Intramolecular Sila-Matteson Rearrangement: a General Access to Silylated Heterocycles Cyril François, Thomas Boddaert, Muriel Durandetti, Olivier Querolle, Luc Van Hijfte, Lieven Meerpoel, Patrick Angibaud, Jacques Maddaluno CNRS UMR 6014 COBRA & FR 3038 INC3M, Université de Rouen and INSA de Rouen, 76821 Mont St Aignan Cedex, France and Department of Medicinal Chemistry, Janssen, Campus de Maigremont, BP615, 27106 Val de Reuil, France Supporting Information 1. General Experimental...2 2. Supplementary experiments: experimental conditions screening...2 3. Supplementary methods: Details synthetic procedures for precursor preparations...3 4. Supplementary methods: Details synthetic procedures for cyclisation steps...12 5. Supplementary methods: Details synthetic procedures for the rearrangement study...24 6. Supplementary figures: Plot of log (b/a) against Hammett constants ( )...26 7. Supplementary figures: 1 H and 13 C NMR spectra...27 - S1 -
1. General Experimental All reactions were conducted under an argon atmosphere unless otherwise stated and oven flamed glassware was used. THF was distilled under argon from sodium using benzophenone as indicator. Toluene was distilled over calcium hydride under a nitrogen atmosphere. Anhydrous acetonitrile and N,N-dimethylformamide were purchased from Fisher scientific and Carlo Erba respectively. All other solvents and commercially available reagents were used as received. Reactions were monitored by TLC performed using 0,25 mm E. Merck 5735 Kiegelsel silica gel coated aluminium plates (60F254) using UV radiation (254 nm) as visualizing agent and 7% ethanolic phosphomolybdic acid or aqueous KMnO 4 and heat as developing agent or by GC 24-m HP-methyl silicon capillary column. Flash column chromatography was carried out under pressure on Merck silica gel 40-60 mesh. 1 H NMR and 13 C NMR spectra were recorded at 25 C on a Brucker Avance 300 or 200 MHz ( 1 H) and 75 or 50 MHz ( 13 C), and calibrated using solvent as internal standard ( H: CDCl 3 7.26 ppm; C CDCl 3 77.16 ppm). Splitting patterns are abbreviated as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), broad (br), apparent (ap) or a combination of these. IR spectra were recorded on a Perkin Elmer Spectrum 100 FT-IR spectrometer using a ZnSe plate (ATR). High resolution mass spectra (HRMS) were recorded on a Thermo Finnigan MAT95XP and accurate to ± 0.001. Melting points were measured on a Kofler bench and are uncorrected. 2. Supplementary experiments: experimental conditions screening Halogen on the aromatic ring and leaving group on the side chain: entry X Z ratio (a/b) 1 I Cl 60:40 2 Br Cl 59:41 3 I I 60:40 4 I OMs 70:30 5 I OTs 75:25 - S2 -
Temperature and structure of the organometallic: entry RM temperature ratio (a/b) 1 n-buli (1.2 equiv.) -40 C 60:40 2 n-buli (1.2 equiv.) -78 C 60:40 3 n-buli (1.2 equiv.) -20 C 62:38 4 n-buli (1.2 equiv.) 0 C 60:40 5 t-buli (2.4 equiv.) -78 C 62:38 6 MeLi (1.2 equiv.) -40 C 54:46 7 MeLi.LiBr (1.2 equiv.) -40 C 55:45 8 i-prmgcl (1.8 equiv.) 0 C then 40 C 60:40 9 i-prmgcl.licl (1.8 equiv.) 0 C then 40 C 60:40 3. Supplementary methods: Details synthetic procedures for precursor preparations General procedure A: alkylation of phenol derivative To a solution of phenol (1.0 equiv.) in anhydrous acetonitrile (7 ml/mmol) were added K 2 CO 3 (3.0 equiv.) and. bis(chloromethyl)dimethylsilane (1.3 equiv.). Then the reaction mixture was heated under reflux until total disappearance of the starting material (TLC or GC). The medium was allowed to cool down to room temperature, filtered through a pad of celite and concentrated under reduced pressure. The crude mixture was finally purified by flash chromatography on silica gel using the appropriate mixture of eluents. General procedure B: alkylation of aniline derivatives To a solution of aniline (1.0 equiv.) in anhydrous DMF (5 ml/mmol) was added NaH (60% in oil, 1.3 equiv.). After 5 min. bis(chloromethyl)dimethylsilane (1.3 equiv.) was added pure, then the reaction mixture was heated at 80 C until total disappearance of the starting material (GC, 2-3h). The medium was allowed to cool down to room temperature and quenched with a saturated aqueous solution of NH 4 Cl and extracted with diethyl ether. The resulting organic phase was then washed three times with water, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude mixture was finally purified by flash chromatography on silica gel using the appropriate mixture of eluents. - S3 -
tert-butyl ((chloromethyl)dimethylsilyl)methyl(2-iodophenyl)carbamate 6 From the protected iodoaniline 1 (638 mg, 2.00 mmol), following the general procedure B, the halogenoaryl 6 was obtained as a colorless oil (632 mg, 72%). Rf (5% diethyl ether/pentane): 0.52; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.84 (d, J = 7.4 Hz, 1H), 7.33 (dd, J = 7.5, 7.4 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 6.96 (dd, J = 7.6, 7.5 Hz, 1H), 3.25-3.13 (m, 2H), 2.85-2.79 (m, 2H), 1.53 (s, 1.5H), 1.33 (s, 7.5H), 0.26 (s, 3H), 0.24 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.7, 146.8, 139.6, 129.2, 128.8, 128.6, 99.4, 80.3, 39.7, 31.5, 28.3 (3C), -3.4, -3.6; IR (neat) : υ 2974, 2931, 1690, 1365, 839, 758 cm -1 ; HRMS (ESI+): theor. 440.0310 (calc. for C 15 H 24 NO 2 SiClI), meas. 440.0306. (chloromethyl)((2-iodophenoxy)methyl)dimethylsilane 7 From 2-iodophenol (1.54 g, 7.00 mmol), following the general procedure A, the halogenoaryl 7 was obtained as a colorless oil (1.95 g, 82%). Rf (pentane): 0.68; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.74 (dd, J = 7.7, 1.6 Hz, 1H), 7.31 (ddd, J = 8.3, 7.5, 1.6 Hz, 1H), 6.91 (dd, J = 8.3, 1.2 Hz, 1H), 6.70 (ddd, J = 7.7, 7.5, 1.2 Hz, 1H), 3.75 (s, 2H), 3.04 (s, 2H), 0.34 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 159.3, 139.3, 129.6, 122.5, 111.3, 88.6, 59.5, 28.8, -5.7 (2C); IR (neat) : υ 2960, 2897, 1468, 1233, 1017, 839, 745, 643 cm -1 ; Elem. anal.: %C theor. 35.26 meas. 35.33, %H theor. 4.14 meas. 4.19. tert-butyl 2-bromo-5-(trifluoromethyl)phenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 12 1 Boger, D. L.; McKie, J. A. J. Org. Chem. 1995, 60, 1271-1275. - S4 -
