Rh(III)-catalyzed Redox-Neutral Unsymmetrical C-H. Alkylation and Amidation Reactions of

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1 Rh(III)-catalyzed Redox-Neutral Unsymmetrical C-H Alkylation and Amidation Reactions of N-Phenoxyacetamides Yunxiang Wu, a,b, Zhaoqiang Chen, c, Yaxi Yang, a,b Weiliang Zhu,*,c Bing Zhou*,a,b a Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences b University of Chinese Academy of Sciences, Beijing , China c Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences These authors contributed equally. (B.Z.): zhoubing2012@hotmail.com; zhoubing@simm.ac.cn; (W. Z.): wlzhu@mail.shcnc.ac.cn Table of contents: General Methods and Materials.S2 Table S1. Optimization studies..s5 Experimental Procedures and Characterizations S6 Experimental Mechanistic Studies.S16 DFT studies...s19 1 H and 13 C NMR Spectra of Compounds S31 S1

2 General Methods 1 H NMR (400 or 300 MHz) and 13 C NMR (125, 100 MHz) spectra were determined with CDCl 3 as solvent and tetramethylsilane (TMS) as internal standard. Chemical shifts were reported in ppm from internal TMS (δ). All coupling constants (J values) were reported in hertz (Hz). High-resolution mass spectra were recorded using the EI method with a double focusing magnetic mass analyzer. Reactions were monitored by thin-layer chromatography or LC-MS analysis. Column chromatography (petroleum ether/ethyl acetate) was performed on silica gel ( mesh). Materials General Procedure for the synthesis of N-phenoxyacetamides 1 Method A 1 A mixture of N-hydroxyphthalimide (1.0 equiv), arylboronic acid (2.0 equiv), CuCl (1.0equiv), freshly activated 4Å molecular sieves (250mg/mmol) and pyridine (1.1 equiv.)were dissolved in 1,2-dichloroethane (0.25 M) and stirred at room temperature under air. After 48 hours, the reaction mixture turned green. Silica gel was added to the flask and the solvent was evaporated under reduced pressure. The purification was performed by flashcolumn chromatography on silica gel to afford desired N-aryloxyphthalimides. The productwas directly used for the next step. Hydrazine monohydrate (4.00 equiv., 51%-64%) was added to the solution of Naryloxyphthalimide (1.0 equiv) in DCM (0.25 M). The reaction was stirred at room temperature overnight. MgSO4 was added to the mixture and the suspension was stirred for additional 10 minutes. The precipitate was filtered off and washed with DCM followed by EtOAc. The filtrate was concentrated and the resulting oil was directly used without further purification. N-aryloxyamine (1.0 equiv.) was dissolved in EtOAc/H 2 O (0.3 M, 2:1) followed by the addition of Na 2 CO 3 (1.2 equiv.). The resulting solution was cooled to 0 C and acetylchloride(1.10 equiv.) was added dropwise to the mixture. After stirring at room S2

3 temperature overnight, the reaction was quenched with saturated NaHCO 3 and extracted with EtOAc. The organicphase was washed three times with saturated NaHCO 3 and dried over MgSO 4, followed by filtration. The solvent was evaporated under reduced pressure. The crude product was purified by recrystallization from EtOAc/pentane to afford the desired N-aryloxyacetamide. Method B O-mesitylsulfonylhydroxylamine (MSH) was prepared according to the literature. 2 Phenols (2.76 mmol) was dissolved in 4 ml of methanol, and then potassium tert-butoxide (309 mg, 2.76 mmol) was added. The mixture was allowed to stir for 0.5 h under N2 atmosphere. The methanol was removed, and the residue was taken up in 2 ml of DMF. Then the freshly prepared O-mesitylsulfonylhydroxylamine (378 mg, 1.76 mmol) in 2 ml of DMF was added under ice cooling. The mixture was allowed to stir for 1 h, diluted with 15 ml of ethyl acetate, and washed with brine. The aqueous layer was extracted with EtOAc. Ethyl acetate was then removed under reduce pressure to afford the corresponding N-aryloxyamine. A biphasic mixture of Na 2 CO 3 (222 mg, 2.1 mmol) in 1 ml of H 2 O and 2 ml of EtOAc was next added to the reaction flask. The resulting solution was keeped under ice followed by dropwise addition of acyl chloride (138 mg, 1.76 mmol). After stirring at 0 ºC for 2 h, the reaction was quenched with sat. NaHCO 3 and diluted with EtOAc. The organic phase was washed twice with sat. NaHCO 3, dried over Na 2 SO 4, filtered, and evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (DCM/ethyl acetate = 3/1, v/v) to provide the desired product. Method C 3 Ethyl N-hydroxylacetimidate (1.0 equiv.) was dissolved in dry DMF (0.4 M), the resulting solution was cooled to 0 C, and then NaH (1.2 equiv., 60% dispersion in mineral oil) was added. The resulting solvent was allowed to stir for 1 hour at r.t. Add 4-fluoro-benzonitrile (1.0 equiv.) to the reaction mixture, and then stir overnight S3

