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1 Supporting Information The Discovery of The First α-amino-3-hydroxy-5- Methyl-4-Isoxazolepropionic Acid (AMPA) Receptor Antagonist Dependent Upon Transmembrane AMPA Receptor Regulatory Protein (TARP) Gamma-8 Kevin M. Gardinier*, Douglas L. Gernert, Warren J. Porter, Jon K. Reel, Paul L. rnstein, Patrick Spinazze, F. Craig Stevens, Patric Hahn, Sean P. Hollinshead, Daniel Mayhugh, Jeff Schkeryantz, Albert Khilevich, scar De Frutos, Scott D. Gleason, Akihiko S. Kato, Debra Luffer-Atlas, Prashant V. Desai, Steven Swanson, Kevin D. Burris, Chunjin Ding, Beverly A. Heinz, Anne B. eed, Vanessa. Barth, Gregory A. Stephenson, Benjamin A. Diseroad, Tim A. Woods, Hong Yu, David Bredt, and Jeffrey M. Witkin SI Contents: 1. Figure 11. X-Ray structure of (+) Schemes Full experimentals for final targets 7, 8, 22, 23, 24. S1

2 Figure 11. Molecular conformation and stereochemistry observed within the unit cell in the crystal structures of (+)-13. Scheme 6. Syntheses of indazole analog 7. a H 2 + a b Br H c H 41 7 S2

3 a Reagents and conditions: (a) t-butyl-x-phos, Pd(Ac) 2, amylene hydrate/water, 100 o C; 40 48%; (b) MeI, ah, DMF, 0 o C; 41 87%; (c) HCl, MeH; 7 91%. S3

4 Scheme 7. Syntheses of benzothiazolone analog 8. a Si Si H 2 + Br S a H S b Si S c H S 44 8 a Reagents and conditions: (a) t-butyl-x-phos, Pd(Ac) 2, amylene hydrate/water, 100 o C; 43 72%; (b) MeI, ah, DMF, 0 o C; 44 15%; (c) TFA, DCM; H 4 H, THF; 8 82%. S4

5 S5 Scheme 8. Synthesis of 5-flouro analog 22. a b a c (+) F S H S H S F S H F a Reagents and conditions: (a) Lit-Bu, DMF, 2,5-difluoropyridine, 140 o C; 45; (b) (i) TFA, reflux; (ii) H 4 H, THF; 22 84% two steps; (c) chiral chromatography; (+)-22 37%.

6 Scheme 9. Synthesis of gem-dimethyl analog 23. a 46 a b c d e (+)-23 a Reagents and conditions: (a) Lit-Bu, DMF, 140 o C; 47 54%; (b) bis(triphenylphosphine)palladium(ii) chloride, copper(i) iodide, 3-methyl butynol, DMF, TEA, 70 o C; 48 79%; (c) hydrogen, 10% Pd on carbon, MeH; 49 69%; (d) (i) TFA, reflux; (ii) H 4 H, THF; 23 42%; (e) chiral chromatography; (+)-23 41%. S6

7 Scheme 10. Synthesis of hydroxyethyl analog 24. a a b c d e 24 (+)-24 a Reagents and conditions: (a) n-buli, MTBE; 50 62%; (b) p-tsa, DCM; 51 77%;(c) Lit-Bu, DMF, 140 o C; 52 61%; (d) (i) TFA, reflux; (ii) H 4 H, THF; 24 81%; (e) chiral chromatography; (+)-24 42%. S7

