Intramolecular Stetter Reactions

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). 

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...

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]. 

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. 

Table 6 Variation of heteroatom linker in the intramolecular Stetter reaction O...

In 2004 and 2005, respectively, Bach and Miller independently described the use of chiral thiazolium salts as pre-catalysts for the enantioselective intramolecular Stetter reaction. Bach and co-workers employed an axially chiral A-arylthiazolium salt 109 to obtain chromanone 73 in 75% yield and 50% ee (Scheme 16) [77]. Miller and co-workers found that thiazolium salts embedded in a peptide backbone 65 could impart modest enantioselectivity on the intramolecular Stetter reaction [78]. In 2006, Tomioka reported a C -symmetric imidazolinylidene 112 that is also effective in the aliphatic Stetter reaction, providing three examples in moderate enantioselectivities (Scheme 17) [79]. 

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]. 

In addition to the stabilized carbanions, electron-rich aromatic compounds, for example indole derivatives have emerged as new Michael donors [25], In these reactions, aromatic sp2-C-H transformation is involved. These reactions are described in detail in Section 111.1.3.1.3. A highly enantioselective intramolecular Stetter reaction, in which umpolung reactivity of a formyl group was accomplished using a chiral triazolium salt, has also been reported by Rovis [26]. 

Scheme 9.8 Intramolecular Stetter reaction, as described by Rovis et al.

Scheme 9.9 Intramolecular Stetter reaction of aliphatic substrates.

Very recently, Rovis examined the intramolecular Stetter reaction with a,/ -disubstituted acceptors 38 (Scheme 9.11) [42]. The key challenge is to secure a diastereoselective proton transfer onto the enolate intermediate. HMDS (from the KHMDS base) was shown to cause a deterioration in diastereoselectivity, but this problem was overcome by using the free carbene catalyst - that is, HMDS was removed in high vacuum prior to the reaction. Using the free carbene catalyst 39, the desired chromanone 40 could be obtained in excellent yield (94%),... 

In related investigations, the group of Rovis examined the effect of pre-existing stereocenters in the intramolecular asymmetric Stetter reaction [43]. The same group also exploited the concept of desymmetrization for the asymmetric synthesis of hydrobenzofuranones in an intramolecular Stetter reaction [44]. 

The triazolium salt 2 has also been used as a purely organic catalyst [17]. It is an active catalyst for asymmetric benzoin-type condensation reactions yielding the reaction products with enantiomeric excesses of 20-80%, which at the time marked a major advance with respect to the previously established catalysts (Scheme 5, Eq. 1) [18]. It was also found to catalyze the asymmetric intramolecular Stetter reaction with moderate to good enantioselectivities (41-74% ee) (Scheme 5, Eq. 2) [19]. 

The use of species 118 for the umpolung of a carbonyl group, the Stetter reaction, was demonstrated for the intramolecular asymmetric conjugate addition of a formyl group to the enoate moiety of 119 to give the cyclization product 120 in high ee and yield (Scheme 15) [64]. 

What starting material would be required for formation of the natural product ds-jasmone by an intramolecular aldol reaction (Chapter 27). How would you make this compound using a Stetter reaction ... 

In 1995 Ciganek reported an intramolecular version of the Stetter reaction (Ciganek 1995). 2-Formyl phenoxycrotonates and -acrylates 137 have been shown to be highly active substrates for the Stetter reaction. The reactivity of the substrates was considerably enhanced may be due to entropic factors. The reaction also proceeds in the absence of triethy-lamine as base. The catalyst is presumably activated by DMF taking the place of the amine. 

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). 

CiganekE (1995) Esters of 2,3-dihydro-3-oxobenzofuran-2-acetic acid and 3,4-dihydro-4-oxo-2H-l-benzopyran-3-acetic acid by intramolecular Stetter reactions. Synthesis 1995 1311-1314... 

Enders D, Breuer K, Runsink J, Teles JH (1996c) The first asymmetric intramolecular Stetter reaction. Preliminary communication. Helv Chim Acta 79 1899... 

Kerr MS, Rovis T (2003) Effect of the Michael Acceptor in the asymmetric intramolecular Stetter reaction. Synlett 2003 1934-1936... 

Kerr MS, Read de Alaniz J, Rovis T (2002) A highly enantio selective catalytic intramolecular Stetter reaction. J Am Chem Soc 124 10298... 

Moore JL, Kerr MS, Rovis T (2006) Enantioselective formation of quaternary stereocenters using the catalytic intramolecular Stetter reaction. Tetrahedron 62 11477-11482... 

Nakamura T, Hara O, Tamura T, Makino K, Hamada Y (2005) A facile synthesis of chroman-4-ones and 2,3-dihydroquinolin-4-ones with quaternary carbon using intramolecular Stetter reaction catalyzed by thiazolium salt. Synlett 2005 155-157... 

Pesch J, Harms K, Bach T (2004) Preparation of axially chiral N.N -diarylimi-dazolium and N-arylthiazolium salts and evaluation of their catalytic potential in the benzoin and in the intramolecular stetter reactions. Eur J Chem 9 2025-2035... 

---