Photoredox-Catalyzed Intramolecular Difluoromethylation of -Benzylacrylamides Coupled with a Dearomatizing Spirocyclization: Access to CF2H Containing 2- Azaspiro[4.5]deca-6,9-diene-3,8-diones. Zuxiao Zhang, Xiaojun Tang and William R. Dolbier, Jr.* Department of Chemistry, University of Florida, Gainesville, FL 32611-7200 Supporting Information Table of Contents I, General information (S2) II, Characterization of starting materials (S3-S9) III, Experimental procedures and data (S9-S20) IV, References (S21) V, MR Spectra for new compounds (S22-S141) 1
I. General information: All reactions were carried out under 2 atmosphere. All anhydrous solvents were purchased from Aldrich and stored over 4A molecular sieves. Reagents were purchased at commercial quality and were used without further purification. All MR spectra were run using CDCl 3 as solvent, unless otherwise specified. 1 H MR spectra were recorded at 500 MHz or 300 MHz, and chemical shifts are reported in ppm relative to TMS. 19 F MR spectra were recorded at 282 MHz, and chemical shifts are reported in ppm relative to CFCl 3 as the external standard. 13 C MR spectra were recorded at 125 MHz or 75 MHz with proton decoupling, and chemical shifts are reported in ppm relative to CDCl 3 (-77.0 ppm) as the reference. The visible light was generated from a fluorescent light bulb (daylight GE Energy Smart, 26 W, 1600 lumens). n-c 4 F 9 S 2 Cl, CF 3 CH 2 S 2 Cl, BrCF 2 CEt and CF 3 S 2 Cl were purchased from Synquest or Aldrich. HCF 2 S 2 Cl and FCH 2 S 2 Clwere prepared according to literature procedures. 2
II. Characterization of starting materials 1. Synthesis of substrates All starting materials were prepared according to previously reported procedures. 1 Characterization of non-previously reported compounds is given. -tert-butyl--(4-methoxybenzyl)methacrylamide (1a) Me 1 H MR (500 MHz, CDCl 3 ) δ 7.12 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.01 (s, 1H), 4.93 (s, 1H), 4.60 (s, 2H), 3.79 (d, J = 0.9 Hz, 3H), 1.92 (s, 3H), 1.41 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 174.77 (s), 158.67 (s), 143.31 (s), 132.18 (s), 127.35 (s), 114.04 (s), 113.48 (s), 57.71 (s), 55.40 (s), 50.32 (s), 28.75 (s), 20.97 (s). HRMS (ESI) calcd for C 16 H 24 + 2 (M+H + ): 262.1802, found: 262.1796. -(4-(benzyloxy)benzyl)--tert-butylmethacrylamide (1b) 1 H MR (500 MHz, CDCl 3 ) δ 7.43 (d, J = 7.0 Hz, 2H), 7.41 7.36 (m, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.13 (d, J = 8.7 Hz, 2H), 6.95 (d, J = 8.7 Hz, 2H), Bn 5.05 (s, 2H), 5.02 (s, 1H), 4.96 4.91 (m, 1H), 4.61 (s, 2H), 1.93 (s, 3H), 1.42 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 174.78 (s), 157.95 (s), 143.33 (s), 137.06 (s), 132.54 (s), 128.74 (s), 128.15 (s), 127.65 (s), 127.39 (s), 115.00 (s), 113.52 (s), 70.26 (s), 57.73 (s), 50.35 (s), 28.78 (s), 20.99 (s). HRMS (ESI) calcd for C 22 H 28 + 2 (M+H + ): 338.2115, found: 338.2111. -tert-butyl--(4-(4-methoxybenzyloxy)benzyl)methacrylamide (1c) 1 H MR (500 MHz, CDCl 3 ) δ 7.37 (d, J = 8.7 Hz, 2H), 7.14 (d, J = 8.7 Hz, 2H), 6.95 (t, J = 9.0 Hz, 4H), 5.04 (s, 1H), 4.99 (s, 2H), 4.98 4.94 (m, 1H), PMB 4.63 (s, 2H), 3.84 (s, 3H), 1.95 (d, J = 1.3 Hz, 3H), 1.44 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 175.91 173.51 (m), 159.63 (s), 158.01 (s), 143.22 (s), 132.33 (s), 129.41 (s), 129.06 (s), 127.36 (s), 115.00 (s), 114.16 (s), 113.61 (s), 70.03 (s), 57.81 (s), 55.46 3
(s), 50.38 (s), 28.89 (s), 28.77 (s), 20.97 (s). HRMS (ESI) calcd for C 23 H 30 2 + (M+H + ): 368.2220, found: 368.2218. -(4-(benzyloxy)benzyl)--butylmethacrylamide (1d) 1 H MR (500 MHz, CDCl 3 ) δ 7.43 (d, J = 7.1 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 38.1 Hz, 2H), 6.94 (d, J = 7.8 Hz, Bn 2H), 5.14 (s, 1H), 5.05 (s, 3H), 4.55 (s, 2H), 3.26 (d, J = 38.6 Hz, 2H), 1.98 (s, 3H), 1.55 1.44 (m, 2H), 1.24 (s, 2H), 0.89 (t, J = 7.2 Hz, 3H). 13 C MR (75 MHz, DMS) δ 171.49 (s), 157.49 (s), 140.90 (s), 137.06 (s), 128.37 (s), 127.77 (s), 127.63 (s), 114.80 (s), 114.06 (s), 69.17 (s), 20.43 (s), 19.44 (s), 19.41 (s), 13.61 (s). HRMS (ESI) calcd for C 22 H 28 + 2 (M+H + ): 338.2115, found: 338.2116. -(4-(benzyloxy)benzyl)--isopropylmethacrylamide (1e) 1 H MR (500 MHz, CDCl 3 ) δ 7.43 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.32 (t, J = 7.1 Hz, 1H), 7.18 (d, J = 6.6 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), Bn 5.12 (s, 1H), 5.06 (s, 1H), 5.04 (s, 2H), 4.49 (s, 2H), 4.35 (s, 1H), 2.01 (s, 3H), 1.13 (d, J = 6.5 Hz, 6H). 13 C MR (75 MHz, DMS) δ 171.71 (s), 157.00 (s), 141.60 (s), 137.13 (s), 128.36 (s), 127.93 (s), 127.74 (s), 127.62 (s), 114.45 (s), 113.38 (s), 69.16 (s), 21.56 20.52 (m), 20.38 (s). HRMS (ESI) calcd for C 21 H 26 + 2 (M+H + ): 324.1958, found: 324.1955. -(4-(benzyloxy)benzyl)--cyclohexylmethacrylamide (1f) 1 H MR (300 MHz, DMS) δ 7.37 (ddd, J = 19.3, 14.1, 7.3 Hz, 5H), 7.15 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.2 Hz, 2H), 5.11 (s, 1H), 5.04 (d, J = 13.6 Bn Hz, 2H), 4.99 (s, 1H), 4.45 (s, 2H), 3.76 (s, 1H), 1.90 (s, 3H), 1.65 (t, J = 14.7 Hz, 2H), 1.45 (dd, J = 28.0, 15.8 Hz, 5H), 1.32 0.85 (m, 3H). 13 C MR (75 MHz, DMS) δ 172.29 (s), 157.44 (s), 142.09 (s), 137.60 (s), 128.81 (s), 128.30 (s), 128.19 (s), 128.08 (s), 114.87 (s), 113.75 (s), 69.63 (s), 58.41 (s), 42.88 (s), 31.75 (s), 25.94 (s), 25.16 (s), 20.92 (s). HRMS (ESI) calcd for C 24 H 30 + 2 (M+H + ): 364.2271, found: 364.2276. 4