From the protected bromoaniline 2 (3.20 g, 9.40 mmol), following the general procedure B, the halogenoaryl 12 was obtained as a colorless oil (2.73 g, 63%). Rf (5% diethyl ether/pentane): 0.62; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.72 (d, J = 8.4 Hz, 1H), 7.46 (s, 1H), 7.37 (d, J = 8.4 Hz, 1H), 3.17 (A of AB quartet, J = 15.3 Hz, 1H), 2.94 (B of AB quartet, J = 15.3 Hz, 1H), 2.90-2.80 (m, 2H), 1.55 (s, 1H), 1.33 (s, 8H), 0.24 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.4, 144.2, 134.1, 130.9 (q, J = 30Hz), 127.3, 126.5 (q, J = 3Hz), 125.0 (q, J = 3Hz), 123.4 (q, J = 270Hz), 81.0, 39.7, 31.2, 28.1 (3C), -3.7, -3.8; IR (neat) : υ 2978, 1699, 1334, 1129, 823 cm -1 ; HRMS (ESI+): theor. 460.0322 (calc. for C 16 H 23 NO 2 SiBrClF 3 ), meas. 460.0331. tert-butyl 2-bromo-5-chlorophenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 13 From the protected bromoaniline 3 (900 mg, 2.93 mmol), following the general procedure B, the halogenoaryl 13 was obtained as a colorless oil (912 mg, 73%). Rf (5% diethyl ether/pentane): 0.61; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.50 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.10 (dd, J = 8.4, 2.4 Hz, 1H), 3.12 (A of AB quartet, J = 15.4 Hz, 1H), 2.94 (B of AB quartet, J = 15.4 Hz, 1H), 2.90-2.85 (m, 2H), 1.34 (s, 9H), 0.25 (s, 3H), 0.24 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.4, 144.5, 134.0, 133.5, 129.5, 128.5, 121.3, 80.7, 39.8, 31.2, 28.1 (3C), -3.7, -3.8; IR (neat) : υ 2980, 2932, 2097, 1695, 1364, 1144, 838, 459 cm -1 ; HRMS (ESI+): theor. 426.0058 (calc. for C 15 H 23 NO 2 SiCl 2 Br), meas. 426.0064. tert-butyl 2-bromo-5-fluorophenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 14 From the protected bromoaniline 2 (2.05 g, 7.06 mmol), following the general procedure B, the halogenoaryl 14 was obtained as a colorless oil (1.96 g, 67%). Rf (5% diethyl ether/pentane): 0.67; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.53 (dd, J = 8.7, 5.9 Hz, 1H), 6.97 (dd, J = 9.0, 2.7 Hz, 1H), 6.89 (ddd, J = 8.7, 8.3, 2.7 Hz, 1H), 3.15 (A of AB quartet, J = 15.2 Hz, 1H), 2.93 (B of AB quartet, J = 15.2 Hz, 1H), 2.88 (A of AB quartet, J = 13.8 Hz, 1H), 2.82 (B of AB 2 Thansandote, P.; Hulcoop, D. H.; Langer, M.; Lautens, M. J. Org. Chem. 2009, 74, 1673-1678. 3 Darnbrough, S.; Mervic, M.; Condon, S.; Burns, C. Synthetic Comm. 2001, 31, 3273-3280. - S5 -
quartet, J = 13.8 Hz, 1H), 1.53 (br s, 1H), 1.34 (s, 8H), 0.24 (s, 3H), 0.23 (s, 3H) ; 13 C NMR (75 MHz, CDCl 3 ) δ = 161.9 (d, J = 247 Hz), 154.4, 144.6 (d, J = 10 Hz), 133.9 (d, J = 8 Hz), 117.6 (d, J = 4 Hz), 116.7 (d, J = 22 Hz), 115.7 (d, J = 22 Hz), 80.6, 39.6, 31.1, 28.1 (3C), -3.8, -3.9; IR (neat) : υ 2980, 1697, 1472, 1250, 1161, 840, 599, 468 cm -1 ; HRMS (ESI+): theor. 410.0354 (calc. for C 15 H 23 NO 2 SiClBrF), meas. 410.0373. tert-butyl 2-bromo-4-(trifluoromethyl)phenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 15 From the protected bromoaniline 4 (1.60 g, 4.70 mmol), following the general procedure B, the halogenoaryl 15 was obtained as a colorless oil (990 mg, 46%). Rf (5% diethyl ether/pentane): 0.55; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.86 (s, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 3.15 (A of AB quartet, J = 15 Hz, 1H), 2.92 (B of AB quartet, J = 15 Hz, 1H), 2.89 (A of AB quartet, J = 13.6 Hz, 1H), 2.86 (B of AB quartet, J = 13.6 Hz, 1H), 1.54 (s, 1.5H), 1.34 (s, 7.5H), 0.25 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.3, 146.8, 130.5 (q, J = 4 Hz), 130.4 (q, J = 34 Hz), 129.8, 125.3 (q, J = 3 Hz), 123.6, 123.1 (q, J = 271 Hz), 81.0, 39.7, 31.2, 28.1 (3C), -3.7, -3.8; IR (neat) : υ 2975, 2928, 1699, 1321, 1128, 837 cm -1 ; HRMS (ESI+): theor. 460.0322 (calc. for C 16 H 23 NO 2 F 3 SiBrCl), meas. 460.0338. tert-butyl 2-bromo-4-fluorophenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 16 From the protected bromoaniline 2 (867 mg, 2.99 mmol), following the general procedure B, the halogenoaryl 16 was obtained as a colorless oil (868 mg, 71%). Rf (5% diethyl ether/pentane): 0.51; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.32 (dd, J = 7.9, 2.7 Hz, 1H), 7.19 (dd, J = 8.7, 5.6 Hz, 1H), 7.01 (ddd, J = 8.7, 7.9, 2.7 Hz, 1H), 3.17 (A of AB quartet, J = 15.1 Hz, 1H), 2.88 (B of AB quartet, J = 15.1 Hz, 1H), 2.86 (A of AB quartet, J = 13.6 Hz, 1H), 2.81 (B of AB quartet, J = 13.6 Hz, 1H), 1.32 (s, 9H), 0.23 (s, 3H), 0.22 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 161.0 (d, J = 249 Hz), 154.9, 139.9, 130.2 (d, J = 9 Hz), 123.6 (d, J = 10 Hz), 120.3 (d, J = 25 Hz), 4 Bellezza, F.; Cipiciani, A.; Ruzziconi, R.; Spizzichino, S. J. Fluorine Chem. 2008, 129, 97-107. - S6 -
115.3 (d, J = 22 Hz), 80.5, 39.7, 31.2, 28.2 (3C), -3.7, -3.8; IR (neat) : υ 2977, 1697, 1489, 1367, 845 cm -1 ; HRMS (ESI+): theor. 410.0354 (calc. for C 15 H 23 NO 2 SiClBrF), meas. 410.0352. tert-butyl 2-bromo-4-methoxyphenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 17 From the protected bromoaniline 2 (819 mg, 2.71 mmol), following the general procedure B, the halogenoaryl 17 was obtained as a colorless oil (815 mg, 71%). Rf (5% diethyl ether/pentane): 0.35; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.10-7.08 (m, 2H), 6.80 (dd, J = 8.7, 2.7 Hz, 1H), 3.79 (s, 3H), 3.19 (A of AB quartet, J = 15.3 Hz, 1H), 2.89 (B of AB quartet, J = 15.3 Hz, 1H), 2.82 (A of AB quartet, J = 13.7 Hz, 1H), 2.79 (A of AB quartet, J = 13.7 Hz, 1H), 1.32 (s, 9H), 0.22 (s, 3H), 0.20 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 158.7, 155.2, 136.4, 129.7, 123.5, 118.1, 113.9, 80.1, 55.8, 39.8, 31.3, 28.2 (3C), -3.8, -3.9; IR (neat) : υ 2975, 1689, 1493, 1365, 1165, 840, 601, 459 cm -1 ; HRMS (ESI+): theor. 422.0554 (calc. for C 16 H 26 NO 3 SiBrCl), meas. 422.0548. tert-butyl 2-bromo-5-methoxyphenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 18 From the protected bromoaniline 5 (903 mg, 2.99 mmol), following the general procedure B, the halogenoaryl 18 was obtained as a colorless oil (912 mg, 72%). Rf (5% diethyl ether/pentane): 0.36; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.44 (d, J = 8.7 Hz, 1H), 6.77 (d, J = 3.0 Hz, 1H), 6.69 (dd, J = 8.7, 3.0 Hz, 1H), 3.79 (s, 3H), 3.17 (A of AB quartet, J = 15 Hz, 1H), 2.96 (B of AB quartet, J = 15 Hz, 1H), 2.87 (A of AB quartet, J = 13.6 Hz, 1H), 2.81 (B of AB quartet, J = 13.6 Hz, 1H), 1.53 (br s, 1.5H), 1.34 (s, 7.5H), 0.23 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 159.4, 154.8, 144.1, 133.4, 115.4, 114.1, 113.6, 80.3, 55.7, 39.7, 31.3, 28.2 (3C), -3.7, -3.9; IR (neat) : υ 2971, 1692, 1364, 1165, 839, 614 cm -1 ; HRMS (ESI+): theor. 422.0554 (calc. for C 16 H 26 NO 3 SiBrCl), meas. 422.0571. 5 Wu, T. Y.-H.; Li, Y.; Cortez, A.; Zou, Y.; Mishra, P.; Zhang, X.; Skibinski, D.; Singh, M.; Valiante, N. Novartis AG. PCT Int. Appl. WO/2009/111337. - S7 -