4 at 40 C, diluted with EtOAc and washed with brine twice, dried over Na 2 SO 4, filtered, purified by column chromatography on silica gel (petrol-etoac 99:1-97:3), to obtain ethyl N-aryloxyacetimidate. Cool a solution of ethyl N-aryloxyacetimidate (1.0 equiv.) in dioxane (1M) to 0 ºC, treat the solution with HClO 4 (10.0 equiv., 70% in H 2 O), the resulting mixture is allowed to stir for 4 hours at 0 C, then adjust the ph to 7 with NaOH pellets, then extract the aqueous layer with EtOAc twice, dried over Na 2 SO 4, filtered, purified by column chromatography on silica gel (CH 2 Cl 2 : NH 4 OH 99.9 : 0.01) to obtain O-(4-cyanophenyl)hydroxylamine. N-aryloxyamine (1.0 equiv.) was dissolved in EtOAc/H 2 O (0.3 M, 2:1) followed by the addition of Na 2 CO 3 (1.2 equiv.). The resulting solution was cooled to 0 C and acetylchloride(1.10 equiv.) was added dropwise to the mixture. After stirring at room temperature overnight, the reaction was quenched with saturated NaHCO 3 and extracted with EtOAc. The organicphase was washed three times with saturated NaHCO 3 and dried over MgSO 4, followed by filtration. The solvent was evaporated under reduced pressure. The crude product was purified by recrystallization from EtOAc/pentane to afford the desired N-aryloxyacetamide. Compounds 1a-1i, 1k-1r were synthesized according to method A and compounds 4, 6 were synthesized according to method B, compound 1j was synthesized according method C. General Procedure for the synthesis of diazo compounds 2 4 Into a flame-dried 250 ml round bottom flask equipped with a magnetic stir bar, was added p-absa (12.3 g, 51 mmol). The vessel was evacuated and backfilled with argon before a solution of dimethyl malonate (5.7 ml, 50 mmol) in dry acetonitrile (50 ml) was added. The mixture was allowed to cool to 0 C and stirred for 5 min before slowly adding triethylamine (21 ml, 150 mmol) via syringe. The solution was subsequently allowed to warm to room temperature and stirred overnight. The S4

5 white mixture was filtered using a Buchner funnel and rinsed with additional acetonitrile (10 ml). The yellow filtrate was concentrated and the residue was triturated with 200 ml (50:50) hexane/diethyl ether. After filtration, the filtrate was concentrated and purified by medium pressure liquid chromatography (1:1 ethyl acetatehexanes) to yield 7.4 g (94%) of dimethyl 2-diazomalonate. Table S1. Optimization studies. a entry catalyst additive solvent yield (%) 1 (RhCp*Cl 2 ) 2 AgSbF 6 DCE 8 2 (RhCp*Cl 2 ) 2 AgSbF 6 / AcOH DCE 0 3 (RhCp*Cl 2 ) 2 CsOAc DCE 74 4 (Cp*IrCl 2 ) 2 CsOAc DCE 0 5 (Cp*CoI 2 ) 2 AgSbF 6 /CsOAc DCE 0 6 [RuCl 2 (p-cymene)] 2 AgSbF 6 /CsOAc DCE 0 7 (RhCp*Cl 2 ) 2 CsOAc toluene 60 8 (RhCp*Cl 2 ) 2 CsOAc 1,4-dioxane 31 9 (RhCp*Cl 2 ) 2 CsOAc MeOH 0 10 _ CsOAc DCE 0 11 b (RhCp*Cl 2 ) 2 CsOAc DCE 87 a Reactions were carried out by using (RhCp*Cl 2 ) 2 (2.5 mol%), additive (10 mol%), 1a (0.2 mmol) and 2a (0.24 mmol) in a solvent (2 ml) at room temperature for 12 h; lsolated yield. b The reaction was carried out at 40 o C for 12 h. S5

