Catalysts squaramide

As described above, cinchona-based (thio)ureas have proven to be highly efficient H-bond donor catalysts. In 2008, Rawal and coworkers developed a highly promising new family of cinchona-based H-bond donor catalysts such as 157 by replacing the thiourea moiety of cinchona-based thiourea catalysts with the squaramide unit [47]. The squaramide moiety of 157 is able to form two H-bonds to a reactant due to the more accessible reaction site and fixed syn-orientation of the NH-protons. Using only 0.5 mol% of the cinchonine-derived squaramide catalyst 157, various Michael donors 158 and nitroalkenes 130 were smoothly converted to the desired adducts 159 in excellent yield and ee values (up to 99% ee) (Scheme 9.54). 

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... 

The group of Aleman and Parra reported the AFC reaction of phenol with Z-bromonitroalkene followed by a nucleophilic substitution on the bromide carbon. With 10 mol% of squaramide catalyst 157, the chiral trans-dihydroarylfuran derivatives 158 were efficiently synthesized from Z-bromonitroalkene and naphthol or phenol derivatives with moderate to good yields (28-94%) and excellent enantioselectivity (66-98% ee). The key of this eat-alytic system is the neutralization of the generated HBr by a stoichiometrie eo-base (Scheme 6.73). 

Scheme 15.32 CincAona-squaramide catalysts in cascade reactions with dithiane dithiol.

Similar chemical outcome was also obtained through the use of an emerging class of bielectro-philic synthons (Z)-bromonitroalkenes 51b. In particular, it was envisioned that Michael-type FCA followed by the nucleophilic substitution of the bromine atom by the hydroxy naphthol group could provide chiral tranj-dihydroarylfuran derivatives 60 directly [31], Extensive survey of reaction conditions led the authors to optimize the catalytic system with the squaramide catalyst 59 (10mol%) and an external base (i.e., NaOAc) in order to neutralize the stoichiometric amount of HBr delivered by the catalytic cycle (Scheme 5.18). Unfortunately, the method appeared limited to naphthols. As a matter of fact, when substituted phenols were tested, the cascade process became sluggish despite still good stereochemical profiles were recorded. 

Keto-enone (106) undergoes an intramolecular Michael reaction, giving the pharmaceutically valuable frani-dihydrobenzofuran skeleton (107). Using a bifunctional primary amine-squaramide catalyst, yielAldelee of up to 98/94/>99% have been achieved. 

A bifunctional squaramide catalyst (460) has been utilised in the efficient and highly regio- and stereoselective synthesis of optically active dihydropyran phosphonates (457) by dual activation of both substrates used in the reaction. Thus, the hetero-Diels-Alder reaction of aliphatic and aromatic a,p-unsaturated acyl phosphonates (455) and a,(3-unsaturated aldehydes (456) afforded dihydropyran derivatives (457) in good yields ranging from 52% to 84% and up to 92% ee. The potential of the reaction has been also demonstrated by transformation of the products (457) into valuable and complex synthons (458) and (459) bearing five stereogenic centers (Scheme 138). ... 

The low catalyst loading (as low as 0.1mol%) demonstrated the remarkably high catalytic activity of squaramide catalyst 13. This work estabhshed the squaramide unit as an effective scaffold on which to build chiral H-bond donor catalysts. 

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. 

In an effort to demonstrate a different facet of squaramide s capability, Zhao and Rawal et al. have successfully developed a squaramide-catalyzed enantioselective Friedel-Crafts reaction of indoles with imines (Scheme 10.27) [105]. To overcome the slow reaction rate at room temperature, the authors performed the reactions at an elevated temperature. Notably, the reaction at 50 °C afforded the desired product in much improved yield with only a slight decrease in enantioselectivity. Using 2.5 mol% cyclohexanediamine-derived squaramide catalyst 27, the reactions between various indoles and a diverse range of N-arylsulfonyl imines of both electron-rich and electron-deficient aromatic as well as aliphatic aldehydes proceeded with high yield and high enantioselectivity. This transformation represents an efficient synthesis of enantioenriched indolyl-sulfonamides. 

Considering that the a-proton-exchange of racemic azlactones occurred rapidly in the presence of a tertiary amine base. Song and coworkers demonstrated enan-tioselective synthesis of a-deuterated a-amino acids via dynamic kinetic resolution (DKR) of azlactones with EtOD using cinchona-derived dimeric squaramide catalyst 33 (Scheme 10.34) [112]. The authors noted that by increasing the amount of EtOD, the level of deuterium incorporation increased, whereas the enantioselectivity decreased. By using 50 equivalents of EtOD, the products were obtained with... 

Song and coworkers further utilized squaramide 33 for methanolytic desym-metrization of meso-glutaric anhydrides (Scheme 10.35) [113, 114]. The authors attributed the high enantioselectivity to the fact that the cinchona-derived dimeric squaramide catalyst does not self-associate. The catalyst can be easily recovered from the reaction mixture after extractive acid/base work up. A thiourea-catalyzed version of this process had been reported by the same authors in 2008 [115]. 

The examples presented in this section have demonstrated the extensive capability of squaramide to function as an effechve activation unit for hydrogen-bond donor catalysis. While clearly resembling its well-established urea and thiourea counterparts, squaramide catalysts clearly perform differently in terms of the cata-... 

Dai L, Wang S, Chen F. A bifunctional cinchona alkaloid-squaramide catalyst for the highly enantioselective addition of thiols to trans-chalcones. Adv. Synth. Catal. 2010 352 2137-2141. 

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