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1 Organocatalytic Aerobic Oxidation of Benzylic sp 3 C-H Bonds of Ethers and Alkylarenes Promoted by a Recyclable TEMPO Catalyst Zhiguang Zhang, Yuan Gao, Yuan Liu, Jianjun Li, Hexin Xie, Hao Li,*, and Wei Wang*, Shanghai Key Laboratory of New Drug Design, School of Pharmacy, and State Key Laboratory of Bioengineering Reactor, East China University of Science and Technology, 130 Mei-long Road, Shanghai, , China Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, NM , USA Supporting Information Table of contents 1. General 2 2. General Procedure for the Synthesis of Catalyst I 3 3.Synthesis of the Substrates General Procedures for I Catalyzed Aerobic Oxidation of Isochromans and Alkylarenes 3 5. Recyclability of Catalytic Aerobic Oxidation 9 6. Proposed Mechanism 9 7. Synthetic Applications References H and 13 C-NMR spectra data Chiral HPLC analysis spectra 33 S1

2 1. General Unless otherwise noted, all reagents were obtained commercially and used without further purification. Unless otherwise specified, all other reagents were purchased from Acros, Aldrich, Fisher, Adamas-beta Co. Ltd. or TCI and used without further purification. 1 H NMR spectra was recorded at 400 MHz, 13 C NMR spectra was recorded at 100 MHz. 1 H NMR spectra was recorded with tetramethylsilane (δ = 0.00 ppm) as internal reference; 13 C NMR spectra was recorded with CDCl 3 (δ = ppm) as internal reference. Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Proton coupling patterns are described as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad (br). S2

3 2. General Procedure for the Synthesis of Catalyst I. All glassware used was pre-dried at 120 o C for more than 12 h. Sodium hydride (20 mmol) and anhydrous toluene (30 ml) were added into a 200 ml single-necked round bottom flask. 4-OH-TEMPO (10 mmol) in toluene (50 ml) was added dropwise into the reaction mixture for 3 h. The reaction mixture was stirred until no gas was produced. Then butane sultone (15 mmol) in toluene (10 ml) was added dropwise into the flask for another 3 h. The reaction mixture was heated at 90 o C for 8 h. The organic layer was evaporated under reduced pressure and the residue was purified by a flash column chromatography (DCM/MeOH = 2:1) to give I in 69% yield as a red solid. HRMS (ESI) m/z calcd for C 13 H 25 NO 5 S (M) , found Synthesis of the Substrates. Isochroman derivatives were synthesized according to the methods reported in the literature. 1-2 Substituted xanthenes were synthesized according to the corresponding literature Methyl-9,10-dihydroacridine was obtained through reduction of 10-methyl-9(10H)-Acridone. 4 6H-Benzo[c]chromene was synthesized by direct arylation with aryl bromides. 5 1,3-Dihydrobenzo[de]isochromene and 5,7-dihydrodibenzo[c,e]oxepine were obtained through cyclization of the corresponding diols. 6 Bis(4-Methoxyphenyl)methane was obtained through reduction of Bis(4-methoxyphenyl)methanone. 7 Acridane was obtained through hydrogenation of acridine General Procedures for 3 Catalyzed Aerobic Oxidation of Isochromans (2). The oxidation of isochromans was carried out in a 25 ml long-necked, round-bottomed flask equipped with a magnetic stirrer with an oxygen balloon at 35 o C. Typically, I (0.025 mmol, 7.7 mg), NaNO 2 (0.2 mmol, 14 mg) and isochroman (5 mmol, 670 mg) were charged sequentially into the flask with 3 ml CH 3 CN. The flask was then evacuated under reduced pressure, followed by the attachment of an oxygen balloon. Then HCl (0.5 mmol, ml of 12 M HCl) was added into the flask quickly. The resulting mixture was stirred at 35 o C. When the reaction was completed, the solvent was evaporated. Ether and water was added. The water layer was evaporated under reduced pressure to afford I for the next reaction. Then the organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (PE/EA = 10:1-3:1) to afford the desired product 2a in 80% yield as a colorless liquid, 592 mg. S3

