(E)-3-Phenylprop-2-en-2-d-1-ol (2.10). To a flame-dried two-neck 100 mL round-bottomed flask equipped with a condenser and a septum under an atmosphere of argon was added lithium aluminum deuteride (0.877 g, 20.9 mmol). The round-bottomed flask was evacuated and refilled with argon (3x), and THF (35 mL) was added via syringe with stirring. 3-Phenyl-2-propyn-1-ol 2.9 (2.0 mL, 16 mmol) in THF (5 mL) was then added slowly dropwise via syringe, and bubbling occurred along with a color change from dark to light grey. The reaction mixture was heated to reflux in an oil bath for 5 h, turning the reaction mixture brown, followed by cooling to rt then 0 °C in an ice bath. To quench the reaction, water was added slowly dropwise and vigorous bubbling occurred. Once bubbling had ceased and the reaction mixture had become white in color, diethyl ether was added and the aqueous layer was separated. The aqueous layer was then extracted with diethyl ether (2x), and the combined organic layers were washed with brine, dried over magnesium sulfate, gravity filtered, and concentrated under reduced pressure to yield the title compound as a clear oil (2.23 g, quant). The crude material was carried on without purification. Data 2.10 1 H NMR (500 MHz, CDCl3) 7.39 (d, J = 7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.26 (t, J = 7.5 Hz, 1H), 6.61 (s, 1H), 4.32 (s, 2H) ppm 13 C NMR (100 MHz, CDCl3) 136.8, 131.2, 128.7 (2C), 128.3 (t, J = 24.0 Hz, 1C), 127.8 (2C), 126.6, 63.8 ppm
IR (thin film)
3338, 3080, 3059, 2919, 2863, 1600, 1493, 1449 cm-1
HRMS (ESI)
[M-H]+ calcd for C9H8DO: 134.0722, found 134.0711 TLC Rf = 0.4 (40% ethyl acetate/hexanes) [silica gel, UV]
(E)-4-Methyl-N-(3-phenylallyl-2-d)-N-(prop-2-yn-1-yl)benzenesulfonamide (2.12). To a flame-dried two-neck 100 mL round-bottomed flask equipped with an argon inlet adapter and a septum was added (E)-3-phenylprop-2-en-2-d-1-ol (2.10) (1.00 g, 7.40 mmol), 4-methyl-N- (prop-2-yn-1-yl)benzenesulfonamide (2.11) (1.55 g, 7.40 mmol), and triphenylphosphine (1.94 g, 7.40 mmol). The round-bottomed flask was evacuated and refilled with argon (3x), and THF (69 mL) was added via syringe with stirring. Diisopropyl azodicarboxylate (1.46 mL, 7.40 mmol) was added dropwise via syringe, and the reaction mixture turned bright yellow in color. The reaction mixture was stirred at rt for 20 h, and was then concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (5 cm column, 5- 15% ethyl acetate/hexanes) to yield the title compound as a white solid (2.04 g, 85%). The preparation of 4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide (2.11) followed the procedure reported by Gilbertson.78
Data 2.12
MP 74-75 °C
1
7.77 (d, J = 8.1 Hz, 2H), 7.35-7.26 (m, 7H), 6.56 (s, 1H), 4.13 (d, J = 2.4 Hz, 2H), 3.99 (s, 2H), 2.44 (s, 3H), 2.04 (t, J = 2.4 Hz, 1H) ppm 13 C NMR (100 MHz, CDCl3) 143.7, 136.2 (2C), 134.9, 129.6 (2C), 128.7 (2C), 128.2, 127.9 (2C), 126.7 (2C), 122.7 (t, J = 24.0 Hz, 1C), 76.8, 74.0, 48.6, 36.0, 21.7 ppm IR (thin film) 3026, 2921, 2119, 1598, 1495, 1348, 1162 cm-1 HRMS (ESI)
[M + H]+ calcd for C19H19DO2NS: 327.1278, found 327.1269 TLC Rf = 0.5 (25% ethyl acetate/hexanes) [silica gel, UV]
