10.1002/ejoc.201801684
European Journal of Organic Chemistry
FULL PAPER
eluting with a 1N HCl solution in water and MeCN or by flash
chromatography. Then, volatiles were removed in vacuo to yield
the desired semi-saturated bicyclic product.
5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic
acid (23): 6 (200mg, 1.20mmol) in EtOH (20ml), water (4ml) and
1M NaOH aq.sol. (1.2ml), 10 % Pd/C cartridge, 60 bar H2, 60° C,
1 mL min-1 flow rate. Purification by isolute SCX-2 column to yield
23 (202mg, 1.18mmol, 99%) as a white solid. ¹H-NMR (400 MHz,
MeOD-d4): δ 8.37 (s, 1H), 4.27 (dd, J = 5.5, 12.6 Hz, 1H), 4.20
(dd, J = 8.1, 12.6 Hz, 1H), 3.04 (qd, J = 5.7, 11.5 Hz, 1H), 2.93 -
2.77 (m, 2H), 2.32 - 2.24 (m, 1H), 2.16 - 2.05 (m, 1H); 13C NMR
(100 MHz, DMSO-d6): δ 173.0, 151.5, 143.5, 45.4, 21.6, 21.5,
19.4; HRMS (ESI): [M+H]+ calcd. for C7H9N3O2: 168.0768, found:
168.0770.
methyl
4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine-6-
carboxylate (18): 1 (200mg, 1.105mmol) in EtOH (18ml), water
(4ml) and AcOH (0.08ml), 10 % Pd/C cartridge, 100 bar H2, 100°
C, 1 mL min-1 flow rate. Purification by isolute SCX-2 column to
yield 18 (203mg, 1.093mmol, 99%) as a pale yellow solid. ¹H-
NMR (400 MHz, MeOD-d4): δ 7.09 (s, 1H), 3.72 (s, 3H), 3.38 (d,
J = 12.0 Hz, 2H), 3.16 (dd, J = 8.0, 12.2 Hz, 1H), 2.97 - 2.91 (m,
3H); 13C NMR (100 MHz, MeOD-d4): δ 172.5, 124.8, 49.6, 43.6,
37.6, 21.6; HRMS (ESI): [M+H]+ calcd. for C8H11N3O2: 182.0924,
found: 182.0932.
5,6,7,8-tetrahydroimidazo[1,2-a]pyridine-5-carboxylic
acid
(24). 7 (200mg, 1.21mmol) in EtOH (20ml), water (4ml) and NaOH
(1.2ml), 10 % Pd/C cartridge, 50 bar H2, 50° C, 1 mL min-1 flow
rate. Purification by isolute PE-AX column to yield 24 (202mg,
1.19mmol, 99%) as a white solid. ¹H-NMR (500 MHz, DMSO-d6)
δ 14.08 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.59 (d, J = 2.1 Hz, 1H),
5.21 (dd, J = 4.9, 4.9 Hz, 1H), 3.11 (ddd, J = 4.0, 5.7, 17.9 Hz,
1H), 3.04 - 2.95 (m, 1H), 2.30 - 2.26 (m, 2H), 2.03 - 1.96 (m, 1H),
1.76 - 1.65 (m, 1H); 13C NMR (125 MHz, DMSO-d6): δ 170.8,
163.4, 145.0, 122.6, 118.4, 57.6, 25.1, 21.2, 16.3; HRMS (ESI):
[M+H]+ calcd. for C8H10N2O2: 167.0815, found: 167.0817.
N-(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-b]pyridin-5-
yl)acetamide (19): 2 (200mg, 1.11mmol) in EtOH (18ml), water
(4ml) and AcOH (0.08ml), 10 % Pd/C cartridge, 50 bar H2, 50° C,
1 mL min-1 flow rate. Purification by isolute SCX-2 column to yield
19 (204mg, 1.10mmol, 99%) as a white solid.¹H-NMR (400 MHz,
MeOD-d4): δ 7.20 (s, 1H), 4.15 (ddd, J = 2.8, 6.9, 12.3 Hz, 1H),
4.18-4.12 (m, 1H), 3.10 (dd, J = 7.2, 11.6 Hz, 1H), 2.82 (dd, J =
5.3, 15.2 Hz, 1H), 2.53 (dd, J = 6.8, 15.2 Hz, 1H), 1.94 (s, 3H);
13C NMR (100 MHz, MeOD-d4): δ 171.5, 152.3, 127.4, 99.04,
45.8, 44.1, 24.8, 21.2; HRMS (ESI): [M+H]+ calcd. for C8H12N4O:
181.1084, found: 181.1102.
ethyl 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carboxylate
(25): 8 (200mg, 1.03mmol) in EtOH (16ml) and water (4ml), 10 %
Pd/C cartridge, 100 bar H2, 100° C, 1 mL min-1 flow rate.
Purification by isolute SCX-2 column to yield 25 (202mg,
1.02mmol, 99%) as a pale yellow oil. ¹H-NMR (400 MHz, MeOD-
d4): δ 7.80 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.12 (t, J = 6.1 Hz,
2H), 3.04 (t, J = 6.4 Hz, 2H), 2.09 - 2.01 (m, 2H), 1.93 - 1.85 (m,
2H), 1.33 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, MeOD-d4): δ
163.7, 144.0, 144.2, 110.2, 59.6, 22.6, 22.3, 19.0, 13.3; HRMS
(ESI): [M+H]+ calcd. for C10H14N2O2: 195.1128, found: 195.1138.
