Michael addition Of heteroatom nucleophiles

The Michael addition of heteroatom nucleophiles to nitroalkenes (Section 4.1.1) followed by denitration provides a useful method for the preparation of various natural products. 

D.5. CATALYTIC ASYMMETRIC MICHAEL ADDITION OF HETEROATOM NUCLEOPHILES... 

Besides the Michael addition of heteroatomic nucleophiles initiating cyclocondensations, acceptor substituted unsaturated systems can also be reacted with carbon nucleophiles stemming from aldehydes in the sense of an umpolung, generally referred to as the Stetter reaction [244-246]. This process is organocatalytic and furnishes in turn 1,4-dicarbonyl compounds, intermediates that are well suited for Paal-Knorr cyclocondensations giving rise to furans or pyrroles. Among numerous heterocycles furans and pyrroles have always been the most prominent ones since they constitute important classes of natural products [247-249], of synthetic... 

A Michael Reaction Coupled to a Photochemical Cyclisation Copper Again Michael Additions of Heteroatom Nucleophiles... 

The addition of heteroatom nucleophiles to Q , -unsaturated carbonyl compounds has also been promoted using TBDMS triflate. An intermolecular aza-double Michael reaction has been developed as a route to functionalized piperidin-2-ones (eq 27). Due to its relative ease of handling, TBDMS triflate was generally preferred to TMSI-HMDS as an additive in such reactions. 

The Michael addition of nucleophiles on oc,P-unsaturated electron withdrawing groups, often carbonyl-containing functional groups, is a widely used reaction for the formation of C—C or C—heteroatom bonds. When the Michael acceptor bears a substituent on the a-position to the carbonyl, then an asymmetric carbon is created upon protonation of the transient enolate generated by the nucleophilic addition (Scheme 7.9). 

Perhaps the major disadvantage of the copper-catalysed Michael reaction is the need to protect functional groups. Michael reactions with heteroatom nucleophiles or functionalised carbon nucleophiles are usually carried out without copper. Many such nucleophiles, particularly enol equivalents, are excellent at Michael reactions, and are often to be preferred for ease of working. Silyl enol ethers, enamines, and stabilised enolates all carry out Michael reactions. In the next chapter we shall look at specific enol equivalents in more detail and note which ones are good at Michael additions. 

The conjugate addition of oxygen nucleophiles to acceptor-substituted olefins is the oxa-Michael reaction (Scheme 15). The term is derived from heteroatom replacement nomenclature, meaning that oxygen takes the place of a CH2 unit (RCH2 RO ). Oxa-Michael reactions have been known for many years and are often catalyzed by bases or acids [7]. Catalysis by metals has been reported sporadically in the older literature, e.g. for the case of alcohol addition to vinyl ketones with a Nieuwland catalyst (HgO, BF3-OEt2, ROH) [75-77]. A patent describes a PdCl2-catalyzed addition of alcohols to acrolein or methacrolein [78]. 

The Michael-type reaction, which involves the addition of a nucleophile to an a,p-imsaturated carbonyl compoimd, is an important conjugate addition reaction used for the formation of new C—C and carbon-heteroatom bonds. The reaction traditionally requires either strongly basic or acidic conditions, leading to the generation of hazardous waste products and imwanted side reactions [3]. To discover a greener... 

The chemical behavior of heteroatom-substituted vinylcarbene complexes is similar to that of a,(3-unsaturated carbonyl compounds (Figure 2.17) [206]. It is possible to perform Michael additions [217,230], 1,4-addition of cuprates [151], additions of nucleophilic radicals [231], 1,3-dipolar cycloadditions [232,233], inter-[234-241] or intramolecular [220,242] Diels-Alder reactions, as well as Simmons-Smith- [243], sulfur ylide- [244] or diazomethane-mediated [151] cyclopropanati-ons of the vinylcarbene C-C double bond. The treatment of arylcarbene complexes with organolithium reagents ean lead via conjugate addition to substituted 1,4-cyclohexadien-6-ylidene complexes [245]. 

The conjugate addition of heteronucleophiles to activated alkenes has been used very often in organic synthesis to prepare compounds with heteroatoms [3 to various activating functional groups, e.g. ketones, esters, nitriles, sulfones, sulfoxides and nitro groups. As in the Michael reaction, a catalytic amount of a weak base is usually used in these reactions (with amines as nucleophiles, no additional base is added). 

Several heteroatom nucleophiles, for example, amines, alcohols, thiols, carboxylates, and dialkylphosphines, undergo Michael addition reactions with alkene- and alkyne-substituted carbene complexes. Reaction of alkyne-substituted chromium carbenes with urea affords products derived from Michael... 

The term Michael addition has been used to describe 1,4- (conjugate) additions of a variety of nucleophiles including organometallics, heteroatom nucleophiles such as sulfides and amines, enolates, and allylic organometals to so-called Michael acceptors such as a,p-unsaturated aldehydes, ketones, esters, nitriles, sulfoxides, and nitro compounds. Here, the term is restricted to the classical Michael reaction, which employs resonance-stabilized anions such as enolates and azaenolates, but a few examples of enamines are also included because of the close mechanistic similarities. 

Heteroatom nucleophiles were described less often. Ye and coworkers published a phospha-Michael addition catalysed by prolinol silyl ether catalyst. Another method for constructing a new C-N bond is the aza-Michael addition, that is the addition of nitrogen-based nucleophiles to a,(3-unsaturated aldehydes. Several groups published these type of reactions using diatylprolinol silyl ether as catalyst. " Fustero and coworkers used this reaction as a key step in the synthesis of biologically active chiral heterocycles. Recently, the authors showed the synthesis of quinolizidine alkaloids, such as (-l-)-myrtine, (-)-lupine and (-l-)-epiquinamide. Vicario applied 5-mercaptotetrazoles as nucleophiles towards a range of unsaturated aldehydes. The reaction proceeded via the iminium activation. The... 

The nucleophilic 1,4-addition of stabilized carbon nucleophiles to electron-poor olefins, generally a,fS-unsaturated carbonyl compounds, is known as Michael addition, although it was first reported by Komnenos [14] in 1883. Michael-type reactions can be considered as one of the most powerful and reliable tools for the stereo-controlled formation of carbon-carbon and carbon-heteroatom bonds [15], as has been demonstrated by the huge number of examples in which it has been applied as a key strategic transformation in total synthesis. As a consequence, in recent years, many different organocatalytic versions of this important transformation... 

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