Michael addition nucleophilic aliphatic

Scheme 6.104 Key intermediates of the proposed catalytic cycle for the 100-catalyzed Michael addition of a,a-disubstituted aldehydes to aliphatic and aromatic nitroalkenes Formation of imine (A) and F-enamine (B), double hydrogen-bonding activation of the nitroalkene and nucleophilic enamine attack (C), zwitterionic structure (D), product-forming proton transfer, and hydrolysis.

The most common preparations of amines on insoluble supports include nucleophilic aliphatic and aromatic substitutions, Michael-type additions, and the reduction of imines, amides, nitro groups, and azides (Figure 10.1). Further methods include the addition of carbon nucleophiles to imines (e.g. the Mannich reaction) and oxidative degradation of carboxylic acids or amides. Linkers for primary, secondary, and tertiary amines are discussed in Sections 3.6, 3.7, and 3.8. 

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 vinyl- and ethynyl-substituted compounds are able to participate in Michael addition reactions with a variety of nucleophiles, particularly if the group is attached to C-2. When the sodium salt of 2-ethynyl-l-methyIbenzimidazole is treated in liquid ammonia with an aliphatic alcohol, the vinyl ether (211) is produced, but KOH in ethanol surprisingly gives 1,2-dimethylbenzimidazole (Scheme 113) (75jouil30). 

Michael additions are among the most important organocatalytic transformations.The ability of prolinol silyl ethers to form enamines, diena-mines, trienamines or iminium ions makes them appealing in a number of chemical transformations based on addition of a nucleophile to an a,p-unsaturated carbonyl compound or other Michael acceptor. The first example of Michael addition catalysed by a prolinol silyl ether was published by Hayashi and coworkers. Aliphatic aldehydes added to a range of aryl-substituted nitroalkenes. Prolinol silyl ether Cla presumably formed chiral enamines with aldehydes. The F-anh-enamine was formed and it reacted with nitroalkene via an acyclic synclinal transition state, originally proposed... 

In 1997 Katritzky reported that the Michael addition of a-benzotriazole nitrile 12 to a,p-unsaturated ketones 11 in the presence of a secondary amine generated 2-aminopyridines, IS. This innovative [3+3] strategy provides an alternative to the typical method of preparing 2-aminopyridines by reacting 2-halopyridines with aliphatic amines. Following the initial Michael addition reaction, nucleophilic attack by the secondary amine on the nitrile moiety initiates the cyclization. This is followed by loss of benzotriazole and water to generate the 2-aminopyridine 13. 

Apart from hydrazoic acid, purine derivatives were also used as the nucleophiles by the Jacobsen group (Scheme 19.33). With ent-4 as the catalyst, the aza-Michael addition of 6-substituted purines to various a,p-unsaturated ketones bearing aliphatic p-substituents proceeded well, delivering the corresponding adducts in 60-95% yields, 14 1- > 99 1 of N9/N7, and 90-99% enantiomeric excess. Meanwhile, cx,p-unsaturated imides were... 

A series of Michael adducts has been synthesized with high yields by solvent-free microwave promoted Michael addition of aza-nucleophiles to benzo[b]thiophen-2-yl-2-propenone (Pessoa-Mahana et al., 2009). In this method, aliphatic and aromatic amines act as Michael donors and on treatment with l-(4,7-dimetho2 benzo[b] thiophen-2-yl)-2-propen-l-one led to formation of P-aminoketones and azahetero-cyclic compounds. These aza-nucleophiles were impregnated on silica gel-manganese dioxide as solid inorganic support. 

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 exceptional nucleofugality of the phenyliodonio group has been determined in an alkenyl salt and it is about 106 times greater than that of triflate [30]. This remarkable property makes alkenyl iodonium salts excellent vinyl cation equivalents in nucleophilic substitutions. The chemistry of alkenyl iodonium salts is dominated by the transfer of their aliphatic moiety to a variety of nucleophiles other important reactions involve Michael-type addition and alkylidenecarbene generation, along with elimination to alkynes which is actually an undesirable side-reaction. 

The utility of polymer-supported superbase catalysts has been established in the Michael-type conjugate addition using hetero-atom nucleophiles such as amines and thiols [34,37,41]. For example, a variety of primary/secondary/aliphatic/aromatic amines and aliphatic/aromatic thiols could smoothly react with activated olefins in the presence of 10mol% of a nitrate salt of PS-PAPT or PS-N3PAPT [34] (Scheme 6.10). 

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