Supporting Information Indium Triflate-Assisted ucleophilic Aromatic Substitution Reactions of itrosobezene-derived Cycloadducts with Alcohols Baiyuan Yang and Marvin J. Miller* Department of Chemistry and Biochemistry, University of otre Dame, otre Dame, Indiana 46556 mmiller1@nd.edu Table of Content General Methods S2 Experimental Details and Spectroscopic Data...S2 Presentation of MR Spectral Data 1 MR spectrum of 1d.......... S8 13 C MR spectrum of 1d...........S9 1 MR spectrum of 4a............S10 13 C MR spectrum of 4a.........S11 1 MR spectrum of 4b.............S12 13 C MR spectrum of 4b.........S13 gcsy spectrum of 4b........ S14 gsqc spectrum of 4b........ S15 1 MR spectrum of 5b............S16 13 C MR spectrum of 5b.........S17 gcsy spectrum of 5b........ S18 gsqc spectrum of 5b...........S19 1 MR spectrum of 4c.............S20 13 C MR spectrum of 4c.........S21 1 MR spectrum of 5c............S22 13 C MR spectrum of 5c.........S23 1 MR spectrum of 5d.............S24 13 C MR spectrum of 5d.........S25 1 MR spectrum of 5e.............S26 13 C MR spectrum of 5e.........S27 1 MR spectrum of 4f...........S28 13 C MR spectrum of 4f.........S29 1 MR spectrum of 5f............S30 13 C MR spectrum of 5f.........S31 1 MR spectrum of 5g............S32 13 C MR spectrum of 5g.........S33 -S1-
1 MR spectrum of 5h............S34 13 C MR spectrum of 5h..........S35 1 MR spectrum of 5i.............S36 13 C MR spectrum of 5i...........S37 1 MR spectrum of 5j.............S38 13 C MR spectrum of 5j...........S39 1 MR spectrum of 6...........S40 13 C MR spectrum of 6...........S41 1 MR spectrum of 10............S42 13 C MR spectrum of 10..........S43 1 MR spectrum of 12............S44 13 C MR spectrum of 12..........S45 1 MR spectrum of 12 and 13.............S46 13 C MR spectrum of 12 and 13..........S47 General Methods: Commercially available reagents were used without further purification except as indicated. Reactions were carried out in oven-dried glassware under an atmosphere of dry argon. All reactions were magnetically stirred and monitored by analytical thin-layer chromatography using aluminum-backed 0.2 mm silica gel 60 F-254 plates. Visualization was accomplished by UV light (254 nm), or by staining with potassium permanganate. Flash chromatography was performed with silica gel 60 (230 400 mesh). 1 MR and 13 C MR spectra were recorded at ambient temperature with the residual solvent peaks as internal standards. The line positions of multiplets are given in ppm (δ) and the coupling constants (J) are given as absolute values in ertz. Infrared spectra were recorded with a FT-IR spectrometer and reported as cm -1. All melting points were recorded uncorrected. igh-resolution mass spectra (RMS) data were obtained as specified. Yields refer to chromatographically and spectrographically pure compounds, unless otherwise noted. 