Squaramides addition with

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 ... 

Song and coworkers compared the squaramide 31 with the sulfonamide 28 and the related C9 thiourea derivative as catalyst for the conjugate addition of 1,3-dicarbonyls to [i-nitroalkenes in brine [89] and the conjugate addition of malonic acid half thioester to various nitro alkenes [90]. In the latter reaction (Scheme 6.41), 31 afforded the best results with respect to enantioselectivity that is, the ee was 93% for 31 but only 63% for thiourea and 23% for the sulfonamide analog. 

The addition of diphenyl phosphite to ketimines derived from isatin was attempted using several Cinchona derived organocatalysts. The best results were achieved with a quinine-derived bifunctional squaramide (Q-SQ 1),... 

Chalchones were recently also used as substrates for addition of indolines catalysed by quinine-derived squaramides and for addition of pyrazole catalysed by 9-epi-QA in combination with l-hydro)y-2-naphthoic acid additive. 

The addition of thioacetic acid to tra 5-chalcones furnished only moderate enantioselectivity (33-65% ee with Takemoto s catalyst 11) [33]. Better results were obtained by the Chen group, with various thiols employing quinine-derived squaramide 13 [34]. It is worth noting that, in this case, substituted benzyl thiols, furfuryl thiol, and aliphatic thiols were better donors than thiophenol (Scheme 14.6). 

An enantioselective sulfa-Michael addition of thiols to a,y3-unsaturated A-acylated oxazolidinones, catalysed the quinine-derived squaramide (134), has been reported to afford the corresponding products with <99% ee °... 

Squaramides offer yet another variant of the bis-NH proton donor with different geometry compared to thioureas and their congeners. Thus, the quinine-derived squaramide (238b) can catalyse Michael addition of -dicarbonyls to ArCH=CHN02. Here, brine has been found to provide remarkable rate acceleration and a higher level of stereoselectivity (>98% ee) over organic solvents, presumably because of the hydrophobic hydration effect. ... 

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 Michael addition of a-substituted isocyanoacetates ArCH(NC)C02R A-aryl maleimides, catalysed by the cyclohexane-1,2-diamine-derived squaramide (293), afforded adducts (294) with <91% ee and >20 1 dr. Enantiomers of (293) (with <94% ee) were obtained in the same reaction catalysed by the quinine-derived squaramide (283b).252... 

Squaramide (283b) has also been shown to catalyse the vinylogous Michael addition of the A-Boc-protected a,/ -unsaturated y-butyrolactam to ArCH=CHCOCCl3, producing (295) with <93% ee and up to <24 1... 

The bifunctional squaramide (304), in combination with AcOH, enabled the catalytic formation of tra i-2,3-disubstituted dihydrobenzofurans (303) from keto-enones (302) with up to >99% ee and <97 3 dr via an intramolecular Michael addition. ... 

Squaramide (386), as a close analogue of Takemoto s thiourea, has been shown to catalyse the Michael addition of Meldrum s acid to nitroalkenes RCH=CHN02 with <94% ee Squaramide (283b), cited earlier, has also been successful in the vinylogous... 

A one-pot approach to the 0- and A-heterocycles (392) (X = O, NCOPh, NTs) has been developed, starting with the Michael addition of malonate to the o-substituted / -nitrostyrenes (390), catalysed by the quinine-derived squaramide (283c). The... 

In 2003, Rawal reported the use of TADDOLs 177 as chiral H-bonding catalysts to facilitate highly enantioselec-tive hetero-Diels-Alder reactions between dienes 181 and different aldehydes 86 (Scheme 6.29A) [82], and also BINOL-based catalysts 178 were found to facilitate this reaction with excellent selectivities [83]. TADDOLs were also successfully used as organocatalysts for other asymmetric transformations like Mukaiyama aldol reactions, nitroso aldol reactions, or Strecker reactions to mention a few examples only [84]. In addition, also BINOL derivatives have been employed as efficient chiral H-bonding activators as exemplified in the Morita-Baylis-Hilhnan reaction of enone 184 with different carbaldehydes 86 [85]. The use of chiral squaramides for asymmetric reactions dates back to 2005 when Xie et al. first used camphor-derived squaric amino alcohols as ligands in borane reductions [86]. The first truly organocatalytic application was described by Rawal et al. in 2008 who found that minute amounts of the bifunctional cinchona alkaloid-based squaramide 180 are... 

Rawal and coworkers prepared a squaramide derivative of cinchonine (30) and proved this cinchona alkaloid analog to be an efficient catalyst for the conjugate addition of 2,4-pentadione to P-nitrostyrene [59] (Scheme 6.39). With sub-shtuted 2,4-pentadiones, the diastereoselectivity was low, except for the methyl ester of 2-oxocyclopentanecarboxylic acid, which gave rise to a raho of 50 1 for the diastereoisomers. 

The C9 squaramide derivatives of quinine (31) and quinidine have also been prepared and shown to catalyze the addition of nitromethane to chalcones (Scheme 6.40). Catalysts with a 3,5-(CF3)2C,5H3 group attached to the second nitrogen performed slightly better than if a 4-CF3C5H4 or 4-FC5H4 group was present [87]. 

Comparable results were obtained for asymmetric conjugate addition of aromatic and aliphatic thiols to chalcones [88]. For this reaction it was also observed that 31 was a more suitable catalyst than derivatives with, for example, a 4-CH3OQH4, a 3,5-(CH3)2QH3, or a cydohexyl group, which is in line with the expectation that the acidity of the squaramide N-H groups is related to the stereoselectivity and yield of the catalytic reaction. 

A Study by Xu and coworkers examined a series of cinchona alkaloid derivatives with a benzyl or 1-phenylethyl group at the second nitrogen atom of the squaramide moiety [91]. The catalyst with 1-phenylethyl group and a C6 methoxy group (32) gave the highest yield and enantioselectivity for the conjugate addition of 4-hydroxycoumarins to a-keto esters (Scheme 6.42). 

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. 

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