Michael thiourea catalysts

This bifunctionnal amino-thiourea organocatalyst led to high selectivity because it was activating both the nitrone and the malonate, in its enol form, due to the acidic hydrogen atoms of the thiourea. Thus, the amino-thiourea catalyst promoted the Michael reaction of malonates to various nitroolefins... 

Scheme 6 Enantioselective Michael-addition of acetylacetone to nitrostyrene catalyzed by a bifunctional thiourea catalyst...

Papai et al. selected as model reaction the addition of 2,4-pentanedione (acetylacetone) to trans-(R)-mtrostyvQnQ, catalyzed by the bifunctional thiourea catalyst shown in Scheme 6 [46]. The analogous Michael-addition involving dimethyl malonate and nitroethylene as substrates, and a simplified catalyst was calculated at the same level of theory by Liu et al. [47]. Himo et al. performed a density functional study on the related cinchona-thiouTQa catalyzed Henry-reaction between nitromethane and benzaldehyde [48]. 

Dicarbonyl donors are excellent Michael donors in asymmetric conjugate addition to a,p-nnsatnrated ketones. Wang and co-workers [79] applied chiral Cinchona-thiourea catalyst 131 to various carbon donors in the addition to aromatic enones. A diverse array of nucleophiles, mainly 1,3-dicarbonyls proceeded smoothly in the conjugate addition to a,p-unsaturated enone 132 (Scheme 29). 

Sods [80] reported novel thiourea catalyst 134 in an efficient Michael reaction between nitromethane and chalcones to access chiral nitrocarbonyls in high enan-tioselectivity (Scheme 30). 

Following work on Michael addition of triazoles to nitro-olefins (discussed in Sect. 2.5), bifunctional chiral thiourea catalysts were used in the addition of triazoles to chalcones [83]. The catalytic system was applicable to enones bearing aromatic groups of varying electronic natures to provide good yields and moderate selectivity. a-Cyanoacetates [84] were also applied in Michael addition to chalcones under similar catalytic conditions (Scheme 33). 

The scope of Michael additions with catalysts containing cyclohexane-diamine scaffolds was broadened by Li and co-workers [95]. When screening for a catalyst for the addition of phenylthiol to a,p-nnsatnrated imides, the anthors fonnd that thiourea catalyst 170 provided optimal enantioselectivities when compared to Cinchon alkaloids derivatives (Scheme 41). Electrophile scope inclnded both cyclic and acyclic substrates. Li attributed the enantioselectivity to activation of the diketone electrophiles via hydrogen-bonding to the thiourea, with simultaneous deprotonation of the thiol by the tertiary amine moiety of the diamine (170a and 170b). Based on the observed selectivity, the anthors hypothesized that the snbstrate-catalyst... 

The modification of thiourea catalyst 93 through incorporation of the (S,S)-diaminocyclohexane backbone as an additional chirality element and a Schiff base imidazoyl-moiety led to the bifunctional catalyst 94 that, in contrast to 93 in the Strecker reaction (Scheme 6.99), exhibited enantioinduction (83-87% ee) in the nitro-Michael addition of acetone to trons-P-nitrostyrenes. The desired adducts were isolated in moderate yields (46-62%) as depicted in Scheme 6.100) [259]. 

In the presence of thiourea catalyst 122, the authors converted various (hetero) aromatic and aliphatic trons-P-nitroalkenes with dimethyl malonate to the desired (S)-configured Michael adducts 1-8. The reaction occurred at low 122-loading (2-5 mol%) in toluene at -20 to 20 °C and furnished very good yields (88-95%) and ee values (75-99%) for the respective products (Scheme 6.120). The dependency of the catalytic efficiency and selectivity on both the presence of the (thio) urea functionality and the relative stereochemistry at the key stereogenic centers C8/C9 suggested bifunctional catalysis, that is, a quinuclidine-moiety-assisted generation of the deprotonated malonate nucleophile and its asymmetric addition to the (thio)urea-bound nitroalkene Michael acceptor [279]. 

Figure 6.47 Various thiourea catalysts screened in the Michael addition of O-benzylhydroxylamine to 2,4-dimethyl pyrazole crotonate.

Thiourea catalyst 139 was also screened in the asymmetric Friedel-Crafts reaction between 2-naphthol trans-nitrostyrene (73% yield 0% ee 18 h in toluene at -20 °C and 10 mol%) [277], in the asymmetric aza-Michael reaction of O-benzyl-hydroxylamine to chalcone (72% conv. 19% ee 72 h in toluene at 20 °C and 20mol% catalyst loading) [293], and in the asymmetric Morita-BayUs-HiUman [176, 177] reaction between cyclohexenecarbaldehyde and 2-cyclohexene-l-one (20% yield 31% ee 46 h at rt and 20mol% DABCO and 139) [310]. In aU these transformations, thiourea 139 proved to be not competitive to the organocatalysts probed for these transformations under identical screening conditions and thus was not employed in the optimized protocols. 