-(4-(benzyloxy)benzyl)--phenylmethacrylamide (1g) 1 H MR (500 MHz, CDCl 3 ) δ 7.42 (d, J = 7.0 Hz, 2H), 7.38 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.1 Hz, 1H), 7.27 (d, J = 5.1 Hz, 1H), 7.22 (dd, J = 14.4, Bn 7.4 Hz, 2H), 7.14 (d, J = 8.4 Hz, 2H), 6.99 6.93 (m, 2H), 6.87 (d, J = 8.5 Hz, 2H), 5.03 (s, 2H), 5.02 (s, 1H), 4.99 (d, J = 0.9 Hz, 1H), 4.90 (s, 2H), 1.77 (s, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 171.92 (s), 158.25 (s), 143.26 (s), 140.95 (s), 137.12 (s), 130.10 (s), 130.04 (s), 129.16 (s), 128.71 (s), 128.10 (s), 127.78 (s), 127.64 (s), 127.22 (s), 119.46 (s), 114.85 (s), 70.14 (s), 52.74 (s), 20.57 (s). HRMS (ESI) calcd for C 24 H 24 + 2 (M+H + ): 358.1802, found: 358.1800. -benzyl--(4-(benzyloxy)benzyl)methacrylamide (1h) 1 H MR (500 MHz, CDCl 3 ) δ 7.45 (d, J = 7.3 Hz, 2H), 7.40 (t, J = 7.5 Hz, 2H), 7.38 7.27 (m, 4H), 7.15 (d, J = 35.3 Hz, 4H), 6.96 (s, 2H), 5.19 (s, 1H), 5.15 (s, 1H), 5.07 (s, 2H), 4.48 (d, J = 26.7 Hz, 4H), 2.03 (s, 3H). 13 C MR (75 MHz, DMS) δ 171.92 (s), 157.63 (s), 140.45 (s), 137.04 (s), 128.88 (s), Bn 128.61 (s), 128.38 (s), 127.78 (s), 127.63 (s), 127.20 (s), 126.95 126.70 (m), + 114.90 (s), 114.67 (s), 69.20 (s), 20.43 (s). HRMS (ESI) calcd for C 25 H 26 2 (M+H + ): 372.1958, found: 372.1943. -(4-(benzyloxy)benzyl)--methylmethacrylamide (1i) 1 H MR (300 MHz, DMS) δ 7.55 7.28 (m, 5H), 7.15 (s, 2H), 7.08 6.87 (m, 2H), 5.18 (s, 1H), 5.08 (s, 2H), 5.00 (s, 1H), 4.47 (s, 2H), 2.97 2.65 (m, Bn 3H), 1.88 (s, 3H). 13 C MR (75 MHz, DMS) δ 157.57 (s), 140.61 (s), + 137.06 (s), 128.39 (s), 127.79 (s), 127.65 (s), 114.88 (s), 69.19 (s). HRMS (ESI) calcd for C 19 H 22 2 (M+H + ): 296.1645, found: 296.1636. -(4-(benzyloxy)-3-methoxybenzyl)--tert-butylmethacrylamide (1j) 1 H MR (500 MHz, CDCl 3 ) δ 7.43 (d, J = 7.4 Hz, 2H), 7.36 (t, J = 7.4 Hz, Me Bn 2H), 7.30 (t, J = 7.3 Hz, 1H), 6.85 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.69 (dd, J = 8.2, 2.0 Hz, 1H), 5.13 (s, 2H), 5.01 (s, 1H), 4.96 4.92 (m, 5
1H), 4.60 (s, 2H), 3.86 (s, 3H), 1.93 (s, 3H), 1.43 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 174.76 (s), 149.87 (s), 147.20 (s), 143.24 (s), 137.24 (s), 133.42 (s), 128.66 (s), 127.99 (s), 127.45 (s), 118.28 (s), 114.23 (s), 113.56 (s), 109.95 (s), 71.33 (s), 57.78 (s), 56.08 (s), 50.56 (s), 28.76 (s), 21.00 (s). HRMS (ESI) calcd for C 23 H 30 + 3 (M+H + ): 368.2220, found: 368.2214. -(4-(benzyloxy)-3-fluorobenzyl)--tert-butylmethacrylamide (1k) F 1 H MR (500 MHz, CDCl 3 ) δ 7.43 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.4 Hz, 2H), 7.32 (t, J = 7.2 Hz, 1H), 6.96 (dd, J = 15.2, 7.0 Hz, 2H), 6.89 (d, J = 8.3 Bn Hz, 1H), 5.12 (s, 2H), 4.99 (s, 1H), 4.93 (s, 1H), 4.58 (s, 2H), 1.91 (s, 3H), 1.42 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 174.75 (s), 152.96 (d, J = 247.1 Hz), 145.62 (d, J = 10.9 Hz), 143.05 (s), 136.53 (s), 133.95 (d, J = 5.4 Hz), 128.69 (s), 128.23 (s), 127.55 (s), 121.70 (d, J = 3.5 Hz), 115.90 (d, J = 1.9 Hz), 114.29 (d, J = 19.2 Hz), 113.62 (s), 71.62 (s), 57.81 (s), 49.96 (s), 28.77 (d, J = 13.8 Hz), 20.88 (s). 19 F MR (282 MHz, CDCl 3 ) δ -132.81 (dd, J = 11.7, 8.3 Hz). HRMS (ESI) calcd for C 22 H 27 F + 2 (M+H + ): 356.2020, found: 356.2028. -(4-(benzyloxy)-3-chlorobenzyl)--tert-butylmethacrylamide (1l) Cl 1 H MR (500 MHz, CDCl 3 ) δ 7.46 (d, J = 7.4 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.33 (t, J = 7.3 Hz, 1H), 7.23 (d, J = 2.2 Hz, 1H), 7.04 (dd, J = 8.4, 2.2 Bn Hz, 1H), 6.94 (d, J = 8.5 Hz, 1H), 5.14 (s, 1H), 4.99 (s, 1H), 4.95 4.91 (m, 1H), 4.58 (s, 1H), 1.92 (d, J = 1.1 Hz, 2H), 1.42 (s, 5H). 13 C MR (126 MHz, CDCl 3 ) δ 174.75 (s), 153.28 (s), 143.15 (s), 136.56 (s), 133.86 (s), 128.76 (s), 128.19 (s), 127.25 (s), 125.35 (s), 123.62 (s), 114.20 (s), 113.64 (s), 71.13 (s), 57.85 (s), 49.88 (s), 28.81 (s), 20.96 (s). HRMS (ESI) calcd C 22 H 27 Cl + 2, For (M+H + ): 372.1725, found: 372.1720. -(4-(benzyloxy)-3-bromobenzyl)--tert-butylmethacrylamide (1m) 1 H MR (500 MHz, CDCl 3 ) δ 7.47 (d, J = 7.5 Hz, 2H), 7.42 7.37 (m, 3H), Br Bn 7.33 (t, J = 7.3 Hz, 1H), 7.09 (dd, J = 8.4, 2.2 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 5.14 (s, 2H), 5.00 4.98 (m, 1H), 4.96 4.91 (m, 1H), 4.58 (s, 2H), 1.93 1.90 (m, 3H), 1.42 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 174.75 (s), 6
154.16 (s), 143.12 (s), 136.54 (s), 134.24 (s), 131.22 (s), 128.74 (s), 128.14 (s), 127.17 (s), 126.13 (s), 113.91 (s), 113.64 (s), 112.81 (s), 71.12 (s), 57.87 (s), 49.78 (s), 28.81 (s), 20.96 (s). HRMS (ESI) calcd for C 22 H 27 Br + 2 (M+H + ): 416.1220, found: 416.1227. -(4-(benzyloxy)-3,5-dimethoxybenzyl)--tert-butylmethacrylamide (1o) Me 1 H MR (500 MHz, CDCl 3 ) δ 7.46 (d, J = 7.0 Hz, 2H), 7.35 7.30 (m, 2H), 7.30 7.27 (m, 1H), 6.41 (s, 2H), 5.00 (d, J = 2.6 Hz, 3H), 4.95 (dd, J = 13.3, Bn 12.0 Hz, 1H), 4.61 (s, 2H), 3.79 (s, 6H), 1.93 (s, 3H), 1.45 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 174.81 (s), 153.81 (s), 143.12 (s), 137.88 (s), 136.12 (s), Me 135.64 (s), 128.62 (s), 128.21 (s), 127.95 (s), 113.63 (s), 103.12 (s), 75.12 (s), 57.90 (s), 56.22 (s), 51.01 (s), 28.76 (s), 21.02 (s). HRMS (ESI) calcd for C 24 H 32 + 4 (M+H + ): 398.2326, found: 398.2327. -(4-(benzyloxy)-3,5-dimethylbenzyl)--tert-butylmethacrylamide (1n) tbu Bn 1 H MR (500 MHz, CDCl 3 ) δ 7.47 (d, J = 6.9 Hz, 2H), 7.40 (t, J = 7.3 Hz, 2H), 7.35 (t, J = 7.2 Hz, 1H), 6.86 (s, 2H), 5.02 (s, 1H), 4.94 (s, 1H), 4.81 (s, 2H), 4.58 (s, 2H), 2.28 (s, 6H), 1.94 (s, 3H), 1.44 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 174.75 (s), 154.65 (s), 143.31 (s), 137.74 (s), 135.57 (s), 131.32 (s), 128.65 (s), 128.13 (s), 127.86 (s), 126.64 (s), 113.45 (s), 110.50 109.92 (m), 74.16 (s), 57.79 (s), 50.48 (s), 31.74 (s), 28.81 (s), 21.01 (s), 16.69 (s). HRMS (ESI) calcd for C 24 H 32 + 2 (M+H + ): 366.2428, found: 366.2413. -((4-(benzyloxy)naphthalen-1-yl)methyl)--tert-butylmethacrylamide (1p) tbu 1 H MR (500 MHz, CDCl 3 ) δ 8.45 (d, J = 8.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, Bn 1H), 7.63 7.49 (m, 4H), 7.45 (t, J = 7.4 Hz, 3H), 7.37 (dd, J = 18.3, 11.0 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 5.26 (s, 2H), 5.03 (s, 2H), 4.99 (s, 1H), 4.80 (s, 1H), 1.95 (s, 3H), 1.54 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 175.02 (s), 153.92 (s), 142.75 (s), 137.08 (s), 130.84 (s), 128.70 (s), 128.10 (s), 127.56 (s), 127.43 (s), 126.90 (s), 125.98 (s), 125.32 (s), 124.03 (s), 7