1d 3-Phenyl-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene (1d). To a solution of nitrosobenzene (150 mg, 1.40 mmol) in DCM (3 ml) at 0 o C was added 1,3-cyclohexadiene (0.267 ml, 2.80 mmol), and the reaction mixture was stirred at 0 o C for 30 min. The solvent was removed under reduced pressure and the crude product was purified using silica gel column chromatography (hexanes:etac, 3:1) to afford 1d as a white solid (247 mg, 87% yield). mp: 65 67 o C; IR (neat): 3054, 2986, 1595, 1486, 1421, 1265, 738, 705 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 7.23 7.21 (m, 2 ), 7.02 7.01 (m, 2 ), 6.95 6.92 (m, 1 ), 6.59 (ddd, J = 8.0, 5.9, 1.8 z, 1 ), 6.15 (ddd, J = 7.8, 5.7, 1.5 z, 1 ), 4.72 4.70 (m, 1 ), 4.45 4.43 (m, 1 ), 2.33 2.29 (m, 1 ), 2.27 2.22 (m, 1 ), 1.62-1.56 (m, 1 ), 1.41 1.36 (m, 1 ); 13 C MR (150 Mz, CDCl 3 ) δ 152.5, 131.7, 130.1, 128.5, 122.1, 117.6, 69.3, 56.6, 24.1, 21.5. Me 4a -S2-
(+)-cis-4-(4-methoxyphenylamino)cyclopent-2-enol (4a). To a solution of nitrosobenzene (100 mg, 0.93 mmol) in DCM (2 ml) at rt was added 1,3-cyclopentadiene (0.15 ml, 1.86 mmol) and stirred for 30 min until nitrosobenzene was consumed (TLC analysis). Then methanol (3 ml) was added, followed by the addition of In(Tf) 3 (262 mg, 0.47 mmol). The mixture was stirred under Ar for 12 h, then solvent was removed under reduced pressure. Water and EtAc (3 + 5 ml) were added and separated. The aqueous layer was extracted with EtAc (3 x 5 ml). The combined organic layers were washed with brine, dried over a 2 S 4, filtered and concentrated by rotary evaporation. The crude product was purified using silica gel column chromatography (hexanes:etac, 1:1) to afford 4a as a yellow oil (51.3 mg, 31% yield in two steps). 1 MR (600 Mz, DMS-d 6 ) δ 6.70 (d, J = 8.8 z, 2 ), 6.57 (d, J = 8.8 z, 2 ), 5.85 (br m, 2 ), 5.14 (d, J = 8.5 z, 1 ), 4.88 (d, J = 5.8 z, 1 ), 4.58 4.55 (m, 1 ), 4.18 4.15 (m, 1 ), 3.63 (s, 3 ), 2.66 (dt, J = 12.9, 7.3 z, 1 ), 1.29 (dt, J = 12.9, 5.9 z, 1 ); 13 C MR (150 Mz, DMS-d 6 ) δ 150.6, 142.4, 136.3, 133.7, 114.5, 113.6, 73.6, 57.2, 55.2, 41.8; RMS (ESI) [M + ] + C 12 16 2 calcd for 206.1176, found 206.1174. General procedure for In(Tf) 3 -assisted nucleophilic aromatic substitution of 1d with alcohols. A solution of cycloadduct 1d (50 mg, 0.27 mmol) in alcohol (2 ml) was treated with anhydrous In(Tf) 3 (75 mg, 0.13 mmol) and quickly heated to 70 o C. The reaction mixture was stirred under Ar until 1d was consumed (TLC analysis). Then the mixture was cooled to rt and concentrated in vacuo to a slurry. Water (3 ml) and EtAc (5 ml) were added and separated. The aqueous layer was extracted with EtAc (3 x 5 ml). The combined organic layers were washed with brine, dried over a 2 S 4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography. Me Me 4b 5b (+)-cis-4-(2-methoxyphenylamino)cyclohex-2-enol (4b) and (+)-cis-4-(4-methoxyphenylamino)cyclohex-2-enol (5b). Prepared following the general procedure with 2 ml of Me. The crude product was purified by column chromatography using solvent gradient from hexanes:etac (1:1) to afford 4b (6.5 mg, 11% yield) as a colorless oil, then hexanes:etac (1:1 to 1:2) to afford 5b (35.3 mg, 60%) as a colorless oil (71% total combined yield). Products ratio was determined by 1 MR spectroscopy of the crude reaction mixture. 