Aza-[4 + 2]-cycloaddition of benzocyclobutenones into isoquinolinone derivatives enabled by photoinduced regio-specific C-C bond cleavage

Abstract

The activation of C-C bond of benzocyclobutenones under mild reaction conditions remains a challenge. We herein report a photoinduced catalyst-free regio-specific C1-C8 bond cleavage of benzocyclobutenones, enabling the generation of versatile ortho-quinoid ketene methides for aza-[4 + 2]-cycloaddition with imines, which offers a facile route to isoquinolinone derivatives, including seven family members of protoberberine alkaloids, gusanlung A, B, D, 8-oxotetrahydroplamatine, tetrahydrothalifendine, tetrahydropalmatine, and xylopinine. Furthermore, the catalytic enantioselective version of this strategy is also realized by merging synergistic photocatalysis and chiral Lewis acid catalysis. Mechanistic studies provide compelling evidence to rationalize the photoisomerization/cycloaddition cascade process.

Fig. 1. C−C bond cleavage of benzocyclobutenones and regio-selective aza-[4+2]-photocycloaddition with imines.

a Two strategies for C−C bond cleavage of BCBs. b This work: photoinduced regio-specific aza-[4+2]-photocycloaddition of BCBs and asymmetric version.

Fig. 2. Substrate scope of cycloaddition of BCBs with 3,4-dihydroisoquinolines.

Conditions: A (0.1 mmol), B (0.1 mmol) in Et₂O (1.0 mL) under N₂ atmosphere and 5 W LED (λ_max = 365 nm) irradiation at 10 °C, yield of isolated product. ^a10 W instead of 5 W. ^bAfter 12 h, another portion A (0.1 mmol) was added and reacted for further 12 h; ^c10 W LED in THF was used.

Fig. 3. Substrate scope of asymmetric cycloaddition of BCBs and benzosulfonimides.

Conditions: A (2.0 equiv), D (0.1 mmol), Ni(NTf₂)₂/L₃-PisEPh (1.2:1, 10 mol%) and 3 Å MS (25 mg) in CH₂Cl₂ (3.0 mL) at 10 °C under N₂ atmosphere and irradiation (20 W LED, λ_max = 365 nm). Yield of isolated product. Ee was determined by UPC².

Fig. 4. Synthetic application.

a Gram-scale synthesis. b Further transformations.

Fig. 5. Mechanistic studies.

a Radical trapping experiments. b Control experiments. c Proposed mechanism and DFT calculation.