![Aza-[4 + 2]-cycloaddition of benzocyclobutenones into isoquinolinone derivatives enabled by photoinduced regio-specific C–C bond cleavage](https://degreesoffreedom.cyou/wp-content/uploads/2025/01/Aza-4 2-cycloaddition-of-benzocyclobutenones-into-isoquinolinone-derivatives-enabled-by-photoinduced-regio-specific.png)
Chen, F., Wang, T. & Jiao, N. Recent advances in transition-metal-catalyzed functionalization of unstrained carbon–carbon bonds. Chem. Rev. 114, 8613–8661 (2014).
Souillart, L. & Cramer, N. Catalytic C–C bond activations via oxidative addition to transition metals. Chem. Rev. 115, 9410–9464 (2015).
Murakami, M. & Ishida, N. Potential of metal-catalyzed C–C single bond cleavage for organic synthesis. J. Am. Chem. Soc. 138, 13759–13769 (2016).
Fumagalli, G., Stanton, S. & Bower, J. F. Recent methodologies that exploit C–C single-bond cleavage of strained ring systems by transition metal complexes. Chem. Rev. 117, 9404–9432 (2017).
Kim, D.-S., Park, W.-J. & Jun, C.-H. Metal–organic cooperative catalysis in C–H and C–C bond activation. Chem. Rev. 117, 8977–9015 (2017).
Song, F., Gou, T., Wang, B.-Q. & Shi, Z.-J. Catalytic activations of unstrained C–C bond involving organometallic intermediates. Chem. Soc. Rev. 47, 7078–7115 (2018).
Xu, T. Synthetic applications of C−C bond activation reactions. Compr. Organomet. Chem. 12, 332–346 (2022).
Flores-Gaspar, A. & Martin, R. Recent advances in the synthesis and application of benzocyclobutenones and related compounds. Synthesis 45, 563–580 (2013).
Chen, P.-H. & Dong, G. Cyclobutenones and benzocyclobutenones: versatile synthons in organic synthesis. Chem. Eur. J. 22, 18290–18315 (2016).
Deng, L. & Dong, G. Carbon‒carbon bond activation of ketones. Trends Chem. 2, 183–198 (2020).
Murakami, M. & Ishida, N. Cleavage of carbon–carbon σ-bonds of four-membered rings. Chem. Rev. 121, 264–299 (2021).
Xue, Y. & Dong, G. Deconstructive synthesis of bridged and fused rings via transition-metal-catalyzed “cut-and-sew” reactions of benzocyclobutenones and cyclobutanones. Acc. Chem. Res. 55, 2341–2354 (2022).
Huffman, M. A., Liebeskind, L. S. & Pennington, W. T. Jr. Synthesis of metallacyclopentenones by insertion of rhodium into cyclobutenones. Organometallics 9, 2194–2196 (1990).
Lu, G., Fang, C., Xu, T., Dong, G. & Liu, P. Computational study of Rh-catalyzed carboacylation of olefins: ligand-promoted rhodacycle isomerization enables regioselective C–C bond functionalization of benzocyclobutenones. J. Am. Chem. Soc. 137, 8274–8283 (2015).
Lu, Q., Wang, B., Yu, H. & Fu, Y. Mechanistic study on ligand-controlled Rh(I)-catalyzed coupling reaction of alkene-benzocyclobutenone. ACS Catal. 5, 4881–4889 (2015).
Yang, S., Xu, Y. & Li, J. Theoretical study of nickel-catalyzed proximal C–C cleavage in benzocyclobutenones with insertion of 1,3-diene: origin of selectivity and role of ligand. Org. Lett. 18, 6244–6247 (2016).
Zou, H., Wang, Z.-L. & Huang, G. Mechanism and origins of the chemo- and regioselectivities in nickel-catalyzed intermolecular cycloadditions of benzocyclobutenones with 1,3-dienes. Chem. Eur. J. 23, 12593–12603 (2017).
Xu, Z.-Y. et al. Mechanism and origins of chemo- and regioselectivities of Pd-catalyzed intermolecular σ-bond exchange between benzocyclobutenones and silacyclobutanes: a computational study. Organometallics 37, 592–602 (2018).
Xu, T., Ko, H. M., Savage, N. A. & Dong, G. Highly enantioselective Rh-catalyzed carboacylation of olefins: efficient syntheses of chiral poly-fused rings. J. Am. Chem. Soc. 134, 20005–20008 (2012).