4b: IR (neat): 3424, 3019, 1511, 1424, 1215, 1041, 755, 669 cm -1 ; 1 MR (600 Mz, DMS-d 6 ) δ 6.82 (dd, J = 8.0, 1.2 z, 1 ), 6.77 (ddd, J = 8.0, 7.6, 1.2 z, 1 ), 6.62 (dd, J = 8.2, 1.4 z, 1 ), 6.56 (ddd, J = 8.2, 7.6, 1.4 z, 1 ), 5.80 5.77 (m, 1 ), 5.71 5.69 (m, 1 ), 4.76 (d, J = 5.9 z, 1 ), 4.31 (d, J = 9.1 z, 1 ), 3.98 (br m, 1 ), 3.90 (br m, 1 ), 3.77 (s, 3 ), 1.73 1.66 (m, 3 ), 1.55 1.50 (m, 1 ); 13 C MR (150 Mz, DMS-d 6 ) δ 146.4, 136.5, 133.8, 129.2, 121.0, 115.9, 109.8, 63.7, 55.3, 46.4, 28.5, 24.4; RMS (ESI) [M + a] + calcd for C 13 17 a 2 242.1151, found 242.1141. 5b: IR (neat): 3404, 3019, 2977, 1521, 1476, 1424, 1216, 1046, 772, 669 cm -1 ; 1 MR (600 Mz, DMS-d 6 ) δ 6.69 (d, J = 9.1 z, 2 ), 6.56 (dd, J = 9.1 z, 2 ), 5.73 (m, 1 ), 5.67 (m, 1 ), 5.06 (d, J = 8.5 z, 1 ), 4.74 (d, J = 4.4 z, 1 ), 3.99 (br m, 1 ), 3.72 (br m, 1 ), 3.63 (s, 3 ), 1.68 1.58 (m, 4 ); 13 C MR (150 Mz, DMS-d 6 ) δ 150.5, 142.0, 132.9, 129.8, 114.6, 113.6, 63.6, 55.2, 47.5, 28.6, 24.5; RMS (ESI) [M + a] + calcd for C 13 17 a 2 242.1151, found 242.1155. 4c 5c (+)-cis-4-(2-isopropoxyphenylamino)cyclohex-2-enol (4c) and -S3-
(+)-cis-4-(4-isopropoxyphenylamino)cyclohex-2-enol (5c). Prepared following the general procedure with 2 ml of i Pr. The crude product was purified by column chromatography using solvent gradient from hexanes:etac (1:1) to afford 4c (4.7 mg, 7% yield) as a colorless oil, then hexanes:etac (1:1 to 1:2) to afford 5c (33.5 mg, 51%) as a yellowish oil (58% total combined yield). Products ratio was determined by 1 MR spectroscopy of the crude reaction mixture. 4c: IR (neat): 3405, 3054, 2986, 1599, 1508, 1422, 1265, 896, 705 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 6.86 6.84 (m, 1 ), 6.81 6.79 (m, 1 ), 6.66 6.63 (m, 2 ), 5.94 5.89 (m, 2 ), 4.56 4.50 (m, 1 ), 4.30 (br s, 1 ), 4.24 (br s, 1 ), 3.94 (m, 1 ), 1.92 1.85 (m, 2 ), 1.82 1.75 (m, 2 ), 1.35 (d, J = 6.2 z, 6 ); 13 C MR (150 Mz, CDCl 3 ) δ 145.2, 138.0, 132.1, 131.9, 121.3, 116.6, 112.9, 110.7, 70.9, 65.5, 47.9, 29.3, 25.0, 22.5, 22.5; RMS (ESI) [M + ] + calcd for C 15 22 2 248.1645, found 248.1620. 5c: IR (neat): 3400, 3054, 2987, 1607, 1508, 1421, 1265, 896, 738 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 6.79 (d, J = 8.8 z, 2 ), 6.58 (dd, J = 8.8 z, 2 ), 5.92 5.87 (m, 2 ), 4.40 4.32 (m, 1 ), 4.22 (m, 1 ), 3.87 (m, 1 ), 1.91 1.87 (m, 2 ), 1.78 1.73 (m, 2 ), 1.30 (d, J = 6.2 z, 6 ); 13 C MR (150 Mz, CDCl 3 ) δ 150.3, 141.3, 132.0, 131.8, 118.2, 114.9, 71.3, 65.3, 49.0, 29.1, 25.0, 22.3; RMS (ESI) [M + ] + calcd for C 15 22 2 248.1645, found 248.1667. 