8 -Methyl--[1-(2-pyridyl)pyrazol-3-yl]-1H-indazol-5-amine (7). To a solution of 41 (254 mg, mmol) in methanol (6.5 ml) was added a 4M aqueous solution of hydrogen chloride (1.5 ml, 6.8 mmol). After 2 hrs, this material was diluted with ethylacetate (50mL) and washed with a saturated aqueous solution of sodium bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. This material was then purified via silica gel chromatography using EtAc/hexanes (20:80) to give 7 (179 mg, 91%) as a white foam in >95% purity. HPLC-MS (low ph) rt= 2.01 min, m/z = (M+1). 1 H MR ( MHz, CDCl 3 ): δ (br s, 1H), (m, 2H), 8.03 (d, J = 0.9 Hz, 1H), 7.85 (dt, J = 8.3, 0.9 Hz, 1H), (m, 1H), 7.61 (dd, J = 0.7, 1.9 Hz, 1H), (m, 2H), (m, 1H), 5.87 (d, J = 2.8 Hz, 1H), 3.52 (s, 3H). 6-[Methyl-[1-(2-pyridyl)pyrazol-3-yl]amino]-3H-1,3-benzothiazol-2-one (8). Compound 44 (0.12 g, 0.26 mmol) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (2 ml). After stirring for 1 h, the solution was concentrated and the residue dissolved in tetrahydrofuran (4 ml) and ammonium hydroxide (4 ml). After 1 h the solution was concentrated, partitioned between ethylacetate and a saturated aqueous sodium carbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. This material was then purified via silica gel chromatography to give 8 (0.07 g, 82%) as a white solid in >95% purity. HPLC-MS (low ph) rt= 2.07 min, m/z = (M+1). 1 H MR ( MHz, CDCl 3 ): δ 8.87 (br s, 1H), 8.38 (d, J = 2.7 Hz, 1H), (m, 1H), 7.83 (d, J = 8.2 Hz, 1H), (m, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.21 (dd, J = 2.3, 8.6 Hz, 1H), (m, 2H), 5.96 (d, J = 2.9 Hz, 1H), 3.47 (s, 3H). 6-[1-[1-(5-Fluoro-2-pyridyl)pyrazol-3-yl]ethyl]-3H-1,3-benzothiazol-2-one (22) 2,5- Difluoropyridine (0.800 g, 8 mmol) was dissolved in dimethylformamide (13 ml), and to this S8

9 solution was added lithium tert-butoxide (1M solution in THF)(12 ml, 12 mmol). After stirring for 15min., 19 (0.5 g, 2.0 mmol) was added and the reaction heated in an oil bath to 140 C, purging the reaction with 2 to remove the THF. After 5 hrs. the reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride. The mixture was then extracted with EtAc and the organic layer washed with water and brine before being dried over a 2 S 4, filtered, and concentrated. The material was purified by silica gel chromatography by eluting with hexanes/etac (2:5) to give a white foam which was dissolved in trifluoroacetic acid (5 ml) and heated to reflux (~72 C) under 2 atmosphere for 2 hr. After this time the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is then dissolved in THF (8 ml) and treated with a 28% aqueous 28% ammonium hydroxide solution (8 ml). This mixture was stirred at room temperature for 1 h. After this time the reaction is diluted with EtAc (10 ml) and washed with brine. The combined organic layer was then dried over sodium sulfate, filtered and concentrated. The material was purified by silica gel chromatography by eluting with hexanes/etac (gradient of 60%-80%) to give 22 (0.18 g, 84%) as a white solid in >95% purity. HPLC-MS (low ph) rt= 2.23 min, m/z = (M+1). 1 H MR ( MHz, DMS-d6): δ (m, 1H), (m, 2H), (m, 2H), 7.54 (d, J = 1.6 Hz, 1H), (m, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 2.5 Hz, 1H), (m, 1H), (m, 3H). This racemic material was then resolved into enantiomers by chiral chromatography using Chiracel J-H (4.6 x 150 mm, 5 µm column, Chiral Technologies Europe), eluting with 30% MeH/liquid C 2, 5 ml/min., detecting at 225 nm, characterized Isomer 1, (+)-22, with rt = 2.71 min and >98% ee. [α] 20 D = (c = 1.04, EtH). S9

