Iridium-catalyzed asymmetric ring-opening reactions of oxabicyclic alkenes with secondary amine nucleophiles
Dingqiao Yang,* Ping Hu, Yuhua Long, Yujuan Wu, Heping Zeng, Hui Wang, and Xiongjun Zuo
School of Chemistry and Environment, South China Normal University, Guangzhou 510006, China
*Corresponding author e-mail:
Supporting Information
Table of Contents Page
Experimental procedures and characterization data S2
Crystal structure and data of 3f S26
Copies of 1H and 13C NMR spectra of 2a-l, 3a-j and 4a-d S39
Experimental procedures and characterization data
General：All flasks were flame-dried under a stream of nitrogen and cooled before use. Solvents and solutions were transferred with syringes and cannulae using standard inert atmosphere techniques. NMR spectra were recorded at 400 MHz using a Varian INOVA NMR spectrometer with CDCl3 as reference standard (d 7.27 ppm) for 1H NMR and (d 77.23 ppm) for 13C NMR. Spectral features are tabulated in the following order: Chemical shift (d, ppm); number of protons; multiplicity (s-singlet, d-doublet, t-triplet, m-complex multiplet and br-broad); coupling constants (J, Hz). IR spectra were obtained using a Nicolet DX FT-IR spectrometer as a KBr pellet or using a Perkin-Elmer Spectrum 1000 FT-IR spectrometer as a neat film on a NaCl plate. MS spectra were recorded on a Bruker esquire 6000 mass spectrometer (ESI). Optical rotations were measured on a Perkin-Elmer Model 243 Polarimeter using the sodium D line with spectra-grade CHCl3 in a 1 dm cell. Melting points were taken on an XT4 binocular micro melting point apparatus. HPLC analysis was performed on an Agilent 1100 Series HPLC with a Chiralcel AD column. Elemental analysis was conducted on a Thermo. Flash EA.TM.1112. Crystal structure determination was carried out on a Bruker SMART-1000 X-ray diffraction apparatus.
Materials: DME was distilled from sodium benzophenone ketyl and stored. THP, THF, dioxane, and toluene were distilled from sodium benzophenone ketyl immediately prior to use. CH3CN was distilled from calcium hydride. DMF was dried over MgSO4 and stored over activated molecular sieves.
Preparation of di-m-chlorobis(1,5-cyclooctadiene)diiridium (I)
To a 150.0 mL 3-neck flask was added IrCl3·3H2O (1.0 g, 3.0 mmol) followed by addition of 95% of ethanol (17.0 mL), water (8.5 mL) and 1,5-cyclooctadiene (3.0 mL, 24.5 mmol) under nitrogen atmosphere. The resulting mixture was stirred under reflux for 24 h and formed a brick red precipitate. It was allowed to cool to room temperature and filtered. The precipitate was rinsed with cold methanol to remove the trace amount of 1,5-cyclooctadiene unreacted. Then the product was dried in vacuum for 8 h. And [Ir(COD)Cl]2 was obtained in 67% yield as a brick red solid. mp 200–202 °C.
Preparation of 1,4-dihydro-1,4-epoxynaphthalene (1a)
To a 100 mL round bottom flask with straight condenser tube 10 mL furan and 10 mL DME were added. Taking two 25 mL dropping bottles, one with 4 mL isoamyl nitrite and 10 mL DME (A), the other with 2.75 g (20.06 mmol) 2-aminobenzoic acid dissolved by 10 mL DME (B). Then 1 mL A and 1 mL B were added to the refluxing furan solution per 4 min. Firstly the A was added, then the B. The solution became red brown, giving off gas when the reagents were added. Let the mixture refluxing till the solution did not release gas after all the reactants were added (about 15 min). After completion 25 mL 2% sodium hydroxide was added to the mixture and transferred to separating funnel to rinse, which we can get the organic phase and the aqueous solution extracted three times by 15 mL petroleum ether (bp 30–60 °C). Then the extractive solution and the organic phase were mixed together. The mixture was washed by water (15 mL × 4) and dried by anhydrous magnesium sulfate. After completion the reaction mixture was concentrated in vacuo and the solvents were removed, the crude mixture was purified by flash chromatography gave 1a a yellow solid (1.72 g, 60%). Rf = 0.45 on silica gel (25% ethyl acetate in petroleum ether). mp 55–56 °C. IR (thin film, cm–1): 3125(s), 3040(s), 3020(s), 1958(s), 1916(s), 1814(s), 1620(s), 1562(s), 1449(s), 1345(s), 1278(s), 1195(s), 1164(s), 1128(s), 1073(s), 986(s), 938(s), 844(s), 765(s), 689(s), 635(s). MS (ESI) m/z Calcd for C10H8O (M+): 144.06; Found: 145.06.
