7214
A.A. Bisset et al. / Tetrahedron 70 (2014) 7207e7220
(10% w/w, 13 mg, 1.22ꢃ10ꢂ2 mmol) in methanol (1 mL), following
a reaction time of 20 h, at room temperature and 25 bar. Following
concentration under reduced pressure, (ꢁ)-4a (30 mg, 0.129 mmol,
99% yield) was obtained as a colourless oil. dH (400 MHz, CDCl3)
10.40 (1H, br s, OH), 7.28e7.10 (5H, m, ArH), 4.68 (1H, d, J 14.7, CH2),
4.36 (1H, d, J 14.7, CH2), 3.47e3.25 (2H, m, H4), 2.75e2.62 (1H, m,
H3), 2.56 (1H, dt, J 17.9, 4.5, H1A), 2.42 (1H, dt, J 17.9, 6.5, H1B),
2.11e1.99 (1H, m, H2A), 1.98e1.82 (1H, m, H2B); dC (101 MHz, CDCl3)
176.9, 170.4, 136.1, 128.6, 128.1, 127.6, 50.6, 48.0, 38.8, 31.5, 25.5.
25.17 mmol) and glutarimide (2.90 g, 25.64 mmol) in THF (75 mL)
was stirred at 0 ꢀC for 5 min. A solution of diisopropyl azodi-
carboxylate (4.99 mL, 5.19 g, 25.66 mmol) in THF (50 mL) was
added dropwise over 1 h at 0 ꢀC and the solution was allowed to
warm to room temperature and stirred for 18 h. Following con-
centration under reduced pressure and purification by column
chromatography (ethyl acetateehexane 1:1), product 2d (3.03 g,
12.94 mmol, 50% yield) was obtained as a colourless oil; (found
(ESI): MþþH, 235.10750. C12H15N2O3 requires M, 235.10772); nmax
2966, 1716, 1666, 1607, 1572, 1491, 1171 cmꢂ1
; dH (400 MHz,
3.1.12. Methyl 1-benzyl-6-oxopiperidine-3-carboxylate, (ꢁ)-4b.29 This
compound was prepared following the general procedure for alkene
hydrogenation, using methyl 1-benzyl-6-oxo-1,6-dihydropyridine-
3-carboxylate, 3b (100 mg, 0.411 mmol) and palladium on carbon
(5% w/w, 88 mg, 4.13ꢃ10ꢂ2 mmol) in methanol (1 mL) following
a reaction time of 1 d, at 40 ꢀC under a balloon of hydrogen. Fol-
lowing solvent removal and purification by column chromatography
(ethyl acetateehexane 9:1), the product (ꢁ)-4b (30 mg, 0.121 mmol,
29% yield) was obtained as colourless oil; dH (400 MHz, CDCl3)
7.30e7.14 (5H, m, ArH), 4.62 (1H, d, J 14.6, CH2), 4.46 (1H, d, J 14.6,
CH2), 3.59 (3H, s, CH3), 3.42e3.28 (2H, m, H4), 2.78e2.65 (1H, m, H3),
2.54 (1H, dt, J 17.8, 5.3, H1A), 2.47e2.35 (1H, m, H1B), 2.13e2.02 (1H,
m, H2A), 2.00e1.89 (1H, m, H2B); dC (75 MHz, CDCl3) 172.5, 168.8,
136.7, 128.5, 128.0, 127.4, 52.1, 50.1, 47.9, 39.0, 30.7, 23.9; Enantio-
meric separation was achieved by HPLC analysis (Chiralpak IA,
4.6 mmꢃ250 mm, hexane:IPA 85:15, 1 mL/min, T¼30 ꢀC, 13.3 min,
14.9 min).
CDCl3) 8.22 (1H, d, J 2.5, H3), 7.63 (1H, dd, J 8.5, 2.5, H2), 6.67 (1H,
d, J 8.5, H1), 4.87 (2H, s, H4), 3.90 (3H, s, CH3), 2.65 (4H, t, J 6.7, H5),
1.92 (2H, quin, J 6.7, H6); dC (101 MHz, DMSO) 172.7, 162.7, 146.2,
139.0, 126.2, 110.0, 53.00, 52.9, 32.0, 16.4; m/z (ESI) 234.97
(Mþþ1).
