Cinchonine derived thioureas

Dixon et al. screened cinchonine-derived thioureas 117-120 for their performance in the dimethyl malonate Michael addition to tra s-(5-nitrostyrene in dichlo-romethane at room temperature and at -20°C [274]. As shown in Figure 6.38, all candidates revealed comparable activity, but monodentate hydrogen-bond donor 118 exhibited very low asymmetric induction producing the desired Michael... 

Scheme 6.112 Michael addition of thiophenol to an a,p-unsaturated imide catalyzed by cinchonidine-derived thiourea 116 and cinchonine-derived thiourea 117, the first representatives of this class of bifunctional hydrogen-bonding cinchona alkaloid-thioureas.

Figure 6.38 Cinchonine-derived thioureas (10mol% loading) screened in the Michael reaction of dimethyl malonate to trans- 3-nitrostyrene.

Dixon and co-workers independently reported the asymmetric hydrogenbonding catalyzed 1,4-additions of dimethyl malonate to nitroolefins using a cinchonine-derived thiourea catalyst 30 [54]. Catalyst 30 gave good to high yields (81-99%) and good to high enantioselectivities (82-97% ee) for a variety of aromatic, heteroaromatic and aliphatic nitroolefins (Scheme 6.4). Optical purity... 

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]. 

Therefore, under the optimized conditions, 9-ep -dihydroquinine-derived thiourea 71a performed very well in the Michael reaction of diethyl malonate with nitroalkenes, furnishing the final compounds with enantioselectivities around 90% ee (Scheme 4.8). Remarkably, this catalyst also seemed to tolerate the use of (3-alkyl substituted nitroalkenes as substrates, furnishing the expected final compounds with only a small decrease in enantioselectivity, although only a few examples were studied in that case. In an independent work, 9-e i-cinchonine-derived thiourea 72b was also reported to be a very efficient catalyst for this reaction, obtaining the final Michael adducts in... 

On the other hand, 2-naphthols have been used with different success as Michael donors in conjugate Friedel Crafts reactions with nitroalkenes and related substrates (Scheme 4.53). For example, cinchonine-derived thiourea 72b was identified as an excellent promoter for the reaction of a wide variety of 2-naphthols and nitroolefins, providing excellent yields and enantioselectivities. Remarkably, the more challenging p-alkyl substituted nitroalkenes were also found to undergo the reaction in a highly stereoselective way and with comparable yields to those obtained when nitrostyrene derivatives were employed. 

A strategy for the desymmetrization of cyclohexadienones via asymmetric aza-Michael reaction using cinchonine-derived thiourea 52 was developed by You s group (Scheme 11.33) [113]. A series of highly enantioenriched bicyclic pyrrolidine and morpholine derivatives were obtained in excellent yields and enantioselectivities. 

A vinylogous Michael addition of Q, j0-unsaturated y-butyrolactams (175) to a,p-unsaturated ketones has been shown to produce (176) (>30 1 dr, <99% ee) when catalysed by the triamine derivative (177). Catalysis by the cinchonine-derived thiourea (166b) afforded its diastereoisomer (>40 1 dr, <99% ee) ... 

Michael addition of thioacetic acid to a series of a-substituted (V-acryloyloxazolidin-2-ones, followed by enantioselective protonation, catalysed by the cinchonidine-derived thiourea (288a), has been reported to proceed with <97% ee The pseudo-enantiomeric, cinchonine-derived thiourea (289a) can catalyse the Michael addition of dimedone to enone RCH=CHCO( -Py) with <98% ee The isosteviol-derived thiourea (290) represents yet another variation this organocatalyst has been reported to facilitate the Michael addition of a-substituted cyanoacetates NCCH(Ar)C02R and maleimides in toluene at -30 °C (with <93% ee and <98 2 dr) as a method for the construction of quaternary chiral centres " ... 

Another pioneering study [16] by the Dixon group, published in 2006, involved the addition of malonates to carbamate-protected imines (Scheme 6.6). Using the cinchonine-derived thiourea catalyst 32, the Mannich-type products were obtained in good to excellent enantioselectivity and good yields. 

Scheme 6.6 Chiral Mannich adducts are obtained with the cinchonine-derived thiourea catalyst 32 from dimethyl malonate and A -Boc as well as A -Cbz aldimines...

Recently, Chen and coworkers demonstrated that the cinchonine- or cinchonidine-derived thioureas, 63 and 66, respectively, were also able to catalyze the enantioselective... 

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... 

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 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... 

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