Unsaturated Michael-type reactions

Michael-type reactions of thiols with a,p-unsaturated carbonyl compounds R R C=CHCOR ... 

Crossed Michael-type reactions of thioacetates MeCOSCH(R )CH,CHO with a,(3-unsaturated... 

The preparation of warfarin derivatives via the catalysed Michael-type reaction of 4-hydroxycoumarins with 4-arylbut-3-en-2-ones is achieved with a ca. 20-fold increase in reaction rate and a twofold increase in yields, compared with traditional methods [60]. Similarly, tetra-H-butylammonium fluoride catalyses the reaction of nitrotoluenes with a,p-unsaturated esters under mild soliddiquid two-phase conditions [14] with increased yields, compared with those observed in the absence of the catalyst. 

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) ... 

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). 

As previously mentioned, 1-alkynyltrialkylborates (18) have become increasingly important in the formation of carbon-carbon bonds via attack of electrophiles. However, such complexes cannot react with simple Qc,P-unsaturated carbonyl compounds such as methyl vinyl ketone, because of their weak electrophilicity. Recently it was ascertained that ,P-unsaturated carbonyl compounds react with 18 via a Michael-type reaction in the presence of titanium tetrachloride, and the usual alkaline hydrogen peroxide oxidation leads to the synthesis of 5-dicarbonyl compounds... 

Thione adds to the unsaturated carbon—carbon linkage of maleic anhydride probably by a Michael-type reaction, subsequent cyclization results in the synthesis of 4-thiazolidinone derivatives. The reaction of thi-... 

Cyclopropane derivatives have been prepared from reactions of arsonium ylides with conjugated enones " and a, jS-unsaturated esters "" . Initial Michael-type reaction is followed by intramolecular elimination of triphenylarsine, e.g. equation 22. These reactions often give high yields and show high stereoselectivity. 

Because Michael-type reactions are among the most useful base-mediated cyclizations, the first examples presented in this chapter center around this chemistry. Thus, utilizing Wittig methodology, Vyplel et al. [37] prepared the hydroxyolefin (shown in Scheme 7.93) from the starting protected glucosamine. Treatment of this intermediate species with DBU effected cyclization of the 5-hydroxy group to the unsaturated ester in a Michael fashion. Notably, the cyclization provided the a anomer in 43% yield, with an additional 7% accounted for in the isolation of the (3 anomer. 

The intermediate of the ElcB mechanism is a carbanion, and thus any factors that stabilise such an ion should favour this mechanism. We have already noted above that on the face of it, elimination reactions are the reverse of addition reactions. However, we also noted that the actual mechanistic pathways involved in elimination reactions were more similar to substitution reactions than addition reactions. This is because normally elimination reactions proceed via a carbonium ion or in a single step that has certain similarities to an SN2 substitution reaction. However, there are also addition reactions that proceed via a carbanion intermediate, for example the Michael-type reaction, in which a carbanion adds to an a,(3-unsaturated carbonyl compound. Indicate the Michael-type addition between the anion formed from the diester of propandioic acid (or malonic acid) and 2-butenal. 

In a Michael-type reaction, unsaturated phosphorus substrates such as diethyl styrylphosphonatc°°° and tetraethyl ethenylidenediphosphonate (Scheme 6.26) undergo smooth addition of cyanide... 

In Michael-type reactions, unsaturated phosphorus substrates such as dimethyl vinylphosphonate and tetraethyl ethenylidenediphosphonate undergo addition of carbanions from ethyl... 

The titanium(IV) chloride-promoted reactions of enol silyl ethers with aldehydes, ketones, and acetals, known as Mukaiyama reaction, are useful as aldol type reactions which proceed under acidic conditions (eq (23)) [20], Enol silyl ethers also undergo the Michael type reactions with enones or p.y-unsaturated acetals (eq (24)) [21]. Under similar reaction conditions, enol silyl ethers are alkylated with reactive alkyl halides such as tertiary halides or chloromethyl sulfides (eq (25)) [22], and acylated with acid halides to give 1,3-diketones (eq (26)) [23]. 

Table 10.30 clearly shows that water and ethylene glycol promote the Michael-type reactions. Excellent yields of /i-aminonitriles are obtained in these media when a,yS-unsaturated nitriles are reacted. In all cases the yields are higher than those reached at 300 MPa in acetonitrile solution [100]. Notable exceptions are observed with methyl methacrylate reactions. In these reactions no Michael adduct is formed in aqueous solution, at variance with the pressure-assisted reaction which leads to modest yields (11-23 %). Such a dichotomy in reactivity is relevant to the prevalence of the reverse reaction. yff-Aminoesters undergo rapid reversion to reactants in aqueous solutions which are highly polar, while they are quite stable in acetonitrile [74]. The absence of reactivity in water persists even at 300 MPa meaning that the use of higher pressure is unable to shift the equilibrium toward the aminoester. 

