7.2 Hz, 2H), 4.11-4.04 (m, 1H), 3.22-3.16 (m, 1H), 1.81-1.64
(m, 4H), 1.65 (d, J ) 6.6 Hz, 3H), 1.50-1.46 (m, 2H), 1.32-1.25
(m, 6H); 13C NMR (75 MHz, CDCl3) δ 197.4, 163.4, 64.7, 59.8,
51.2, 40.8, 40.6, 34.2, 26.5, 25.2, 19.5, 13.8; IR (KBr) 1759, 1732
cm-1; MS (FAB) m/z 455, 453, 451, 449 (M + 1); HRMS m/z cacld
for C12H20Br3O3 (M + 1) 452.8916, 450.8936, found 452.8920,
450.8948,
(m, 2H), 2.41-2.37 (m, 1H), 2.28-2.25 (m, 1H), 1.87-1.77 (m,
2H), 1.68-1.64 (m, 1H), 1.28 (t, J ) 7.2 Hz, 3H), 1.24-1.17 (m,
2H), 0.98 (d, J ) 6.6 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 170.8,
168.4, 80.5, 58.3, 42.7, 38.2, 36.6, 34.4, 33.6, 22.9, 14.7; IR (KBr)
3309, 1649, 1606 cm-1; MS (EI) m/z 197 (M+, 62) 152 (100), 125
(95), 108 (20), 96(42); HRMS m/z calcd for C11H20NO2 (M + 1)
197.1410, found 197.1408.
Eth yl 2,2-Dibr om o-3-{en d o-7-br om obicyclo[3.3.1]n on yl}-
3-oxop r op ion a te (6e). White crystals; yield 87%; mp 48-49
Eth yl 2-(3,7-Dim eth yl-2-a zep in ylid en e)a ceta te (8d ). Col-
orless oil; yield 28% (method A), 72% (method B); 1H NMR (300
MHz, CDCl3) δ 8.82 (s, 1H), 4.50 (s, 1H), 4.12 (q, J ) 7.2 Hz,
2H), 3.62 (m, 1H), 2.62-2.57 (m, 2H); 13C NMR (75 MHz, CDCl3)
δ 171.1, 171.0, 170.3, 80.9, 76.3, 58.2, 50.4, 49.8, 40.6, 38.1, 37.4,
36.1, 34.8, 31.4, 29.1, 23.2, 23.1, 22.7, 19.2, 16.6, 14.6; IR (KBr)
3272, 1651, 1604 cm-1; MS (EI) m/z 211 (M+, 100), 196 (32), 182
1
°C; H NMR (300 MHz, CDCl3) δ 4.60-4.50 (m, 1H), 4.33 (q, J
) 7.2 Hz, 2H), 3.23-3.12 (m, 1H), 2.34-2.14 (m, 6H), 1.86(t, J
) 12.3 Hz, 2H), 1.70 (d, J ) 13.2 Hz, 1H) 1.52 (t, J ) 12.3 Hz,
2H), 1.31 (t, J ) 7.2 Hz, 3H), 1.23 (d, J ) 13.2 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 197.5, 163.3, 64.6, 59.9, 45.8, 44.8, 38.2, 31.6,
27.5, 27.2, 13.6; IR (KBr) 1756, 1726 cm-1; MS (FAB) m/z 477,
475, 473 (M + 1). Anal. Calcd for C14H19Br3O3: C, 35.40; H, 4.03.
Found: C, 34.95; H, 3.92.
(35), 166 (66), 150 (43), 138 (73); HRMS m/z calcd for C12H22
NO2 (M + 1) 212.1645, found 212.1646.
-
Eth yl 2-(2-Azocin ylid en e)a ceta te (8f).13 Colorless oil; yield
35%; 1H NMR (300 MHz, CDCl3) δ 8.76 (br, 1H), 4.41 (s, 1H),
4.09 (q, J ) 7.2 Hz, 2H), 3.39-3.32 (m, 2H), 2.28 (t, J ) 6.6 Hz,
2H), 1.71-1.51 (m, 6H), 1.28 (t, J ) 7.2 Hz, 3 H).
