Notes
J . Org. Chem., Vol. 66, No. 7, 2001 2491
130.6, 138.5, 150.2, 158.8, 158.9. MS (FAB) m/z (relative
intensity) 377 (M+, 81Br, 96), 375 (M+, 79Br, 100). HRMS (FAB,
M+ + 1): calcd for C19H24N2OBr, 375.1072; found, 375.1069.
1-(4-Meth yl)ben zen esu lfon yl-4-[(5-br om o-2-p yr id in yl)m -
eth yl]p ip er id in e (26): as a white solid in 52% yield. Mp 149-
6.8 Hz, 2H), 3.41 (bs, 2H), 3.70 (t, J ) 6.9 Hz, 2H)). To a
suspension of methyltriphenylphosphonium bromide (13.22 g,
37 mmol) in anhydrous THF (200 mL) at -78 °C was added
n-BuLi (2.5 M in hexanes; 14.8 mL, 37 mmol). After stirring for
15 min, the intermediate described above (4.55 g, 20 mmol) and
THF (200 mL) were added. The resulting solution was warmed
to room temperature, stirred for 18 h, poured into ice-cooled
water, and extracted with diethyl ether. The organic layer was
washed with water and brine, dried over Na2SO4, and concen-
trated. Purification by flash chromatography over silica gel (3:1
CH2Cl2:hexanes eluant) afforded 37 (2.40 g) as an oil in 19%
1
150 °C. H NMR (300 MHz, CDCl3) δ 1.36 (dq, J ) 3.6 and 12.0
Hz, 2H), 1.60-1.78 (m, 2H), 1.84-1.1.99 (m, 1H), 2.19 (dt, J )
2.1, 11.7 Hz, 2H), 2.41 (s, 3H), 2.62 (d, J ) 6.6 Hz, 2H), 3.73 (d,
J ) 11.7 Hz, 2H), 6.97 (d, J ) 8.1 Hz, 1H), 7.28 (d, J ) 8.4 Hz,
2H), 7.60 (d, J ) 8.4 Hz, 2H), 7.68 (dd, J ) 8.4, 2.7 Hz, 1H),
8.52 (d, J ) 2.7 Hz, 1H). 13C NMR (75 Hz, CDCl3) δ 21.4, 31.1,
35.5, 43.8, 46.3, 118.1, 124.9, 127.6 (2C), 129.5 (2C), 132.9, 138.8,
143.4, 150.2, 158.3. MS (ESI) m/z (relative intensity) 410 (M +
1, 100). MS (FAB) m/z (relative intensity) 411 (M+, 81Br, 96),
409 (M+, 79Br, 100). HRMS (FAB, M+ + 1): calcd for C18H22N2O2-
SBr, 409.0585; found, 409.0591.
4-[(5-Br om o-2-p yr id in yl)m eth yl]p ip er id in -1-yl-(4-m eth -
oxy)p h en yl Meth a n on e (27): as a white solid in 55% yield.
Mp 101-104 °C. 1H NMR (300 MHz, CDCl3) δ 1.15-1.39 (bm,
2H), 1.55-1.76 (bm, 2H), 1.97-2.17 (m, 2H), 2.54 (d, J ) 7.2
Hz, 0.25H), 2.70 (d, J ) 7.2 Hz, 1.75H), 2.75-3.01 (bm, 2H),
3.82 (s, 3H), 4.03-4.80 (b, 1H), 6.89 (d, J ) 8.7 Hz, 2H), 7.02 (d,
J ) 8.4 Hz, 1H), 7.36 (d, J ) 8.7 Hz, 2H), 7.72 (dd, J ) 8.4, 2.4
Hz, 1H), 8.59 (d, J ) 2.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ
32.1, 32.5, 36.8, 44.2, 55.3, 113.6, 118.2, 125.0, 127.7, 128.3,
128.9, 138.9, 150.3, 158.4, 160.5, 170.3. MS (ESI) m/z (relative
intensity) 391 (M+, 81Br, 96), 389 (M+, 79Br, 100). HRMS (FAB,
M+ 81Br): calcd for C19H21N2O2Br, 391.0844; found, 391.0838.
