Thioureas co-catalysts

TBD alone demonstrated remarkable activities for the ROP of 5-valerolactone and -caprolactone, while both DBU and MTBD can only polymerize these monomers in the presence of the thiourea co-catalyst, due to the discussed monofimctionality. 

In a first batch of lactide ROPs an appropriate solvent and catalyst were determined, see Table3.3. The polydispersity of poly(lactic acid) synthesized in TCM compared to DCM was significantly lower. The addition of thiourea co-catalyst lead to an improved PDI in case of DCM, while no change was observed in TCM. However, when using poly(4-X-styrene)-OH as macroinitiator only the DBU/thiourea co-catalyst system was found to yield copolymer. Considering Fig. 3.12b, the lactide... 

When l,8-diaza[5.4.0]bicycloundec-7-ene (DBU) and N-methylated TBD (MTBD) were used as catalysts instead of TBD, no polymerization was observed, even with catalyst loading of up to 20 mol% [89]. The lack of activity of these amines was accounted for by the absence of any activation of the lactone, and the activation of the alcohol turned out to be not sufficient. However, the polymerization was successfully carried out by the addition of a thiourea as a co-catalyst to activate lactones, as shown in Fig. 23. Again, p-butyrolactone was not reactive enough and was not polymerized [89]. 

Nagasawa and co-worker, in 2004, introduced the first bis-thiourea-type catalyst... 

The low reaction rates usually associated with the MBH reaction can be increased either by pressure [15a, 22, 34], by the use of ultrasound [35] and micro-wave radiation [14a], or by the addition of co-catalysts. Various intra- or inter-molecular Lewis acid co-catalysts have been tested [26, 36, 37] in particular, mild Bronsted acids such as methanol [36, 57d], formamide [38], diarylureas and thioureas [39] and water [27a, 40] were examined and found to provide an additional acceleration of the MBH reaction rate (Table 5.1). 

The superbase DBU was chosen as catalyst for the ROP of lactide because of its fast kinetics, high efficiency, and prevention of transesterification. However, it was decided to add bis(3,5-trifiuoromethyl)phenyl cyclohexylthiourea (thiourea) as co-catalyst to further increase the efficiency and overcome possible steric hindrance arising from the bulkiness of macromolecular initiators. The thiourea was synthesized according to Pratt et al. [41]. Briefly, 3,5-bis(trifluoromethyl)phenyl isothiocyanate (3.37 ml, 18.5 mmol) and anhydrous tetrahydrofuran (20 ml) were added to a flame-dried two-neck round bottom flask. Cyclohexylamine (2.11 ml, 18.5 mmol) was added dropwise via a syringe at room temperature to the stirring solution. After... 

In some cases, the polymerisation is performed in the presence of a thiourea compound as co-catalyst to extend the application of organo-catalysis towards less reactive monomers [63, 65, 69]. These compounds activate the carbonyl group via hydrogen bonding and thus render the carbonyl carbon more electrophilic as shown in Fig. 21.7. 

There is also a modified version of Takemoto s catalyst, which incorporates a benzimidazole heterocycle as the H-bonding donor site in place of the thiourea moiety." This catalyst 82 has been tested with success in several Michael-type reactions of 1,3-dicarbonyl compounds to nitroalkenes, in particular focused on the use of malonates as donors (Scheme 4.20), providing the corresponding adducts in excellent yields and enantioselectivities. p-Ketoesters have also been tested, although in this case the performance of the catalyst was found to be highly dependent on the structure of the p-ketoester employed. It has also to be pointed out that the reaction required the incorporation of a Bronsted acid cocatalyst such as TFA for achieving the best enantioselectivity, although the presence of this co-catalyst did not have any influence in the catalytic activity. 

