Squaramide catalysts Michael addition

The enantioselective Michael addition of nitroalkanes to enones provides an attractive synthetic route towards chiral pyrrolidines, y-lactams, and y-amino acids. Du and coworkers have developed a squaramide-catalyzed Michael addition reaction of nitroalkanes to chalcones (Scheme 10.20) [98]. The authors noted that electron-withdrawing substituents on the aryl portion of squaramide enhanced the activity of the catalyst owing to the increased acidity of the squaramide N-H. Interestingly, the yield and enantioselectivity both increased when the reaction was performed at an elevated temperature. The reactions between nitromethane and various chalcones afforded the Michael adducts in high yields and high enantioselectivities at 80 °C. Varying the substituents on chalcones showed some effect on... 

Xn et al. have carried ont asymmetric Michael addition reaction in ball mill using squaramide catalyst (Scheme 2.32) [23]. Optimal reaction conditions in planetary ball mill feature milling of 1,3-diones 83 and aryl styrenes in the presence of the cinchona-derived squaramide catalyst CA (5mol%). In these conditions, high yields... 

Squaramide (244) with two quinine-derived units has been developed as a catalyst (2mol%) for Michael addition of nitroalkanes RCH2NO2 (R=Me, Et) to R CH=CHN02 (R = aryl, alkyl, heteroaryl), which occurs in CH2CI2 at —20 °C with <95 5 dr and 97% ee ... 

Polysubstituted 3,4-dihydro-3-nitro-2ff-chromans are obtained from the enantioselective Michael—Michael cascade reaction of chalcone enolates and nitromethane catalyzed by bifunctional thiourea 19 (Scheme 31) (13JOC6488) and tandem Friedel—Crafts alkylation—Michael addition reaction of nitroolefin enoates and 1-methylindole promoted by Zn(OTf)2 (13S601).A squaramide-tertiary amine catalyst promotes the asymmetric sulfa-Michael—Michael cascade reaction of thiosalicylates with nitroalkene enoates which leads to polysubstituted chromans in high yields with excellent stereoselectivities (13OL1190). 

A new class of chiral squaramides give de/ee up to 98/99% as catalysts for Michael addition of nitroolefins to 1,3-dicarbonyls. ... 

The rather complex BINOL-quinine-squaramide (393) has been reported as an optimal catalyst for the Michael addition / -dicarbonyls to nitroalkenes, attaining <99%... 

Subsequently, several groups have studied related squaramide-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes. High enantioselectivities have been achieved using pyrrolidine-cinchonine-squaramide catalyst 14 [81], quinine-squaramide catalyst 15 [82, 83], and Cs-symmetrical cinchonine-squaramide catalyst 16 (Figure 10.4) [84]. Notably, the reaction time... 

Figure 10.4 Squaramide catalysts used for Michael additions to nitroalkenes.

Dong and coworkers have developed a pyrrolidine-cinchonine-squaramide catalyst for enantioselective Michael addition of ketones to nitroalkenes (Scheme 10.16) [81]. The assembly of two privileged chiral motifs, pyrrolidine and cinchonine, with a squaramide core enabled the catalyst in promoting the addition of both cyclohexanone and 1,3-diketones to aryl-substituted nitroalkenes, providing the corresponding products in modest to high diastereo- and enantioselectivities. The authors pointed out that the match between the chiralities of pyrrolidine and cinchonine is important for the high enantioselectivity. 

Enantioselective Michael reactions of thiols provide a convenient route to diverse chiral sulfides. Chen and coworkers have demonstrated that a chiral squaramide catalyst was effective in promoting a sulfa-Michael conjugated addition of various aromatic and aliphatic thiols to a wide range of trans-chalcones (Scheme 10.19) [97]. Moderate to excellent yields and enantioselectivities were achieved. Notably, the reactions between various benzylthiol and trans-chalcones bearing electron-donating or electron-withdrawing substituents proceeded with high enantioselectivities. 

A chiral quinine-derived squaramide catalysed the highly enantioselective Michael addition of malononitrile to chalcones. The reactions take place at a very low catalyst loading (0.5 mol%) and provide the Michael adducts with high yields and good enan-tioselectivities (up to 96% ee). Chiral bifunctional squaramides have also been used as multiple hydrogen-bond donor-acceptor organocatalysts for the asymmetric Michael addition of nitroolefins to 1,3-dicarbonyl compounds. ... 

The bifunctional squaramide (343) has been found to catalyse Michael addition of cyclic -diketones (e.g. dimedone) to / ,y-unsaturated a-keto esters with <99% ee at 2.5 mol% catalyst loading. The reaction model (344) has been proposed to rationalize the enantioselectivity. i... 

The first report on the development and use of chiral squaramide derivatives as hydrogen-bond donor catalysts appeared in 2008 by Rawal and coworkers [78]. The authors showcased the usefulness of this new scaffold by evaluating the Michael addition of 1,3-dicarbonyl compounds to nitroalkenes, the same reaction that was used to illustrate the capabihty of a thiourea catalyst by Takemoto [45]. Of the catalysts examined, the cinchonine-derived squaramide 13 functioned well as a bifunctional catalyst and provided the conjugate addition product in high yield and excellent enantioselectivity (Scheme 10.12). Less reactive substrates such as a-substituted 1,3-dicarbonyl compounds also participate in the desired reaction. 

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