123.31 (s), 121.72 (s), 112.84 (s), 104.40 (s), 70.25 (s), 57.85 (s), 47.88 (s), 28.59 (s), 21.00 (s). HRMS (ESI) calcd for C 26 H 30 + 2 (M+H + ): 388.2271, found: 388.2258. -(4-(benzyloxy)benzyl)--tert-butylacrylamide (1q) 1 H MR (500 MHz, CDCl 3 ) δ 7.44 (d, J = 7.1 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.15 (d, J = 8.5 Hz, 2H), 6.97 (d, J = 8.6 Hz, Bn 2H), 6.39 (dd, J = 16.6, 10.1 Hz, 1H), 6.30 (dd, J = 16.7, 2.3 Hz, 1H), 5.54 (dd, J = 10.1, 2.3 Hz, 1H), 5.06 (s, 2H), 4.57 (s, 2H), 1.45 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 168.59 (s), 158.07 (s), 137.05 (s), 131.79 (s), 131.74 (s), 128.74 (s), 128.16 (s), 127.63 (s), 127.27 (s), 126.95 (s), 115.24 (s), 70.26 (s), 57.82 (s), 48.53 (s), 28.68 (s). HRMS (ESI) calcd for C 21 H 26 + 2 (M+H + ): 324.1958, found: 324.1948. 2. Synthesis of mono and difluoromethyl sulfonyl chloride The Difluoromethyl sulfonyl chloride was prepared according to literature procedures, and its 1 H MR and 19 F MR were consistent with those reported in the literature. 2 Cl SH i) ah ii) H 2CFCl SCH 2 F Cl 2 DMF, 70 C Cl H2/DCM, -10 C H 2 CFS 2 Cl SH 1.5 eq HCF 2 Cl 2.5 eq ah Hexanes/60 C 2 h S CF 2 H Cl 2, H 2-10 C HCF 2 S 2 Cl III. Experimental procedures and data fac-ir(ppy) 3 catalyzed difluoromethylation of -benzylacrylamides coupled with dearomatization To an oven-dried 17 60 mm (8 ml) borosilicate vial equipped with a magnetic stirrer, were added -benzylacrylamide (64.6 mg, 0.2 mmol), fac-ir(ppy) 3 (2.4 mg, 0.004 mmol, 0.002 eq) and K 2 HP 4 (68 mg, 0.4 mmol, 2.0 equiv). To this mixture were added 2 ml CH 3 C, 8 mg deionized 8
water and CF 2 HS 2 Cl (60 mg, 0.4 mmol, 2 equiv) under a blanket of nitrogen. The vial was sealed, and stirred under visible light at room temperature for 18 hr. After this time, the CH 3 C was removed in vacuo, and the residue purified by column chromatography on silica gel eluting with hexanes/ethyl acetate (2:1). This gave product 2a as light yellow oil (48.7 mg, 82% yield). CF 2 H 2-tert-butyl-4-(2,2-difluoroethyl)-4-methyl-2-azaspiro[4.5]deca-6,9-diene-3,8- dione (2a) 1 H MR (500 MHz, CDCl 3 ) δ 6.86 (ddd, J = 8.4, 5.9, 3.0 Hz, 2H), 6.37 (ddd, J = 12.2, 10.0, 4.7 Hz, 2H), 6.08 (tdd, J = 56.4, 5.6, 3.6 Hz, 1H), 3.51 (d, J = 10.5 Hz, 1H), 3.27 (d, J = 10.5 Hz, 1H), 2.18 2.03 (m, 1H), 1.68 (qd, J = 15.1, 5.7 Hz, 1H), 1.37 (s, 9H), 1.20 (s, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 184.60 (s), 175.54 (s), 148.09 (s), 147.16 (s), 132.05 (s), 130.79 (s), 115.24 (dd, J = 239.7, 238.3 Hz), 54.73 (s), 50.19 (dd, J = 6.7, 3.0 Hz), 49.94 (s), 47.44 (s), 38.24 (t, J = 22.4 Hz), 27.52 (s), 17.86 (d, J = 1.8 Hz). 19 F MR (282 MHz, CDCl 3 ) δ -109.3 (AB, ddddd, J = 284.8, 38.7, 22.6, 15.5, 1.5 Hz, 1F), -111.0 (AB, ddt, J = 287.6, 55.8, 14.6 Hz, 1F). HRMS (ESI) calcd for C 16 H 22 F 2 + 2 (M+H + ): 298.1613, found: 298.1615. 2-butyl-4-(2,2-difluoroethyl)-4-methyl-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (2d) Prepared according to general method and isolated in 83% yield after chromoatography as light yellow oil (49.5 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.87 (ddd, J = 17.0, 10.2, 3.0 Hz, 2H), 6.41 (ddd, J = 23.0, 10.0, 1.4 Hz, 2H), CF 2 H 6.14 (tdd, J = 56.2, 5.7, 3.4 Hz, 1H), 3.53 (d, J = 10.5 Hz, 1H), 3.39 3.26 (m, 2H), 3.19 (d, J = 10.5 Hz, 1H), 2.25 2.07 (m, 1H), 1.75 (ddd, J = 30.0, 15.2, 5.8 Hz, 1H), 1.54 1.44 (m, 2H), 1.32 (dq, J = 14.6, 7.3 Hz, 2H), 1.26 (s, 3H), 0.93 (t, J = 7.3 Hz, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 184.56 (s), 175.33 (s), 147.94 (s), 146.92 (s), 132.21 (s), 130.79 (s), 115.17 (dd, J = 240.0, 238.3 Hz), 51.79 (s), 49.76 (dd, J = 7.0, 2.8 Hz), 48.34 (s), 42.77 (s), 38.94 37.80 (m), 29.28 (s), 20.13 (s), 18.28 (d, J = 2.2 Hz), 13.77 (s). 19 F MR (282 MHz, CDCl 3 ) δ -109.4 (AB, ddddd, J = 288.2, 23.8, 17.3, 16.0, 1.9 Hz, 1F), -111.1 (AB, ddt, J = 288.2, 55.8, 14.3 Hz, 1F). HRMS (ESI) calcd for C 16 H 22 F 2 + 2 (M+H + ): 298.1613, found: 298.1622. 9
diene-3,8-dione (2f) Prepared according to general method and isolated in 80% yield after CF 2 H chromoatography as yellow oil (51.7 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.87 (dd, J = 10.2, 3.1 Hz, 1H), 6.83 (dd, J = 10.2, 3.1 Hz, 1H), 6.42 (dd, J = 10.2, 1.9 Hz, 1H), 6.37 (dd, J = 10.2, 1.9 Hz, 1H), 6.13 (tdd, J = 55.9, 5.7, 3.4 Hz, 1H), 3.95 (tt, J = 11.6, 3.7 Hz, 1H), 3.44 (d, J = 10.5 Hz, 1H), 3.19 (d, J = 10.5 Hz, 1H), 2.23 2.07 (m, 1H), 1.88 1.61 (m, 6H), 1.45 1.26 (m, 4H), 1.24 (d, J = 1.5 Hz, 3H), 1.14 0.98 (m, 1H). 13 C MR (126 MHz, CDCl 3 ) δ 184.58 (s), 174.73 (s), 147.91 (s), 147.03 (s), 132.14 (s), 130.82 (s), 115.22 (dd, J = 239.9, 238.4 Hz), 51.12 (s), 49.89 (dd, J = 6.9, 3.0 Hz), 48.22 (s), 47.95 (s), 38.55 37.84 (m), 30.11 (s), 30.06 (s), 25.34 (s), 25.31 (s), 25.29 (s), 18.11 (d, J = 2.1 Hz). 19 F MR (282 MHz, CDCl 3 ) δ -109.3 (AB, ddddd, J = 287.9, 56.5, 23.4, 15.7, 1.8 Hz, 1F), -111.1 (AB, ddt, J = 287.9, 55.9, 14.6 Hz, 1F). HRMS (ESI) calcd for C 18 H 24 F 2 + 2 (M+H + ): 324.1770, found: 324.1760. 4-(2,2-difluoroethyl)-2-isopropyl-4-methyl-2-azaspiro[4.5]deca-6,9- diene-3,8-dione (2e) Prepared according to general method and isolated in 82% yield after chromoatography as light yellow oil (46.5 mg): 1 H MR (500 MHz, CDCl 3 ) δ CF 2 H 6.88 (dd, J = 10.2, 3.0 Hz, 1H), 6.83 (dd, J = 10.2, 3.1 Hz, 1H), 6.43 (dd, J = 10.3, 1.8 Hz, 1H), 6.39 (dd, J = 10.2, 1.8 Hz, 1H), 6.14 (tdd, J = 56.3, 5.7, 3.4 Hz, 1H), 4.38 (hept, J = 6.8 Hz, 1H), 3.43 (d, J = 10.5 Hz, 1H), 3.17 (d, J = 10.5 Hz, 1H), 2.23 2.07 (m, 1H), 1.74 (qd, J = 15.1, 5.8 Hz, 1H), 1.25 (d, J = 1.4 Hz, 3H), 1.14 (t, J = 7.0 Hz, 6H). 13 C MR (126 MHz, CDCl 3 ) δ 184.57 (s), 174.65 (s), 147.80 (s), 146.97 (s), 132.19 (s), 130.87 (s), 115.20 (dd, J = 239.9, 238.4 Hz), 49.93 (dd, J = 6.8, 3.0 Hz), 48.04 (s), 46.92 (s), 43.21 (s), 38.40 37.87 (m), 19.64 (s), 19.51 (s), 18.05 (d, J = 2.1 Hz). 19 F MR (282 MHz, CDCl 3 ) δ -109.3 (AB, ddddd, J = 287.9, 56.6, 23.4, 15.7, 1.7 Hz, 1F), -111.1 (AB, ddt, J = 287.9, 55.8, 14.6 Hz, 1F). HRMS (ESI) calcd for C 15 H 20 F 2 + 2 (M+H + ): 284.1457, found: 284.1457. 2-cyclohexyl-4-(2,2-difluoroethyl)-4-methyl-2-azaspiro[4.5]deca-6,9-4-(2,2-difluoroethyl)-4-methyl-2-phenyl-2-azaspiro[4.5]deca-6,9-diene- 3,8-dione (2g) CF 2 H Prepared according to general method and isolated in 48% yield after chromoatography as yellow oil (30.4 mg): 1 H MR (500 MHz, CDCl 3 ) δ 7.57 (dd, J = 8.7, 1.1 Hz, 2H), 7.44 7.39 (m, 2H), 7.25 7.19 (m, 1H), 7.00 (dd, J 10
