C.M. Marson, K.C. Yau / Tetrahedron xxx (2015) 1e11
9
1496 cmꢁ1; 1H NMR (500 MHz, CDCl3) (presence of rotamers)
d
8.57
d, J¼6.7 Hz); 13C NMR (500 MHz, CDCl3)
d
204.6, 166.2, 140.0, 128.8,
(1H, s) 8.40 (1H, m) 7.82 (1H, d, J¼7.3 Hz) 7.64 (1H, m) 7.45e7.17
(5H, m) 5.08 (1H, q, J¼6.5 Hz) 4.86 (1H, dd, J¼7.7, 5.6 Hz) 3.74 (3H, s)
3.58 (2H, s) 3.43 (3H, s) 2.60 (1H, dd, J¼17.1, 7.7 Hz) 2.27 (1H, dd,
J¼17.1, 5.6 Hz) 1.60 (3H, d, J¼6.5 Hz); 13C NMR (500 MHz, CDCl3)
128.1,127.2, 50.9, 47.4, 46.5, 45.1, 22.7,16.9; m/z (CI, %) 232 ([MþH]þ,
100) 105 (C8Hþ9 , 35). HRMS C14H18NO2 calcd 232.1338, found
232.1334.
d
171.6, 168.1, 166.2, 149.0, 148.5, 136.1, 135.7, 132.1, 132.0, 129.1,
3.1.45. (1S,6R)-1-(a-Methylbenzyl)-6-phenylpiperidine-2,4-dione
128.8, 128.4, 127.2, 123.3, 57.3, 53.3, 52.6, 51.8, 42.7, 38.7, 18.4; m/z
(CI, %) 385 ([MþH]þ, 100) 279 ([MꢁC8H8]þ, 55). HRMS C21H25N2O5
calcd 385.1764, found 385.1761.
(12f). The piperidine-2,4-dione sodium salt 11f (0.10 g, 0.28 mmol)
was added to hydrochloric acid (1.3 M, 5 mL). The mixture was
heated under reflux for 1 h, then allowed to cool to 20 ꢀC and
extracted with dichloromethane (2ꢂ5 mL). The combined organic
layers were dried (MgSO4) and evaporated, and the residue was
purified by flash chromatography (1:1 ethyl acetate:hexane) to give
3.1. 41. Methyl (3 R, aS)-3-[N-(a-methylbenzyl ), N -(2-
methoxycarbonylacetyl)]-3-cyclohexylpropanoate (10k). Following
general procedure B, reaction of amine 9k (0.25 g, 0.86 mmol),
triethylamine (0.16 mL, 1.12 mmol) and methyl 3-chloro-3-
oxopropanoate (0.11 mL, 1.04 mmol) in dichloromethane (4 mL)
afforded a pale yellow oil that was purified by flash chromatogra-
phy (1:1 ethyl acetate:hexane) to give 10k (0.22 g, 66%) as a pale
12f (69 mg, 85%) as pale yellow solid, mp 104e107 ꢀC; ½a D21
þ103.4
ꢃ
(c 2.95, CHCl3); IR nmax 2923, 1730, 1648 cmꢁ1; 1H NMR (500 MHz,
CDCl3)
d
7.39e7.11 (10H, m) 6.31 (1H, q, J¼7.2 Hz) 4.65 (1H, dd,
J¼6.1, 2.2 Hz) 3.39 (2H, s) 2.68 (1H, dd, J¼16.4, 2.2 Hz) 2.51 (1H, dd,
J¼16.4, 6.1 Hz) 1.35 (3H, d, J¼7.2 Hz); 13C NMR (500 MHz, CDCl3)
yellow oil,
½
a 2D5
1H NMR (500 MHz, CDCl3) (presence of rotamers)
ꢃ
þ22.5 (c 1.00, CHCl3); IR nmax 2925, 1737,
d 203.2, 167.4, 140.1, 140.0, 129.2, 128.9, 128.1, 128.0, 127.5, 125.7,
1648 cmꢁ1
;
53.0, 51.6, 48.8, 47.9, 16.4; m/z (EI, %) 293 ([MþH]þ, 100) 105 (C8H9þ,
d
7.32e7.16 (5H, m) 4.99e4.95 and 4.30e4.28 (1H, m) 3.77 (3H, s)
35) 77 (C6Hþ5 , 10). HRMS C19H19NO2 calcd 293.1416, found 293.1413.
