Michael Thiourea catalyzed

Hoashi, Y., Yabuta, T., Takemoto, Y. (2004) Bifunctional Thiourea-Catalyzed Enantioselective Double Michael Reaction of y,5-Unsaturated fS-Ketoesterto Nitroalkene Asymmetric Synthesis of (—)-Epibatidine. Tetrahedron Letters, 45, 9185-9188. 

Papai et al. selected as model reaction the addition of 2,4-pentanedione (acety-lacetone) to trans-(H)-nitrostyrene, catalyzed by the bifunctional thiourea catalyst as shown in Scheme 3.6 [32]. 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. [33]. Himo et al. performed a density functional study on the related cinchona-thiourea catalyzed Henry-reaction between nitromethane and benzaldehyde [34]. 

Scheme 6.2 Thiourea-catalyzed Michael additions of nitromethane to chalcones.

Table 6.6 Thiourea-catalyzed double Michael reactions of unsaturated /M

Soon afterward, a broad spectrum of Michael donors and Michael acceptors were successfully employed in the thiourea-catalyzed Michael addition [24—27]. Selected examples are outlined in Schemes 9.31-9.33. 

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... 

Inokuma, T, Hoashi, Y. and Takemoto, Y. (2006) Thiourea-catalyzed asymmetric Michael addition of activated methylene compounds to a,P-unsaturated imides Dual activation of imide by intra- and intermolecular hydrogen bonding. Journal of the American Chemical Society, 128, 9413-9419. 

Reproduced from Hestericova M, Sebesta R. Higher enantloselectivltles In thiourea-catalyzed Michael additions under solvent-free conditions. Tetrahedron 2014 70 901-5. Copyright (2014), with permission from Elsevier. 

There is also an interesting example of an enantioselective thiourea-catalyzed oxa-Michael reaction using enones as Michael acceptors in which phe-nylboronic acid was employed as hydroxyl anion equivalent (Scheme 4.64) The authors demonstrated that amine bases were able to activate these kinds of reagents by complexation, thus becoming effective reagents for the transfer of the OH group to the Michael acceptor. The reaction had to proceed in an intramolecular way and, for this reason, y-hydroxy-a,(3-unsaturated ketones had to be employed as substrates. In the enantioselective version, 71b was identified as a very efficient catalyst, providing a series of (3,y-dihydroxy ketones in excellent yields and enantioselectivities, after oxidative work-up. The process consists of the initial reaction of the boronic add first with the y-hydroxy... 

The mechanisms of the primary amine-thiourea-catalyzed Michael additions of ketones to nitroolefins [184] and of Mannich additions of ketones to A -benzoyl hydrazones [185] have been theoretically studied by Tsogoeva and co-workers. While in the first case the calculations support a transition state according to the conceptual framework of Figure 2.42, involving an enamine intermediate (Figure 2.44A), in the second one the calculations provide evidence in favor of a nonconventional enol mechanism (Figure 2.44B) [186]. 

FIGURE 2.44. Transition state models for (A) the primary amine-thiourea-catalyzed Michael additions of ketones to nitroolehns and (B) Mannich additions of ketones to A-benzoyl hydrazones. 

SCHEME 11.22. Enantioselective aza-Michael additions catalyzed by chiral thioureas. 

Scheme 106 Bifunctional thiourea-catalyzed Michael addition...

SCHEME 2.42 Chiral thiourea-catalyzed Mannich-Michael cascade reaction. 

SCHEME 243 Chiral thiourea-catalyzed Michael-aldol cascade reaction. 

SCHEME 2.52 Chiral thiourea-catalyzed Michael/hemiketalization/acyl transfer reaction. 

SCHEME 2.56 Chiral thioureas-catalyzed Michael-Henry reaction for the construction of pyrrolidines. 

Employing cyclohexa-l,4-dione derivative 215 as the nucleophile. Tan et al. developed a thiourea-catalyzed domino Michael-Henry process with p-nitrostyrenes, constructing bicyclo[3.2.1]octane derivatives 216 with highly enantio- and diastereo-selectivities (Scheme 2.59) [85]. 

SCHEME 2.59 Chiral thioureas-catalyzed Michael-Henry process between cyclohexa-1,4-dione and P-nitrostyrenes. 

A typical procedure for the Michael addition catalyzed by chiral primary amine-thiourea catalyst. To a... 

TABLE 9.10. Michael Addition Catalyzed by Multifunctional Primary Amine-thiourea Catalyst... 

Hoashi Y, Yabuta T, Takemoto Y. Bifunctional thiourea-catalyzed enantioselective double Michael reaction of y,8-unsaturated p-ketoester to nitroalkene asymmetric synthesis of (—)-epihatidine. Tetrahedron Lett. 5004 45 (50) 9185-9188. 

Scheme 7.29 Fluorous thiourea-catalyzed Michael reaction.

This Michael-type addition is catalyzed by lanthanum(3+) [16096-89-2] (80). Ethylene glycol [107-21-1] reacts with maleate under similar conditions (81). A wide range of nucleophilic reagents add to the maleate and fumarate frameworks including alcohols, ammonia, amines, sulfinic acids, thioureas, Grignard reagents, Michael reagents, and alkali cyanides (25). 

The Michael reaction of malonates to nitroolefins and the aza-Henry reaction of nitroalkanes to Al-phosphinoylimines are catalyzed by thiourea derivative 5a to provide the respective products in good and moderate enantioselectivities. Thiourea... 

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

Novel aldol-type reactions under Cinchona-deriwed chiral thiourea catalysis was reported by Wang et al. [78]. In their report, a novel cascade Michael-aldol reaction was presented. The reaction involves a tandem reaction catalyzed via hydrogen-bonding with as little as 1 mol% catalyst loading to generate a product with three stereogenic centers (Scheme 28). hi the reaction of 2-mercaptobenzaldehyde 128 and a,P-unsatnrated oxazolidinone 129, the desired benzothiopyran 130 was formed smoothly in high yield and excellent stereoselectivity. 

At reduced reaction temperatures (-50 °C tort) bifunctional thiourea 12 (10mol% loading) catalyzes the stereoselective Michael addition [149-152] of prochiral a-substituted P-ketoesters to trons-P-nitrostyrene affording the respective adducts 1-5 in yields ranging from 76 to 97%, in high enantioselectivities (85-95%), and... 

---