Michael reactions cinchona alkaloid derivatives

Scheme 19. Asymmetric Michael reaction by use of cinchona alkaloid derivatives.

Anthracenones are another class of C-H acidic compounds suitable to be employed in this reaction (Scheme 4.16) and, in fact, Takemoto s catalyst has been identified as the most efficient catalyst among a series of different thioureas tested, which also included a family of different cinchona alkaloid-derived candidates." The reaction proceeded satisfactorily for a wide variety of aromatic nitroalkenes tested but poorer results were obtained in the case of the p-alkyl substituted Michael acceptors. 

Moreover, as is usually found in most of the asymmetric reactions catalyzed by cinchona alkaloid derivatives, the opposite enantiomer of each diaster-eomeric Michael adduct could also be obtained by simply changing the catalyst to the corresponding pseudoenantiomeric quinidine-based compounds of type 83 or 71. Once again, a model was proposed to account for the observed results, involving a conformationally rigid intermediate in which both the pronucleophile and the electrophile were attached to the catalyst by the formation of multiple H-bonds, explaining the reversal of the diastereoselection by the epimeric nature of C-9 in catalyst 71b with respect to 84c. The stereochemical... 

In this context, there is a relevant example of a newly designed cinchona-alkaloid derived bis-ammonium salt 105 employed as catalyst in the Michael reaction of cyclic p-ketoesters with methyl vinyl ketone (Scheme 5.12). Excellent yields and moderate enantioselectivities of the corresponding Michael adducts were obtained under the best reaction conditions, which also allowed the use of an organic base (Hiinig base) for the deprotonation of the p-ketoester. However, perhaps the most relevant feature associated to the use of this catalyst is the fact that it can be easily separated from the reaction medium by precipitation in ether, which allowed its recycling for further uses without loss of activity. 

The addition of nitroalkanes to chalcones is more attractive since the Michael adducts are useful intermediates for a variety of further elaborated stmctures such as chiral aminocarbonyls, pyrrolidines, y-lactams, and y-amino acids. Thus, many elegant organocatalysts such as cinchona alkaloid-derived chiral tertiary amine thiourea 69 [67] or suqaramide 70 [68] and bisquaternary ammonium salts [69] 71a or 71b have been developed for such a reaction in recent years (Scheme 5.33). In addition, a,(3-unsaturated A -acylpyrroles [70] and 4-oxo-enoates [71] were also applicable in the highly enantioselective conjugated addition with nitroalkanes (Scheme 5.34). 

The Michael-type 5(0) -exo-trig and 6(0)"-cxo-trig cycloetherifications of e-hydroxy-a,/3-unsaturated ketones HO(CH2) CH=CHCOR (n = 3 or 4), catalysed by the bifunctional Cinchona alkaloid-derived thioureas, such as the quinidine derivative (131), have been reported to produce the corresponding a-substituted THFs and tetrahydropyrans, respectively, with <95% ee at room temperature over 24 h at 3mol% catalyst loading. The reaction is believed to proceed via the doubly activated species (132). ... 

Scheme 1.72 Oxa-Michael reactions of y-hydroxy-a,P-unsaturated ketones catalysed by cinchona alkaloid-derived thiourea.

Scheme 2.3 Domino Michael-cyclisation reactions catalysed by a combination of a chiral cinchona alkaloid-derived primary amine and a chiral phosphoric acid.

In 2012, a chiral cinchona alkaloid-derived primary amine was associated by Wang et al. to a (R)-BINOL-derived phosphoric acid to induce a three-component domino Knoevenagel-Michael reaction between isatins, malononitrile, and acetone, providing the corresponding domino products in generally excellent yields and enantioselectivities, as shown in Scheme 2.13. A hypothetic cooperative catalysis can be envisaged to explain these excellent results. 

Cooperative catalysis using cinchona alkaloid derivatives in combination with metals such as silver have also been widely developed. On the basis of this concept, Escolano et al. have disclosed an enantioselective domino Michael-cyclisation reaction. This formal [3 + 2] cycloaddition occurred between isocyanoacetates and enones in the presence of a combination of a chiral hifunctional cinchona alkaloid, such as cupreine, and AgNOs to provide the corresponding chiral 2,3-dihydropyrroles in low to high yields and... 

In 2010, Jorgensen et al. developed an enantioselective tandem reaction of propargylated malononitriles with cyclic enones sequentially catalysed by a cinchona alkaloid-derived primary amine catalyst in the presence of (J )-mandelic acid as an additive for the first Michael step, and a gold catalyst for the second tandem exo-dig cyclisation-isomerisation reaction. " As shown in Scheme 7.62, the corresponding chiral bicyclic enones were achieved in good yields and high enantioselectivities of up to 96% ee, albeit low to moderate diastereoselectivities (34-66% de). 

List and coworkers reported an oxa-Michael reaction with aliphatic acyclic enones 94 using hydrogen peroxide as oxygen source [111]. Treatment of enones with catalytic amounts of cinchona alkaloid derived primary amine 33 (as its salt), followed by excess hydrogen peroxide furnished the intermediate peroxy-hemiketals with high yields and stereoselectivities. Subsequent reduction of these compounds led to the corresponding p-hydroxyketones 124 without loss of enantioselectivity (Scheme 33.36). The same research group developed the asymmetric epoxidation of enones with excellent results [112],... 

In 2010, Singh and coworkers reported the use of cinchona alkaloid derived urea 113 as catalyst for the Michael addition of aromatic thiols to enones [118]. The reaction renders excellent yields and enantioselectivities with aliphatic or cyclic enones, while aromatic enones afford sUghtly worst enantioselectivities (Scheme 33.37). 

In 2007, Scheidt reported an intramolecular oxa-Michael reaction of a-substituted chalcones 114 catalyzed by cinchona alkaloid derived thiourea 113. Chromanones 115 were efficiently produced after an acid-promoted decarboxylation process (Scheme 36.31) [39a]. 

A general procedure for the Michael addition catalyzed hy cinchona alkaloid derivatives. Enone (12.5 mmol) was added dropwise to a solution of QD-h or Q-c (0.05 mmol) and (3-ketoester (5.0 mmol) in CH2CI2 (10.0 mL) at room temperature. The resulting clear solution was stirred at room temperature for 3 hours, when p-ketoester was completely consumed as indicated by TLC analysis. The reaction mixture was concentrated under vacuum and subjected to chromatography (Si02, hexanes/EtOAc 10 1, v/v) to give the desired 1,4-adduct. 

An effective asymmetric synthesis of optically active 1,3-dinitro compounds via the Michael addition of nitroalkanes to nitroalkenes has been described to afford the corresponding adducts with 72 8 dr and up to 94% eeP The catalytic system, a modified cinchona alkaloid derivative (9), performs well with a broad variety of substrates, and the catalyst loading can be decreased to 2 mol% without compromising the asymmetric induction or the reaction rate. 

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