ... 

Chiral A-heterocyclic carbenes (NHC), weU known as potent nucleophihc organocatalysts in numerous transformations such as benzoin condensation and Stetter reaction [22], have also recently been reported to catalyze asymmetric esterification of ketenes [23]. By surveying different alcohols and optimizing the reaction conditions, it was found that the addition of benzhydrol to a range of ketenes was efficiently catalyzed by a catalytic amount of NHC 54 , the later being formed in situ from the precatalyst 54 (12 mol%) and cesium carbonate (10 mol%). Some selected results presented in Scheme 3.24 show that enantioenriched esters 53 could be obtained in up to 95% ee, although both the enantioselectivity and the yield appeared to be highly substrate dependent. 

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