The Journal of Organic Chemistry
Note
(6-Benzyl-3-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (12). Using Method
A; the reaction was heated to 80 °C for 1 h. Isolated 12 as a white
dioxaborolan-2-yl)-1H-pyrazole (341 mg, 1.64 mmol), and K3PO4
(464 mg, 2.19 mmol) in THF (10 mL)/water (3.33 mL), and the
reaction was stirred for 30 min at 40 °C. Isolated 17 as a white solid,
mp 112.3 °C (354 mg, 79%). 1H NMR (400 MHz, DMSO) δ 1.07 (s,
9H), 2.62 (t, J = 5.1 Hz, 2H), 2.73 (t, J = 5.5 Hz, 2H), 3.58 (s, 2H),
3.72 (s, 2H), 3.87 (s, 3H), 5.87 (s, 2H), 7.22−7.31 (m, 1H), 7.3−7.41
(m, 4H), 7.69 (s, 1H), 7.98 (s, 1H); 13C NMR (101 MHz, DMSO) δ
21.0, 26.6, 38.2, 38.5, 47.8, 49.7, 60.5, 70.7, 112.1, 114.7, 127.0, 128.1,
128.2, 128.6, 136.1, 138.3, 138.7, 142.3, 176.5; IR (DCM) ν 2973,
2933, 1735, 1602, 1276, 1128 cm−1; HRMS (ESI-TOF) calcd for
C23H30N5O2 [M + H]+ m/z 408.2394, found 408.2394.
(6-Benzyl-3-(2,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (19). Using Method
B; XPhos precatalyst 18 (9.6 mg, 2 mol %). The reaction was stirred at
rt for 30 min and isolated 19 as a yellow gum (258 mg, 92%).1H NMR
(400 MHz, CDCl3) δ 1.16 (s, 9H), 2.63 (t, J = 5.1 Hz, 2H), 2.76 (t, J =
5.7 Hz, 2H), 3.65 (s, 2H), 3.77 (s, 2H), 5.89 (s, 2H), 6.97 (td, J = 6.6,
9.8 Hz, 1H), 7.25−7.42 (m, 5H), 7.47 (ddd, J = 6.6, 8.9, 10.7 Hz, 1H);
13C NMR (176 MHz, CDCl3) δ 21.7 (d, J = 7.3 Hz), 26.9, 38.8, 48.6,
1
solid, mp 109.8 °C (435 mg, 86%). H NMR (400 MHz, CDCl3) δ
1.08 (s, 9H), 2.73 (s, 4H), 3.63 (s, 2H), 3.74 (s, 2H), 5.93 (s, 2H),
7.2−7.31 (m, 3H), 7.31−7.42 (m, 4H), 7.71−7.8 (m, 2H); 13C NMR
(101 MHz, DMSO) δ 21.9, 26.5, 38.2, 47.8, 49.8, 60.6, 70.8, 112.5,
115.5 (d, J = 21.5 Hz), 127.0, 128.1 (d, J = 8.1 Hz), 128.2, 128.6, 129.8
(d, J = 3 Hz), 138.2, 139.5, 146.8, 161.6 (d, J = 244 Hz), 176.4; IR
(DCM) ν 2973, 2931, 2802, 1735, 1527, 1488, 1112 cm−1; HRMS
(ESI-TOF) calcd for C25H29FN3O2 [M + H]+ m/z 422.2238, found
422.2236.
(6-Benzyl-3-(4-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (13). Using
Method A; the reaction was heated to 80 °C for 30 min. Isolated
13 as a white solid, mp 96.7 °C (372 mg, 79%). 1H NMR (400 MHz,
CDCl3) δ 1.16 (s, 9H), 2.75−2.91 (m, 4H), 3.66 (s, 2H), 3.78 (s, 2H),
5.90 (s, 2H), 7.27−7.44 (m, 5H), 7.65 (d, J = 8.2 Hz, 2H), 7.85 (d, J =
8.2 Hz, 2H); 13C NMR (101 MHz, CDCl3) 22.7, 26.9, 38.9, 48.7, 50.3,
61.8, 70.8, 113.9, 125.5 (q, J = 3.7), 127.1 (q, J = 252 Hz), 125.6,
126.8, 127.5, 128.5, 129.5 (q, J = 33 Hz), 137.1, 137.9, 139.6, 147.9,
177.5; IR (DCM) ν 3062, 3022, 2975, 2933, 2806, 2761, 1735, 1819,
1324, 1124 cm−1; HRMS (ESI-TOF) calcd for C26H29F3N3O2 [M +
H]+ m/z 472.2206, found 472.2209.
50.3, 61.8, 70.6, 105.9 (dd, J = 20.9, 28.4 Hz), 115.3, 117.7 (d, J = 17.2
Hz), 118.2 (dd, J = 5.9, 20 Hz), 127.4, 128.5, 128.9, 137.9, 139.2,
143.9, 146.9 (ddd, J = 3.2, 12.3, 236 Hz), 149.9 (dt, J = 1.8, 13.3, 252.3
Hz), 155.0 (dd, J = 7.7, 256 Hz), 177.4; IR ν 2973, 2929, 2873, 1739,
1531, 1470, 1139; HRMS (ESI-TOF) calcd for C25H27F3N3O2 [M +
H]+ m/z 458.2050, found 458.2050.
(6-Benzyl-3-(2-(trifluoromethyl)phenyl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (14). Using
Method A; the reaction was heated to 80 °C for 6 h. Isolated 14 as
a colorless gum (83 mg, 17%).