6 Experimental Procedures and Characterizations General procedure for the Rh-catalyzed C-H difunctionalization A mixture of 1 (0.2 mmol), 2 (0.24mmol, 1.2 equiv.), [Cp*RhCl 2 ] 2 (0.005 mmol, 2.5% equiv.), CsOAc (0.02 mmol, 0.1 equiv.) were dissolved in 2 ml DCE in a pressure tube under argon. The mixture was allowed to stir at 40 ºC for 12h and filtered through a celite pad, and washed with EtOAc. The organic phase was then washed with brine, and dried over Na 2 SO 4. Then organic solvent was removed under reduced pressure and the residue was purified by column chromatography PE/EA (2:1) to afford desired product. Compound 3a was obtained as a white amorphous solid in 87% yield (49 mg), isolated by column chromatography PE/EA 2:1(Rf=0.4, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.71 (s, 1H), 8.31 (s, 1H), (m, 2H), 6.76 (t, J = 7.8 Hz, 1H), 5.10 (s, 1H), 3.81 (s, 6H), 2.08 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 53.25, 52.97, 23.51; HRMS (EI) Calcd for C 13 H 15 NO 6 [M] , found Compound 3b was obtained as a white amorphous solid in 92% yield (54 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.5, PE/EA=2:1), 1 H NMR (400 S6

7 MHz, CDCl 3 ) δ 9.72 (s, 1H), 8.23 (s, 1H), (m, 2H), 6.74 (t, J = 7.8 Hz, 1H), 5.09 (s, 1H), 3.82 (s, 6H), 2.34 (q, J = 7.5 Hz, 2H), 1.19 (t, J = 7.5 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 53.20, 52.95, 29.83, 9.86; HRMS (EI) Calcd for C 14 H 17 NO 6 [M] , found Compound 3c was obtained as a white amorphous solid in 76% yield (47 mg), isolated by column chromatography PE/EA 3:1 (Rf=0.5, PE/EA=3:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.54 (s, 1H), 8.04 (s, 1H), 7.12 (d, J = 8.0 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 6.79 (t, J = 7.8 Hz, 1H), 5.07 (s, 1H), 3.80 (s, 6H), 2.58 (dt, J = 13.7, 6.8 Hz, 1H), 1.23 (d, J = 6.8 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 53.21, 53.16, 36.13, 19.73; HRMS (EI) Calcd for C 15 H 19 NO 6 [M] , found Compound 3d was obtained as a white amorphous solid in 81% yield (50 mg), isolated by column chromatography PE/EA 3:1 (Rf=0.5, PE/EA=3:1), 1 H NMR (400 MHz, CDCl 3 ) δ (s, 1H), 8.49 (s, 1H), 6.93 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 7.8 Hz, 1H), 6.74 (t, J = 7.8 Hz, 1H), 5.11 (s, 1H), 3.82 (s, 6H), 1.58 (dt, J = 11.9, 4.0 Hz, 1H), (m, 2H), 0.85 (m, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 53.17, 52.82, 14.95, 8.66; HRMS (EI) Calcd for C 15 H 17 NO 6 [M] , found S7