Compound 39 To a solution of 2-bromo-5-nitroaniline (1.14 g, 5.24 mmol, 1.0 equiv.) in anhydrous dichloromethane (50 ml) were added Boc 2 O (2.86 g, 13.1 mmol, 2.5 equiv.) and a catalytic amount of N,N-dimethyl-4- aminopyridine. After total disappearance of the starting material (TLC), the reaction mixture was concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (10% diethyl ether/pentane) to give compound 39, as a yellow solid (2.05 g, 94%). Rf (10% diethyl ether/pentane): 0.38; 1 H NMR (300 MHz, CDCl 3 ) δ = 8.08-8.02 (m, 2H), 7.80 (d, J = 8.6 Hz, 1H), 1.39 (s, 18H); 13 C NMR (75 MHz, CDCl 3 ) δ = 149.6 (2C), 147.2, 139.8, 133.4, 131.2, 124.9, 123.6, 83.9 (2C), 27.7 (6C); IR (neat) : υ 2980, 2939, 1699, 1525, 1342, 1115, 740 cm -1 ; HRMS (ESI+): theor. 455.0220 (calc. for C 16 H 21 N 2 O 6 BrK), meas. 455.0227; mp: 100 C. Compound 40 To a solution of protected aniline 39 (2.09 g, 5.0 mmol, 1.0 equiv.) in anhydrous acetone (100 ml) were added Zn powder (3.93 g, 60 mmol, 12.0 equiv.) and ammonium chloride (5.35 g, 100 mmol, 20 equiv.). The reaction mixture was then heated under reflux for 6h. The medium was allowed to cool down to room temperature and quenched with water and extracted with dichloromethane. The resulting organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give the crude mixture which was directly engaged in the next step. To a solution of the resulting bis-aniline (1.0 equiv.) in anhydrous DMF (40 ml) were added methyliodide (3.55 g, 25.0 mmol, 5.0 equiv.) and K 2 CO 3 (1.69 g, 12.3 mmol, 2.5 equiv.). After 20h at room temperature, the reaction mixture was quenched with a saturated aqueous solution of NH 4 Cl and extracted with diethyl ether. The resulting organic phase was washed five times with water, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (30% diethyl ether/pentane) to give dimethylaniline 40 as a yellow oil (747 mg, 36% over 2 steps). Rf (30% diethyl ether/pentane): 0.30; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.34 (d, J = 8.9 Hz, 1H), 6.54-6.46 (m, 2H), 2.90 (s, 6H), 1.41 (s, 18H); 13 C NMR (75 MHz, CDCl 3 ) δ = 150.8 (2C), 150.3, 138.7, 132.3, 113.6, 113.1, 109.0, 82.4 (2C), 40.4 (2C), 27.82 (6C); IR (neat) : υ 2975, 1753, 1366, 1114, 805 cm -1 ; HRMS (ESI+): theor. 415.1232 (calc. for C 18 H 28 N 2 O 4 Br), meas. 415.1245. - S8 -
tert-butyl 2-bromo-5-(dimethylamino)phenylcarbamate 41 To a solution of protected bis-aniline 40 (564 mg, 1.4 mmol, 1.0 equiv.) in anhydrous methanol (10 ml) was added K 2 CO 3 (563 mg, 4.1 mmol, 3.0 equiv.). The reaction mixture was then heated under reflux for 3h. The medium was allowed to cool down to room temperature and quenched with water and extracted with ethyl acetate. The resulting organic phase was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (10% diethyl ether/pentane) to give the carbamate 41 as a yellow oil (403 mg, 94%). Rf (30% diethyl ether/pentane): 0.81; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.64 (d, J = 2.9 Hz, 1H), 7.26 (d, J = 8.9 Hz, 1H), 6.97 (br s, 1H), 6.26 (dd, J = 8.9, 2.9 Hz, 1H), 2.94 (s, 6H), 1.55 (s, 9H) ; 13 C NMR (75 MHz, CDCl 3 ) δ = 152.2, 150.4, 136.3, 131.8, 108.2, 103.6, 98.4, 80.5, 40.4 (2C), 28.2 (3C); IR (neat) : υ 3414, 2977, 2793, 1729, 1518, 1148, 765 cm -1 ; HRMS (ESI+): theor. 315.0708 (calc. for C 13 H 20 N 2 O 2 Br), meas. 315.0695. tert-butyl 2-bromo-5-(dimethyllamino)phenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 19 N Br N Si Cl Boc 19 C 17 H 28 BrClN 2 O 2 Si MW = 435.86 g/mol From the protected bromoaniline 41 (354 mg, 1.12 mmol), following the general procedure B, the halogenoaryl 19 was obtained as a white solid (300 mg, 62%). Rf (10% diethyl ether/pentane): 0.57; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.33 (d, J = 8.9 Hz, 1H), 6.53 (d, J = 2.9 Hz, 1H), 7.47 (dd, J = 8.9, 2.9 Hz, 1H), 3.18 (A of AB quartet, J = 15.3 Hz, 1H), 2.97 (B of AB quartet, J = 15.3 Hz, 1H), 2.93 (s, 6H), 2.87 (A of AB quartet, J = 13.6 Hz, 1H), 2.80 (B of AB quartet, J = 13.6 Hz, 1H), 1.53 (s, 1.5H), 1.35 (s, 7.5H), 0.23 (s, 3H), 0.23 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 155.0, 150.4, 143.5, 132.9, 113.0, 112.4, 108.5, 79.9, 40.4 (2C), 39.6, 31.3, 28.1 (3C), -3.8, -4.0; IR (neat) : υ 2980, 2927, 2805, 1688, 1364, 1145, 787 cm -1 ; HRMS (ESI+): theor. 435.0870 (calc. for C 17 H 29 N 2 O 2 SiClBr), meas. 435.0879; mp: 64 C. - S9 -
tert-butyl 2-bromo-4-methylphenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 20 From the protected bromoaniline 2 (757 mg, 2.65 mmol), following the general procedure B, the halogenoaryl 20 was obtained as a colorless oil (756 mg, 70%) Rf (5% diethyl ether/pentane): 0.68; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.37 (br s, 1H), 7.06 (br s, 2H), 3.17 (A of AB quartet, J = 15.3 Hz, 1H), 2.90 (B of AB quartet, J = 15.3 Hz, 1H), 2.84 (A of AB quartet, J = 13.5 Hz, 1H), 2.88 (B of AB quartet, J = 13.5 Hz, 1H), 2.30 (s, 3H), 1.32 (s, 9H), 0.21 (s, 3H), 0.20 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.8, 140.5, 138.3, 133.4, 128.73, 128.70, 122.4, 79.8, 39.5, 31.0, 28.0 (3C), 20.6, -4.0, -4.1; IR (neat) : υ 2980, 2928, 1690, 1364, 819, 452 cm -1 ; HRMS (ESI+): theor. 406.0605 (calc. for C 16 H 26 NO 2 SiClBr), meas. 406.0599. tert-butyl 2-bromo-5-methylphenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 21 From the protected bromoaniline 5 (429 mg, 1.50 mmol), following the general procedure B, the halogenoaryl 21 was obtained as a colorless oil (416 mg, 68%) Rf (5% diethyl ether/pentane): 0.55; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.40 (d, J = 8.4 Hz, 1H), 7.00 (s, 1H), 6.88 (d, J = 8.4 Hz, 1H), 3.12 (A of AB quartet, J =15.2 Hz, 1H), 2.93 (B of AB quartet, J = 15.2 Hz, 1H), 2.83 (A of AB quartet, J = 13.6 Hz, 1H), 2.77 (B of AB quartet, J = 13.6 Hz, 1H), 2.27 (s, 3H), 1.31 (s, 9H), 0.22 (s, 3H), 0.20 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ =154.6, 142.8, 138.0, 132.6, 129.6, 129.0, 119.3, 79.9, 39.5, 31.1, 27.9 (3C), 20.7, -4.0, -4.1; IR (neat) : υ 2980, 2934, 1692, 1364, 1155, 840, 460 cm -1 ; HRMS (ESI+): theor. 406.0605 (calc. for C 16 H 26 NO 2 SiClBr), meas. 406.0615. Allyl ((chloromethyl)dimethylsilyl)methyl(2-iodophenyl)carbamate 32 - S10 -
