M.-Y. Chang et al. / Tetrahedron 67 (2011) 7673e7680
7679
and EtOAc); IR (CHCl3) 3321, 2928, 1428, 1122, 718 cmꢀ1; HRMS
NMR (400 MHz):
d
7.81e7.76 (m, 2H), 7.52e7.48 (m, 1H), 7.44e7.34
(ESI, Mþþ1) calcd for C28H30NO4S 476.1896, found 476.1897; 1H
(m, 2H), 6.09 (dd, J¼11.2, 17.6 Hz, 1H), 5.96e5.86 (m, 1H), 5.47 (t,
J¼4.0 Hz, 1H), 5.18e5.03 (m, 4H), 4.70 (d, J¼10.0 Hz, 1H), 3.86 (dt,
J¼4.0, 15.2 Hz, 1H), 3.29 (dt, J¼8.4, 16.8 Hz, 1H), 2.57e2.51 (m, 1H),
NMR (400 MHz):
d
7.63 (d, J¼8.0 Hz, 2H), 7.31 (d, J¼8.0 Hz, 2H), 7.12
(d, J¼8.8 Hz, 2H), 7.06 (d, J¼8.0 Hz, 2H), 6.89 (s, 1H), 6.83 (d,
J¼8.0 Hz, 2H), 6.79 (d, J¼8.8 Hz, 2H), 6.42 (s, 1H), 3.82 (s, 3H), 3.78
(s, 3H), 3.28 (t, J¼5.6 Hz, 2H), 2.42 (s, 3H), 1.58e1.52 (m, 2H),
2.39e2.31 (m,1H),1.88e1.85 (m, 2H); 13C NMR (100 MHz):
d 141.25,
136.80, 136.61, 134.87, 132.32, 128.71 (2ꢂ), 126.94 (2ꢂ), 126.30,
1.51e1.43 (m, 2H); 13C NMR (100 MHz):
d
158.58, 158.54, 143.58,
117.00, 111.98, 52.84, 37.62, 37.40, 23.21.
137.26, 136.45, 134.85, 133.27, 131.46 (2ꢂ), 129.69 (2ꢂ), 128.16 (2ꢂ),
126.88 (2ꢂ), 126.85 (2ꢂ), 119.31, 113.36 (2ꢂ), 113.12 (2ꢂ), 55.15,
55.06, 43.36, 24.39, 21.46, 20.92. Single-crystal X-ray diagram:
crystal of compound 12b was grown by slow diffusion of EtOAc into
a solution of compound 12b in DCM to yield colorless prism. The
compound crystallizes in the monoclinic crystal system, space
4.10. 1-Benzenesulfonyl-2,3,7,7a-tetrahydro-1H-[1]pyrindine
(14)
Grubbs second catalyst (12 mg, 1.4% mmol) was added to a so-
lution of compound 3 (61 mg, 0.21 mmol) in 1,2-dichloroethane
(5 mL) at reflux. The reaction mixture was stirred at reflux for
1 h. Water (1 mL) was added to the reaction mixture and the sol-
vent was concentrated. The residue was extracted with EtOAc
(3ꢂ20 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product under re-
duced pressure. Purification on silica gel (hexane/EtOAc¼8/1)
afforded compound 14 (41 mg, 75%). Colorless oil; IR (CHCl3) 3361,
2952, 1460, 1152, 972, 722 cmꢀ1; HRMS (ESI, Mþþ1) calcd for
C14H16NO2S 262.0902, found 262.0904; 1H NMR (400 MHz):
ꢀ
ꢀ
ꢀ
group P1 21/n1, a¼14.3704(11) A, b¼10.2927(8) A, c¼16.1666(13) A,
3
V¼2383.1(3) A , Z¼4, dcalcd¼1.326 g/cm3, F(000)¼1008, 2
q
range
ꢀ
1.82e26.41ꢁ, R indices (all data) R1¼0.0463, wR2¼0.1107.