3.1.16. 1-[(1-Benzyl-6-oxo-1,6-dihydropyridin-3-yl)methyl]piperi-
dine-2,6-dione, 3d. Under nitrogen, a mixture of benzyl bromide
(1.02 mL, 1.47 g, 8.59 mmol), 1-((6-methoxypyridin-3-yl)methyl)
piperidine-2,6-dione, 2d (1.82 g, 7.77 mmol) and potassium car-
bonate (2.15 g, 15.56 mmol) in dry acetonitrile (31 mL) was stirred
at 80 ꢀC for 24 h before the solution was filtered. The resulting
filtrate was concentrated under reduced pressure followed by
recrystallisation (ethanol), to give product 3d (1.42 g, 4.58 mmol,
59% yield) as a white powder; Mp 154e156 ꢀC; (found (ESI):
MþþNa, 333.1205. C18H18N2NaO3 requires M, 333.1210); nmax 2926,
1722, 1666, 1601, 1537, 1496, 1134, 730, 699 cmꢂ1
; dH (400 MHz,
CDCl3) 7.49e7.41 (2H, m, H2, H3), 7.37e7.25 (5H, m, ArH), 6.52 (1H,
d, J 9.3, H1), 5.10 (2H, s, CH2), 4.62 (2H, s, CH2), 2.64 (4H, t, J 6.4, H5),
1.93 (2H, quin, J 6.4, H6); dC (101 MHz, CDCl3) 172.4, 161.9, 141.5,
138.6, 136.2, 128.7, 128.1, 127.9, 120.6, 115.4, 52.0, 39.2, 32.6, 16.9; m/
z (ESI) 333.1 (Mþþ23). Further recrystallisation (EtOH) provided
crystals of sufficient quality for X-diffraction, enabling confirmation
of the structure.11
3.1.13. 1-Benzyl-3-hydroxymethyl 6-oxopiperidine, (ꢁ)-4c.30 This
compound was prepared following the general procedure for al-
kene hydrogenation, using 1-benzyl-5-(hydroxymethyl)pyridin-
2(1H)-one 3c (30 mg, 0.139 mmol) and platinum oxide (3 mg,
1.32ꢃ10ꢂ2 mmol) in methanol (1 mL), following a reaction time of
18 h at room temperature under 5 bar of hydrogen. Following
concentration under reduced pressure, (ꢁ)-4c (20 mg, 0.091 mmol,
66% yield) was obtained as an oil; dH (400 MHz, CDCl3) 7.37e7.19
(5H, m, ArH), 4.60 (2H, s, CH2Ph), 3.64e3.54 (1H, m, H4A), 3.53e3.45
(1H, m, H4B), 3.32 (1H, ddd, J 12.1, 5.1, 1.8, H5A), 3.02 (1H, dd, J 12.1,
10.0, H5B), 2.57 (1H, ddd, J 17.8, 6.3, 3.5, H1A), 2.44 (1H, ddd, J 17.8,
11.1, 6.5, H1B), 2.11e1.97 (1H, m, H3), 1.94e1.85 (1H, m, H2A), 1.53
(1H, dtd, J 13.1, 11.1, 6.3, H2B). A signal attributable to OH was not
observed; dC (75 MHz, CDCl3) 170.0, 136.9, 128.5, 127.9, 127.3, 64.3,
50.3, 49.78, 36.3, 31.2, 23.8.
3.1.17. 1-[(1-Benzyl-6-oxopiperidin-3-yl)methyl]piperidine-2,6-
dione, (ꢁ)-4d. This compound was prepared following the general
procedure for alkene hydrogenation, using 1-[(1-benzyl-6-oxo-1,6-
dihydropyridin-3-yl)-methyl]-piperidine-2,6-dione, 3d (1.14 g,
3.68 mmol) and platinum oxide (42 mg, 0.185 mmol) following
a reaction time of 20 h, at 30 ꢀC. Following concentration under
reduced pressure, product (ꢁ)-4d (1.10 g, 3.50 mmol, 95% yield)
was obtained as colourless oil, following column chromatography
(methanoleethyl acetate 2:8); (found (ESI): MþþNa, 337.1522.