The interest in functionalized ionic liquids is growing because ionic liquids bearing ether, amino or alcohol functionalities have been shown to display special properties, including the ability to dissolve a larger amoimt of metal halide salts and to extract heavy metal ions from aqueous solutions. Imidazolium-based ionic liquids with ether and hydroxyl (see Section 2.2.1), thiourea, thioether and urea (see Section 2.2.8) " have been prepared following the standard quatemization procedure. A straightforward approach has been described for the preparation of imidazolium (as well as pyridinium) cations with ester, ketone or cyanide functionalities 1-methylimidazole reacts with methanesulfonic acid to provide the imidazolium salt 11, which undergoes a Michael-type reaction with methyl vinyl ketone as a ,j8-unsaturated compound to produce the ionic liquid 12 (Scheme 5). ... 

Enamines, the products of the acid-catalyzed addition of secondary amines to aldehydes or ketones, can be viewed as weakly nudeophihc enolate anions. Enamines react with a,p-unsaturated carbonyl systems in a Michael-type reaction, introducing new carbon-carbon bonds adjacent to the carbonyl group. Endocyclic enamines, such as pyrroHnes and tetrahydropyridines, are useful for the synthesis of complex heterocycHc compounds, as found in many alkaloids (Scheme 3.19). 

The catalytic cycle operating for a generic Michael-type reaction of a nucleophile (Nu-H) to an a, 3-unsaturated aldehyde or ketone proceeding via iminium activation has been indicated in Scheme 3.1. As it can be seen in this proposed mechanism, all the steps involving iminium formation and hydrolysis are supposed to be in dynamic equilibrium, therefore concluding that the conjugate... 

There are numerous reports of the P-addition of organometallic reagents to racemic a,p-unsaturated sulfoxides [62,63]. For example, the Michael-type reaction of dialkylcuprates with p-chlorophenyl vinyl sulfoxide (65), followed by reaction of the initially formed a-sulfinyl carbanion (66) with electrophiles such as benzophenone, gave the products (67) (Scheme 5.21) [66]. 

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... 

Michael-type reactions have been achieved with baker s yeast using trifluoroethanol as the co-substrate (Scheme 5.17). These transformations probably are related to the acyloin condensation in that it has been proposed that the trifluoroethanol is initially oxidized enzymically to the aldehyde, which is then converted to a reactive acyl anion that can add to the electrophilic enone in a conjugate manner. The a, -unsaturated ketones are good Michael acceptors, leading to the corresponding y-hydroxyketones (via the diketone intermediate) in moderate yields (26-40%) and good optical purities (e.e. = 79%). The absolute configurations of the products (16) were not determined. 

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). 

Mechanism of action. Acrolein has two functional groups that can contribute to its biocidal activity. It is an a, jS-unsaturated aldehyde and as such the carbon-carbon double bond is extremely reactive. Nucleophiles, typically sulfur based nucleophiles, can react with the terminal carbon in a Michael type reaction (March, 1992), while the aldehyde group can undergo reactions typical of all aldehydes. From a biocidal point of view, those sulfur-based nucleophiles would include cysteine residues of the cell wall and those proteins associated with the cell wall. The amine containing amino acids (lysine and arginine) may also react with the aldehyde group of acrolein. 

The same mixed organozinc species participate in Michael-type reactions with a wide range of a,/3-unsaturated ketones and aldehydes (eq 6). Transition metal catalysts are not required for an effective process. 

Michael-type Reactions. The Michael reaction of indoles with a series of electron-deficient olefins, like a , -unsaturated ketones and -nitrostyrene, is catalyzed by Y(OTf)3 to give the corresponding 3-substituted indoles in high yield (eq 5). In this case, Y(OTf)3 was found to be the superior catalyst compared to BiCl3, SbCls, ZnCl2, LaCls, AICI3, and La(OTf)3. 

Fig. 8.25 Examples of the Michael-type reaction of silyl enol ethers with a -unsaturated carbonyl compounds catalyzed by lnCl3.

As well as the traditional benzoin and Stetter reactions, some new synthetic transformations were disclosed via carbene catalysis. In 2007, the Scheldt group developed an intramolecular Michael-type reaction with unsaturated substrates 56 through catalysis with chiral triazolium salt 55. The intermediates 57 were generated via a domino Michael addition/lactonization sequence, and bicyclic products 58 were afforded in satisfactory yields and with excellent enantioselectivity after... 

In the reaction of Q,/3-unsaturated ketones and esters, sometimes simple Michael-type addition (insertion and hydrogenolysis, or hydroarylation, and hydroalkenylation) of alkenes is observed[53,54]. For example, a simple addition product 56 to methyl vinyl ketone was obtained by the reaction of the heteroaromatic iodide 55[S5]. The corresponding bromide affords the usual insertion-elimination product. Saturated ketones are obtained cleanly by hydroarylation of o,/3l-unsaturated ketones with aryl halides in the presence of sodium formate, which hydrogenolyses the R—Pd—I intermediate to R— Pd—H[56]. Intramolecular hydroarylation is a useful reaction. The diiodide 57 reacts smoothly with sodium formate to give a model compound for the afla-toxin 58. (see Section 1.1.6)[57]. Use of triethylammonium formate and BU4NCI gives better results. 

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