8 Compound 3e was obtained as a white amorphous solid in 82% yield (58 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.3, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.33 (s, 1H), 8.00 (s, 1H), (m, 5H), 7.09 (dd, J = 8.1, 1.5 Hz, 1H), 6.97 (dd, J = 7.7, 1.4 Hz, 1H), 6.76 (t, J = 7.9 Hz, 1H), 5.04 (s, 1H), 3.79 (s, 6H), 3.71 (s, 2H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , , 53.26, 53.20, 43.93; HRMS (EI) Calcd for C 19 H 19 NO 6 [M] , found Compound 3g was obtained as a white amorphous solid in 85% yield (50 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.5, PE/EA=2:1), 1 H NMR (500 MHz, CDCl 3 ) δ 9.39 (s, 1H), 8.15 (s, 1H), 6.77 (s, 1H), 6.76 (s, 1H), 5.06 (s, 1H), 3.82 (s, 6H), 2.18 (s, 3H), 2.10 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 53.09, 52.76, 23.39, 20.49; HRMS (EI) Calcd for C 14 H 17 NO 6 [M] , found Compound 3h was obtained as a yellow amorphous solid in 76% yield (54 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.4, PE/EA=2:1), 1 H NMR (500 MHz, CDCl 3 ) δ 9.77 (s, 1H), 8.42 (s, 1H), 7.45 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H), 7.21 (s, 2H), 5.16 (s, 1H), 3.86 (s, 6H), 2.01 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , , 53.33, 53.21, 23.36; HRMS (EI) Calcd for C 19 H 19 NO 6 [M] , found S8

9 Compound 3i was obtained as a yellow amorphous solid in 83% yield (56 mg), isolated by column chromatography PE/EA 1:1 (Rf=0.4, PE/EA=1:1), 1 H NMR (400 MHz, CDCl 3 ) δ (s, 1H), 8.58 (s, 1H), 7.67 (d, J = 1.7 Hz, 1H), 7.42 (d, J = 1.8 Hz, 1H), 5.13 (s, 1H), 3.84 (d, J = 3.6 Hz, 6H), 3.83 (s, 3H), 2.16 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , 53.40, 52.54, 52.20, 23.38; HRMS (EI) Calcd for C 15 H 17 NO 8 [M] , found Compound 3j was obtained as a yellow amorphous solid in 72% yield (44 mg), isolated by column chromatography PE/EA 1:1 (Rf=0.4, PE/EA=1:1), 1 H NMR (500 MHz, CDCl 3 ) δ (s, 1H), 8.35 (s, 1H), 7.51 (s, 1H), 7.32 (s, 1H), 5.01 (s, 1H), 3.83 (d, J = 14.1 Hz, 6H), 2.21 (s, 3H); 13 C NMR (126 MHz, CDCl 3 ) δ , , , , , , , , , 53.75, 53.11, 23.78; HRMS (EI) Calcd for C 14 H 14 N 2 O 6 [M] , found Compound 3k was obtained as a yellow amorphous solid in 83% yield (58 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.5, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 8.60 (s, 1H), 7.20 (s, 1H), 7.17 (s, 1H), 5.10 (s, 1H), 3.87 (s, 6H), 2.09 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ , , , , (q, J = Hz), , (d, J = 3.4 Hz), (q, J = 27.6 Hz) (d, S9

10 J = 3.6 Hz), 53.51, 52.91, 23.12; HRMS (EI) Calcd for C 14 H 14 F 3 NO 6 [M] , found Compound 3l was obtained as a yellow amorphous solid in 85% yield (51 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.4, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.23 (s, 1H), 8.41 (s, 1H), 6.87 (dd, J = 9.3, 2.7 Hz, 1H), 6.74 (dd, J = 8.4, 2.6 Hz, 1H), 4.99 (s, 1H), 3.83 (s, 6H), 2.13 (s, 3H); 13 C NMR (150 MHz, CDCl 3 ) δ (d, J = 2.8 Hz), , (d, J = Hz), , (d, J = 10.6 Hz), (d, J = 7.4 Hz), (d, J = 24.2 Hz), (d, J = 26.6 Hz), 53.50, 53.34, 23.73; HRMS (EI) Calcd for C 13 H 14 FNO 6 [M] , found Compound 3m was obtained as a white amorphous solid in 82% yield (52 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.4, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.77 (s, 1H), 8.44 (s, 1H), 6.98 (d, J = 2.2 Hz, 1H), 6.96 (d, J = 2.1 Hz, 1H), 5.06 (s, 1H), 3.87 (s, 6H), 2.15 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 53.52, 52.91, 23.48; HRMS (EI) Calcd for C 13 H 14 ClNO 6 [M] , found Compound 3n was obtained as a yellow amorphous solid in 82% yield (59 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.3, PE/EA=2:1), 1 H NMR (500 S10

