∑
td, J = 11.7 and 4.4 Hz); 13C NMR (125 MHz) d 210.0 (C),
138.6 (C), 136.9 (C), 129.2 (CH), 129.1 (CH), 128.6, (CH), 128.2
(CH), 127.9 (CH), 126.9 (CH), 70.3 (C), 63.1 (CH2), 62.1 (CH2),
58.0 (CH), 53.7 (CH2), 53.2 (CH2), 49.2 (CH2), 49.0 (CH2), 41.8
(CH2), 36.5 (CH2), 36.1 (CH2); IR (NaCl, film) nmax 3270, 3028,
2941, 2815, 1707, 1453, 1345, 1120, 1027, 998, 909, 812 cm-1;
1285, 1191, 1126, 1027, 1004 cm-1; MS (EI) m/z 360 (M+ , 51%),
332 (6), 269 (45), 241 (37), 198 (42), 134 (52), 91 (100); HRMS
∑
calcd for C24H28N2O (M+ ) 360.2202. Found 360.2199.
Compound 8. A magnetically stirred solution of diisopropy-
lamine (3.9 mL, 28 mmol, 1.4 equiv) in dry DME (100 mL)
maintained at 0 ◦C was treated with n-BuLi (10.8 mL of a 2.4 M
solution in hexanes, 26 mmol, 1.3 mole equiv). ◦After stirring for
0.08 h the reaction mixture was cooled to -78 C and 1-benzyl-
4-piperidinone (6) (3.79 g, 20.0 mmol, ex. Aldrich Chemical Co.)
was added dropwise. Dry DMPU (4.8 mL, 40 mmol, 2 equiv)
was then added to aid solubility. After 0.16 h at -78 ◦C the
reaction mixture was treated with allyl bromide (2.6 mL, 30
∑
MS (EI) m/z 378 (M+ , 5%), 360 (5), 287 (8), 269 (8), 191 (73),
∑
91 (100); HRMS calcd for C24H30N2O2 (M+ ) 378.2307. Found
378.2300.
When the procedure described above was followed except for
allowing the reaction mixture to stand to 18 ◦C for 2 h then a ca.
1 : 4 mixture of compound 4 and it conjugated isomer (238 mg,
66% combined yield) was obtained.
◦
mmol, 1.5 mole equiv) then slowly warmed to -40 C and after
Compound 4. A magnetically stirred solution of 1-benzyl-4-
piperidinone (6) (8.5 mL, 45.9 mmol, ex. Aldrich Chemical Co.) in
dry 1,2-dichloroethane (15 mL) maintained at 40 ◦C was treated
with BF3·OEt2 (11.6 mL, 91.5 mmol, 2 mole equiv). The resulting
mixture was heated at reflux for 16 h (during the course of which
0.5 h at this temperature quenched with NaHCO3 solution (100
mL of a saturated aqueous solution). The resulting mixture was
warmed to 18 ◦C then diluted with water (100 mL) and diethyl
ether (50 mL). The separated aqueous phase was extracted with
CH2Cl2 (3 ¥ 50 mL) and the combined organic phases washed with
brine (1 ¥ 50 mL) before being dried (Na2SO4), filtered and then
concentrated under reduced pressure to give a clear, colourless oil.
Subjection of this material to flash chromatography (silica, 1 : 1
v/v ethyl acetate/hexane elution) provided, after concentration
of the appropriate fractions (Rf 0.6), compound 814 (2.05 g, 45%)
◦
a viscous brown gum formed) then cooled to 18 C and poured
into NaHCO3 (200 mL of a saturated aqueous solution). The
residual gum was treated with MeOH (30 mL) and the mixture
heated at reflux for 0.5 h and the ensuing methanolic solution
then cooled to 18 ◦C before being poured into the NaHCO3 (200
mL of a saturated aqueous solution). Water (50 mL) and CHCl3
(100 mL) were added and the phases were separated. The aqueous
phase was extracted with CHCl3 (3 ¥ 50 mL), the combined
organic portions were washed with NaHCO3 (1 ¥ 50 mL of a
saturated aqueous solution), water (1 ¥ 50 mL) and brine (1 ¥
50 mL) before being dried (Na2SO4), filtered and then concentrated
under reduced pressure to afford a brown oil. Subjection of this
material to flash chromatography (silica, 3 : 2 → 4 : 1 v/v ethyl
acetate/hexane gradient elution) provided two fractions, A and B.