Eth yl 3-Oxo-2,2,9-tr ibr om on on a n oa te (6f). Pale yellow oil;
1
yield 41%; H NMR (CDCl3) δ 4.41 (q, J ) 7.2 Hz, 2H), 3.46 (t,
J ) 6.6 Hz, 2H), 2.97 (t, J ) 7.2 Hz, 2H), 1.92 (quin, J ) 7.0 Hz,
2H), 1.77 (quin, J ) 7.4 Hz, 2H), 1.55-1.44 (m, 4H), 1.39 (t, J )
7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 193.4, 163.5, 64.5, 59.8,
Gen er a l P r oced u r e for th e P r ep a r a tion of Heter ocyclic
Ter tia r y En a m in es 9.14 To a mixture of ω-bromo-â-ketoester
5a (2 mmol) and amine (2 mmol) were added a small amount of
iodine, disodium hydrogen phosphate (2 mmol), and anhydrous
sodium sulfate (2 mmol). The resulting heterogeneous mixture
was heated in an oil bath at 65 °C for 24 h with stirring. After
the mixture was cooled to room temperature, dichloromethane
(100 mL) was added immediately, and the mixture was washed
with water (100-150 mL). The aqueous phase was then ex-
tracted with dichloromethane. The combined organic layer was
washed with brine, dried over anhydrous MgSO4 and subjected
to chromatography using a silica gel column with a mixture of
petroleum ether and ethyl acetate (8:1) as an eluent to give
N-substituted heterocyclic enamines 9.
Eth yl 2-[2-(N-Ben zyl)piper din yliden e]acetate (9a). White
solid; mp 70-71 °C (lit.20 mp 66 °C); yield 48%; 1H NMR (300
MHz, CDCl3) δ 7.38-7.24 (m, 3H), 7.18 (d, J ) 7.5 Hz, 2H), 4.69
(s, 1H), 4.42 (s, 2H), 4.04 (q, J ) 7.2 Hz, 2H), 3.28 (t, J ) 6.0
Hz, 2H), 3.23 (t, J ) 6.0 Hz, 2H), 1.86-1.72 (m, 4H), 1.21 (t, J
) 7.2 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 168.9, 162.4, 135.9,
128.5, 126.9, 126.4, 82.5, 57.9, 55.0, 49.6, 26.7, 23.2, 19.5, 14.5;
IR (KBr) 1681, 1565, 1135 cm-1; MS (EI) m/z 259 (M+, 26), 214-
(46), 186(75), 91(100), 82(72). Anal. Calcd for C16H21NO2: C,
74.10; H, 8.16; N, 5.40. Found: C, 73.85; H, 8.19; N, 5.12.
Eth yl 2-[2-(N-P h en yl)piper din yliden e]acetate (9b). White
solid; mp 94-95 °C; yield 42%; 1H NMR (300 MHz, CDCl3) δ
7.39 (t, J ) 7.5 Hz, 2H), 7.27-7.25 (m, 1H), 7.15 (d, J ) 7.8 Hz,
2H), 4.33 (s, 1H), 3.97 (q, J ) 6.9 Hz, 2H), 3.45 (t, J ) 6.0 Hz,
2H), 3.23 (t, J ) 6.3 Hz, 2H), 1.91-1.76 (m, 4H), 1.14 (t, J ) 6.9
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 168.7, 163.2, 146.1, 129.9,
126.9, 126.8, 86.7, 58.2, 52.0, 26.4, 23.7, 20.1, 14.6; IR (KBr)
1673, 1556, 1132 cm-1; MS (EI) m/z 245 (M+, 13), 200 (22), 172
(71), 130 (32), 77 (100). Anal. Calcd for C15H19NO2: C, 73.44; H,
7.81; N, 5.71. Found: C, 73.27; H, 7.84; N, 5.43.
35.5, 33.6, 32.3, 27.7, 27.6, 24.5, 13.6; IR (KBr) 1750, 1738 cm-1
;
MS (FAB) m/z 441, 439, 437, 435 (M + 1); HRMS m/z calcd for
C11H18Br3O3 (M + 1) 438.8760, 436.8780, found 438.8755,
436.8784.
