Supporting Information for:
Catalytic, Asymmetric α-Bromination of Acid Chlorides General. Unless otherwise stated, all reactions were carried out under strictly anhydrous, air-free conditions. All reagents used were commercially available. All solvents were dried and/or distilled by standard methods. Halogenating reagents 4a,1 4b,2 4c,3 and 4d,4 were prepared according to literature procedures. All acid halides were purified by standard procedures, usually distillation. Ultra Pure Silica Gel (particle size: 40-63µm, 230-400 mesh) was used for column chromatography. 1H and 13C NMR spectra were acquired on a Bruker 300 or 400 MHz instrument in CDCl3. The 1H (400 MHz) and 13C (101 MHz) chemical shifts are given in parts per million (δ) with respect to internal TMS standard or residual solvent peaks. Optical rotations were recorded at room temperature. HPLC analysis was performed with either a Chiralcel AD, OD, or Whelk-01 analytical column. Racemates were made by standard reaction conditions with equimolar mixtures of catalyst 3a5 and its “pseudoenantiomer” derived from quinidine (both have essentially the same catalytic activity). General Procedure for Synthesis of Catalysts 3b and 3c. Quinine (5.0 g, 15.4 mmol), N-Boc-L-Proline (3.3 g, 15.4 mmol) and dimethylaminopyridine (0.2 g, 1.5 mmol) were dissolved in 30 mL CH2Cl2 and the solution was cooled to 0 oC. Dicyclohexylcarbodiimide (3.5 g, 17 mmol) dissolved in 10 mL CH2Cl2 was then added and the reaction allowed to warm to room temperature overnight. The reaction mixture was filtered and the filtrate concentrated. The crude residue was purified on a short plug of silica with 99.5% EtOAc/0.5% triethylamine to yield a white solid (foam). The solid was recrystallized from boiling Et2O/hexanes to yield 3b (6.21 g, 94%). N-Boc-L-Proline Quinine (3b). White crystalline solid: mp = 134 oC; [α]25 = -78 (c = 0.01, CHCl3); 1H NMR (CDCl3): δ 8.7 (d, 1H), 8.0 (dd, 1H), 7.5-7.4, (m, 1H), 7.4-7.3 (m, 2H), 6.5 (m, 1H), 5.8 (m, 1H), 5.0 (m, 2H), 4.4-4.3 (m, 1H), 4.0 (d, 3H), 3.5-3.4 (m, 3H), 3.2-3.0 (m 2H), 2.7-2.6 (m, 2H), 2.3-2.1 (m, 2H), 2.0-1.7 (m, 6H), 1.6 (m, 2H), 1.5-1.3 (m, 9H); 13C NMR (CDCl3): δ 172.3, 157.9, 157.8, 147.5, 147.4, 143.0, 141.8, 141.7, 131.8, 127.3, 121.8, 114.6, 101.5, 79.9, 76.8, 59.2, 58.9, 56.6, 56.3, 55.6, 46.5, 39.7, 30.9, 29.7, 28.4, 27.8, 27.7, 23.5; IR (CHCl3): 1693, 1748 cm-1. Anal Calcd for C30H39N3O5; C, 69.07; H, 7.54; N, 8.06; O, 15.34. Found C, 69.23; H, 7.57; N, 7.97; O, 15.23. N-Boc-D-Proline Quinine (3c). Prepared by substituting N-Boc-D-Proline in the general preparation method above. White crystalline solid: mp = 116 oC; [α]25 = + 17 (c = 0.01, CHCl3); All other data are consistent with (3b).
