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. 

Table 5.7 Bifunctional tertiary amine/thiourea catalyst in MBH reaction of cyclohexenone and selected aldehydes.

Chen and co-workers later reported the successful asymmetric 1,4-addition of aryl thiols to a,/ -unsaturated cyclic enones and imides using Takemoto s elegantly simple catalyst (3) [43]. This bifunctional amine-thiourea catalyst gives optimal reactivity and reproducibility when used at 10 mol% loading in the presence of freshly dried 4 A molecular sieves (MS). This combination afforded the expected addition products in high yields (90-99%) and moderate to good enantioselectiv-ities (55-85% ee) for a variety of cyclic and acyclic Michael acceptors (Table 6.2). 

Disubstituted thiochroman-4-ols are formed with excellent enantio- and diastereo-selectivity when thiosalicylaldehydes react with an a,P-unsaturated oxazolidinone in the presence of a chiral bifunctional amine-thiourea catalyst. A tandem Michael - aldol process is involved (Scheme 43) <07JA1036>. 

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...

In the domino Michael/alkylation reaction applied to the synthesis of 3-(2H)-furanones, the ethyl 4-bromoacetoacetate 203 and nitrostyrene 204 were first trialed with a range of catalysts. In this instance, the so-called modified Feist Binary reaction was completed with an I-threonine bifunctional tertiary amine/thiourea catalyst 205 to produce the furanone 206 in excellent yield and high enantioselec-tivity (Scheme 7.42) [107]. In another report, the furan ring as part of other bicyclic or tricyclic systems was also prepared through an enantioselective Michael addi-tion/nucleophilic substitution reaction (Scheme 7.43) [108]. When diketones and ( )-P,P-bromonitrostyrenes 207 were stirred, again with a bifunctional thiourea... 

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... 

In 2012, Cobb and co-workers [41] developed a cyclopentanation reaction between nitrostyrenes and E-nitro-a, 3-unsaturated esters (62). The reaction is catalyzed by bifunctional tertiary amine-thiourea catalysts, affording the highly substituted cyclohexanes 63 in good yields and enantioselectivities (Scheme 10.19). 

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]. 

A bifunctional amine/thiourea catalyst gives high ee in a direct vinylogous aldol reaction of allyl ketones with isatins, giving biologically important 3-hydroxy-2-oxindoles. ... 

Barbas and coworkers reported a formal [3-1-2] cyclization between 17a and isothiocyanato imides 53 [24]. The reaction was catalyzed by bifunctional tertiary amine-thiourea catalyst XII and afforded the spiro products 54 in excellent yields and stereoselectivities. The only limitation of the reaction was the use of alkylideneindolones bearing an electron-withdrawing group (Scheme 10.17). 

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