Deng, L., Xu, T., Li, H. & Dong, G. Enantioselective Rh-catalyzed carboacylation of C=N bonds via C–C activation of benzocyclobutenones. J. Am. Chem. Soc. 138, 369–374 (2016).
Deng, L., Chen, M. & Dong, G. Concise synthesis of (−)-cycloclavine and (−)-5-epi-cycloclavine via asymmetric C–C activation. J. Am. Chem. Soc. 140, 9652–9658 (2018).
Hou, S.-H., Prichina, A. Y. & Dong, G. Deconstructive asymmetric total synthesis of morphine-family alkaloid (−)-thebainonea. Angew. Chem. Int. Ed. 60, 13057–13064 (2021).
Ambler, B. R. et al. Enantioselective ruthenium-catalyzed benzocyclobutenone–ketol cycloaddition: merging C–C bond activation and transfer hydrogenative coupling for type II polyketide construction. J. Am. Chem. Soc. 140, 9091–9094 (2018).
Huynh, N. O., Hodík, T. & Krische, M. J. Enantioselective transfer hydrogenative cycloaddition unlocks the total synthesis of SF2446 B3: An aglycone of arenimycin and SF2446 type II polyketide antibiotics. J. Am. Chem. Soc. 145, 17461–17467 (2023).
Qiu, B. et al. Catalytic enantioselective synthesis of 3,4-polyfused oxindoles with quaternary all-carbon stereocenters: a Rh-catalyzed C–C activation approach. Org. Lett. 20, 7689–7693 (2018).
Li, X. et al. Divergent Rh catalysis: asymmetric dearomatization versus C–H activation initiated by C–C activation. ACS Catal. 13, 4873–4881 (2023).
Bender, M., Turnbull, B. W. H., Ambler, B. R. & Krische, M. J. Ruthenium-catalyzed insertion of adjacent diol carbon atoms into C–C bonds: entry to type II polyketides. Science 357, 779–781 (2017).
Lu, H. et al. Divergent coupling of benzocyclobutenones with indoles via C−H and C−C activations. Angew. Chem. Int. Ed. 59, 23537–23543 (2020).
Guo, J.-H. et al. Site-selective C–C cleavage of benzocyclobutenones enabled by a blocking strategy using nickel catalysis. Angew. Chem. Int. Ed. 60, 19079–19084 (2021).
Xu, T. & Dong, G. Rhodium-catalyzed regioselective carboacylation of olefins: a C−C bond activation approach for accessing fused-ring systems. Angew. Chem. Int. Ed. 51, 7567–7571 (2012).
Chen, P.-H., Xu, T. & Dong, G. Divergent syntheses of fused β-naphthol and indene scaffolds by rhodium-catalyzed direct and decarbonylative alkyne–benzocyclobutenone couplings. Angew. Chem. Int. Ed. 53, 1674–1678 (2014).
Xu, T., Savage, N. A. & Dong, G. Rhodium(I)-catalyzed decarbonylative spirocyclization through C–C bond cleavage of benzocyclobutenones: An efficient approach to functionalized spirocycles. Angew. Chem. Int. Ed. 53, 1891–1895 (2014).
Xu, T. & Dong, G. Coupling of sterically hindered trisubstituted olefins and benzocyclobutenones by C–C activation: total synthesis and structural revision of cycloinumakiol. Angew. Chem. Int. Ed. 53, 10733–10736 (2014).
Sun, T. et al. Rhodium(I)-catalyzed carboacylation/aromatization cascade initiated by regioselective C−C activation of benzocyclobutenones. Angew. Chem. Int. Ed. 57, 2859–2863 (2018).
Zhu, Z. et al. Cobalt-catalyzed intramolecular alkyne/benzocyclobutenone coupling: C–C bond cleavage via a tetrahedral dicobalt intermediate. ACS Catal. 8, 845–849 (2018).
Qin, Y., Zhan, J.-L., Shan, T.-T. & Xu, T. Total synthesis of penta-Me amurensin H and diptoindonesin G featuring a Rh-catalyzed carboacylation/aromatization cascade enabled by C−C activation. Tetrahedron Lett. 60, 925–927 (2019).