1
Hedayatullah, M.; Lion, C.; Tourki. A. Bull. Soc. Chim. Belg. 1993, 102, 281-291. Denivelle, L. Bull. Soc. Chim. Fr. 1956, 1834-1836. 3 Ramirez, F.; Tasaka, K.; Desai, N. B.; Smith, C. P. J. Org. Chem. 1968, 33, 25-28. 4 Denivelle L. Bull Soc. Chim Fr. 1957, 724-728. 5 Pracejus, H; Maetje, H.; J. Prakt Chem. 1964, 24 195 2
S-1
Preparation of Brominating Agent (4a) 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one. A 9:1 glacial acetic acid/distilled water solution (635 mL) was added to 2,4,6tribromophenol (10.0 g, 30 mmol). The solution was heated to dissolve the 2,4,6tribromophenol, then cooled to 0 oC. Bromine (5.3 g, 33 mmol) was added in five portions over 10 minutes. The reaction was stirred at 0 oC for 30 minutes. Ice was added to the reaction causing the formation of a light yellow precipitate, which was collected on a coarse glass frit and washed with distilled water. The solid was dissolved in CH2Cl2, dried with MgSO4, filtered and concentrated. Additional drying was performed using five freeze/thaw cycles, with liquid nitrogen under high vacuum, yielding 4a as a light yellow, crystalline solid (11.0 g, 90% yield). Preparation of Brominating Agent (4b) 1,1,3,6-tetrabromonaphthalen-2-(1H)-one. Sodium acetate (15 g, 182.9 mmol) and 2-naphthol (3.8 g, 26.4 mmol) were dissolved in glacial acetic acid (112 mL) with heating. The solution was then cooled to 0 oC and bromine (33.4 g, 209.0 mmol) was added in five portions over 10 mins. The reaction was stirred for 2h at room temperature. Ice was added to the reaction causing the formation of a light yellow precipitate, which was collected on a coarse glass frit and washed with cold water, followed by petroleum ether and left to air dry. The crude solid was recrystallized from toluene and dried using five freeze/thaw cycles with liquid nitrogen under high vacuum, yielding 4b as a bright yellow solid (4.2 g, 35% yield). mp = 168 oC. 1H NMR (CDCl3): δ 8.0 (d, 1H), 7.8 (s, 1H), 7.7 (dd, 1H), 7.4 (d, 1H); 13C NMR (CDCl3): δ 144.7, 134.3, 133.2, 131.8, 131.2, 130.7, 129.3, 128.0, 127.8; IR (CH2Cl2): 1701 cm-1. Anal Calcd for C10H4Br4O; C, 26.12; H, 0.88; O, 3.48; Br, 69.52. Found C, 26.27; H, 0.87; O, 3.08; Br, 69.79. General Preparation of Brominating Agent (4d) 5,7,7-tribromoquinolin-8-(7H)-one. A 9:1 glacial acetic acid/distilled water solution (300 mL) was added to 8hydroxyquinoline (5.0 g, 30 mmol). The solution was heated to dissolve the 8hydroxyquinoline, then cooled to 0 oC. Bromine (15.8 g, 99 mmol) was added in five portions over 10 minutes. The reaction was stirred at 0 oC for 30 minutes. Ice was then added, causing the formation of a light brown precipitate, which was collected on a coarse glass frit and washed with distilled water followed by CH2Cl2. The solid was then dried using five freeze/thaw cycles with liquid nitrogen under high vacuum, yielding 4d as a light brown crystalline solid (6.1 g, 47% yield). General Procedure for the Synthesis of β-Aryl-α-Bromoesters. To a stirred suspension of catalyst 3b (0.044 mmol), 15-crown-5 (0.044 mmol) and sodium hydride (0.522 mmol) in 3 mL THF at –78 ˚C, a solution of phenylacetyl chloride 1a (0.609 mmol) in 1 mL THF was added dropwise. Next, a solution of 4b (0.435 mmol) in 3 mL THF was added dropwise over 5 min. The resulting solution was allowed to stir for 5 h at –78oC. The reaction mixture was then quenched with methanolic HCl (4 drops of HCl in 3ml methanol) and extracted three times with Et2O. The organic layers were combined, dried, and purified by column chromatography (100% hexanes) to yield 6a in 55% yield.