From the protected bromoaniline 6 (872 mg, 2.88 mmol), following the general procedure B, the halogenoaryl 32 was obtained as a colorless oil (758 mg, 62%). Rf (5% diethyl ether/pentane): 0.44; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.87 (dd, J = 7.8, 1.5 Hz, 1H), 7.37 (ddd, J = 7.8, 7.5, 1.5 Hz, 1H), 7.26-7.22 (m, 1H), 7.01 (ddd, J = 7.8, 7.5, 1.8 Hz, 1H), 5.86-5.77 (m, 1H), 5.10-5.05 (m, 2H), 4.53 (dd, J = 3.6, 1.5 Hz, 2H), 3.32 (A of AB quartet, J = 15.2 Hz, 1H), 2.88 (B of AB quartet, J = 15.2 Hz, 1H), 2.88-2.80 (m, 2H), 0.28 (s, 3H), 0.26 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 155.2, 145.9, 139.7, 132.6, 129.3, 129.0, 128.7, 116.9, 99.0, 66.7, 40.4, 31.1, -3.6, - 3.7; IR (neat) : υ 2954, 1699, 1469, 839, 761 cm -1 ; HRMS (ESI+): theor. 423.9997 (calc. for C 14 H 20 NO 2 SiClI), meas. 423.9987. N-(((chloromethyl)dimethylsilyl)methyl)-N-(2-iodophenyl)-4-methylbenzenesulfonamide 33 From the protected iodoaniline 7 (1.11 g, 2.97 mmol), following the general procedure B, the halogenoaryl 33 was obtained as a white solid (852 mg, 58%). Rf (5% diethyl ether/pentane): 0.13; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.95 (dd, J = 7.8, 1.2 Hz, 1H), 7.59 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.25-7.22 (m, 1H), 7.03 (ddd, J = 7.8, 7.5, 1.5 Hz, 1H), 6.75 (dd, J = 7.8, 1.5 Hz, 1H), 3.46 (A of AB quartet, J = 14.8 Hz, 1H), 2.82 (B of AB quartet, J = 14.8 Hz, 1H), 2.64 (A of AB quartet, J = 13.8 Hz, 1H), 2.54 (B of AB quartet, J = 13.8 Hz, 1H), 2.46 (s, 3H), 0.06 (s, 3H), 0.04 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 144.1, 143.6, 140.7, 133.2, 130.0, 129.5 (2C), 128.9 (2C), 128.8, 128.6, 103.1, 40.0, 29.5, 21.7, -4.5 (2C); IR (neat) : υ 3059, 2943, 1345, 1160, 816, 711, 650 cm -1 ; HRMS (ESI+): theor. 493.9874 (calc. for C 17 H 22 NO 2 SiSClI), meas. 493.9872; mp: 98 C. N-(((chloromethyl)dimethylsilyl)methyl)-N-(2-iodophenyl)methanesulfonamide 34 6 Lebel, H.; Leogane, O. Org. Lett. 2006, 8, 5717-5720. 7 Zenner, J. M.; Larock, R. C. J. Org. Chem. 1999, 64, 7312-7322. - S11 -
From the protected iodoaniline 8 (888 mg, 2.99 mmol), following the general procedure B, the halogenoaryl 34 was obtained as a colorless oil (672 mg, 54%). Rf (50% diethyl ether/pentane): 0.47; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.93 (d, J = 7.9 Hz, 1H), 7.43-7.40 (m, 2H), 7.10-7.04 (m, 1H), 3.47 (A of AB quartet, J = 20 Hz, 1H), 3.27 (B of AB quartet, J = 20 Hz, 1H), 3.08 (s, 3H), 2.72 (A of AB quartet, J = 14 Hz, 1H), 2.60 (B of AB quartet, J = 14 Hz, 1H), 0.09 (s, 3H), 0.06 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 143.1, 140.6, 130.1, 129.7, 129.3, 101.7, 39.4, 37.5, 29.3, -4.7, -4.8; IR (neat) : υ 2930, 1332, 1148, 782, 672 cm -1 ; HRMS (ESI+): theor. 417.9561 (calc. for C 11 H 18 NO 2 SiSClI), meas. 417.9563. 4. Supplementary methods: Details synthetic procedures for cyclisation steps General procedure C: cyclisation using n-butyllithium (Conditions A) To a solution of halogenoaryl (1.0 equiv.) in anhydrous THF (10 ml/mmol) was added dropwise at -40 C a solution of n-buli in hexane (1.6 M, 1.2 equiv.). After 1h, the reaction mixture was quenched at -40 C with a saturated aqueous solution of NH 4 Cl, allowed to warm up to room temperature and extracted with diethyl ether. The resulting organic phase was then dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude mixture was finally purified by flash chromatography on silica gel using the appropriate mixture of eluents. General procedure D: cyclisation using t-butyllithium (Conditions B) To a solution of halogenoaryl (1.0 equiv.) in anhydrous THF (10 ml/mmol) was added dropwise at -78 C a solution of t-buli in hexane (1.7 M, 2.4 equiv.). After 1h, the reaction mixture was quenched at -78 C with a saturated aqueous solution of NH 4 Cl, allowed to warm up to room temperature and extracted with diethyl ether. The resulting organic phase was then dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude mixture was finally purified by flash chromatography on silica gel using the appropriate mixture of eluents. tert-butyl 3,3-dimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 4a tert-butyl 4,4-dimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 4b 8 Sakamoto, T.; Kondo, Y.; Iwashita, S.; Nagano, T.; Yamanaka, H. Chem. Pharm. Bull. 1988, 36, 1305-1308. - S12 -
From the halogenoaryl 6 (559 mg, 1.27 mmol), following the general procedure C, the silylated compound 4a was obtained as a white solid (141 mg, 40%). Rf (5% diethyl ether/pentane): 0.29; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.10-7.05 (m, 4H), 3.05 (s, 2H), 1.94 (s, 2H) 1.47 (s, 9H), 0.10 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 155.1, 140.9, 134.1, 130.0, 127.3, 125.8, 125.3, 79.9, 35.4, 28.4 (3C), 19.2, -2.7 (2C); IR (neat) : υ 2970, 1681, 1363, 1155, 822, 751 cm -1 ; HRMS (ESI+): theor. 278.1576 (calc. for C 15 H 24 NO 2 Si), meas. 278.1577; mp: 102 C. From the halogenoaryl 6 (559 mg, 1.27 mmol), following the general procedure C, the silylated compound 4b was obtained as a colorless oil (155 mg, 44%). Rf (5% diethyl ether/pentane): 0.39; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.41 (d, J = 7.1 Hz, 1H), 7.34-7.28 (m, 2H), 7.16-7.11 (m, 1H), 3.83-3.79 (m, 2H), 1.47 (s, 9H), 1.17-1.13 (m, 2H), 0.26 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.1, 148.6, 133.5, 130.6, 128.9, 126.0, 124.7, 80.1, 45.0, 28.4 (3C), 13.8, -1.2 (2C); IR (neat) : υ 2980, 1694, 1365, 1149, 832 cm -1 ; HRMS (ESI+): theor. 278.1576 (calc. for C 15 H 24 NO 2 Si), meas. 278.1579 3,3-dimethyl-3,4-dihydro-2H-benzo[e][1,3]oxasiline 5a 4,4-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxasiline 5b From the halogenoaryl 7 (680 mg, 2.00 mmol), following the general procedure C, the silylated compound 5a was obtained as a colorless oil (183 mg, 51%). Rf (pentane): 0.23; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.10-7.05 (m, 2H), 6.95-6.89 (m, 2H), 3.76 (s, 2H), 2.00 (s, 2H), 0.17 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 158.2, 131.9, 128.1, 126.6, 122.7, 119.6, 63.7, 16.3, -3.1 (2C); IR (neat) : υ 2952, 2872, 1477, 1245, 1210, 973, 822, 742 cm -1 ; HRMS (ESI+): theor. 179.0892 (calc. for C 10 H 15 OSi), meas. 179.0895. From the halogenoaryl 7 (680 mg, 2.00 mmol), following the general procedure C, the silylated compound 5b was obtained as a colorless oil (122 mg, 34%). - S13 -