11 MHz, CDCl 3 ) δ 9.78 (s, 1H), 8.41 (s, 1H), 7.12 (dd, J = 9.7, 2.2 Hz, 2H), 5.06 (s, 1H), 3.86 (s, 6H), 2.16 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 53.51, 52.77, 23.49; HRMS (EI) Calcd for C 13 H 14 BrNO 6 [M] , found Compound 3o was obtained as a white amorphous solid in 87% yield (55 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.4, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.55 (s, 1H), 7.88 (s, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.96 (d, J = 8.4 Hz, 1H), 5.23 (s, 1H), 3.75 (s, 6H), 2.31 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 52.99, 50.92, 23.71; HRMS (EI) Calcd for C 13 H 14 ClNO 6 [M] , found Compound 3p was obtained as a white amorphous solid in 85% yield (50 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.5, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 8.69 (s, 1H), 7.65 (s, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.69 (d, J = 7.9 Hz, 1H), 5.17 (s, 1H), 3.77 (s, 6H), 2.16 (s, 3H), 2.09 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 52.95, 51.67, 23.20, 18.15; HRMS (EI) Calcd for C 14 H 17 NO 6 [M] , found S11

12 Compound 3q was obtained as a white amorphous solid in 78% yield (48 mg), isolated by column chromatography PE/EA 3:1 (Rf=0.6, PE/EA=3:1), 1 H NMR (400 MHz, CDCl 3 ) δ 8.26 (s, 1H), 7.42 (s, 1H), 6.99 (s, 1H), 5.17 (s, 1H), 3.77 (s, 6H), 2.21 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 52.99, 51.50, 23.36, 20.11, 14.48; HRMS (EI) Calcd for C 15 H 19 NO 6 [M] found Compound 3r was obtained as a white amorphous solid in 78% yield (51 mg), isolated by column chromatography PE/EA 3:1 (Rf=0.5, PE/EA=3:1), 1 H NMR (300 MHz, CDCl 3 ) δ 8.30 (s, 1H), 7.47 (s, 1H), 7.20 (d, J = 7.9 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 5.20 (s, 1H), 3.76 (s, 6H), 2.95 (dt, J = 13.5, 6.7 Hz, 1H), 2.23 (s, 3H), 1.19 (d, J = 6.8 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 52.93, 51.55, 28.47, 23.52, 23.02; HRMS (EI) Calcd for C 16 H 21 NO 6 [M] found Compound 3s was obtained as a white amorphous solid in 92% yield (57 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.6, PE/EA=2:1), 1 H NMR (500 MHz, CDCl 3 ) δ 9.69 (s, 1H), 8.41 (s, 1H), 6.93 (dd, J = 18.2, 7.8 Hz, 2H), 6.74 (t, J = 7.8 Hz, 1H), 5.03 (s, 1H), (m, 4H), 2.06 (s, 3H), 1.31 (t, J = 7.1 Hz, 6H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 62.33, 53.54, 23.43, 14.14; HRMS (EI) Calcd for C 15 H 19 NO 6 [M] , found S12

13 Compound 3t was obtained as a white amorphous solid in 87% yield (57 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.6, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.66 (s, 1H), 8.48 (s, 1H), (m, 2H), 6.72 (t, J = 7.8 Hz, 1H), (m, 2H), 4.91 (s, 1H), 2.02 (s, 3H), 1.28 (s, 12H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 70.10, 54.21, 23.50, 21.73, 21.70; HRMS (EI) Calcd for C 17 H 23 NO 6 [M] , found Compound 3u was obtained as a white amorphous solid in 81% yield (70 mg), isolated by column chromatography PE/EA 2:1 (Rf=0.3, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.78 (s, 1H), 8.35 (s, 1H), (m, 10H), 6.88 (dd, J = 7.5, 1.4 Hz, 1H), 6.74 (dd, J = 8.1, 1.5 Hz, 1H), 6.66 (t, J = 7.8 Hz, 1H), (m, 5H), 1.98 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , , , , 67.94, 53.31, 23.36; HRMS (EI) Calcd for C 25 H 23 NO 6 [M] , found Compound 5 was obtained as a white amorphous solid in 81% yield (74 mg), isolated by column chromatography PE/EA 1:1 (Rf=0.4, PE/EA=1:1), 1 H NMR (500 MHz, CDCl 3 ) δ 8.37 (s, 1H), 7.33 (s, 1H), 7.20 (s, 1H), 5.22 (s, 1H), 3.77 (s, 6H), 2.67 (m, 1H), (m, 2H), (m, 1H), 2.21 (s, 3H), (m, 2H), (m, 2H), 1.94 (dd, J = 8.9, 2.3 Hz, 1H), (m, 6H), 0.88 (s, J = 6.4 Hz, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , S13

