Takemoto’s catalyst

Remarkably, the reaction also tolerated the use of differently substituted a-alkyl-p-ketoesters as Michael donors, leading to the formation of compounds containing two contiguous stereogenic centers, one of them a quaternary one, in good diastereo- and enantioselectivities (Scheme 4.6). Masked cyclic 1,3-diketones such as 2-hydroxy-1,4-naphthoquinols have also been successfully applied in this context also showing the extraordinary performance of catalyst 68a in terms of both yields and enantioselectivities. There is also one example of a vinylogous Michael reaction between a,a-disubstituted dicyanoacrylates and nitroalkenes for which Takemoto s catalyst has also been identified as the most efficient promoter of the reaction. Moreover a solid-supported version of this catalyst has also been developed by Takemoto himself and tested in the reaction of diethylmalonate with nitrostyrene with success. ... 

Acetylacetone has also been the subject of several studies when used as 1,3-dicarbonyl compound suitable to engage in a Michael reaction with nitroalkenes under H-bonding catalysis. In this context, Takemoto s catalyst 68a and valine-derived thiourea 74 have been tested in the reaction with acetylacetone with nitrostyrene furnishing good results, although no extensive study was carried out in order to evaluate the substrate scope with regard to the substitution at the nitroalkene. On the other hand, several functionalized thioureas have been expressly surveyed in this reaction, providing a detailed study... 

Racemic 3-alkyl oxindoles have also been found to be useful pro-nucleophiles in this context (Scheme 4.IS)." For this transformation, a modified version of Takemoto s catalyst was identified as the most efficient promoter of the reaction, which was found to have a remarkably wide substrate scope, allowing many different substitution patterns both at the oxindole and at the nitroalkene reagent, and even tolerating well the use of p-alkyl substituted nitroalkenes as Michael acceptors. Yields, diastereo- and enantioselectivities were found to be excellent in almost all the cases studied. The reaction also accepted very well the use of the simple nitroethene, another very challenging... 

Anthracenones are another class of C-H acidic compounds suitable to be employed in this reaction (Scheme 4.16) and, in fact, Takemoto s catalyst has been identified as the most efficient catalyst among a series of different thioureas tested, which also included a family of different cinchona alkaloid-derived candidates." The reaction proceeded satisfactorily for a wide variety of aromatic nitroalkenes tested but poorer results were obtained in the case of the p-alkyl substituted Michael acceptors. 

There is also a modified version of Takemoto s catalyst, which incorporates a benzimidazole heterocycle as the H-bonding donor site in place of the thiourea moiety." This catalyst 82 has been tested with success in several Michael-type reactions of 1,3-dicarbonyl compounds to nitroalkenes, in particular focused on the use of malonates as donors (Scheme 4.20), providing the corresponding adducts in excellent yields and enantioselectivities. p-Ketoesters have also been tested, although in this case the performance of the catalyst was found to be highly dependent on the structure of the p-ketoester employed. It has also to be pointed out that the reaction required the incorporation of a Bronsted acid cocatalyst such as TFA for achieving the best enantioselectivity, although the presence of this co-catalyst did not have any influence in the catalytic activity. 

Takemoto s catalyst has been employed in the Michael addition of a-sub-stituted cyanoacetates to aryl vinyl ketones (Scheme 4.29). The substitution... 

The structural and electronic analogies between the nitro and the imide groups have also been surveyed in this transformation (Scheme 4.69). Takemoto s catalyst has been employed in the reaction of thiophenol to imides derived from benzoic add, furnishing excellent yields of the sulfa-Michael... 

In a similar context, y,5-unsaturated p-ketoesters (Nazarov reagents) have also been employed as suitable functionalized Michael donor substrates for a Michael/Michael cascade reaction with nitroalkenes using, in this case, Takemoto s catalyst 68a (Scheme 7.65). This reaction proceeded in a tandem... 

Scheme 3 Addition of acetylacetcme to /ra/i -p-nitrostyrene by Takemoto s catalyst...

The roles of the catalytic functions are not necessarily opposite or limited to Lewis acid/base pairs. For example, amine thiourea derivatives like Takemoto s catalyst 4 merge the hydrogen bond donor capability of the thiourea moiety with Bronsted base functionality of the amine function and revealed itself particularly efficient organocatalysts for Michael reactions of various 1,3-dicarbonyl compounds with nitroolefins (Scheme 3) [17-19]. 

In the field of constructing S-heterocycles, a reaction involving a low loading of Takemoto s catalyst 3 was used in the synthesis of succinimide-containing... 

The synthesis of six-membered all-carbon rings have been extensively studied in the literature, mainly because of their importance as constituents in natural products and biologically relevant compounds. The first example of an enantioselective organocatalytic domino reaction with nitroalkenes to furnish cyclohexanes was disclosed by Takemoto and co-workers [38] in 2004. In this work, a domino Michael addition of 7,8-unsaturated-(3-ketoesters (58) to nitroalkenes (28) catalyzed by a bifunctional amino-thiourea (Takemoto s catalyst, XVIII) and 1,1,3,3-tetramethylguanidine (TMG) was reported with excellent results and diastereoselectivities (up to 71% yield, up to >99% ee) and was recently applied to the synthesis of (-)-epibatidine. 

The addition of thioacetic acid to tra 5-chalcones furnished only moderate enantioselectivity (33-65% ee with Takemoto s catalyst 11) [33]. Better results were obtained by the Chen group, with various thiols employing quinine-derived squaramide 13 [34]. It is worth noting that, in this case, substituted benzyl thiols, furfuryl thiol, and aliphatic thiols were better donors than thiophenol (Scheme 14.6). 

The Takemoto s catalyst (9) was extensively employed for the enantioselective addition of arylthiols to a,P-unsaturated carbonyl compounds and P-arylthio ketones were obtained in good ees [90]. Conjugate addition of thioacetic acid to nitroalkene and to enone have been also reported by Wang [91]. 

Recently, Takemoto s catalyst 27 was also employed in the addition of P-ketoamides [34] with excellent results. Bonne, Constantieux, Rodriguez et cA. [35] reported the use of a-ketoamides as pronucleophiles in the Michael addition to nitroalkenes catalyzed by the bifunctional Takemoto s aminothiourea 27. During this study it appeared that the nature of the amide moiety was crucial, indeed tertiary amides were poorly reactive during conjugate addition while secondary amides gave excellent results in terms of yields (67-94%), enantioselectivity (99% > ee > 85%), and diastereoselectivity (20 1 > dr > 10 1) (Scheme 34.7). The authors... 

Strecker reaction 895 tagged organocatalysts 834 Takemoto s catalyst 317, 318, 330 Tamiflu 1307,1308... 

An interesting variation on the original Takemoto s catalyst with a chiral piperidine moiety (434) has been reported to catalyse the Michel addition 2-nitrocyclohexanone to -nitrostyrene with <84% gg 286... 

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