4.8. Methanesulfonic acid 2-(2-allyl-1-benzenesulfonyl-3-
bromo-piperidin-3-yl)-ethyl ester (13)
A solution of DIBALH (1.0 M in THF, 1.5 mL, 1.5 mmol) was added
to a stirred solution of compound 4 (130 mg, 0.3 mmol) in THF
(10 mL) at ice bath. The mixture was further stirred for 5 h at rt. The
reaction was quenched with NH4Cl(aq) (15%, 1 mL) at ice bath and
the mixture was concentrated under reduced pressure. The residue
was extracted with EtOAc (3ꢂ30 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to afford
crude bromoalcohol product 4a under reduced pressure. 1H NMR
d
7.82e7.72 (m, 2H), 7.65e7.48 (m, 3H), 6.19e6.08 (m, 1H),
6.00e5.98 (m, 1H), 5.54 (dd, J¼4.0, 7.2 Hz, 1H), 3.73 (ddd, J¼4.0, 4.8,
11.6 Hz, 1H), 3.56 (ddt, J¼2.0, 4.8, 13.6 Hz, 1H), 2.87e2.81 (m, 1H),
2.75 (ddd, J¼4.8, 9.2, 13.6 Hz, 1H), 2.40e2.33 (m, 2H), 2.06e2.00 (m,
1H); 13C NMR (100 MHz):
d 134.30, 132.85, 130.08, 129.15, 129.07
(2ꢂ), 127.94, 127.77 (2ꢂ), 114.94, 58.87, 45.65, 39.21, 24.99.
(200 MHz):
d 7.92e7.87 (m, 2H), 7.51e7.45 (m, 3H), 5.91e5.67 (m,
1H), 5.17e4.98 (m, 2H), 4.58e4.43 (m, 1H), 4.02 (t, J¼6.6 Hz, 2H),
3.73e3.60 (m, 1H), 2.99e2.84 (m, 1H), 2.58e2.29 (m, 3H),
2.08e1.45 (m, 6H). Without further purification, methanesulfonyl
chloride (115 mg,1.0 mmol) was added to a stirred solution of crude
product 4a in the co-solvent of pyridine (5 mL) and DCM (10 mL) at
ice bath. The reaction mixture was stirred at rt for 10e12 h. Water
(5 mL) was added to the reaction mixture and the mixture was
filtered through a short plug of Celite. The filtrate was concentrated
under reduced pressure. The residue was extracted with EtOAc
(3ꢂ50 mL). The combined organic layers were washed with brine,
dried, filtered, and evaporated to afford crude product under re-
duced pressure. Purification on silica gel (hexane/EtOAc¼4/1)
afforded compound 13 (100 mg, 71% of two-steps). Colorless oil; IR
(CHCl3) 3372, 2948, 1428, 1119, 821 cmꢀ1; HRMS (ESI, Mþþ1) calcd
for C17H25BrNO5S2 466.0358, found 466.0361; 1H NMR (400 MHz):
4.11. 1-Benzenesulfonyl-octahydro-[1]pyrindine (rodocaine
core, 2) and 1-benzenesulfonyl-2,3,5,6,7,7a-hexahydro-1H-[1]
pyrindine (15)
Palladium on activated carbon (10%, 5 mg) was added to a so-
lution of compound 14 (52 mg, 0.2 mmol) in EtOH (10 mL) at rt.