Anal. Calcd for C19H21BrN2O2: C, 58.62; H, 5.44; N, 7.20.
Found: C, 58.29; H, 5.45; N, 6.88.
1
yield over two steps. H NMR (300 MHz, CDCl3) δ 1.06 (s, 6H),
1.46 (s, 9H), 2.27 (bt, J ) 6.0 Hz, 2H), 3.12 (bs, 2H), 3.43 (t, J )
5.8 Hz, 2H), 4.71 (bs, 2H). 13C NMR (75 MHz, CDCl3) δ 24.8
(2C), 28.4 (3C), 32.1, 37.6, 45.2, 56.4, 79.3, 106.7, 152.9, 155.0.
1-P ip er id in eca r boxylic Acid , 4-[[4-[(3-Ch lor op h en yl)-
su lfon yl]p h en yl]m eth yl]-3-h yd r oxy 1,1-Dim eth yleth yl Es-
ter (40). The general procedure for the formation of 4 above was
used, except K3PO4 was used instead of K2CO3. Purification of
the crude oil was carried out using silica gel chromatography
(4:1 hexanes:EtOAc eluant) to give 40 as a colorless oil in 78%
yield as a 1:1 mixture of isomers. A second treatment by silica
gel chromatography led to the collection of a small sample of
each isomer. 40cis: 1H NMR (300 MHz, CDCl3) δ 1.34-1.44 (m
(obscured by singlet at 1.49), 1H), 1.49 (s, 9H), 1.55-1.75 (m,
2H), 1.78-1.93 (b, 1H), 2.59-2.68 (m, 2H), 2.79-2.88 (m, 2H),
3.60 (bs, 1H), 4.06-4.21(m, 2H), 7.37 (d, J ) 8.3 Hz, 2H), 7.44
(t, J ) 8.3 Hz, 1H), 7.53 (d, J ) 8.3 Hz, 1H), 7.81-7.88 (m, 3H),
7.93 (bs, 1H). Treatment of 40cis with 5:1 CH2Cl2:TFA produced
a derivative with the following properties. Mp (HCl salt) 155-
165 °C (with decompostion). 1H NMR (300 MHz, CDCl3) (free
base) δ 1.33-1.41 (m, 1H), 1.46-1.59 (m, 1H), 1.60-1.68 (m,
1H), 1.85 (b, 2H), 2.51 (dt, J ) 2.1 Hz; J ) 8.7 Hz, 1H), 2.56-
2.64 (m, 2H), 2.81(dd, J ) 6.0 Hz; J ) 9.9 Hz, 1H), 2.94-3.04
(m, 2H), 3.47 (bs, 1H), 7.36 (d, J ) 6.6 Hz, 2H), 7.44 (t, J ) 5.7
Hz, 1H), 7.49-7.53 (m, 1H), 7.80-7.86 (m, 3H), 7.91 (t, J ) 1.5
Hz, 1H). 13C NMR (75 MHz, CDCl3) (free base form) δ 28.4, 40.4,
43.6, 47.6, 54.1, 67.0, 126.7, 128.6 (2C), 128.8, 131.3, 131.6 (2C),
134.2, 136.4, 139.3, 144.6, 148.3. HRMS (FAB, M+ + 1): calcd
for C18H21NO3SCl, 366.0931; found, 366.0936.
