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1 Supporting Information SmI 2 -Mediated Carbon-Carbon Bond Fragmentation in α-aminomethyl Malonates Qiongfeng Xu,, Bin Cheng, $, Xinshan Ye,*, and Hongbin Zhai*,,,$ The State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, 38 Xue Yuan Rd, Beijing , China, The Key Laboratory of Synthetic Chemistry of Natural Substances and the State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai , China, and $ Hefei National Laboratory for Physical Science at Microscale and Department of Chemistry, University of Science and Technology of China, Hefei, Anhui , China CONTENTS Part 1. Experimental Procedures and Analytical Data Page S2 Part 2. Copies of NMR Spectra for All Compounds.Page S8 S1

2 Part 1. Experimental Procedures and Analytical Data General Methods. Melting points are uncorrected. All solvents and reagents were obtained from commercial sources and used without further purification unless otherwise stated. NMR spectra were recorded in CDCl 3 or D 2 O ( 1 H at 300 MHz and 13 C at 75 MHz) using TMS as the internal standard. Analytical samples were obtained by chromatography on silica gel. Anhydrous solvents and reagents were obtained as follows: dichloromethane was distilled over calcium hydride under N 2 ; THF and benzene were distilled over sodium benzophenone ketyl under N 2. General procedure for preparation of malonates 1a-e, 1g, and 1j. To a solution of diester 2a, 2d, or 2j (1.0 mmol) in dioxane (4 ml) were added 37% aqueous formaldehyde (1.2 mmol) and dialkylamine hydrochloride (1.2 mmol) and dialkylamine (1.2 mmol). The reaction mixture was stirred at room temperature for 24 h, and saturated aqueous NaHCO 3 solution was added. The resulting mixture was extracted with EtOAc for three times. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4. The dried solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with petroleum ether/etoac as eluent to afford the corresponding products 1a-e, 1g, or 1j. BnO 2 C Me BnO 2 C NMe 2 1a Compound 1a. (yield 56%, PE:EA=20:1) 1 H NMR (CDCl 3, 300 MHz) δ 1.55 (s, 3H), 2.21 (s, 6H), 2.90 (s, 2H), 5.11 (s, 4H), (m, 10H); 13 C NMR (CDCl 3, 75 MHz) δ 19.1, 47.5, 55.2, 63.5, 66.8, 128.0, 128.1, 128.4, 135.4, MS (ESI) (M + H). HRMS (MALDI) calcd for C 21 H 25 NO 4 + H, ; found: BnO 2 C Me BnO 2 C NBn 2 1b Compound 1b. (yield 68%, PE:EA =20:1) mp o C; 1 H NMR (CDCl 3, 300 MHz) δ 1.42 (s, 3H), 3.23 (s, 2H), 3.51 (s, 4H), 4.99 (d, J = 12.0 Hz, 2H), 5.07 (d, J = 12.6 Hz, 2H), (m, 20H); 13 C NMR (CDCl 3, 75 MHz) δ 19.2, 55.0, 58.1, 59.1, S2

3 66.8, 126.9, 128.0, 128.1, 128.4, 129.1, 135.3, 138.9, MS (ESI) (M + H). Anal. Calcd for C 33 H 33 NO 4 : C, 78.08; H, 6.55; N, Found: C, 78.05; H, 6.44; N, BnO 2 C Me BnO 2 C N 1c Compound 1c. (yield 54%, PE:EA:TEA=20:1:0.2) mp o C; 1 H NMR (CDCl 3, 300 MHz) δ (m, 6H), 1.52 (s, 3H), 2.35 (m, 4H), 2.88 (s, 2H), 5.10 (s, 4H), (m, 10H); 13 C NMR (CDCl 3, 75 MHz) δ 19.3, 23.9, 26.2, 55.5, 56.3, 62.6, 66.7, 128.0, 128.1, 128.4, 135.5, MS (ESI) (M + H). HRMS (ESI) calcd for C 24 H 29 NO 4 + H, ; Found: MeO 2 C Bn MeO 2 C NMe 2 1d Compound 1d. (yield 47%, PE:EA:TEA=20:1:0.2) 1H NMR (CDCl 3, 300 MHz) δ 2.23 (s, 6H), 2.76 (s, 2H), 3.38 (s, 2H), 3.71 (s, 6H), (m, 5H). MeO 2 C Bn MeO 2 C N O 1e Compound 1e. (yield 47%, PE:EA:TEA=20:1:0.2) mp o C; 1 H NMR (CDCl 3, 300 MHz) δ 2.42 (t, J = 4.5 Hz, 4H), 2.80 (s, 2H), 3.40 (s, 2H), 3.68 (t, J = 4.5 Hz, 4H), 3.71 (s, 6H), (m, 5H); 13 C NMR (CDCl 3, 75 MHz) δ 37.3, 52.3, 54.2, 59.1, 59.3, 67.0, 126.8, 128.1, 129.8, 136.1, MS (ESI) (M + H). Anal. Calcd for C 17 H 23 NO 5 : C, 63.54; H, 7.21; N, Found: C, 63.58; H, 7.10; N, EtO 2 C Me EtO 2 C NEt 2 1g Compound 1g. (yield 51%, PE:EA:TEA=20:1:0.2) 1 H NMR (CDCl 3, 300 MHz) δ 0.96 (t, J = 7.2 Hz, 6H), 1.26 (t, J = 6.9 Hz, 6H), 1.48 (s, 3H), 2.54 (q, J = 7.2 Hz, 4H), 3.00 (s, 2H), (m, 4H). O O EtO 2 C NMe 2 1j S3

