Pyrrolidine-thioureas

The Michael reactions [149-152] between cyclohexanone and trons-nitroalkenes were also explored by Xiao and co-workers utilizing bifunctional pyrrolidine-thiourea 213 and the pyrrolidine-thioureas 214-217 (Figure 6.61) [344]. The model Michael reaction between cyclohexanone and trons-nitrostyrene identified water as the best solvent and 217 to be the most efficient catalysts concerning the activity and asymmetric induction (90% yield 96% ee dr 98 2 in 12 h at 35 °C) in the presence of benzoic acid (10mol%) as additive. The optimized catalytic system allowed the formation of a broad spectrum of Michael adducts such as 1-6 resulting from... 

A pyrrolidine-thiourea organocatalyst (69) facilitates Michael addition of cyclohexanone to both aryl and alkyl nitroalkenes with up to 98% de and ee 202 The bifunctional catalyst (69) can doubly hydrogen bond to the nitro group, leaving the chiral heterocycles positioned for cyclohexyl enamine formation over one face of the alkene. 

Tang and coworkers" used bifunctional urea and thiourea-derived orga-nocatalysts (4a,b) for the Michael addition of cyclohexanone to nitro-olefins (Scheme 9.29). Using pyrrolidine-thiourea 4b afforded the desired y-nitroalkanes with high diastereo- and enantioselectivity under solvent-free conditions (up to 99 1 dr, 88-98% ee). Subsequently, Xiao and coworkers screened various bifunctional pyrrolidine-thiourea organocatalysts and identified 4c to be efficient at catalysing the Michael addition of various ketones to nitrostyrenes. Comparable results were observed (up to 99 1 dr and 99% ee) when the reactions were performed in both aqueous media and organic solvents. 

Scheme 9.31 Pyrrolidine-thiourea organocatalyst (4i) for Michael additions.

Pyrrolidine thiourea derivative 136 (50 mol%) afforded the best results (49% yield, 33% de, 85% ee), among several proline derivatives, in aldol reaction of a-ketoester and 4-pentenal, which was a key step in the total synthesis of (H-)-trachyspic acid [224]. 

Cui and coworkers designed novel polymer supported pyrrolidine-thioureas applied in aqueous medium. The immobilised organocatalysts 59 and 60 were found to be efficient in low catalyst loading (2-2.5 mol%) and could be recovered and reused for at least three cycles without any loss of their activity or selectivity (Scheme 19.68). 

Scheme 19.68 Polymer-supported pyrrolidine-thiourea catalysed direct aldol reaction in aqueous medium.

Enantioselective organocatalytic a-chlorination of aldehydes, via enamine catalysis, was independently reported by the groups of MacMillan and Jprgensen in 2004 (Scheme 13.20) [46, 47]. MacMillan utilized his imidazolidinone catalyst and a perchlorinated quinone as the chlorine source, to obtain the S-enantiomer of the a-chloroaldehyde products. Jprgensen employed NCS as the chlorine source, and either a prolinamide catalyst to access the / -enantiomer of the a-chloroaldehyde products, or a Ci-symmetric amine catalyst to access the 5-enantiomer. A recyclable fluorous pyrrolidine-thiourea bifunctional organocatalyst was later employed as an enamine catalyst in this transformation [48]. 

The Mannich reaction and its variants have been reviewed, mainly focussing on asymmetric catalysis thereof. Catalytic, enantioselective, vinylogous Mannich reactions have also been reviewed, covering both direct and silyl dienolate methods. Another review surveys Mannich-type reactions of nitrones, oximes, and hydrazones. A pyrrolidine-thiourea-tertiary amine catalyses asymmetric Mannich reaction of N-Boc-imines (e.g. Ph-Ch=N-Boc) with ethyl-4-chloro-3-oxobutanoate to give highly functionalized product (16). Addition of triethylamine leads to one-pot intramolecular cyclization to give an 0-ethyl tetronic acid derivative (17). ... 

Li and coworkers have studied the reaction between cyclic ketones 133 and nitroolefins 134 in the presence of the chiral pyrrolidine-thiourea bifunctional catalyst 135 (Scheme 3.41), finding that it allows an enantioselective synthesis of 3-oxa- and 3-azabicyclo[3.3.1]nonan-9-one derivatives 136, probably via a domino process comprising allylic displacement and Michael reactions as the key steps [90],... 

Carbonylation of the tetrasubstituted bispropargyiic amine 23 using PdCP and thiourea under mild conditions affords the carboxylated pyrrolidine derivatives 24a and b in good yields. Thiourea is regarded as effective for the oxidative carbonylation of alkynes, but no oxidative carbonylation was observed in this case[21]. 

A number of interesting five-membered ring heterocycles of other types have been reported in the literature as having been derived from thioureas. The pyrrolidin-2-ones 92 were formed by cyclization of 1-(4-broinobutanoyl)-2-thiourcas.212 In a related reaction, Cherbuliez106 produced the pyrrolidine 93 by treatment of the sulfate ester of l-(4-hydroxybutyl)-3-phenyl-2-thiourea with acid or base. 

In this sequence, substitution by 1 mol of dimethylamine first replaces the benzylmercaptan leading to 5-acetyl-2-dimethylamino-6//-l,3-thiazine (197). The thiazine then undergoes attack by dimethylamine excess at C-6, leading to the thiourea (198). The benzylmercaptan liberated in the first reaction may act as a nucleophile (BzS",H2NMe2+), and a different thiourea substituted by dimethylamino and benzylthio groups is obtained. The action of pyrrolidine on 1,3-thiazine-4-ones (194) can be seen as a Michael addition followed by elimination of H2S. In acidic media, the linear compound obtained is cyclized to the pyrimidone (200) (Scheme 80)... 

The Tang group combined the chiral pyrrolidine core with a thiourea function (Scheme 2.43) [29]. Optimal reaction conditions were obtained with 26 under solvent-free conditions and in the presence of n-butyric acid as additive (10 mol%) at 0 °C (Scheme 2.43). The high selectivity of the addition was attributed to the formation of a rigid three-dimensional H-bonded structure in the transition state, in which the enamine was positioned at the correct distance compared to the nitroolefin and allowed an addition from the Re-face of the enamine. 

Zhang et al. investigated the asymmetric 1,3-dipolar cycloaddition of tert-butyl 2-(diphenylmethyleneamino)acetate and nitroalkenes promoted by bifunctional thiourea compounds derived from cinchona alkaloids, affording chiral pyrrolidine derivatives 13 with multisubstitutions. Catalyst lm delivered the best results in terms of catalytic activity, diastereoselectivity and enantioselectivity. Nevertheless, only moderate ee values could be obtained while the diastereoselectivities were generally good (Scheme 10.18) [22]. 

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