1-P ip er id in eca r boxylic Acid , 3-Hyd r oxy-4-m eth ylen e
1,1-Dim eth yleth yl Ester (34). A mixture of SeO2 (563 mg),
CH2Cl2 (40 mL), and t-BuOOH (90% in decane, 2 mL) was cooled
to 0 °C and stirred for 20 min. A solution of olefin 2 (2.00 g,
10.15 mmol) and CH2Cl2 (5 mL) was added dropwise, the cooling
bath was removed, and the mixture was stirred for 90 min. A
10% NaHSO3 solution was added, and the aqueous layer was
removed and extracted with CH2Cl2. The organic extracts were
combined, dried over MgSO4, filtered, and concentrated to give
an orange oil, which was further purified by silica gel chroma-
tography (3:1 hexanes:EtOAc) to give 34 as an oil (1.41 g) in
65% yield. Rf ) 0.24 (3:1 hexanes:EtOAc). 1H NMR (300 MHz,
CDCl3) δ 1.47 (s, 9H), 1.70-1.90 (b, 1H), 2.10-2.22 (m, 1H),
2.41-2.49 (m, 1H), 3.12-3.32 (m, 2H), 3.46-3.61 (m, 1H), 3.75
(dd, J ) 12.8, 4.1 Hz, 1H), 4.09-4.14 (bm, 1H), 4.88 (s, 1H), 5.02
(s, 1H). 13C NMR (75 MHz, CDCl3) δ 28.3, 32.2, 45.3 (b), 51.3,
69.7, 79.9, 108.0, 147.0, 155.0. HRMS (FAB, M+ + 1): calcd for
40tr a n s: 1H NMR (300 MHz, CDCl3) δ 1.05-1.20 (m, 2H),
1.44 (s, 9H), 1.55-1.70 (m, 1H), 2.05-2.20 (b, 1H), 2.38-2.48
(m, 1H), 2.52-2.66 (m, 2H), 3.25-3.38 (m, 2H), 3.94 (bd, J )
13.0 Hz, 1H), 4.22 (bd, J ) 13.0 Hz, 1H), 7.34 (d, J ) 7.8 Hz,
2H), 7.44 (t, J ) 6.5 Hz, 1H), 7.53 (d, J ) 6.5 Hz, 1H), 7.80-
7.89 (m, 3H), 7.92 (bs, 1H). Treatment of 40tr a n s with 5:1 CH2-
Cl2:TFA produced a derivative with the following properties. Mp
(HCl salt) 130-140 °C (with decompostion). 1H NMR (300 MHz,
CDCl3) (free base) δ 1.06-1.17 (m, 1H), 1.50-1.66 (m, 2H), 1.70-
1.82 (bs, 2H), 2.39-2.52 (m, 3H), 2.87-2.94 (m, 1H), 3.14-3.24
(m, 2H), 3.33 (ddd, J ) 3.3, 7.2, 7.2 Hz, 1H), 7.31-7.35 (m, 2H),
7.44 (t, J ) 6.0 Hz, 1H), 7.50-7.54 (m, 1H), 7.81-7.85 (m, 3H),
7.92 (t, J ) 1.2 Hz, 1H). 13C (75 MHz, CDCl3) (free base form) δ
31.4, 39.6, 46.6, 46.9, 54.8, 72.7, 126.7, 128.6, 128.8, 131.3 (2C),
131.5, 131.6, 134.3, 136.4, 139.3, 144.5, 148.1. HRMS (FAB, M+
+ 1): calcd for C18H21NO3SCl, 366.0931; found, 366.0928.
