Toward a Visible Light Mediated Photocyclization: Cu- Based Sensitizers for the Synthesis of [5]Helicene

Transcription

1 Toward a Visible Light Mediated Photocyclization: Cu- Based Sensitizers for the Synthesis of [5]Helicene Augusto C. Hernandez-Perez, Anna Vlassova and Shawn K. Collins* Département de chimie, Université de Montréal, P.O. Box 6128, Station Downtown, Montréal, Québec, Canada H3C 3J7. shawn.collins@umontreal.ca SUPPORTING INFORMATION TABLE OF CONTENTS: GENERAL ADDITIONAL DATA SYNTHETIC PROCEDURES SPECTRAL DATA S2 S3 S3 S8 S1

2 General: All reactions that were carried out under anhydrous conditions were performed under an inert argon or nitrogen atmosphere in glassware that had previously been dried overnight at 120 o C or had been flame dried and cooled under a stream of argon or nitrogen. 1 All chemical products were obtained from Sigma-Aldrich Chemical Company or Strem Chemicals and were reagent quality. The stilbene precursor 1 was prepared according to published procedures. 2 The pyrimidine derivative 12 3 and the bis-imidazole derivative 11 4 were prepared accordingly to reported procedures. Copper catalyst 7 was prepared according to the procedure of McMillin and co-weorkers. 5 Technical solvents were obtained from VWR International Co. Anhydrous solvents (CH 2 Cl 2, Et 2 O, THF, DMF, Toluene, and n-hexane) were dried and deoxygenated using a GlassContour system (Irvine, CA). Isolated yields reflect the mass obtained following flash column silica gel chromatography. Organic compounds were purified using the method reported by W. C. Still 6 and using silica gel obtained from Silicycle Chemical division (40-63 nm; mesh). Analytical thin-layer chromatography (TLC) was performed on glass-backed silica gel 60 coated with a fluorescence indicator (Silicycle Chemical division, 0.25 mm, F 254.). Visualization of TLC plate was performed by UV (254 nm), KMnO 4 or p- anisaldehyde stains. All mixed solvent eluents are reported as v/v solutions. Concentration refers to removal of volatiles at low pressure on a rotary evaporator. All reported compounds were homogeneous by thin layer chromatography (TLC) and by 1 H NMR. NMR spectra were taken in deuterated CDCl 3 using Bruker AV-300 and AV-400 instruments unless otherwise noted. Signals due to the solvent served as the internal standard (CHCl 3 : δ 7.27 for 1 H, δ 77.0 for 13 C). The acquisition parameters are shown on all spectra. The 1 H NMR chemical shifts and coupling constants were determined assuming first-order behavior. Multiplicity is indicated by one or more of the following: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), br (broad); the list of couplings constants (J) corresponds to the order of the multiplicity assignment. High resolution mass spectroscopy (HRMS) was done by the Centre régional de spectrométrie de masse at the Département de Chimie, Université de Montréal from an Agilent LC-MSD TOF system using ESI mode of ionization unless otherwise noted. 1 Shriver, D. F.; Drezdon, M. A. in The Manipulation of Air-Sensitive Compounds; Wiley-VCH: New York, Maya, A. B. S.; Perez-Melero, C.; Mateo, C.; Alonso, D.; Fernandez, J. L.; Gajate, C.; Mollinedo, F.; Pelaez, R.; Caballero, M. J. Med. Chem. 2005, 48, Laferty, J. J.; Case, F. H. J. Org. Chem. 1967, 32, Xiao, J.-C.; Twamley, B.; Shreeve, J. M. Org. Lett. 2004, 21, Kuang, S.-M.; Cuttell, D. G.; McMillin, D. R.; Fanwick, P. E.; Walton, R. A. Inorg. Chem. 2002, 41, Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, S2

