NNMeMeH2NNH2Ar–N=C=Snn(±)-5:n=1(±)-6:n=0NNMeMeHNNHnnHNArSNHSAr(±)-2:n=1,Ar=Ph,52% (±)-3:n=1,Ar=3,5-(CF3)2C6H3,71% (±)-4:n=0,Ar=3,5-(CF3)2C6H3,60% THF
Scheme 1. Synthesis of the new thiourea catalysts (±)-2–4.
At first, we focused on the catalytic activity of racemic thiourea derivatives of Tröger’s base for Michael additions. The issue was worth being investigated since the basicity of Tröger’s base markedly differs from that of trialkylamines, which are typically used in the design of bifunctional catalysts. We studied the reactivity of thiourea catalysts (±)-2–4 in a popular and well-studied model reaction, namely, in the addition of selected malonate nucleophiles to trans- ß-nitrostyrene. The results obtained are summarized in Table 1.
When trans-ß-nitrostyrene was treated with 2 equivalents of ethylmalonate 7a and 10% of catalysts (±)-2–4 in toluene, no conversion was observed (Table 1, entries 3–5). However, the addition of Et3N to the system resulted in a quantitative conversion (Table 1, entry 6). These first results clearly highlighted that the tertiary amines of Tröger’s base scaffold (pKa1 = 3.25)10 are not basic enough to activate the malonate (pKa = 16.4),11 while more basic Et3N (pKa = 9.0)11 in the presence of thiourea is highly efficient. This observation supported the early suggested bifunctional mechanism of catalytic activation,8 since only 16% conversion was observed when Et3N was used as a catalyst and no conversion when Tröger’s base (±)-1 was used as a catalyst (Table 1, entries 1,2).
On the basis of this correlation between pKa of the activating base and the rate of conjugate addition, one may expect a higher activity of bifunctional catalysts (±)-2–4 for more acidic nucleophiles. Indeed, the reaction of CH2(CN)2 7b with trans-ß-nitrostyrene in the presence of (±)-2–4 resulted in the formation of the desired product (±)-8b. Prolonged reaction time only slightly increased conversion (Table 1,entries 7–10). Catalyst (±)-3 demonstrated the best performance in the addition of Meldrum’s acid 7c to give (±)-8c (Table 1, entries 15,16). The recurrent inactivity of catalyst (±)-4 may suggest that the introduction of the additional CH2 linkage in (±)-2,3 between the aromatic ring and the thiourea provides an additional flexibility to the molecule, which is crucial for the activation of the reagents.