(E)-4-Methyl-N-(4-oxopent-2-yn-1-yl)-N-(3-phenylallyl-2-d)benzenesulfonamide (2.14). To a flame-dried two-neck 15 mL round-bottomed flask equipped with an argon inlet adapter and a septum was added enyne 2.12 (0.112 g, 0.34 mmol) in THF (7.8 mL). The solution was cooled to -78 °C in a dry ice-acetone bath, and then lithium diisopropylamide (0.17 mL of a 2.0 M solution in THF/heptanes/ethylbenzene, 0.34 mmol) was added slowly dropwise via syringe, turning the reaction mixture dark purple. The reaction mixture was stirred at -78 °C for 1 h and became green in color. N-Methoxy-N-methylacetamide (2.13) (33 μL, 0.31 mmol) was subsequently added via syringe and the reaction mixture turned light purple. The reaction mixture was stirred at -78 °C for 15 min and at rt for 1.5 h, and overtime the color became a dark brown. The reaction mixture was poured into brine, and sat’d aq ammonium chloride was added. The
aqueous layer was separated and extracted with ethyl acetate (2x), and the combined organic layers were washed with brine, dried over magnesium sulfate, gravity filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (2.5 cm column, 15% ethyl acetate/hexanes) to yield the title compound as a light yellow solid (0.052 g, 46%).
Data 2.14 MP 93-94 °C 1 H NMR (400 MHz, CDCl3) 7.76 (d, J = 8.0 Hz, 2H), 7.35-7.24 (m, 7H), 6.55 (s, 1H), 4.27 (s, 2H), 3.99 (s, 2H), 2.43 (s, 3H), 2.10 (s, 3H) ppm 13 C NMR (100 MHz, CDCl3) 183.3, 144.2, 135.9, 135.7, 135.4, 129.9 (2C), 128.8 (2C), 128.4, 127.9 (2C), 126.7 (2C), 122.2 (t, J = 24.0 Hz, 1C), 84.9, 84.4, 49.3, 36.2, 32.4, 21.6 ppm IR (thin film) 3026, 2921, 2210, 1679, 1597, 1495, 1350, 1163 cm-1 HRMS (ESI)
[M + H]+ calcd for C21H21DO3NS: 369.1374, found 369.1383 TLC Rf = 0.3 (25% ethyl acetate/hexanes) [silica gel, UV]
12.3 mmol) and water (62 mL). Propargyl alcohol (2.16) (1.1 mL, 19 mmol), pyrrolidine (1.52 mL, 18.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.071 g, 0.062 mmol), and copper(I) iodide (0.023 g, 0.12 mmol) were added sequentially. The reaction mixture was stirred at 70 °C for 1 h, turning the reaction mixture from yellow to light green. The reaction mixture was then cooled to rt and diethyl ether was added. The aqueous layer was separated and extracted with diethyl ether (2x), and the combined organic layers were washed with water and brine, dried over magnesium sulfate, gravity filtered, and concentrated under reduced pressure. The crude material was filtered through a pad of silica gel with diethyl ether washings, and then was placed under high vacuum to yield the title compound as a yellow oil (0.844 g, 50%.). Characterization data is consistent with previously reported literature data.79
Data S1 1
H NMR (300 MHz, CDCl3)
4.51 (s, 2H), 1.64 (bs, 1H) ppm
TLC Rf = 0.3 (20% ethyl acetate/hexanes) [silica gel, UV]
(E)-3-(Phenyl-d5)prop-2-en-1-ol (2.17). To a flame-dried two-neck 15 mL round-bottomed flask equipped with a condenser and a septum under an atmosphere of argon was added lithium aluminum hydride (0.164 g, 4.33 mmol). The round-bottomed flask was evacuated and refilled with argon (3x), and THF (7.2 mL) was added via syringe with stirring. 3-(Phenyl-d5)prop-2-yn- 1-ol (S1) (0.457 g, 3.33 mmol) in THF (1.1 mL) was then added slowly dropwise via syringe, and bubbling occurred. The reaction mixture was heated to reflux in an oil bath for 1 h, turning
the reaction mixture from light grey to light brown, followed by cooling to rt then 0 °C in an ice bath. To quench the reaction, water was added slowly dropwise and vigorous bubbling occurred. Once bubbling had ceased and the reaction mixture had become white in color, diethyl ether was added and the aqueous layer was separated. The aqueous layer was then extracted with diethyl ether (4x), and the combined organic layers were washed with brine, dried over magnesium sulfate, gravity filtered, and concentrated under reduced pressure to yield the title compound as an amber oil (0.257 g, 56%). The crude material was carried on without purification.
