Switchable Chemoselectivity in [3 + 3] Annulation of β,γ-Unsaturated α-Ketoesters and 1H-Pyrazol-5-amines by Cooperative Acid Catalysis with Ni^II and In^I

Abstract

The exchange of the metal ion from Ni(II) to In(I) leads to a switch in the chemoselectivity of the [3 + 3] annulation of β,γunsaturated α-ketoesters and 1H-pyrazol-5-amines in the presence of phosphoric acid 1, affording functionalized 1H-pyrazolo [3,4-b]pyridines 4 in up to 97% yields and highly enantioselective 4,5-dihydro-1Hpyrazolo [3,4-b]pyridines 5 in up to 92% yield and 99% ee. pyridine and dihydro-1H-pyrazolo[3,4-b]pyridine derivatives are privileged structural motifs, occurring frequently in numerous natural products, pharmaceuticals, and biologically active molecules (Figure 1). 1−3 Therefore, numerous efforts have been devoted to developing efficient catalysts for the selective addition of α,β-unsaturated carbonyls with 1H-pyrazol-5-amines. 4−11 Although many efforts have focused on the α,β-unsaturated carbonyls in formal [3 + 3] cycloaddition with enamines, 12−14 the exploitation of β,γunsaturated α-ketoesters remains less studied. 15−18 This is speculatively attributed to chemoselectivity issues arising from the differentiation of 1,2-and 1,4-addition pathways. In 2010, we first developed asymmetric binary-acid catalysis, 19 which resulted in a synergistic effect for catalysis in regio-, 20 diastereo-, 21 and enantiodivergent 22,23 reactions. Herein, we report a metal salt-regulated strategy for the manipulation of the chemoselectivity in cooperative acid-catalyzed [3 + 3] annulation of β,γ-unsaturated α-ketoesters and 1H-pyrazol-5-amines (Scheme 1), which was initiated via 1,4-addition. In two catalytic systems, a simple swap of the metal salt from Ni(OTf) 2 to InCl switches the enamine-imine tautomerism, giving the 1H-pyrazolo [3,4-b]pyridines 4 in up to 97% yield in an oxidation of enamines and 4,5-dihydro-1H-pyrazolo [3,4b]pyridines 5 as imines in up to 92% yield and with up to >99% ee, respectively. In fact, compared to other metal