4 Isochroman-1-one (2a). 1 80% yield, colorless liquid, 592 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.03 (d, J = 8.0 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.50 (t, J = 6.0 Hz, 2H), 3.05 (t, J = 6.0 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 164.9, 139.4, 133.7, 130.1, 127.4, 125.0, 67.2, Methylisochroman-1-one (2b). 1 The title compound was prepared according to the general procedure as described above in 84% yield as colorless oil, 680 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 7.90 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.51 (t, J = 6.0 Hz, 2H), 3.02 (t, J = 6.0 Hz, 2H), 2.38 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 165.4, 137.5, 136.6, 134.6, 130.5, 127.2, 125.0, 67.5, 27.4, (tert-Butyl)isochroman-1-one (2c). The title compound was prepared according to the general procedure as described above in 89% yield as colorless oil, 908 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.12 (d, J = 2.0 Hz, 1H), 7.59 (dd, J 1 = 8.0 Hz, J 2 = 2.4 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 4.51 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H), 1.34 (s, 9H); 13 C NMR (100 MHz, CDCl 3 ): δ 165.6, 150.9, 136.7, 131.0, 127.1, 126.9, 124.8, 67.4, 34.7, 31.2, HRMS (EI) m/z calcd for C 13 H 16 O 2 (M) , found Methoxyisochroman-1-one (2d). 1 The title compound was prepared according to the general procedure as described above in 73% yield as colorless oil, 650 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 7.58 (s, 1H), 7.18 (dd, J 1 = 7.6 Hz, J 2 = 2.8 Hz, 1H), 7.11 (dd, J 1 = 7.6 Hz, J 2 = 2.8 Hz, 1H), (m, 2H), 3.85 (d, J = 2.8 Hz, 3H), (m, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 159.0, 131.9, 128.4, 126.1, 121.6, , 67.7, 55.6, S4

5 5-Methylisochroman-1-one (2e). The title compound was prepared according to the general procedure as described above in 80% yield as colorless oil, 648 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 7.93 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 4.51 (t, J = 6.0 Hz, 2H), 2.96 (t, J = 6.0 Hz, 2H), 2.32 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 165.5, 138.3, 135.2, 135.0, 128.0, 127.0, 125.2, 66.7, 24.9, HRMS (EI) m/z calcd for C 10 H 10 O 2 (M) , found Fluoroisochroman-1-one (2f). 1 The title compound was prepared according to the general procedure as described above in 34% yield as colorless solid, 282 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 7.74 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 4.55 (d, J = 4.0 Hz, 2H), 3.06 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 164.1, 163.0, 160.5, 135.4, 129.3, 126.9, 121.2, 116.7, 67.5, Methylisochroman-1-one (2g). 1 The title compound was prepared according to the general procedure as described above in 83% yield as white solid, 672 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 8.09 (d, J = 8.0 Hz, 1H), (m, 1H), 7.39 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 7.2 Hz, 1H), 4.52 (dd, J 1 = 7.2Hz, J 2 = 4.0 Hz, 1H), 4.24 (dd, J 1 = 8.2 Hz, J 1 = 6.4 Hz, 1H), (m, 1H), 1.37 (d, J = 7.2 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 165.3, 144.3, 134.0, 130.0, 127.4, 125.8, 124.3, 72.1, 31.7, Methylisochroman-1-one (2h, 2i). 1 The title compound was prepared according to the general procedure as described above in 80% yield as white solid, 648 mg. 1 H NMR (400 MHz, CDCl 3 ) δ 8.06 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), (m, 1H), 2.94 (d, J = 7.2 Hz, 2H), 1.51 (d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 165.6, 139.2, 133.7, 130.1, 127.6, 127.4, 124.9, 74.7, 34.4, S5