Concentration of fraction A (Rf 0.25 in 3 : 2 v/v ethyl ac-
etate/hexane) afforded compound 4 (5.30 g, 64%) as a clear, yellow
oil. 1H NMR (500 MHz) d 7.35–7.24 (10H, complex m), 5.56 (1H,
broad s), 3.60 (2H, ABq), 3.58 (2H, ABq), 3.12 (1H, broad dd, J =
9.3 and 5.2 Hz), 3.01 (2H, dd, J = 5.2 and 2.2 Hz), 2.98 (1H, m),
2.94 (1H, m), 2.78 (1H, m), 2.62 (1H, dd, J = 11.3 and 9.2 Hz),
2.58–2.42 (4H, complex m), 2.08 (2H, m); 13C NMR (125 MHz)
d 208.6 (C), 138.1 (C), 138.0 (C), 132.6 (CH), 129.2 (CH), 128.9,
(CH), 128.3 (CH), 128.2 (CH), 127.3 (CH), 127.0 (CH), 123.1 (C),
62.8 (CH2), 62.2 (CH2), 57.1 (CH2), 56.7 (CH), 53.6 (CH2), 52.9
(CH2), 49.6 (CH2), 40.9 (CH2), 28.5 (CH2); IR (NaCl, film) nmax
3026, 2908, 2800, 2759, 1715, 1493, 1453, 1364, 1349, 1186, 1123,
1
as a clear, colourless oil. H NMR (300 MHz) d 7.36–7.25 (5H,
complex m), 5.73 (1H, m), 5.05–4.96 (2H, complex m), 3.68 (1H,
d, J = 13.1 Hz), 3.54 (1H, d, J = 13.1 Hz), 3.10–2.96 (2H, complex
m), 2.66–2.35 (5H, complex m), 2.24 (1H, dd, J = 11.2 and 9.7
Hz), 2.05 (1H, m); 13C NMR (75 MHz) d 210.1 (C), 138.2 (C),
135.7 (CH), 128.9 (CH), 128.4 (CH), 127.3 (CH), 116.7 (CH2),
62.0 (CH2), 58.6 (CH2), 53.6 (CH2), 49.4 (CH), 41.1 (CH2), 32.0
(CH2); IR (NaCl, film) nmax 3064, 3028, 2911, 2801, 1715, 1640,
1453, 1354, 1188, 1133, 1028, 999, 915 cm-1; MS (EI) m/z 229
∑
(M+ , 26%), 228 (16), 214 (8), 200 (27), 187 (35), 172 (6), 152 (10),
∑
146 927), 91 (100); HRMS calcd for C15H19NO (M+ ) 229.1467.
Found 229.1466.
Compound 9. A magnetically stirred solution of diisopropy-
lamine (1.1 mL, 7.8 mmol, 1.6 equiv) in dry THF (100 mL)
maintained at 0 ◦C was treated n-BuLi (3.1 mL of a 2.4 M solution
in hexanes, 7.4 mmol, 1.5 mole equiv). After stirring for 0.08 h the
reaction mixture was cooled to -78 ◦C and TMS-Cl (1.3 mL,
10 mmol, 2 mole equiv) was added dropwise. A solution of ketone
8 (3.79 g, 20.0 mmol) in THF (8 mL) was then added via cannula
over 0.8 h and the resulting mixture stirred at -78 ◦C for 0.33 h.
Triethylamine (0.5 mL) was then added to the mixture, followed by
NaHCO3 (10 mL of a saturated aqueous) and the resulting mixture
warmed to 18 ◦C before being diluted with water (10 mL) and
hexane (10 mL). The separated aqueous phase was extracted with
hexane (2 ¥ 10 mL) and the combined organic phases were then
dried (Na2SO4), filtered and concentrated under reduced pressure
to afford compound 9 (1.51 g, quant.) as a clear, colourless but
unstable oil. 1H NMR (300 MHz) d 7.36–7.22 (5H, complex m),
5.69 (1H, m), 4.92–4.85 (2H, complex m), 4.76 (1H, broad t, J =
ca. 3 Hz), 3.64 (1H, d, J = 13.0 Hz), 3.46 (1H, d, J = 13.0 Hz), 3.02
(1H, ddd, J = 14.8, 3.7 and 1.2 Hz), 2.91 (1H, ddd, J = 14.8, 3.5 and
1.1 Hz), 2.53–2.34 (3H, complex m), 2.16 (2H, m), 0.21 (9H, s).
Compound 10. Step (i): A magnetically stirred solution of
compound 9 (1.51 g, 5.00 mmol) in dry THF (25 mL) maintained
at 0 ◦C was treated with NBS (1.16 g, 6.50 mmol, 1.3 mole equiv).
After stirring for a further 0.5 h at 0 ◦C the reaction mixture was
∑
1027 cm-1; MS (EI) m/z 360 (M+ , 19%), 325 (5), 269 (13), 241
(40), 199 (36), 185 (10), 172 (15), 134 (11), 91 (100); HRMS calcd
∑
for C24H28N2O (M+ ) 360.2202. Found 360.2201.
Concentration of fraction B (Rf 0.15 in 1 : 99 v/v ammo-
nia/ethyl acetate) afforded 1,1¢-dibenzyl-2¢,3¢,5,5¢,6,6¢-hexahydro-
1H,1¢H[3,4¢-bipyridinylidene]-4(2H)-one (the conjugated isomer of
1
compound 4) (1.36 g, 16%) as a clear, yellow oil. H NMR (300
MHz) d 7.36–7.23 (10H, complex m), 3.65 (2H, s), 3.51 (2H, s),
3.39 (2H, broad s), 2.80 (2H, m), 2.78 (2H, m), 2.55 (2H, app t,
J = 6.3 Hz), 2.49 (4H, m), 2.22 (2H, app t, J = 5.7 Hz); 13C NMR
(75 MHz) d 201.6 (C), 147.2 (C), 138.1 (C), 138.0 (C), 129.1 (CH),
128.8 (CH), 128.4 (CH), 128.2 (CH), 127.7 (C), 127.3 (CH), 127.0
(CH), 62.8 (CH2), 62.0 (CH2), 55.7 (CH2), 54.7 (CH2), 53.9 (CH2),
51.1 (CH2), 41.5 (CH2), 30.7 (CH2), 30.1 (CH2); IR (NaCl, film)
nmax 3027, 2904, 2800, 2757, 1682, 1602, 1494, 1453, 1364, 1347,
This journal is
The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 154–161 | 159
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