= 10.5, 2.0 Hz, 2H), 6.56 6.41 (m, 2H), 6.20 (tdd, J = 55.7, 5.8, 3.4 Hz, 1H), 4.03 (d, J = 10.4 Hz, 1H), 3.69 (d, J = 10.4 Hz, 1H), 2.38 2.24 (m, 1H), 1.89 (ddd, J = 30.1, 15.1, 5.8 Hz, 1H), 1.41 (d, J = 1.7 Hz, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 184.43 (s), 174.66 (s), 147.42 (s), 146.27 (s), 138.35 (s), 132.69 (s), 131.18 (s), 129.37 (s), 125.82 (s), 120.20 (s), 115.08 (dd, J = 240.2, 238.5 Hz), 53.06 (s), 50.61 (dd, J = 7.0, 2.9 Hz), 47.74 (s), 38.48 (dd, J = 23.2, 22.3 Hz), 18.40 (d, J = 2.3 Hz). 19 F MR (282 MHz, CDCl 3 ) δ - 109.31 (AB, ddddd, J = 287.9, 56.5, 23.5, 15.6, 1.9 Hz, 1F), -111.10 (AB, ddt, J = 287.9, 55.6, 14.3 Hz, 1F).HRMS (ESI) calcd for C 18 H 18 F 2 + 2 (M+H + ): 318.1300, found: 318.1310. 1-(4-(benzyloxy)benzyl)-3-(2,2-difluoroethyl)-3-methylindolin-2-one (2g ) Bn Prepared according to general method and isolated in 50% yield after chromoatography as yellow oil (41.0 mg): 1 H MR (500 MHz, CDCl 3 ) δ 7.37 (ddd, J = 27.9, 14.0, 7.0 Hz, 5H), 7.27 7.15 (m, 4H), 7.06 (t, J = 7.5 Hz, 1H), 6.93 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 7.8 Hz, 1H), 5.61 (tdd, J = CF 2 H 56.1, 6.4, 3.3 Hz, 1H), 5.03 (s, 2H), 4.93 (d, J = 15.4 Hz, 1H), 4.81 (d, J = 15.4 Hz, 1H), 2.59 (qd, J = 14.2, 6.6 Hz, 1H), 2.42 2.26 (m, 1H), 1.46 (s, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 179.27 (s), 158.44 (s), 142.17 (s), 136.98 (s), 132.08 (s), 128.80 (s), 128.70 (s), 128.49 (s), 128.23 (s), 128.11 (s), 127.58 (s), 122.93 (s), 122.82 (s), 115.25 (t, J = 239.8 Hz), 115.23 (s), 109.72 (s), 70.15 (s), 44.69 (t, J = 5.3 Hz), 43.47 (s), 41.37 (t, J = 21.9 Hz), 25.02 (s). 19 F MR (282 MHz, CDCl 3 ) δ -114.04 + (ddd, J = 56.0, 14.5, 4.2 Hz δ -114.10 (dd, J = 56.1, 14.8 Hz). HRMS (ESI) calcd for C 25 H 24 F 2 2 (M+H + ): 408.1770, found: 408.1767. 2-benzyl-4-(2,2-difluoroethyl)-4-methyl-2-azaspiro[4.5]deca-6,9-diene- 3,8-dione (2h) Bn CF 2 H Prepared according to general method and isolated in 82% yield after chromoatography as yellow oil (54.4 mg): 1 H MR (500 MHz, CDCl 3 ) δ 7.38 7.29 (m, 3H), 7.23 (d, J = 6.8 Hz, 2H), 6.79 (ddd, J = 16.9, 10.2, 3.1 Hz, 2H), 6.39 (dd, J = 10.2, 1.8 Hz, 1H), 6.33 (dd, J = 10.1, 1.8 Hz, 1H), 6.19 (tdd, J = 56.1, 5.8, 3.4 Hz, 1H), 4.55 (d, J = 14.5 Hz, 1H), 4.45 (d, J = 14.4 Hz, 1H), 3.36 (d, J = 10.6 Hz, 1H), 3.06 (d, J = 10.6 Hz, 1H), 2.27 2.13 (m, 1H), 1.79 (qd, J = 15.2, 5.8 Hz, 1H), 1.28 (d, J = 1.5 Hz, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 184.47 (s), 175.40 (s), 147.69 (s), 146.70 (s), 135.34 (s), 132.21 (s), 130.75 (s), 129.18 (s), 128.42 (s), 128.38 (s), 115.13 (dd, J = 240.1, 238.4 Hz), 51.12 (s), 49.66 (dd, J = 7.0, 2.8 Hz), 48.10 (s), 47.17 (s), 38.47 37.94 (m), 18.19 (d, J = 2.1 Hz). 19 F MR (282 MHz, 11
CDCl 3 ) δ -109.3 (AB, ddddd, J = 289.05, 56.4, 23.5, 15.6, 1.6 Hz, 1F), -111.1 (AB, ddt, J = 289.05, 55.8, 14.4 Hz, 1F). HRMS (ESI) calcd for C 19 H 20 F 2 2 + (M+H + ): 332.1457, found: 332.1451. 2-tert-butyl-4-(2,2-difluoroethyl)-7-methoxy-4-methyl-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (2j) Prepared according to general method and isolated in 76% yield after chromoatography as yellow oil (50.0 mg): 1 H MR (500 MHz, CDCl 3 ) δ Me 6.90 (ddd, J = 12.9, 10.1, 2.7 Hz, 1H (both isomers)), 6.44 (dd, J = 12.0, 10.2 CF 2 H Hz, 1H (both isomers)), 6.31 6.07 (m, 1H (isomers A)), δ 6.09 (tdd, J = 56.0, 5.5, 3.5 Hz, 1H (isomers B)), 5.69 (dd, J = 14.1, 2.6 Hz, 1H (isomers A)), 5.68 (d, J = 2.6 Hz, 1H (isomers B)), 3.70 (s, 1H (isomers A)), 3.68 (s, 3H (isomers B)), 3.56 (d, J = 10.5 Hz, 1H (isomers A)), 3.54 (d, J = 10.5 Hz, 1H (isomers B)), 3.36 (d, J = 10.4 Hz, 1H (isomers A)), 3.28 (d, J = 10.4 Hz, 1H (isomers B)), 2.28 2.02 (m, 1H (both isomers)), 1.83 1.61 (m, 1H (both isomers)), 1.42 (s, 9H (isomers A)), 1.41 (s, 9H (isomers B)), 1.27 (d, J = 1.7 Hz, 3H (isomers A)), 1.19 (s, 3H (isomers B)). 13 C MR (126 MHz, CDCl 3 ) δ 179.96 (s), 179.91 (s), 176.04 (s), 175.71 (s), 153.31 (s), 152.80 (s), 148.80 (s), 147.91 (s), 131.06 (s), 130.00 (s), 115.40 (dd, J = 239.9, 238.6 Hz), δ 115.31 (dd, J = 239.8, 238.4 Hz), 113.90 (s), 112.86 (s), 55.20 (s), 55.17 (s), 54.83 (s), 54.77 (s), 50.47 (dd, J = 6.2, 3.4 Hz), 49.98 (dd, J = 6.5, 3.1 Hz), 48.43 (s), 48.24 (s), 38.67 (t, J = 22.4 Hz), 38.15 (t, J = 22.3 Hz), 27.70 (d, J = 1.6 Hz), 18.28 (s), 17.87 (s). 19 + F MR (282 MHz, CDCl 3 ) δ -108.37-111.81 (m). HRMS (ESI) calcd for C 17 H 24 F 2 3 (M+H + ): 328.1719, found: 328.1708. F 2-tert-butyl-4-(2,2-difluoroethyl)-7-fluoro-4-methyl-2- azaspiro[4.5]deca-6,9-diene-3,8-dione (2k) Prepared according to general method and isolated in 77% yield after CF 2 H chromoatography as pale yellow oil (48.6 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.91 (td, J = 9.7, 2.7 Hz, 1H (both isomers)), 6.48 6.36 (m, 2H (both isomers)), 6.14 (tdd, J = 56.4, 6.1, 2.8 Hz, 1H (isomers A)), 6.10 (tdd, J = 56.2, 5.7, 3.2 Hz, 1H (isomers B)), 3.58 (d, J = 10.6 Hz, 1H (isomers A)), 3.56 (dd, J = 10.5, 1.2 Hz, 1H (isomers B)), 3.38 (d, J = 10.6 Hz, 1H (isomers A)), 3.32 (d, J = 10.6 Hz, 1H (isomers B)), 2.23 2.06 (m, 1H (both isomers)), 1.81 1.63 (m, 1H (both isomers) ), 1.40 (s, 9H (both isomers)), 1.24 (s, 3H (isomers A)), 1.21 (s, 3H (isomers B)). 13 C MR (126 MHz, CDCl 3 ) δ 177.48 (s), 177.30 (s), 175.30 (s), 175.02 (s), 156.38 (d, J = 48.5 Hz), 154.26 (d, J = 48.4 Hz), 148.90 (d, J = 2.1 Hz), 148.00 (d, J = 2.1 Hz), 131.22 (d, J = 4.5 Hz), 130.00 (d, J = 4.6 Hz), 123.50 (d, J = 13.9 Hz), 122.53 (d, J = 14.7 Hz), 117.77 112.28 (m), 54.96 (s), 54.93 (s), 50.77 50.59 (m), 50.31 (s), 50.05 (t, J = 2.9 Hz), 49.29 (d, J = 5.2 Hz), 49.06 (d, J = 5.5 Hz), 38.76 38.25 (m), 38.24 12