The use of chiral diols as co-catalyst in aldol reaction led to an improvanent of the achieved results [41]. Thus, when acetone (3a, 8.18 equiv.) was reacted with benzaldehyde (2 h) in DMSO at 0°C catalyzed by (5)-proline (30 mol%) the expected product 4 was obtained in 72% ee, while a 96% ee was achieved in the presence of (R)-BINOL (0.5 mol%). A hypothetical explanation from the authors for this effect is the possible template effect of the chiral diol which may activate and ordered the aldehyde and enamine nucleophile. The same reason was claimed for the beneficial effect achieved by addition of a 10 mol% of (3,5-bistrifluoromethylphenyl)thiourea in the aldol reaction between cyclohexanone (3b) and several aromatic aldehydes catalyzed by proline (1,10 mol%) in hexane a 25°C [42], In this case, reaction times, yields as well as diastereo- and enantioselectivities were improved (75-98%, 76-88% de, 98-99% ee), with these results being also attributed to the enhancement of the proline solubility by the formation of a host-guest proline-thiourea complex. 

Recently, 4-substituted prochiral cyclohexanones (10 equiv.) have been efficiently desymmetrized by their reaction with aromatic aldehydes catalyzed by (5)-prohne (1, 20 mol%) in the presence of 3,5-dimethylphenyl 3,5-bisfluoromethylphenyl thiourea as co-catalyst (20 mol%) in toluene at 25°C [53], affording the corresponding aldol products in good yields (68-87%), diastereoselectivities up to 78% de and in high enantioselectivities (94-99% ee). 

Nagasawa and co-workers [108] were the first to introduce chiral thiourea catalyst to the BH reaction. They synthesized a tra 5-(li ,2i )-l,2-diaminocy-clohexane-derived bisthiourea 57 as catalyst to promote the BH reaction of cyclohexanone and aldehydes in the presence of DMAP co-catalyst (Scheme 9.31). The dual activations of both substrates were proposed to account for excellent enantioselectivites (for aliphatic aldehydes) and reactivity enhancement. Later on, chiral bisthiourea 58 was prepared and applied as catalyst under solvent-free conditions [109]. Around at the same time, Raheem and Jacobsen [110] demonstrated that chiral thiourea 59 was an efficient catalyst for the DABCO promoted aza-BH reaction of IV-nosyl imines and methyl acrylate. Chiral Hg-binaphthyl bisthiourea 60 was then prepared by Shi and Liu [111] and used as the co-catalyst of DABCO in the reaction of cyclic enones with aldehydes, providing the products in high enantioselectivities. The application of chiral bisthiourea 61 as catalyst resulted in the formation of S configurational products in good to excellent enantioselectivities (Scheme 9.31) [112]. Moreover, thiourea 62 turned out to be an efficient catalyst in the reaction of cyclohex-2-enone with aldehydes co-catalyzed by triethylamine under solvent-free conditions [113]. 

Lactol (134, 2-hydroxy-THF) can a-alkylate pentan-2-one under mild conditions, using a proline derivative and an unsymmetrical (but achiral) thiourea as co-catalysts, to give THF derivatives (135), with some enantioselectivity. However, kinetic studies show that the ee is time-dependent, and typically decreasing. While racemization of (135) explains some of the effect, it also appears that there are two competing mechanisms with opposing enantioselectivities operating." ... 

L-Threonine-derived catalysts were demonstrated to be remarkably effective for the direct aldol reaction. Lu et al. investigated the potential of serine and threonine analogs in the direct asymmetric aldol reaction in aqueous medium [28]. While L-serine and L-threonine were found to be ineffective, sUylated threonine and serine derivatives were wonderful catalysts for the direct aldol reaction of cyclohexanone and aromatic aldehydes in the presence of water, affording the aldol adducts in excellent yields and with nearly perfect enantioselectivities. L-Serine-derived 9a was inferior to the corresponding threonine-based catalysts. The reaction could be extended to hydroxyacetone, and sy -diols were obtained with very good enantioselectivities (Scheme 3.6). Subsequently, Teo and coworkers also employed silylated serine catalysts for the same reaction [29]. Very recently, Cordova et al. [30] reported a co-catalyst system consisting of 8a and l,3-bis[3,5-bis(trifluoromethyl)phenyl]thiourea, and applied such catalytic pairs to the direct aldol reaction between ketones and aromatic aldehydes both cyclic and acycUc ketones were found to be suitable substrates. 