3.65 (1H, s) 3.60 (1H, s) 3.40 (3H, s) 2.72 and 2.46 (1H, d, J¼7.0 Hz)
2.45e2.02 (2H, m) 1.84 (3H, d, J¼7.0 Hz) 1.73e1.61 (5H, m)
3.1.46. (1S,6R)-1-(a-Methylbenzyl)-6-(pyridin-3-yl)piperidine-2,4-
1.29e0.82 (6H, m); 13C NMR (500 MHz, CDCl3)
d
173.5, 172.7, 168.7,
dione (12g). Following general procedure C, reaction of diester 10g
(0.25 g, 0.65 mmol), and sodium methoxide in methanol (2.0 M,
0.65 mL, 1.30 mmol) in methanol (3 mL) gave 12g (0.19 g, 99%) as
168.4, 167.6, 165.8, 142.6, 139.3, 128.7, 128.3, 128.2, 127.9, 126.9,
126.8, 61.4, 57.2, 57.0, 55.5, 52.5, 51.5, 51.3, 50.0, 43.0, 42.8 41.8, 40.8,
35.9, 31.5, 30.6, 30.1, 29.2, 29.1, 26.6, 26.5, 26.4, 26.3, 26.1, 26.0, 25.0,
21.2; m/z (CI, %) 412 ([MþNa]þ, 100). HRMS C22H31NO5Na calcd
412.2100, found 412.2115.
a brown oil, ½a 2D5
ꢁ84.7 (c 1.00, CHCl3); IR nmax 2977, 1730,
ꢃ
1642 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
8.57 (1H, d, J¼4.5 Hz) 8.48
(1H, s) 7.65 (1H, m) 7.53e7.26 (6H, m) 6.31 (1H, q, J¼7.2 Hz) 4.66
(1H, dd, J¼6.0, 1.8 Hz) 3.46 (1H, d, J¼20.6 Hz) 3.35 (1H, d, J¼20.6 Hz)
2.66 (1H, dd, J¼16.4, 1.8 Hz) 2.56 (1H, dd, J¼16.4, 6.0 Hz) 1.34 (3H, d,
3.1.42. (1S,6R)-1-(a-Methylbenzyl)-3-methoxycarbonyl-6-
phenylpiperidine-2,4-dione sodium salt (11f). Sodium methoxide in
methanol (1.97 M, 0.2 mL, 0.38 mmol) was added to a stirred so-
lution of diester 10f (0.13 g, 0.34 mmol) in methanol (0.70 mL) at
20 ꢀC, under nitrogen. The mixture was then heated under reflux
for 1 h, allowed to cool to 20 ꢀC, then diluted with diethyl ether and
filtered to give 11f (0.12 g, 97%) as a white solid, mp 230 ꢀC
J¼7.2 Hz); 13C NMR (500 MHz, CDCl3)
d 202.1, 167.1, 149.6, 147.6,
139.5, 135.7, 133.2, 132.2, 129.1, 128.6, 128.3, 127.4, 123.8, 51.6, 51.1,
48.6, 47.7, 16.6; m/z (EI, %) 294 (Mþ, 15). HRMS C18H18N2O2 calcd
294.1368, found 294.1366.
3.1.47. (1S,6R)-1-(a-Methylbenzyl)-6-isopropylpiperidine-2,4-dione
(decomp.); IR nmax 3220, 2972, 1671, 1650, 1589 cmꢁ1
(500 MHz, CDCl3)
;
1H NMR
(12j). Following general procedure C, reaction of diester 10j (0.15 g,
0.47 mmol) and sodium methoxide in methanol (2.0 M, 0.50 mL,
1.0 mmol) in methanol (3 mL) afforded 12j (0.12 g, 95%) as a pale
d
7.38e7.14 (10H, m) 6.21 (1H, q, J¼7.2 Hz) 4.33
(1H, dd, J¼6.9, 1.3 Hz) 3.67 (3H, s) 2.64 (1H, dd, J¼15.7, 6.9 Hz) 2.15
(1H, dd, J¼15.7, 1.3 Hz) 1.24 (3H, d, J¼7.2 Hz); 13C NMR (500 MHz,
yellow oil, ½a 2D1
ꢃ
ꢁ177.9 (c 1.31, CHCl3); IR nmax 2968, 1726,
CDCl3)
d
186.6, 171.8, 170.6, 144.1, 143.9, 129.5, 129.2, 128.3, 128.1,
1644 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 7.37e7.26 (5H, m) 6.07 (1H,
127.9, 127.7, 97.5, 53.6, 51.4, 50.5, 44.9, 17.0.