3 Additional Data: Full Table 1. Optimization of the Visible Light Mediated Synthesis of [5]Helicene. photocatalyst (10 mol %) visible light oxidant (equiv) solvent O 1 time 9 2 entry photocatalyst (d) (%) a oxidant (eq.); solvent; time yield 1 5 I 2 (1), 9 (50); THF; 3 < I 2 (1), 9 (50); THF; 3 < I 2 (1), 9 (50); THF; I 2 (1), 9 (50); THF; I 2 (1), 9 (50); THF; I 2 (1), 9 (50); THF; 5 0 b 7 7 I 2 (1), 9 (50); H; I 2 (1), 9 (50); hexanes; 3 <5 9 7 I 2 (1), 9 (50); DMF; I 2 (1), 9 (50); CH 2 Cl 2 ; I 2 (1), 9 (50); dioxane; I 2 (1), 9 (50); PhH; I 2 (0.1), O 2 (1 atm); THF; DDQ (2); THF; t-buooh (4), ; THF; 3 29 a Isolated yields following flash chromatography. b Reaction performed in the absence of light. Synthetic Procedures: General Procedure for Visible Light Mediated Cyclization of 1: In a round bottom flask was added the stilbene precursor 1 (44.5 mg, 0.16 mmol), and [Cu(DPEPhos)(neo)]BF 4 (17.9 mg, 0.02 mmol) and dissolved in THF (32 ml). Upon dissolution, iodine (40.2 mg, 0.16 mmol) and propylene oxide (0.56 ml, 7.94 mmol) were added to the solution. The reaction was stirred next to a compact fluorescent lamp (energy saving light bulb, 30W) for 5 days. The reaction was quenched with Na 2 S 2 O 3(sat.) (30 ml). The organic layer was diluted with ethyl acetate and was washed with Na 2 S 2 O 3(sat.) until the complete consumption of iodine, and then washed with brine. The organic phase was dried over anhydrous Na 2 SO 4, filtered and concentrated. The crude product is purified by flash chromatography (2% to 8% PhMe/hexanes) to give the product (20.8 mg, 47%) as a white solid. S3

4 General Procedure for Visible Light Mediated Cyclization using In-situ Generated Catalyst: In a round bottom flask was added [Cu(NCCH 3 ) 4 ]BF 4 7 (9.3 mg, 0.04 mmol) and Xantphos (21.4 mg, 0.04 mmol) and dissolved in THF (7.4 ml). The solution was allowed to stir at room temperature for 1h and a solution of neocuproine (7.7 mg, 0.04 mmol) in THF (0.9 ml) was added in one portion. The resulting solution was stirred for an additional hour. In a separate round bottom flask containing the stilbene precursor 1 (41 mg, 0.15 mmol) was added the solution containing the in-situ generated copper complex and THF was added to achieve a final concentration of 5mM with respect to 1. Iodine (37.0 mg, 0.15 mmol) and propylene oxide (0.51 ml, 7.30 mmol) were then added to the solution. The reaction is stirred in front of a compact fluorescent lamp (energy saving lightbulb 30W) for 5 days. The reaction was diluted with EtOAc and quenched with Na 2 S 2 O 3 (sat.) (30 ml). The organic layer was washed with Na 2 S 2 O 3 (sat.) until the complete consumption of iodine and then with brine. The organic phase was dried over Na 2 SO 4, filtered and concentrated. The crude product was purified by flash chromatography (2% to 8% PhMe/hexanes) to give [5]helicene 2 (22.9 mg, 57%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ): δ ppm = 8.55 (d, J = 8.4 Hz, 2H), (m, 8H), 7.55 (t, J = 7.44 Hz, 2H), (m, 2H); 13 C NMR (75 MHz, CDCl 3 ): δ ppm 134.8, 133.4, 132.6, 130.5, 128.1, 127.9, 127.6, 127.5, ppm; HRMS (ESI+) for C 22 H 14 (M + ): calculated: , found: General Procedure for Visible Light Mediated Cyclization of 1 in the Flow System using In-situ Generated Catalyst: The flow reaction was conducted in a FlowSyn Multi-X reactor purchased from Uniqsis and equipped with an HPLC pump modified. The reactor was connected to FEP tubing (fluorinated ethylene polymer tubing purchased from IDEX Health & Science, #1673) of natural colour with an outside diameter (OD) of 2 mm and inside diameter (ID) of 1 mm. The FEP tubing was wrapped tightly around two compact fluorescent lamps (30W energy saving light bulbs). FEP tubing was chosen due to its high transmittance, high chemical resistance and flexibility. Mild heating of the tubing during the reaction was observed. In a round bottom flask was added [Cu(NCCH 3 ) 4 ]BF 7 4 (9.3 mg, 0.04 mmol) and Xantphos (21.4 mg, 0.04 mmol) and dissolved in THF (7.4 ml). The solution was allowed to stir at room temperature for 1h and a solution of neocuproine (7.7 mg, 0.04 mmol) in THF (0.9 ml) was added in one portion. The resulting solution was stirred for an additional hour. In a separate round bottom flask containing the stilbene precursor 1 (41 mg, 0.15 mmol) was added the solution containing the in-situ generated copper complex and THF was added to achieve a final concentration of 5mM with respect to 1. Iodine (37.0 mg, 0.15 mmol) and propylene oxide (0.51 ml, 7.30 mmol) were then added to the solution. The solution was passed through the flow system 20 times, 30 minutes per run at a flow rate of 1ml/min, giving an overall reaction time of 10 hours. The reaction mixture was then collected and quenched with Na 2 S 2 O 3 (sat.) and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered and concentrated. The crude product was purified by flash chromatography (100% hexanes) to give [5]helicene 2 (18.1 mg, 40%). 7 Tang, X.; Woodward, S.; Krause, N. Eur. J. Org. Chem. 2009, S4