S-2
General Procedure for the Synthesis of β-Alkyl-α-Bromoesters. To a stirred solution of catalyst 3b (0.044 mmol), and Hünig’s base (0.435 mmol) in 3 mL THF at –78 ˚C, a solution of dihydrocinnamoyl chloride 1e (0.522 mmol) in 1 mL THF was added dropwise. Next, a solution of 4b (0.435 mmol) in 3 mL THF was added dropwise over 5 minutes. The resulting solution was allowed to stir for 5 h at –78 oC. The reaction mixture was then quenched with methanolic HCl (4 drops of HCl in 3ml methanol) and extracted three times with Et2O. The organic layers were combined, dried and purified by column chromatography (100% hexanes) to yield 6e in 48% yield. (S)-2-Bromo-2-phenylacetic acid 1,3,6-tribromo-2-naphthyl ester (6a). White crystalline solid (analytical sample was recrystallized from hexanes): mp= 114 ˚C; [α]25 = + 45 (c = 0.01, CHCl3) HPLC: AD (99.5% hexanes/0.5% i-PrOH, 1.0 mL/min) (S) = 38.1, (R) = 48.0 min. 1H NMR (CDCl3): δ 8.0-7.9 (m, 3H), 7.7-7.6 (m, 3H), 7.4 (m, 3H), 5.7 (s, 1H); 13C NMR (CDCl3): δ 164.8, 143.5, 134.6, 133.7, 133.6, 131.6, 130.8, 130.3, 129.8, 129.7, 129.2, 129.2, 129.0, 128.9, 122.0, 116.5, 45.8; IR (CH2Cl2): 1775 cm-1. Anal Calcd for C18H10Br4O2; C, 37.41; H, 1.74; Br, 55.31; O, 5.54. Found C, 37.38; H, 1.79; Br, 55.28; O, 5.55. Proof of absolute configuration was obtained for the ethyl ester of (S)-2-Chloro-2-phenyl acetic acid ethyl ester.6 (R)-2-Bromo-2-phenylacetic acid 1,3,6-tribromo-2-napthyl ester (6a). [α]25 = - 46 (c= 0.01, CHCl3). All other data are consistent with (S)-6a. (S)-2-Bromo-2-(m-methoxyphenyl)acetic acid 1,3,6-tribromo-2-napthyl ester (6b). White crystalline solid (analytical sample was recrystallized from hexanes): mp = 78 oC; [α]25 = + 38 (c = 0.01, CHCl3); HPLC AD (99% hexanes/1% i-PrOH, 1.0 mL/min) (S) = 56.5, (R) = 61.3 min. 1H NMR (CDCl3): δ 7.9 (m, 2H), 7.8 (s, 1H), 7.6 (d, 1H), 7.3 (m, 3H), 6.9 (m, 1H), 5.7 (s, 1H), 3.8 (s, 3H); 13C NMR (CDCl3): δ 164.7, 159.9, 143.5, 135.9, 133.7, 131.6, 130.8, 130.3, 129.9, 129.2, 129.0, 122.0, 121.5, 117.2, 116.2, 115.7, 114.5, 55.5, 45.7; IR (CH2Cl2): 1775 cm-1. Anal Calcd for C19H12Br4O3; C, 37.54; H, 1.99; Br, 52.58; O, 7.90. Found C, 37.59; H, 2.02; Br, 52.50; O, 8.19. (S)-2-Bromo-2-(1-napthyl)acetic acid 1,3,6-tribromo-2-napthyl ester (6c). White crystalline solid (analytical sample was recrystallized from hexanes): mp = 142 oC; [α]25 = - 1.1 (c = 0.01, CHCl3); HPLC: AD (95 % hexanes/5 % i-PrOH, 1.0 mL/min) (S) = 30.1, (R) = 25.9 min. 1H NMR (CDCl3): δ 8.3 (d, 1H), 8.0 (d, 1H), 7.9 (m, 5H), 7.6 (m, 4H), 6.6 (s, 1H); 13C NMR (CDCl3): δ 164.9, 143.6, 134.0, 133.6, 131.6, 130.8, 130.7, 130.6, 130.2, 130.1, 129.2, 129.1, 128.9, 128.5, 127.1, 126.4, 125.5, 123.4, 122.0, 116.1, 43.9; IR (CH2Cl2): 1779, cm-1. Anal Calcd for C22H12Br4O2; C, 42.08; H, 1.93; Br, 50.90; O, 5.10. Found C, 42.02; H,1.98; Br, 50.87; O, 5.13. (S)-2-Bromohexanoic acid 1,3,6-tribromo-2-napthyl ester (6d). White crystalline solid (analytical sample was recrystallized from hexanes): mp = 55 oC; [α]25 = - 3.7 (c = 0.01, CHCl3); HPLC: Whelk (99.9% hexanes/0.1% i-PrOH, 1.0 mL/min) (S) = 11.32, (R) 6
Puy, C. H.; Breitbeil, F. W.; DeBruin, K. R. J. Am. Chem. Soc. 1966, 88, 3347-3354.
