Thiourea chiral derivatives

Scheme 6.55 Design principle of amine-functionalized bifunctional thiourea organocatalysts derived from privileged monofunctional thiourea 9 cooperating with an amine base additive (A) and basic bifunctional mode of action of chiral amine...

As to the nucleophiles that can be applied in the nucleophilic reactions, ammonia and amines, water and alcohols, and mercaptans have been mentioned already. Sulfide and thiourea have been used only with the achiral ferrocenylmethylium ion [97]. To obtain chiral derivatives of 1-ferrocenyl-ethylmercaptan, substitution of the acetate with potassium thioacetate in acetic acid, followed by reduction with LiAlH4, was found appropriate [98, 99]. Reaction of (R)-l-ferrocenylethanol with NaH and... 

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]. 

H-pyrane] derivatives in the presence of isatins, malononitrile, and acetylacetone/ethyl 3-oxobutanoate [103]. Yan and coworkers showed in 2012 that chiral tertiary amine-thiourea (158) derived from quinine can catalyze a three-component reaction between isatins 118, malononitrile (119), and a-phenyl-isocyanoacetate (217) (Scheme 2.75) [104]. The process affords dihydropyrryl-spirooxindoles 218 and involves an initial Knoevenagel condensation of 118 and 119 followed by the nucleophilic anion attack of 217 (see the key transition state intermediate on Scheme 2.75). Final intramolecular cyclo-addition affords the expected compounds where H bond interactions are supposed to direct the attack of isocyanate anion and, consequently, contfol the enantioselectivity. One year later, Xu s group used a bifunctional cinchona-based squaramide to catalyze multicomponent cascade reaction to synthesize spiro[pyrrolidin-3,2 -oxindoles] via 1,3-proton shift and [3h-2]... 

A new class of chiral bifunctional thiourea catalysts derived from trans-2-amino-l-(diphenylphosphino)cyclohexane was developed by Jacobsen and Fang in order to be applied to a highly enantioselective synthesis of a wide range of 2-aryl-2,5-dihydropyrrole derivatives. This strategy was based on a [3-1-2] cycloaddition between an A-phosphinoyl imine and an allene in the presence of TEA and water as additives. High yields combined with excellent enantioselectivities of up to 98% ee were observed in all cases of substrates, as shown in Scheme 6.19. 

Besides dihomooxacalix[4]arenes bearing carbonyl groups at their lower rims (28-32) reported before 2000 [26, 27], 9a has been used to prepare the inherently chiral triethyl ester 33 [28] and the tetra(2-pyridyl) 34 [29] derivatives. Depending on the reaction conditions (use of 80 % NaH instead of 95 % NaH and less reaction time), partial 0-alkylation of 9a with 2-(chloromethyl)pyridine hydrochloride was also achieved by Marcos and coworkers [29]. Five of the eight possible partially alkylated compounds 35 (mono-substituted 35b and di-substituted 35c-f) were obtained in the cone conformation. Recently, the same group reported the preparation of a series of bidentate urea (36-41) and thiourea (42) derivatives in a four step synthesis from the parent compound 9a [30, 31]. Their structure determination in solution by NMR spectroscopy (and in the solid state for compounds 38 and 41 by single crystal X-ray crystallography) indicated the cone conformation for all the compounds. The cone tetraethyl ester 43 was also described [11]. 

Treatment of cyclic carbonates of 1,2-diols with thiocyanate ion at temperatures of 100 °C or higher yields thiiranes (Scheme 145) (66CRV297, 75RCR138). Thiourea cannot replace thiocyanate satisfactorily, and yields decrease as the carbonate becomes more sterically hindered. The reaction mechanism is similar to the reaction of oxiranes with thiocyanate (Scheme 139). As Scheme 145 shows, chiral thiiranes can be derived from chiral 1,2-diols (77T999, 75MI50600). 

Except this particular example, the other possibilities such as the desulfurization of cyclic thioureas or the vacuum thermolysis of methoxy derivatives [1-5], has never been used for the preparation of chiral diaminocar-... 

Chiral amines and diamines are readily available substrates for the synthesis of ligands for transition metal-catalysed reactions since they can easily be transformed into chiral ureas and thioureas. Therefore, several groups have prepared chiral symmetrical ureas and thioureas, dissymmetrical ureas and thioureas, amino-urea and thiourea derivatives. Finally polyureas and non-soluble polythioureas were also prepared and tested as ligands for asymmetric catalysis. 

Treatment of a chiral amine with phosgene is the cheapest way to prepare symmetrical ureas [29]. Nevertheless, due to the toxicity and reactivity of that reagent, it can advantageously be replaced by triphosgene [30] or l,l -carbonyldiimidazole [31-34] or other derivatives such as l,l -carbonyldi-2(lH)-pyridinone [35]. This procedure can be extended to thiophosgene (Scheme 1) and its thio-analogues, such as l,l -thiocarbonyldi-2(lH)-pyridinone to produce thioureas [36] chiral diamines can thus be transformed into the corresponding monoureas or monothioureas. 

Finally, nitrone cyanation were performed with non-chiral urea and thiourea derivatives, the latter being more efficient for this process. No chiral compound has been described yet (Scheme 41) [ 159]. 

Aromatic thioureas were more active than alkyl (octyl, cyclohexyl) derivatives. Thioureas with trilluoromethyl substituents were even more effective. The same group also showed that these organocatalysts can act as weak Lewis acids and are thus able to alter the stereochemistry of the Diels-Alder reaction between cyclopentadiene and chiral acrylamide derivatives (Scheme 49) [167]. 

Chiral thioureas have been synthesized and used as ligands for the asymmetric hydroformylation of styrene catalyzed by rhodium(I) complexes. The best results were obtained with /V-phenyl-TV -OS )-(l-phenylethyl)thiourea associated with a cationic rhodium(I) precursor, and asymmetric induction of 40% was then achieved.387,388 Chiral polyether-phosphite ligands derived from (5)-binaphthol were prepared and combined with [Rh(cod)2]BF4. These systems showed high activity, chemo- and regio-selectivity for the catalytic enantioselective hydroformylation of styrene in thermoregulated phase-transfer conditions. Ee values of up to 25% were obtained and recycling was possible without loss of enantioselectivity.389... 

Chiral fe-thiourea-type catalysts effectively provide the Baylis Hillman reaction with cyclohexenone and aldehydes.181 In several reactions, thiourea derivatives have been used as significant and specific catalyst because of their intermolecular hydrogen bonding ability (Scheme 74).182 186... 

Since Curran and Kuo and Schreiner and coworkers reported that urea and thiourea derivatives act like Lewis acid catalysts, several chiral urea and thiourea catalysts have been designed by Jacobsen et al. and Takemoto et al. ... 

The acyl-Pictet-Spengler reaction is also catalyzed by chiral thiourea derivative 6 to provide M-acetyl p-carbolines in high enantioselectivities. Notably, thiourea derivatives can activate not only electronically distinct imine derivatives such as N-alkyl and N-Boc imines but also a weakly Lewis basic N-acyhminium ion with high enantioselectivity using a chiral hydrogen bond donor (Scheme 12.4). 

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