ARTICLE https://doi.org/10.1038/s41467-020-18274-2 OPEN Photo-mediated selective deconstructive geminal dihalogenation of trisubstituted alkenes ✉ Han Wang1,4, Ren Wei Toh1,4, Xiangcheng Shi1, Tonglin Wang2, Xu Cong1 & Jie Wu 1,3 Selective deconstructive functionalization of alkenes, other than the well-established olefin metathesis and ozonolysis, to produce densely functionalized molecular scaffolds is highly attractive but challenging. Here we report an efficient photo-mediated deconstructive 1234567890():,; germinal dihalogenation of carbon-carbon double bonds. A wide range of geminal diio- doalkanes and bromo(iodo)alkanes (>40 examples) are directly prepared from various tri- substituted alkenes, including both cyclic and acyclic olefins. This C=C cleavage is highly chemoselective and produces geminal dihalide ketones in good yields. Mechanistic investi- gations suggest a formation of alkyl hypoiodites from benzyl alcohols and N-iodoimides, which undergo light-induced homolytic cleavage to generate active oxygen radical species. 1 Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Republic of Singapore. 2 College of Chemistry and Chemical Engineering, Northwest Normal University, 730070 Lanzhou, Gansu, China. 3 National University of Singapore (Suzhou) Research Institute, 377 Lin Quan ✉ Street, Suzhou Industrial Park, 215123 Suzhou, Jiangsu, China. 4These authors contributed equally: Han Wang, Ren Wei Toh. email: [email protected] NATURE COMMUNICATIONS | (2020) 11:4462 | https://doi.org/10.1038/s41467-020-18274-2 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-18274-2 n organic synthesis, common functionalization usually focuses Results on the installation or modification of functional groups Reaction optimization. We initially designed a cascade hydro- I fi without signi cantly changing the backbones of molecules. In halogenation of trisubstituted alkenes and subsequent photo- stark contrast, deconstructive functionalization is attractive as it induced β-scission of the generated alcohol intermediates. Based can drastically change the scaffolds of molecules to introduce new on previous reports from groups of Chen and Zhu on photo- chemical space, unmask dormant functional groups, and create mediated conversion of alcohols to oxygen radicals36–42, our functionalities tethered at a predefined distance determined by study commenced by using 1-phenyl-1-cyclohexene (1)asa ring sizes of the reactants. model substrate. As illustrated in Table 1, treatment of 1 with The carbon-carbon double bond is one of the most funda- eosin Y (1 mol%) as the photocatalyst, N-iodosuccinimide (NIS, 4 mental functionalities in organic molecules. Various methods equiv), H2O (50 equiv) and acetoxyl benziodoxole (BIOAc, 2 have been developed to convert alkenes to important inter- equiv) in MeCN under blue light-emitting diode (LED) irradia- mediates and fine chemical products, which play vital roles in the tion, the desired product, 6,6-diiodo-1-phenylhexan-1-one (2) fields of material science, biochemistry, pharmaceutical science, was obtained in 40% yield (entry 1). Further investigation and the chemical industry1–8. Deconstructive functionalization of revealed that a similar result could be obtained in the absence of alkenes has been well developed to introduce two functional any photocatalyst (entry 2). To our surprise, 2 could be generated groups at different sites of olefins (Fig. 1a). For instance, in 28% yield even without BIOAc (entry 3). A moderate tem- transition-metal-catalyzed C=C bond cleavage processes, such as perature (50 °C) significantly accelerated the reaction (entries olefin metathesis, have found wide application in natural product 4–5). Evaluation of solvents indicated that a mixed solvent of 9–12 and material synthesis . Ozonolysis and other similar oxida- EtOAc/MeNO2 (10:1) was the optimal choice, leading to the tions with various organic and inorganic oxidants were robust to generation of 2 in 81% yield (entries 6–9). Using 1,3-diiodo-5,5- introduce two carbonyl derivatives from a single C=C bond13–17. dimethyl-hydantoin (DIH) as the iodination agent afforded an Aside from such well-established strategies, other types of improved yield compared to that with NIS (entry 10). Light deconstructive functionalization of alkenes producing densely irradiation was essential as no product 2 could be detected in the functionalized scaffolds remain rare and challenging18–27. absence of light (entry 11). Organohalides are versatile building blocks in synthetic chemistry. They are widely utilized