14 132.63, , , , , 53.02, 53.00, 51.40, 50.36, 47.97, 44.11, 37.31, 35.95, 31.58, 26.13, 25.52, 23.44, 21.64, 13.92; HRMS (EI) Calcd for C 25 H 31 NO 7 [M] , found Compound 7 was obtained as a white amorphous solid in 85% yield (72 mg); isolated by column chromatography PE/EA 2:1 (Rf=0.5, PE/EA=2:1), 1 H NMR (400 MHz, CDCl 3 ) δ 9.52 (s, 1H), 8.50 (s, 1H), 6.81 (s, 2H), 5.07 (s, 1H), 4.71 (s, 1H), 3.80 (s, 6H), 3.25 (t, J = 6.7 Hz,, 2H), 2.61 (t, J = 6.7 Hz, 2H), 2.13 (s, 3H), 1.42 (s, 9H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , , 53.23, 52.75, 41.72, 35.37, 29.81, 28.52, 23.52; HRMS (EI) Calcd for C 20 H 28 N 2 O 8 [M] , found Synthesis of 8a and 9a A mixture of 3a (0.2 mmol) and TsOH (10 mg) were dissolved in PhMe (1 ml) in a pressure tube under argon. The resulting mixture was allowed to stir for 3h at 100 ºC. The solvent was removed under reduced pressure. The residue was purified by chrome chromatography PE/EA (4:1) to afford 8a (Rf=0.3, PE/EA=4:1). Compound 8a was obtained as a white amorphous solid in 79% yield (41 mg), 1 H NMR (400 MHz, CDCl 3 ) δ 7.65 (dd, J = 7.8, 1.0 Hz, 1H), (dd, J = 7.8, 1.0 Hz, 1H), 7.34 (t, J = 7.8 Hz, 1H), 5.17 (s, 1H), 3.81 (s, 6H), 2.67 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 53.23, 51.92, 14.72; HRMS (EI) Calcd for C 13 H 13 NO 5 [M] , found S14

15 The mixture of 8a (0.2 mmol, 1 equiv.), LiOH (0.8 mmol, 4 equiv.) in MeOH:H 2 O (5:1, 1.2 ml) was stirred at room temperature for 5h. Then organic solvent was removed under reduced pressure and the mixture was acidified by 1M HCl and stirred for 2h at rt. The mixture was extracted with EtOAc (10 ml) twice and the organic solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using PE/EA (3:1) to afford 9a (Rf=0.4, PE/EA=3:1). Compound 9a was obtained as a white amorphous solid in 83% yield (32 mg); 1 H NMR (400 MHz, CDCl 3 ) δ 7.61 (d, J = 7.9 Hz, 1H), (m, 1H), 7.21 (d, J = 7.3 Hz, 1H), 3.93 (s, 2H), 2.66 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , , , , , 35.16, 14.69; HRMS (EI) Calcd for C 10 H 9 NO 3 [M] , found Synthesis of 10a The mixture of 3a (0.2 mmol, 1 equiv.), LiOH (0.8 mmol, 4 equiv.) was stirred in MeOH/H 2 O (5:1, 1.2 ml) at room temperature for 5h. Then organic solvent was removed under reduced pressure. The mixture was acidified by 1M HCl and was stirred for 2h and extracted with EtOAc (10 ml) twice. The organic phase was then washed with brine, dried over Na 2 SO 4. After that, the solvent was removed under reduced pressure and the residue was purified by silica gel chromatography using PE/EA (3:1) to afford 10a (Rf=0.6, PE/EA=3:1). Compound 10a was obtained as a white amorphous solid in 72% yield (27 mg), 1 H NMR (400 MHz, CDCl 3 ) δ 8.22 (d, J = 8.3 Hz, 1H), 7.33 (s, 1H), 7.12 (t, J = 8.0 Hz, 1H), 7.01 (d, J = 7.4 Hz, 1H), 3.80 (s, 2H), 2.22 (s, 3H); 13 C NMR (125 MHz, CDCl 3 ) δ , , , , S15

