Michael addition thiourea catalysis

The conjugate addition of nitro olefins under chiral Cmc/mna-thiourea catalysis has shown promising results with a variety of Michael donors. Dixon conducted a screen of various chiral thioureas and identified catalyst 117 as a versatile catalyst that works well with p-substituted nitro-olefms (78) [74]. Aromatic, heteroaromatic... 

The Takemoto group synthesized a series ofdiaminocyclohexane-based thiourea derivatives (e.g., 12, 40, 57, and 58) for catalysis of the Michael addition [149-152] ofmalonates to trons-j3-nitrostyrenes (Figure 6.18) [129, 207]. In the model, Michael addition of diethyl malonate to trons-]3-nitrostyrene at room temperature and in toluene as the solvent tertiary amine-functionalized thiourea 12 (10mol% loading) was identified to be the most efficient catalyst in terms of catalytic activity (86%... 

The same group utilized thiourea 12 (10mol% loading) for the catalysis of the enantioselective Michael addition of thioacetic acid to various chalcones [214]. At room temperature and otherwise unchanged conditions, in comparison to the... 

Scheme 6.102 Bifunctional catalysis with primary amine thiourea 99 Proposed transition states to explain the onfi-diastereoselectivity (A) and the syn- diastereoselectivity (B) of the Michael addition of both acylic and cyclic ketones to frans-P-nitrostyrene.

Regarding the hydroxylation of nitroolefins, the reaction is performed under hydrogen-bonding catalysis using quinine-derived thiourea 170 (5 mol%), ethyl glyoxylate oxime as nucleophile in toluene at -24°C [374], This process, which constitutes a valid alternative to the Henry reaction, yields the corresponding hydroxylated nitrocompounds in good yields (63-83%) and enantioselectivities (48-93% ee) from ahphatic electrophiles (styrene derivatives are prone to retio-Michael addition) and has been successfully employed in the synthesis of optically active P-amino alcohols (Scheme 2.132) [375]. 

FIGURE 2.41. Takemoto s (A) and Papai s (B) alternative transition states for the bifunctional amine-thiourea catalysis of Michael addition to nitroolelins. 

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) ... 

Later, the same group succeeded in achieving a cascade Michael/nitro-Mannich/ acetalization reaction by the combination of covalent enamine catalysis and noncovalent bifunctional base/Br0nsted acid catalysis [32]. The fuUy substituted piperidines with diverse substitution patterns were prepared efficiently starting from simple aliphatic aldehydes, Ts-protected imines, and trani -P-nitro alkenes (Scheme 9.36). This finding effectively incorporated prolinol silyl ether-catalyzed Michael addition of aldehyde 65 to nitroalkene 75 and valine-derived bifunctional thiourea-mediated nitro-Mannich reaction of y-nitro aldehyde 106 to imine 105 in the cascade process, providing a complementary contribution to the well-known single catalyst-promoted triple cascade reactions and two catalyst-promoted reaction cascades. 

Dual catalysis with o-proline and the quinine-derived thiourea (5 mol% each), has been shown to operate in the Michael addition of cyclohexanone to o-hydroxy- -nitrostyrenes... 

Chen et al. [26] reported the use of a bifunctional thiourea catalyst 61 during the organocatalyzed thia-Michael addition of thiophenol to unsaturated imide 58c (Scheme 3.29). Michael adduct 60c was obtained in 60% ee and 97% yield by conducting the reaction in dichloromethane at -78°C. The authors speculated that while the tertiary amine of the bifunctional catalyst 61 would act as a proton shuttle according to a Brpnsted acid/base catalysis, the presence of the thiourea moiety might possibly cooperate in the stabilization of the more stable Z-enolate intermediate via hydrogen bond formation as illustrated in Scheme 3.31. 

In the realm of secondary antino catalysis, acyclic aliphatic ketone donors have remained as challenging substrates in asymmetric Michael additions to nitrostyrene. Breakthroughs came with chiral primary amine-thioureas catalysts. Tsogoeva group [35] and Jacobsen group [36] have independently developed chiral primary antine-thiourea catalysts for the Michael reaction of acyclic ketones with nitrooleiins (Schemes 5.18 and 5.19). In both cases, good activity and enantioselectivity have been achieved in the reactions of acetones. Notably, anti-stereoselectivities were obtained in... 

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]. 

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