10.1002/ejoc.201900399
European Journal of Organic Chemistry
FULL PAPER
0.64 g (5.1 mmol, 85%.) of 3,4,5,6-tetrahydro-4-propylpyridine 5c. An 1.0
mmol aliquot of 5c (125 mg, 1 equiv) was then used in the U-3CR together
with pivalic acid (123 mg, 1.2 mmol, 1.2 equiv) and cyclohexyl isocyanide
(151 µL, 1.2 mmol, 1.2 equiv) following the general procedure IV. Flash
chromatography (cyclohexane/EtOAc = 5:1) provided 6c as a slowly
crystalizing oil (254 mg, 0.78 mmol, 78%.). RF = 0.58 (cyclohexane/EtOAc
= 2:1); 1H NMR (CDCl3, 500 MHz): δ 6.21 (bs, 1H), 5.10 (bs, 1H), 4.15 (m,
1H), 3.26 (m, 1H), 3.11 (m, 1H), 2.92 (m, 1H), 2.27 (d, J = 12.9 Hz, 1H),
1.85 (m, 1H), 1.67 (d, J = 12.9 Hz, 1H), 1.42 (m, 2H), 1.33-1.10 (m, 17H),
1.10-0.99 (m, 2H), 0.86 (m, 6H) ppm; 13C NMR (CDCl3, 125 MHz): δ 178.3
(Cq), 171.0 (Cq), 45.3 (CH), 44.2 (Cq), 39.1 (CH2), 38.9 (CH2), 38.9 (CH2),
32.0 (CH2), 31.8 (CH2), 31.4 (CH), 29.3 (CH2), 29.0 (CH2), 28.2 (CH3), 22.2
(CH2), 19.5 (CH2), 14.2 (CH3), 13.9 (CH3) ppm; IR (neat): νmax (cm-1) =
3337, 2955, 2928, 1670, 1612, 1521, 1412, 1186, 630, 532; HRMS (ESI):
m/z calculated for C19H36N2NaO2 [M+Na]+ 347.2669, found 347.2670.
41.0 (CH2), 40.8 (CH2), 39.5 (CH2), 36.3 (CH2), 36.1 (CH2), 33.0 (CH2),
32.1 (CH), 31.9 (CH2), 31.7 (CH2), 31.5 (CH), 31.2 (CH2), 29.7 (CH2), 28.5
(CH2), 28.5 (CH2), 22.7 (CH2), 21.7 (CH3), 21.7 (CH3), 14.0 (CH3), 14.0
(CH3) ppm; IR (neat): νmax (cm-1) = 3330, 2925, 1751, 1629, 1521, 1423,
1363, 1201, 644, 572, 463; HRMS (ESI): m/z calculated for C15H27N2O4
[M+H]+ 299.1965, found 299.1949.
Synthesis
of
N-(tert-butyl)-4-butyl-1-(pent-4-enoyl)piperidine-2-
carboxamide (6f). Another 1.0 mmol aliquot of 5d (139 mg, 1 equiv) was
then used in the U-3CR together with 4-pentenoic acid (123 µL, 1.2 mmol,
1.2 equiv) and tert-butyl isocyanide (135 µL, 1.2 mmol, 1.2 equiv) following
the general procedure IV. Flash chromatography (cyclohexane/EtOAc =
4:1) provided 6f as a white solid (270 mg, 0.84 mmol, 84%). Two rotamers
were present on NMR-timescale in
a 1 : 0.25 ratio. RF = 0.58
(cyclohexane/EtOAc = 2:1) m.p.: 89 ˚C; 1H NMR (CDCl3, 500 MHz): δ 5.97
(s, 1H), 5.84 (m, 1.25H), 5.70 (s, 0.25H), 5.11 (d, J = 6.5Hz, 1H), 5.05 (d,
J = 17.2 Hz, 1.25H), 4.99 (d, J = 10.2 Hz, 1.25H), 4.63 (d, J = 11.7 Hz,
0.25H), 4.38 (d, J = 5.4 Hz, 0.25H), 3.76 (d, J = 13.6 Hz, 1H), 3.05 (dt, J =
13.3, 2.5 Hz, 1H), 2.55-2.31 (m, 5.5H), 2.18 (d, J = 13.5 Hz, 1H), 1.83 (m,
1H), 1.70 (m, 1.25H), 1.31-1.12 (m, 19.0H) 1.08-0.95 (m, 2.5H), 0.85 (t, J
= 7.0 Hz, 3.75H) ppm; 13C NMR (CDCl3, 125 MHz): δ 172.4 (Cq), 172.0
(Cq), 170.2 (Cq), 168.7 (Cq), 137.1 (CH2)2), 137.0 (CH2)2), 115.6 (CH),
115.4 (CH), 57.7 (CH), 52.5 (CH), 51.5 (Cq), 50.8 (Cq), 43.5 (CH2)2), 39.7
(CH2)2), 36.4 (CH2)2), 36.1 (CH2)2), 33.0 (CH2)2), 32.7 (CH2)2), 32.6 (CH2)2),
32.3 (CH), 32.1 (CH2)2), 31.8 (CH2)2), 31.6 (CH), 31.2 (CH2)2), 29.2 (CH2)2),
29.2 (CH2)2), 28.7 (CH3), 28.7 (CH3), 28.6 (CH2)2), 28.5 (CH2), 22.8 (CH2),
22.8 (CH2), 14.0 (CH2), 14.0 (CH2) ppm; IR (neat): νmax (cm-1) = 3329, 2924
1676, 1628, 1541, 1452, 1425, 1363, 910, 731, 646; HRMS (ESI): m/z
calculated for C19H34N2NaO2 [M+Na]+ 345.2512, found 345.2528.
