Michael reactions continued

Intermolecular Michael reactions continue to be developed. Karl Anker Jorgensen of Aarhus University, Denmark, has found (Angew. Chem. Ini. Ed. 2004,43, 1272) that the organocatalyst 3 mediates the addition of 2 to 1 with high enantiomeric excess. What is more, under the reaction conditions the intial Michael addition is followed by an aldol condensation, to give 4 as essentially a single diastereomer. 

The Michael reaction plays a part in some more extended synthetic sequences of great importance. Analyse TM 116 as an a,p-unsaturated carbonyl compound and continue your analysis by the Michael reaction. 

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

Amberlyst 21 (59) and solid-supported cinchonidine (60) have been used to catalyze the Michael reaction between 61 and methyl vinyl ketone 62 in flow (Scheme 4.80). The reactions using Amberlyst 21 were run at 50 °C and required a residence time of 6h (120 pl/min) for the reaction to reach completion (99% yield). The asymmetric reactions using 60 under the same conditions formed 63 in 97% yield with 52% ee of the S-isomer the system could be run continuously for 72 h without any observed loss of activity [181]. 

Base-catalysed reactions such as the Knoevenagel, Michael and aldol reactions continue to be of importance in industrial routes to synthetic chemicals and are often inherently clean, with water (or nothing) as the by-product. Traditional homogeneous methods of catalysis often require upwards of 40 mol% catalyst (such as piperidine) with the attendant difficulties in recovery and reuse of the catalyst. They often offer extremely poor selectivity to the desired products, either due to competing processes (side reactions) or further reaction of the first-formed product. 

The second chapter, by David A. Oare and Clayton H. Heathcock, deals with the stereochemistry of uncatalyzed Michael reactions of enamines and of Lewis acid catalyzed reactions of enol ethers with a,/ -unsaturated carbonyl compounds. It is effectively a continuation of their definitive review of base-promoted Michael addition reaction stereochemistry that appeared in the preceding volume of the series. 

Aldol reaction. A new catalyst for the Mukaiyama version of an aldol reaction is [Ir(cod)(PPh3)2]OTf. Actually, after activation by hydrogen, it promotes a Michael reaction of enones with silyl enol ethers and the system can be modified to continue an aldol reaction. 

This overview about developments in the field of proline-catalysis unfortunately cannot take into full account the vast field of proline-derived catalysts, such as diarylprolinols, 4-silo)yprolines or proline-silyl-ether, to name only a few. These are covered in subsequent chapters of this volume. Furthermore, other great improvements have been made by using immobilised proline catalysts, such as PEG-supported proline or polyelectrolyte-bound pro-line. Going one step further, supported proline catalysts are then applicable in the striving field of continuous-flow reactions. Recent examples include aldol, a-amination reactions and Michael reactions under such conditions. ... 

Chapters 12—16 continue the study of organic compounds, including aldehydes and ketones, carboxyUc acids, and finally carboxylic acids and their derivatives. Chapter 15 concludes with an introduction to the aldol, Claisen, and Michael reactions, all three ofwhich are important means for the formation of new carbon-carbon bonds. Chapter 16 provides a brief introduction to organic polymer chemistry. 

Fossey and Richards have already reported the synthesis of Pt and Pd bisoxazo-line containing NCN-pincer complexes these complexes were found to be active as catalysts for the Michael reaction of activated nitriles and the aldol reaction between isonitriles and aldehydes [43]. Recently, they continuously studied on the addition of trimethylsilyl cyanide to benzaldehyde (la) catalyzed by complexes (139) (Scheme 16.37) [44]. The most effective catalyst was found when trifluo-romethanesulfonate (OTf) was used as counteranion, resulting in good conversion of benzaldehyde under the standard conditions used. Furthermore, in the addition of trimethylsilylcyanide (TMSCN) to N-benzylideneaniline (110a) in the presence of (130) (1 mol%) provided (141) in a 77% conversion. 

Phosphonate analogues of nucleotides continue to attract attention. S -Hydrogen-phosphonates and 5 -methylphosphonates of various anti-HIV nucleosides have been made, and the H-phosphonates from AZT and 3 -deoxy-3 -fluorothymidine were highly active. 5 -Fluoro-methyl- and -difluoromethyl-phosphonatcs have been prepared from d4T,26 AZT,264,265 gnj various other nucleosides and deoxynucleosides,265 and phosphonates 199 (n = 1,2) were prepared from the 5 -bis(TMS)phosphite by Arbusov or Michael reaction. The non-hydrolysable analogue 200 of phosphoadenosine phosphosulfate ( active sulfate ) has been described. The 3 -phosphale was put on in the last step using trimetaphosphate, and the desired product was sq>arated from die 2 -phosphate by hplc.267... 

Stork enamine reaction uses an enamine as a nucleophile in a Michael reaction, straight-chain alkane (normal alkane) an alkane in which the carbons form a continuous chain with no branches. 

The use of supported organocatalysts in flow chemistry is not new. A pioneering work using an organic base catalyst was reported by Venturello. Knoevenagel condensations of aromatic aldehydes, cyclohexanone, and acetophenone with acetoa-cetate, cyanoacetate, or malonate were catalyzed by aminopropyl-functionalized silica gel (56), which was packed in a gravity-fed column, under continuous-flow conditions (Scheme 7.40) [149]. A flowcell microreactor, whose wall surfaces were coated with aminopropylsilica, was utilized in Knoevenagel and Michael reactions [150]. 

Organocatalysis Continuing efforts to harness the cooperative activity of bifunctional organocatalysts have led to the examinations of chiral calix[4]arenes containing amino phenol stractures and chiral per-6-amino-P-cyclodextrin in the asymmetric sulfa-Michael reactions to cyclic and acylic enones.The preliminary results indicated that further structural modification would be required to allow more efficient asymmetric catalyst systems. 

In continuation of the aforementioned reaction, Hiroya and coworkers used cop-per(II) acetate for the synthesis of indoles 2-943 in reasonable yields from the corresponding ethynylanilines 2-941 by a domino intermolecular Michael addition/cop-per-assisted nucleophilic tosylate displacement reaction via 2-942 (Scheme 2.211) [482],... 

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