5 Me Ph 2 P N Cu O N Ph 2 P Me BF 4 Cu(DPEPhos)(neo)BF 4 Copper complex (7): [Cu(DPEPhos)(dmp)](BF 4 ): A mixture of [Cu(NCCH 3 ) 4 ]BF 4 (428 mg, 1.68 mmol) and bis[2-(diphenylphosphino)phenyl]ether (1.04g, 1.94 mmol) in CH 2 Cl 2 (336 ml) was stirred at room temperature for 1h and then treated with a solution of 2,9-dimethyl 1,10-phenanthroline (350.7 mg, 1.68 mmol) in CH 2 Cl 2 (42 ml). The reaction mixture was stirred for an additional 1h. The reaction mixture was concentrated to a fifth of the volume and Et 2 O was added to precipitate the product. Filtration afforded a yellow-orange solid (1.28 g, 85%). The spectroscopic data was identical to what was reported in the literature. 5 Me Ph 2 P N Cu N Ph 2 P Me BF 4 O Me Me Cu(XantPhos)(neo)BF 4 Copper complex (8): [Cu(XantPhos)(dmp)](BF 4 ): A mixture of [Cu(NCCH 3 ) 4 ]BF 4 (45 mg, 0.18 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (108 mg, 0.19 mmol) in CH 2 Cl 2 (38 ml) was stirred at room temperature for 1h and then treated with a solution of 2,9-dimethyl 1,10-phenanthroline (40 mg, 0.19 mmol) in of CH 2 Cl 2 (5 ml). Thie reaction mixture was stirred for an additional 1h. The reaction mixture was concentrated to a fifth of the volume and Et 2 O was added to precipitate the product. Filtration afforded the product as a yellow solid (120 mg, 71%). The spectroscopic data was identical to what was reported in the literature. 8 General Procedure for Wittig reaction: In a round bottom flask the phosphonium bromide salt (1.11 eq.) was added and suspended in dry THF and cooled with an ice-bath. n-butyllithium (1.18 M in hexanes, 1.13 eq.) was added dropwise and the resulting solution was stirred at 0 C for 60 minutes. The reaction mixture was cooled to -78 C and the aldehyde (1.0 eq.) was added in one portion. The reaction was allowed to warm to room temperature overnight. The reaction was quenched with distilled water. The layers were separated and the aqueous layer was extracted with ethyl acetate (2X). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography to afford the E- and Z-isomers in variables yields. 8 Smith, C. S.; Branham, C. W.; Marquardt, B. J.; Mann, K. R. J. Am. Chem. Soc. 2010, 132, S5