4 Compound 1j. (yield 54%, PE:EA:TEA=20:1:0.2) 1 H NMR (CDCl 3, 300 MHz) δ 1.30 (t, J = 6.9 Hz, 3H), 2.29 (s, 6H), (m, 2H), 2.82 (d, J = 13.5 Hz, 1H), 3.04 (d, J = 13.5 Hz, 1H), (m, 2H), (m, 2H). MeO 2 C Bn MeO 2 C N + Me 3 I - Compound 1f. To a solution of dimethyl 2-benzylmalonate (671 mg, 3.02 mmol) in dioxane (4 ml) was added 37% aqueous formaldehyde (0.23 ml, 3.02 mmol), dimethylamine hydrochloride (246 mg, 3.02 mmol) and 33% aqueous dimethylamine (0.48 ml, 3.02 mmol) at room temperature. The reaction mixture was stirred at room temperature for 24 h and saturated aquous NaHCO 3 solution was added. The resulting mixture was extracted with EtOAc for three times. The combined organic layers were washed with brine and dried over anhydrous Na 2 SO 4. The dried solution was concentrated in vacuo. The residue was dissolved in EtOAc (4 ml), and iodomethane (0.26 ml, 4.53 mmol) was added. After stirring for 7 h, the precipitate was collected by filtration and washed with anhydrous ether to afford 1f as a white solid (220 mg, 17%). 1 H NMR (D 2 O, 300 MHz) δ 3.15 (s, 9H), 3.42 (s, 2H), 3.81 (s, 6H), 4.16 (s, 2H), (m, 2H), (m, 3H). Benzyl azide (4). A stock solution of 0.5 M NaN 3 in DMSO was prepared by stirring NaN 3 (1.30 g) in DMSO (40 ml) at room temperature for 24 h. To this solution was added benzyl bromide 3 (3.11 g, 18.2 mmol). The reaction mixture was stirred at room temperature for 1 h and was then diluted slowly with water (slightly exothermic). Stirring continued until it cooled to room temperature. The resulting mixture was extracted with EtOAc for three times. The combined organic layers were washed with brine, and dried over anhydrous MgSO 4. The dried solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with petroleum ether/etoac (20:1) as eluent to afford 4 (2.36 g, 97%). 1 H NMR (300 MHz, CDCl 3 ) δ 4.34 (s, 2H), (m, 5H). 1f EtO 2 C Me EtO 2 C NHPh 1h Compound 1h. To a solution of benzyl azide (4, 560 mg, 4.21 mmol) in S4

5 dichloromethane (8 ml) was added diethyl 2-methylmalonate (733 mg, 4.21 mmol) at 0 C. The mixture was stirred for 10 min and TfOH (0.41 ml, 4.63 mmol) was added dropwise. Gas evolution was observed. The reaction mixture was allowed to warm to room temperature and stirred for 20 h. Solid NaHCO 3 (0.2 g), dichloromethane (10 ml), and water (20 ml) were added. The resulting mixture was extracted with dichloromethane for three times. The combined organic layers were washed with brine, and dried over anhydrous MgSO 4. The dried solution was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with petroleum ether/etoac (20:1) as eluent to afford 1h as a pale yellow oil (593 mg, 50%). 1 H NMR (CDCl 3, 300 MHz) δ 1.22 (t, J = 7.2 Hz, 6H), 1.51 (s, 3H), 3.58 (s, 2H), (m, 5H), 6.63 (d, J = 8.1 Hz, 2H), 6.68 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 7.5 Hz, 2H); 13 C NMR (CDCl 3, 75 MHz) δ 13.8, 19.0, 48.9, 54.8, 61.4, 112.9, 117.5, 129.1, 147.9, MS (ESI) (M + H), (M + Na). Anal. Calcd for C 15 H 21 NO 4 : C, 64.50; H, 7.58; N, Found: C, 64.57; H, 7.62; N, EtO 2 C Me EtO 2 C NPhAc 1i Compound 1i. To a solution of 1h (123 mg, 0.44 mmol) in dichloromethane (4 ml) was added acetic chloride (38 µl, 0.53 mmol). The reaction mixture was stirred at room temperature for 16 h, and saturated aqueous NaHCO 3 solution was added. The resulting mixture was extracted with dichloromethane for three times. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with petroleum ether/etoac (10:1) as eluent to afford 1i as a colorless oil, which solidified white after being dried in vacuo (125 mg, 88%). 1 H NMR (CDCl 3, 300 MHz) δ 1.07 (t, J = 7.2 Hz, 6H), 1.50 (s, 3H), 1.83 (s, 3H), (m, 2H), (m, 2H), 4.42 (s, 2H), 7.17 (d, J = 7.5 Hz, 2H), (m, 3H); 13 C NMR (CDCl 3, 75 MHz) δ 13.7, 18.4, 22.8, 52.1, 54.0, 61.2, 127.8, 128.2, 129.3, 143.0, 170.6, MS (ESI) (M + Na); Anal. Calcd for C 17 H 23 NO 5 : C, 63.54; H, 7.21; N, Found: C, 63.39; H, 7.07; N, General procedure for SmI 2 -promoted carbon-carbon bond fragmentation S5