37.86 (m), 27.57 (s), 18.02 (d, J = 2.3 Hz), 17.83 (d, J = 2.1 Hz). 19 F MR (282 MHz, CDCl 3 ) δ -108.30-112.89 (m, 2F), -124.30 (dd, J = 13.1, 6.9 Hz, 1F (isomers A)), -126.31 (dd, J = 13.0, 6.9 Hz 1F, (isomers B)). HRMS (ESI) calcd for C 16 H 21 F 3 2 + (M+H + ): 316.1519, found: 316.1511. 2-tert-butyl-7-chloro-4-(2,2-difluoroethyl)-4-methyl-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (2l) Prepared according to general method and isolated in 84% yield after chromoatography as yellow oil (55.7 mg): 1 H MR (500 MHz, CDCl 3 ) δ 7.03 Cl (d, J = 1.6 Hz, 1H (both isomers)), 6.90 (td, J = 9.7, 2.7 Hz, 1H (both isomers)), CF 2 H 6.49 (dd, J = 14.0, 10.2 Hz, 1H (both isomers)), 6.27 5.94 (m, 1H (both isomers)), 3.58 (d, J = 10.6 Hz, 1H (isomers A)), δ 3.55 (d, J = 10.7 Hz, 1H (isomers B)), 3.37 (d, J = 10.6 Hz, 1H (isomers A)), 3.33 (d, J = 10.6 Hz, 1H (isomers B)), 2.24 2.06 (m, 1H (both isomers)), 1.79 1.64 (m, 1H (both isomers)), 1.40 (s, 9H (isomers A)), 1.40 (s, 9H (isomers B)), 1.25 (s, 3H (isomers A)), 1.22 (s, 3H (isomers B)). 13 C MR (126 MHz, CDCl 3 ) δ 177.74 (s), 177.74 (s), 175.10 (s), 175.06 (s), 148.28 (s), 147.39 (s), 143.80 (s), 143.00 (s), 135.54 (s), 134.84 (s), 130.87 (s), 129.66 (s), 115.20 (dd, J = 239.9, 238.5 Hz), δ 115.16 (dd, J = 240.0, 238.6 Hz), 54.99 (s), 54.98 (s), 50.80 (dd, J = 7.0, 2.3 Hz), 50.66 (dd, J = 7.3, 2.2 Hz), 50.08 (s), 49.96 (s), 49.77 (s), 49.68 (s), 38.33 (dd, J = 22.1, 14.2 Hz), 38.15 (dd, J = 23.1, 14.2 Hz), 27.57 (s), 17.99 (s), 17.98 (s). 19 F MR (282 MHz, CDCl 3 ) δ -108.58-112.34 (m). HRMS (ESI) calcd for C 16 H 21 ClF 2 + 2 (M+H + ): 332.1223, found: 332.1216. 7-bromo-2-tert-butyl-4-(2,2-difluoroethyl)-4-methyl-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (2m) Prepared according to general method and isolated in 61% yield after chromoatography as yellow oil (45.9 mg): 1 H MR (500 MHz, CDCl 3 ) δ 7.31 Br (d, J = 2.8 Hz, 1H), 6.91 (dd, J = 10.1, 2.8 Hz, 1H), 6.54 (d, J = 10.1 Hz, 1H), CF 2 H 6.15 (tdd, J = 55.7, 5.9, 3.0 Hz, 1H), 3.55 (d, J = 10.7 Hz, 1H), 3.39 (d, J = 10.6 Hz, 1H), 2.25 2.11 (m, 1H), 1.82 1.69 (m, 1H), 1.43 (s, 9H), 1.25 (d, J = 1.7 Hz, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 177.65 (s), 175.14 (s), 148.19 (s), 147.28 (s), 130.46 (s), 126.80 (s), 115.17 (dd, J = 240.1, 238.7 Hz), 55.07 (s), 51.04 (s), 50.75 (dd, J = 7.1, 2.4 Hz), 49.56 (s), 38.35 (dd, J = 23.1, 22.2 Hz), 27.67 (s), 18.13 (d, J = 2.4 Hz). 19 F MR (282 MHz, CDCl 3 ) δ -108.60-111.76 (m). HRMS (ESI) calcd for C 16 H 21 BrF 2 + 2 (M+H + ): 376.0718, found: 376.0717. 2-tert-butyl-4-(2,2-difluoroethyl)-4,7,9-trimethyl-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (2n) 13
Prepared according to general method and isolated in 93% yield after chromoatography as white solide (60.7 mg): 1 H MR (500 MHz, CDCl 3 ) δ CF 2 H 6.61 (s, 2H), 6.10 (t, J = 56.4 Hz, 1H), 3.49 (d, J = 10.2 Hz, 1H), 3.24 (d, J = 10.3 Hz, 1H), 2.19 1.99 (m, 1H), 1.93 (s, 6H), 1.67 (d, J = 14.8 Hz, 1H), 1.40 (s, 9H), 1.19 (s, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 185.99 (s), 176.23 (s), 142.99 (s), 142.03 (s), 138.34 (s), 137.06 (s), 115.52 (dd, J = 239.7, 238.2 Hz), 54.65 (s), 50.43 (s), 50.10 (dd, J = 6.6, 2.8 Hz), 46.73 (s), 38.38 (t, J = 22.3 Hz), 27.66 (s), 18.04 (s), 16.67 (s), 16.52 (s). 19 F MR (282 MHz, CDCl 3 ) δ -109.2 (AB, ddddd, J = 287.08, 56.7, 22.8, 15.9, 1.9 Hz Hz, 1F), -110.7 (AB, ddt, J = 287.08, 56.1, 15.0 Hz, 1F). HRMS (ESI) calcd for C 18 H 26 F 2 + 2 (M+H + ): 326.1926, found: 326.1914. 2-tert-butyl-4-(2,2-difluoroethyl)-7,9-dimethoxy-4-methyl-2-azaspiro[4.5]deca-6,9-diene-3,8- dione (2o) Prepared according to general method and isolated in 53% yield after Me chromoatography as yellow oil (37.9 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.10 (ddd, J = 56.1, 7.9, 3.9 Hz, 1H), 5.76 (s, 1H), 5.72 (s, 1H), 3.67 (s, 3H), CF 2 H 3.65 (s, 3H), 3.55 (d, J = 10.3 Hz, 1H), 3.31 (d, J = 10.3 Hz, 1H), 2.09 (ddd, Me J = 19.8, 17.3, 8.5 Hz, 1H), 1.67 (qd, J = 15.1, 5.6 Hz, 1H), 1.40 (d, J = 0.5 Hz, 10H), 1.20 (s, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 176.12 (s), 175.44 (s), 152.53 (s), 152.00 (s), 115.41 (dd, J = 239.6, 238.4 Hz), 114.84 (s), 113.68 (s), 55.50 (s), 55.46 (s), 54.70 (s), 52.13 (s), 50.29 (dd, J = 6.6, 2.9 Hz), 46.05 (s), 38.35 (t, J = 22.3 Hz), 27.68 (s), 18.12 (s). 19 F MR (282 MHz, CDCl 3 ) δ -109.2 (AB, dddd, J = 287.08, 38.9, 23.0, 16.6 Hz, 1F), -110.7 (AB, ddt, J = 287.08, 56.0, 14.8 Hz, 1F). HRMS (ESI) calcd for C 18 H 26 F 2 + 4 (M+H + ): 358.1824, found: 358.1814. 1'-tert-butyl-4'-(2,2-difluoroethyl)-4'-methyl-4H-spiro[naphthalene-1,3'-pyrrolidine]-4,5'-dione (2p) Prepared according to general method and isolated in 78% yield after chromoatography as yellow oil (54.3 mg): 1 H MR (500 MHz, CDCl 3 ) δ 8.22 CF 2 H (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.02 (d, J = 10.4 Hz, 1H), 6.62 (d, J = 10.4 Hz, 1H), 6.00 (tdd, J = 56.3, 5.9, 2.8 Hz, 1H), 3.85 (d, J = 10.6 Hz, 1H), 3.72 (d, J = 10.6 Hz, 1H), 1.86 1.70 (m, 1H), 1.52 1.49 (m, 9H), 1.42 (dd, J = 15.6, 9.5 Hz, 1H), 1.37 (d, J = 8.6 Hz, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 183.62 (s), 177.31 (s), 148.98 (s), 144.36 (s), 133.45 (s), 131.53 (s), 131.19 (s), 128.42 (s), 127.80 (s), 125.19 (s), 115.45 (dd, J = 239.7, 238.1 Hz), 55.05 (s), 53.74 (s), 52.16 (dd, J = 7.5, 2.2 Hz), 46.56 (s), 14