5d (+)-cis-4-(4-(exyloxy)phenylamino)cyclohex-2-enol (5d). Prepared following the general procedure with 2 ml of 1-hexanol. The crude product was purified by column chromatography using solvent hexanes:etac (1:1 to 1:2) to afford 5d (43.1 mg, 56% yield) as a white glass. IR (neat): 3440, 3054, 2987, 1510, 1421, 1265, 896, 705 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 6.79 (d, J = 8.9 z, 2 ), 6.59 (d, J = 8.9 z, 2 ), 5.92 5.87 (m, 2 ), 4.21 (m, 1 ), 3.89 (t, J = 6.6 z, 2 ), 3.87 (m, 1 ), 1.90 1.83 (m, 2 ), 1.78 1.72 (m, 4 ), 1.47 1.42 (m, 2 ), 1.35 1.32 (m, 4 ), 0.91 (m, 3 ); 13 C MR (150 Mz, CDCl 3 ) δ 151.9, 141.0, 132.0, 131.9, 116.0, 115.1, 68.9, 65.4, 49.2, 31.8, 29.6, 29.1, 25.9, 25.0, 22.8, 14.2; RMS (ESI) [M + ] + calcd for C 18 28 2 290.2115, found 290.2127. 5e (+)-cis-4-(4-tert-butoxyphenylamino)cyclohex-2-enol (5e). Prepared following the general procedure with 2 ml of t Bu. The crude product was purified by column chromatography using solvent hexanes:etac (1:2) to afford 5e (26.2 mg, 37% yield) as a yellowish oil. IR (neat): 3430, 3054, 2987, 1642, 1512, 1421, 1265, 896 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 6.69 (d, J = 8.8 z, 2 ), 6.51 (d, J = 8.8 z, 2 ), 5.83 (m, 1 ), 5.75 (m, 1 ), 4.00 (m, 1 ), 3.81 (m, 1 ), 1.79 1.68 (m, 4 ), 1,23 (s, 9 ); 13 C MR (150 Mz, CDCl 3 ) δ 147.9, 141.2, 133.5, 130.5, 116.4, 115.3, 74.2, 65.3, 48.5, 28.5, 28.3, 25.4; RMS (ESI) [M + a] + calcd for C 16 23 a 2 284.1621, found 284.1597. 4f 5f (+)-cis-4-(2-(allyloxy)phenylamino)cyclohex-2-enol (4f) and (+)-cis-4-(4-(allyloxy)phenylamino)cyclohex-2-enol (5f). Prepared following the general procedure with 2 ml of allyl alcohol. The crude product was purified by column chromatography using solvent gradient from hexanes:etac (1:1) to afford 4f (9.5 mg, 8 % yield) as a yellowish oil, then hexanes:etac (1:1 to 1:2) to afford 5f (53.0 mg, 60%) as a yellowish glass (68% total combined yield). Products ratio was determined by 1 MR -S4-
spectroscopy of the crude reaction mixture. 4f: IR (neat): 3442, 3054, 2986, 1422, 1265, 909, 744, 650 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 6.87 (m, 1 ), 6.79 (dd, J = 8.4, 1.5 z, 1 ), 6.65 (m, 2 ), 6.11 6.05 (m, 1 ), 5.92 (m, 2 ), 5.39 (ddd, J = 17.3, 3.1, 1.6 z, 1 ), 5.29 (ddd, J = 10.4, 2.8, 1.4 z, 1 ), 4.57 (dt, J = 5.4, 1.5 z, 2 ), 4.34 (br s, 1 ), 4.23 (br m, 1 ), 3.96 (m, 1 ), 1.92 1.85 (m, 2 ), 1.83 1.75 (m, 2 ); 13 C MR (150 Mz, CDCl 3 ) δ 146.1, 137.2, 133.7, 132.1, 131.9, 121.7, 117.8, 116.6, 111.4, 110.6, 69.4, 65.5, 47.7, 29.2, 25.0; RMS (ESI) [M + ] + calcd for C 15 20 2 246.1489, found 246.1512. 5f: IR (neat): 3447, 3054, 2987, 1509, 1422, 1265, 1026, 896, 821, 748 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 6.81 (d, J = 8.8 z, 2 ), 6.58 (d, J = 8.8 z, 2 ), 6.09 6.02 (m, 1 ), 5.90 (m, 2 ), 5.40 (ddd, J = 17.3, 3.1, 1.6 z, 1 ), 5.26 (ddd, J = 10.6, 2.6, 1.5 z, 1 ), 4.47 (dt, J = 5.3, 1.5 z, 2 ), 4.23 (br m, 1 ), 3.96 (m, 1 ), 4.22 (m, 1 ), 3.87 (m, 1 ), 1.91 1.83 (m, 2 ), 1.78 1.73 (m, 2 ); 13 C MR (150 Mz, CDCl 3 ) δ 151.4, 141.3, 134.0, 132.0, 132.0, 117.5, 116.3, 116.0, 115.0, 114.9, 69.8, 65.4, 49.1, 29.1, 25.1; RMS (ESI) [M + ] + calcd for C 15 20 2 246.1489, found 246.1515. 