10 6-[1-[1-[5-(3-Hydroxy-3-methyl-butyl)-2-pyridyl]pyrazol-3-yl]ethyl]-3H-1,3- benzothiazol-2-one (23). Compound 49 (0.66 g, 1.46 mmol) was dissolved in trifluoroacetic acid (15 ml) and heated to reflux (~72 C) under 2 for 2 hr. After this time the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is then dissolved in THF (20 ml) and treated with an aqueous 28% ammonium hydroxide solution (20 ml). This mixture was stirred at room temperature for 1 h. After this time the reaction is diluted with EtAc (100 ml) and washed with brine. The combined organic layer was then dried over sodium sulfate, filtered and concentrated. The material was purified by silica gel chromatography by eluting with hexanes/etac (gradient of 60%-80%) to give 23 (0.25 g, 42%) as a clear thick oil. HPLC-MS (low ph) rt= 2.07 min, m/z = (M+1). 1 H MR ( MHz, DMS-d6): δ (m, 1H), 8.42 (d, J = 2.5 Hz, 1H), 8.23 (s, 1H), 7.74 (s, 2H), (m, 1H), (m, 1H), 7.00 (d, J = 8.2 Hz, 1H), 6.35 (d, J = 2.5 Hz, 1H), 4.27 (s, 1H), (m, 1H), 3.29 (s, 1H), (m, 2H), (m, 4H), 1.11 (s, 6H). This racemic material was then resolved into enantiomers by chiral chromatography using Chiralcel J-H (4.6 x 150 mm, 5 µm column, Chiral Technologies Europe), eluting with 30% MeH/liquid C 2, 5 ml/min., detecting at 225 nm, (+)-23 was Isomer 1 with rt = 2.00 min and >98%ee. [α] 20 D = (c = 1.00, EtH). 6-[1-[1-[5-(2-Hydroxyethyl)-2-pyridyl]pyrazol-3-yl]ethyl]-3H-1,3-benzothiazol-2-one (24). Compound 51 (0.64 g, 116 mmol) was dissolved in dimethylformamide (10 ml) and the solution was treated with lithium tert-butoxide (1M solution in THF)(0.174 ml, 174 mmol). After stirring for 15min., 19 (0.5 g, 2.0 mmol) was added and the reaction heated in an oil bath to 140 C, purging the reaction with 2 to remove the THF. After 5 hrs. the reaction mixture was cooled to room temperature and quenched with saturated ammonium chloride. The mixture was S10

11 then extracted with EtAc and the organic layer washed with water and brine before being dried over a 2 S 4, filtered, and concentrated. The material was purified by silica gel chromatography by eluting with hexanes/etac (2:5) to give give 52 as a white foam which was used without further purification. Compound 52 (1.49 g, 4 mmol) was dissolved in trifluoroacetic acid (30 ml) and heated to reflux (~72 C) under 2 for 2 hr. After this time the reaction is cooled to room temperature and concentrated under reduced pressure. The residue is then dissolved in THF (50 ml) and treated with an aqueous 28% ammonium hydroxide solution (50 ml). This mixture was stirred at room temperature for 1 h. After this time the reaction was diluted with EtAc (100 ml) and washed with brine. The combined organic layer was then dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography by eluting with hexanes/etac (gradient of 60%-80%) to give 24 (1.49 g, 81%) as a white solid in >95% purity. HPLC-MS (low ph) rt= 1.86 min, m/z = (M+1). 1 H MR ( MHz, DMS-d6): δ (m, 1H), 8.46 (d, J = 2.5 Hz, 1H), 8.27 (d, J = 1.9 Hz, 1H), (m, 2H), 7.53 (d, J = 1.6 Hz, 1H), (m, 1H), 7.04 (d, J = 8.2 Hz, 1H), 6.39 (d, J = 2.5 Hz, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 2H), 1.61 (d, J = 7.3 Hz, 3H). This racemic material was then resolved into enantiomers by chiral chromatography using Chiralcel J-H (4.6 x 150 mm, 5 µm column, Chiral Technologies Europe), eluting with 30% MeH/liquid C 2, 5 ml/min., detecting at 225 nm, to Isomer 1, (+)-24 (>98%ee), with rt = 2.00 min. [α] 20 D = 4.23 (c = 1.02, EtH). The absolute structure was confirmed by single crystal X-Ray crystallography. Isomer 2, (-)-24 (>98%ee) had a retention time of 2.66 min and [α] 20 D = (c = 1.07, EtH). S11