Synthesis of 1-benzoyl-N-(tert-butyl)-4-propylpiperidine-2-carbox-
amide (6d). Another 1.0 mmol aliquot of 5c (125 mg, 1 equiv, see
preparation of 6c) was then used in the U-3CR together with benzoic acid
(147 mg, 1.2 mmol, 1.2 equiv) and tert-butyl isocyanide (135 µL, 1.2 mmol,
1.2 equiv) following the general procedure IV. Flash chromatography
(cyclohexane/EtOAc = 4:1) provided 6d as a slowly crystallizing white solid
(271 mg, 0.82 mmol, 82%). Two rotamers were present on NMR-timescale
1
in a 1 : 0.21 ratio. RF = 0.57 (cyclohexane/EtOAc = 2:1); m.p.: 92 ˚C; H
NMR (CDCl3, 500 MHz): δ 7.44-7.26 (m, 6.05H), 6.41 (s, 1H), 5.81 (s,
0.21H), 5.17 (d, J = 5.4Hz, 1H), 4.72 (d, J = 12.8 Hz, 0.21H), 4.29 (bs,
0.21H), 3.76 (d, J = 13.6 Hz, 1H), 3.01 (t, J = 11.6 Hz, 1H), 2.79 (t, J = 12.6
Hz, 0.21H), 2.78 (d, J = 13.2 Hz, 1.21H), 1.96 (m, 1H), 1.75 (d, J = 12.7
Hz, 0.21H), 1.62 (d, J = 12.8 Hz, 1H), 1.50 (m, 0.42H), 1.40-1.02 (m,
18.15H), 0.87 (m, 3.63H) ppm; 13C NMR (CDCl3, 125 MHz): δ 172.0 (Cq),
171.8 (Cq), 170.0 (Cq), 168.8 (Cq), 135.5 (Cq), 135.3 (Cq), 130.1 (CH),
129.9 (CH), 128.7 (CH), 128.5 (CH), 126.9 (CH), 126.1 (CH), 59.7 (CH),
53.2 (CH), 51.5 (Cq), 50.9 (Cq), 45.8 (CH2), 40.2 (CH2), 39.0 (CH2), 38.6
(CH2), 33.4 (CH2), 33.1 (CH2), 32.1 (CH2), 31.8 (CH), 31.4 (CH), 31.3 (CH2),
28.8 (CH3), 28.7 (CH3), 19.5 (CH2), 19.4 (CH2), 14.3 (CH3), 14.1 (CH3)
ppm; IR (neat): νmax (cm-1) = 3337, 2959, 2926, 1683, 1616, 1522, 1423,
1363, 1253, 1224, 1203, 921, 730, 700, 646; HRMS (ESI): m/z calculated
for C20H31N2O2 [M+H]+ 331.2380, found 331.2367.