Data 2.17 1
H NMR (300 MHz, CDCl3)
6.63 (d, J = 15.9 Hz, 1H), 6.37 (dt, J = 15.9, 5.4 Hz, 1H), 4.33 (d, J = 5.4 Hz, 2H), 1.55 (bs, 1H) ppm
TLC Rf = 0.2 (20% ethyl acetate/hexanes) [silica gel, UV]
(E)-4-Methyl-N-(3-(phenyl-d5)allyl)-N-(prop-2-yn-1-yl)benzenesulfonamide (2.18). To a flame-dried two-neck 25 mL round-bottomed flask equipped with an argon inlet adapter and a septum was added (E)-3-(phenyl-d5)prop-2-en-1-ol (2.17) (0.253 g, 1.82 mmol), 4-methyl-N- (prop-2-yn-1-yl)benzenesulfonamide (2.11) (0.381 g, 1.82 mmol), and triphenylphosphine (0.478 g, 1.82 mmol). The round-bottomed flask was evacuated and refilled with argon (3x), and THF (17 mL) was added via syringe with stirring. Diisopropyl azodicarboxylate (0.36 mL, 1.82 mmol) was added dropwise via syringe, and the reaction mixture turned bright yellow in color.
The reaction mixture was stirred at rt for 16 h, and was then concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (2.5 cm column, 15% ethyl acetate/hexanes) to yield the title compound as an off-white solid (0.517 g, 86%). Data 2.18 MP 69-71 °C 1 H NMR (300 MHz, CDCl3) 7.77 (dd, J = 8.4, 1.8 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 6.58 (td, J = 15.9, 1.2 Hz, 1H), 6.08 (dt, J = 15.9, 6.9 Hz, 1H), 4.13 (d, J = 2.4 Hz, 2H), 3.99 (dd, J = 6.9, 1.2 Hz, 2H), 2.44 (s, 3H), 2.04 (t, J = 1.2 Hz, 1H) ppm 13 C NMR (100 MHz, CDCl3) 143.7, 136.2, 136.1, 135.0, 129.6 (2C), 128.5-127.5 (m, 5C), 126.2 (t, J = 24.0 Hz, 2C), 123.0, 76.7, 73.9, 48.7, 36.0, 21.7 ppm IR (thin film) 3289, 3034, 2923, 2276, 2118, 1598, 1494, 1346, 1161 cm-1 HRMS (ESIMSMS)
[M + H]+ calcd for C19H15D5O2NS: 331.1518, found 331.1529 TLC Rf = 0.5 (25% ethyl acetate/hexanes) [silica gel, UV]
(E)-4-Methyl-N-(4-oxopent-2-yn-1-yl)-N-(3-(phenyl-d5)allyl)benzenesulfonamide (2.19). To a flame-dried two-neck 25 mL round-bottomed flask equipped with an argon inlet adapter and a septum was added enyne 2.18 (0.200 g, 0.61 mmol) in THF (14 mL). The solution was cooled to -78 °C in a dry ice-acetone bath, and then lithium diisopropylamide (0.30 mL of a 2.0 M solution in THF/heptanes/ethylbenzene, 0.61 mmol) was added slowly dropwise via syringe, turning the reaction mixture dark purple. The reaction mixture was stirred at -78 °C for 80 min and became light yellow. N-Methoxy-N-methylacetamide (2.13) (58 μL, 0.55 mmol) was subsequently added dropwise via syringe and the reaction mixture was stirred at -78 °C for 15 min and at rt for 1 h. Over time, the color of the reaction mixture turned reddish in color. The reaction mixture was quenched with sat’d aq ammonium chloride, and the aqueous layer was separated and extracted with ethyl acetate (2x). The combined organic layers were washed with brine, dried over magnesium sulfate, gravity filtered, and concentrated under reduced pressure. The crude material was purified by silica gel flash column chromatography (2.5 cm column, 15% ethyl acetate/hexanes) to yield the title compound as a white solid (0.163 g, 80%).