37.84 (dd, J = 23.1, 21.7 Hz), 27.63 (s), 20.80 (d, J = 2.4 Hz). 19 F MR (282 MHz, CDCl 3 ) δ -108.42-112.25 (m). HRMS (ESI) calcd for C 20 H 24 F 2 2 + (M+H + ): 348.1770, found: 348.1784. 2-tert-butyl-4-(2,2-difluoroethyl)-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (2q) Prepared according to general method and isolated in 82% yield after chromoatography as yellow oil (46.5 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.84 CF 2 H (dd, J = 10.2, 2.9 Hz, 1H), 6.80 (dd, J = 10.1, 2.9 Hz, 1H), 6.40 (s, 1H), 6.38 (s, 1H), 6.10 (tdd, J = 57.1, 6.3, 3.3 Hz, 1H), 3.58 (d, J = 10.2 Hz, 1H), 3.29 (d, J = 10.2 Hz, 1H), 2.83 (dd, J = 7.8, 5.8 Hz, 1H), 2.16 2.01 (m, 1H), 1.57 1.44 (m, 1H), 1.40 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 185.02 (s), 172.28 (s), 149.25 (s), 146.66 (s), 132.07 (s), 131.21 (s), 115.27 (t, J = 239.4 Hz), 54.95 (s), 51.69 (s), 46.40 (dd, J = 7.1, 3.6 Hz), 45.88 (s), 31.08 (dd, J = 23.4, 22.1 Hz), 27.72 (s). 19 F MR (282 MHz, CDCl 3 ) δ -114.7 (AB, dddd, J = 283.1, 56.7, 14.7, 11.1 Hz, 1F), -119.3 (AB, ddt, J = 283.1, 57.5, 26.4, 14.3 Hz, 1F). HRMS (ESI) calcd for C 15 H 20 F 2 + 2 (M+H + ): 284.1457, found: 284.1448. ethyl 3-(2-tert-butyl-4-methyl-3,8-dioxo-2-azaspiro[4.5]deca-6,9-dien-4-yl)-2,2-difluoropropanoate (3b) Prepared according to general method and isolated in 72% yield after chromoatography as yellow oil (53.2 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.94 6.86 (m, 2H), 6.43 (dd, J = 8.4, 3.8 Hz, 1H), 6.40 6.35 (m, 1H), CF 2 C 2 Et 4.26 (q, J = 7.1 Hz, 2H), 3.55 (d, J = 10.4 Hz, 1H), 3.20 (d, J = 10.4 Hz, 1H), 2.63 (ddd, J = 24.6, 17.3, 16.1 Hz, 1H), 2.06 (ddd, J = 24.7, 15.9, 8.8 Hz, 1H), 1.40 (s, 9H), 1.35 (d, J = 2.2 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 185.01 (s), 175.05 (s), 163.83 (t, J = 32.5 Hz), 148.36 (s), 147.02 (d, J = 1.0 Hz), 132.03 (d, J = 1.9 Hz), 130.43 (s), 115.97 (dd, J = 255.3, 249.9 Hz), 63.13 (s), 54.84 (s), 52.01 (s), 50.53 (s), 47.48 (s), 37.20 (dd, J = 24.3, 21.7 Hz), 27.61 (s), 17.96 (d, J = 4.8 Hz), 14.00 (s). 19 F MR (282 MHz, CDCl 3 ) δ -97.3 (AB, ddd, J = 264.2, 24.3, 9.0 Hz, 1F), -101.7 (AB, ddd, J = 264.2, 23.9, 18.3 Hz, 1F). HRMS (ESI) calcd for C 19 H 26 F 2 + 4 (M+H + ): 370.1824, found: 370.1831. 2-tert-butyl-4-methyl-4-(2,2,2-trifluoroethyl)-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (4b) 15
Prepared according to general method and isolated in 88% yield after chromoatography as yellow oil (55.6 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.89 CF 3 (dd, J = 10.2, 3.1 Hz, 1H), 6.85 (dd, J = 10.2, 3.1 Hz, 1H), 6.41 (dd, J = 10.3, 1.5 Hz, 1H), 6.39 6.35 (m, 1H), 3.57 (d, J = 10.5 Hz, 1H), 3.18 (d, J = 10.5 Hz, 1H), 2.65 (dq, J = 15.9, 12.3 Hz, 1H), 2.14 (dq, J = 15.8, 11.3 Hz, 1H), 1.40 (s, 9H), 1.33 (s, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 184.85 (s), 174.59 (s), 147.88 (s), 146.63 (s), 132.09 (s), 130.47 (s), 126.52 (q, J = 277.8 Hz), 54.91 (s), 50.94 (s), 50.62 (s), 47.03 (s), 37.19 (q, J = 29.3 Hz), 27.55 (s), 17.22 (d, J = 1.6 Hz). 19 F MR (282 MHz, CDCl 3 ) δ -58.34 (t, J = 11.8 Hz). HRMS (ESI) calcd for C 16 H 21 F 3 + 2 (M+H + ): 316.1519, found: 316.1509. CF 2 CF 2 CF 2 CF 3 Prepared according to general method and isolated in 85% yield after chromoatography as yellow oil (79.2 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.92 (d, J = 10.3 Hz, 1H), 6.86 (d, J = 10.3 Hz, 1H), 6.43 (d, J = 10.4 Hz, 1H), 6.36 (d, J = 10.4 Hz, 1H), 3.60 (d, J = 10.4 Hz, 1H), 3.18 (d, J = 10.5 Hz, 1H), 2.77 2.49 (m, 1H), 2.16 (dd, J = 36.8, 16.4 Hz, 1H), 1.41 (s, 12H). 13 C MR (126 MHz, CDCl 3 ) δ 184.80 (s), 174.71 (s), 147.81 (s), 146.78 (d, J = 2.5 Hz), 132.02 (d, J = 3.8 Hz), 130.28 (s), 122.18 108.22 (m), 55.00 (s), 52.13 (s), 50.76 (s), 47.04 (s), 33.51 (t, J = 21.0 Hz), 27.56 (s), 17.65 (d, J = 5.2 Hz). 19 F MR (282 MHz, CDCl 3 ) δ -81.14 (ddd, J = 12.6, 6.3, 3.0 Hz, 3F), -106.84 (d, J = 259.1 Hz, 1F), -107.68-110.78 (m, 1F), -124.28-125.04 (m, 2F), -125.74 (ddd, J = 27.1, 16.2, 8.0 Hz, 2F). HRMS (ESI) calcd for C 19 H 21 F 9 2 + (M+H + ): 466.1423, found: 466.1416. S 2 CH 2 F 2-tert-butyl-4-methyl-4-(2,2,3,3,4,4,5,5,5-nonafluoropentyl)-2- azaspiro[4.5]deca-6,9-diene-3,8-dione (5b) 2-tert-butyl-4-((fluoromethylsulfonyl)methyl)-4-methyl-2- azaspiro[4.5]deca-6,9-diene-3,8-dione (6a) Prepared according to general method and isolated in 78% yield after chromoatography as yellow oil (53.6 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.92 6.84 (m, 2H), 6.45 (dd, J = 10.4, 1.6 Hz, 1H), 6.40 (dd, J = 10.4, 1.6 Hz, 1H), 5.17 (dd, J = 47.0, 10.3 Hz, 1H), 5.00 (dd, J = 46.8, 10.3 Hz, 1H), 3.59 (d, J = 10.6 Hz, 1H), 3.49 (d, J = 15.0 Hz, 1H), 3.27 (d, J = 10.6 Hz, 1H), 3.00 (d, J = 15.0 Hz, 1H), 1.52 (s, 3H), 1.39 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 184.63 (s), 173.62 (s), 146.71 (s), 145.73 (s), 132.65 (s), 131.26 (s), 92.02 (d, J = 219.6 Hz), 55.12 (s), 53.89 (s), 52.55 (s), 50.46 (s), 47.02 (s), 27.49 (s), 17.99 (s). 19 F MR (282 MHz, 16
CDCl 3 ) δ -210.18 (t, J = 46.9 Hz). HRMS (ESI) calcd for C 16 H 23 F 4 S + (M+H + ): 344.1326, found: 344.1322. Prepared according to general method and isolated in 81% yield after S 2 CH 2 CF 3 chromoatography as yellow oil (63.8 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.90 6.84 (m, 2H), 6.44 (dd, J = 8.6, 3.3 Hz, 1H), 6.39 (dd, J = 8.5, 3.2 Hz, 1H), 4.22 4.02 (m, 1H), 3.88 (dq, J = 15.6, 9.3 Hz, 1H), 3.58 (dd, J = 16.4, 12.8 Hz, 2H), 3.26 (d, J = 10.6 Hz, 1H), 3.05 (d, J = 15.0 Hz, 1H), 1.53 (s, 3H), 1.39 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 184.59 (s), 173.70 (s), 146.70 (s), 145.59 (s), 132.75 (s), 131.25 (s), 121.40 (q, J = 277.7 Hz), 58.36 (d, J = 2.1 Hz), 57.92 (q, J = 31.4 Hz), 55.19 (s), 52.93 (s), 50.48 (s), 47.10 (s), 27.47 (s), 18.02 (s). 19 F MR (282 MHz, CDCl 3 ) δ -61.06 (t, J = 9.3 Hz). HRMS (ESI) calcd for C 17 H 23 F 3 4 S + (M+H + ): 394.1294, found: 394.1288. 