Michael reaction aliphatic acceptors

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]. 

The y-keto nitriles shown in Table I were prepared by the cyanide-catalyzed procedure described here. This procedure is generally applicable to the synthesis of y-diketones, y-keto esters, and other y-keto nitriles. However, the addition of 2-furancarboxaldehyde is more difficult, and a somewhat modified procedure should be employed. Although the cyanide-catalyzed reaction is generally limited to aromatic and heterocyclic aldehydes, the addition of aliphatic aldehydes to various Michael acceptors may be accomplished in the presence of thioazolium ions, which are also effective catalysts for the additions. 

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... 

Also alkynylcarbene complexes can react as Michael acceptors with nucleophiles, forming 1,3-dien-l-ylcarbene complexes (Figure 2.17). Both carbon nucleophiles, such as, e.g., enamines [246-249], and non-carbon nucleophiles, such as imidates [250], amines [64,131,251], aliphatic alcohols [48,79,252], phenols [252], and thiols [252] can add to the C-C triple bond of alkynylcarbene complexes. Further reactions of the C-C triple bond of alkynylcarbene complexes include 1,3-dipolar [253,254], Diels-Alder [64,234,238,255-258] and [2 -i- 2] cycloadditions [259 -261], intramolecular Pauson-Khand reactions [43,262], and C-metallation of ethynylcarbene complexes [263]. 

Aliphatic compounds containing terminal gem-dinitro functionality form adducts with Michael acceptors.Of particular interest is the reaction of a,a,o),a)-tetranitroalkanes with Michael acceptors. ° Most a, o, y, y-tetranitroalkanes will react with two equivalents of Michael acceptor to form bis-adducts, like in the case of 1,1,4,4-tetranitrobutane, which reacts with two equivalents of methyl vinyl ketone, methyl acrylate, acrylonitrile etc. ° The influence of steric effects becomes apparent with a,a,y,Y-tetranitroalkanes, like 1,1,3,3-tetranitropropane, which can form either mono-adducts or bis-adducts depending on the Michael acceptor used 1,1,3,3-tetranitropropane will only react with one equivalent of methyl acrylate and the sole product of this reaction is methyl 4,4,6,6-tetranitrohexanoate. °... 

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 presence of thiourea catalyst 122, the authors converted various (hetero) aromatic and aliphatic trons-P-nitroalkenes with dimethyl malonate to the desired (S)-configured Michael adducts 1-8. The reaction occurred at low 122-loading (2-5 mol%) in toluene at -20 to 20 °C and furnished very good yields (88-95%) and ee values (75-99%) for the respective products (Scheme 6.120). The dependency of the catalytic efficiency and selectivity on both the presence of the (thio) urea functionality and the relative stereochemistry at the key stereogenic centers C8/C9 suggested bifunctional catalysis, that is, a quinuclidine-moiety-assisted generation of the deprotonated malonate nucleophile and its asymmetric addition to the (thio)urea-bound nitroalkene Michael acceptor [279]. 

The most conspicuous property of aliphatic amines, apart from their fishy smell, is their high basicity, which usually precludes N-alkylations under acidic reaction conditions (last reaction, Scheme 6.3). Hence, alkylation of amines with tertiary alkyl groups is not usually possible without the use of highly stabilized carbocations which can be formed under basic reaction conditions. Rare exceptions are N-alkyla-tions of amines via radicals (Scheme 4.2), copper-catalyzed propargylations (Scheme 6.3), and the addition of amines to some Michael acceptors and allyl palladium or iridium complexes. Better strategies for the preparation of tert-alkylamines include the addition of Grignard reagents to ketone-derived imines [13] or the reduction of tert-alkyl nitro compounds. 

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). 

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). 

Chen et al. have hypothesized that substituted acrylates may provide stereo-and/or stereoelectronic effects that stabilize the oxy anion intermediate, which would shift the equilibrium forward and subsequently accelerate the following aldol reaction. Thus, they screened a range of substituted acrylates and found that an extremely rapid rate can be achieved by using a-naphthyl acrylate as the Michael acceptor for the MBH reaction.The reaction of a-naphthyl acrylate with both aliphatic and aromatic aldehydes in the presence of DABCO provided the desired adducts 13 in reasonable yields within 20 min, which is one of the best rate acceleration systems for a wide range of aldehydes in the MBH reaction under atmospheric pressure (Scheme 2.10). 

Later, Liu and coworkers [31] showed that substrates such as nitrodienes, nitroenynes, or p-nitrostyrenes are valuable Michael acceptors for the reaction with enals in the presence of 10 mol% of R,R)-52, leading to anti-57 with a diastereomeric ratio of up to 12 1 (antiisyn) and excellent enantiomeric excess. Aliphatic nitroalkenes, such as p-cyclohexylnitroalkene, do not participate in this catalytic transformation. 

Du and coworkers have developed a stereoselective direct Michael addition of nitroalkanes to nitroalkenes catalyzed by quinine-derived dimeric squaramide 21 [93]. This transformation provided facile access to 1,3-dinitro compounds in high diastereo- and enantioselectivities starting from aryl-substituted nitroalkenes (Scheme 10.18). However, the use of an aliphatic nitroalkene as Michael acceptor resulted in a low yield and diminished enantioselectivity. While nitroethane and 1-nitropropane are excellent substrates, branched 2-nitropropane did not undergo the Michael addition reaction. The authors also noted that slightly reduced dias-... 

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