10600
P. K. Koech, M. J. Krische / Tetrahedron 62 (2006) 10594–10602
CDCl3): d 7.29 (m, 2H), 6.99 (t, J¼8.7 Hz, 2H), 5.76 (s, 1H),
4.28 (m, 1H), 3.95 (m, 2H), 3.87 (d, J¼18.8 Hz, 1H), 3.71 (s,
3H), 3.28 (dd, J¼13.2, 3.3 Hz, 1H), 2.87 (s, 1H), 1.12 (2d,
J¼6.2 Hz, 6H), 0.68 (2d, J¼10.8 Hz, 1H), 0.55 (2s, 1H),
0.09 (s, 6H). 13C NMR (75 MHz, CDCl3): d 162.1 (d,
J¼246.0 Hz), 156.6, 141.6, 135.9, 127.6 (d, J¼7.3 Hz),
119.5, 115.1 (d, J¼21.1 Hz), 64.9, 52.4, 46.3, 43.8, 32.3,
25.8, 19.5, ꢀ0.78. IR (film): 3081, 2956, 2889, 1706,
1601, 1510, 1448, 1412, 1375, 1335, 1250, 1231, 1191,
1118, 1025, 958, 880, 836, 813 cmꢀ1. HRMS: Calcd for
C19H27NO3FSi [Mꢀ1] 364.1744, found 364.1745.
HRMS: Calcd for C14H19NO3F [M+1] 268.1349, found
268.1350.
The saturated alcohol (100 mg, 0.37 mmol, 100 mol %) was
dissolved in THF (3 mL) and PPh3 (120 mg, 0.45 mmol,
120 mol %) was added. The solution was cooled to 0 ꢂC
and DIAD was added dropwise. The solution was allowed
to stir at 0 ꢂC for 10 min, at which point sesamol (100 mg,
0.75 mmol, 200 mol %) in THF (1 mL) was added dropwise
and the reaction mixture was allowed to stir for another
10 min at 0 ꢂC. The reaction mixture was heated to 50 ꢂC
and was allowed to stir at this temperature for 2 h, at which
point the reaction mixture was allowed to reach ambient tem-
perature. The reaction mixture was evaporated to dryness,
and the residue was dissolved in CH2Cl2 (5 mL). In order
to remove excess sesamol, the organic layer was washed with
aqueous NaOH (2 M, 2ꢃ10 mL) and the aqueous extracts
were back-extracted with CH2Cl2 (10 mL). The combined
organic layers were dried (MgSO4), filtered and evaporated
onto silica gel. Purification via column chromatography
(SiO2, 4:1 hexane/ethyl acetate) gives the phenolic ether
(110 mg, 2.84 mmol) in 76% yield as a pale yellow oil.
3.2.16. Homo-allyl alcohol 10. To a solution of 9 (0.82 g,
2.24 mmol, 100 mol %) in DMF (12 mL) at room tempera-
ture were added potassium fluoride (0.52 g, 8.98 mmol,
400 mol %) and 30% aqueous hydrogen peroxide (3 mL,
26.9 mmol, 1200 mol %). The reaction mixture was allowed
to stir at room temperature for 18 h, at which point H2O
(60 mL) was added. The resulting mixture was extracted
with diethyl ether (3ꢃ20 mL), and the combined organic ex-
tracts were washed with saturated aqueous Na2S2O3 (20 mL)
dried (MgSO4), and evaporated to afford a colorless oil.
Purification via column chromatography (SiO2, 4:1 to 1:1
hexane/ethyl acetate) gives 10 (0.41 g, 1.54 mmol) in 70%
yield as a colorless oil. [a]2D3 +84 (c 3.06, CH2Cl2). Chiral
HPLC (Daicel Chiralpak OJ-H column, 90:10 hexanes/
1
[a]2D3 ꢀ13 (c 1.5, CH2Cl2). H NMR (500 MHz, DMSO-d6
at 100 ꢂC): d 7.27 (dd, J¼8.6, 5.6 Hz, 2H), 7.06 (t,
J¼8.9 Hz, 2H), 6.9 (d, J¼8.5 Hz, 1H), 6.40 (d, J¼2.4 Hz,
1H), 6.18 (dd, J¼8.3, 2.4 Hz, 1H), 5.89 (s, 2H), 4.31 (dd,
J¼13.4, 3.0 Hz, 1H), 4.09 (dt, J¼13.3, 2.0 Hz, 1H), 3.64 (s,
3H), 3.41 (m, 2H), 2.89 (td, J¼12.8, 2.8 Hz, 1H), 2.82 (t,
J¼11.6 Hz, 1H), 2.70 (td, J¼5.8 Hz, 1H), 2.05 (m, 1H),
1.73 (dd, J¼13.2, 3.1 Hz, 1H), 1.67 (qd, J¼12.1, 4.4 Hz,
i-PrOH, l¼254 nm, 0.4 mL minꢀ1, tmajor¼31.0 min, tminor
¼
45.9 min, ee¼92%). 1H NMR (500 MHz, DMSO-d6 at
100 ꢂC): d 7.43 (dd, J¼8.8, 2.1 Hz, 2H), 7.12 (t, J¼8.9 Hz,
2H), 6.00 (t, J¼2.4 Hz, 1H), 4.27 (s, 1H), 4.18 (m, 2H),
3.82 (dt, J¼19.1, 2.8 Hz, 1H), 3.65 (s, 3H), 3.32 (dt,
J¼10.6, 3.8 Hz, 1H), 3.18 (m, 2H), 2.83 (dd, J¼4.2,
13
1H). C NMR (125 MHz, DMSO-d6 at 100 ꢂC): 160.5 (d,
J¼242.6 Hz), 154.7, 153.6, 147.4, 141.0, 139.7 (d, J¼
3.0 Hz), 128.6 (d, J¼8.1 Hz), 114.5 (d, J¼21.4 Hz), 107.3,
105.9, 100.4, 97.6, 69.0, 51.6, 46.4, 43.5, 42.9, 40.6, 32.9.