Zhang, Y., Shen, S., Fang, H. & Xu, T. Total synthesis of galanthamine and lycoramine featuring an early-stage C–C and a late-stage dehydrogenation via C–H activation. Org. Lett. 22, 1244–1248 (2020).
Zhang, J., Wang, X. & Xu, T. Regioselective activation of benzocyclobutenones and dienamides lead to anti-bredt bridged-ring systems by a [4+4] cycloaddition. Nat. Commun. 12, 3022 (2021).
Wang, Y., Ma, P., Ma, N. & Wang, J. Ligand-controlled nickel-catalyzed reactions of benzocyclobutenones with alkynyltrifluoroborates: diverse construction of polysubstituted naphthols. Org. Lett. 25, 3527–3532 (2023).
Zhang, J. et al. Reversing site-selectivity in formal cross-dimerization of benzocyclobutenones and silacyclobutanes. CCS Chem. 5, 1753–1762 (2023).
Jiang, C. et al. Type I [4σ+4π] versus [4σ+4π−1] cycloaddition to access medium-sized carbocycles and discovery of a liver X receptor β-selective ligand. Angew. Chem. Int. Ed. 63, e202405838 (2024).
Chen, P.-H., Sieber, J., Senanayake, C. H. & Dong, G. Rh-catalyzed reagent-free ring expansion of cyclobutenones and benzocyclobutenones. Chem. Sci. 6, 5440–5445 (2015).
Juliá-Hernández, F., Ziadi, A., Nishimura, A. & Martin, R. Nickel-catalyzed chemo-, regio- and diastereoselective bond formation through proximal C-C cleavage of benzocyclobutenones. Angew. Chem. Int. Ed. 54, 9537–9541 (2015).
Okumura, S., Sun, F., Ishida, N. & Murakami, M. Palladium-catalyzed intermolecular exchange between C–C and C–Si σ-bonds. J. Am. Chem. Soc. 139, 12414–12417 (2017).
Li, R. et al. A ring expansion strategy towards diverse azaheterocycles. Nat. Chem. 13, 1006–1016 (2021).
Ochi, S., Zhang, Z., Xia, Y. & Dong, G. Rhodium-catalyzed (4+1) cycloaddition between benzocyclobutenones and styrene-type alkenes. Angew. Chem. Int. Ed. 61, e202202703 (2022).
Hoffmann, N. Photochemical reactions as key steps in organic synthesis. Chem. Rev. 108, 1052–1103 (2008).
Xuan, J. & Xiao, W.-J. Visible-light photoredox catalysis. Angew. Chem. Int. Ed. 51, 6828–6838 (2012).
Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).
Schultz, D. M. & Yoon, T. P. Solar synthesis: prospects in visible light photocatalysis. Science 343, 1239176 (2014).
Brimioulle, R., Lenhart, D., Maturi, M. M. & Bach, T. Enantioselective catalysis of photochemical reactions. Angew. Chem. Int. Ed. 54, 3872–3890 (2015).
Skubi, K. L., Blum, T. R. & Yoon, T. P. Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016).
Strieth-Kalthoff, F., James, M. J., Teders, M., Pitzer, L. & Glorius, F. Energy transfer catalysis mediated by visible light: principles, applications, directions. Chem. Soc. Rev. 47, 7190–7202 (2018).
Zhou, Q.-Q., Zou, Y.-Q., Lu, L.-Q. & Xiao, W.-J. Visible-light-induced organic photochemical reactions through energy-transfer pathways. Angew. Chem. Int. Ed. 58, 1586–1604 (2019).
Strieth-Kalthoff, F. & Glorius, F. Triplet energy transfer photocatalysis: unlocking the next level. Chem 6, 1888–1903 (2020).
Yu, X.-Y., Chen, J.-R. & Xiao, W.-J. Visible light-driven radical-mediated C–C bond cleavage/functionalization in organic synthesis. Chem. Rev. 121, 506–561 (2021).
Melchiorre, P. Introduction: photochemical catalytic processes. Chem. Rev. 122, 1483–1484 (2022).
Hou, L. Z., Liu, X. H., Cao, W. D. & Feng, X. M. Recent advances in visible light-induced asymmetric transformations of carbonyl compounds into chiral alcohols. ChemCatChem 15, e202300893 (2023).