Preparation of 1,4-dihydro-5,8-dimethoxy-1,4-epoxynaphthalene (1b)
A stirred solution of 2-chloro-1,4-dimethoxy-benzene (1.208 g, 7.0 mmol) in anhydrous THF (12.5 mL), furan (15 mL) was cooled to -78 °C under N2 and was treated dropwise with n-butyllithium (1.29 mol/L) in hexane (5.3 mL). The solution was stirred at -78 °C for 1 h and added 20 mL distilled water to warm up to room temperature. The reaction mixture was extracted from diethyl ether and dried over Na2SO4. The ether was then removed in vacuo, the crude mixture was purified by flash chromatography (15% ethyl acetate in petroleum ether) gave 1b a white solid (0.89 g, 63%). Rf = 0.21 on silica gel (15% ethyl acetate in petroleum ether); mp 147–149 °C. MS (ESI) m/z Calcd for C12H12O3 (M+): 204.22; Found: 205.20. IR (thin film, cm–1): 2960(m), 2934(m), 1736(m), 1598(m), 1467(s), 1326(s), 1287(s), 1063(s). 1H NMR (400 MHz, CDCl3): d 7.01 (2H, s), 6.94 (2H, s), 5.64 (2H, s), 3.81 (6H, s). 13C NMR (100 MHz, CDCl3): d 145.8, 143.3, 141.7, 106.8, 82.6, 56.5.
Preparation of 1,4-dihydro-6,7-dimethoxy-1,4-epoxynaphthalene (1c)
A solution of LDA was freshly prepared by addition of 7.4 mL (1.1 equiv) in anhydrous THF (15 mL) at -78 °C, followed by a brief warm-up to room temperature. Furan (15 mL) was slowly added at -78 °C and the resulting colorless solution was treated dropwise with a solution of 1-bromo-2,5-dimethoxy-benzene (2.16 g, 10 mmol) in anhydrous THF (5 mL). The yellow solution was kept at -78 °C for 30 min, then quenched with water and left to warm up. Standard extractive work-up with diethyl ether and brine yielded the crude product which was purified by flash chromatography (50% ethyl acetate in hexanes) to give 1c a white solid (2.10 g, 86%). Rf = 0.17 on silica gel (50% ethyl acetate in hexanes). mp 86–87 °C (Et2O). IR (KBr, cm–1): 3085(s), 2989(s), 2839(s), 1619(m), 1438(s), 1253(s), 1139(s), 1075(s), 997(s). 1H NMR (400 MHz, CDCl3): d 7.06 (2H, s), 6.97 (2H, s), 6.54 (2H, s), 5.92 (2H, s), 3.78 (6H, s). 13C NMR (100 MHz, CDCl3): d 148.1, 143.1, 111.9, 80.6, 56.6.
General Procedure (I) for the asymmetric ring-opening reactions of oxabenzonorbornadiene 1a with substituted N-alkylaniline: A 5.0 mL round bottom flask fitted with a reflux condenser was flame-dried under a stream of nitrogen and cooled to room temperature. [Ir(COD)Cl]2 (5.8 mg, 2.5 mol %) and (S)-p-Tol-BINAP (10.7 mg, 5 mol %) were simultaneously added and followed by addition of anhydrous tetrahydrofuran (2.0 mL). After they were stirred for about 10 min, oxabenzonorbornadiene 1a (50.0 mg, 0.347 mmol) was added and the resulting mixture was heated to reflux. On the first sign of reflux, nucleophile (3.0 equiv to 1a) was added. Then the temperature was continuously increased to 80 °C until the reaction was completed as judged by thin layer chromatography. The reaction mixture was then concentrated in vacuo and purified by column chromatography (silica gel: 200–300 mesh) to give the target product.
General Procedure (II) for the asymmetric ring-opening reactions of Oxabenzonorbornadiene 1a with aliphatic secondary amines: A 5.0 mL round bottom flask fitted with a reflux condenser was flame-dried under a stream of nitrogen and cooled to room temperature. [Ir(COD)Cl]2 (5.8 mg, 2.5 mol %) and (S)-p-Tol-BINAP (10.7 mg, 5 mol %) were simultaneously added and followed by addition of anhydrous tetrahydrofuran (2.0 mL). After they were stirred for about 5 min, NH4I (50 mg, 1 equiv to 1a) was added. After they were stirred for about 10 min, oxabenzonorbornadiene 1a (50.0 mg, 0.347 mmol) was added and the resulting mixture was heated to reflux. On the first sign of reflux, aliphatic secondary amine (3 equiv to 1a) was added. The temperature was then continuously increased to 80 °C until the reaction was completed as judged by thin layer chromatography. The reaction mixture was then concentrated in vacuo and purified by column chromatography (silica gel: 200–300 mesh) to give the target product.