Synthesis of N-cyclohexyl-4-isobutyl-1-pivaloylpiperidine-2-carbox-
amide (6g). The general procedure IV with 1.07 g (6.0 mmol, 1 equiv) of
4d gave 0.75 g (5.4 mmol, 90%.) of 3,4,5,6-tetrahydro-4-isobutylpyridine
5e. An 1.0 mmol aliquot of 5e (139 mg, 1 equiv) was then used in the U-
3CR together with pivalic acid (123 mg, 1.2 mmol, 1.2 equiv) and
cyclohexyl isocyanide (149 µL, 1.2 mmol, 1.2 equiv) following the general
procedure IV. Flash chromatography (cyclohexane/EtOAc = 6:1) provided
the 6g as a white crystalline solid (286 mg, 0.81 mmol, 81%). RF = 0.64
(cyclohexane/EtOAc = 2:1); m.p.: 96 ˚C; 1H NMR (CDCl3, 500 MHz): δ 6.13
(bs, 1H), 5.10 (bs, 1H), 4.16 (bs, 1H), 3.74 (m, 1H), 2.91 (m, 1H), 2.27 (d,
J = 11.8 Hz, 1H), 1.95 (bs, 1H), 1.84 (d, J = 9.2 Hz, 1H), 1.76 (d, J = 9.1
Hz, 1H), 1.72-1.59 (m, 4H), 2.27 (d, J = 9.1 Hz, 1H), 1.40-1.24 (m, 1H),
1.20-0.96 (m, 7H), 0.89 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.6 Hz, 3H) ppm;
13C NMR (CDCl3, 125 MHz): δ 178.3 (Cq), 170.1 (Cq), 47.6 (CH), 46.1
(CH2), 44.2 (CH), 38.8 (Cq), 33.2 (CH2), 32.8 (CH2), 32.3 (CH2), 31.9 (CH2),
29.4 (CH), 28.2 (CH3), 25.4 (CH2), 24.6 (CH2), 24.5 (CH), 22.9 (CH3), 22.5
(CH3) ppm; IR (neat): νmax (cm-1) = 3339, 2930, 2853, 1678, 1610, 1518,
1412, 1366, 1186, 976, 920, 731, 646, 467; HRMS (ESI): m/z calculated
for C21H38N2NaO2 [M+Na]+ 373.2825, found 373.2833.
Synthesis of methyl (1-acetyl-4-butylpiperidine-2-carbonyl)glycinate
(6e). The general procedure IV with 1.07 g (6.0 mmol, 1 equiv) of 4c gave
0.78 g (5.6 mmol, 93%.) of 3,4,5,6-tetrahydro-4-butylpyridine 5d. An 1.0
mmol aliquot of 5d (139 mg, 1 equiv) was then used in the U-3CR together
with acetic acid (69 µL, 1.2 mmol, 1.2 equiv) and methyl isocyanoacetate
(109 µL, 1.2 mmol, 1.2 equiv) following the general procedure IV. Flash
chromatography (EtOAc) provided 6e as a slowly crystalizing oil (205 mg,
0.69 mmol, 69%). Two rotamers were present on NMR-timescale in a 1 :
0.27 ratio. RF = 0.25 (EtOAc); 1H NMR (CDCl3, 500 MHz): δ 7.27 (bs,
0.27H), 6.69 (bs, 1H), 5.28 (d, J = 5.5 Hz, 1H), 4.59 (d, J = 13.5 Hz, 0.27H),
4.46 (d, J = 5.2 Hz, 0.27H), 4.14 (m, 1.27H), (dd, J = 17.8, 5.5 Hz, 0.27H),
3.80-3.70 (m, 5.81H), 3.21 (dt, J = 13.8, 2.2 Hz, 1H), 2.71 (dt, J = 13.3, 2.5
Hz, 0.27H), 2.52 (d, J = 12.4 Hz, 0.27H), 2.26 (d, J = 12.2 Hz, 1H), 2.16 (s,
3H), 2.11 (s, 0.81H), 1.93 (bs, 0.27H), 1.80-1.63 (m, 2.27H), 1.43 (bs,
0.27H), 1.80-1.63 (m, 9.89H), 0.86 (t, J = 6.8 Hz, 3.81H) ppm; 13C NMR
(CDCl3, 125 MHz): δ 171.4 (Cq), 170.9 (Cq), 170.4 (Cq), 170.4 (Cq), 170.3
(Cq), 170.2 (Cq), 58.2 (CH), 52.3 (CH), 52.2 (CH3), 51.8 (CH3), 44.4 (CH2),
Synthesis of 1-benzoyl-N-(tert-butyl)-4-isobutylpiperidine-2-carbox-
amide (6h). Another 1.0 mmol aliquot of 5e (139 mg, 1 equiv, see
preparation of 6g) was then used in the U-3CR together with benzoic acid
(147 mg, 1.2 mmol, 1.2 equiv) and tert-butyl isocyanide (135 µL, 1.2 mmol,
1.2 equiv) following the general procedure IV. Flash chromatography
(cyclohexane/EtOAc = 7:2) provided 6h as a white solid (294 mg, 0.91
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