Stetter reactions developments

Scheme 6.4 The 119a-catalyzed intramolecular Stetter reaction developed by Rovis.

Scheme 6.11 The ent-120c-catalyzed intermolecular Stetter reaction developed by Enders.

The first asymmetric intramolecular Stetter reactions were reported by Enders and co-workers utilising triazolium salt pre-catalyst 125. Treatment of substrate 123 generated 1,4-dicarbonyl compound 124 in good yield and enantioselectivity [56]. These salicylaldehyde-derived substrates 123 have since become the standard test substrates for the development of new catalysts for the asymmetric intramolecular Stetter reaction. Bach and co-workers have achieved moderate enantioselectivities using axially-chiral thiazolium pre-catalyst 126 [41], whilst Miller and co-workers have developed peptidic thiazolium pre-catalyst 127 [57]. In 2005, Rovis and coworkers showed that the NHCs derived from triazolium salts 128-130 were excellent catalysts for the asymmetric intramolecular Stetter reaction of a wide range of substrates, giving typically excellent yields and enantioselectivities [58]. The iV-pentafluorophenyl catalyst 129 currently represents the state of the art in asymmetric Stetter reactions (Scheme 12.24) [59]. 

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 direct nucleophilic addition of acyl anions to nitroalkenes using silyl-protected thiazolium carbinols <06JA4932>. In the presence of a fluoride anion, carbinol 186 is not cleaved to an aldehyde... 

An efficient high yielding synthesis of 3-substituted 2,3-dihydroquinolin-4-ones 90 was developed by using a one-pot sequential multi-catalytic process <06TL4365>. The scheme below shows the one-pot sequential multi-catalytic Stetter reaction of aldehyde 91 and a, (3-unsaturated esters 92, resulting in the formation of the desired dihydroquinolines 90. 

In 2002, Rovis and co-workers developed a series of triazolinm pre-catalysts, 75 and 76, and reported a highly enantioselective intramolecnlar Stetter reaction [66]. These tetracyclic strnctnres bear a fnsed-ring system in order to restrict rotation, taking advantage of the concept first introduced by keeper and Rawal, and further provide the ability to add steric bulk on both sides of the reacting site, blocking three of the fonr quadrants (Scheme 11, contrast Model A vs Model B) [67]. 

In the process of developing the Stetter reaction in ionic liquids, Gree and coworkers applied their methodology to the synthesis of haloperidol (Scheme 25) [101], A variety of aromatic aldehydes react with methyl acrylate 160 when butyl-methylimidazolium tetrafluoroborate [bmim][BF ] is used as solvent. In the synthesis of haloperidol, electron-deficient aldehyde 153 was subjected to standard reaction conditions with 160 to provide 161 in good yield. 

This chapter exemplifies how the development of highly active catalysts and creative reaction design have revitalized the interest in Stetter reactions as a valuable tool for efficient C-C-bond-forming reactions. The next challenges to be met in this field are the reduction of the catalyst loading and the catalytic asymmetric intermolecular Stetter reactions. 

Christmann M (2005) New developments in the asymmetric Stetter reaction. Angew Chem Int Ed Engl 44 2632-2634... 

Abstract. Within the context of Lewis base catalysis /V-heterocyclic carbenes represent an extremely versatile class of organocatalyst that allows for a great variety of different transformations. Starting from the early investigations on benzoin, and later Stetter reactions, the mechanistic diversity of /V-hctcrocyclic carbenes, depending on their properties, has led to the development of several unprecedented catalytic reactions. This article will provide an overview of the versatile reactivity of A-heterocyclic carbenes. 

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). 

A possible ronte ont of this apparent dilemma was shown by Enders et al. [27] in adapting the protocol of Ciganek [28] to an asynunetric intramolecnlar Stetter reaction. Favourable entropic effects result in increased yields and thns in an overall significantly improved reaction. Although initial studies were focused on triazolium based catalysts [11,29,30], the development of thiazolium based catalysts was not neglected [31]. 

An interesting new development came with the realisation of Miller that a range of enan-tioselective reactions for which peptides based on the imiodazole sidechain of histidine were used as organocatalysts could possibly serve as a model for the asymmetric intramolecular Michael-Stetter reaction as well [32]. To this end. Miller synthesised thiazole based peptide-modified organocatalysts that can be described as having a thio-histidine as the crucial anuno acid (see Hgure 6.7). The respective amino acid was reported as thiazolylalanine (Taz). 

The first attempts to develop a heterazolium-catalyzed asymmetric variant of the Stetter reaction were carried out by our group [44,45,46], employing the chiral thiazolium salt 9 to catalyze the addition of butanal to chalcone. The resultant 1,4-dicarbonyl compound 10 was obtained in 29% yield with enantiomeric excesses up to 30% (Scheme 6). 

