Primary amine-thiourea catalyst

With ketone donors, both syn and anti selective reactions are possible. Typically, a,p-unsaturated nitro compounds are used as acceptors. The majority of these reactions are syn selective (Scheme 28) [94, 269, 271, 278, 279, 288-309]. This is a result of favored formation of the (fj-configured enamine and favorable electrostatic interactions between the nitro group and the enamine (Scheme 29) [290, 291, 310]. Of the known anti selective reactions, primary amine-thiourea catalysts such as 158 appear to perform best (Scheme 28) [271, 299, 301]. 

The highly enantioselective direct conjugate addition of ketones to nitroalkenes has been promoted by a chiral primary amine-thiourea catalyst (7).31 The observed anti diastereoselectivity has suggested participation of a (Z)-enamine intermediate, given (g) the complementary diastereoselectivity obtained in analogous reactions involving (E)-enamines generated from secondary amine catalysts. 

Scheme 2.9 Enantioselective Michael reactions of ketones with nitrost5renes catalyzed by primary amine-thiourea catalysts.

Using the bifunctional chiral primary amine thiourea catalyst 41 (20 mol%) in CH Clj and in the presence of five equivalents of H O as additive, a highly enanti-oselective direct conjugate addition of a wide range of a,a-unsymmetrically dis-ubstituted aldehydes (only a twofold excess of aldehyde relative to nitroaUcene) to nitroolefins is obtained (see Table 2.1, entry 15, for a representative example) [61], The beneficial role of water is proposed to lie in increasing turnover by eliminating potential catalyst deactivation pathways, and accelerating the final imine hydrolysis. 

On the other hand, chiral primary amine-thiourea catalysts 85 and 90 developed by Tsogoeva [125] and Jacobsen [130], respectively, show an opposite sense of relative stereoinduction in the conjugate addition of acyclic ketones to nitroolefins (see Scheme 2.41 for 90). These anti selective catalysts stand in contrast to the usually obtained results which lead to selective formation of the i yn-conflgured diastereoiso-mers. The unexpected situation suggests participation of a Z-enamine intermediate. Moreover, with respect to the electrophile activation by the urea-type catalysts, it is also demonstrated that only one oxygen of the nitro group is bound to the thiourea moiety in an out-of-plane arrangement [125,130]. 

Anthrones [204] and 3-substituted oxindoles [205] possess activated methylenes which have been able to react under asymmetric iminium catalysis with a,p-unsaturated aldehydes. The reaction with 3-substituted oxindoles is especially attractive, since chiral quaternary stereocenters are generated. For this purpose, chiral primary amine thiourea catalyst 132 has been demonstrated as a very efficient promoter for the addition of 3-alkyl substituted oxindoles to P-aryl substituted enals in the presence of benzoic acid as cocatalyst in toluene at rt to afford the corresponding Michael adducts in good diastereoselectivities (dr up to >19/1) and good enantioselectivities (73-93% ee) (Scheme 2.75) [205a], P-Alkyl substituted enals are not suitable partners for the reaction affording very low diastereo- and enanti-... 

Scheme 5.35 Employment of primary amine thiourea catalyst 73...

Scheme 19.45 Aqmametric intramolecular Michael reaction promoted by a chiral primary amine-thiourea catalyst.

Later, Melchiorre and coworkers accomplished a challenging direct vinylogous aldol reaction of 3-methyl-2-(yclohexen-l-one with a-keto esters utilising a bifunctional primary amine-thiourea. Catalyst 48 based on the (l/ ,2/ )Kiiphenylethylene-l,2-diamine backbone combined with benzoic acid as cocatalyst promoted the reaction by means of a concomitant activation of both reacting partners (see TS in Scheme 19.55), the ketone via dienamine catalysis and the ester via hydrogen-bonding interactions (Scheme 19.55). 

On the other hand, primary amine catalysts showed improved catalytic activity and stereoselectivity for a,a-disubstituted aldehydes in asymmetric Michael reactions (Scheme 5.7). As described by Jacobsen and co-workers, outstanding activity and selectivity were observed for the primary amine thiourea catalyst 20, applicable for a broad range of a,a-disubstituted aldehydes and nitroalkenes (up to... 

More recently, it has been reported that primary amines derived from cinchona alkaloids [75] as well as proline derivatives [76], combined with achiral Brpnsted or Lewis acids, may also efficiently catalyze the enantioselective Biginelli reaction. Alternatively, a carbohydrate-based bifnnctional primary amine-thiourea catalyst was developed for this transformation, with similar enantiocontrol [77]. 

Wang and coworkers developed an intriguing strategy for the inverse-electron-demand Diels-Alder reaction to afford spiro compounds [51]. The reaction of a cyclopentyl keto-enolate salt 89 with A-tosyl-2-methylenebut-3-enoate 88 was catalyzed by the bifunctional primary amine-thiourea catalyst derived from rosin XXII to afford the spirocycles 90 in excellent yields (85-99%), excellent diastereoselec-tivities (up to >20 1 dr), and excellent enantioselectivities (90-99%, Scheme 10.31). 

Ye, Liang, and coworkers reported the addition of diphenylphosphine oxide to enones catalyzed by a bifunctional primary amine thiourea catalyst (127) derived from cinchona alkaloid (Scheme 33.38) [119], Cyclic and acyclic enones react with phosphine oxides under the optimized conditions to furnish the phosphine derivatives 128 in excellent yields and enantioselectivities. The primary amine of the catalyst activates the enone via an iminium, while the thiourea moiety activates and directs the phosphine group. 

With the multifunctional primary amine-thiourea catalyst (which was prepared from (l/ ,2/ )-l, 2-diaminocyclo-hexane and 9-amino (9-deoxy) epiquinine) in the absence of additives, the asymmetric Michael addition of malonate to cyclic enone proceeded well to afford 1,4-adducts in excellent yields and enantioselectivities (Table 9.10). Particularly noteworthy is that all examined malonates afforded higher than 95% enantioselectivities. In general, the reaction could even complete within a short period of time (12-18 hours) to give >90% yields and high enantioselectivity (93-96% ee) when the reactions were carried out at an elevated reaction temperature. Moreover, the reaction of 2-cyclohepten-l-one also afforded more than 90% ee and 83% yield. Furthermore, the use of 4,4-dimethylcyclohex-2-enone resulted in 77% yield with 91% ee. Only 2-cyclo-penten-l-one furnished medium yield and enantioselectivity. In contrast to previous reports, this reaction system exhibits excellent catalytic activity in asymmetric Michael addition with a broad scope of both malonate and cyclic enone. 

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

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... 

Asyimnetric catalytic method to generate C-C bond with adjacent quatemaiy-tertiary stereocenters ranains a challenging synthetic task. In this regard, the use of 3-substituted oxindoles as carbon-nucleophiles has attracted intensive interests due to their relevance in synthesizing bioactive indole alkaloids. Melchiorre recently reported asymmetric Michael addition of 3-substituted oxindoles to a,P-unsaturated aldehydes catalyzed by a primary amine thiourea catalyst 114 (Scheme 5.29). Good diasteieoselectivity and enantioselectivity have been achieved in most cases. However, the reactions were generally sluggish [56]. 

Fig. 5.6 Primary amine amide and primary amine thiourea catalysts...

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