6 reaction. To a SmI 2 solution (0.1 M in THF, 2.2 mmol) was added a solution of 1 (1.0 mmol) in THF (3 ml) dropwise. The reaction mixture was stirred at room temperature for 2 h and saturated aqueous NaHCO 3 solution was added. The resulting mixture was extracted with EtOAc for three times. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with petroleum ether/etoac as eluent to afford product 2. BnO 2 C Me BnO 2 C Compound 2a. 1 H NMR (CDCl 3, 300 MHz) δ 1.48 (d, J = 7.2 Hz, 3H), 3.56 (q, J = 7.2 Hz, 1H), 5.17 (s, 4H), (m, 10H). MeO 2 C Bn MeO 2 C Compound 2d. 1 H NMR (CDCl 3, 300 MHz) δ 3.22 (d, J = 7.8 Hz, 2H), (m, 1H), 3.70 (s, 6H), (m, 5H). EtO 2 C Me EtO 2 C Compound 2g. 1 H NMR (CDCl 3, 300 MHz) δ 1.26 (t, J = 7.2 Hz, 6H), 1.41 (d, J = 7.2 Hz, 3H), 3.41 (q, J = 7.2 Hz, 1H), 4.19 (q, J = 7.2 Hz, 4H). O 2a 2d 2g O CO 2 Et 2j Compound 2j. 1 H NMR(CDCl 3, 300 MHz) δ 1.32 (t, J = 7.2 Hz, 3H), (m, 1H), (m, 1H), (m, 1H), (m, 3H), (m, 1H). BnO 2 C Me SmI 2 (1.2 eq), THF, rt BnO 2 C Me BnO 2 C NBn 2 BnO 2 C 1b 2a (57%) + Bn 2 N 3b (63%) NBn 2 Reaction of compound 1b with SmI 2 (1.2 eq). To a solution of 1b (84 mg, 0.17 mmol) in dry tetrahydrofuran (3 ml) was added SmI 2 solution (0.1 M in THF, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 h and saturated S6

7 aqueous NaHCO 3 solution was added. The resulting mixture was extracted with EtOAc for three times. The combined organic layers were washed with brine, dried over anhydrous Na 2 SO 4, and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel with petroleum ether/etoac as eluent to afford 3b as a yellow solid (22 mg, 63%) and 2a as a colorless oil (28 mg, 57%). 3b: 1 H NMR (CDCl 3, 300 MHz) δ 2.61 (s, 4H), 3.51 (s, 8H), (m, 20H). S7

8 Part 2. Copies of NMR Spectra for All Compounds Fig. S1. 1 H NMR of Compound 1a S8

9 Fig. S2. 13 C NMR of Compound 1a S9

10 Fig. S3. 1 H NMR of Compound 1b S10

11 Fig. S4. 13 C NMR of Compound 1b S11

12 Fig. S5. 1 H NMR of Compound 1c S12

13 Fig. S6. 13 C NMR of Compound 1c S13

14 Fig. S7. 1 H NMR of Compound 1d S14

15 Fig. S8. 1 H NMR of Compound 1e S15

16 Fig. S9. 13 C NMR of Compound 1e S16

17 Fig. S10. 1 H NMR of Compound 1f S17

18 Fig. S11. 1 H NMR of Compound 1g S18

19 Fig. S12. 1 H NMR of Compound 1h S19

20 Fig. S C NMR of Compound 1h S20

21 Fig. S14. 1 H NMR of Compound 1i S21

22 Fig. S C NMR of Compound 1i S22

23 Fig. S16. 1 H NMR of Compound 1j S23

24 Fig. S17. 1 H NMR of Compound 2a S24

25 Fig. S18. 1 H NMR of Compound 2d S25

26 Fig. S19. 1 H NMR of Compound 2g S26

27 Fig. S20. 1 H NMR of Compound 2j S27

28 Fig. S21. 1 H NMR of Compound 3b S28

29 Fig. S22. 1 H NMR of Compound 4 S29