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). 

Fig. 1.P23. Molecular interaction potential maps for planar (left) and twisted (right)conformations of formamide, 3-aminoacrolein and squaramide.

Prohens and co-workers have synthesized compounds 8a and 8b, simple squaramido-based receptors and investigated their ability to coordinate car-boxylate anion in competitive solvents [16]. The amide NH groups of the squaramide form a more open cleft (similar to ureas) than the isophthala-mides. Receptors 8a and 8b therefore adopt a more suitable geometry for the coordination of bidentate anions, such as carboxylate anions, through two approximately linear hydrogen bonds. Proton NMR titration experiments revealed association constants of 217 M and 1980 for the binding of acetate by 8a and 8b respectively in DMSO-de at 295 K. 

Costa and co-workers have reported 80, a fluorescent squaramide-containing macrocyclic receptor for monitoring sulfate in water [97]. Isothermal titration calorimetry was employed to characterize the host-guest association of 80 with S04 , PhOPOs " and 204 dianions (titration carried out in methanol at 294 K). The data was fitted to a 1 1 binding model and it was foimd that 80 boimd S04 (4.6 1.0 x 10 M ) with the... 

In a different approach to carboxylate coniplexation, squaramide (i.e., 3,4-diamino-cyclobutene-1,2-dione) derivatives have been used by Prohens et al. as selective receptors (Fig. Ih). These receptors possess a parallel ditopic hydrogen bond donor array (c.f. urea) that show good to moderate association constants with acetate anions. A variety of mono-, di-. and tritopic receptors were synthesized, including the -squaramide receptor 19 that forms strong complexes with m-carboxylates such as trimesoate and cfs-cyclohexentricarboxylate (i a=3.9 X 1(PM and 7.7 x 10 M . respectively, in 10% DoO/DMSO.)... 

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... 

Several chiral organocatalysts such as chiral squaramide 31, chiral phosphoric acid (S)-32a, and binaphthyl-based chiral sulfonimide (i )-33 have also been successfully applied in the AFC reaction of indoles with N-sulfonyl imines (Scheme 6.14). 

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). 

Optically active trifluoromethyl-substituted tetrahydroimidazo[l, 5-c] quinazoline derivatives 44 were synthesized by Zhao and coworkers via a diastereo- and enantioselective Mannich-type cyclization cascade reaction of a-aryl isocyanoacetates and trifluoromethyl-substituted cyclic ketimines, using a multihydrogen-bonding donor squaramide/AgOAc cooperative catalytic system in THF at 0°C (Scheme 30) (140L4566). The products were obtained in 76—99% yield with a diastereomeric ratio of greater than 15 1 and 58-98% enantiomeric excess. 

The authors reported that the phenoxide anion is a key interaction in the receptor-antagonist interaction that may explain the differences in potency between the two compounds. Compound 35 has a pK of 8.6, compared to a pfQ, of 9.1 for the corresponding urea 34. Interestingly, the squaramide series has generally lower clearance and lower volume of distribution, suggesting higher plasma protein binding. 

Figure 3.19 Comparison of potencies of the urea 34 and the squaramide 35 in a series of CXCR2 antagonists.

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),... 

Scheme 15.4 Hydrophosphonylation of isatine derivatives catalysed hy squaramide.

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. 

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

Briere and coworkers reported an original approaeh to 3-isoxazoline carboiylate derivatives (Seheme 15.28). In a one-pot oxa-Miehael-eyelo-condensation reaction, catalysed by quinine-squaramide Q-SQ 1, IV-proteeted hydrojylamine reacted with unsaturated a-ketoesters to form a eyelie intermediate that by treatment with TFA provided deproteeted 3-isoxazolines. 

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