Then hydrogen was bubbled into the mixture for 10 min, and stir-
ring occurred at rt for 20 h. The reaction mixture was filtered and
evaporated to yield crude product. Purification on silica gel (hex-
ane/EtOAc¼4/1) afforded compounds 2 (26 mg, 50%) and 15
(15 mg, 29%). For compound 2: Colorless oil; IR (CHCl3) 3310, 2891,
1412, 1080 cmꢀ1; HRMS (ESI, MþþNa) calcd for C14H19NO2SNa
288.1034, found 288.1035; 1H NMR (400 MHz):
d 7.83e7.79 (m, 2H),
7.57e7.52 (m, 1H), 7.51e7.46 (m, 2H), 4.24e4.18 (m, 1H), 3.76e3.72
(m, 1H), 2.79 (dt, J¼2.8, 12.8 Hz, 1H), 1.92e1.85 (m, 1H), 1.68e1.31
d
7.90e7.87 (m, 2H), 7.56e7.52 (m, 1H), 7.49e7.45 (m, 2H),
(m, 9H), 1.10 (dq, J¼3.6, 12.8 Hz, 1H); 13C NMR (100 MHz):
d 140.57,
5.79e5.69 (m, 1H), 5.11e5.00 (m, 2H), 4.60 (t, J¼7.2 Hz, 2H), 4.44
(dd, J¼5.6, 9.2 Hz, 1H), 3.66 (ddd, J¼1.6, 4.0, 13.2 Hz, 1H), 3.06 (s,
3H), 2.92 (dt, J¼3.2, 13.2 Hz, 1H), 2.46e2.25 (m, 4H), 2.00e1.81 (m,
132.17, 128.90 (2ꢂ), 127.08 (2ꢂ), 57.12, 40.38, 36.78, 28.76, 25.59,
24.42, 22.46, 19.95. For compound 15: Colorless oil; HRMS (ESI,
Mþþ1) calcd for C14H18NO2S 264.1058, found 264.1059; 1H NMR
3H), 1.56e1.53 (m, 1H); 13C NMR (100 MHz):
d
140.80, 133.55,
(400 MHz): d 7.84e7.80 (m, 2H), 7.59e7.47 (m, 3H), 5.52e5.49 (m,
132.36, 128.59 (2x), 127.62 (2x), 118.43, 70.48, 67.63, 62.75, 41.75,
39.42, 37.51, 34.28, 32.72, 21.57; Anal. Calcd for C17H24BrNO5S2: C,
43.78; H, 5.19; N, 3.00. Found: C, 44.01; H, 5.31; N, 3.20.
1H), 4.24e4.18 (m, 1H), 3.76e3.70 (m, 1H), 3.46e3.33 (m, 1H), 2.80
(dt, J¼2.0, 13.2 Hz, 2H), 2.39e2.29 (m, 2H), 1.98e1.67 (m, 2H),
1.52e1.48 (m, 2H); 13C NMR (100 MHz):
d 132.70, 132.59, 132.15,
128.88 (2ꢂ), 127.06 (2ꢂ), 116.61, 57.10, 40.37, 36.76, 28.75, 25.57,
4.9. 6-Allyl-1-benzenesulfonyl-5-vinyl-1,2,3,6-
tetrahydropyridine (3)
24.39.
4.12. N-(2-Chloro-6-methylphenyl)-3-(octahydro-[1]
DBU (150 mg, 1.0 mmol) was added to a solution of compound
13 (90 mg, 0.19 mmol) in THF (10 mL) at reflux. The reaction mix-
ture was stirred at reflux for 2 h. Water (1 mL) was added to the
reaction mixture and the solvent was concentrated. The residue
was extracted with EtOAc (3ꢂ20 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to afford
crude product under reduced pressure. Purification on silica gel
(hexane/EtOAc¼10/1) afforded compound 3 (32 mg, 57%). Colorless
oil; IR (CHCl3) 3352, 2940, 1429, 1138, 712 cmꢀ1; HRMS (ESI,
MþþNa) calcd for C16H19NO2SNa 312.1034, found 312.1037; 1H
pyrindin-1-yl)propionamide (rodocaine, 1)
Magnesium (10 mg, 0.42 mmol) was added to a solution of
compound 2 (30 mg, 0.11 mmol) in MeOH (3 mL) at rt. The reaction
mixture was stirred at reflux for 4 h. Water (1 mL) was added to the
reaction mixture and the solvent was concentrated. The residue
was extracted with EtOAc (3ꢂ20 mL). The combined organic layers
were washed with brine, dried, filtered, and evaporated to afford
crude product under reduced pressure. Without further purifica-
tion, potassium carbonate (28 mg, 0.20 mmol) was added to