C18H22N2NaO3 requires M, 337.1523); nmax 2929, 1722, 1668, 1634,
3.1.14. 1-Benzyl-5-methylpiperidin-2-one, (ꢁ)-21. This compound
was prepared following the general procedure for alkene hydro-
genation, using 1-benzyl-5-(hydroxymethyl)pyridin-2(1H)-one 3c
(30 mg, 0.139 mmol) and palladium on barium sulfate (5% w/w,
30 mg, 1.41ꢃ10ꢂ2 mmol) in methanol (1 mL), following a reaction
time of 18 h at room temperature and 5 bar of hydrogen. Following
concentration under reduced pressure and purification by column
chromatography (ethyl acetateehexane 8:2), (ꢁ)-21 (20 mg,
0.098 mmol, 71% yield) was obtained as an oil; (found (ESI):
MþþNa, 226.1203. C13H17NNaO requires M, 226.1202); nmax 2955,
1492, 1134 cmꢂ1
(1H, d, J 14.6, CH2), 4.42 (1H, d, J 14.6, CH2), 3.77 (1H, dd, J 12.4, 7.3,
5A), 3.68 (1H, dd, J 12.4, 7.5, H5B), 3.11 (1H, ddd, J 11.0, 5.0, 1.3, H4A),
; dH (400 MHz, CDCl3) 7.36e7.19 (5H, m, ArH), 4.73
H
2.98 (1H, t, J 11.0, H4B), 2.63 (4H, t, J 6.6, H6), 2.58 (1H, ddd, J 18.0, 5.8,
3, H1A), 2.39 (1H, ddd, J 18.0, 11.5, 6.2, H1B), 2.20e2.07 (1H, m, H3),
1.89 (2H, quin, J 6.6, H7), 1.53 (2H, dtd, J 13.1, 11.5, 6.2, H2); dC
(101 MHz, CDCl3) 172.3, 169.0, 136.5, 128.1, 127.5, 126.9, 50.1, 49.7,
41.1, 32.8, 32.3, 30.7, 24.8, 16.57; m/z (ESI) 337.1 (MþþNa). Enan-
tiomeric separation was achieved by HPLC analysis (Chiralpak IB,
4.6 mmꢃ250 mm, hexane:IPA 80:20, 1.0 mL/min, T¼30 ꢀC,
38.1 min, 41.0 min).
2926,1619,1493 cmꢂ1
; dH (400 MHz, CDCl3) 7.22e7.36 (5H, m, ArH),
4.67 (1H, d, J 14.6, CH2), 4.50 (1H, d, J 14.6, CH2), 3.16 (1H, ddd, J 12.0,
5.1, 2.0, H4A), 2.83 (1H, dd, J 12.0, 10.4, H4B), 2.55 (1H, ddd, J 17.7, 6.0,
3.0, H1A), 2.44 (1H, ddd, J 17.7, 11.5, 6.3, H1B), 1.88e1.99 (1H, m, H3),
1.84 (1H, dddd, J 13.2, 6.3, 3.0, 2.0, H2A),1.47 (1H, dtd, J 13.2,11.5, 6.0,
3.1.18. 1-Benzyl-5-[(2-hydroxy-6-oxopiperidin-1-yl)methyl]piper-
idin-2-one, (ꢁ)-22. Under nitrogen, a solution of cerium chloride
heptahydrate (574 mg, 1.54 mmol) and 1-[(1-benzyl-6-
oxopiperidin-3-yl)methyl]piperidine-2,6-dione, (ꢁ)-4d (484 mg,
1.54 mmol) in dry methanol (3.85 mL) was stirred at 0 ꢀC for 5 min.
Sodium borohydride (118 mg, 3.12 mmol) was added and the
mixture was stirred at 0 ꢀC for 4 h before saturated aqueous sodium
hydrocarbonate (5 mL) was added. Following extraction with DCM
(3ꢃ10 mL), the organic extracts were dried (MgSO4), concentrated
H2B), 0.95 (3H, d, J 6.5, H5) dC (100 MHz, CDCl3) 169.8, 137.3, 129.0,
128.6, 127.3, 60.3, 54.2, 31.7, 29.5, 29.0, 18.6; m/z (ESI) 203.8
(Mþþ1).
3.1.15. 1-((6-Methoxypyridin-3-yl)methyl)piperidine-2,6-dione,
2d. Under nitrogen, a solution of triphenylphosphine (6.73 g,
25.66 mmol), (6-methoxypyridin-3-yl)methanol 2c (3.50 g,