5g (+)-cis-4-(4-(propynyloxy)phenylamino)cyclohex-2-enol (5g). Prepared following the general procedure with 2 ml of propargyl alcohol. The crude product was purified by column chromatography using hexanes:etac (1:1) to afford 5g (35.1 mg, 58% yield) as a yellowish oil. IR (neat): 3402, 3054, 2987, 1509, 1421, 1265, 1034, 896, 705 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 6.87 (d, J = 8.8 z, 2 ), 6.59 (d, J = 8.8 z, 2 ), 5.89 (m, 2 ), 4.62 (d, J = 2.3 z, 2 ), 4.22 (m, 1 ), 3.88 (m, 1 ), 2.50 (t, J = 2.6 z, 1 ), 1.91 1.83 (m, 2 ), 1.78 1.73 (m, 2 ); 13 C MR (150 Mz, CDCl 3 ) δ 150.2, 142.0, 132.1, 131.8, 116.8, 114.7, 79.3, 75.3, 65.4, 57.0, 48.9, 29.1, 25.0; RMS (ESI) [M + a] + calcd for C 15 17 a 2 266.1151, found 266.1140. 5h (+)-cis-4-(4-(benzyloxy)phenylamino)cyclohex-2-enol (5h). A solution of cycloadduct 1d (50 mg, 0.27 mmol) in TF (2 ml) was treated with benzyl alcohol (0.14 ml, 1.33 ml) and anhydrous In(Tf) 3 (75 mg, 0.13 mmol). The reaction was quickly heated to 70 o C. The reaction mixture was stirred under Ar until 1d was consumed (TLC analysis). Then the mixture was cooled to rt and concentrated in vacuo to a slurry. Water (3 ml) and EtAc (5 ml) were added and separated. The aqueous layer was extracted with EtAc (3 x 5 ml). The combined organic layers were washed with brine, dried over a 2 S 4 and filtered. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography using solvent hexanes:etac (2:3) to afford 5h (43.2 mg, 55% yield) as a white solid. mp: 90 92 o C; IR (neat): 3413, 3055, 1640, 1509, 1422, 1264, 895, 748 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 7.44 7.42 (m, 2 ), 7.39 7.37 (m, 2 ), 7.33-7.31 (m, 1 ), 6.86 (d, J = 8.9 z, 2 ), 6.59 (d, J = 8.9 z, 2 ), 5.92 5.87 (m, 2 ), 5.00 (s, 2 ), 4.22 (m, 1 ), 3.87 (m, 1 ), 3.41 (br s, 1 ), 1.90 1.83 (m, 2 ), 1.78 1.73 (m, 2 ); 13 C MR (150 Mz, CDCl 3 ) δ 151.6, 141.4, 137.7, 132.0, 131.9, 128.6, 127.9, 127.6, 116.4, 114.9, 71.0, 65.3, 49.0, 29.1, 25.0; RMS (ESI) [M + ] + calcd for C 19 22 2 296.1645, found 296.1621. Me 5i (+)-cis-4-(4-(4-methoxybenzyloxy)phenylamino)cyclohex-2-enol (5i). Prepared following the procedure for synthesis of 5h. Crude material was purified by silica gel column chromatography using solvent hexanes:etac -S5-
