3970
T. Schläger et al.
FEATURE ARTICLE
1-Phenyl-4-(pyrrolidin-1-ylmethyl)-1,4,6,7-tetrahydropyra-
no[4,3-c]pyrazole (3a); Typical Procedure
1-Phenyl-4-(4-phenylpiperidin-1-ylmethyl)-1,4,6,7-tetrahydro-
pyrano[4,3-c]pyrazole (3c)
K2CO3 (377 mg, 2.73 mmol) and freshly distilled pyrrolidine (56.0
mL, 0.68 mmol) were successively added to a soln of bromomethyl
derivative 8 (100 mg, 0.34 mmol) in MeCN (5 mL). The mixture
was heated to reflux for 29 h. It was then filtered, the solvent was
removed in vacuo, and the residue (94 mg) was purified by flash
chromatography (3 cm, n-hexane–EtOAc, 5:5 + 1% Me2NEt, 20
mL, Rf = 0.06) to give a colorless solid; yield: 46 mg (48%); mp 89
°C.
Following the typical procedure for 3a using K2CO3 (302 mg, 2.18
mmol), 4-phenylpiperidine (132 mg, 0.82 mmol), and 8 (80 mg,
0.27 mmol) in MeCN (5 mL) with heating to reflux for 25 h gave a
residue (190 mg) which was purified by flash chromatography (3
cm, n-hexane–EtOAc, 5:5 + 1% Me2NEt, 20 mL, Rf = 0.25) to give
a colorless resin; yield: 41 mg (41%).
IR (neat): 3058, 3026 (C–Harom), 2932 (C–Haliph), 2847 (C–H),
1598, 1504 (C=C), 1091 cm–1 (C–O).
IR (neat): 3061 (C–Harom), 2961, 2929 (C–Haliph), 2854 (C–H),
1598, 1504 (C=C), 1090 cm–1 (C–O).
1H NMR (CDCl3): d = 1.82–1.98 (m, 4 H, piperidine 3-CH2, 5-
CH2), 2.19–2.30 (m, 2 H, piperidine 2-CH2, 6-CH2), 2.50–2.59 (m,
1 H, piperidine 4-CH), 2.65–2.73 [m, 2 H, ArCH2CH2O (1 H),
CHCH2N (1 H)], 2.81 (dd, J = 13.3, 8.2 Hz, 1 H, CHCH2N), 3.07
(dddd, J = 15.8, 10.2, 5.6, 1.5 Hz, 1 H, ArCH2CH2O), 3.22 (br t,
J = 10.0 Hz, 2 H, piperidine 2-CH2, 6-CH2), 3.70 (ddd, J = 11.3,
10.2, 3.9 Hz, 1 H, ArCH2CH2O), 4.27 (ddd, J = 11.5, 5.7, 2.2 Hz, 1
H, ArCH2CH2O), 4.91–4.97 (m, 1 H, CHCH2N), 7.20 (t, J = 7.0 Hz,
1 H, p-CHPh), 7.25–7.38 (m, 5 H, CHPh), 7.43–7.56 (m, 4 H, CHPh),
7.60 (s, 1 H, CHpyrazole).
1H NMR (CDCl3): d = 1.72–1.83 (m, 4 H, pyrrolidine 3-CH2, 4-
CH2), 2.55–2.64 [m, 5 H, pyrrolidine 2-CH2, 5-CH2 (4 H),
ArCH2CH2O (1 H)], 2.73 (dd, J = 12.7, 3.3 Hz, 1 H, CHCH2N),
2.82 (dd, J = 12.9, 9.0 Hz, 1 H, CHCH2N), 2.98 (dddd, J = 15.8,
10.0, 5.6, 1.6 Hz, 1 H, ArCH2CH2O), 3.61 (ddd, J = 11.2, 10.3, 3.7
Hz, 1 H, ArCH2CH2O), 4.09 (ddd, J = 11.4, 5.6, 2.3 Hz, 1 H,
ArCH2CH2O), 4.77–4.84 (m, 1 H, CHCH2N), 7.27 (t, J = 7.2 Hz, 1
H, p-CHPh), 7.35–7.44 (m, 4 H, CHPh), 7.46 (s, 1 H, H3pyrazole).