Rf (pentane): 0.37; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.36 (dd, J = 7.2, 1.7 Hz, 1H), 7.28-7.22 (m, 1H), 6.95 (td ap, J = 7.2, 1.2 Hz, 1H), 6.83 (d, J = 8.2 Hz, 1H), 4.33-4.29 (m, 2H), 1.16-1.12 (m, 2H), 0.30 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 164.6, 134.7, 130.9, 121.6, 121.1, 117.6, 66.7, 13.8, -1.4 (2C); IR (neat) : υ 2952, 2862, 1432, 1266, 1215, 1039, 757 cm -1 ; HRMS (ESI+): theor. 179.0892 (calc. for C 10 H 15 OSi), meas. 179.0893. tert-butyl-3,3-dimethyl-7-(trifluoromethyl)-3,4-dihydrobenzo[e][1,3]azasiline-1(2h)-carboxylate 22a tert-butyl 4,4-dimethyl-7-(trifluoromethyl)-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 22b From the halogenoaryl 12 (359 mg, 0.78 mmol), following the general procedure C, the silylated compound 22a was obtained as a white solid (120 mg, 45%). From the halogenoaryl 12 (554 mg, 1.20 mmol), following the general procedure D, the silylated compound 22a was obtained as a white solid (269 mg, 65%). Rf (5% diethyl ether/pentane): 0.34; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.44 (br s, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 3.06 (s, 2H), 2.00 (s, 2H), 1.44 (s, 9H), 0.12 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.8, 141.0, 138.6, 130.3, 127.6 (q, J = 32 Hz), 124.6 (q, J = 4 Hz), 124.2 (q, J = 270 Hz), 122.2 (q, J = 4 Hz), 80.6, 34.8, 28.3 (3C), 19.7, -2.8 (2C); IR (neat) : υ 2976, 1693, 1329, 1120, 837, 688 cm -1 ; HRMS (ESI+): theor. 346.1450 (calc. for C 16 H 23 NO 2 F 3 Si), meas. 346.1450; mp: 67 C. From the halogenoaryl 12 (359 mg, 0.78 mmol), following the general procedure C, the silylated compound 22b was obtained as a colorless oil (19 mg, 7%). From the halogenoaryl 12 (554 mg, 1.20 mmol), following the general procedure D, the silylated compound 22b was obtained as a colorless oil (27 mg, 7%). Rf (5% diethyl ether/pentane): 0.47; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.61 (br s, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 3.86-3.80 (m, 2H), 1.47 (s, 9H), 1.20-1.14 (m, 2H), 0.28 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 153.8, 149.0, 135.2, 134.2, 131.1 (q, J = 32 Hz), 124.1 (q, J = 272 Hz), 123.0 (q, J = 4 Hz), 120.8 (q, J = 4 Hz), 81.1, 44.9, 28.4 (3C), 13.7, -1.3 (2C); IR (neat) : υ 2936, - S14 -
2850, 1692, 1329, 1167, 1129, 838 cm -1 ; HRMS (ESI+): theor. 346.1450 (calc. for C 16 H 23 NO 2 F 3 Si), meas. 346.1450. tert-butyl 7-chloro-3,3-dimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 23a tert-butyl 7-chloro-4,4-dimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 23b From the halogenoaryl 13 (609 mg, 1.42 mmol), following the general procedure C, the silylated compound 23a was obtained as a white solid (279 mg, 63%). From the halogenoaryl 13 (895 mg, 2.09 mmol), following the general procedure D, the silylated compound 23a was obtained as a white solid (458 mg, 70%). Rf (5% diethyl ether/pentane): 0.35; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.19 (br s, 1H), 7.06-6.99 (m, 2H), 3.02 (s, 2H), 1.90 (s, 2H), 1.45 (s, 9H), 0.10 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.7, 141.7, 132.7, 130.8, 130.2, 127.5, 125.8, 80.4, 35.0, 28.4 (3C), 18.8, -2.7 (2C); IR (neat) : υ 2976, 2949, 1688, 1344, 1158, 835, 616 cm -1 ; HRMS (ESI+): theor. 312.1187 (calc. for C 15 H 23 NO 2 SiCl), meas. 312.1184, mp : 88 C. From the halogenoaryl 13 (609 mg, 1.42 mmol), following the general procedure C, the silylated compound 23b was obtained as a colorless oil (50 mg, 11%). From the halogenoaryl 13 (895 mg, 2.09 mmol), following the general procedure D, the silylated compound 23b was obtained as a colorless oil (75 mg, 11%). Rf (5% diethyl ether/pentane): 0.49; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.37 (d, J = 1.9 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.11 (dd, J = 7.9, 1.9 Hz, 1H), 3.81-3.77 (m, 2H), 1.48 (s, 9H), 1.15-1.10 (m, 2H), 0.25 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 153.8, 149.7, 134.7, 134.6, 128.9, 126.2, 125.0, 80.8, 45.0, 28.4 (3C), 13.7, -1.2 (2C); IR (neat) : υ 2976, 2899, 1696, 1365, 1149, 828 cm -1 ; HRMS (ESI+): theor. 312.1187 (calc. for C 15 H 23 NO 2 SiCl), meas. 312.1188. - S15 -
tert-butyl 7-fluoro-3,3-dimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 24a tert-butyl 7-fluoro-4,4-dimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 24b From the halogenoaryl 14 (1.23 g, 2.99 mmol), following the general procedure C, the silylated compound 24a was obtained as a white solid (371 mg, 42%). Rf (5% diethyl ether/pentane): 0.34; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.02 (dd, J = 8.4, 6.3 Hz, 1H), 6.94-6.91 (m, 1H), 6.79 (dt ap, J = 8.4, 2.7 Hz, 1H), 3.03 (s, 2H), 1.89 (s, 2H), 1.45 (s, 9H), 0.10 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 160.4 (d, J = 241 Hz), 154.8, 141.7 (d, J = 10 Hz), 130.6 (d, J = 8 Hz), 129.7 (d, J = 3 Hz), 114.4 (d, J = 22 Hz), 112.7 (d, J = 21 Hz), 80.3, 35.1, 28.4 (3C), 18.4, -2.8 (2C); IR (neat) : υ 2975, 1692, 1365, 1155, 833, 460 cm -1 ; HRMS (ESI+): theor. 296.1482 (calc. for C 15 H 23 NO 2 FSi), meas. 296.1476; mp: 65 C. F Si N Boc 24b C 15 H 22 FNO 2 Si MW = 295.42 g/mol From the halogenoaryl 14 (1.23 g, 2.99 mmol), following the general procedure C, the silylated compound 24b was obtained as a colorless oil (280 mg, 32%). Rf (5% diethyl ether/pentane): 0.47; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.33 (dd, J = 8.4, 1.2 Hz, 1H), 7.12-7.08 (m, 1H), 6.86 (ddd, 8.4, 8.2, 2.3 Hz, 1H), 3.82-3.78 (m, 2H), 1.48 (s, 9H), 1.14-1.10 (m, 2H), 0.24 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 163.0 (d, J = 244 Hz), 153.7, 150.2 (d, J = 10 Hz), 134.9 (d, J = 8 Hz), 125.9 (d, J = 4 Hz), 113.2 (d, J = 22 Hz), 112.2 (d, J = 22 Hz), 80.7, 45.0, 28.3 (3C), 13.6, -1.1 (2C); IR (neat) : υ 2970, 1697, 1366, 1143, 833, 467 cm -1 ; HRMS (ESI+): theor. 296.1482 (calc. for C 15 H 23 NO 2 FSi), meas. 296.1480. tert-butyl-3,3-dimethyl-6-(trifluoromethyl)-3,4-dihydrobenzo[e][1,3]azasiline-1(2h)-carboxylate 25a tert-butyl-4,4-dimethyl-6-(trifluoromethyl)-3,4-dihydrobenzo[b][1,4]azasiline-1(2h)-carboxylate 25b From the halogenoaryl 15 (860 mg, 1.87 mmol), following the general procedure D, the silylated compound 25a was obtained as a white solid (438 mg, 68%). - S16 -
