Reactions Stetter

In the early 1970s, Stetter and Schreckenberg discovered the conjugate addition of aldehydes onto Michael acceptors employing cyanide [36] or thiazolium salts as 

A highly efficient olefin hydroacylation known as the Stetter reaction resulted from the discovery that an activated olefin could intercept the putative acylanion intermediate of the classical benzoin reaction. Metal cyanides and heterocyclic carbenes are commonly employed catalysts for the Stetter reaction. Chiral heterocyclic carbenes as well as chiral metallophosphites have been developed as catalysts to provide 1,4-dicarbonyl compounds with high levels of enantiomeric purity.  

In a series of publications beginning in 1973, Hermann Stetter and coworkers reported that activated olefins could intercept the putative acylanion intermediate of the benzoin reaction. Typical catalysts for the benzoin reaction, sodium cyanide and thiazolylidine carbenes, were found to perform well in this new reaction. Stetter also established that the success of the reaction is due to the reversible nature of the benzoin condensation relative to the irreversible formation of 1,4-dicarbonyl products. As a consequence, benzoins or aldehydes can be used interchangeably as reactants. The reaction has proven to be a highly efficient method for the synthesis of 1,4-dicarbonyl compounds and 4-oxonitriles. A resurgence of interest in acyl anion chemistry has resulted in many new discoveries, including alternative acyl donors, as well as catalysts capable of highly enantioselective intra- and intermolecular Stetter reactions.  

The widely accepted Breslow mechanism for carbene-catalyzed acylanion chemistry is illustrated for the Stetter reaction. The thiazolium precatlyst is deprotonated by base to give the active thiazolylidine carbene, and the reaction is initiated by nucleophilic addition of the catalyst to aldehyde 1, giving intermediate 4. The thiazolium substituent is sufficiently electron- 

Initial work in the early 1970s by Stetter and co-workers established the scope of the intermolecular reaction. Aromatic and heteroaromatic aldehydes are smoothly coupled to a,(3-unsaturated ketones, esters and nitriles under sodium cyanide or thiazolylidine catalysis (entries 1-5, 3a-d). In contrast, the coupling of aliphatic aldehydes and activated olefins (entry 6, 3e) is successful only under thiazolylidine catalysis.  

Entry R2 Catalyst Base Solvent Product Yield (%) 

4-Dicarbonyl derivatives from aldehydes and a, 3-unsaturated ketones and esters. The thiazolium catalyst serves as a safe surrogate for CN. Also known as the Michael-Stetter reaetion. Cf. Benzoin condensation. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 244, Springer-Verlag Berlin Heidelberg 2009 

(a) Stetter, H. Schreckenberg, H. Angew. Chem. 1973, 85, 89. Hermann Stetter 

Castells, J. Dunach, E. Geijo, F. Lopez-Calahorra, F. Prats, M. Sanahnja, O. Villa-nova, L. Tetrahedron Lett. 1980, 21, 2291. 

Kobayashi, N. Kaku, Y. Higurashi, K. Yamauchi, T. Ishibashi, A. Okamoto, Y. Bioorg. Med. Chem. Lett. 2002, 12, 1747. 

heteroaryl R = alkyl, aryl nucleophilic catalyst NaCN, KCN, thiazolium salts/base solvent DMF, DMSO 

Formation of catalytically active species from thiazolium salts  

In the laboratory of A. Millar, the convergent enantloselective synthesis of CI-981, a potent and tissue-selective Inhibitor of HMG-CoA reductase was achieved. The central tetrasubstituted pyrrole ring was prepared via the Paal-Knorr pyrrole synthesis. The required 1,4-diketone precursor was efficiently prepared by the Stetter reaction between p-fluorobenzaldehyde and an unsaturated amide. Interestingly, the A/-benzyl thiazolium chloride catalyst afforded only the benzoin condensation product and none of the desired diketone. However, when the A/-ethyl thiazolium bromide catalyst was employed, under anhydrous and concentrated reaction conditions, the 1,4-diketone was formed in good yield. The authors also noted that the simple dilution of the reaction mixture resulted in a dramatic increase in the formation of the undesired benzoin condensation product. 