13C NMR (CDCl3): d = 23.8 (2 C, pyrrolidine 3-CH2, 4-CH2), 25.1
(1 C, ArCH2CH2O), 55.1 (2 C, pyrrolidine 2-CH2, 5-CH2), 61.6 (1
C, CHCH2N), 63.5 (1 C, ArCH2CH2O), 72.5 (1 C, CHCH2N), 77.4
(1 C, 4-Cpyrazole), 122.9 (2 C, o-CHPh), 127.2 (1 C, p-CHPh), 129.5 (2
C, m-CHPh), 136.1 (1 C, CPh quat), 136.2 (1 C, 3-CHpyrazole), 139.8
(1 C, 5-Cpyrazole).
13C NMR (CDCl3): d = 25.1 (1 C, ArCH2CH2O), 33.7 (2 C, piperi-
dine 3-CH2, 5-CH2), 42.9 (1 C, piperidine 4-CH), 55.1, 55.6 (1 C,
piperidine 2-CH2, 6-CH2), 63.6 (1 C, ArCH2CH2O), 64.3 (1 C,
CHCH2N), 71.3 (1 C, CHCH2N), 77.5 (1 C, 4-Cpyrazole), 119.4 (1 C,
C4-Ph quat), 112.9 (2 C, o-CHPh), 126.4 (1 C, p-CH4-Ph), 127.1 (2 C,
o-CH4-Ph), 127.2 (1 C, p-CHPh), 128.7 (2 C, m-CH4-Ph), 129.5 (2 C,
m-CHPh), 136.1 (1 C, CPh quat), 136.4 (1 C, 3-CHpyrazole), 139.8 (1
C, 5-Cpyrazole).
MS (ESI): m/z [M] calcd for C17H21N3O: 283.4; found: m/z
(%) = 284 [MH+, 100], 589 [2 M + Na+, 13].
MS (ESI): m/z [M] calcd for C24H27N3O: 373.5; found: m/z
Anal. Calcd for C17H21N3O (283.4): C, 72.1; H, 7.47; N, 14.8.
Found: C, 71.6; H, 7.49; N, 14.5.
(%) = 374 [MH+, 100], 769 [2 M + Na+, 47].
Anal. Calcd for C24H27N3O (373.5): C, 77.2; H, 7.29; N, 11.3.
Found: C, 77.0; H, 7.34; N, 11.1.
1-Phenyl-4-(piperidin-1-ylmethyl)-1,4,6,7-tetrahydropyra-
no[4,3-c]pyrazole (3b)
Following the typical procedure for 3a using K2CO3 (302 mg, 2.18
mmol), freshly distilled piperidine (81 mL, 0.81 mmol), and 8 (80
mg, 0.27 mmol) in MeCN (5 mL) with heating to reflux for 42 h
gave a residue (89 mg) which was purified by flash chromatography
(3 cm, n-hexane–EtOAc, 5:5 + 1% Me2NEt, 20 mL, Rf = 0.11) to
give a colorless solid; yield: 47 mg (58%); mp 91 °C.
4-(Morpholin-4-ylmethyl)-1-phenyl-1,4,6,7-tetrahydropyra-
no[4,3-c]pyrazole (3d)
Following the typical procedure for 3a using K2CO3 (377 mg, 2.73
mmol), morpholine (59.7 mL, 0.68 mmol), and 8 (100 mg, 0.34
mmol) in MeCN (5 mL) with heating to reflux for 47 h gave a resi-
due (105 mg) which was purified by flash chromatography (3 cm,
n-hexane–EtOAc, 2:8, 20 mL, Rf = 0.06) to give a colorless solid;
yield: 59 mg (58%); mp 115 °C.
IR (neat): 3059 (C–Harom), 2930 (C–Haliph), 2850 (C–H), 1599, 1504
(C=C), 1091 (C–O), 758, 693 cm–1 (C–H).
IR (neat): 3061 (C–Harom), 2967, 2918 (C–Haliph), 2850 (C–H),
1599, 1505 (C=C), 1114, 1087 cm–1 (C–O).