q, J¼7.1 Hz) 3.42 (1H, d, J¼21.3 Hz) 3.20 (1H, d, J¼21.3 Hz) 3.16 (1H,
m) 2.52 (1H, dd, J¼16.7, 5.0 Hz) 2.02e1.96 (2H, m) 1.65 (3H, d,
J¼7.1 Hz) 0.90 (3H, d, J¼6.9 Hz) 0.84 (3H, d, J¼6.9 Hz); 13C NMR
3.1.43. (1S,6R)-1-( -Methylbenzyl)-3-methoxycarbonyl-6-(E)-prope-
a
nylpiperidine-2,4-dione sodium salt (11l). Sodium methoxide in
methanol (2.14 M, 2.3 mL, 5.0 mmol) was added to a stirred solution
of diester 10l (1.58 g, 4.6 mmol) in methanol (6 mL) at 20 ꢀC, under
nitrogen. The mixture was then heated under reflux for 1 h. After
allowing to cool to 20 ꢀC, the mixture was diluted with diethyl ether
and filtered to give 11l (1.46 g, 95%) as a white solid, mp
(500 MHz, CDCl3) d 208.2, 170.2, 142.5, 131.5, 130.7, 130.2, 58.3, 55.4,
50.1, 43.7, 35.9, 22.9, 20.4, 20.2; m/z (EIþ) 259 (Mþ, 100) 216
([MꢁC3H7]þ, 99) 105 (C8H9þ, 75) 77 (C6Hþ5 , 40). HRMS C16H21NO2
calcd 259.1572, found 259.1575.
3.1.48. (1S,6R)-1-(a-Methylbenzyl)-6-cyclohexylpiperidine-2,4-dione
203e207 ꢀC; IR nmax 3064, 2974, 1660 cmꢁ1
CDCl3)
;
1H NMR (500 MHz,
(12k). Following general procedure C, reaction of diester 10k
(0.22 g, 0.57 mmol) and sodium methoxide in methanol (2.0 M,
0.6 mL, 1.2 mmol) in methanol (3 mL) gave 12k (0.13 g, 76%) as
d
7.35e7.22 (5H, m) 6.04 (1H, q, J¼7.2 Hz) 5.66 (1H, m) 5.53
(1H, m) 3.66 (3H, s) 3.60 (1H, m) 2.33 (1H, dd, J¼15.7, 6.2 Hz) 2.18
(1H, dd, J¼15.7, 2.4 Hz) 1.61 (3H, d, J¼6.2 Hz) 1.49 (3H, d, J¼7.2 Hz);
a colourless oil, ½a D25
ꢃ
ꢁ133.1 (c 3.40, CHCl3); IR nmax 2926, 1726,
13C NMR (500 MHz, CDCl3)
d
188.1, 170.8, 170.7, 144.1, 132.7, 129.4,
1640 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d 7.46e7.25 (5H, m) 6.03 (1H,
128.2, 128.2, 127.3, 96.4, 51.8, 51.4, 50.4, 43.4, 17.8, 17.3. HRMS
18H21NO4Na calcd 338.1368, found 338.1360.
q, J¼7.2 Hz) 3.38 (1H, d, J¼21.2 Hz) 3.26 (1H, d, J¼21.2 Hz) 3.13 (1H,
m) 2.49 (1H, dd, J¼16.7, 3.6 Hz) 1.95 (1H, dd, J¼16.7, 6.5 Hz) 1.74
(2H, m) 1.61 (3H, d, J¼7.2 Hz) 1.59e1.47 (3H, m) 1.14e0.80 (6H, m);
C
3.1.44. (1S,6S)-1-(
a
-Methylbenzyl)-6-methylpiperidine-2,4-dione
13C NMR (500 MHz, CDCl3)
d 205.6, 169.5, 139.9, 128.8, 128.0, 127.5,
(12a). Following general procedure C, reaction of diester 10a
(0.23 g, 0.70 mmol), and sodium methoxide in methanol (2.0 M,
0.70 mL, 1.4 mmol) in methanol (5 mL) gave 12a (0.16 g, 97%) as
55.2, 52.8, 47.7, 43.6, 41.7, 30.7, 28.6, 26.6, 26.4, 26.0, 17.6; m/z (CI, %)
300 ([MþH]þ, 100). HRMS C19H26NO2 calcd 300.1964, found
300.1953.
a pale yellow oil, ½a D21
ꢃ
ꢁ198.1 (c 3.09, CHCl3); IR nmax 2975, 1730,
1642 cmꢁ1; 1H NMR (500 MHz, CDCl3)
d
7.36e7.25 (5H, m) 6.10 (1H,
3.1.49. (1S,6R)-1-(a-Methylbenzyl)-6-(E)-propenylpiperidine-2,4-
q, J¼6.9 Hz) 3.55 (1H, m) 3.41e3.29 (2H, m) 2.24 (1H, dd, J¼16.5,
dione (12l). The piperidine-2,4-dione sodium salt 11l (1.0 g,
2.96 mmol) was added to hydrochloric acid (1.3 M, 30 mL). The
8.6 Hz) 2.17 (1H, dd, J¼16.5, 5.0 Hz) 1.59 (3H, d, J¼6.9 Hz) 1.25 (3H,