(1:2) to afford 5i (42.8 mg, 49% yield) as a white glass. IR (neat): 3415, 3054, 2987, 1510, 1422, 1265, 896, 705 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 7.35 (d, J = 8.8 z, 2 ), 6.91 (d, J = 8.8 z, 2 ), 6.85 (d, J = 8.9 z, 2 ), 6.59 (d, J = 8.9 z, 2 ), 5.91 5.87 (m, 2 ), 4.92 (s, 2 ), 4.21 (m, 1 ), 3.87 (m, 1 ), 3.82 (s, 3 ), 1.90 1.83 (m, 2 ), 1.77 1.73 (m, 2 ); 13 C MR (150 Mz, CDCl 3 ) δ 159.5, 151.7, 141.3, 132.0, 131.9, 129.7, 129.4, 116.4, 115.0, 114.1, 70.8, 65.3, 55.4, 49.1, 29.1, 25.0; RMS (ESI) [M + ] + calcd for C 20 24 3 326.1751, found 326.1729. 2 5j (+)-cis-4-(4-(4-itrobenzyloxy)phenylamino)cyclohex-2-enol (5j). Prepared following the procedure for synthesis of 5h. Crude material was purified by silica gel column chromatography using solvent hexanes:etac (1:2) to afford 5j (35.5 mg, 39% yield) as a yellow oil. IR (neat): 3435, 3054, 2987, 1604, 1510, 1421, 1348, 1265, 896, 738, 705 cm -1 ; 1 MR (600 Mz, CDCl 3 ) δ 8.24 (d, J = 8.8 z, 2 ), 7.61 7.59 (m, 2 ), 6.84 (d, J = 9.0 z, 2 ), 6.59 (d, J = 9.0 z, 2 ), 5.89 (d, J = 1.3 z, 2 ), 5.10 (s, 2 ), 4.21 (m, 1 ), 3.87 (m, 1 ), 3.43 (br s, 1 ), 1.90 1.83 (m, 2 ), 1.78 1.72 (m, 2 ); 13 C MR (150 Mz, CDCl 3 ) δ 150.8, 147.6, 145.3, 141.9, 132.2, 131.7, 127.7, 123.9, 116.4, 114.8, 69.7, 65.3, 48.9, 29.1, 25.0; RMS (ESI) [M + ] + calcd for C 19 21 2 4 341.1496, found 341.1470. (+)-cis-4-(phenylamino)cyclohex-2-enol (6). A solution of cycloadduct 1d (50 mg, 0.26 mmol) in Me (2 ml) was treated with anhydrous CuCl (26.4 mg, 0.26 mmol) and quickly heated to 70 o C. The reaction mixture was stirred under Ar for 3 h. Then the mixture was cooled to rt and concentrated in vacuo to a slurry, then water (3 ml) and EtAc (5 ml) were added and separated. The aqueous layer was extracted with EtAc (3 x 5 ml). The combined organic layers were washed with brine, dried over a 2 S 4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography. The crude product was purified by column chromatography using solvent hexanes:etac (1:2) to afford 6 (35.4 mg, 70% yield) as a yellowish solid. mp: 58 60 o C; IR (neat): 3445, 3054, 2987, 1601, 1503, 1422, 1265, 896, 705 cm -1 ; 1 MR (600 Mz, DMS-d 6 ) δ 7.04 (dd, J = 8.5, 7.3 z, 2 ), 6.60 (d, J = 7.6 z, 2 ), 6.49 (t, J = 7.3 z, 1 ), 5.75 (m, 1 ), 5.68 (m, 1 ), 5.53 (d, J = 8.5 z, 1 ), 4.76 (d, J = 4.4 z, 1 ), 4.00 (m, 1 ), 3.81 (m, 1 ), 1.71 1.59 (m, 4 ); 13 C MR (150 Mz, DMS-d 6 ) δ 146.7, 132.1, 131.4, 129.3, 117.5, 113.2, 65.2, 47.8, 28.9, 24.8. 6 10 3-(2-Pyridyl)-2-oxa-3-aza-bicyclo[2.2.2]oct-5-ene (10). To a solution of 2-nitrosopyridine (100 mg, 0.93 mmol) in DCM (3 ml) at 0 o C was added 1,3-cyclohexadiene (0.178 ml, 1.87 mmol), and the reaction mixture was stirred at 0 o C for 30 min. The solvent was removed under reduced pressure and the crude product was purified using silica gel column chromatography (hexanes:etac, 5:1) to afford 10 as a white solid (165 mg, 95% yield). mp: 76 78 o C; 1 MR (600 Mz, CDCl 3 ) δ 8.20 (ddd, J = 4.8, 1.9, 0.9 z, 1 ), 7.51 (ddd, J = 9.2, 7.3, 1.9 z, 1 ), 6.91 (dt, J = 8.4, 1.0 z, 1 ), 6.76 (ddd, J = 7.2, 4.8, 1.0 z, 1 ), 6.48 (ddd, J = 8.2, 5.8, 1.9 z, 1 ), 6.32 (ddd, J = 8.2, 5.8, 1.6 z, 1 ), 5.29 (m, 1 ), 4.72 (m, 1 ), 2.28 2.22 (m, 2 ), 1.63 1.57 (m, 1 ), 1.43 1.38 -S6-