2-tert-butyl-4-methyl-4-((2,2,2-trifluoroethylsulfonyl)methyl)-2-azaspiro[4.5]deca-6,9-diene-3,8- dione (7a) 2-cyclohexyl-4-((fluoromethylsulfonyl)methyl)-4-methyl-2- azaspiro[4.5]deca-6,9-diene-3,8-dione (6f) Prepared according to general method and isolated in 52% yield after chromoatography as yellow oil (38.4 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.88 (ddd, J = 19.7, 10.3, 2.9 Hz, 2H), 6.43 (ddd, J = 31.6, 10.1, 0.8 Hz, S 2 CH 2 F 2H), 5.22 (dt, J = 19.6, 9.8 Hz, 1H), 5.12 4.94 (m, 1H), 3.95 (td, J = 11.5, 3.6 Hz, 1H), 3.51 (dd, J = 12.8, 6.1 Hz, 2H), 3.21 (d, J = 10.6 Hz, 1H), 3.10 2.96 (m, 1H), 1.85 1.60 (m, 6H), 1.54 (s, 3H), 1.45 1.25 (m, 4H). 13 C MR (126 MHz, CDCl 3 ) δ 184.53 (s), 172.94 (s), 146.44 (s), 145.62 (s), 132.67 (s), 131.39 (s), 92.05 (d, J = 219.8 Hz), 53.88 (s), 52.14 (s), 51.58 (s), 48.41 (s), 47.83 (s), 30.05 (s), 29.94 (s), 25.33 (s), 25.28 (s), 25.26 (s), 18.37 (s). 19 F MR (282 MHz, CDCl 3 ) δ -210.14 (t, J = 46.9 Hz). HRMS (ESI) calcd for C 18 H 25 F 4 S + (M+H + ): 370.1483, found: 370.1471. 2-cyclohexyl-4-methyl-4-((2,2,2-trifluoroethylsulfonyl)methyl)-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (7f) Prepared according to general method and isolated in 51% yield after chromoatography as yellow oil (42.8 mg): 1 H MR (500 MHz, CDCl 3 ) δ 6.87 (dd, J = 23.4, 10.4 Hz, 2H), 6.46 (dd, J = 33.6, 10.4 Hz, 2H), S 2 CH 2 CF 3 17
4.26 (dq, J = 17.8, 8.9 Hz, 1H), 4.04 3.80 (m, 2H), 3.59 (d, J = 15.2 Hz, 1H), 3.53 (d, J = 10.7 Hz, 1H), 3.22 (d, J = 10.4 Hz, 1H), 3.04 (d, J = 15.2 Hz, 1H), 1.83 (s, 2H), 1.79 1.65 (m, 3H), 1.57 (s, 3H), 1.46 1.26 (m, 4H), 1.08 (d, J = 12.7 Hz, 1H). 13 C MR (126 MHz, CDCl 3 ) δ 184.38 (s), 173.10 (s), 146.30 (s), 145.30 (s), 132.97 (s), 131.51 (s), 121.43 (q, J = 277.7 Hz), 58.38 (s), 58.05 (dd, J = 62.8, 31.2 Hz), 52.51 (s), 51.67 (s), 48.48 (s), 47.99 (s), 30.12 (s), 30.00 (s), 25.38 (s), 25.33 (s), 25.30 (s), 18.48 (s). 19 F MR (282 MHz, CDCl 3 ) δ -61.10 (t, J = 9.2 Hz). HRMS (ESI) calcd for C 19 H 25 F 3 4 S + (M+H + ): 420.1451, found: 420.1438. 2-tert-butyl-4-((fluoromethylsulfonyl)methyl)-7-methoxy-4-methyl-2-azaspiro[4.5]deca-6,9-diene-3,8- dione (6j) Prepared according to general method and isolated in 80% yield after chromoatography as yellow oil (59.8 mg): 1 H MR (500 MHz, CDCl 3 ) Me δ 6.89 (dd, J = 2.7, 1.6 Hz, 1H (isomer A)), 6.87 (dd, J = 2.7, 1.6 Hz, S 2 CH 2 F 1H (isomer B)), 6.46 (d, J = 10.2 Hz, 1H (isomer A)), 6.42 (d, J = 10.1 Hz, 1H (isomer B)), 5.75 (dd, J = 63.6, 2.7 Hz, 2H (both isomer)), 5.29 4.90 (m, 4H (both isomer)), 3.71 (s, 3H (isomer A)), 3.67 (s, 3H (isomer B)), 3.61 (d, J = 10.5 Hz, 2H (both isomer)), 3.45 (t, J = 15.7 Hz, 2H (both isomer)), 3.35 (d, J = 10.4 Hz, 1H (isomer A)), 3.26 (d, J = 10.5 Hz, 1H (isomer B)), 3.13 (d, J = 15.0 Hz, 1H (isomer A)), 2.91 (d, J = 15.0 Hz, 1H (isomer B)), 1.57 (s, 3H (isomer A)), 1.47 (s, 3H (isomer B)), 1.41 (s, 9H (isomer A)), 1.40 (s, 9H (isomer B)). 13 C MR (126 MHz, CDCl 3 ) δ 179.91 (s), 179.88 (s), 173.96 (s), 173.77 (s), 153.76 (s), 152.95 (s), 147.12 (s), 146.57 (s), 131.60 (s), 130.58 (s), 113.34 (s), 111.72 (s), 92.11 (d, J = 219.7 Hz), 92.04 (d, J = 219.3 Hz), 55.25 (s), 55.22 (s), 55.13 (s), 55.04 (s), 54.32 (s), 53.82 (s), 52.96 (s), 52.56 (s), 51.62 (s), 51.13 (s), 47.92 (s), 47.90 (s), 27.56 (s), 27.55 (s), 18.70 (s), 18.10 (s). 19 F MR (282 MHz, CDCl 3 ) δ -210.03 (t, J = 46.8 Hz (isomer A)), -210.35 (t, J = 46.9 Hz (isomer B)). HRMS (ESI) calcd for C 17 H 25 F 5 S + (M+H + ): 374.1432, found: 374.1422. 2-tert-butyl-7-methoxy-4-methyl-4-((2,2,2-trifluoroethylsulfonyl)methyl)-2-azaspiro[4.5]deca-6,9-diene- 3,8-dione (7j) Prepared according to general method and isolated in 85% yield after chromoatography as yellow oil (72.0 mg): 1 H MR (500 MHz, Me CDCl 3 ) δ 6.88 (t, J = 3.2 Hz, 1H (isomers A)), 6.86 (t, J = 3.2 Hz, S 2 CH 2 CF 3 1H (isomers B)), 6.44 (d, J = 10.2 Hz, 1H (isomers A)), 6.40 (d, J = 10.1 Hz, 1H (isomers B)), 5.79 (d, J = 2.6 Hz, 1H (isomers A)), 5.67 (d, J = 2.6 Hz, 1H (isomers B)), 4.25 4.07 (m, 2H (isomers A)), 3.91 (ddd, J = 18.4, 15.7, 9.3 Hz, 2H (isomers B)), 3.69 (s, 3H (isomers A)), 3.65 (s, 3H (isomers B)), 3.63 (d, J = 4.9 Hz, 1H (isomers A)), 3.61 18
(d, J = 5.0 Hz, 1H (isomers B)), 3.53 (d, J = 15.1 Hz, 1H (both isomers)), 3.34 (d, J = 10.5 Hz, 1H (isomers A)), 3.25 (d, J = 10.6 Hz, 1H (isomers B)), 3.16 (d, J = 15.1 Hz, 1H (isomers A)), 2.97 (d, J = 15.0 Hz, 1H (isomers B)), 1.57 (s, 3H (isomers A)), 1.48 (s, 3H (isomers B)), 1.40 (s, 9H (isomers A)), 1.39 (s, 9H (isomers B)). 13 C MR (126 MHz, CDCl 3 ) δ 179.86 (s), 179.84 (s), 174.03 (s), 173.81 (s), 153.79 (s), 152.89 (s), 147.13 (s), 146.36 (s), 131.72 (s), 130.54 (s), 121.46 (q, J = 277.4 Hz), δ 121.43 (q, J = 277.6 Hz), 113.33 (s), 111.56 (d, J = 2.4 Hz), 58.78 (s), 57.97 (q, J = 31.3 Hz), δ 57.89 (q, J = 31.4 Hz), 55.20 (d, J = 6.0 Hz), 55.07 (d, J = 3.8 Hz), 53.39 (s), 52.87 (s), 51.62 (s), 51.11 (s), 48.02 (s), 27.52 (d, J = 2.6 Hz), 18.78 (s), 18.10 (s). 19 F MR (282 MHz, CDCl 3 ) δ -61.09 (t, J = 9.2 Hz), -61.09-61.18 (m). HRMS (ESI) calcd for C 18 H 25 F 3 5 S + (M+H + ): 424.1400, found: 424.1405. 2-tert-butyl-7-fluoro-4-((fluoromethylsulfonyl)methyl)-4-methyl-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (6k) Prepared according to general method and isolated in 70% yield after chromoatography as yellow oil (50.7 mg): 1 H MR (500 MHz, CDCl 3 ) δ F 6.93 (ddd, J = 9.9, 5.8, 2.7 Hz, 1H (both isomer)), 6.50 (dd, J = 10.2, 7.0 S 2 CH 2 F Hz, 1H (isomer A)), 6.45 (dd, J = 9.7, 2.9 Hz, 1H (both isomer)), 6.42 (dd, J = 6.5, 3.3 Hz, 1H (isomer B)), 5.15 (dd, J = 12.7, 10.5 Hz, 1H (isomer A)), 5.05 (dt, J = 10.4, 8.0 Hz, 1H (both isomer)), 4.95 (dd, J = 10.4, 5.6 Hz, 1H (isomer B)), 3.70 3.61 (m, 1H(both isomer)), 3.56 3.48 (m, 1H(both isomer)), 3.33 (dd, J = 17.6, 10.6 Hz, 1H (both isomer)), 3.05 (dd, J = 23.4, 14.9 Hz, 1H (both isomer)), 1.55 (t, J = 4.8 Hz, 3H (both isomer)), 1.41 (d, J = 1.0 Hz, 9H (both isomer)). 