Background and Originality Content
Spirocyclic skeletons have attracted tremendous interest among synthetic and medicinal chemists, not only due to their peculiar high rigidity and unique three-dimensional geometries, but also because they are ubiquitous in natural products and possess multiple pharmaceutical activities.[1] In particular, spiro-isoindolinone is an important scaffold that constitutes the core structure in biologically active molecules endowed with anticancer, aldose reductase inhibiting, and TNF-α inhibiting activities (Figure 1).[2] Owing to its significance, the development of practical and economical methods for the preparation of spiro-isoindolinone derivatives have always attracted considerable interest for the synthetic community.[3]
Figure 1 Bioactive molecules containing spiro isoindolinone moieties.
In recent years, directing group-assisted C−H bond activation (CHA) strategy catalyzed by transition metal (TM) has evolved into one of the practical tools for the construction of C−C and C−heteroatom bond due to its excellent atom- and step-economy.[4] In particular, as the high natural abundance of the first row (3d) transition metals renders the catalytic process cost-effective, it is a great privilege to develop earth-abundant metal-catalyzed inert CHA system performing reactions with common substrates.[5] In this regard, cobalt has emerged as a versatile, efficient and less toxic metal-catalyst for CHA to construct polycyclic molecular frameworks.[5-6] On the other hand, a -diazo carbonyl compounds have been frequently used as intriguing coupling partners in CHA through dediazonization to generate metal-carbene species with high flexibility and diverse reactivity for the synthesis of various organic functional molecules.[7] However, cobalt-catalyzed CHA carbene insertion reaction has not been well exploited owing to lack of efficient catalytic systems, and most of these transformations were promoted by cyclopentadienyl (Cp*) Co(III) complexes, rather than cheap and commercially available cobalt salt. Based on the fact that 8-aminoquinoline moiety are effective bidentate directing group and can be conveniently removed, it has been used as a popular directing group in TM-catalyzed CHA reactions.[8] Recently, Li and co-workers developed a unique strategy to provide a controllable α- or β-functionalization of α-diazoketones with aromatic amides for the synthesis of isoindolinones via using a non-Cp* cobalt catalyst under ligand-free conditions (Scheme 1a).[9] Very recently, Song’s group disclosed an efficient Co(acac)2catalyzed three-component coupling of benzamides with diazo compounds and tert -butyl hydroperoxide, providing products with a quaternary carbon center in moderate to excellent yields (Scheme 1b).[10] However, the cobalt-catalyzed C−H bond activation/spiroannulation reaction using diazo compound as carbene precursor to construct spirocyclic framework has not been reported. Enlightened by the aforementioned research and as a continuation of our interest in TM-catalyzed CHA[11] and diazo chemistry,[12] we envisaged a tentative plan to obtain spiro indene-2,1’-isoindolinones from Co-catalyzed [4 + 1] spiroannulation reaction of aromatic amides with 2-diazo-1H -indene-1,3(2H )-dione. Experimental studies showed that the reaction could selectively furnish the initially designed spirocyclic product through [4 + 1] spiroannulation or the unexpected spiro isochroman-3,1’-isoindolinone derivative through [4 + 1 + 1] oxidative spirocyclization under different reaction conditions. Notably, the formation of spiro isochroman-3,1’-isoindolinone derivatives should involve a Baeyer-Villiger oxidation of the in situ formed spiro indene-2,1’-isoindolinones with O2 as a cheaper and cleaner oxygen source (Scheme 1c). It is worth mentioning that [Cp*RhCl2]2, [Cp*IrCl2]2 and [Ru(p -cymene)Cl2]2 were found to be inactive in the oxidative spiroannulation process. To the best of our knowledge, such reaction patterns have not been disclosed previously. Herein, we would like to report the detailed results.
Scheme 1 Co-catalyzed CHA of aromatic amides with diazo compounds
Results and Discussion
At the outset of our studies, the reaction feasibility was tested using 8-aminoquinolinebenzamide (1a ) with 2-diazo-1H -indene- 1,3(2H )-dione (2 ) as the model substrates in the presence of 10 mol % [Cp*Co(CO)I2]2and 2 equiv. of Ag2CO3 in 1,2-dichloroethane (DCE) at 100 °C for 15 h (Table 1, entry 1). It is gratifying that the desired product was obtained in 18% yield as a white solid. Inspired by this positive result, we then screened other simple cobalt salts including Co(OAc)2, Co(acac)2, Co(acac)3 and Co(NO3)2· 6H2O (Table 1, entries 2-5). Among them, Co(acac)2 was the most effective catalyst that outperformed others to deliver 3ain 86% yield. Subsequently, we tested various solvents (toluene, CH3CN, tetrahydrofuran (THF), dioxane, ethyl acetate (EA), CH3OH) as alternative solvents, and the results confirmed that EA was the most appropriate solvent for this [4 + 1] oxidative spirocyclization (Table 1, entries 6-11). Next, Ag2O, AgOAc, Cu(OAc)2 and Mn(OAc)2 were tried as oxidant in place of Ag2CO3. It turned out that they were less effective (Table 1, entries 12-15). As for the loading of oxidant, we found that using 3 equiv. of Ag2CO3increased the yield of 3a to 97% (Table 1, entries 16-17). Moreover, decreasing or increasing the reaction temperature did not give better yield of 3a (Table 1, entries 18-19). Furthermore, it should be noted that the reaction run in CH3CN or dioxane not only afford 3a in 57% and 73% yields, but also generate another unexpected spiro product 4a in 26% and 19% yields, respectively (Table 1, entries 7 and 9). It should be noteworthy that the structure of 4a was ascertained by X-ray single-crystal diffraction (see the SI). This interesting result prompted us to have a further optimization study with the prospect to find suitable reaction conditions to realize selective and efficient synthesis of 4a . When the reaction was carried out in the presence of 3 equiv. of oxidant in CH3CN for 24 h, the yield of 4a increased to 41% (Table 1, entry 20). Other oxidant such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO),tert -butyl hydroperoxide (TBHP) and K2S2O8 were found to be ineffective and delivered only product 3a (Table 1, entries 21-23). To our delight, when this [4 + 1 +1] oxidative spirocyclization reaction was carried out under an oxygen atmosphere,4a was generated in 78% yield. In this case, only trace amount of 3a was detected (Table 1, entry 24).
Table 1 Optimization studies on the formation of 3aand 4a a