IR (film): 3008, 2916, 1701, 1510, 1488, 1450, 1412, 1276,
1223, 1185, 1132, 1037, 937, 832, 765 cmꢀ1. HRMS: Calcd
for C21H23NO5F [M+1] 388.1560, found 388.1561.
13
2.1 Hz, 1H). C NMR (125 MHz, DMSO-d6 at 100 ꢂC):
d 161.0 (d, J¼2.44.1 Hz), 155.3, 135.7 (d, J¼3.0 Hz),
135.0, 126.9 (d, J¼8.1 Hz), 121.9, 114.4 (d, J¼21.4 Hz),
60.3, 51.5, 43.1, 41.5. IR (film): 3426, 3056, 2954, 2876,
1686, 1601, 1510, 1448, 1412, 1375, 1228, 1131, 1091,
1039, 953, 836, 814, 768, 735 cmꢀ1. HRMS: Calcd for
C14H17NO3F [M+1] 266.1192, found 266.1199.
To a reaction vessel charged with the phenolic ether (50 mg,
0.13 mmol, 100 mol %) and KOH (94 mg, 1.68 mmol %,
1300 mol %) were added ethylene glycol (1.5 mL), and wa-
ter (0.6 mL). The mixture was heated to 100 ꢂC for 20 h
and then cooled to room temperature, diluted with water
(10 mL), and extracted with CH2Cl2 (3ꢃ5 mL). The com-
bined organic layers were washed with H2O (2ꢃ5 mL), dried
(MgSO4), filtered, and evaporated to provide an oily residue.
The residue was dissolved in ether (5 mL) and the resulting
solution was treated with 4 M HCl in dioxane (5 mL) to
give a white solid. The white solid was filtered, washed
with ether, and dried to afford (45 mg, 0.12 mmol) paroxetine
hydrochloride in 92% yield. Mp 132–134 ꢂC. Lit10i 136–
3.2.17. Conversion of 10 to paroxetine hydrochloride. A
solution containing 10 (300 mg, 1.13 mmol, 100 mol %) in
CH2Cl2 (11 mL) was cooled to ꢀ78 ꢂC, evacuated and filled
with Ar(g). This process was repeated twice. The solution
was allowed towarm to room temperature and Crabtree’s cat-
alyst (45 mg, 0.056 mmol, 5 mol %) was added as a solid in
one portion. The mixture was purged with H2(g) for 5 min
and allowed to stir under 1 atm of hydrogen for 20 h. The
reaction mixture was evaporated onto silica gel. Purification
via column chromatography (SiO2, 4:1 to 3:2 hexane/ethyl
acetate) gives the saturated alcohol (210 mg, 0.78 mmol) in
69% yield. [a]2D3 ꢀ40 (c 2.0, CH2Cl2). 1H NMR (500 MHz,
DMSO-d6 at 100 ꢂC): d 7.23 (dd, J¼7.9, 6.1 Hz, 2H), 7.06
(t, J¼8.9 Hz, 2H), 4.30 (dd, J¼13.3, 2.5 Hz, 1H), 4.09 (d,
J¼5.6 Hz, 1H), 4.07 (d, J¼15.7 Hz, 1H), 3.64 (s, 3H), 3.18
(m, 1H), 3.02 (m, 1H), 2.83 (t, J¼13.0 Hz, 1H), 2.66 (t,
J¼11.4 Hz, 1H), 2.53 (td, J¼11.6, 3.2 Hz, 1H), 1.72 (m,
2H), 1.57 (qd, J¼12.6, 4.4 Hz, 1H). 13C NMR (125 MHz,
DMSO-d6 at 100 ꢂC): d 160.3 (d, J¼244.1 Hz), 154.7,
139.8 (d, J¼3.0 Hz), 128.5 (d, J¼7.6 Hz), 114.3 (d, J¼
21.4 Hz), 60.8, 51.5, 46.7, 43.6, 43.0, 42.8, 33.2. IR (film):
3435, 3009, 2918, 2853, 1697, 1603, 1510, 1476, 1451,
1
138 ꢂC. [a]D23 ꢀ85 (c 1.0, CH3OH). Lit10i ꢀ86.5. H NMR
(400 MHz, CDCl3): d 7.20 (dd, J¼8.2, 5.5 Hz, 2H), 7.00 (t,
J¼8.5 Hz, 2H), 6.61 (d, J¼8.2 Hz, 1H), 6.32 (d, J¼
2.73 Hz, 1H), 6.10 (dd, J¼8.5, 2.4 Hz, 1H), 5.88 (s, 2H),
3.73 (dd, J¼21.5, 14.4 Hz, 2H), 3.60 (d, J¼8.2 Hz, 1H),
3.48 (dd, J¼9.9, 4.4 Hz, 1H), 3.17 (t, J¼10.9 Hz, 1H), 2.04
(m, 1H), 2.90 (t, J¼11.3 Hz, 1H), 2.64 (m, 1H), 2.38 (q,
J¼13.3 Hz, 2H), 2.03 (d, J¼6.3 Hz, 1H). IR (film): 3401,
2925, 1605, 1510, 1224, 1185, 1037, 831 cmꢀ1
.
3.2.18. Phenolic ether 12. To a stirred solution of 11
(240 mg, 0.54 mmol, 300 mol %) in THF (3 mL) at ꢀ78 ꢂC
1413, 1279, 1223, 1159, 1129, 1064, 1014, 832, 767 cmꢀ1
.