(m, 1 ); 13 C MR (150 Mz, CDCl 3 ) δ 164.3, 147.4, 137.6, 132.1, 131.0, 116.7, 111.5, 69.9, 52.3, 24.4, 20.7. Me Me 12 13 anti-1-(-(2-pyridyl)--hydroxyamino)-2-methoxycyclohex-3-ene (12) and anti-1-(-(2-pyridyl)--hydroxyamino)-4-methoxycyclohex-2-ene (13). A solution of cycloadduct 10 (62 mg, 0.33 mmol) in Me (2 ml) was treated with anhydrous In(Tf) 3 (92 mg, 0.16 mmol) and quickly heated to 70 o C. The reaction mixture was stirred under Ar for 3 h until 10 was consumed. The mixture was cooled to rt and concentrated in vacuo to a slurry, then water (3 ml) and EtAc (5 ml) were added and separated. The aqueous layer was extracted with EtAc (3 x 5 ml). The combined organic layers were washed with brine, dried over a 2 S 4 and filtered. The solvent was removed in vacuo and the residue was purified by column chromatography. The crude product was purified by column chromatography using solvent gradient from hexanes:etac (3:1) to afford 12 (24.3 mg, 33% yield) as a white glass, and hexanes:etac (2:1) to afford a mixture of 12 and 13 (40.9 mg, 57% yield) as a white glass (90% total combined yield). Products ratio was determined by 1 MR spectroscopy of the crude reaction mixture. 12: IR (neat): 3416, 3020, 1520, 1421, 1363, 1216, 1090, 766, 669 cm -1 ; 1 MR (600 Mz, DMS-d 6 ) δ 8.99 (s, 1 ), 8.11 (ddd, J = 4.8, 1.9, 0.9 z, 1 ), 7.58 (ddd, J = 9.1, 7.2, 1.9 z, 1 ), 7.05 (dt, J = 8.4, 0.9 z, 1 ), 6.69 (ddd, J = 7.2, 4.8, 0.9 z, 1 ), 5.77 (m, 1 ), 5.71 (m, 1 ), 4.59 (ddd, J = 12.3, 8.9, 3.4 z, 1 ), 4.24 (m, 1 ), 3.21 (s, 3 ), 2.08 (br m, 2 ), 1.83 1.76 (m, 1 ), 1.54 1.51 (m, 1 ); 13 C MR (150 Mz, DMS-d 6 ) δ 163.0, 147.0, 137.4, 128.8, 127.8, 114.1, 108.5, 74.7, 58.9, 54.7, 24.8, 23.2; RMS (ESI) [M + ] + calcd for C 12 17 2 2 221.1285, found 221.1271. 13: IR (neat): 3406, 3020, 1521, 1424, 1216, 1046, 766, 669 cm -1 ; 1 MR (600 Mz, DMS-d 6 ) δ 8.96 (s, 1 ), 8.15 (ddd, J = 4.8, 1.9, 0.9 z, 1 ), 7.61 (ddd, J = 9.1, 7.2, 1.9 z, 1 ), 7.06 (dt, J = 8.4, 0.9 z, 1 ), 6.75 (ddd, J = 7.2, 4.8, 0.9 z, 1 ), 5.84 (m, 1 ), 5.62 (m, 1 ), 5.12 (m, 1 ), 3.84 (m, 1 ), 3.26 (s, 3 ), 2.15 (br m, 1 ), 1.84 1.73 (m, 2 ), 1.45 1.38 (m, 1 ); 13 C MR (150 Mz, DMS-d 6 ) δ 162.5, 147.1, 137.6, 131.3, 130.9, 114.8, 109.2, 74.9, 56.3, 54.8, 27.9, 22.5; RMS (ESI) [M + ] + calcd for C 12 17 2 2 221.1285, found 221.1275. -S7-
1.56 1d ( 1 MR, 600 Mz, CDCl 3 ) 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0.0 -S8-
1d ( 13 C MR, 150 Mz, CDCl 3 ) 200 150 100 50 0 -S9-
5.0 -S10-0.0 1.9 2.0 2.0 1.1 1.0 1.0 1.1 2.9 1.2 1.2 Me 4a ( 1 MR, 600 Mz, DMS-d 6 )
Me 4a ( 13 C MR, 150 Mz, DMS-d 6 ) 200 150 100 50 0 -S11-
Me 4b ( 1 MR, 600 Mz, DMS-d 6 ) 5.0 0.0 -S12-
Me 4b ( 13 C MR, 150 Mz, DMS-d 6 ) 200 150 100 50 0 -S13-
1.0 2.0 3.0 4.0 5.0 Spectrum Title: Std proton Frequency (Mz): (f2) 599.878 (f1) 599.873 riginal Points Count: (f2) 1153 (f1) 256 Actual Points Count: (f2) 2048 (f1) 1024 Acquisition Time (sec): (f2) 0.2131 (f1) 0.0473 Spectral Width (ppm): (f2) 9.021 (f1) 9.021 Pulse Program: gcsy umber of Scans: 16 6.0 Me 7.0 8.0 4b (gcsy, DMS-d 6 ) ppm (f1 8.0 ppm (f2) 7.0 6.0 5.0 4.0 3.0 2.0 1.0 -S14-
