Intermolecular Stetter Reactions

The first attempted asymmetric intermolecular Stetter reaction was reported by Enders and co-workers who showed in 1989 that reaction of n-butanal 142 with chalcone 143 in the presence of the NHC derived from thiazolium salt 144 generated Stetter product 145 in 39% ee but only 4% yield (Scheme 12.30) [66],... 

Scheme 12.30 The first asymmetric intermolecular Stetter reaction...

Rovis and co-workers have recently shown that the NHC derived from triazoUum pre-catalyst 151 catalyses the intermolecular Stetter reaction of glyoxamides 149 with alkylidene malonates 150. Enantioselectivities of np to 91% have been obtained with typically good to excellent yields of the corresponding Stetter prod-nets (Scheme 12.32) [68]. 

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],... 

While catalysts and reaction protocols are well established for the enantioselective intramolecular Stetter reaction, asymmetric intermolecular Stetter products are much more difficult to obtain using known methodologies. A report by Enders and co-workers described the first asymmetric intermolecular Stetter reaction utilizing n-butanal and chalcone [4], When thiazolium salt 114 is used in this system the reaction proceeds in 39% ee, albeit in 4% yield of 113. The authors comment that both thiazolium and triazolium pre-catalysts perform poorly. The yield was increased to 29% yield with thiazolium pre-catalyst 115 although a loss in enanti-oselectivity was observed (Scheme 18) [80]. 

There seems to be one example only of a catalytic intermolecular asymmetric Stetter reaction. As shown in Scheme 6.107, Enders reported that the thiazolium cation 243 afforded a moderate enantiomeric excess in the coupling of w-butanal with F-chalcone to give the 1,4-diketone 244 [257]. 

In the intermolecular Stetter reaction, self-condensation of the donor aldehyde usually dominates over the conjugate addition, leading to benzoins as the major... 

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. 

DiRocco DA, Oberg KM, Dalton DM, Rovis T (2009) Catalytic asymmetric intermolecular Stetter reaction of heterocyclic aldehydes with nitroalkenes backbone fluorination improves selectivity. J Am Chem Soc 131 10872-10874... 

Enders D, Jianwei H (2008) Asymmetric intermolecular Stetter reactions of aromatic heterocyclic aldehydes—with arylidenemalonates. Synthesis 23 3864-3868... 

Enders D, Han J, Henseler A (2008) Asymmetric intermolecular Stetter reactions catalyzed by a novel triazolium derived N-heterocyclic carbene. Chem Commun 34 3989-3991... 

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... 

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. 

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

Scheme 6.12 The 120d-catalyzed intermolecular Stetter reaction.

In 2008, the Enders group presented the first synthetically useful NHC-catalyzed intermolecular Stetter reactions of aldehydes and chalcones in... 

Subsequently, the Rovis group reported an intermolecular Stetter reaction of morpholine-derived glyoxamides with p-substituted alkylidene malonates or alkylidene ketoamides in the presence of a phenylalanine-derived carbene catalyst. During the reaction condition optimization, it was found to be necessary to use one equivalent of Hiinig s base and add magnesium sulfate to ensure the high enantioselectivity (Scheme 7.25). 

Scheme 7.24 NHC-catalyzed asymmetric intermolecular Stetter reaction of aromatic aldehydes with chalcones reported by Enders.

Houk, Rovis, and their co-workers later extended the scope of the asymmetric intermolecular Stetter reaction of p-nitrostyrenes to unactivated aliphatic aldehydes, which have rarely been utilized in this reaction due to their relatively lower electrophilicity compared with aryl aldehydes. Comparing to known scaffolds, tert-leucine derived trans-fluorinated catalyst leads to improved reactivity and enantioselectivity in this transformation. Computational studies show that the optimized catalyst is the most stereoselective one because the Re-face attack is stabilized by favorable electrostatic interactions between the phenyl group and the fluorine on the catalyst backbone (Scheme 7.31). 

Scheme 7.29 NHC-catal3 ed asymmetric intermolecular Stetter reaction of heteroaromatic aldehydes with p-alkyl substituted nitroalkenes...

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