Rf (5% diethyl ether/pentane): 0.39; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.36-7.30 (m, 3H), 3.05 (s, 2H), 2.00 (s, 2H), 1.45 (s, 9H), 0.13 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.7, 144.0, 135.1, 127.7, 127.6 (q, J = 32 Hz), 126.9 (q, J = 4 Hz), 124.3 (q, J = 270 Hz), 122.2 (q, J = 4 Hz), 80.6, 34.9, 28.3 (3C), 19.4, -2.8 (2C); IR (neat) : υ 2976, 1695, 1319, 1120, 826, 743, 615 cm -1 ; HRMS (ESI+): theor. 346.1446 (calc. for C 16 H 23 NO 2 F 3 Si), meas. 346.1450; mp : 80 C. From the halogenoaryl 15 (860 mg, 1.87 mmol), following the general procedure D, the silylated compound 25b was obtained as a colorless oil (51 mg, 8%). Rf (5% diethyl ether/pentane): 0.41; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.62 (br s, 1H), 7.51 (d, J = 8.6 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 3.85-3.80 (m, 2H), 1.48 (s, 9H), 1.19-1.14 (m, 2H), 0.29 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 153.8, 151.7, 131.5, 130.5 (q, J = 4 Hz), 126.5 (q, J = 32 Hz), 126.2, 125.9 (q, J = 3Hz), 124.4 (J = 270 Hz), 81.1, 44.9, 28.4 (3C), 13.7, -1.2 (2C); IR (neat) : υ 2973, 1697, 1118, 812 cm -1 ; HRMS (ESI+): theor. 346.1446 (calc. for C 16 H 23 NO 2 F 3 Si), meas. 346.1434. tert-butyl 6-fluoro-3,3-dimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 26a tert-butyl 6-fluoro-4,4-dimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 26b F Si N Boc 26a C 15 H 22 FNO 2 Si MW = 295.42 g/mol From the halogenoaryl 16 (483 mg, 1.17 mmol), following the general procedure C, the silylated compound 26a was obtained as a white solid (131 mg, 38%). From the halogenoaryl 16 (180 mg, 0.44 mmol), following the general procedure D, the silylated compound 26a was obtained as a white solid (94 mg, 72%). Rf (5% diethyl ether/pentane): 0.34; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.09 (br s, 1H), 6.82-6.76 (m, 2H), 3.04 (br s, 2H), 1.92 (s, 2H), 1.43 (s, 9H), 0.11 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 160.4 (d, J = 242 Hz), 155.1, 136.8 (d, J = 3 Hz), 136.6 (d, J = 8 Hz), 128.6 (d, J = 8 Hz), 116.1 (d, J = 22 Hz), 112.1 (d, J = 22 Hz), 80.1, 35.1, 28.4 (3C), 19.6, -2.7 (2C); IR (neat) : υ 2969, 2892, 1686, 1364, 1157, 836, 460 cm -1 ; HRMS (ESI+): theor. 318.1302 (calc. for C 15 H 22 NO 2 FNaSi), meas. 318.1288; mp : 66 C. - S17 -
From the halogenoaryl 16 (483 mg, 1.17 mmol), following the general procedure C, the silylated compound 26b was obtained as a colorless oil (31 mg, 9%). From the halogenoaryl 16 (180 mg, 0.44 mmol), following the general procedure D, the silylated compound 26b was obtained as a colorless oil (13 mg, 10%). Rf (5% diethyl ether/pentane): 0.46; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.29 (br s, 1H), 7.05 (dd, J = 7.8, 3.0 Hz, 1H), 6.96 (ddd, J = 8.7, 8.4, 3.0 Hz, 1H), 3.79-3.75 (m, 2H), 1.46 (s, 9H), 1.16-1.12 (m, 2H), 0.26 (s, 6H); 13 C NMR (50 MHz, CDCl 3 ) δ = 160.0 (d, J = 245 Hz), 154.3, 144.5 (d, J = 3Hz), 133.5 (d, J = 5 Hz), 128.0 (d, J = 7 Hz), 119.01 (d, J = 20 Hz), 116.0 (d, J = 22 Hz), 80.5, 45.1, 28.5 (3C), 13.6, -1.3 (2C); IR (neat) : υ 2973, 1699, 1362, 1141, 837 cm -1 ; HRMS (ESI+): theor. 296.1482 (calc. for C 15 H 23 NO 2 FSi), meas. 296.1470. tert-butyl 6-methoxy-3,3-dimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 27a tert-butyl 6-methoxy-4,4-dimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 27b From the halogenoaryl 17 (813 mg, 1.92 mmol), following the general procedure D, the silylated compound 27a was obtained as an oil (280 mg, 48%). Rf (5% diethyl ether/pentane): 0.17; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.05 (br s, 1H), 6.66-6.63 (m, 2H), 3.79 (s, 3H), 3.04 (br s, 2H), 1.91 (s, 2H), 1.43 (s, 9H), 0.10 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 157.3, 155.3, 135.5, 134.1, 128.1, 114.6, 110.7, 79.7, 55.3, 35.4, 28.5 (3C), 19.7, -2.6 (2C); IR (neat) : υ 2969, 2899, 2839, 1684, 1363, 1157, 840 cm -1 ; HRMS (ESI+): theor. 308.1682 (calc. for C 16 H 26 NO 3 Si), meas. 308.1689. From the halogenoaryl 17 (813 mg, 1.92 mmol), following the general procedure D, the silylated compound 27b was obtained as an oil (181 mg, 31%). Rf (5% diethyl ether/pentane): 0.25; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.24 (d, J = 8.7 Hz, 1H), 6.90 (d, J = 3.0 Hz, 1H), 6.84 (dd, J = 8.7, 3.0 Hz, 1H), 3.80 (s, 3H), 3.80-3.75 (m, 2H), 1.46 (s, 9H), 1.16- - S18 -
1.11 (m, 2H), 0.25 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 156.4, 154.4, 141.8, 132.1, 127.3, 117.8, 114.6, 80.0, 55.3, 45.0, 28.4 (3C), 13.7, -1.2 (2C); IR (neat) : υ 2953, 2899, 2834, 1690, 1150, 828 cm- 1 ; HRMS (ESI+): theor. 308.1682 (calc. for C 16 H 26 NO 3 Si), meas. 308.1684. tert-butyl 7-methoxy-3,3-dimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 28a tert-butyl 7-methoxy-4,4-dimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 28b From the halogenoaryl 18 (262 mg, 0.62 mmol), following the general procedure D, the silylated compound 28a was obtained as a colorless oil (25 mg, 13%). Rf (10% diethyl ether/pentane): 0.19; 1 H NMR (300 MHz, CDCl 3 ) δ = 6.98 (d, J = 8.4 Hz, 1H), 6.75 (br s, 1H), 6.65 (dd, J = 8.4, 2.4 Hz, 1H), 3.76 (s, 3H), 3.03 (br s, 2H), 1.86 (s, 2H), 1.45 (s, 9H), 0.09 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 157.4, 155.1, 141.7, 130.5, 126.1, 112.9, 112.2, 80.1, 55.5, 35.5, 28.6 (3C), 18.0, -2.6 (2C); IR (neat) : υ 2971, 1688, 1363, 1158, 831 cm -1 ; HRMS (ESI+): theor. 308.1682 (calc. for C 16 H 26 NO 3 Si), meas. 308.1687. MeO Si N Boc 28b C 16 H 25 NO 3 Si MW = 307.46 g/mol From the halogenoaryl 18 (262 mg, 0.62 mmol), following the general procedure D, the silylated compound 28b was obtained as a colorless oil (114 mg, 60%). Rf (10% diethyl ether/pentane): 0.30; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.30 (d, J = 9.1 Hz, 1H), 6.92 (d, J = 2.1 Hz, 1H), 6.74 (dd, J = 9.1, 2.1 Hz, 1H), 3.81-3.77 (m, 5H), 1.48 (s, 9H), 1.13-1.09 (m, 2H), 0.23 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 160.3, 154.0, 150.1, 134.5, 121.7, 111.8, 111.4, 80.3, 55.2, 45.3, 28.5 (3C), 13.8, -0.9 (2C); IR (neat) : υ 2991, 2947, 2898, 1690, 1596, 1146, 833 cm -1 ; HRMS (ESI+): theor. 308.1682 (calc. for C 16 H 26 NO 3 Si), meas. 308.1688. - S19 -
