Henry Thiourea catalyzed

Papai et al. selected as model reaction the addition of 2,4-pentanedione (acety-lacetone) to trans-(H)-nitrostyrene, catalyzed by the bifunctional thiourea catalyst as shown in Scheme 3.6 [32]. The analogous Michael addition involving dimethyl malonate and nitroethylene as substrates, and a simplified catalyst was calculated at the same level of theory by Liu et al. [33]. Himo et al. performed a density functional study on the related cinchona-thiourea catalyzed Henry-reaction between nitromethane and benzaldehyde [34]. 

Scheme 6.162 Mechanistic proposal for the Henry reaction catalyzed by bifunctional double hydrogen-bonding thiourea derivative 163.

Table 6.23 Thiourea-catalyzed aza-Henry reactions of N-phosphinoylimines.

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. 

Hammar, R Marcelli, T. Hiemstra, H. Himo, R Density Functional Theory Study of the Cinchona Thiourea-Catalyzed Henry Reaction Mechanism and Enantioselectivity. Adv. Synth. Catal. 2007, 349, 2537-2548. 

An ensuing computational study of the thiourea-catalyzed Henry reaction indicated that the both substrates are activated simultaneously in two ways that is, the thiourea can interact either with the aldehyde (pathway A) or with the nucleophile (pathway B) (Figure 6.12) [70]. The computed reaction barriers for the bond-forming steps in the two pathways differed by less than 8kJ moT and therefore both could be important under the experimental conditions for the catalytic Henry reaction. 

SCHEME 2.56 Chiral thioureas-catalyzed Michael-Henry reaction for the construction of pyrrolidines. 

Employing cyclohexa-l,4-dione derivative 215 as the nucleophile. Tan et al. developed a thiourea-catalyzed domino Michael-Henry process with p-nitrostyrenes, constructing bicyclo[3.2.1]octane derivatives 216 with highly enantio- and diastereo-selectivities (Scheme 2.59) [85]. 

SCHEME 2.59 Chiral thioureas-catalyzed Michael-Henry process between cyclohexa-1,4-dione and P-nitrostyrenes. 

The Michael reaction of malonates to nitroolefins and the aza-Henry reaction of nitroalkanes to Al-phosphinoylimines are catalyzed by thiourea derivative 5a to provide the respective products in good and moderate enantioselectivities. Thiourea... 

Scheme 6.147 visualizes two proposals for the mechanism of the 131-catalyzed Henry addition of nitromethane to benzaldehyde. In (A), benzaldehyde is achvated by the thiourea moiety through double hydrogen bonding to the carbonyl funchon, while the nitromethane is deprotonated and activated by the basic quinuclidine nitrogen [298] proposal (B), however, based on detailed DFT computations... 

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). 

In 2010, Zhong and co-workers [32] tried a similar approach using nitrotyrenes and cyclic ketoesters. The reaction occurs through a Michael-Henry cascade reaction catalyzed by bifunctional thiourea catalysts derived from cinchona alkaloids. The reaction furnished the desired bicyclic products 43 in good yields and excellent stereoselectivities (Scheme 10.14). 

Recently, a Henry reaction between aldehydes (e.g., benzaldehyde 26) and nitroalkanes (e.g., nitromethane 27) catalyzed by cyclophane-based thiourea 28 was reported (Scheme 3.27). ... 

Another enantioselective approach to tetrahydroquinolines (compounds 87) was developed by Xu and is based on a Michael-aza-Henry domino process, which is shown in Scheme 3.26 [68]. The reactions were catalyzed by a bifunctional thiourea 86 and proceeded in excellent yields and enantioselectivities, with diastereomeric excesses of up to 90%. 

Connon introduced binaphthyl-derived bis-thiourea 31 and demonstrated that it could catalyze the addihon of N-methyhndole to various nitroalkenes, including those incorporating P-aliphahc substituents, although the enantioselectivity was generally moderate (Scheme 7.56) [84]. The utility of 31 was also proven by Wulff through use with a sub-catalytic amount of triethylamine for stereoselectively facilitating the aza-Henry reaction of nitroalkanes with N-Boc imines [85]. 

Scheme 29.3 Bifunctional thiourea 3 catalyzed Henry reaction.

Scheme 29.20 Chiral thiourea 37 catalyzed aza-Henry reaction.

Mannich Reaction Carbamate-protected alkyl imines are important building blocks in the synthesis of chiral alkyl amines. However, they are usually unstable, and most of them cannot be prepared in pure form. As the optimal substitutes, a-amido sulfones 142 were first used in the PTC-catalyzed enantioselective aza-Henry reaction in 2005 [57]. Subsequently, Song et al. reported a chiral Cinchona alkaloid thiourea (130b)-catalyzed Mannich reaction with in situ generation of... 

Jia et al. reported a novel Michael/aza-Henry reaction of well-designed chalcones 217 and nitromethane 218 catalyzed by thiourea 130c (Scheme 2.60). Initiated by the Michael addition of nitromethane to an electron-deficient double bond, the resulting intermediate subsequently underwent an aza-Henry reaction to furnish multisubsti-tuted tetrahydroquinolines 219a with up to 20 1 dr and >99% ee [86a], Later, the same group presented an alternative way to construct the same skeletons with different diastereoselectivities [86b], which employed nitrogen as the nucleophilic site to trigger the cascade process (Scheme 2.60). Very recently, a multifunctional... 

Jiang XX, Zhang YF, Wu LP, Zhang G, Liu X, Zhang HL, Fu D, Wang R. Doubly stereocontrolled asymmetric aza-Henry reaction with in situ generation of A -Boc-imines catalyzed by novel rosin-derived amine thiourea catalysts. Adv. Synth. Catal. 2009 351(13) 2096-2100. 

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