1H NMR (CDCl3): d = 1.38–1.45 (m, 2 H, piperidine 4-CH2), 1.52–
1.63 (m, 4 H, piperidine 3-CH2, 5-CH2), 2.40–2.69 [m, 7 H, piperi-
dine 2-CH2, 6-CH2 (4 H), ArCH2CH2O (1 H), CHCH2N (2 H)], 2.98
(dddd, J = 15.8, 10.1, 5.6, 1.6 Hz, 1 H, ArCH2CH2O), 3.61 (ddd,
J = 11.3, 10.2, 3.9 Hz, 1 H, ArCH2CH2O), 4.97 (ddd, J = 11.5, 5.7,
2.2 Hz, 1 H, ArCH2CH2O), 4.78–4.84 (m, 1 H, CHCH2N), 7.25 (t,
J = 7.0 Hz, 1 H, CHPh), 7.35–7.48 (m, 4 H, CHPh), 7.51 (s, 1 H,
H3pyrazole).
13C NMR (CDCl3): d = 24.5 (1 C, piperidine 4-CH2), 25.1 (1 C,
ArCH2CH2O), 26.1 (2 C, piperidine 3-CH2, 5-CH2), 55.5 (2 C, pip-
eridine 2-CH2, 6-CH2), 63.6 (1 C, ArCH2CH2O), 64.5 (1 C,
CHCH2N), 71.2 (1 C, CHCH2N), 77.4 (1 C, 4-Cpyrazole), 122.8 (2 C,
o-CHPh), 127.2 (1 C, p-CHPh), 129.5 (2 C, m-CHPh), 136.0 (1 C, CPh
quat), 136.5 (1 C, 3-CHpyrazole), 139.8 (1 C, 5-Cpyrazole).
1H NMR (CDCl3): d = 2.48–2.73 [m, 7 H, morpholine 2-CH2, 6-
CH2 (4 H), ArCH2CH2O (1 H), CHCH2N (2 H)], 2.99 (dddd,
J = 15.8, 10.2, 5.7, 1.7 Hz, 1 H, ArCH2CH2O), 3.61 (ddd, J = 11.4,
10.4, 3.7 Hz, 1 H, ArCH2CH2O), 3.68–3.77 (m, 4 H, morpholine 3-
CH2, 5-CH2), 4.18 (ddd, J = 11.4, 5.7, 2.2 Hz, 1 H, ArCH2CH2O),
4.81–4.89 (m, 1 H, CHCH2N), 7.28 (t, J = 7.2 Hz, 1 H, p-CHPh),
7.35–7.49 (m, 4 H, CHPh), 7.51 (s, 1 H, H3pyrazole).
13C NMR (CDCl3): d = 25.4 (1 C, ArCH2CH2O), 54.9 (2 C, morpho-
line 2-CH2, 6-CH2), 64.0 (1 C, ArCH2CH2O), 64.5 (1 C, CHCH2N),
67.5 (2 C, morpholine 3-CH2, 5-CH2), 71.2 (1 C, CHCH2N), 77.8 (1
C, 4-Cpyrazole), 123.2 (2 C, o-CHPh), 127.6 (1 C, p-CHPh), 129.8 (2 C,
m-CHPh), 136.4 (1 C, CPh quat), 136.6 (1 C, 3-CHpyrazole), 140.0 (1
C, 5-Cpyrazole).
MS (ESI): m/z [M] calcd for C18H23N3O: 297.4; found: m/z
(%) = 298 [MH+, 100], 617 [2 M + Na+, 15].
MS (ESI): m/z [M] calcd for C17H21N3O2: 299.4; found: m/z
(%) = 300 [MH+, 100], 621 [2 M + Na+, 43].
Anal. Calcd for C18H23N3O (297.4): C, 72.7; H, 7.80; N, 14.1.
Found: C, 72.5; H, 7.80; N, 13.8.
Anal. Calcd for C17H21N3O2 (299.4): C, 68.2; H, 7.07; N, 14.0.
Found: C, 68.3; H, 7.06; N, 13.9.
Synthesis 2011, No. 24, 3965–3974 © Thieme Stuttgart · New York