Michael squaramides

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... 

Scheme 15.27 Highly enantioselective intramolecular oxa-Michael reaction of alkojg boronate employing squaramide eatalyst.

SCHEME 14.6. Sulfa-Michael addition to tra/M-chalcones catalyzed by squaramide 13. 

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 °... 

The cinchona alkaloid-derived thioureas (237a,b) and their squaramide counterparts (238a,b) have been employed to catalyse the Michael addition of a-alkyl and of-phenylselenenyl ketones R CH(X)COR (X=alkyl, SePh) and the corresponding... 

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. ... 

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 squaramide-tertiary amine catalyst is used in the oxa-Michael-Michael cascade reaction of N-protected 3-methyleneindolin-2-ones with 2- E) (2-nitrovinyl)phenols to give spiro-indolinone chromans, with high stereoselectivity (Scheme 35) (13OL4062). 

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. 

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

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 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... 

In a similar way, spirooxindole tetrahydroquinolines (301) were prepared in 94% ee and >25 1 dr via the aza-Michael-Michael domino addition of tosylamide (299) to oxindoles (300), catalysed by the quinine-derived squaramide (283c).2 ... 

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... 

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

In 2012, Maikov and coworkers reported a similar strategy for the synthesis of spirocyclopropanes bearing two quaternary centers. In this approach, 2-chloroacetoacetates (49) reacted with 17c via a Michael/a-alkylation domino reaction (Scheme 10.16) [22]. The reaction was catalyzed by bifunctional Brpnsted Acid-Lewis base X. The final spirocyclopropanes 50 were obtained under optimized conditions in good yields and excellent diastereo and enantioselectivities. A similar approach was developed by the same research group using 3-chlorooxindoles (51) instead of 2-chloroacetoacetates [23]. This time, the catalyst was a bifiinctional squaramide-tertiary amine XI derived from cinchona alkaloids, rendering the final spirocyclopropanes 52 in good yields and excellent enantioselectivities. 

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 addihon of 1,3-dicarbonyl compounds to nitroalkenes, the same reaction that was used to illustrate the capabilily 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 enanhoselectivity (Scheme 10.12). Less reactive substrates such as a-substituted 1,3-dicarbonyl compounds also participate in the desired reaction. 

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. 

Kim and coworkers have developed a binaphthyl-modified chiral squaramide (20) bearing both central and axial chiralities [89]. The Michael addition of anthrone to nitroalkenes catalyzed by squaramide 20 afforded the products in high yield and good enantioselectivity (Scheme 10.17). Notably, the reaction at lower temperature (0 °C) resulted in a reduced enantioselectivily. This transformation has also been shown to be catalyzed by cinchona alkaloid and thiourea derivatives [90-92]. 

Du and coworkers have developed a stereoselective direct Michael addition of nitroalkanes to nitroalkenes catalyzed by quinine-derived dimeric squaramide 21 [93]. This transformation provided facile access to 1,3-dinitro compounds in high diastereo- and enantioselectivities starting from aryl-substituted nitroalkenes (Scheme 10.18). However, the use of an aliphatic nitroalkene as Michael acceptor resulted in a low yield and diminished enantioselectivity. While nitroethane and 1-nitropropane are excellent substrates, branched 2-nitropropane did not undergo the Michael addition reaction. The authors also noted that slightly reduced dias-... 

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. 

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... 

Scheme 10.23 Enantioselective Michael reactions catalyzed by squaramide 25.

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