6 6H-Benzo[c]chromen-6-one (2j). 9 The title compound was prepared according to the general procedure as described above in 83% yield as white solid, 813 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.25 (dd, J 1 = 8.0 Hz, J 2 = 0.8 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), (m, 1H), (m, 1H ), (m, 1H), (m, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 161.1, 151.2, 134.8, 134.7, 130.5, 130.4, 128.8, 124.5, 122.7, 121.7, 121.1, 118.0, Benzo[de]isochromen-1(3H)-one (2k). 10 The title compound was prepared according to the general procedure as described above in 71% yield as white solid, 653 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.15 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.15 (d, J 1 = 7.2 Hz, J 1 = 0.8 Hz, 1H), 5.59 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 164.1, 133.5, 131.9, 128.9, 128.1, 127.0, 126.7, 126.5, 126.4, 121.5, 120.0, H-Thieno[2,3-c]pyran-7(5H)-one (2l). 1 The title compound was prepared according to the general procedure as described above in 66% yield as white solid, 508 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 7.66 (d, J = 4.8 Hz, 1H), 7.01 (d, J = 4.8 Hz, 1H), 4.59 (t, J = 6.0 Hz, 2H), 3.03 (t, J = 6.0 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 161.3, 147.6, 134.5, 126.7, H-Xanthen-9-one (4a). 11 The title compound was prepared according to the general procedure as described above in 91% yield as white solid, 892 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.23 (d, J = 8.0 Hz, 2H), (m, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.26 (t, J = 7.2 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 177.7, 156.1, 134.8, 126.7, 123.9, 121.8, S6

7 7H-Benzo[c]xanthen-7-one (4b). 12 The title compound was prepared according to the general procedure as described above in 92% yield as white solid, 1132 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.34 (d, J = 8.0 Hz, 1H), 8.25 (dd, J 1 = 8.0 Hz, J 2 = 1.2 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.68 (d, J = 7.6 Hz, 1H), (m, 1H), (m, 4H), 7.29 (t, J = 7.6 Hz, 1H); 13 C NMR (100 MHz, CDCl 3 ): δ 176.6, 155.4,153.3,136.3,134.1,129.4,127.8,126.7,126.3,124.2, 123.8, 122.6, 122.2, 121.2, 117.9, H-Benzo[a]xanthen-12-one (4c). 13 The title compound was prepared according to the general procedure as described above in 90% yield as white solid, 984 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 9.93 (d, J = 8.8 Hz, 1H), 8.26 (dd, J 1 = 7.6 Hz, J 2 = 1.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 1H), 7.62 (t, J = 8.0 Hz, 2H), (m, 1H), 7.40 (t, J = 7.6 Hz, 1H), (m, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 178.5, 157.6, 154.6, 136.7, 133.9, 131.3, 130.1, 129.6, 128.4, 127.0, 126.7, 126.1, 124.3, 123.5, 118.1, 117.5, Methyl-7H-benzo[c]xanthen-7-one (4d). The title compound was prepared according to the general procedure as described above in 81% yield as white solid, 1053 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.44 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.8 Hz, 1H), 8.04 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), (m, 3H), (m, 2H), 2.39 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 176.7, 153.8, 153.4, 135.4, 129.3, 127.9, 125.7, 123.7, 122.8, 121.4, 117.7, HRMS (EI) m/z calcd for C 18 H 12 O 2 (M) , found H-Thioxanthen-9-one (4e). 14 The title compound was prepared according to the general procedure as described above in 92% yield as yellow solid, 975 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.53 (d, J = 8.0 Hz, 2H), (m, 4H), 7.39 (t, J = 7.6 Hz, 2H); 13 C NMR (100 MHz, S7

8 CDCl 3 ): δ 180.0, 137.3, 132.3, 129.9, 129.2, 126.3, Methyl-10,10a-dihydroacridin-9(8aH)-one (4f). 15 The title compound was prepared according to the general procedure as described above in 63% yield as white solid, 658 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.56 (d, J = 8.0 Hz, 2H), 7.72 (t, J = 8.0 Hz, 2H), 7.50 (d, J = 8.8 Hz, 2H), 7.29 (t, J = 7.6 Hz, 2H), 3.89 (s, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 178.1, 142.5, 133.8, 127.7, 122.5, 121.2, 114.8, Acridine (4g). 6 The title compound was prepared according to the general procedure as described above in 79% yield as colorless solid, 707 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 8.42 (s, 1H), 8.20 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.65 (t, J = 8.0 Hz, 2H), 7.35 (t, J = 7.6 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 148.9, 135.8, 130.2, 129.3, 128.1, 126.4, Bis(4-Methoxyphenyl)methanone (4h). 13 The title compound was prepared according to the general procedure as described above in 52% yield as white solid, 629 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 7.78 (d, J = 8.8 Hz, 4H), 6.95 (d, J = 8.8 Hz, 4H), 3.87 (s, 6H); 13 C NMR (100 MHz, CDCl 3 ): δ 194.4, 162.9, 132.2, 130.7, 113.5, S8