as precursors in transition- metal-catalyzed cross-coupling, radical reactions, nucleophilic Substrate scope. With the optimized conditions established, we substitutions, and metal-halide exchanges28–30. Among them, investigated the scope of the deconstructive geminal diiodination geminal dihalides represent a unique class of compounds and of cyclic alkenes. As shown in Fig. 2, a variety of aryl-substituted have been used as carbene precursors and multi-functional syn- cyclohexene derivatives underwent deconstructive geminal diio- thons. However, efficient synthetic pathways to synthesize gem- dination effectively to deliver products 2–15 in moderate to good inal dihalides are quite limited, which significantly restricts the yields. Cyclohexenes containing aryl rings with electronically investigation and wide application of this unique family of distinct substituents in the ortho-, meta-orpara-position affor- compounds31–35. Herein, we report a direct synthetic route to ded products 2–10 in similar yields, with the exception of a geminal dihalides by photo-mediated deconstructive fragmenta- tion of cyclic or acyclic trisubstituted alkenes (Fig. 1b). Table 1 Optimization of oxidative deconstructive geminal diiodinationa. I I Ph PC (1 mol%), NIS (4 equiv), H2O (50 equiv), Ph Additive (x equiv), solvent (0.1 M), O a argon, blue LED (80 W), 36 h 1 2 O O entry catalyst solvent additive yield (x equiv) (%)b 1 eosin Y MeCN BIOAc (2) 40 Olefin metathesis Ozonolysis / oxidation 2 – MeCN BIOAc (2) 41 Ru, Mo, etc. O , mCPBA, etc. 3 3 – MeCN – 28 c – – b O 4 MeCN 60 5d – MeCN – 41 DIH + H O I 2 6c – DCE – 34 I 7c – EtOAc – 79 c O 8 – acetone – n.d. 9c – EtOAc/ – 81 NBS + DIH + H2O I MeNO2 (10:1) Br c,e – – f I O 10 EtOAc/ 91(84) N MeNO2 (10:1) c,e,g O N Br 11 – EtOAc/ – n.d. MeNO (10:1) O N Catalyst-free 2 I O visible-light-mediation additive-free NIS N-iodosuccinimide, DCE 1,2-dichloroethane, n.d. not determined. DIH NBS a multifunctional synthon Standard conditions: 1 (0.2 mmol), NIS (0.8 mmol), and H2O (10 mmol) in solvent (0.1 M), irradiated under blue LED lamps (80 W) for 36 h at 30 °C. bYields determined by analysis of the crude 1H-NMR spectra using dibromomethane as an Fig. 1 Deconstructive functionalization of alkenes. a Common strategies internal standard. for C=C bond cleavage. b Visible-light-mediated deconstructive oxidative cReaction was performed at 50 °C. dReaction was performed at 80 °C. geminal dihalogenation of trisubstituted alkenes (this work). DIH 1,3- eDIH (0.4 mmol, 2 equiv) was used instead of NIS. diiodo-5,5-dimethyl-hydantoin, NBS N-bromosuccinimide, mCPBA meta- fIsolated yields. gNo light irradiation. chloroperoxybenzoic acid. 2 NATURE COMMUNICATIONS | (2020) 11:4462 | https://doi.org/10.1038/s41467-020-18274-2 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-020-18274-2 ARTICLE I Br DIH, H O, EtOAc:MeNO (10:1) I I Ar 2 2 Ar Ar NBS, H2O, MeCN, 12 h; Ar O O 50 °C, blue LED (80 W), argon, 36 h then, DIH, blue LED (80 W), 50 °C, 24 h n n n n n = 0, 1, 2 n = 0, 1, 2 O O O I O 2: R = H (84%) 5: R = OMe (68%) Br I I 3: R = Ph (81%) 6: R = tBu (72%) I 4: R = Me (80%) 7: R = F (80%) R I R Me Br 2–7 OMe Br 24–31 O O Me O O 32, 66%, (dr = 1:1)a 33, 64%, (dr = 1:1)a I I I I 24: R = 4-H (63%) 25: R = 4-Ph (69%) I I I I O O 26: R = 4-tBu (67%) 27: R = 4-CF3 (50%) I I tBu F OMe 28: R= 4-F (61%) 29: R= 3-tBu (70%) tBu Br Ph Br 30: R= 3-F (73%) 8, 77% 9, 86% 10, 77% 11, 79% 31: R= 2-Me (63%) a a O O O O 34, 66%, (dr = 1:1) 35, 71%, (dr = 1:1) I I I I I I I I O O O I I I O Me Et Ph F F F F Br Br S Br 12, 83% 13, 75% 14, 74% 15, 60% 36, 59% 37, 67% 38, 58% O O O I I O Br O Br O Br F I I I S I S I I a 16, 86% 17, 62% 18, 68% 39, 59% 40, 66% 41, 0% O I O I Fig. 3 Scope of oxidative deconstructive geminal bromo-iodination of 19: R′ = 4-H (70%) 20: R′ = 3-F (71%) I I cyclic alkenes. Isolated yields unless otherwise indicated. Performed with R′ 21: R′ = 3-tBu (60%) ′ 22: R = 4-CF3 (63%) alkene (0.2 mmol), NBS (0.21 mmol), H2O (10 mmol), DIH (0.3 mmol) in a 19–22 23, 44% MeCN. See Supplementary Information for experimental details. Dr values were determined by analysis of 1H NMR spectra of the crude Fig. 2 Scope of oxidative deconstructive geminal diiodination of cyclic product mixture. alkenes. Isolated yields unless otherwise indicated. Performed with alkene (0.2 mmol), H2O (10 mmol), DIH (0.4 mmol) in EtOAc:MeNO2 (10:1), afford the corresponding bromo(iodo)alkane product 41 under irradiated under blue LED lamps (80 W) for 36 h at 50 °C. a4 equiv NIS our reaction conditions. instead of DIH.