tert-butyl 7-(dimethylamino)-3,3-dimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 29a tert-butyl 7-(dimethylamino)-4,4-dimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 29b N Si N Boc 29a C 17 H 28 N 2 O 2 Si MW = 320.50 g/mol From the halogenoaryl 19 (250 mg, 0.57 mmol), following the general procedure D, the silylated compound 29a was obtained as a colorless oil (18 mg, 10%). Rf (10% diethyl ether/pentane): 0.12; 1 H NMR (300 MHz, CDCl 3 ) δ = 6.95 (d, J = 8.3 Hz, 1H), 6.62-6.58 (m, 1H), 6.53 (dd, J = 8.3, 2.7 Hz, 1H), 3.04 (br s, 2H), 2.88 (s, 6H), 1.82 (s, 2H), 1.45 (s, 9H), -0.09 (s, 6H); 13 C NMR (50 MHz, CDCl 3 ) δ = 155.1, 149.0, 141.5, 130.2, 122.2, 111.3, 110.8, 79.7, 41.1 (2C), 35.6, 28.5 (3C), 17.5, -2.6 (2C); IR (neat) : υ 2971, 2883, 2796, 1687, 1363, 1161, 828 cm -1 ; HRMS (ESI+): theor. 321.1998 (calc. for C 17 H 29 N 2 O 2 Si), meas. 321.1993. From the halogenoaryl 19 (250 mg, 0.57 mmol), following the general procedure D, the silylated compound 29b was obtained as a colorless oil (150 mg, 82%). Rf (10% diethyl ether/pentane): 0.23; 1 H NMR (200 MHz, CDCl 3 ) δ = 7.25 (d, J = 8.2 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.57 (dd, J = 8.2, 2.4 Hz, 1H), 3.83-3.74 (m, 2H), 2.94 (s, 6H), 1.48 (s, 9H), 1.15-1.06 (m, 2H), 0.21 (s, 6H); 13 C NMR (50 MHz, CDCl 3 ) δ = 154.1, 151.2, 149.7, 134.1, 116.3, 110.2, 109.7, 79.8, 45.2, 40.2 (2C), 28.4 (3C), 13.8, -0.9 (2C); IR (neat) : υ 2985, 2893, 2801, 1691, 1378, 1147, 1081, 831 cm -1 ; HRMS (ESI+): theor. 321.1998 (calc. for C 17 H 29 N 2 O 2 Si), meas. 321.1993. tert-butyl 3,3,6-trimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 30a tert-butyl 4,4,6-trimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 30b Si N Boc 30a C 16 H 25 NO 2 Si MW = 291.46 g/mol From the halogenoaryl 20 (710 mg, 1.74 mmol), following the general procedure D, the silylated compound 30a was obtained as a white solid (198 mg, 39%). - S20 -
Rf (5% diethyl ether/pentane): 0.25; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.02 (br s, 1H), 6.91-6.88 (m, 2H), 3.04 (br s, 2H), 2.28 (s, 3H), 1.89 (s, 2H), 1.43 (s, 9H), 0.10 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 155.1, 138.2, 135.2, 133.6, 130.4, 126.8, 125.9, 79.7, 34.9, 28.4 (3C), 20.9, 19.0, -2.7 (2C); IR (neat) : υ 2963, 2922, 2870, 1683, 1158, 826 cm -1 ; HRMS (ESI+): theor. 292.1733 (calc. for C 16 H 26 NO 2 Si), meas. 292.1725; mp : 71 C. Si C 16 H 25 NO 2 Si N MW = 291.46 g/mol Boc 30b From the halogenoaryl 20 (710 mg, 1.74 mmol), following the general procedure D, the silylated compound 30b was obtained as a colorless oil (256 mg, 50%). Rf (5% diethyl ether/pentane): 0.41; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.28 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 1.2 Hz, 1H), 7.15 (dd, J = 8.4, 1.2 Hz, 1H), 3.87-3.83 (m, 2H), 2.37 (s, 3H), 1.53 (s, 9H), 1.22-1.17 (2H), 0.31 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.1, 146.0, 133.8, 133.7, 130.2, 129.7, 125.6, 79.9, 44.8, 28.3 (3C), 20.8, 13.7, -1.3 (2C); IR (neat) : υ 2974, 2893, 1694, 1364, 1149, 821 cm - 1 ; HRMS (ESI+): theor. 292.1733 (calc. for C 16 H 26 NO 2 Si), meas. 292.1733. tert-butyl 3,3,7-trimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 31a tert-butyl 4,4,7-trimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 31b From the halogenoaryl 21 (305 mg, 0.75 mmol), following the general procedure D, the silylated compound 31a was obtained as a colorless oil (71 mg, 33%). Rf (5% diethyl ether/pentane): 0.28; 1 H NMR (300 MHz, CDCl 3 ) δ = 6.97 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 1.2 Hz, 1H), 6.86 (dd, J = 7.5, 1.2 Hz, 1H), 3.04 (br s, 2H), 2.29 (s, 3H), 1.89 (s, 2H), 1.45 (s, 9H), 0.01 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 155.0, 140.6, 134.7, 130.7, 129.7, 127.7, 126.5, 79.7, 35.2, 28.3 (3C), 20.9, 18.4, -2.7 (2C). IR (neat) : υ 2970, 2920, 1692, 1150, 830 cm -1 ; HRMS (ESI+): theor. 292.1733 (calc. for C 16 H 26 NO 2 Si), meas. 292.1725. From the halogenoaryl 21 (305 mg, 0.75 mmol), following the general procedure D, the silylated compound 31b was obtained as a colorless oil (132 mg, 60%). - S21 -
Rf (5% diethyl ether/pentane): 0.44; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.32 (d, J = 7.2 Hz, 1H), 7.22 (br s, 1H), 6.99 (d, J = 7.2 Hz, 1H), 3.84-3.80 (m, 2H), 2.35 (s, 3H), 1.51 (s, 9H), 1.17-1.13 (m, 2H), 0.27 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.0, 148.5, 138.9, 133.3, 126.8, 126.4, 125.6, 79.9, 44.9, 28.3 (3C), 21.4, 13.7, -1.2 (2C); IR (neat) : υ 2974, 2899, 1694, 1146, 833 cm -1 ; HRMS (ESI+): theor. 292.1733 (calc. for C 16 H 26 NO 2 Si), meas. 292.1738. Allyl 3,3-dimethyl-3,4-dihydrobenzo[e][1,3]azasiline-1(2H)-carboxylate 35a Allyl 4,4-dimethyl-3,4-dihydrobenzo[b][1,4]azasiline-1(2H)-carboxylate 35b Si N Alloc 35a C 14 H 19 NO 2 Si MW = 261.39 g/mol From the halogenoaryl 32 (529 mg, 1.25 mmol), following the general procedure C, the silylated compound 35a was obtained as a colorless oil (89 mg, 34%). Rf (5% diethyl ether/pentane): 0.40; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.24-7.08 (m, 4H), 6.02-5.80 (m, 1H), 5.33-5.07 (m, 2H), 4.62 (d, J = 4.6 Hz, 2H), 3.14 (br s, 2H), 1.96 (s, 2H), 0.11 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 155.6, 140.2, 134.4, 133.0, 130.1, 127.2, 126.4, 125.6, 117.2, 66.3, 35.9, 19.2, -2.7 (2C); IR (neat) : υ 2948, 2880, 1694, 1250, 840, 758 cm -1 ; HRMS (ESI+): theor. 262.1263 (calc. for C 14 H 20 NO 2 Si), meas. 262.1257. From the halogenoaryl 32 (529 mg, 1.25 mmol), following the general procedure C, the silylated compound 35b was obtained as a colorless oil (93 mg, 36%). Rf (5% diethyl ether/pentane): 0.27; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.32-7.12 (m, 3H), 7.08-7.01 (m, 1H), 5.81 (ddt, J = 17.2, 10.5, 5.4 Hz, 1H), 5.15 (d, J = 17.2 Hz, 2H), 5.06 (d, J = 10.5 Hz, 1H), 4.52 (d, J = 5.4 Hz, 1H), 3.79-3.71 (m, 2H), 1.01-1.08 (m, 2H), 0.13 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.8, 148.1, 133.7, 133.0, 130.9, 129.3, 125.8, 125.2, 117.5, 66.3, 45.4, 14.0, -1.1 (2C); IR (neat) : υ 2953, 2894, 1699, 1388, 1264, 833, 768, 456 cm -1 ; HRMS (ESI+): theor. 262.1263 (calc. for C 14 H 20 NO 2 Si), meas. 262.1267. 4,4-dimethyl-1-tosyl-1,2,3,4-tetrahydrobenzo[b][1,4]azasiline 36b - S22 -