General Procedure (III) for the asymmetric ring-opening reactions of substituted oxabenzonorbornadiene 1b with substituted N-alkylaniline: A 5.0 mL round bottom flask fitted with a reflux condenser was flame-dried under a stream of nitrogen and cooled to room temperature. [Ir(COD)Cl]2 (5.8 mg, 2.5 mol %) and (S)-p-Tol-BINAP (10.7 mg, 5 mol %) were simultaneously added and followed by addition of anhydrous tetrahydrofuran (2.0 mL). After they were stirred for about 5 min, NH4I (50 mg, 1 equiv to 1a) was added. After they were stirred for about 10 min, substituted oxabenzonorbornadiene 1b (71.0 mg, 0.347 mmol) was added and the resulting mixture was heated to reflux. On the first sign of reflux, substituted N-alkylaniline (3 equiv to 1b) was added. Then the temperature was continuously increased to 100 °C until the reaction was completed as judged by thin layer chromatography. The reaction mixture was then concentrated in vacuo and purified by column chromatography (silica gel: 200–300 mesh) to give the target product.
General Procedure (IV) for the asymmetric ring-opening reactions of substituted oxabenzonorbornadiene 1b with aliphatic secondary amines: A 5.0 mL round bottom flask fitted with a reflux condenser was flame-dried under a stream of nitrogen and cooled to room temperature. [Ir(COD)Cl]2 (5.8 mg, 2.5 mol %) and (S)-p-Tol-BINAP (10.7 mg, 5 mol %) were simultaneously added and followed by addition of anhydrous tetrahydrofuran (2.0 mL). After they were stirred for about 5 min, NH4I (50.0 mg, 1 equiv to 1b) was added. After they were stirred for about 10 min, substituted oxabenzonorbornadiene 1b (71.0 mg, 0.347 mmol) was added and the resulting mixture was heated to reflux. On the first sign of reflux, substituted aliphatic secondary amine (3 equiv to 1b) was added. Then the temperature was continuously increased to 100 °C until the reaction was completed as judged by thin layer chromatography. The reaction mixture was then concentrated in vacuo and purified by column chromatography (silica gel: 200–300 mesh) to give the target product.
(1S,2S)-2-[Methyl(phenyl)amino]-1,2-dihydronaphthalen-1-ol (2a)
Following the general procedure (I), 2a was obtained as colorless oil (76.0 mg, 87%). Rf = 0.17 on silica gel (ethyl acetate:petroleum ether = 1:20, v/v). The ee was determined to be 52% using HPLC analysis on a Chiralcel AD column (hexane/2-propanol = 95/5, 0.5 mL/min, λ = 254 nm); Retention times were 32.9 min (major) and 36.5 min (minor). [α]D20 +110.8 (c 1.00, CHCl3). IR (KBr, cm–1): 3514(s), 2980(s), 2869(s), 1645(w), 1599(w), 1500(s), 1381(s), 1297(m), 1136(s), 934(m), 845(m), 794(m). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 4.8 Hz, 1H), 7.28–7.23 (m, 4H), 7.13–7.10 (m, 1H), 6.96 (d, J = 8.4 Hz, 2H), 6.80 (t, J = 7.2 Hz, 1H), 6.58 (d, J = 10.0 Hz, 1H), 5.94–5.90 (m, 1H), 5.10 (d, J = 9.6 Hz, 1H), 4.73 (dd, J = 2.4, 2.4 Hz, 1H), 2.84 (d, J = 2.4 Hz, 3H), 2.38 (br s, 1H). 13C NMR (100 MHz, CDCl3): δ 150.2, 136.5, 131.9, 129.7, 129.2, 128.1, 127.9, 127.7, 126.4, 125.6, 118.1, 114.7, 70.0, 63.5, 33.4. MS (ESI) m/z Calcd for C17H17NO (M+): 251.13; Found: 251.83. Anal. Calcd for C17H17NO: C, 81.24; H, 6.82; N, 5.57. Found: C, 81.52; H, 6.92; N, 5.73.