Spectrum Title: Std proton 50 100 Frequency (Mz): (f2) 599.879 (f1) 150.852 riginal Points Count: (f2) 2048 (f1) 512 Actual Points Count: (f2) 2048 (f1) 2048 Acquisition Time (sec): (f2) 0.2130 (f1) 0.0189 Spectral Width (ppm): (f2) 16.029 (f1) 180.013 Pulse Program: gsqc umber of Scans: 16 Me 150 4b (gsqc, DMS-d 6 ) ppm (f1 8.0 ppm (f2) 7.0 6.0 5.0 4.0 3.0 2.0 1.0 -S15-
Me 5b ( 1 MR, 600 Mz, DMS-d 6 ) 10.0 5.0 -S16-
Me 5b ( 13 C MR, 150 Mz, DMS-d 6 ) 200 150 100 50 0 -S17-
1.0 2.0 3.0 4.0 5.0 Spectrum Title: Std proton Frequency (Mz): (f2) 599.878 (f1) 599.876 riginal Points Count: (f2) 1153 (f1) 256 Actual Points Count: (f2) 2048 (f1) 1024 Acquisition Time (sec): (f2) 0.2131 (f1) 0.0473 Spectral Width (ppm): (f2) 9.021 (f1) 9.021 Pulse Program: gcsy umber of Scans: 8 6.0 7.0 8.0 Me 5b (gcsy, DMS-d 6 ) ppm (t1 8.0 ppm (t2) 7.0 6.0 5.0 4.0 3.0 2.0 1.0 -S18-
Spectrum Title: new experiment 50 100 Frequency (Mz): (f2) 599.879 (f1) 150.852 riginal Points Count: (f2) 2048 (f1) 512 Actual Points Count: (f2) 2048 (f1) 2048 Acquisition Time (sec): (f2) 0.2130 (f1) 0.0189 Spectral Width (ppm): (f2) 16.029 (f1) 180.013 Pulse Program: gsqc umber of Scans: 8 150 Me 5b (gsqc, DMS-d 6 ) ppm (f1 ppm (f2) 5.0 0.0 -S19-
4c ( 1 MR, 600 Mz, CDCl 3 ) ppm (f1) 10.0 5.0 0.0 -S20-
4c ( 13 C MR, 150 Mz, CDCl 3 ) 200 ppm (f1) 150 100 50 0 -S21-
5c ( 1 MR, 600 Mz, CDCl 3 ) 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) -S22-
5c ( 13 C MR, 150 Mz, CDCl 3 ) 200 150 100 50 0 -S23-
5d ( 1 MR, 600 Mz, CDCl 3 ) ppm (f1) 10.0 5.0 0.0 -S24-
5d ( 13 C MR, 150 Mz, CDCl 3 ) ppm (f1) 200 150 100 50 0 -S25-
5e ( 1 MR, 600 Mz, CDCl 3 ) 10.0 5.0 0.0 -S26-
5e ( 13 C MR, 150 Mz, CDCl 3 ) 200 150 100 50 0 -S27-
4f ( 1 MR, 600 Mz, CDCl 3 ) ppm (f1) 10.0 5.0 0.0 -S28-
4f ( 13 C MR, 150 Mz, CDCl 3 ) ppm (f1) 150 100 50 0 -S29-
5f ( 1 MR, 600 Mz, CDCl 3 ) 10.0 ppm (f1) 5.0 0.0 -S30-
5f ( 13 C MR, 150 Mz, CDCl 3 ) ppm (f1) 200 150 100 50 0 -S31-
5g ( 1 MR, 600 Mz, CDCl 3 ) 10.0 5.0 0.0 -S32-
5g ( 13 C MR, 150 Mz, CDCl 3 ) 200 150 100 50 0 -S33-
5h ( 1 MR, 600 Mz, CDCl 3 ) 10.0 5.0 0.0 -S34-
5h ( 13 C MR, 150 Mz, CDCl 3 ) 200 150 100 50 0 -S35-
Me 5i ( 1 MR, 600 Mz, CDCl 3 ) 10.0 5.0 0.0 -S36-
Me 5i ( 13 C MR, 150 Mz, CDCl 3 ) 200 150 100 50 0 -S37-
2 5j ( 1 MR, 600 Mz, CDCl 3 ) 10.0 5.0 0.0 -S38-
2 5j ( 13 C MR, 150 Mz, CDCl 3 ) 200 150 100 50 0 -S39-
6 ( 1 MR, 600 Mz, DMS-d 6 ) 10.0 5.0 0.0 -S40-
6 ( 13 C MR, 150 Mz, DMS-d 6 ) 200 150 100 50 0 -S41-
10 ( 1 MR, 600 Mz, CDCl 3 ) 10.0 5.0 0.0 -S42-
10 ( 13 C MR, 150 Mz, CDCl 3 ) 200 150 100 50 0 -S43-
Me 12 ( 1 MR, 600 Mz, DMS-d 6 ) 10.0 5.0 0.0 -S44-
Me 12 ( 13 C MR, 150 Mz, DMS-d 6 ) ppm (f1) 200 150 100 50 0 -S45-
+ Me Me 12 13 ( 1 MR, 600 Mz, DMS-d 6 ) 10.0 5.0 0.0 -S46-
+ Me Me 12 13 ( 13 C MR, 150 Mz, DMS-d 6 ) 200 150 100 50 0 -S47-