16 122.24, , , , 32.99, 24.14; HRMS (EI) Calcd for C 10 H 9 NO 3 [M] , found Experimental Mechanistic Studies The cross-over experiment A mixture of 1c (0.2 mmol), 1k (0.2 mmol), 2a (0.48mmol, 2.4 equiv.), [Cp*RhCl 2 ] 2 (0.01 mmol, 5% equiv.), CsOAc (0.04 mmol, 0.2 equiv.) were dissolved in 2 ml DCE in a pressure under argon. The resulting mixture was allowed to at 40 ºC for 12h. Filtered through a celite pad, washed with EtOAc. The organic phase was then washed with brine, dried over Na 2 SO 4. Organic solvent was removed under reduced pressure. This residue was purified by column chromatography PE/EA (5:1-2:1) to afford 3c (75%) and 3k (79%). The use of rhodacycle complex A as the active catalyst A mixture of 1 (0.2 mmol), 2 (0.24mmol, 1.2 equiv.), A (0.005 mmol, 2.5% equiv.), CsOAc (0.02 mmol, 0.1 equiv.) was dissolved in 2 ml DCE in a pressure under argon. The resulting mixture was allowed to at 40 ºC for 12h. Filtered through a celite pad, washed with EtOAc (10 ml). The organic phase was washed with brine, dried over Na 2 SO 4. Then organic solvent was removed under reduced pressure. This S16

17 residue was purified by column chromatography PE/EA (2:1) to afford desired product. Kinetic Isotope Effect Experiments An equimolar mixture of 1a (0.2 mmol, 1 equiv.), 1a-d 5 (0.2 mmol, 1 equiv.), [Cp*RhCl 2 ] 2 (0.005 mmol, 2.5 mol %), CsOAc (0.02 mmol, 10 mol %), 2a (0.2 mmol, 1 equiv.), and DCE (2 ml) were charged into a pressure tube under argon. The reaction mixtures were stirred at 40 C for 20 min. The solvent was rapidly removed under reduced pressure and the residues of the reaction was purified by silica gel chromatography using EA/PE to afford the products. KIE value (k H /k D = 4.26 was determined on the basis of 1 H NMR analysis. S17

18 Two Parallel Reactions A mixture of 1a or 1a-d5 (0.4 mmol), [Cp*RhCl 2 ] 2 (2.5 mol %, 7mg), CsOAc (20 mol %, 15 mg), 2a (0.4 mmol, 63mg), and DCE (4 ml) were charged into a 10 ml round-bottom flask sealed with a rubber plug under Ar. The resulting mixture was stirred at 40 C. Aperiodic aliquot (200 µl) was removed by a syringe and concentrated, 1 H NMR analysis using dibromoethane as an internal standard to provide the following conversions: Time(min) a(%) a-d 3 (%) k H /k D =2.3 Competitive Reaction S18