(1S,2S)-2-[Ethyl(phenyl)amino]-1,2-dihydronaphthalen-1-ol (2b)
Following the general procedure (I), 2b was obtained as colorless oil (69.0 mg, 75%). Rf = 0.15 on silica gel (ethyl acetate:petroleum ether = 1:20, v/v). The ee was determined to be 56% using HPLC analysis on a Chiralcel AD column (hexane/2-propanol = 95/5, 0.5 mL/min, λ = 254 nm); Retention times were 27.0 min (major) and 28.6 min (minor). [α]D20 +113.2 (c 1.00, CHCl3). IR (KBr, cm–1): 3434(m), 3057(w), 3031(w), 2928(s), 2843(m), 1645(w), 1597(s), 1504(s), 1375(m), 1255(m), 989(m). 1H NMR (400 MHz, CDCl3): δ 7.5 (br s, 1H), 7.26–7.21 (m, 4H), 7.12–7.05 (m, 1H), 7.00 (dd, J = 4.8, 2.8 Hz, 2H), 6.77 (br s, 1H), 6.58 (d, J = 8.4 Hz, 1H), 5.95–5.92 (m, 1H), 5.1 (s, 1H), 4.6 (s, 1H), 3.35 (s, 2H), 2.33 (br s, 1H), 1.50 (s, 3H). 13C NMR (100 MHz, CDCl3): d 148.3, 136.4, 132.0, 129.5, 129.3, 128.7, 128.1, 126.6, 126.0, 117.7, 114.8, 112.8, 70.3, 63.3, 41.6, 14.5. MS (ESI) m/z Calcd for C18H19NO (M+): 265.15; Found: 266.02 (M+H)+. Anal. Calcd for C18H19NO: C, 81.47; H, 7.22; N, 5.28. Found: C, 81.71; H, 7.43; N, 5.41.
(1S,2S)-2-[Allyl(phenyl)amino]-1,2-dihydronaphthalen-1-ol (2c)
Following the general procedure (I), 2c was obtained as colorless oil (46.0 mg, 48%). Rf = 0.18 on silica gel (ethyl acetate:petroleum ether = 1:20, v/v). The ee was determined to be 74% using HPLC analysis on a Chiralcel AD column (hexane/2-propanol = 95/5, 0.5 mL/min, λ = 254 nm); Retention times were 29.7 min (major) and 31.4 min (minor). [α]D20 +153.4 (c 1.00, CHCl3). IR (KBr, cm–1): 3418(s), 3055(w), 3048(w), 2928(w), 2851(s), 2353(w), 1642(m), 1600(s), 1481(s), 1161(w), 974(w), 923(w). 1H NMR (400 MHz, CDCl3): δ 7.52 (d, J = 3.6 Hz, 1H), 7.30–7.22 (m, 4H), 7.14 (t, J = 4.0 Hz, 1H), 6.95–6.93 (m, 2H), 6.80–6.76 (m, 1H), 6.63 (br d, J = 9.6 Hz, 1H), 5.97–5.93 (m, 2H), 5.25–5.09 (m, 3H), 4.77 (br s, 1H), 3.91 (d, J = 11.0 Hz, 2H), 2.31 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 148.7, 136.3, 136.0, 131.9, 129.9, 129.2, 128.2, 128.1, 126.6, 126.1, 119.3, 117.7, 116.0, 114.4, 70.3, 62.3, 50.1. MS (ESI) m/z Calcd for C19H19NO (M+): 277.15; Found: 277.97. Anal. Calcd for C19H19NO: C, 82.28; H, 6.90; N, 5.05. Found: C, 82.41; H, 7.11; N, 4.86.
(1S,2S)-2-[(3-Chlorophenyl)(methyl)amino]-1,2-dihydronaphthalen-1-ol (2d)
Following the general procedure (I), 2d was obtained as colorless oil (56.0 mg, 56%). Rf = 0.12 on silica gel (ethyl acetate:petroleum ether = 1:20, v/v). The ee was determined to be 72% using HPLC analysis on a Chiralcel AD column (hexane/2-propanol = 95/5, 0.5 mL/min, λ = 254 nm); Retention times were 38.6 min (major) and 45.3 min (minor). [α]D20 +151.8 (c 1.00, CHCl3). IR (KBr, cm–1): 3426(m), 2935(m), 2919(m), 1600(w), 1597(s), 1495(s), 1358(w), 1100(m), 972(m). 1H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 3.6 Hz, 1H), 7.32–7.26 (m, 2H), 7.17–7.12 (m, 2H), 6.92–6.74 (m, 3H), 6.62 (dd, J = 2.4, 2.4 Hz, 1H), 5.89 (dd, J = 3.2, 2.8 Hz, 1H), 5.07 (d, J = 9.2 Hz, 1H), 4.75–4.69 (m, 1H), 2.83 (s, 3H), 1.26 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 151.3, 136.3, 135.2, 131.8, 130.1, 130.0, 128.3, 128.1, 127.2, 126.6, 125.8, 117.7, 114.2, 112.4, 70.2, 63.2, 33.4. MS (ESI) m/z Calcd for C17H16ClNO (M+): 285.09; Found: 285.91. Anal. Calcd for C17H16ClNO: C, 71.45; H, 5.64; N, 4.90. Found: C, 71.52; H, 5.48; N, 4.73.