1-P ip er id in eca r boxylic Acid , 4-[[4-[(4-Meth oxyp h en yl)-
su lfon yl]p h en yl]m eth yl]-3- d im eth yl(1,1-d im eth yleth yl)-
siloxy, 1,1-Dim eth yleth yl Ester (41). The general procedure
for the formation of 4 above was used, except K3PO4 was used
instead of K2CO3. Purification of the crude oil was carried out
using silica gel chromatography (5:1 then 1:1 hexanes:EtOAc
eluant) to give 41 as a yellow oil (Rf ) 0.18 (5:1 hexanes:EtOAc))-
in 65% yield as a 1:1 mixture of isomers. A second treatment by
silica gel chromatography led to the collection of a small sample
of each isomer. 41cis: 1H NMR (300 MHz, CDCl3) δ 0.03 (s, 3H),
0.11 (s, 3H), 0.99 (s, 9H), 1.12-1.27 (m, 1H), 1.43 (s, 9H), 1.50-
1.75 (m, 2H), 2.47-2.60 (m, 1H), 2.62-2.96 (m, 3H), 3.75 (bs,
1H), 3.83 (s, 3H), 3.85-4.05 (m, 2H), 6.96 (d, J ) 9.0 Hz, 2H),
7.25 (d, J ) 8.7 Hz, 2H), 7.82 (d, J ) 8.7 Hz, 2H), 7.86 (d, J )
9.0 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ -4.7, -4.1, 18.2, 24.7,
25.9 (3C), 28.5 (3C), 38.2, 42.4, 42.8, 48.7, 50.0, 55.7, 68.2, 114.3
(2C), 127.2 (2C), 129.6 (2C), 129.7 (2C), 133.2, 139.8, 146.2, 154.7,
163.0. 41tr a n s: 1H NMR (300 MHz, CDCl3) δ 0.10 (s, 3H), 0.13
(s, 3H), 0.91 (s, 9H), 0.99-1.14 (m, 1H), 1.44 (s, 9H), 1.50-1.63
(m, 2H), 2.09 (t, J ) 10.5 Hz, 1H), 2.42-2.56 (bm, 2H), 3.20-
3.36 (bm, 2H), 3.83 (s, 3H), 3.87-4.00 (bm, 1H), 4.06 (bm, 1H),
C
11H20NO3, 214.1443; found, 214.1441.
1-P ip er id in eca r boxylic Acid , 3-[Dim eth yl(1,1-d im eth -
yleth yl)siloxy]-4-m eth ylen e 1,1-Dim eth yleth yl Ester (35).
Alcohol 34 (64 mg, 0.30 mmol), TBDMSCl (60 mg, 0.36 mmol),
and imidazole (31 mg, 0.45 mmol) were dissolved in DMF (3 mL)
and stirred for 18 h at room temperature. A second portion of
TBDMSCl (54 mg) was added, and the solution was heated at
45 °C for 24 h. After the mixture was cooled to room tempera-
ture, Et2O and H2O were added. The aqueous layer was removed
and extracted with Et2O. The organic extracts were combined,
washed with water and brine, dried with Na2SO4, filtered, and
evaporated to give a crude yellow oil. Purification by silica gel
column chromatography (4:1 hexanes:Et2O) gave 35 as a clear
oil (78 mg) in 80% yield. 1H NMR (300 MHz, CDCl3) δ 0.09 (s,
3H), 0.10 (s, 3H), 0.92 (s, 9H), 1.47 (s, 9H), 2.06-2.18 (m, 1H),
2.37 (td, J ) 3.80, 13.7 Hz, 1H), 2.80-2.90 (m, 1H), 2.92-3.01
(m, 1H), 3.74-4.05 (m, 3H), 4.82 (s, 1H), 5.02 (s, 1H). 13C NMR
(75 MHz, CDCl3) δ -4.9 (2C), 18.3, 25.8 (3C), 28.5 (3C), 32.9,
44.8, 52.5, 70.5 (b), 79.5, 107.3, 147.4, 154.3.
1-P ip er id in eca r boxylic Acid , 3,3-Dim eth yl-4-m eth ylen e
1,1-Dim eth yleth yl Ester (37). To a solution of N-BOC 4-pip-
eridone (15.95 g, 80 mmol) in anhydrous THF (400 mL) at 10
°C were successively added NaH (60% in hexanes; 6.72 g, 0.17
mol) and iodomethane (12.5 mL, 0.20 mol). The resulting
solution was allowed to warm to room temperature and stirred
for 2 days. The residue obtained after evaporation was taken
up in diethyl ether, washed with brine, dried over Na2SO4, and
concentrated. Two recrystallizations from pentane gave 6.60 g
of a white solid which was used directly in the next step (1H
NMR (300 MHz, CDCl3) δ 1.08 (s, 6H), 1.49 (s, 9H), 2.48 (t, J )