Amines primary amine-thiourea

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]. 

Scheme 6.102 Bifunctional catalysis with primary amine thiourea 99 Proposed transition states to explain the onfi-diastereoselectivity (A) and the syn- diastereoselectivity (B) of the Michael addition of both acylic and cyclic ketones to frans-P-nitrostyrene.

Scheme 6.105 Asymmetric Michael addition of phenylpropionaldehyde to trar)s- 3-nitrostyrene catalyzed by primary amine thioureas 102, 104, and 105.

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. 

Chiral bifunctional primary amine-thiourea/ f-BuNH2.TFA/DCM/25 °C (09MI1) 12/EtOH/rt (09MI2)... 

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

There is an interesting variant of this reaction which involves the use of tert-butyldimethylsilyloxyacetaldehyde as Michael donors and chiral primary amine thiourea bifunctional catalyst 37b (Scheme 2.13). In this case, the diastereoselectivity of the reaction changed from the usually observed syn relative stereochemistry at the final Michael adduct to the formation of the anti diastereoisomer as the major product. This change in diastereoselectivity was explained in terms of the generation of a Z-enamine intermediate assisted by the formation of an intramolecular hydrogen bond between the secondary... 

Axial-to-central chirality transfer in cyclization processes 13CSR8434. Bifunctional primary amine-thioureas in asymmetric organocatalysis 13OBC7051. 

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. 

Scheme 2.41 Jacobsen s chiral primary amine-thiourea addition of ketones to nitroalkenes...

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]. 

A highly enantioselective conjugate addition of nitromethane and nitroethane to acyclic enones has been recently achieved using chiral cyclohexanediamine-derived primary amine thiourea 48 (Scheme 2.57) [168], With respect to the electrophile, the reaction shows a broad substrate scope and not only 1-aryl- but also 1-alkyl enones afford the corresponding chiral y-nitroketones with good yields and excellent enantioselectivities (92-99% ee). 

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-... 

Tsogoeva et al. described the use of the primary amine thiourea-based organocatalyst 73 in an asymmetric Mannich-type reaction of unmodified aldehydes and ketones 7 with readily available and stable a-hydrazonoesters 74 (Scheme 5.35) [46]. Moderate to good yields and excellent enantioselectivities (90-99% ee) were reported. However, the anti-diastereoselectivity appeared generally poor (8-72% de). 

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

The first primary amine-thioureas as effective bifunctional organocatalysts were reported in 2006. Tsogoeva and Wei synthesised a thiourea based on (l5,25)-diphenylethylene-l,2-diamine and a chiral arylethyl moiety, for the Michael reaction between aliphatic ketones and aromatic nitro-olefins (Scheme 19.36). Utilising catalyst 29 (15 mol%) and acetone as the Michael donor, the Michael products were obtained in high yields (84-99%) and enantioselectivities (90-91% enantiomeric excess). When cyclohexanone 31 was employed, product 33 was obtained in high yields (82 and 89%, respectively), good diastereoselectivity (up to 83 17 symanti) and excellent enantioselectivity (96 and 98% enantiomeric excess, respectively). 

Scheme 19.38 Michael addition of disubstituted aldehydes to nitroalkenes promoted by a chiral primary amine-thiourea.

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. 

Scheme 19.44 Primary amine-thiourea catalysed the reaction between nitroalkenes and 3-hydro)g -substituted oxindoles.

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... 

Mei and coworkers utilised primary amine thiourea 44 based on the (IS,25 )-diphenylethylene-l,2-diamine backbone for the enantioselective Michael reaction between 4-hydro>ycoumarin and a,p-unsaturated ketones (Scheme 19.49). The products were isolated in high to excellent yields (up to 97%) and in good to high enantiomeric excesses (up to 95% enantiomeric excess). This method gives access to enantiopure (S)-warfarin, which is an anticoagulant agent. 

Kwiatkowski and coworkers utilised thiourea 39 in order to provide a practical and straightforward Michael addition of malonates and other nucleophiles to cyclic and acyclic enones, catalysed by primary amine thiourea 39 in the presence of benzoic acid as cocatalyst. The advantages of this highly sustainable protocol were the low catalyst loading (0.5-5 mol%) and the ability to increase the temperature without any loss of enantios-electivity. The products were obtained in good yields and in high enantios-electivity (up to 98% enantiomeric excess) (Scheme 19.50). 

Melchiorre and coworkers disclosed a primary amine-thiourea-mediated iminium ion activation of ot,p-unsaturated aldehydes. Catalyst 45 was applied successfully leading to high efficiency and stereocontrol in the challenging synthesis of compounds containing contiguous quaternary and... 

Scheme 19.52 Chiral primary amine-thiourea catalysed conjugate addition of aldehydes to maleimides.

Scheme 19.55 Direct vinylogous aldol reaction promoted by a chiral bifunctional primary amine-thiourea.

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). 

Scheme 19.56 The sole example of primary amine-thiourea catalysed Martnich reaction.

In 2011, Jacobsen and coworkers developed a dual catalyst system consisting of a chiral primary amine-thiourea and an achiral thiourea for the intramolecular [5-1-2] cycloaddition based on oxidopyiylium intermediates (Scheme 19.57). This cooperative catal)4ic system provided easy access to tricyclic structures in moderate yields (37-77%) and good to high enantioselectivities (80-95% enantiomeric excess). Schreiner s thiourea 8 is proposed to be a carboxylate-binding agent, acting in cooperation with primary amine-thiourea 50. 

Scheme 19.59 Highly enantioselective aza-Diels-Alder reaction promoted by a primary amine-thiourea.

The asymmetric a-allqrlation of carbonyl compounds constitutes one of the fundamental organic transformations for the construction of carbon-carbon bonds, and has long been the Achilles heel for asymmetric aminocatalysis. Towards a solution to this long-standing problem, Jacobsen and coworkers have shown that the enantioselective a-allqrlation of a-arylpropionaldehydes with diarylbromonethane can be carried out under the catalysis of primary-amine thiourea 39 (Scheme 19.60). Catalyst 39 reacted with the aldehyde to form an enamine, followed by a S -l-type substitution induced by the bromide anion. 

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. 

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