9 5. TableS1. Recyclability of catalytic aerobic oxidation 1a 0.5 mol % I 10 mol % HCl 4 mol % NaNO 2 CH 3 CN, O 2 (1 atm) 35 o C 2a 3a 0.5 mol % I 10 mol % HCl 4 mol % NaNO 2 CH 3 CN, O 2 (1 atm) 35 o C 4a entry t (h) 2a yield (%) 4a yield (%) Proposed mechanism for catalytic aerobic oxidation. R O 2 NO 2 NO N O R R HNO 2 (NaNO 2 + HCl) 2a NOCl O O HCl N III OH HCl 1a H TEMPO catalyst I is oxidized to generate TEMPO(I) + Cl - (II) by HNO 2 produced from NaNO 2 and HCl (aq.), which will oxidize 1a to give isochroman-1-ol (1a ) and form TEMPO(I)H (III). Re-oxidation of III could be realized by NOCl to release NO. The reaction between HCl and NaNO 2 will give HNO 2, which can disproportionate to NO 2 and NO. NO 2 reacts with HCl to afford NOCl. NO can be oxidized to NO 2 by O 2. Isochromans (2a) will be generated from 1a by the second oxidation. 16 I N II O Cl 1a' OH O [O] O S9

10 7. Synthetic Applications. Dibenzo[c,e]oxepin-5(7H)-one (5). 17 The title compound was prepared according to the general procedure, as described above in 69% yield as white solid, 724 mg. 1 H NMR (400 MHz, CDCl 3 ): δ 7.90 (d, J = 7.6 Hz, 1H), (m, 3H), (m, 2H), (m, 2H), 4.93 (s, 2H); 13 C NMR (100 MHz, CDCl 3 ): δ 170.4, 139.0, 137.3, 134.9, 132.7, 132.0, 130.7, 130.2, 128.8, 128.7, 128.6, 128.5, (S)-Mellein (9). (1) I (0.1 mmol, 30.7 mg), NaNO 2 (0.2 mmol, 13.8 mg) and 7 16 (5 mmol, 890 mg) were charged sequentially into the flask with 3 ml CH 3 CN. The flask was evaporated under reduced pressure to remove the air in the flask, followed by the attachment of an oxygen balloon. Then HCl (0.5 mmol, ml of 12 M HCl) was added into the flask quickly. The resulting mixture was stirred at 35 o C. When the reaction was completed, the solvent was evaporated. Ether and water was added. Then the organic layer was washed with brine, dried over anhydrous Na 2 SO 4, filtered, and evaporated under reduced pressure. The residue was purified by column chromatography (PE/EA = 10:1-3:1) to give compound 8 in 69% yield as a white solid; (2) To a solution of 8 (0.96 g, 5 mmol) in dry CH 2 Cl 2 (20 ml) was added dropwise a solution boron tribromide in CH 2 Cl 2 (1.0M, 10 ml, 10 mmol) at -78 C. After 1 hour, the reaction mixture was raised to 0 C and stirred for 1 h. The resulting mixture was quenched with saturated aqueous NH 4 Cl, and extracted with CH 2 Cl 2. The combined extracts were washed with brine, dried over Na 2 SO 4, and concentrated in vacuo. The residue was purified by silica gel chromatography (PE/EA = 3: 1) to afford (S)-Mellein (9) in 88% as white solid, 540 mg. The spectroscopic data correspond to those previously reported in the literature H NMR (400 MHz, CDCl 3 ): δ (s, 1H), 7.43 (t, J = 8.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.72 (d, J = S10