The absolute stereochemistry of natural roseophilin was determined by means of asymmetric total synthesis by M.A. Tius and co-workers. The trisubstituted pyrrole moiety of the natural product was installed using the Paai-Knorr pyrrole synthesis starting from a macrocyclic 1,4-diketone. This diketone was prepared by reacting an exocyclic a, 3-unsaturated ketone with excess 6-heptenal in the presence of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride as the catalyst. The major product was the trans diastereomer and the macrocyclization was achieved via aikene metathesis. It is worth noting that when the aldehyde was tethered to the cyclopentenone, all attempts to close the macrocycle in an intramolecular Stetter reaction failed. 

The short synthesis of (+)-frans-sabinene hydrate, an important flavor chemical found in a variety of essential oils from mint and herbs, was developed by C.C. Galopin. The key intermediate of the synthetic sequence was 3-isopropyl-2-cyclopentenone. Initially a Nazarov cyclization of a dienone substrate was attempted for the synthesis of this compound, but the cyclization did not take place under a variety of conditions. For this reason, a sequential Stetter reactionlintramolecular aldol condensation approach was successfully implemented. 

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Conversion of aldehydes to ketones via cyanohydrin derivatives (ethers) by alkylation or Michael addition also used with sdyl ethers, dialtylamlnonitnies (see also Stetter reaction). 

The Paal synthesis of thiophenes from 1,4-diketones, 4-ketoaldehydes and 1,4-dialdehydes has found great use in the synthesis of medicinally active compounds, polymers, liquid crystals and other important materials. Furthermore, the discovery of the catalyzed nucleophilic 1,4-conjugate addition of aldehydes, known as the Stetter reaction (Eq. 5.4.1), has enabled widespread use of the Paal thiophene synthesis, by providing 1,4-diketones from readily available starting materials. ... 

An interesting application of the Paal thiophene synthesis was documented for the synthesis of a polystyrene-oligothiophene-polystyrene copolymer. In the Stetter reaction of aldehyde 13 and P-dimethylaminoketone 14, in situ generation of the a,p-unsaturated ketone preceded nucleophilic 1,4-conjugate addition by the acyl anion... 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

Two other examples of microwave-assisted Paal-Knorr reactions were reported in 2004, describing the synthesis of a larger set of pyrroles with different substituents around the ring. The methods differ mainly in the syntheses employed to produce the 1,4 dicarbonyl compounds required for the cyclization. A variation of the Stetter reaction between an acyl silane and dif-... 

An interesting family of polycyclic pyrroles was described in 2005 using again the synthetic sequence of a Stetter reaction for the preparation of the starting 1,4 diketones followed by a microwave-assisted Paal-Knorr condensation [35]. For example, cyclopentenone 23 (obtained in a Pauson-Khand cyclization) reacted imder Stetter reaction conditions to give the amino ketone 25 (Scheme 8). The microwave-assisted Paal-Knorr cyclization of 25 with different amines gave a small collection of tricychc pyrrole 2-carbox-amides. 

Formylphenoxy)but-2-enoates, available from salicyclaldehydes and 4-bromo-crotonates, undergo an intramolecular Stetter reaction, which, in the presence of a chiral triazolium salt, affords chroman-4-ones with good enantiomeric excesses <96HCA1899>. 

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]. 

Scheme 12.25 Scope of the asymmetric intramolecular Stetter reaction...

The intramolecular asymmetric Stetter reaction of aliphatic aldehydes is generally more difficult to achieve due to the presence of acidic a-protons. Rovis and co-workers have demonstrated that the NHC derived from pre-catalyst 130 promotes the intramolecular Stetter cyclisation with enoate and alkyhdene malonate Michael acceptors 133. Cyclopentanones are generally accessed in excellent yields and enantioselectivities, however cyclohexanones are obtained in significantly lower yields unless very electron-deficient Michael acceptors are employed... 

Scheme 12.26 Asymmetric intramolecular Stetter reactions with aliphatic aldehydes...

Scheme 12.28 Generation of contiguous stereocentres in the Stetter reaction...

Rovis and co-workers have applied the asymmetric intramolecular Stetter reaction to the desymmetrisation of cyclohexadienones 140, generating a quaternary stereocentre and forming hydrobenzofuranones 141 in excellent yields and enantiose-lectivities. Substitution at the two, four and six-positions is tolerated, and even substitution at the three-position is accommodated (Scheme 12.29) [65]. 

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],... 

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],... 

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. 

Cyanide-catalyzed condensation of aryl aldehyde to benzoin. Now cyanide is mostly replaced by a thiazolium salt. Cf. Stetter reaction. 

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... 

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