The first enantioselective synthesis of biologically active 6-amino-5-cyanodihydropyrano [2,3-c] pyrazoles has been achieved through a cinchona alkaloid-catalyzed tandem Michael addition and Thorpe-Ziegler type reaction between 2-pyrazolin-5-ones and benzylidenemalononitriles. The reaction may also be carried out in a three-component or a four-component fashion via the in situ formation of these two components from simple and readily available starting materials. The desired products were obtained in excellent yields with mediocre to excellent enantioselectivities (up to >99% ee).
KeywordsDihydropyrano [2, 3-c] (Fig. 1). 1g Due to their biological significance, 1 there has been considerable interest in developing synthetic methods for 6-amino-5-cyanodihydro-pyrano [ 2,3-c]pyrazoles. [2][3][4][5][6] These compounds may be readily obtained from the reaction of 4-arylmethylene-5-pyrazolone and malononitrile, 2,3 or 2-pyrazolin-5-ones and benzylidenemalononitriles. 3 The overall reaction is a tandem Michael addition and a Thorpe-Ziegler type reaction (an enol addition to a cyano group) followed by tautomerization. 3 It should be pointed out that these compounds may exist in the 1,4-dihydro or 2,4-dihydro tautomeric forms when the N1 position is unsubstituted. Although most studies assigned the 1,4-dihydro structure to these derivatives, 2-4 recent X-ray crystallographic data prefer the 2,4-dihydro tautomer. 5,6 Since benzylidenemalononitriles may be synthesized in situ from aromatic aldehydes and malononitrile under the reaction conditions, these compounds may also be synthesized through a three-component reaction of 2-pyrazolin-5-ones, malononitrile, and aromatic aldehydes. 4,5 Most recently, a four-component synthesis by using hydrazine hydrate, acetoacetate, malononitrile, and aromatic aldehydes has also been demonstrated. 6 Initially we studied the synthesis with 3-methyl-2-pyrazolin-5-one (10a) and benzylidenemalononitrile (11a) as the model substrates. Several readily available cinchona alkaloid derivatives (Scheme 1) were screened as the catalysts. The results are summarized in Table 1.As shown in Table 1, when quinine (1) was used as the catalyst in CH 2 Cl 2 at rt, a yield of 80% of the product 12a was obtained with a low ee value of 23% (entry 1). In contrast, when cupreine (2) was used as the catalyst, product 12a was obtained in high yield of 92% with an excellent ee value of 96% (entry 2). Nevertheless, 9-epi-cupreine (3) leads to a lower ee value of 65% (entry 3). When 9-epi-amino-9-deoxyquinine (4) was applied as the catalyst, a racemic product was obtained (entry 4). Similarly, poor enantioselectivities were achieved with quinine-derived thiourea catalysts 5-7 (entries 5-7). A low ee value of 22% for the opposite enantiomer was also obtained when quinidine (8) was used as the catalyst (entry 8). It is most surprising that cupreidine (9), the pseudo-enantiomer of cupreine (2), also leads to poor enantioselectivity of the other enantiomer (6%, entry 9). Thus, this screening identified cupre...