From the halogenoaryl 33 (764 mg, 1.55 mmol), following the general procedure C, the silylated compound 36b was obtained as a yellow solid (326 mg, 63%). Rf (10% diethyl ether/pentane): 0.36; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.63 (dd, J = 8.4, 1.5 Hz, 1H), 7.43 (d, J = 6.6 Hz, 2H), 7.38-7.32 (m, 2H), 7.21 (m, 1H), 7.16 (d, J = 6.6 Hz, 2H), 4.04-3.99 (m, 2H), 2.36 (s, 3H), 0.98-0.94 (m, 2H), -0.09 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 146.4, 143.3, 138.4, 134.3, 132.0, 129.8, 129.5, 127.5, 126.9, 126.1, 47.8, 21.5, 12.0, -1.5 (2C); IR (neat) : υ 2931, 1338, 1151, 670 cm -1 ; HRMS (ESI+): theor. 332.1141 (calc. for C 17 H 22 NO 2 SiS), meas. 332.1133; mp : 90 C 3,3-dimethyl-1-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[e][1,3]azasiline 37a 4,4-dimethyl-1-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[b][1,4]azasiline 37b Sulfonamide 42 From the halogenoaryl 34 (520 mg, 1.24 mmol), following the general procedure C, the silylated compound 37a was obtained as a yellow solid (28 mg, 9%). Rf (50% diethyl ether/pentane): 0.62; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.28-7.25 (m, 1H), 7.10-7.06 (m, 3H), 2.98 (s, 3H), 2.97 (s, 2H), 1.98 (s, 2H), 0.06 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 137.8, 134.2, 129.5, 125.9, 125.3, 125.0, 38.4, 35.8, 18.3, -3.9 (2C); IR (neat) : υ 3064, 2949, 1326, 1145, 825 cm -1 ; HRMS (ESI+): theor. 256.0828 (calc. for C 11 H 18 NO 2 SiS), meas. 256.0827; mp : 62 C. Si N Ms 37b C 11 H 17 NO 2 SSi MW = 255.41 g/mol From the halogenoaryl 34 (520 mg, 1.24 mmol), following the general procedure C, the silylated compound 37b was obtained as a yellow solid (61 mg, 19%). Rf (50% diethyl ether/pentane): 0.77; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.53-7.44 (m, 2H), 7.38-7.29 (m, 1H), 7.26-7.19 (m, 1H), 3.98-3.91 (m, 2H), 2.92 (s, 3H), 1.29-1.22 (m, 2H), 0.31 (s, 6H); 13 C NMR (50 MHz, CDCl 3 ) δ = 146.5, 134.7, 131.2, 130.1, 126.1, 125.6, 47.3, 41.0, 13.5, -0.9 (2C); IR (neat) : υ 2948, 2902, 1339, 1148, 776 cm -1 ; HRMS (ESI+): theor. 256.0828 (calc. for C 11 H 18 NO 2 SiS), meas. 256.0829; mp : 55 C. 42 O I N S O Si C 11 H 16 INO 2 SSi MW = 381.31 g/mol - S23 -
From the halogenoaryl 34 (520 mg, 1.2 mmol), following the general procedure C, the sulfonamide 42 was obtained as a colorless oil (75 mg, 16%). Rf (50% diethyl ether/pentane): 0.72; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.80 (dd, J = 7.9, 1.1 Hz, 1H), 7.42 (dd, J = 7.9, 1.4 Hz, 1H), 7.31 (ddd, J = 7.9, 7.6, 1.1 Hz, 1H), 6.94 (ddd, J = 7.9, 7.6, 1.4 Hz, 1H), 3.53-3.41 (m, 2H), 3.38 (A of AB quartet, J = 13.9 Hz, 1H), 2.70 (B of AB quartet, J = 13.9 Hz, 1H), 1.65-1.46 (m, 1H), 1.27-1.13 (m, 1H), 0.39 (s, 3H), 0.13 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ = 145.7, 139.8, 129.8 (2C), 128.2, 101.8, 49.8, 46.0, 11.1, -2.8, -3.8; IR (neat) : υ 2951, 2725, 2489, 1591, 1524, 1091, 811, 795 cm -1 ; HRMS (ESI+): theor. 381.9794 (calc. for C 11 H 17 NO 2 SiSI), meas. 381.9783. 5. Supplementary methods: Details synthetic procedures for the rearrangement study (chloromethyl)(2-iodophenoxy)dimethylsilane 43 A mixture of 2-iodophenol (6.6 g, 30 mmol, 1 equiv.) and chloromethyldimethylchlorosilane (8.59 g, 60 mmol, 2.0 equiv.) was heated neat at 130 C under reflux. After 48h, the reaction mixture was distillated under reduced pressure to afford 43 as a colorless oil (7.6 g, 73%). Rf (pentane): 0.45; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.76 (dd, J = 7.9, 1.6 Hz, 1H), 7.76 (ddd, J = 8.1, 7.6, 1.6 Hz, 1H), 6.87 (dd, J = 8.1, 1.4 Hz, 1H), 6.74 (ddd, J = 7.9, 7.6, 1.4 Hz, 1H), 3.00 (s, 2H), 0.45 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 154.3, 139.4, 129.5, 123.8, 119.3, 90.7, 29.4, -2.7 (2C); IR (neat) : υ 2957, 2899, 1469, 1234, 1017, 841, 745, 646 cm -1 ; HRMS (EI): theor. 325.9391 (calc. for C 9 H 12 ClIOSi), meas. 325.9391. 3,3-dimethyl-2,3-dihydrobenzo[d][1,3]oxasilole 38 To a suspension of sodium (860 mg, 37.4 mmol, 2 equiv.) in toluene (60 ml) was added a solution of starting material 43 (6.11 g, 18.7 mmol, 1 equiv.) in toluene (10 ml) and the reaction mixture was heated under reflux. After 3.5 h, the reaction was cooled down to -40 C and quenched with a saturated aqueous solution of NaHPO 4 and extracted with diethyl ether. The resulting organic phase was washed with brine, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure. The crude mixture was purified by flash chromatography on silica gel (1% diethyl ether/pentane) to give product 38 as a colorless oil (1.91 g, 62%). - S24 -
Rf (1% diethyl ether/pentane): 0.37; 1 H NMR (300 MHz, CDCl 3 ) δ = 7.46 (dd, J = 7.2, 1.5 Hz, 1H), 7.29 (ddd, J = 8.3, 7.0, 1.5 Hz, 1H), 6.91 (ddd, J = 7.2, 8.3, 0.8 Hz, 1H), 6.86 (dd, J = 7.0, 0.8Hz, 1H), 3.91 (s, 2H), 0.41 (s, 6H); 13 C NMR (75 MHz, CDCl 3 ) δ = 168.4, 132.6, 131.7, 120.5, 120.1, 112.7, 62.0, -2.0 (2C); IR (neat) : υ 2957, 2899, 1591, 1442, 1183, 802, 755 cm -1 ; HRMS (EI): theor. 164.0665 (calc. for C 9 H 12 OSi), meas. 164.0657. Procedure for the ring expansion To a solution of 5-membered ring 38 (164 mg, 1.0 mmol, 1.0 equiv.) in anhydrous THF (5 ml) was added iodochloromethane (265 mg, 1.5 mmol, 1.5 equiv.). The reaction mixture was cooled down to - 100 C and MeLi.LiBr (1.5M in hexane, 1.33 ml, 2.0 mmol, 2.0 equiv.) was added dropwise. The medium was allowed to warm up to -78 C and maintained at this temperature for 1h. The reaction mixture was then quenched with a saturated aqueous solution of NH 4 Cl, warmed up to room temperature and extracted with diethyl ether, washed with brine, dried over Na 2 SO 4 and concentrated over reduced pressure. The crude mixture was purified by flash chromatography on silica gel (pentane) to give 6-membered rings 5a and 5b as colorless oils (82 mg, 46%). - S25 -
6. Supplementary figures: Plot of log (b/a) against Hammett constants ( ) Hammett constants are literature data, measured in aqueous solution for para- and meta-substituted benzoic acid. 9 entry R Hammett constant ( ) ratio (b/a) Log (b/a) 1 5-CF 3 0.54 10/90-0.9542425 2 4-CF 3 0.43 11/89-0.9079973 3 4-F 0.34 18/82-0.6585413 4 5-Cl 0.23 17/83-0.6886292 5 4-OMe 0.12 39/61-0.1942652 6 5-F 0.06 43/57-0. 1224064 7 H 0 55/45 0. 0871502 8 4-CH 3-0.07 57/43 0.1224064 9 5-CH 3-0.17 63/37 0.2311388 10 5-OMe -0.27 75/25 0.4771213 11 5-NMe 2-0.83 90/10 0.9542425 log (b/a) 2 1,5 1 0,5 0-0,5-1 -1,5 5-NMe 2 R 2 = 0,940 5-OMe 4-Me H 5-Me 4-OMe 5-F 4-F 5-Cl 5-CF 3 4-CF 3-2 -1,2-0,7-0,2 0,3 0,8 σ 9 Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165-195. - S26 -
7. Supplementary figures: 1 H and 13 C NMR spectra tert-butyl ((chloromethyl)dimethylsilyl)methyl(2-iodophenyl)carbamate 6 I N Si Cl Boc - S27 -
(chloromethyl)((2-iodophenoxy)methyl)dimethylsilane 7 - S28 -
tert-butyl 2-bromo-5-(trifluoromethyl)phenyl(((chloromethyl)dimethylsilyl)methyl)carbamate 12 - S29 -