Bifunctional catalysts squaramide

In 2011, Wu and co-workers [118] designed and synthesized a new bifunctional catalyst 66 that is comprised of phosphine and squaramide units and fliat efficiently promoted the asymmetric intramolecular BH reaction in modest to good yields with good to excellent enantioselectivities (Scheme 9.33). 

Nitrocyclopropanation of a,p-unsaturated ketones 16usingbromonitromethaneas an ambiphilic substrate in the presence of organocatalysts E-I allows the preparation of several interesting trisubstituted cyclopropanes 17 in high levels of both diastereo and enantioselectivities. A general scheme compiling selected recent achievements on this purpose is depicted in Scheme 5.7. Chiral primary [25] and secondary [26, 27] amines as well as thiourea [28] and squaramide [29] derivatives E-I (all of them as bifunctional catalysts) were capable of catalyzing the transformation. 

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. 

The extension of the thiourea-tertiary amine concept to the cinchona alkaloids was reported by several groups independently in 2005. The general usefulness of cinchona alkaloids as bifunctional catalysts was recognized by several groups even before this date [9]. The focus herein is on (thio)urea and squaramide catalysts since they are prototypes of more efficient catalysts. The Chen and the Dixon groups screened cinchonine and cinchonidine-derived thiourea catalysts for conjugate... 

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). 

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. 

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. 

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). ... 

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... 

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. 

Bifunctional squaramide-derived chiral catalysts have promoted the addition of cyclic diketones to /0,y-unsaturated a-ketoenols with ee < 99% (Scheme 25). " (S)... 

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... 

Addition of CH2(CN)2 to -substituted 2-enoylpyridines RCH=CHCO(2-Py), catalysed by the cinchona alkaloid-based bifunctional ureas, such as (345) (10mol%), has been reported to proceed with <97% ee in m-xylene at room temperature. Squaramide (346) proved to be even more efficient for the addition of the same nucleophile to enones R CH=CHCOR, which required only 0.5 mol% catalyst loading to attain <96% ee (in CHCI3 at room temperature), ... 

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