13 C MR (126 MHz, CDCl 3 ) δ 177.60 (s), 177.42 (s), 173.33 (s), 173.19 (s), 156.80 (d, J = 52.5 Hz), 154.67 (d, J = 53.3 Hz), 147.26 (d, J = 2.2 Hz), 146.41 (d, J = 2.1 Hz), 132.03 (d, J = 4.5 Hz), 130.52 (d, J = 4.5 Hz), 122.32 (d, J = 14.4 Hz), 121.49 (d, J = 15.8 Hz), 92.03 (d, J = 220.0 Hz), 91.93 (d, J = 220.0 Hz), 55.31 (s), 55.28 (s), 53.87 (s), 53.86 (s), 53.02 (d, J = 1.6 Hz), 52.57 (d, J = 1.5 Hz), 50.70 (d, J = 2.5 Hz), 50.45 (d, J = 3.2 Hz), 48.69 (d, J = 5.4 Hz), 48.45 (d, J = 6.0 Hz), 27.52 (s), 18.15 (s), 18.06 (s). 19 F MR (282 MHz, CDCl 3 ) δ -123.95 (dd, J = 13.0, 6.9 Hz, 1F (isomer A)), -126.48 (dd, J = 12.1, 7.0 Hz, 1F (isomer B)), -210.18 (t, J = 47.0 Hz, 2F (isomer A), -210.19 (t, J = 47.0 Hz, 2F (isomer B)). HRMS (ESI) calcd for C 16 H 22 F 2 4 S + (M+H + ): 362.1232, found: 362.1229. 2-tert-butyl-7-fluoro-4-methyl-4-((2,2,2-trifluoroethylsulfonyl)methyl)-2-azaspiro[4.5]deca-6,9-diene-3,8- dione (7k) Prepared according to general method and isolated in 76% yield after chromoatography as yellow oil (62.6 mg): 1 H MR (500 MHz, CDCl 3 ) F S 2 CH 2 CF 3 δ 6.91 (ddd, J = 9.7, 6.8, 2.8 Hz, 1H (both isomers)), 6.53 6.35 (m, 2H (both isomers)), 4.10 3.93 (m, 1H (isomer A)), 3.85 (dq, J = 18.5, 9.1 19
Hz, 1H (isomer B), 3.71 3.51 (m, 2H (both isomers)), 3.32 (dd, J = 14.2, 10.7 Hz, 1H(both isomers)), 3.12 (dd, J = 33.4, 14.9 Hz, 1H(both isomers)), 1.55 (d, J = 2.3 Hz, 3H(both isomers)), 1.40 (d, J = 0.7 Hz, 9H (both isomers)). 13 C MR (126 MHz, CDCl 3 ) δ 177.56 (s), 177.38 (s), 173.35 (s), 173.19 (s), 156.79 (d, J = 55.7 Hz), 154.66 (d, J = 56.5 Hz), 147.25 (s), 146.36 (s), 132.06 (s), 130.50 (d, J = 4.2 Hz), δ 121.96 (d, J = 114.0 Hz), 121.84 (d, J = 115.1 Hz), 121.33 (q, J = 277.3 Hz), 58.28 (s), 58.02 (q, J = 31.6 Hz), 57.90 (q, J = 31.8 Hz), 55.37 (s), 55.35 (s), 53.38 (s), 52.94 (s), 50.74 (d, J = 1.7 Hz), 50.45 (d, J = 2.7 Hz), 48.72 (d, J = 5.2 Hz), 48.52 (d, J = 6.0 Hz), 27.50 (s), 18.09 (d, J = 11.5 Hz). 19 F MR (282 MHz, CDCl 3 ) δ - 61.11 (t, J = 9.3 Hz, 2F (isomer A)), -61.16 (t, J = 9.2 Hz, 2F (isomer B)), -123.95 (dd, J = 13.0, 6.9 Hz, 1F (isomer A)), -126.65 (dd, J = 12.8, 6.9 Hz, 2F (isomer B)). HRMS (ESI) calcd for C 17 H 22 F 4 4 S + (M+H + ): 412.1200, found: 412.1211. 2-tert-butyl-4-((fluoromethylsulfonyl)methyl)-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (6q) Prepared according to general method and isolated in 82% yield after chromoatography as yellow oil (54.1 mg): 1 H MR (500 MHz, CDCl 3 ) δ S 2 CH 2 F 6.86 (dd, J = 9.9, 2.9 Hz, 1H), 6.77 (dd, J = 10.1, 3.0 Hz, 1H), 6.45 (td, J = 11.9, 1.8 Hz, 2H), 5.56 (dd, J = 46.6, 10.1 Hz, 1H), 5.17 4.92 (m, 1H), 3.67 (d, J = 10.3 Hz, 1H), 3.54 (dd, J = 15.4, 7.4 Hz, 1H), 3.38 (dd, J = 7.4, 4.0 Hz, 1H), 3.34 (d, J = 10.3 Hz, 1H), 2.50 (dd, J = 15.2, 3.4 Hz, 1H), 1.41 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 184.58 (s), 170.48 (s), 147.91 (s), 144.89 (s), 132.88 (s), 132.21 (s), 91.35 (d, J = 219.1 Hz), 55.38 (s), 51.69 (s), 47.56 (s), 46.98 (s), 46.10 (s), 27.71 (s). 19 F MR (282 MHz, CDCl 3 ) δ -211.55 (t, J = 46.6 Hz). HRMS (ESI) calcd for C 15 H 21 F 4 S + (M+H + ): 330.1170, found: 330.1161. 2-tert-butyl-4-((2,2,2-trifluoroethylsulfonyl)methyl)-2-azaspiro[4.5]deca-6,9-diene-3,8-dione (7q) Prepared according to general method and isolated in 83% yield after chromoatography as yellow oil (63.0 mg): 1 H MR (500 MHz, CDCl 3 ) δ S 2 CH 2 CF 3 6.84 (dd, J = 10.0, 3.1 Hz, 1H), 6.78 (dd, J = 10.1, 3.1 Hz, 1H), 6.49 (dd, J = 10.0, 1.8 Hz, 1H), 6.46 (dd, J = 10.1, 1.8 Hz, 1H), 4.63 (dq, J = 18.3, 9.1 Hz, 1H), 4.03 3.86 (m, 1H), 3.69 (d, J = 10.3 Hz, 1H), 3.55 (dd, J = 15.3, 8.2 Hz, 1H), 3.43 (dd, J = 8.2, 3.1 Hz, 1H), 3.37 (d, J = 10.3 Hz, 1H), 2.55 (dd, J = 15.3, 2.2 Hz, 1H), 1.44 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 184.43 (s), 170.78 (s), 147.59 (s), 144.68 (s), 133.19 (s), 132.33 (s), 121.58 (q, J = 277.6 Hz), 56.87 (q, J = 31.6 Hz), 55.54 (s), 52.19 (s), 51.89 (s), 47.69 (s), 46.15 (s), 27.77 (s). 19 F MR (282 MHz, CDCl 3 ) δ -60.96 (t, J = 9.2 Hz). HRMS (ESI) calcd for C 16 H 21 F 3 4 S + (M+H + ): 380.1138, found: 380.1134. 20
IV. References 1. Han, G.; Liu, Y.; Wang, Q. rg. Lett. 2014, 16, 3188. 2. Tang, X.J.; Thomoson, C.S.; Dolbier, W. R. Jr. rg. Lett. 2014, 16, 4594. 21
V. MR Spectra for new compounds 22
Me 1a 23
Me 1a 24
Bn 1b 25
Bn 1b 26
PMB 1c 27
PMB 1c 28
Bn 1d 29
Bn 1d 30
Bn 1e 31
Bn 1e 32
Bn 1f 33
Bn 1f 34
Bn 1g 35
Bn 1g 36
Bn Bn 1h 37
Bn Bn 1h 38
Bn 1i 39
Bn 1i 40
Me Bn 1j 41
Me Bn 1j 42
F Bn 1k 43
F Bn 1k 44
F Bn 1k 45
46
Cl Bn 1l 47
Cl Bn 1l 48
Br Bn 1m 49
Br Bn 1m 50
tbu Bn 1n 51
tbu Bn 1n 52
Me Bn Me 1o 53
Me Bn Me 1o 54
tbu Bn 1p 55
tbu Bn 1p 56
Bn 1q 57
Bn 1q 58
CF 2 H 2a 59
CF 2 H 2a 60
CF 2 H 2a 61
2d CF 2 H 62
2d CF 2 H 63
2d CF 2 H 64
2e CF 2 H 65
2e CF 2 H 66
2e CF 2 H 67
CF 2 H 2f 68
CF 2 H 2f 69
CF 2 H 2f 70
2g CF 2 H 71
2g CF 2 H 72
2g CF 2 H 73
Bn HF 2 C 2g' 74
Bn HF 2 C 2g' 75
Bn HF 2 C 2g' 76
2h CF 2 H 77
2h CF 2 H 78
2h CF 2 H 79
Me 2j CF 2 H 80
Me 2j CF 2 H 81
Me 2j CF 2 H 82
F 2k CF 2 H 83
F 2k CF 2 H 84
F 2k CF 2 H 85
Cl 2l CF 2 H 86
Cl 2l CF 2 H 87
Cl 2l CF 2 H 88
Br 2m CF 2 H 89
Br 2m CF 2 H 90
Br 2m CF 2 H 91
CF 2 H 2n 92
CF 2 H 2n 93
CF 2 H 2n 94
Me Me 2o CF 2 H 95
Me Me 2o CF 2 H 96
Me Me 2o CF 2 H 97
2p CF 2 H 98
2p CF 2 H 99
2p CF 2 H 100
2q CF 2 H 101
2q CF 2 H 102
2q CF 2 H 103
3 CF 2 CEt 104
3 CF 2 CEt 105
3 CF 2 CEt 106
4 CF 3 107
4 CF 3 108
4 CF 3 109
5 CF 2 CF 2 CF 2 CF 3 110
5 CF 2 CF 2 CF 2 CF 3 111
5 CF 2 CF 2 CF 2 CF 3 112
6a S 2 CH 2 F 113
6a S 2 CH 2 F 114
6a S 2 CH 2 F 115
7a S 2 CH 2 CF 3 116
7a S 2 CH 2 CF 3 117
7a S 2 CH 2 CF 3 118
6f S 2 CH 2 F 119
6f S 2 CH 2 F 120
6f S 2 CH 2 F 121
7f S 2 CH 2 CF 3 122
7f S 2 CH 2 CF 3 123
7f S 2 CH 2 CF 3 124
Me S 2 CH 2 F 6j 125
Me S 2 CH 2 F 6j 126
Me S 2 CH 2 F 6j 127
Me 7j S 2 CH 2 CF 3 128
Me 7j S 2 CH 2 CF 3 129
Me 7j S 2 CH 2 CF 3 130
F 6k S 2 CH 2 F 131
F 6k S 2 CH 2 F 132
F 6k S 2 CH 2 F 133
F 7k S 2 CH 2 CF 3 134
F 7k S 2 CH 2 CF 3 135
F 7k S 2 CH 2 CF 3 136
6q S 2 CH 2 F 137
6q S 2 CH 2 F 138
6q S 2 CH 2 F 139
7q S 2 CH 2 CF 3 140
7q S 2 CH 2 CF 3 141
7q S 2 CH 2 CF 3 142