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