S-3
= 12.21 min. 1H NMR (CDCl3): δ 8.0 (m, 1H), 7.9 (s, 1H), 7.8 (d, 1H), 7.6 (m, 1H), 4.6 (dd, 1H), 2.3 (m, 1H), 2.2 (m, 1H), 1.5 (m, 4H), 1.0 (t, 3H) 13C NMR (CDCl3): δ 166.4, 143.5, 133.7, 131.6 131.4, 130.8, 130.6, 130.4, 129.2, 129.1, 122.0, 44.7, 34.7, 29.4, 22.0, 13.9; IR (CH2Cl2): 1773 cm-1. Anal Calcd for C16H14Br4O2; C, 34.45; H, 2.53; Br, 57.29; O, 5.74. Found C, 34.47; H, 2.49; Br, 57.32; O, 5.72. (S)-2-Bromo-3-phenylpropionic acid 1,3,6-tribromo-2-napthyl ester (6e). White crystalline solid (analytical sample was recrystallized from hexanes): mp = 130 oC; [α]25 = - 0.56 (c = 0.01, CHCl3); HPLC: AD (99.5% hexanes/0.5% i-PrOH, 1.0 mL/min) (S) = 38.2, (R) = 25.7 min. 1H NMR (CDCl3): δ 8.0 (m, 2H), 7.9 (m, 1H), 7.6 (d, 1H), 7.3 (m, 5H), 4.8 (dd, 1H), 3.7 (dd, 1H), 3.4 (dd, 1H); 13C NMR (CDCl3): δ 166.0, 143.5, 136.3, 133.8, 132.0, 131.6, 130.7, 130.3, 129.7, 129.1, 128.8, 127.5, 122.0, 117.2, 116.2, 43.7, 41.1; IR (CH2Cl2): 1776 cm-1. Anal Calcd for C19H12Br4O2; C, 38.55; H, 2.04; Br, 54.00; O, 5.41. Found C, 38.51; H, 2.09; Br, 54.02; O, 5.38. (S)-2-Bromo-3-phenoxypropionic acid 1,3,6-tribromo-2-napthyl ester (6f). White crystalline solid (analytical sample was recrystallized from hexanes): mp = 88 oC; [α]25 = - 5 (c = 0.01, CHCl3); HPLC: OD (95% hexanes/5% i-PrOH, 1.0 mL/min) (S) = 16.5, (R) = 9.0 min. 1H NMR (CDCl3): δ 8.0 (m, 2H), 7.9 (s, 1H), 7.6 (d, 1H), 7.3 (t, 2H) 7.0 (m, 3H), 4.9 (dd, 1H), 4.7 (dd, 1H), 4.5 (dd, 1H); 13C NMR (CDCl3): δ 164.6, 157.7, 143.4, 133.7, 131.7, 130.9, 130.3, 129.8, 129.2, 129.1, 122.1, 121.9, 117.2, 116.1, 114.9, 68.6, 40.2; IR (CH2Cl2): 1775 cm-1. Anal Calcd for C19H12Br4O3; C, 37.54; H, 1.99; Br, 52.58; O, 7.90. Found C, 37.53; H, 2.02; Br, 52.59; O, 7.86.
S-4
Representative NMR For Arylacetyl Products:
S-5
Representative NMR For Aliphatic Products:
S-6