Seidel and coworkers have developed a new concept for asymmetric nucleophilic catalysis, in which an achiral nucleophile is used in combination with a chiral hydrogen-bonding catalyst. The application of this concept to the Steglich rearrangement implied the use of simple DMAP as the achiral nucleophile and of the thiourea 17 as the chiral hydrogen-bond donor co-catalyst (Scheme 40.24) [30]. 

Eventually, the use of a catalytic amount of chiral amide-thiourea anion-receptor 116 in conjunction of with achiral nucleophUic co-catalyst 120 allowed for the resolution of several l,2-diaryl-l,2-diaminoethanes (Scheme 41.54) with useful levels... 

Some chiral mono-, acyl- and di-thioureas have been used as ligand for the Rh-catalysed asymmetric hydroformylation of styrene. Although thiourea ligands form inactive systems with [Rh(COD)Cl]2 as the catalyst precursor, in standard conditions (40 °C, 40 bar CO -l- H2 1/1), the cationic Rh complex [Rh(COD)2]Bp4 combined with monothioureas as the ligand showed moderate to good activity (Scheme 29) [114]. 

Dicarbonyl donors are excellent Michael donors in asymmetric conjugate addition to a,p-nnsatnrated ketones. Wang and co-workers [79] applied chiral Cinchona-thiourea catalyst 131 to various carbon donors in the addition to aromatic enones. A diverse array of nucleophiles, mainly 1,3-dicarbonyls proceeded smoothly in the conjugate addition to a,p-unsaturated enone 132 (Scheme 29). 

Ricci et al. [85] reported the use of a quinidine-derived chiral catalyst in the asymmetric addition of nitromethane to iV-Boc imine 40. At around the same time, S chans and co-workers used a dihydroquinidine-derive chiral thiourea DHQD-134 applicable to nitromethane and nitroethane 149 [86]. The application of nitroethane conveniently generates a tertiary stereogenic center in the P-nitroamine product 151. The methodology presented by Schaus is also applicable to novel... 

The scope of Michael additions with catalysts containing cyclohexane-diamine scaffolds was broadened by Li and co-workers [95]. When screening for a catalyst for the addition of phenylthiol to a,p-nnsatnrated imides, the anthors fonnd that thiourea catalyst 170 provided optimal enantioselectivities when compared to Cinchon alkaloids derivatives (Scheme 41). Electrophile scope inclnded both cyclic and acyclic substrates. Li attributed the enantioselectivity to activation of the diketone electrophiles via hydrogen-bonding to the thiourea, with simultaneous deprotonation of the thiol by the tertiary amine moiety of the diamine (170a and 170b). Based on the observed selectivity, the anthors hypothesized that the snbstrate-catalyst... 

Takemoto and co-workers designed a small hbrary of thiourea cyclohexane-diamine derived catalysts for the Michael reaction of malonates to nitrolefins [15]. The authors observed an interesting trend in catalysis the reaction only proceeded enantioselectively and in decent yields when the catalyst possessed both thiourea... 

Berkessel and co-workers have demonstrated the utility of the bifunctional cyclohexane-diamine catalysts in the dynamic kinetic resolution of azalactones (Schemes 60 and 61) [111, 112]. The authors proposed that the urea/thiourea moiety of the catalyst coordinates and activates the electrophilic azlactone. The allyl alcohol nucleophilicity is increased due to the Brpnsted base interaction with the tertiary amine of the catalyst. 

Wang and co-workers reported a novel class of organocatalysts for the asymmetric Michael addition of 2,4-pentandiones to nitro-olefms [131]. A screen of catalyst types showed that the binaphthol-derived amine thiourea promoted the enantiose-lective addition in high yield and selectivity, unlike the cyclohexane-diamine catalysts and Cinchona alkaloids (Scheme 77, Table 5). 

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