In general, however, the activity of the triazolium salts in this asymmetric Stetter protocol is quite low, i.e. the total turnover numbers obtained ranged from 0.5 to 8. The development of more active catalysts which are also suitable for the intermolecular Stetter reaction is desirable. 

Development of Stetter reaction, particularly, in the synthesis of natural compounds 06CJ0906. 

The application of this ability of A -heterocyclic carbenes to activate aldehydes (or ketones) for their participation as nucleophiles in polar reactions to the conjugate addition reaction was discovered by Stetter in 1975, when he found that aldehydes underwent 1,4-addition to electron-deficient olefins in the presence of a carbene generated in situ from a thiazolium salt in the presence of a base (also known as the Stetter reaction). Many attempts have been made since then to develop enantioselective variants of this reaction, although it has to be pointed out that the most important advances have been reported quite recently, as will be shown in this section. 

Other different chiral carbene catalysts have been developed by other authors and tested specifically in intramolecular Stetter reactions (Scheme 6.10). This is the case of menthol-derived thiazolium salt 121 ° and tripeptide 122 incorporating a thiazolylalanine amino acid as constituents, which were used as pre-catalysts in the same reaction shown in Schemes 6.3 and 6.4 leading to chromanones. However, these two new catalytic systems, although active and able to promote rather efficiently the reaction, only furnished moderate levels of enantioselection. In a different approach, a C2-symmetric imidazoli-dinium salt 123 has been employed to generate the corresponding catalytically active carbene species and employed in the cyclization of 7-oxo-2-pentenoates leading to chiral cyclopentenones. In this case, this intramolecular Stetter reaction proceeded with moderate to good yields and enantioselectivities up to 80% ee. 

Scheme 6.10 Other chiral carbene catalysts developed for the intramolecular Stetter reaction.

Dihydrojasmone is also much valued as a scented compound because of its floral and fruity character. A convenient synthetic route is provided by the Stetter reaction (a reaction of aldehydes with Michael acceptors in the presence of thiazohum salts, developed by Hermann Stetter (1917-1993)) of methyl vinyl ketone and heptanal [90], followed by an intramolecular aldol condensation. 

Scheme 7.17 Development of chiral NHCs for intramolecular Stetter reaction.

In 2006, Matsumoto and Tomioka developed a chiral symmetric N-heterocyclic earbene generated from a dihydroimidazolium salt and strong base (potassium hydride or /r-butyllithium) and applied these catalysts to asymmetric intramolecular Stetter reactions with up 80% ee. It is remarkable to note that high temperature (reflux in toluene) is crucial for the formation of cyclic products with relatively high enantioseleetivity. Racemization of the product was almost sufficiently suppressed by adjusting the ratio of base to dihydroimidazolium salt to 1 2. 

You and co-workers successfully developed a series of novel chiral triazolium salts based on the readily available camphor scaffold in 2008. These catalysts are capable of rendering excellent enantioseleetivity in the intramolecular Stetter reaction (up to 97% yield, 97% ee). A later report from the same group delivered the synthesis of chiral NHCs from (lR,2R)-(+)-diphenyl ethylenediamine. With 10 mol% of the catalyst, the intramolecular Stetter reaction was realized in excellent yields with up to 97% ee. These newly developed catalysts from camphor and (lR,2R)-(+)-diphenyl ethylenediamine accumulate in the toolkit of NHCs. 

Guile and Rovis have developed an intramolecular Stetter reaction employing a,p-unsaturated phosphine oxides and phosphonates as electrophilic acceptors. Both aromatic and aliphatic substrates are tolerated, providing keto-phosphonates and phosphine oxides in good to excellent yields and enantioselectivity (up to 99% yield, 96% ee). This extension of the Stetter reaction leads to interesting new enantioenriched scaffolds of phosphorus-containing compounds not easily accessible by other methods (Scheme 7.19). 

In 2009, the Rovis group disclosed a remarkable study on the asymmetric intermoleeular Stetter reaction with heteroaromatic aldehydes and p-alkyl substituted nitroalkenes in excellent enantioselectivity. With the novel backbone-fluorinated NHC initially developed by their group, the Stetter reaction products were afforded with up to 99% yield and 96% ee. With detailed conformational analysis of the catalyst and DFT calculations, the authors demonstrated that the gawcAe-effect from the fluorine on the five-membered backbone of the catalyst plays a crucial role on increasing the enantioselectivity dramatically (Scheme 7.29). 

Another interesting process which falls within this category is a cascade Stetter-reaction Aldol process developed by Ye and co-workers [56]. In this reaction, phtha-laldehyde 171 was reacted with an achiral (V-heterocyclic carbene (NHC) 172. 

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). 

In 2009, a highly enantioselective intermolecular Stetter reaction of het-eroaiylaldehydes with nitroalkenes was developed by Rovis and coworkers. ... 

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