19 An equimolar mixture of 1g (0.2 mmol, 33 mg), 1k (0.2 mmol, 44 mg), [Cp*RhCl 2 ] 2 (2.5 mol %), CsOAc (10 mol %), 2a (0.2 mmol, 32 mg), and DCE (2 ml) were charged into a pressure tube. The reaction mixture was stirred at 40 C for 40 min. The solvent was rapidly removed under reduced pressure and the residues of the reaction was purified by silica gel chromatography using PE/EA 3:1 to afford the products 3g (10 mg), 3k (5 mg). The ratio of 3g: 3k is 7:3. The effect of radical scavengers A mixture of 1 (0.2 mmol), 2 (0.24mmol, 1.2 equiv.), [Cp*RhCl 2 ] 2 (0.005 mmol, 2.5% equiv.), CsOAc (0.02 mmol, 0.1 equiv.), TEMPO or BHT (0.3 mmol, 1.5 equiv.) were dissolved in 2 ml DCE in a pressure under argon. The resulting mixture was allowed to at 40 ºC for 12h. Filtered through a celite pad, washed with EtOAc. Then organic solvent was removed under reduced pressure. This residue was purified by column chromatography PE/EA (2:1) to afford desired product. DFT Studies 1. Computational Methods. All computations were performed with the Gaussian 09 [5] series of programs. All the structures were optimized using the density functional M06methods. [6] A combined basis set was used, the relativistic effective core potential basis set of SDD was used on the rhodium atom, and 6-31G(d) basis set was used on the other atoms, such as C, H, O, N atoms. Solvent effects of dichloroethane were considered by using the SMD model. [7] Frequencies calculations were performed to judge them as local minima or transition states and obtain the thermal corrections to the Gibbs free energies and enthalpies. Single point computations were carried out using the SDD effective core potential basis set for rhodium and the G(d,p) basis set on all other atoms. The solvation single-point energies with Gibbs free energy corrections were used to describe the reaction energies. 2. M06 calculated energies for reported complexes and transition states. S19

20 Geometry E 1 G(coor) 2 E(solv) 3 IF 4 A A B TS C D TS E a F TS G a N HOAc OAc Cp*Rh(OAc) Single point energies calculated by M06 at the 6-31g(d) level in dichloroethane solvent. 2 Thermal corrections for Gibbs free energy calculated by M06 at the 6-31g(d)/Lanl2DZ level. 3 Single point energies calculated by M06 at the g(d,p) level in the dichloroethane solvent. 4 M06/6-31G(d)/Lanl2DZ calculated imaginary frequencies for transition states. The unit of energy values in the above table are Hartree/Particle( a. u.). 3. Cartesian coordinates of minimum energy structures. S20

21 A C C C H C C H C Rh C C C C C H H C H H H C H H H C H H H C H H H H C H H O N C O C H H H A-1 Rh C C C C C H H C H H H C H H H C H H H C H H H C C C C H C C C O O O O C H C S21

22 H H H H H C C H C H O N C O C H H H H H B C C C C C C C O C C C C C C C H H H C H H H C H H H C H H H N O H H H Rh C C H H H H C O O C O O C H H H C H H H H H H TS1 C C C C C S22

23 C C O C C C C C C C H H H C H H H C H H H C H H H N O H H H Rh C C H H H H C O O C O O C H H H C H H H H H H C C C C C C C C O C C C C C C C H H H C H H H C H H H C H H H N O S23

24 H H H Rh C C H H H H C O O C O O C H H H C H H H H H H D C C C C C C C C C C C C C H H H C H H H H H H Rh H H H C H H H C H H H C N O H H H O C H C O O C H H H C H C O O C O O S24

25 C H H H C H H H TS2 C C C C C C C C C C C C C H H H C H H H H H H Rh H H H C H H H C H H H C N O H H H O C H C O O C H H H C H C O O C O O C H H H C H H H E C C C C C C C C C S25

26 C C C C H H H C H H H H H H Rh H H H C H H H C H H H C N O H H H O C H C O O C H H H C H C O O C O O C H H H C H H H a C C C C C C H H H O C H C O O C O O C H H H C H H H N C S26

27 O C H H H H H F C C C C C C C O C C C C C C C H H H C H H H C H H H C H H H N O H H H Rh C C H H H H C O O C O O C H H H C H H H H H H H TS3 C C C C C C C O C C C C C C C H H S27

28 H C H H H C H H H C H H H N O H H H Rh C C H H H H C O O C O O C H H H C H H H H H H H G C C C C C C H H H O H C H C O O C O O C H H H C H H H N C O C H H H C C C C C H H H C S28

29 H H H C H H H C H H H C C H H H Rh a C N N C O O C O O C H H H C H H H N2 N N HOAc C O O H C H H H OAc - C O O C H H H Cp*Rh(OAc) 2 Rh C C C C C C O O C H H H C H H H C H H H C H H H C H S29