12 -[1-(2-Pyridyl)pyrazol-3-yl]-1-tetrahydropyran-2-yl-indazol-5-amine (40). Tert- Butyl-X-Phos (162 mg) and palladium acetate (26 mg, mmol) were mixed with amylene hydrate (10 ml) and water (0.10 ml). This mixture was purged with nitrogen, then heated to 100 o C via microwave for 2 min. After this time, the orange solution was transferred via syringe to a vial containing 1-(2-pyridyl)pyrazol-3-amine (38) (325 mg, 2.03 mmol), 5-bromo-1- tetrahydropyran-2-yl-indazole (39) (513 g, 2.03 mmol), and finely ground potassium phosphate (386 g, 2 mmol). This was then heated to 100 o C for 3 hrs. After this time the reaction mixture was cooled, diluted with MeH (10 ml) and filtered through celite. The filtrate was concentrated and purified via silica gel chromatography using ethylacetate/methanol (98:2) to give 40 (0.35 g, 48%). HPLC-MS (low ph) rt= 2.24 min, m/z = (M+1). 1 H MR ( MHz, CDCl 3 ): δ 8.44 (d, J = 2.8 Hz, 1H), 8.36 (ddd, J= 4.9, 1.8, 0.8 Hz, 1H), 7.96 (d, J = 0.8 Hz, 1H), 7.88 (dt, J = 8.3, 0.9 Hz, 1H), (m, 2H), 7.54 (m, 1H), 7.26 (dd, J = 8.8, 2.1 Hz, 1H), 7.10 (ddd, J = 7.2, 4.9, 1.1 Hz,, 1H), 6.19 (br s, 1H), 6.14 (d, J = 2.6 Hz, 1H), (m, 1H), 4.04 (m, 1H), (m, 1H), (m, 1H), (m, 2H), (m, 3H). -Methyl--[1-(2-pyridyl)pyrazol-3-yl]-1-tetrahydropyran-2-yl-indazol-5-amine (41). Compound 40 (0.35 g, 0.94 mmol) was dissolved in dimethylformamide (10 ml) and cooled to 0 o C. To this solution was added sodium hydride (75 mg, 1.88 mmol). After 10 min, methyl iodide (147 mg, 1 mmol) was added and the reaction allowed to warm to room temperature over 3 hrs. After this time the mixture was diluted with ethylacetate and washed with water and brine. The organic was then dried over sodium sulfate, filtered and evaporated. The material was then purified via silica gel chromatography using EtAc/MeH (98:2) to give 41 (0.32 g, 87%). HPLC-MS (high ph) rt= 2.48 min, m/z = (M+1). 1 H MR ( S12

13 and filtered through celite. The filtrate was concentrated and purified via silica gel MHz, CDCl 3 ): δ (m, 2H), 7.98 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), (m, 1H), (m, 2H), 7.41 (dd, J = 2.0, 8.9 Hz, 1H), (m, 1H), 5.86 (d, J = 2.8 Hz, 1H), 5.71 (dd, J = 2.6, 9.4 Hz, 1H), (m, 1H), (m, 1H), 3.50 (s, 3H), (m, 1H), (m, 2H), (m, 3H). 6-[[1-(2-Pyridyl)pyrazol-3-yl]amino]-3-(2-trimethylsilylethoxymethyl)-1,3- benzothiazol-2-one (43 Tert-Butyl-X-Phos (200 mg) and palladium acetate (32 mg, mmol) were mixed with amylene hydrate (12 ml) and water (0.10 ml). This mixture was purged with nitrogen, then heated to 100 o C via microwave for 2 min. After this time, the orange solution was transferred via syringe to a vial containing 1-(2-pyridyl)pyrazol-3-amine (38) (0.4 g, 2.5 mmol), 6-bromo-3-(2-trimethylsilylethoxy-methyl)-1,3-benzothiazol-2-one (42) (0.99 g, 2.75 mmol), and finely ground potassium phosphate (475 mg, 2.7 mmol). This was then heated to 100 o C for 3 hrs. After this time the reaction mixture was cooled, diluted with MeH (10 ml) chromatography using ethylacetate/methanol (98:2) to give 43 (0.79 g, 72%). HPLC-MS (high ph) rt= 2.70 min, m/z = (M+1), (M-1). 1 H MR ( MHz, CDCl 3 ): δ (m, 1H), (m, 1H), (m, 2H), 7.63 (d, J = 1.9 Hz, 1H), (m, 2H), 7.06 (ddd, J = 7.1, 4.9, 1.1 Hz, 1H), 6.40 (s, 1H), 6.04 (d, J = 2.6 Hz, 1H), 5.30 (s, 2H), (m, 2H), (m, 2H), (d, J = 1.0 Hz, 9H). 6-[Methyl-[1-(2-pyridyl)pyrazol-3-yl]amino]-3-(2-trimethylsilylethoxymethyl)-1,3- benzothiazol-2-one (44). Compound 43 (0.79 g, 1.8 mmol) was dissolved in dimethylformamide (20 ml) and cooled to 0 o C. To this solution was added sodium hydride (145 mg, 3.63 mmol). After 10 min, methyl iodide (283 mg, 2 mmol) was added and the reaction allowed to warm to room temperature over 3 hrs. After this time the mixture was S13