Data 2.19 MP 84-86 °C 1 H NMR (300 MHz, CDCl3) 7.77 (d, J = 8.2 Hz, 2H), 7.34 (d, J = 8.2 Hz, 2H), 6.57 (d, J = 15.9 Hz, 1H), 6.08 (dt, J = 15.9, 6.9 Hz, 1H), 4.27 (s, 2H), 4.00 (dd, J = 6.9, 0.9 Hz, 2H), 2.44 (s, 3H), 2.10 (s, 3H) ppm
13 C NMR (100 MHz, CDCl3) 183.3, 144.2, 135.8 (2C), 135.4, 129.9 (2C), 128.5-127.6 (m, 5C), 126.3 (t, J = 24.0 Hz, 2C), 122.5, 84.9, 84.4, 49.4, 36.2, 32.4, 21.6 ppm IR (thin film) 3031, 2922, 2246, 2209, 1670, 1597, 1494, 1349, 1163 cm-1 HRMS (ESIMSMS)
[M + H]+ calcd for C21H17D5O3NS: 373.1622, found 373.1634 TLC Rf = 0.3 (25% ethyl acetate/hexanes) [silica gel, UV]
Methyl (E)-4-((4-methyl-N-(3-(phenyl-d5)allyl)phenyl)sulfonamido)but-2-ynoate (2.20). To a flame-dried two-neck 5 mL round-bottomed flask equipped with an argon inlet adapter and a septum was added enyne 2.18 (0.100 g, 0.30 mmol) in THF (1.5 mL). The solution was cooled to -78 °C in a dry ice-acetone bath, and then n-butyllithium (0.21 mL of a 1.6 M solution hexanes, 0.33 mmol) was added slowly dropwise via syringe, turning the reaction mixture dark purple. The reaction mixture was stirred at -78 °C for 45 min and became light brown. Methyl chloroformate (30 μL, 0.39 mmol) was subsequently added dropwise via syringe and the reaction mixture was stirred at -78 °C for 1 h, becoming darker brown over time. The reaction mixture was allowed to warm slowly to -10 °C and sat’d aq ammonium chloride was added. The aqueous layer was separated and extracted with ethyl acetate (2x), and the combined organic layers were washed with brine, dried over magnesium sulfate, gravity filtered, and concentrated under
reduced pressure. The crude material was purified by silica gel flash column chromatography (2.5 cm column, 10% ethyl acetate/hexanes) to yield the title compound as a clear oil (0.065 g, 55%). Data 2.20 1 H NMR (400 MHz, CDCl3) 7.76 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 6.58 (td, J = 16.0, 1.2 Hz, 1H), 6.07 (dt, J = 16.0, 6.8 Hz, 1H), 4.24 (s, 2H), 3.98 (dd, J = 6.8, 0.8 Hz, 2H), 3.71 (s, 3H), 2.44 (s, 3H) ppm 13 C NMR (125 MHz, CDCl3) 153.2, 144.2, 135.9, 135.6 (2C), 129.9 (2C), 128.5-127.8 (m, 5C), 126.3 (t, J = 24.0 Hz, 2C), 122.6, 80.8 (2C), 52.9, 49.4, 36.1, 21.7 ppm IR (thin film) 2954, 2240, 1717, 1597, 1435, 1258, 1162 cm-1 HRMS (ESI)
[M + H]+ calcd for C21H17D5O4NS: 389.1556, found 389.1583 TLC Rf = 0.3 (25% ethyl acetate/hexanes) [silica gel, UV]