Urea/thiourea-based catalysts

Initial mechanistic analysis of the Strecker reaction catalyzed by a urea-based organocatalyst (Scheme 3.18) revealed that the catalytic activity is provided by the urea functionality of structurally complex catalyst 1. However, further studies revealed a bifunchonal character of urea and thiourea-based catalysts " as well as the possibility of multiple mechanistic pathways in catalysis of nucleophile-electrophile addition reactions. " Simplified but sufficiently effective (thio)urea catalysts 4a and 4b were used in the hydrocyanation reaction (Scheme 3.19) that was subjected to a combined experimental and computational study. °... 

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. 

The catalytic potential of base functionalities has been referred to in the previous chapter (see Sect. 7.4), wherein the interplay between an acidic (thio-)urea and a basic amine separated by a chiral linker was shown to enable the simultaneous activation of both the electrophile and nucleophile. In addition to such brfunctional thiourea-containing acid-base catalysts, chiral catalysts containing Lewis or Br0nsted-) base functionality as the sole catalyticaUy active group as weU as those having another H-bond donor like a hydroxy group e.g. Cinchona alkaloids) have found widespread applications in asymmetric catalysis (443-449). 

Figure 6.15 Polymer-bound Schiff base thiourea catalyst 41 bearing 5-pivaloyl-substitution and its nonimmobilized urea analog 42 optimized for the asymmetric Strecker reaction of aromatic and aliphatic aldimines.

It was found that both the replacement of the secondary amide unit with a bulkier tertiary amide and the incorporation of a thiourea moiety instead of the urea unit resulted in a significant improvement in stereoinduction (from initial 80% ee obtained with 42 to 97% ee). This led to the identification of hydrogen-bonding Schiff base thiourea catalyst 47, while the urea derivatives 43-46 gave lower ee values (Figure 6.16). 

Ricci and co-workers introduced a new class of amino- alcohol- based thiourea derivatives, which were easily accessible in a one-step coupling reaction in nearly quanitative yield from the commercially available chiral amino alcohols and 3,5-bis(trifluoromethyl)phenyl isothiocyanate or isocyanate, respectively (Figure 6.45) [307]. The screening of (thio)urea derivatives 137-140 in the enantioselective Friedel-Crafts reaction of indole with trans-P-nitrostyrene at 20 °C in toluene demonstrated (lR,2S)-cis-l-amino-2-indanol-derived thiourea 139 to be the most active catalyst regarding conversion (95% conv./60h) as well as stereoinduction (35% ee), while the canditates 137, 138, and the urea derivative 140 displayed a lower accelerating effect and poorer asymmetric induction (Figure 6.45). The uncatalyzed reference reaction performed under otherwise identical conditions showed 17% conversion in 65 h reaction time. 

The catalyst screening experiments were performed in the asymmetric Henry addition of nitromethane (10 equiv.) to 4-nitrobenzaldehyde in the presence of DABCO (20mol %) as the base and (thio)ureas 157, 158, 163, and 170-175 (each 10mol% loading). After 12h in reaction time at room temperature and in THF as the solvent, the corresponding Henry adduct was obtained in excellent yields (99%) but with very low ee values (7-17%) nearly independently of the sterical hindrance of the axiaUy chiral backbone skeleton (e.g., 172 and 174 each 99% yield 11% ee). Thioureas appeared slightly more enantioselective (e.g., 163 83% yield, 33% ee 171 99% yield, 15% ee) than their urea counterparts probably due... 

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