One‐Pot Synthesis of Densely Substituted 1,2,3,4‐Tetrahydro‐1,6‐naphthyridine Mediated by Isocyanide‐Assisted Reduction of C−C Double Bond

Abstract

Molecular architectures possessing the combination of heteroaromatic and saturated N‐heterocycles are of great importance because of their higher solubility in the gastrointestinal tract due to weak crystal packing in the three‐dimensional structure. Other biological activity like selectivity is also increased in a positive way. However, compared to fully aromatic fused heterocycles, synthesis of partially saturated fused heterocycles is much more difficult since the later needs greater control over the reaction conditions. In this context, 1,2,3,4‐tetrahydronaphthyridines (THNADs) are essential part of pharmaceutically important natural products and drug molecules. However, the synthesis of THNAD is seldom reported in literature. To the best of our knowledge, this is the first report of metal‐free one pot synthesis of 1,2,3,4‐tetrahydro‐1,6‐naphthyridines without starting from any nitrogen heterocycles in water. Moreover, this study discloses the involvement of isocyanide in a chemical reaction whose net effect is only to reduce a C=C bond which is unusual in isocyanide literature.

I2-promoted formal [3 + 1 + 1 + 1] cyclization to construct 5-cyano-1H-pyrazolo[3,4-b]pyridine using malononitrile as a C1 synthon

“…Malononitrile has multiple reaction sites and typically participates in multi-component tandem cyclization reactions as a C2 or C3 synthon [Scheme 2A(b and c)]. 3,4 For example, spirooxindole-pyran derivatives and benzopyrano[2,3- c ]pyrazole derivatives were reported by Zhang's group and Jagdamba Singh's group, respectively, using malononitrile as a C2 synthon and C3 synthon under the promotion of visible light, respectively. 5 In recent years, it has also been reported that malononitrile participates in cyclization reactions as a C1 synthon under base- or transition metal-catalyzed reaction conditions for the construction of gem-dicyano compounds [Scheme 2A(a)].…”