Almost simultaneously, the Wang group pubUshed an additional application of binaphthyl thiourea catalyst 148 [314]. Asymmetric Michael reactions [149-152] of... 

Scheme 6.157 Mechanistic proposal for the biflinctional coordination and simultaneous activation of 2,4-pentandione and trans-P-nitrostyrene through thiourea catalyst 148 leading to chiral Michael adducts.

Chen and co-workers later reported the successful asymmetric 1,4-addition of aryl thiols to a,/ -unsaturated cyclic enones and imides using Takemoto s elegantly simple catalyst (3) [43]. This bifunctional amine-thiourea catalyst gives optimal reactivity and reproducibility when used at 10 mol% loading in the presence of freshly dried 4 A molecular sieves (MS). This combination afforded the expected addition products in high yields (90-99%) and moderate to good enantioselectiv-ities (55-85% ee) for a variety of cyclic and acyclic Michael acceptors (Table 6.2). 

Disubstituted thiochroman-4-ols are formed with excellent enantio- and diastereo-selectivity when thiosalicylaldehydes react with an a,P-unsaturated oxazolidinone in the presence of a chiral bifunctional amine-thiourea catalyst. A tandem Michael - aldol process is involved (Scheme 43) <07JA1036>. 

In 2005, Chen and coworkers found that the epi-cinchonidine/cinchonine-derived thiourea catalysts, 79a,b, can serve as highly active promoters of the Michael addition ofthiophenol to the a,P-unsaturated imide 80 however, the reaction proceeded with low enantioselectivity (up to 17% ee) (Scheme 9.28) [22]. 

In 2006, Wang and coworkers reported the asymmetric Michael addition of a broad spectrum of nucleophiles to chalcones (25) using the thiourea catalyst 81a [24],... 

Wang and coworkers found that the quinine-derived thiourea catalyst 81b (1 mol%) was also highly reactive and enantioselective for the tandem thio-Michael-aldol reaction of various 2-mercaptobenzaldehydes (103) with a,P-unsaturated oxazolidi-nones (104), furnishing benzothiopyranes (105) with three stereogenic centers in... 

Soon afterward, various types of carbon [40-44], oxygen [45], and phosphorous [46] Michael donors were successfully employed in the thiourea-catalyzed addition to nitroalkenes. In the presence of the bifunctional epi-9-amino-9-deoxy cinchonine-based thiourea catalyst 79a, the 5-aryl-l,3-dioxolan-4-ones 138 bearing an acidic a-proton derived from mandelic acid derivatives and hexafluoroacetone were identified by Dixon and coworkers as effective pronucleophiles in diastereo- and enantioselective Michael addition reactions to nitrostyrenes 124 [40]. While the diastereoselectivity obtained exceeded 98%, the enantiomeric excess recorded... 

The use of naphthols 145 as the carbon nucleophilic readion component in Friedel-Crafts type Michael addition readions was also reported in 2007 by Chen and coworkers [43], In this system, the pronucleophile is activated by the quinuclidine unit of bifundional cinchona-based thiourea catalysts such as 81a. A range of aryl-and alkyl-substituted nitroalkene derivatives 124 were applicable to this system. The corresponding adducts 146 were obtained with 85-95% ee at low temperature... 

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). 

The bifunctional thiourea catalyst 16 was developed by Takemoto and co-workers in 2003 [61, 62], The Michael reaction of diethyl malonate with nitroalkenes proceeded with excellent enantioselectivities (Equation 10.31). 

A more simple thiourea catalyst with amino functionality catalyses the asymmetric Michael addition of 1,3-dicarbonyl compound to nitroolefin [29,30]. In the reaction of malonate to nitrostyrene (Table 9.11) the adduct is satisfactorily obtained when A-[3,5-bis(trifluor-omethyl)phenyl]-A -(2-dimethylaminocyclohexyl)thiourea is used as a catalyst (ran 1), whereas the reaction proceeds slowly when the 2-amino group is lacking (ran2). In addition, chiral amine without a thiourea moiety gives a poor yield and enantioselectivity of the product (run 3). These facts clearly show that both thiourea and amino functionalities are necessary for rate acceleration and asymmetric induction, suggesting that the catalyst simultaneously activates substrate and nucleophile as a bifunctional catalyst. 

Thiourea catalyst with a modified cinchona alkaloid unit is applied to intramolecular Michael addition of phenol chiral chromanone is produced in high yield with good... 

Scheme 2.9 Enantioselective Michael reactions of ketones with nitrost5renes catalyzed by primary amine-thiourea catalysts.

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