11 8.0 Hz, 1H), (m, 1H), 2.96 (d, J = 7.2 Hz, 2H), 1.56 (d, J = 6.4 Hz, 3H); 13 C NMR (100 MHz, CDCl 3 ): δ 170.0, 162.2, 139.4, 136.2, 117.9, 116.3, 108.3, 76.1, 34.6, 20.8; HPLC (Chiralpak OD-3, i-proh/hexane = 10/90, flow rate = 1.0 ml/min, λ = 254 nm): t major = 6.90 min, t minor = 7.52 min, ee = 93%. 8. References 1) Gonzalez-de-Castro, A.; Robertson, C. M.; Xiao, J. J. Am. Chem. Soc. 2014, 136, ) Zhou, M. Y.; Kong, S. S.; Zhang, L. Q.; Zhao, M.; Duan, J. A.; Zhen, O.; Wang, M. Tetrahedron Lett. 2013, 30, ) Bob, E.; Hillringhaus, T.; Nitsch, J.; Klussmann, M. Org. Biomol. Chem. 2011, 9, ) Han, Y.; Lee, Y. M.; Mariappan, M.; Fukuzumi, S.; Nam, W. Chem. Commun. 2010, 46, ) Campeau, L. C.; Parisien, M.; Jean, A.; Fagnou, K. J. Am. Chem. Soc. 2006, 128, ) Azzena, U.; Demartis, S.; Pilo, L.; Piras, E. Tetrahedron, 2000, 42, ) Li, Z.; Deng, G.; Li, Y. C. Synlett 2008, 19, ) Ren, D.; He, L.; Yu, L.; Ding, R. S.; Liu, Y. M.; Cao, Y.; He, H. Y.; Fan, K. N. J. Am. Chem. Soc. 2012, 134, ) Wang, X.; Donaire, J. G.; Martin, R. Angew. Chem. Int. Ed. 2014, 41, ) Xie, X.; Stahl, S. S. J. Am. Chem. Soc. 2015, 137, ) Shan, G.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem., Int. Ed. 2012, 51, ) Menenedez, C.; Nador, F.; Radivoy, G.; Gerbino, D. Org. Lett. 2014, 16, ) Rao, H.; Ma, X.; Liu, Q.; Li, Z.; Cao, S.; Li, C. Adv. Synth. Catal. 2013, 11, ) Prebil, R.; Stavber, G.; Stavber, S. Eur. J. Org. Chem. 2014, ) Dubrovskiy, A. V.; Larock, R. C. Org. Lett. 2011, 13, ) Wang, X.-L.; Liu, R.-H. Jin, Y.; Liang, X.-M. Chem. Eur. J. 2008, 14, ) Ito, M.; Osaku, A.; Shiibashi, A.; Ikariya, T. Org. Lett. 2007, 9, S11

12 9. 1H and 13 C-NMR spectra Isochroman-1-one (2a). S12

13 7-Methylisochroman-1-one (2b). S13

14 7-(tert-Butyl)isochroman-1-one (2c). S14

15 7-Methoxyisochroman-1-one (2d). S15

16 5-Methylisochroman-1-one (2e). S16

17 7-Fluoroisochroman-1-one (2f). S17

18 4-Methylisochroman-1-one (2g). S18

19 3-Methylisochroman-1-one (2h, 2i). S19

20 6H-Benzo[c]chromen-6-one (2j). S20

21 Benzo[de]isochromen-1(3H)-one (2k). S21

22 4H-Thieno[2,3-c]pyran-7(5H)-one (2l). S22

23 9H-Xanthen-9-one (4a). S23

24 7H-Benzo[c]xanthen-7-one (4b). S24

25 12H-Benzo[a]xanthen-12-one (4c). S25

26 9-Methyl-7H-benzo[c]xanthen-7-one (4d). S26

27 9H-Thioxanthen-9-one (4e). S27

28 10-Methyl-10,10a-dihydroacridin-9(8aH)-one (4f). S28

29 Acridine (4g). S29

30 bis(4-methoxyphenyl)methanone (4h). S30

31 Dibenzo[c,e]oxepin-5(7H)-one (5). S31

32 (S)-Mellein. (9) S32

33 10. Chiral HPLC analysis spectra S33

34 S34