Michael reaction thiourea-catalysed

The enantioselective Michael reaction of malonates to nitroolefins catalysed by bifunctional amino-thioureas has recently been reported by Take-moto [161]. Excellent ee (75-93%) were obtained with diethylmalonate after solvent optimisation, toluene being the best solvent both for the activity and for the selectivity. Substituted malonates were then reacted with various nitroolefins under the same conditions. Excellent enantioselectivities were observed (Scheme 45). 

Bifunctional thiourea-catalysed enantioselective Michael reaction has been achieved. The thiourea moiety and an amino group of the catalyst activated a nitroolefin and a 1,3-dicarbonyl compound, respectively afford the Michael adduct with high enantioselectivity.177,178 Thioureas work as one of the most effective and general enantioselective nitro-Mannich reaction and carbonyl cyanation catalyst.179,180... 

Table 9.13 Thiourea catalysed Michael reaction of nitroolefins with indole...

Figure 9.9 Supposed transition state for thiourea catalysed Michael reaction of nitrostyrene and indole...

Scheme 19.19 Michael reaction of benzimides with malononitrile catalysed by thiourea 15.

The first intramolecular Michael reaction catalysed by a primary amine-thiourea was reported by Lu and coworkers. The synthesis of trans-dihydrobenzofurans proceeded in high yields and enantioselectivities, albeit in unsatisfactory diastereoselectivity transicis 88/12) utilising catalyst 42 (Scheme 19.45). To address the poor selectivity, after the end of the reaction the mixture was heated under reflux, which resulted in the transformation of the ds-isomer to the thermodynamically favourable trarzs-isomer, via an enamine-mediated enolisation. 

Subsequently, the highly enantioselective Michael addition of malonates and 1,2,4-triazole to cyclic and acyclic enones, as well as the first phospha-Michael reaction of cyclic enones and diaryl phosphine oxides was reported using a similar catalyst.In 2012, Huang, Wang and coworkers demonstrated that primary amine-thiourea 39 can efficiently catalyse the... 

Scheme 19.61 Primaiy amine-thiourea catalysed domino Michael-Heniy reaction of 2-aminobenzaldehydes and nitroalkenes.

Scheme 19.75 Michael-elimination-Michael reaction catalysed by a pyrrolidine-based thiourea catalyst.

In 2009, Enders and Hoffman explored the reactivity of a,(3-unsaturated sulfonates and aromatic thiols in sulfa-Michael additions. When the reactions were catalysed by a chiral bifunctional thiourea derived from quinine, the sulfa-Michael adducts were formed in moderate enantioseleetivities of up to 64% ee, albeit with generally good yields, as shown in Seheme 1.70. 

Scheme 1.72 Oxa-Michael reactions of y-hydroxy-a,P-unsaturated ketones catalysed by cinchona alkaloid-derived thiourea.

The domino Henry-Michael reaction of CH3NO2 with 7-oxo-hept-5-en-l-als RC0CH=CH(CH2)3CH=0, catalysed by the quinine-derived thiourea (288b) (<96% ee), followed by the tetramethyl guanidine (TMG)-catalysed retro-Henry-Henry reaction of the initially formed disubstituted cyclohexanols, led to a refinement of diastereoselectivity (to >99 1 dr) ... 

In 2013, Zhao et al. described a highly diastereo- and enantioselective synthesis of trisubstituted cyclohexanols based on a one-pot sequential tandem Henry-Michael reaction catalysed by a combination of a chiral cinchona alkaloid thiourea and 1,1,3,3-tetramethyl guanidine. This process occurred between nitromethane and 7-oxo-hept-5-en-l-als, providing the corresponding tandem chiral products as almost single diastereomers... 

A practical and highly enantioselective Michael addition of malonates to enones catalysed by bifunctional primary amine-thiourea (5) derived from 1,2-diaminocyclohexane has been reported. The addition of weak acids and elevated temperature improved the efficiency of the Michael reaction. This approach enables the efficient synthesis of 1,5-ketoesters with good yields, excellent enantioselectivities (up to 99% ee), and low loading (0.5-5 mol%) of catalysts. A related bifunctional cinchona-thiourea catalyst has been involved in asymmetric organocatalysed conjugate addition reactions of monoth-iomalonates to nitroolefins. ... 

