Indole skeletons are widely used in drug research and development as a “privileged structure”, while spirocyclic scaffold as a common structural unit, usually plays an important role in the bioactivity and physicochemical properties of molecule skeletons. Hence, spiroindoles which incorporate both indole and spirocycle units have great significance and widespread applications in pharmaceutical field, and substantial progress has been made in the field for their construction and modification. C—H Activation via directing group's assistance has emerged as a powerful approach in the field of organic synthesis. To date, various 2- and 3-indolyl-tethered aza-spiro-centres via C—H activation have been successfully achieved. However, due to the inherent reactivity of the pyrrole side of the indole, introduction of spiro-containing systems onto the benzenoid core of indole still remains challenging. Here, by installing an appropriate directing group onto the C(3) position of indole, a mild and efficient method of Rh(III)-catalyzed selectively C(4)—H activation/cyclization of indole with diazo compound was developed. As a result, a series of novel aza-spiro[4,5]indole derivatives were obtained in mild to excellent yields. The protocol showed excellent functional group tolerance. Gram-scale synthesis demonstrated the utility of this protocol, and further modification via click chemistry offered the novel scaffold as a versatile spiro linker. A general procedure for the synthesis of spiroindole derivatives is described as the following: to a solution of N-(pivaloyloxy)-indole- 3-carboxamide (0.1 mmol), [Cp*RhCl₂]₂ (1.6 mg, 2.5 mol%) and NaOAc (1.6 mg, 20 mol%) in CH₃CN (1 mL) was added diazooxindole (0.12 mmol) under air. Then the reaction mixture was stirred at room temperature for 12 h. After completion of the reaction, the resulting mixture was diluted with 25 mL of EtOAc, and filtered through a celite pad. Then the filtrate was concentrated under vacuum to give the crude product, which was purified via silica gel to obtain the corresponding spiroindole product.

Key words: indole spirocycle, C—H activation, Rh-catalyst