Abstract
An efficient two-step synthesis of symmetrical and unsymmetrical tetrahydrospirobiquinolines from o-azidobenzaldehydes is reported. A novel series of tetrahydrospirobiquinolines was prepared by sequential double-aldol condensation with acetone, cyclopentanone, and cyclohexanone to form the corresponding o,o′-diazido-dibenzylidene-acetone, -cyclopentanone, and -cyclohexanone derivatives, respectively, and hydrogenation–spirocyclization. The spirodiamines were further derivatized by electrophilic aromatic bromination, Suzuki coupling, and N-alkylation, all of which proceeded with preservation of the spirocyclic core.
Highlights
Access to a broad range of structurally diverse nitrogen heterocycles is important in probing and understanding biological functions and may lead to the discovery of new medicines and agricultural chemicals
We sought to synthesize a range of tetrahydrospirobiquinolines, 14, from the doublealdol condensation of o-azidobenzaldehydes with ketones to provide the corresponding diazido-dibenzylidene-ketones, followed by reductive cyclization (Figure 3)
Initial studies were directed toward the synthesis of tetrahydrospirobiquinoline 14a. o-Azidobenzaldehyde 15a was allowed to react with acetone in the presence of aqueous sodium hydroxide to afford dienone 17a (94% yield)
Summary
Access to a broad range of structurally diverse nitrogen heterocycles is important in probing and understanding biological functions and may lead to the discovery of new medicines and agricultural chemicals. Fused-ring nitrogen heterocycles are considered privileged scaffolds in both medicinal chemistry and agrochemistry.[1] There is a need to expand the structural classes of amines, especially to those that are C-(sp3)-rich, to enhance the structural complexity and for better interaction with biological targets.[2] Whereas spiroketals, including benzannulated systems,[3−7] are common scaffolds in biologically active heterocyclic compounds and spirocyclic compounds with a single oxygen and single aminonitrogen attached to the spirane center are known,[8,9] spirodiamines, which contain two amino-groups at that center, are far less well studied.[10−13] The spirodiamine core is known in several natural products, including (−)-isochizogamine (1),[14−16] isoschizogaline (2),[17] (+)-melodinine-E (3),[18−20] and the immunosuppressant (±)-spiroreticulatine (4) (Figure 1).[21]. We demonstrated that spirodiamine 6 underwent metal complexation or a reaction with electrophiles, with either preservation of the spirocyclic core or ring opening and derivatization of 4-aminobutyl-1-tetrahydropyridine core 7 (Figure 2).[10]
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