Gen er a l P r oced u r e for Selective Red u ction of r,r,ω-
Tr ibr om o-â-k etoester 6. To a solution of R,R,ω-tribromo-â-
ketoester 6 (2 mmol) in saturated ammonium chloride/methanol
solution (10 mL) was added the cupper-zinc alloy powder (32
mmol), and the resulting mixture was stirred at 10-15 °C for
15 min. After complete consumption of 6, which was monitored
by TLC analysis, the mixture was filtered and the filtrate was
subjected to column chromatography using silica gel with a
mixture of petroleum ether and ethyl acetate (30:1) as an eluent
to give ω-bromo-â-ketoester 5.
Gen er a l P r oced u r e for th e Su bstitu tion Rea ction of
ω-Br om o-â-k eto Ester s by Sod iu m Azid e. To a solution of
ω-bromo-â-ketoester 5 (2 mmol) in dimethyl sulfoxide (10 mL)
were added with stirring powdered sodium azide (3 mmol) and
a catalytic amount of sodium iodide (ca. 10 mg). The mixture
was heated at 60 °C for 18 h. After the mixture was cooled to
room temperature, water (10 mL) was added, and the mixture
was then extracted with diethyl ether (3 × 15 mL). The organic
layer was washed with brine (3 × 10 mL) and dried over
anhydrous Na2SO4. After removal of solvent under vacuum, the
residue was chromatographyed on a silica gel column using a
mixture of petroleum ether and ethyl acetate (30:1) as an eluent
to afford ω-azido-â-ketoester 7.
Gen er a l P r oced u r e for th e P r ep a r a tion of Heter ocyclic
Secon d a r y En a m in es 8. Meth od A. To a solution of azide 7
(3 mmol) in anhydrous benzene or diethyl ether (10 mL) was
added triphenylphosphine (873 mg, 3 mmol), and the mixture
was refluxed for 3 h in benzene or kept at room temperature for
24 h in diethyl ether. After removal of solvent, the residue was
subjected to chromatography using a silica gel column with a
mixture of petroleum ether and ethyl acetate (5:1) as an eluent
to yield heterocyclic secondary enamine 8.
Ack n ow led gm en t. We are grateful to the Major
State Basic Research Development Program of China
(Grant No. G2000077502), Ministry of Science and
Technology, and National Natural Science Foundation
of China for financial support. M.-X.W. and G.W.J .F.
also thank the Chinese Academy of Sciences and the
Royal Society, London, for supporting a joint research
project between the China and U.K. groups.
Meth od B. A mixture of azide 7 (0.86 mmol) and Pd on
charcoal (10%, 10 mg) in methanol was stirred under hydrogen
atmosphere at room temperature for 1 h. Pure heterocyclic
secondary enamine 8 was obtained after a similar workup
procedure.
Eth yl 2-(2-P ip er d in ylid en e)a ceta te (8a ).13 Colorless oil;
1
yield 80%; H NMR (300 MHz, CDCl3) δ 8.69 (br. 1H), 4.31 (s,
Su p p or tin g In for m a tion Ava ila ble: Synthesis of 4 and
the vicinal tricarbonyl derivatives 10, spectral data of 5 and
7, and 1H and 13C NMR of 6, 8c, and 8d . This material is
1H), 4.04 (q, J ) 7.2 Hz, 2H), 3.27-3.23 (m, 2H), 2.31 (t, J )
6.3 Hz, 2H), 1.78-1.60 (m, 4H), 1.20 (d, J ) 7.2 Hz, 3H).
Eth yl 2-(2-Azep in ylid en e)a ceta te (8b).13 Colorless oil; yield
1
89%; H NMR (300 MHz, CDCl3) δ 8.84 (br., 1H), 4.42 (s, 1H),
4.07 (q, J ) 7.2 Hz, 2H), 3.31-3.26 (m, 2H), 2.29-2.26 (m, 2H),
1.67-1.54 (m, 6H), 1.23 (t, J ) 7.2 Hz, 3H).
J O0351320
Eth yl 2-(5-Meth yl-2-a zep in ylid en e)a ceta te (8c). White
solid; mp 41-42 °C; yield 86%; 1H NMR (300 MHz, CDCl3) δ
8.86 (s, 1H), 4.46 (s, 1H), 4.11 (q, J ) 7.2 Hz, 2H), 3.34-3.31
(20) Marchand, P.; Bellassoued, M.-C.; Lhommet, B. G. Synth.
Commun. 1994, 24, 2577-2584.
1000 J . Org. Chem., Vol. 69, No. 3, 2004