Dutta, S., Erchinger, J. E., Strieth-Kalthoff, F., Kleinmans, R. & Glorius, F. Energy transfer photocatalysis: exciting modes of reactivity. Chem. Soc. Rev. 53, 1068–1089 (2024).
Norrish, R. G. W. & Kirkbride, F. W. 204. Primary photochemical processes. Part I. The decomposition of formaldehyde. J. Chem. Soc., 1518–1530 (1932).
Norrish, R. G. W. & Bamford, C. H. Photo-decomposition of aldehydes and ketones. Nature 140, 195–196 (1937).
Dantas, J. A., Correia, J. T. M., Paixão, M. W. & Corrêa, A. G. Photochemistry of carbonyl compounds: application in metal-free reactions. ChemPhotoChem 3, 506–520 (2019).
Cava, M. P. & Spangler, R. J. 2-(Carbomethoxy)benzocyclobutenone. Synthesis of a photochemically sensitive small-ring system by a pyrolytic wolff rearrangement. J. Am. Chem. Soc. 89, 4550–4551 (1967).
Ng, D., Yang, Z. & Garcia-Garibay, M. A. Total synthesis of (±)-herbertenolide by stereospecific formation of vicinal quaternary centers in a crystalline ketone. Org. Lett. 6, 645–647 (2004).
Nicolaou, K. C., Gray, D. L. F. & Tae, J. Total synthesis of hamigerans and analogues thereof. Photochemical generation and Diels−Alder trapping of hydroxy-o-quinodimethanes. J. Am. Chem. Soc. 126, 613–627 (2004).
Okada, M. et al. Photocatalytic one-pot synthesis of homoallyl ketones via a Norrish type I reaction of cyclopentanones. J. Org. Chem. 80, 9365–9369 (2015).
Schiess, P., Eberle, M., Huys-Francotte, M. & Wirz, J. Thermal addition reactions to benzocyclobutenones studied by flash photolysis. Tetrahedron Lett. 25, 2201–2204 (1984).
Wang, Z. Y., Suzzarini, L. & Gao, J. P. Thermal reactions of benzocyclobutenone with alcohols. Tetrahedron Lett. 38, 5745–5746 (1997).
Wurm, T., Turnbull, B. W. H., Ambler, B. R. & Krische, M. J. Thermal hetero-Diels–Alder reaction of benzocyclobutenones with isatins to form 2-oxindole spirolactones. J. Org. Chem. 82, 13751–13755 (2017).
Arnold, D. R., Hedaya, E., Merritt, V. Y., Karnischky, L. A. & Kent, M. E. Benzocyclobutenone: pyrolysis and photochemistry. Tetrahedron Lett. 13, 3917–3920 (1972).
Krantz, A. Laser ultraviolet irradiation of α-pyrone. Extremely rapid isomerization of a transient ketene. J. Am. Chem. Soc. 96, 4992–4993 (1974).
Hacker, N. P. & Turro, N. J. Low temperature photolysis of benzocyclobutanone and 2,2-dihydrocyclobuta[1]phenanthrenone: Evidence for photochromic behavior. J. Photochem. 22, 131–135 (1983).
Bally, T. & Michalak, J. Photochemistry and radiation chemistry of benzocyclobutenone: formation of an o-quinoid ketene and its radical cation. J. Photochem. Photobiol. A 69, 185–190 (1992).
Chou, C.-H., Wu, C.-C. & Chen, W.-K. Synthesis of pyrido[b]cyclobuten-5-one and 1-azafulvenallene by flash vacuum pyrolysis of 3-chloroformyl-2-methylpyridine. Tetrahedron Lett. 36, 5065–5068 (1995).
Chiang, Y., Kresge, A. J. & Zhan, H.-Q. Generation of 6-methylene-2,4-cyclohexadienylidene ketene by flash photolysis of benzocyclobutenone in aqueous solution and study of the reactions of this ketene in that medium. Can. J. Chem. 81, 607–611 (2003).
Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).
Heravi, M. M. & Zadsirjan, V. Prescribed drugs containing nitrogen heterocycles: an overview. RSC Adv. 10, 44247–44311 (2020).
Lang, K. D., Kaur, R., Arora, R., Saini, B. & Arora, S. Nitrogen-containing heterocycles as anticancer agents: an overview. Anticancer Agents Med. Chem. 20, 2150–2168 (2020).