Reactions of phosphonic acids and their derivatives A novel approach to cyclic phosphonates (296) has been developed via a quinine thiourea catalysed, enatioselective Michael addition of quaternary a-nitroallq lphosphonates (293) to enones (294). Selected nitrophos-phonates (295) have been conveniently transformed to the phosphonates (296) and (297) via in situ reduction-intramolecular cyclisation or Baeyer-Villiger oxidation followed by in situ reduction-intramolecular cyclisation, respectively (Scheme 99). ... 

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. 

Tang and coworkers" used bifunctional urea and thiourea-derived orga-nocatalysts (4a,b) for the Michael addition of cyclohexanone to nitro-olefins (Scheme 9.29). Using pyrrolidine-thiourea 4b afforded the desired y-nitroalkanes with high diastereo- and enantioselectivity under solvent-free conditions (up to 99 1 dr, 88-98% ee). Subsequently, Xiao and coworkers screened various bifunctional pyrrolidine-thiourea organocatalysts and identified 4c to be efficient at catalysing the Michael addition of various ketones to nitrostyrenes. Comparable results were observed (up to 99 1 dr and 99% ee) when the reactions were performed in both aqueous media and organic solvents. 

The Michael-type 5(0) -exo-trig and 6(0)"-cxo-trig cycloetherifications of e-hydroxy-a,/3-unsaturated ketones HO(CH2) CH=CHCOR (n = 3 or 4), catalysed by the bifunctional Cinchona alkaloid-derived thioureas, such as the quinidine derivative (131), have been reported to produce the corresponding a-substituted THFs and tetrahydropyrans, respectively, with <95% ee at room temperature over 24 h at 3mol% catalyst loading. The reaction is believed to proceed via the doubly activated species (132). ... 

Michael addition of MeN02 to enone (168), followed by cyclization, has been reported to produce substituted tetrahydroquinolines (169) in <20 1 dr and >98% ee upon a reaction catalysed by various bifunctional thioureas. The first step, that is, the key Michael addition, is believed to involve the activation of both substrates (170), which however portrays a coordination that is the opposite to the generally accepted mechanism. ... 

Aminothiourea-prolinal dithioacetal (234), in the presence of PhC02H, can catalyse Michael addition of ketones R CH2COR and aldehydes to nitroalkenes at 3 mol% loading to afford the 3yn-configured products with <99 1 dr and <99% ee under solvent-free conditions at room temperature. The related carbohydrate-derived thiourea is believed to activate both 8-diketones and nitroalkenes via coordination (235) the Michael adducts were obtained in <89% ee " Another variant of the thiourea motif with a cinchona alkaloid scaffold exhibited higher stereocontrol in the same reaction (<98% ee), carried out in MeCN at —40°C ... 

Scheme 2.12 Pseudo three-component domino Michael-aldol reaction catalysed by a combination of chiral diphenylprolinol trimethyl- or triethylsilyl ether and a thiourea.

In 2012, Wang et al. reported a pseudo-three-component highly enantioselective domino Michael-Michael-Henty reaction catalysed by a combination of chiral diphenylprolinol trimethylsilyl ether and a chiral quinine-derived thiourea. The reaction occurred between aliphatic aldehydes and two equivalents of nitroalkenes, providing the corresponding hexasubstituted chiral cyclohexanols in moderate to good yields and dia-stereoselectivities of up to 60% de, combined with generally excellent enantioselectivities ranging from 96 to >99% ee (Scheme 2.23). The authors... 

In 2013, Li et al. reported a novel synthesis of chiral six-memhered spir-ocyclic oxindoles bearing five consecutive stereocentres on the basis of an enantioselective three-component domino Michael-Michael-aldol reaction catalysed hy a combination of a chiral diphenylprolinol silyl ether and a chiral bifunctional quinine thiourea. " As shown in Scheme 2.26, the reaction between iV-substituted oxindoles, nitrostyrenes, and enals led to the corresponding highly substituted spirocyclic oxindoles in high yields, moderate diastereoselectivities of up to 44% de, and enantioselectivities of up to >99% ee. A large variety of substrates could be used well in this... 

Scheme 2.34 Tandem Henry-Michael-retro-Heniy reaction catalysed by a chiral cinchona alkaloid thiourea and 1,1,3,3-tetramethyl guanidine.

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