Organocatalytic Michael reaction

Scheme 27 Dialkylprolinol ether 65 for the organocatalytic Michael reaction...

A direct organocatalytic Michael reaction of ketones or aldehydes with /3-nitrostyrene has been reported in brine solution, using a bifunctional catalyst system proline-derived diamine (70) and TFA.203 In some cases the conversion, yield, de, and ee all exceeded 95%. Results in water were poor, mainly due to polymerization, which is catalysed by amines. It is proposed that sodium cations stabilize the anionic intermediate formed from (70) and /3-nitrostyrene, thus minimizing polymer formation. While organic co-solvent is not required, an organic-rich phase is proposed to concentrate the Michael reactants and catalysts, thus accelerating the reaction. 

ENAMINE-BASED ORGANOCATALYTIC MICHAEL REACTIONS USING A CHIRAL ONIUM ION-TAGGED PYRROLIDINE... 

Scheme 7.13 Combining an organocatalytic Michael reaction with gold catalysis.

First studies in the direct asymmetric organocatalytic Michael reactions of a,a-disubstituted aldehydes with nitrostyrenes were carried out by Barbas et al. [51] employing 30 mol% of diamine/TFA bifunctional catalyst 31, which afforded... 

In particular, as a more challenging nucleophile, acetaldehyde was also suitable for the Michael addition with nitroalkenes. Using diarylprolinol silyl ether 7 as catalyst. List and co-workers [8] and Hayashi et al. [9] independently developed the first organocatalytic Michael reaction of acetaldehyde to afford a-unsubstituted y-nitro aldehydes in moderate to good yields and with excellent enantioselectivities (Scheme 5.3). The synthetic utility of this reaction was illustrated by List and... 

Palomo C, Landa A, Mielgo A, Oiarbide M, Puente A, Vera S (2007) Water-Compatible Iminium Activation Organocatalytic Michael Reactions of Carbon-Centered Nucleophiles with Enals. Angew Chem Int Ed 46 8431... 

Reaction conditions N,N-Dimethyformamide, room temperature Synthetic strategy Organocatalytic Michael reaction... 

In what can be regarded as the earliest evidence for the participation of enamines in a proline-catalyzed aldol reaction and its in situ detection was provided by Metzeger and coworker. A combination of high-resolution MS/MS and ESI-MS methods could detect the condensahon product between prohne and acetone [9]. Furthermore, the evidence was strongly in favor of enamine as compared to the isomeric oxazolidinone. In a subsequent study, Seebach and coworkers using NMR and IR studies proposed that an oxazolidinone intermediate plays a vital role in asymmetric organocatalytic Michael reactions. Evidence for participation of bicychc as well as spirocyclic oxazolidinones in proline-catalyzed reachons was presented [10]. 

Later, Cid and Ruano reported that aryl-acetonitriles bearing an electron-withdrawing group at the ortho- or poro-position could serve as suitable nucleophiles in organocatalytic Michael reactions with enals [39]. The reaction proceeded with good yields and good enantioselectivities, albeit with low... 

Organocatalysis have emerged recently as one of the cornerstones for the enanti-oselective synthesis of C-C or C-heteroatom bonds. Owing to the easy prediction of the stereochemical outcome of the reactions, iminium activation and specific Michael reactions is one of the most studied reaction types in organocatalysis. In the literature, we can find multiple approaches to the organocatalytic Michael reaction using different catalysts or nucleophiles, most of them with exceptional levels of stereoselectivity. Moreover, these simple additions to enals or enones have inspired multiple organocatalytic tandem and cascade reactions and, in our view, open up a new pathway for the enantioselective construction of complex scaffolds in one-pot procedures. 

Palomo P, Landa A, Mielgo A, Oiarhide M, Puente A, Vera A. Water-compatible iminium activation organocatalytic Michael reactions of carbon-centered nucleophiles with enals. Angew. Chem. Int. Ed. 2007 46(44) 8431-8435. 

Ramachary, D.B. Barbas, C.R III (2004) Towards Organo-Click Chemistry Development of Organocatalytic Multicomponent Reactions Through Combinations of Aldol, Wittig, Knoevenagel, Michael, Diels-Alder and Huisgen Cycloaddition Reactions. Chemistry A European Journal, 10, 5323-5331. 

Scheme 2.63. Organocatalytic synthesis of 2-271 by a domino O-nitroso-aldol/Michael reaction.

Scheme 7 Two alternative reaction routes for the organocatalytic Michael-addition of acetylacetone to nitrostyrene...

Enantioselective organocatalytic conjugate additions such as Michael and aldol reactions have been intensely studied under new catalysts. However, only a few organocatalyzed Michael reactions have been developed. The reaction involves construction of a new C-N bond that is very attractive for syntheses of molecules with biological properties. 

Scheme 54 Organocatalytic Michael/Morita-Baylis-Hillman reaction...

Bertelsen S, Halland N, Bachmann S, Marigo M, Braunton A, Jprgensen KA (2005) Organocatalytic asymmetric alpha-bromination of aldehydes and ketones. Chem Commun (Camb) 14 4821 1823 Betancort JM, Barbas CF 3rd (2001) Catalytic direct asymmetric Michael reactions taming naked aldehyde donors. Qrg Lett 3 3737-3740... 

Brown SP, Goodwin NC, MacMillan DWC (2003b) The first enantioselective organocatalytic Mukaiyama-Michael reaction a direct method for the synthesis of enantioenriched gamma-butenolide architecture. J Am Chem Soc 125 1192-1194... 

Enders D, Seki A (2002) Proline-catalyzed enantioselective Michael additions of ketones to nitrostyrene. Synlett 2002 26-28 Enders D, Vrettou M (2006) Asymmetric synthesis of (+)-polyoxamic acid via an efficient organocatalytic Mannich reaction as the key step. Synthesis 13 2155-2158... 

Other examples of asymmetric reactions involving organocatalysts are (i) Diels-Alder reactions, (ii) Michael reactions, (iii) Mannich reactions and (iv) Shi epoxida-tion and organocatalytic transfer hydrogenation. 

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