Kumar, A. et al. Nitrogen containing heterocycles as anticancer agents: a medicinal chemistry perspective. Pharmaceuticals 16, 299 (2023).
Tan, Z. D., Zhu, S. B., Liu, Y. B. & Feng, X. M. Photoinduced chemo-, site- and stereoselective α-C(sp3)−H functionalization of sulfides. Angew. Chem. Int. Ed. 61, e202203374 (2022).
Hou, L. Z. et al. Enantioselective radical addition to ketones through Lewis acid-enabled photoredox catalysis. J. Am. Chem. Soc. 144, 22140–22149 (2022).
Yang, L. K. et al. NickelII-catalyzed asymmetric photoenolization/Mannich reaction of (2-alkylphenyl) ketones. Chem. Sci. 13, 8576–8582 (2022).
Zhan, T. Y. et al. Chiral Lewis acid-catalyzed Norrish type II cyclization to synthesize α-oxazolidinones via enantioselective protonation. CCS Chem. 5, 2101–2110 (2023).
Yang, L. K. et al. Catalytic asymmetric photocycloaddition of triplet aldehydes with benzocyclobutenones. CCS Chem. 135, 11473-6 (2024).
Hou, L. Z. et al. Catalytic asymmetric dearomative [2 + 2] photocycloaddition/ring-expansion sequence of indoles with diversified alkenes. J. Am. Chem. Soc. 146, 23457–23466 (2024).
Leitao Da-Cunha, E. V., Fechine, L. M., Guedes, D. N., Barbosa-Filho, J. M. & Sobral Da Silva, M. Protoberberine alkaloids. alkaloids: Chem. Biol. 62, 1–75 (2005).
Yu, L.-L. et al. Protoberberine isoquinoline alkaloids from arcangelisia gusanlung. Molecules 19, 13332–13341 (2014).
Liu, X. H., Lin, L. L. & Feng, X. M. Chiral N,N’-dioxides: new ligands and organocatalysts for catalytic asymmetric reactions. Acc. Chem. Res. 44, 574–587 (2011).
Liu, X. H., Zheng, H. F., Xia, Y., Lin, L. L. & Feng, X. M. Asymmetric cycloaddition and cyclization reactions catalyzed by chiral N,N’-dioxide-metal complexes. Acc. Chem. Res. 50, 2621–2631 (2017).
Chen, D.-F. & Gong, L.-Z. Feng chiral N,N’-dioxide ligands: uniqueness and impacts. Org. Chem. Front. 10, 3676–3683 (2023).
Dong, S. X., Cao, W. D., Pu, M. P., Liu, X. H. & Feng, X. M. Ligand acceleration in chiral Lewis acid catalysis. CCS Chem. 5, 2717–2735 (2023).
Xu, N. et al. Iron-catalyzed asymmetric α-alkylation of 2-acylimidazoles via dehydrogenative radical cross-coupling with alkanes. Angew. Chem. Int. Ed. 62, e202314256 (2023).
Wang, K. X. et al. Asymmetric catalytic ring-expansion of 3-methyleneazetidines with α-diazo pyrazoamides towards proline-derivatives. Angew. Chem. Int. Ed. 62, e202307249 (2023).
Chen, M. et al. Regioselective and asymmetric allylic alkylation of vinyl epoxides for the construction of allylic alcohols via synergistic catalysis. Sci. China Chem. 67, 542–550 (2024).
Padwa, A. Photochemistry of the carbon-nitrogen double bond. Chem. Rev. 77, 37–68 (1977).
Pratt, A. C. The photochemistry of imines. Chem. Soc. Rev. 6, 63–81 (1977).
Kandappa, S. K., Valloli, L. K., Ahuja, S., Parthiban, J. & Sivaguru, J. Taming the excited state reactivity of imines – from non-radiative decay to aza Paternò–Büchi reaction. Chem. Soc. Rev. 50, 1617–1641 (2021).
CCDC: 2293174 (E1), contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre.
Kessar, S. V., Singh, P., Vohra, R., Kaur, N. P. & Venugopal, D. Facile generation and trapping of α-oxo-o-quinodimethanes: Synthesis of 3-aryl-3,4-dihydroisocoumarins and protoberberines. J. Org. Chem. 57, 6716–6720 (1992).
Leave a Reply