14 diluted with ethylacetate and washed with water and brine. The organic was then dried over sodium sulfate, filtered and evaporated. The material was then purified via silica gel chromatography using EtAc/MeH (98:2) to give 44 (0.12 g, 15%). HPLC-MS (high ph) rt= 2.92 min, m/z = (M+1). 1 H MR ( MHz, CDCl 3 ): δ 8.36 (d, J = 2.7 Hz, 1H), 8.33 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.82 (dt, J = 8.2, 1.0 Hz, 1H), (m, 1H), 7.37 (d, J = 2.2 Hz, 1H), (m, 2H), 7.06 (ddd, J = 7.3, 4.9, 1.2 Hz, 1H), 5.97 (d, J = 2.7 Hz, 1H), 5.34 (s, 2H), (m, 2H), 3.46 (s, 3H), (m, 2H), (s, 9H). 6-[1-[1-(5-Bromo-2-pyridyl)pyrazol-3-yl]ethyl]-3-(methoxymethyl)-1,3-benzothiazol- 2-one (47). 5-bromo-2-fluoropyridine (24.6 g, 140 mmol) was dissolved in dimethylformamide (400 ml), and to this solution was added lithium tert-butoxide (1M solution in THF)(210 ml, 210 mmol). After stirring for 15min., 19 (80 g, 28 mmol) was added and the solution was heated in an oil bath to 140 C, purging the reaction with 2 to remove the THF. After 5 hrs. the solution was cooled to room temperature and quenched with saturated ammonium chloride. The mixture was then extracted with EtAc and the organic layer washed with water and brine before being dried over a 2 S 4, filtered, and concentrated. The material was purified by silica gel chromatography by eluting with hexanes/etac (2:5) to give 47 (6.78 g, 54%) as a white solid. 1 H MR ( MHz, DMS-d6): δ 8.54 (dd, J = 0.6, 2.5 Hz, 1H), 8.45 (d, J = 2.6 Hz, 1H), 8.15 (dd, J = 2.5, 8.8 Hz, 1H), 7.81 (dd, J = 0.7, 8.8 Hz, 1H), 7.63 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 1.8, 8.5 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.44 (d, J = 2.6 Hz, 1H), 5.27 (s, 2H), (m, 1H), 3.23 (s, 3H), 1.61 (d, J = 7.3 Hz, 3H). 6-[1-[1-[5-(3-Hydroxy-3-methyl-but-1-ynyl)-2-pyridyl]pyrazol-3-yl]ethyl]-3- (methoxymethyl)-1,3-benzothiazol-2-one (48). Compound 47 (1.2 g, 2.7 mmol) was dissolved in DMF (9 ml) and bis(triphenylphosphine)palladium(ii) chloride (189 mg, mmol), S14

