Aliphatic aldehydes 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...

Utilizing prochiral a,a-disubstituted Michael acceptors, the Stetter reaction catalyzed by 76a has proven to be both enantio- and diastereoselective, allowing control of the formation of contiguous stereocenters Eq. 8 [73]. It is noteworthy that a substantial increase in diastereoselectivity is observed, from 3 1 to 15 1, when HMDS, the conjugate acid formed upon pre-catalyst deprotonation, is removed from the reaction vessel. Reproducible results and comparable enantioselectivities are observed with free carbenes for example, free carbene 95 provides 94 in 15 1 diastereoselectivity. The reaction scope is quite general and tolerates both aromatic and aliphatic aldehydes (Table 9). 

In the early 1970s Stetter and co-workers succeeded in transferring the concept of the thiazolium catalyzed nucleophilic acylation to the substrate class of Michael acceptors (Stetter 1976 Stetter and Schreck-enberg 1973). Since then, the catalytic 1,4-addition of aldehydes 6 to an acceptor bearing an activated double bond 131 carries his name. The Stetter reaction enables a new catalytic pathway for the synthesis of 1,4-bifunctional molecules 132, such as 1,4-diketones, 4-ketoesters and 4-ketonitriles (Stetter and Kuhlmann 1991 for a short review, see Christmann 2005). The reaction can be catalyzed by a broad range of thiazolium salts. Stetter and co-workers found the benzyl-substituted thiazolium salt 86a to give the best results for the addition of aliphatic aldehydes, whereas 86b and 86c were chosen for the addition of aromatic aldehydes. Any one of these three was found to be suitable for additions with heterocyclic aldehydes. Salt 86d was utilized with a, )-unsaturated esters (Fig. 15). 

The mechanism of this reaction was hrst described by Breslow as early as 1958 [4], Subsequently, the natural enzyme thiamine, found in yeast, was replaced by related nucleophiles like thiazole [5,6], triazole [7] and imidazole [8], Reactions that follow this mechanism include the very important Stetter reaction (the benzoin condensation of aliphatic aldehydes), the Michael-Stetter reaction (a variant of the Stetter reaction where the aldehyde reacts with an a,P-unsaturated ketone) [1], transesteriflcations [9] or the acylation of alcohols [9,10], All four reactions are carbene catalysed nucleophilic acylation processes. 

Note The Stetter reaction is a benzoin condensation using aliphatic aldehydes. 

Note The Michael-Stetter reaction is a benzoin condensation between an aliphatic aldehyde and an a, jd-unsaturated ketone. 

It is only a small step from the asymmetric benzoin condensation to the asymmetric Stetter reaction, the aliphatic variant of the benzoin condensation. The literatnre refers to the Stetter reaction when at least one of the two reactants is an aliphatic aldehyde. Normally, the reaction is performed as a cross-coupling reaction with two different reactants, one of which is not an aldehyde, bnt an a, 3-unsaturated ketone. Strictly speaking, most thiazole catalysed reactions referred to as Stetter reactions are in fact Michael-Stetter reactions [21,22] (see Fignre 6.4). The reaction received the name because Stetter used a Michael reagent, an acceptor with an activated double bond, as the second component of a cross-coupled Stetter reaction [11]. 

Interestingly, the mild reaction conditions of the CIR are fully compatible with the Stetter reaction. As a result a sequence of transition metal, base and organoca-talysis can be easily conceived. Upon CIR of electron-deficient (hetero)aryl halides 11 and (hetero)aryl propargyl alcohols 12, and after subsequent addition of aliphatic or aromatic aldehydes 92 and catalytic amounts of thiazolium salt 93 1,4-diketones 94 are obtained in moderate to excellent yields in a one-pot procedure (Scheme 50) [259, 260]. For aromatic aldehydes the catalyst precursor of choice is 3,4-dimethyl-5-(2-hydroxyethyl) thiazolium iodide (93a) (R = Me), and for aliphatic aldehydes 3-benzyl-4-methyl-5-(2-hydroxyethyl)-thiazolium chloride (93b) (R = CH2Ph) is applied. 

Various m- and p-hydroxychalcones were anchored to a Wang resin through their phenolic groups. Stetter reactions were performed with various aliphatic, aromatic, and heteroaromatic aldehydes, affording 1,4-diketones. m-Chalcones, as well as aliphatic and aromatic aldehydes, gave superior results. 

Scheme 6.6 The intramolecular Stetter reaction using aliphatic aldehydes as Michael donors.

Intramolecular asymmetric Stetter reactions enjoy a range of acceptable Michael acceptors and acyl anion precursors. These reactions can utilize aromatic, heteroaromatic, and aliphatic aldehydes with a tethered a,p-unsaturated ester, ketone, thioester, malonate, nitrile, or Weinreb amide. In this part, we will give a brief summary about asymmetric intramolecular Stetter reactions and selected recent results in this area (Scheme 7.17). 

In 2013, Law and McErlean demonstrated the intramolecular vinylogous Stetter reaction as a new addition to the collection of NHC-catalyzed transformations. The products of this new transformation possess multiple sites for chemoselective functionalization, including (but not limited to) ketones, esters, and alkenes. Utilizing chiral triazolium salts as the NHC catalyst precursor, aromatic aldehydes or aliphatic aldehydes proceeded with various heteroatom tethered vinylogous Michael acceptors to give five- and sk-membered rings (up to 88% yield, 96% ee) (Scheme 7.20). 

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 7.31 NHC-catalyzed asymmetric intermolecular Stetter reaction of aliphatic aldehydes with p-nitrostyrenes reported by Rovis.

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). 

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. ... 

Although these recent developments show that various substrates can be used to obtain Stetter products in high yields and enantiomeric ratios, the required combination of aldehyde, acceptor, catalyst, and reaction conditions is both critical and difficult to anticipate. The enantioselective Stetter reaction between aliphatic... 

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