Mannich Thiourea catalyzed

Table 6.18 Thiourea-catalyzed Mukaiyama-Mannich reactions of aldimines.

Table 6.22 Thiourea-catalyzed acyl-Mannich reactions of substituted isoquinolines.

Significant levels of syn diastereoselectivities (5 1 to 16 1) were observed for all substrates, with the exception of an ortho-chloro-substituted aryl imine, which provided only 2 1 syn selectivity. The catalyst was viable for a variety of nitroalkanes, and afforded adducts in uniformly high enantioselectivities (92-95% ee). The sense of enantiofacial selectivity in this reaction is identical to that reported for the thiourea-catalyzed Strecker (see Scheme 6.8) and Mannich (see Tables 6.18 and 6.22) reactions, suggesting a commonality in the mode of substrate activation. The asymmetric catalysis is likely to involve hydrogen bonding between the catalyst and the imine or the nitronate, or even dual activation of both substrates. The specific role of the 4 A MS powder in providing more reproducible results remains unclear, as the use of either 3 A or 5 A MS powder was reported to have a detrimental effect on both enantioselectivities and rates of reaction. 

Thiourea-Catalyzed Mukaiyama-Mannich Reactions of Aldimines [12] (p. 215)... 

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. 

A. S. Demir, S. Basceken, Tetrahedron Asymmetry 2013, 24, 515-525. Study of asymmetric aldol and Mannich reactions catalyzed by proline-thiourea host-guest complexes in nonpolar solvents. 

SCHEME 11.21 Bifunctional cinchona aUcaloid/thiourea-catalyzed asymmetric Mannich reaction. 

SCHEME 11.22 Three-component direct asymmetric Mannich reaction catalyzed by a bifunctional quinidine thiourea catalyst. 

Jacobsen et al also synthesized bifunctional thiourea catalysts (Figure 2.17). Jacobsen et al. reported nitro-Mannich reaction catalyzed by a thiourea (10a) to give P-nitro amine in favor of the syn isomer with excellent enantioselectivity (Scheme 2.41) [94]. 

Scheme 28.25 Guanidinium-thiourea-catalyzed Mannich reactions.

Very recently. Song, Yang, and coworkers described a domino Mannich reaction catalyzed by a chiral thiourea derivative of a cinchona alkaloid (111 in Figure 42.5). They showed how amino-benzoxazoles 128 are viable amine components for the imine formation with aldehydes 127 in three-component Mannich reactions (Scheme 42.28) [70]. 

SCHEME 240 Chiral thiourea-catalyzed Mannich reaction with a-amido sulfones. 

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

SCHEME 2.45 Chiral thiourea-catalyzed Mannich-alkylation cascade reaction. 

In 2010, Monge et al. reported a one-pot tandem reaction by combining bifunctional thiourea and Au complex [77], affording dihydropynole derivatives in moderate yields and high enantioselectivities. The reaction was based on a bifunctional thiourea-catalyzed Mannich-type reaction and a subsequent Au-catalyzed alkyne hydroamination and isomerization of propargylated malononitrile and N-Boc-protected imines (Scheme 9.72). Notably, acidic additive proved cracial to prevent deactivation of the gold catalyst and enhance the reactivity and selectivity. 

In Ught of the recent developments in thiourea, diol, and phosphoric-acid-mediated catalysis, far fewer studies have focused on the use of chiral carboxyhc acids as suitable hydrogen bond donors. To this end, Mamoka synthesized binaphthyl-derived dicarboxylic acid 49 which catalyzes the asymmetric Mannich reaction of N-Boc aryl imines and tert-diazoacetate (Scheme 5.65) [120]. The authors postulate that catalytic achvity is enhanced by the presence of an addihonal car-boxyhc acid moiety given that use of 2-napthoic acid as catalyst provided only trace amounts of product... 

Scheme 6.88 Asymmetric Mannich reaction of N-Boc-protected aldimines catalyzed by simplified thiourea 76.

In addition to chiral PTCs, cinchona-based thioureas have also been proved to serve as catalysts for nitro-Mannich reactions. In 2006, Ricci and coworkers first reported that the quinine-based thiourea 40 (20mol%) can catalyze the aza-Henry reaction between nitromethane and the N-protected imines 93 derived from aromatic aldehydes [40]. N-Boc-, N-Cbz-, and N-Fmoc protected imines gave the best results in terms of the chemical yields and enantioselectivities (up to 94% ee at —40°C) (Scheme 8.30). 

Wenzel and Jacobsen reported the thiourea 15b-catalyzed Mannich-type reaction of a ketene silyl acetal with an N-Boc-aldimine, furnishing (3-amino esters with excellent enantioselectivities (Equation 10.30) [59]. Subsequently, Jacobsen and co-workers reported the hydrophosphonylation of dialkyl phosphites with aldimines to yield a-amino phosphonates [60]. 

Later Schaus and co-workers used the cinchona alkaloid-derived thiourea catalyst 60 to catalyze the nucleophilic addition of both nitroalkanes (not shown) and dimethyl malonate to the Al-carbamoyl protected imines 46b, 61a-d to produce the corresponding Mannich adducts 62 in excellent yields and high enantioselectivities (Scheme 5.30) [41], The level of selectivity observed in these reactions is indicative of a catalyst-associated complex with a high degree of coordination. Modelling... 

Recently, the formation of Mannich products via reaction of lactones with a variety of Al-Boc-aldimines, catalyzed by the bifunctional rosin-derived amine thiourea eatalyst 66, was reported by the Wang group (Scheme 5.32) [43]. The formation of... 

Another important type of transformation, which is has inspired the above developments, is the nitro-Mannich (or aza-Henry) reaction catalyzed by Jacobsen thiourea catalysts (Scheme 4.16) [77]. The reaction is highly 5yn-selective, and the corresponding products were isolated in high yields and ees. 

The dual activation mode of the aforementioned cinchona alkaloid-derived thiourea catalysts proved to be highly effective in catalyzing the asynunetric Mannich reaction, among other transformations. These findings prompted the development of new, more simple bifunctional chiral catalysts that are predominately based on tra 5 -l,2-diaminocy-clohexane. For example, the application of the thiourea catalyst 120, which was developed by Takemoto and coworkers, afforded upon the reaction of Af-Boc-protected imines with diethyl malonate the desired chiral amines in good chemical yields (up to 91%) and enantioselectivities (98% ee) (Scheme 11.23) [81]. The catalytic mechanism presumably involves deprotonation and coordination of the active carbonyl compound by the chiral tertiary amine moiety. The formed enolate then attacks the si-face of the... 

It must be noted that chiral thiourea catalysts have been used earlier to catalyze the asymmetric Mannich reaction. Jacobsen and Wenzel reported the enantioselective synthesis of A-Boc-protected p-amino acids from silyl ketene acetals and A-Boc-protected imines using the thiourea catalyst 123 (Scheme 11.24). Here, the chiral thiourea-derived Brpnsted acid catalyst (the application of chiral Brpnsted acids in the... 

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