15 trietylamine (9 ml, 116 mmol), and copper(i) iodide (51 mg, mmol) was added. The mixture was purged with nitrogen for 20 min. After this time 3-methyl butynol (339 mg, 4.04 mmol) was added and the reaction was heated to 70 o C under nitrogen. After 18hrs, the reaction was quenched with sat. ammonium chloride soln and extracted with EtAc. The organic layer was dried with magnesium sulfate, filtered and evaporated. This residue was then purified via silica gel (20-80 % EtAc in hexanes) to give 48 (0.95 g, 79%) as a clear thick oil. HPLC-MS (low ph) rt= 2.53 min, m/z = (M+1). 1 H MR ( MHz, CDCl 3 ): δ 8.43 (d, J = 2.6 Hz, 1H), 8.41 (dd, J = 0.8, 2.1 Hz, 1H), 7.91 (dd, J = 0.8, 8.5 Hz, 1H), (m, 1H), 7.37 (d, J = 1.8 Hz, 1H), (m, 1H), 7.17 (d, J = 8.5 Hz, 1H), 6.23 (d, J = 2.6 Hz, 1H), (m, 2H), (m, 1H), (m, 1H), 3.37 (s, 3H), (m, 3H), 1.64 (s, 6H). 6-[1-[1-[5-(3-Hydroxy-3-methyl-butyl)-2-pyridyl]pyrazol-3-yl]ethyl]-3- (methoxymethyl)-1,3-benzothiazol-2-one (49). Compound 48 (0.950 g, 2.1 mmol) was dissolved in methanol (70 ml). To this solution was added 10% palladium on carbon (120mg, mmol) and the reaction vessel stirred under an atmosphere of hydrogen (1atm) for 18hr. After this time, the reaction was filtered through celite and evaporated to dryness to give 49 (0.69 g, 69%) as a white solid. HPLC-MS (low ph) rt= 2.36 min, m/z = (M+1). 1 H MR ( MHz, CDCl 3 ): δ 8.42 (d, J = 2.5 Hz, 1H), (m, 1H), 7.87 (d, J = 8.5 Hz, 1H), (m, 1H), 7.38 (d, J = 1.9 Hz, 1H), 7.28 (dd, J = 1.9, 8.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.20 (d, J = 2.6 Hz, 1H), 5.31 (s, 2H), (m, 1H), 3.36 (s, 3H), (m, 2H), (m, 2H), 1.70 (d, J = 7.1 Hz, 3H), 1.31 (s, 6H). 2-Fluoro-5-(2-tetrahydropyran-2-yloxyethyl)pyridine (51). A solution of 5-bromo-2- fluoropyridine (46) (280 g, 1.59 mol) in MTBE (3 L) was cooled to -78 o C under nitrogen. To S15

16 this mixture was added n-butyl lithium (2.5 M in hexanes)(636 ml, 1.59 mol) dropwise over 20 min, maintaining temperature below -60 o C. Ethylene oxide (96.6mL, 1.9 mol) was then added and the reaction mixture continued for 1h. After this time the reaction mixture was warmed to 0 o C and quenched with acetic acid (91 ml, 1.59 mol). This slurry was then filtered and the filtrate evaporated to yield the crude product 50 (140 g, 62%) which was used without further purification. Compound 50 (2.7 g, 19 mmol) was then dissolved in CH 2 Cl 2 (50 ml) and the solution was treated with p-toluenesulfonic acid (0.05 eq, 164 mg) followed by dihydropyran (2.1 ml, 23 mmol) and stirred under nitrogen atmosphere for 18 hr. After this time the mixture was quenched with sodium bicarbonate aqueous soln and extracted with DCM (2 x 50 ml). The combined organic layer was then dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography by eluting with hexanes/etac (4/1) to give 51 (3.3 g, 77%) as a clear oil. HPLC-MS (high ph) rt= 1.96 min, m/z = (M+1). 1 H MR ( MHz, CDCl 3 ): δ 8.09 (d, J = 1.9 Hz, 1H), 7.68 (td, J = 8.1, 2.5 Hz, 1H), 6.86 (dd, J = 2.9, 8.4 Hz, 1H), (m, 1H), 3.94 (dt, J = 9.9, 6.6 Hz, 1H), (m, 1H), 3.58 (dt, J = 9.6, 6.6 Hz, 1H), (m, 1H), 2.89 (t, J = 6.4 Hz, 2H), (m, 6H). S16