6 (Z)-1,2-di(naphthalene-2-yl)ethene (1): In a round bottom flask the (naphthalene-2- ylmethyl)triphenylphosphonium bromide (3.43 g, 7.11 mmol ) was added and suspended in dry THF (81 ml) and cooled with an ice-bath. n-butyllithium (6.14 ml, 7.24 mmol, 1.18 M in hexanes) was added dropwise and the resulting solution was stirred at 0 C for 60 minutes. The reaction mixture was then cooled to -78 C and 2-napthaldehyde (1.01 g, 6.46 mmol) was added in one portion. The reaction was allowed to warm to room temperature overnight. The reaction was quenched with distilled water. The layers were separated and the aqueous layer was extracted with ethyl acetate (2X). The combined organic layers were washed with brine, dried over Na 2 SO 4, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (2% to 6% PhMe/hexanes) to afford the product (1.03 g, 57%) as a white solid. The spectral data matched those found in the literature. 9 OMe 1,2,3-trimethoxy-5-styrylbenzene (15): Prepared following the general procedure for the Wittig reaction, except the reaction temperature was maintained at 0 C throughout the addition of the aldehyde. The crude product was purified by silica gel flash chromatography (0% to 10% ethyl acetate in hexanes) to afford the product (94 mg, 33%) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ ppm 7.52 (d, J = 7.5 Hz, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.27 (t, J = 7.3 Hz, 1H), 7.04 (d, J = 7.0 Hz, 2H), 6.75 (s, 2H), 3.93 (s, 6H), 3.88 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ ppm 153.4, 138.0, 137.2, 133.1, 128.7, 128.6, 128.2, , 126.4, 103.6, 60.9, HRMS (ESI+) for C 17 H 19 O 3 [M + H] + calculated: , found: ,3,4-trimethoxyphenanthrene (16): Prepared following the general procedure for the Visible Light Mediated Cyclization using In-situ Generated Catalyst. The crude product was purified by silica gel flash chromatography (0% to 10% ethyl acetate in hexanes) to afford the product (9.1 mg, 22%) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ ppm 9.51 (d, J = 9.5 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), (m, 4H), 7.11 (s, 1H), 4.04 (s, 3H), (s, 3H), 4.03 (s, 3H). 13 C NMR (75 MHz, CDCl 3 ) δ ppm 152.5, 152.5, OMe 9 Maya, A. B. S.; Perez-Melero, C.; Mateo, C.; Alonso, D.; Fernandez, J. L.; Gajate, C.; Mollinedo, F.; Pelaez, R.; Caballero, E.; Medarde, M. J. Med. Chem. 2005, 48, S6

7 142.8, 131.8, 130.2, 129.9, , 127.2, 126.7, 126.5, 125.5, 118.9, 105.2, 61.3, 60.3, HRMS (ESI+) for C 17 H 17 O 3 [M + H] + calculated: , found: S7

8 SPECTRAL DATA S8

9 1 H NMR spectra of 2: ppm (t1) S9

10 13 C NMR spectra of 2: ppm (t1) S10

11 1 H NMR spectra of 1: ppm (t1) S11

12 13 C NMR spectra of 1: ppm (t1) S12

13 1 H NMR spectra of 15: OMe S13

14 13 C NMR spectra of 15: OMe S14

15 1 H NMR spectra of 16: OMe S15

16 13 C NMR spectra of 16: OMe S16