1,2,3,4-tetrahydroquinolin-5-ol (20): 3 (200mg, 1.34mmol) in
EtOH (22ml), water (5ml) and AcOH (0.1ml), RaNi cartridge, 8 bar
H2, 25° C, 1 mL min-1 flow rate. Purification by isolute SCX-2
column to yield 20 (199mg, 1.30mmol, 97%) as a yellow solid. ¹H-
NMR (400 MHz, MeOD-d4): δ 6.71 (dd, J = 8.0, 8.0 Hz, 1H), 6.10
- 6.05 (m, 2H), 3.16 (t, J = 5.4 Hz, 2H), 2.61 (t, J = 6.6 Hz, 2H),
1.93 - 1.85 (m, 2H); 13C NMR (100 MHz, MeOD-d4): δ 155.0,
146.1, 126.0, 108.9, 106.6, 103.6, 41.1, 21.8, 20.3; HRMS (ESI):
[M+H]+ calcd. for C9H11NO: 150.0913, found: 150.0922.
methyl 5,6,7,8-tetrahydroindolizine-7-carboxylate (26):
9
(200mg, 1.15mmol) in EtOH (18ml), water (5ml), RaNi cartridge,
4 bar H2, 25° C, 1 mL min-1 flow rate. Purification by flash
chromatography (EtOAc/Heptane, 15:85) to yield 26 (149mg,
0.83mmol, 73%) as a colourless oil. ¹H-NMR (500 MHz, CDCl3):
δ 6.55 (dd, J = 1.7, 1.7 Hz, 1H), 6.16 (dd, J = 3.1, 3.1 Hz, 1H),
5.89 (br, 1H), 4.12 (ddd, J = 3.3, 5.4, 12.3 Hz, 1H), 3.93 (dt, J =
4.7, 11.8 Hz, 1H), 3.76 (s, 3H), 3.16 (dd, J = 5.0, 15.7 Hz, 1H),
2.93 (dd, J = 11.2, 15.8 Hz, 1H), 2.84 - 2.76 (m, 1H), 2.36 - 2.29
(m, 1H), 2.15 - 2.05 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 174.6,
127.1, 118.7, 108.1, 104.6, 51.9, 44.2, 38.6, 26.5, 26.1; HRMS
(ESI): [M+H]+ calcd. for C7H9N3: 180.1019, found: 180.1023.
1,2,3,4-tetrahydroisoquinolin-6-amine
(21):
4
(200mg,
1.35mmol) in EtOH (22ml), water (5ml) and AcOH (0.2ml), 10 %
Pd/C cartridges, 70 bar H2, 70° C, 1 mL min-1 flow rate.
Purification by isolute SCX-2 column to yield 21 (203mg,
1.33mmol, 99%) as a pale yellow solid. ¹H-NMR (500 MHz,
MeOD-d4): δ 6.78 (d, J=8.1 Hz, 1H), 6.54 (dd, J=2.3, 8.1 Hz, 1H),
6.49 (d, J=2.3 Hz, 1H), 3.83 (s, 2H), 3.03 (t, J=6.0 Hz, 2H), 2.73
(t, J=6.0 Hz, 2H); 13C NMR (125 MHz, MeOD-d4): δ 145.3, 134.6,
126.6, 124.4, 115.4, 113.8, 46.6, 43.1, 28.0; HRMS (ESI): [M+H]+
calcd. for C8H11N3O2: 149.1075, found: 149.1073.
4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine (22): 5 (200mg,
1.62mmol) in EtOH (25ml), water (7ml) and AcOH (0.12ml), 10 %
Pd/C cartridge, 100 bar H2, 100° C, 1 mL min-1 flow rate.
Purification by isolute SCX-2 column to yield 22 (204mg,
1.60mmol, 99%) as a white solid.¹H-NMR (500 MHz, MeOD-d4):
δ 7.35 (s, 1H), 3.90 (s, 2H), 3.01 (t, J = 5.9 Hz, 2H), 2.64 (t, J =
5.9 Hz, 2H); 13C NMR (125 MHz, MeOD-d4): δ 144.0, 127.4,
112.6, 43.1, 42.0, 20.5; HRMS (ESI): [M+H]+ calcd. for C6H9N3:
124.0869, found: 124.0863.
N-(1,2,3,4-tetrahydroquinoxalin-6-yl)acetamide
(27):
10
(200mg, 1.047mmol) in EtOH (16ml), water (4ml) and AcOH
(0.18ml), 10 % Pd/C cartridge, 70 bar H2, 70° C, 1 mL min-1 flow
rate. Purification by isolute SCX-2 column to yield to yield 27
(202mg, 1.036mmol, 99%) as a yellow oil. ¹H-NMR (500 MHz,
DMSO-d6): δ 9.32 (s, 1H), 6.70 (d, J = 2.3 Hz, 1H), 6.48 (dd, J =
2.3, 8.2 Hz, 1H), 6.24 (d, J = 8.2 Hz, 1H), 5.38 (s, 1H), 5.06 (s,
1H), 3.19 - 3.13 (m, 4H), 1.93 (s, 3H); 13C NMR (125 MHz, DMSO-
d6): δ 167.4, 134.5, 130.5, 130.3, 113.5, 108.8, 105.9, 40.9, 40.8,
24.2; HRMS (ESI): [M+H]+ calcd. for C10H13N3O: 192.1131, found:
192.1146.
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