Conjugate addition Michael-type reactions

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

While THF or CH2CI2 are the most commonly used solvents, the solubility of the reagents or the catalyst may dictate the use of other solvents. Reactions are usually slow in DMF and in CH3CN when DABCO, DBU or DMAP were used as catalysts. An often-observed byproduct of the aza-MBH reaction is a bridged compound of type 97. This product is the result of a stepwise addition of 95 to 75 via the Mannich reaction, followed by an intramolecular conjugated addition (Michael addition) of the formed anion to the a,/ -unsaturated ketone, and thus due to the elevated basicity of the catalyst (Scheme 5.21) [92]. 

This catalytic cascade was first realized using propanal, nitrostyrene and cinnamaldehyde in the presence of catalytic amounts of (9TMS-protected diphenylprolinol ((.S )-71,20 mol%), which is capable of catalyzing each step of this triple cascade. In the first step, the catalyst (S)-71 activates component A by enamine formation, which then selectively adds to the nitroalkene B in a Michael-type reaction (Hayashi et al. 2005). The following hydrolysis liberates the catalyst, which is now able to form the iminium ion of the a, 3-unsaturated aldehyde C to accomplish in the second step the conjugate addition of the nitroalkane (Prieto et al. 2005). In the subsequent third step, a further enamine reactivity of the proposed intermediate leads to an intramolecular aldol condensation. Hydrolysis returns the catalyst for further cycles and releases the desired tetrasubstituted cyclohexene carbaldehyde 72 (Fig. 8) (Enders and Hiittl 2006). 

The process mechanism as shown in Figure 2.23 consists of an initial activation of the aldehyde (66) by the catalyst [(5)-67] with the formation of the corresponding chiral enamine, which then, selectively, adds to nitroalkene (65) in a Michael-type reaction. The following hydrolysis liberates the catalyst, which forms the iminium ion of the a,(3-unsaturated aldehyde (62) to accomplish the conjugate addition with the nitroalkane A. In the third step, another enamine activation of the intermediate B leads to an intramolecular aldol condensation via C. Finally, the hydrolysis of it returns the catalyst and releases the desired chiral tetra-substituted cyclohexene carbaldehyde (68). 

In accordance with the generally accepted mechanism ofthe MBH reaction, the aza MBH reaction involves, formally, a sequence of Michael addition, Mannich type reaction, and (3 elimination. A commonly accepted mechanism is depicted in Scheme 13.2. A reversible conjugate addition of the nucleophilic catalyst to the Michael acceptor generates an enolate, which can intercept the acylimine to afford the second zvdtterionic intermediate. A proton shift from the a carbon atom to the P amide followed by P elimination then affords the aza M BH adduct with concurrent regeneration of the catalyst [5]. 

An important type of tandem reaction arises when both steps are conjugate additions (Michael reactions, chapter 9). The most widely used case is the conjugate addition 38 of a kinetic a eno-late from an enone 37 (chapter 11) to a second enone. The resulting enolate than adds back 39 to the first compound in a second conjugate addition. The product 41 contains a six-membered ring formed in the tandem process. 

Michael-type reactions. Complexation of methyl vinyl ketone with Cs Hs Fe(CO)2 as shown in (1) permits conjugate addition reactions under mild... 

Michael-type addition of thiols to the dehydroproline double bond of pristinamycin IIa was investigated. Attempted reaction with alkyl thiols, substituted phenyl thiols, ethyl mercaptoacetate or hydroxy-substituted alkyl thiols using standard conditions [128] (but at room temperature) was unsuccessful. Moderate yields (up to 50%) to conjugate addition products from reaction of pristinamycin 11 with these thiols (Scheme 22) were obtained when the reaction was carried out in the presence of N,N-dimethylethanolamine (see below for discussion of the stereochemistry associated with the conjugate addition products). With sterically hindered thiols, for example, 2-mercapto-pyran, no reaction was observed even under catalytic conditions. Similar results to those described above were obtained for reaction of either of the alcohols (60) or (61). 

Extension of substrate scope in Michael-type reactions was demonstrated in the diatyl prolinol Ij catalysed conjugate addition of malononitrile to t/ fl/is-chalcones (Scheme 7.8). ... 

The simple chiral secondary amine (S)-70 activates the linear aldehyde 139 by enamine formation, which selectively attacks the nitroalkenes 140 in a Michael-type reaction without any interference by the a,p-unsaturated aldehyde 95. Indeed, the latter prefers to be activated as iminium ion by the catalyst (5)-70 and to undergo the subsequent conjugate addition to form the Michael adduct B (Scheme 2.41). 

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... 

A synthetically useful reaction known as the Michael reaction, or Michael addition, involves nucleophilic addition of carbanions to a p unsaturated ketones The most common types of carbanions used are enolate 10ns derived from p diketones These enolates are weak bases (Section 18 6) and react with a p unsaturated ketones by conjugate addition... 

Methacryhc acid and its ester derivatives are Ctfjy -unsaturated carbonyl compounds and exhibit the reactivity typical of this class of compounds, ie, Michael and Michael-type conjugate addition reactions and a variety of cycloaddition and related reactions. Although less reactive than the corresponding acrylates as the result of the electron-donating effect and the steric hindrance of the a-methyl group, methacrylates readily undergo a wide variety of reactions and are valuable intermediates in many synthetic procedures. 

The HX compounds are electrophilic reagents, and many polyhalo and polycyano alkenes, (e.g., Cl2C=CHCl) do not react with them at all in the absence of free-radical conditions. When such reactions do occur, however, they take place by a nucleophilic addition mechanism, (i.e., initial attack is by X ). This type of mechanism also occurs with Michael-type substrates C=C—Z, where the orientation is always such that the halogen goes to the carbon that does not bear the Z, so the product is of the form X—C—CH—Z, even in the presence of free-radical initiators. Hydrogen iodide adds 1,4 to conjugated dienes in the gas phase by a pericyclic mechanism ... 

Other nucleophiles add to conjugated systems to give Michael-type products. Aniline derivatives add to conjugated aldehydes in the presence of a catalytic amount of DBU (p. 488). Amines add to conjugated esters in the presence of InCla, La(OTf)3, or YTb(OTf)3 at 3kbar, for example, to give P-amino esters. This reaction can be initiated photochemically. An intramolecular addition of an amine unit to a conjugated ketone in the presence of a palladium catalyst, or... 

In certain cases, Michael reactions can take place under acidic conditions. Michael-type addition of radicals to conjugated carbonyl compounds is also known.Radical addition can be catalyzed by Yb(OTf)3, but radicals add under standard conditions as well, even intramolecularly. Electrochemical-initiated Michael additions are known, and aryl halides add in the presence of NiBr2. Michael reactions are sometimes applied to substrates of the type C=C—Z, where the co-products are conjugated systems of the type C=C—Indeed, because of the greater susceptibility of triple bonds to nucleophilic attack, it is even possible for nonactivated alkynes (e.g., acetylene), to be substrates in this... 

In an extension of previous work on conjugated enamine carbonyl derivatives, reaction of the pyrazolone 91 with IV.lV-disubstituted hydrazines on heating in an alcohol solvent afforded the hexahydropyrazolo[4,3-Michael-type addition of the alcohol to a pre-formed pyrazolo-diazepine, was excluded <06T8126>. 

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