(6-Benzyl-3-(2-fluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (20). Using Method
B; XPhos precatalyst 18 (35 mg, 8 mol %). The reaction was stirred at
1
Using Method B; XPhos precatalyst 18 (35 mg, 8 mol %). The
reaction was stirred at rt for 3 h and isolated 14 as a colorless gum,
(198 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.44 (t, J
= 5.4 Hz, 2H), 2.75 (t, J = 5.3 Hz, 2H), 3.71 (s, 2H), 3.78 (s, 2H),
7.26−7.43 (m, 7H), 7.47 (t, J = 7.6 Hz, 1H), 7.55 (t, J = 7.1 Hz, 1H),
7.74 (d, J = 7.8 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 20.5, 26.9,
38.8, 48.5, 50.0, 61.6, 70.3, 115.1, 123.9 (q, J = 274 Hz), 126.3 (q, J =
5.1 Hz) 127.4, 128.3, 128.4, 129.1, 129.8 (q, J = 30.3 Hz), 131.2, 132.0,
132.4, 137.9, 138.0, 148.4, 177.5; IR (DCM) ν 2960, 2931, 2872,
1738, 1441, 1315, 1165, 1130, 1036, 966 cm−1; HRMS (ESI-TOF)
calcd for C26H29F3N3O2 [M + H]+ m/z 472.2206, found 472.2210.
(6-Benzyl-3-(quinolin-6-yl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (15). Using Method A; the
reaction was heated to 80 °C for 30 min. Isolated 15 as a white solid,
mp 131.7 °C (236 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 1.17 (s,
9H), 2.85 (t, J = 5.6 Hz, 2H), 2.94 (t, J = 5.4 Hz, 2H), 3.69 (s, 2H),
3.80 (s, 2H), 5.94 (s, 2H), 7.28−7.46 (m, 6H), 8.1−8.23 (m, 4H),
8.89 (dd, J = 4.2, 1.7 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 22.8,
27.0, 38.9, 48.8, 50.4, 61.8, 70.8, 113.9, 121.4, 125.1, 127.4, 128.4,
128.5, 128.6, 129.0, 129.7, 131.9, 136.2, 138.0, 139.6, 148.0, 148.5,
150.4, 177.5; IR (DCM) ν 2973, 2931, 1735, 1276, 1126, 1108 cm−1;
HRMS (ESI-TOF) calcd for C28H31N4O2 [M + H]+ m/z 455.2441,
found 455.2441.
40 °C for 2 h and isolated 20 as an orange gum (214 mg, 94%). H
NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.66 (t, J = 5.3 Hz, 2H), 2.76
(t, J = 5.7 Hz, 2H), 3.66 (s, 2H), 3.77 (s, 2H), 5.91 (s, 2H), 7.07−7.2
(m, 2H), 7.27−7.44 (m, 6H), 7.61 (td, J = 7.5, 1.8 Hz, 1H); 13C NMR
(176 MHz, CDCl3) 21.7 (d, J = 6.9), 26.9, 38.8, 48.7, 50.3, 61.8, 70.7,
115.4, 115.9 (d, J = 22.1 Hz), 121.2 (d, J = 14.6 Hz), 124.1 (d, J = 3.1
Hz), 127.3, 128.4, 129.0, 129.7 (d, J = 8.1 Hz), 130.8 (d, J = 3.6 Hz),
138.0, 138.7, 145.7, 160.1 (d, J = 249), 177; IR (DCM) ν 2972, 2931,
2802, 1738, 1460, 1277, 1128, 1030, 966 cm−1; HRMS (ESI-TOF)
calcd for C25H29FN3O2 [M + H]+ m/z 422.2238, found 422.2241.
(6-Benzyl-3-(2,5-difluorophenyl)-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (21). Using Method
B; XPhos precatalyst 18 (17 mg, 4 mol %). The reaction was stirred at
40 °C for 30 min and isolated 21 as a yellow gum (217 mg, 91%). 1H
NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.66 (t, J = 5.2 Hz, 2H), 2.76
(t, J = 5.7 Hz, 2H), 3.66 (s, 2H), 3.77 (s, 2H), 5.90 (s, 2H), 6.94−7.11
(m, 2H), 7.27−7.42 (m, 6H); 13C NMR (101 MHz, CDCl3) 21.8 (d, J
= 7.5), 27.0, 38.9, 48.7, 50.3, 61.9, 70.7, 115.4, 116.0 (dd, J = 24.2, 8.6
Hz), 116.9 (dd, J = 25.4, 8.8 Hz), 116.9 (dd, J = 24.8, 4.3 Hz), 122.6
(dd, J = 17.6, 8.3 Hz), 127.4, 128.5, 129.0, 138.0, 139.1, 144.8, 156.1
(dd, J = 248, 2.0 Hz), 156.1 (dd, J = 244.4, 2.0 Hz), 177.5; IR (DCM)
ν 2972, 2931, 2804, 1738, 1468, 1127, 972 cm−1; HRMS (ESI-TOF)
calcd for C25H28F2N3O2 440.2144 [M + H]+ m/z, found 440.2147.
(6-Benzyl-3-(pyridin-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (22). Using Method B; XPhos
precatalyst 18 (35 mg, 8 mol %). The reaction was stirred at 40 °C for
3 h and purified by silica gel chromatography (40−100% EtOAc in
heptane, followed by 10% MeOH) to give 22 as a pale brown gum
(219 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 1.16 (s, 9H), 2.82 (s,
4H), 3.65 (s, 2H), 3.78 (s, 2H), 5.90 (s, 2H), 7.26−7.43 (m, 6H), 8.06
(dt, J = 1.9, 7.9 Hz, 1H), 8.55 (dd, J = 1.7, 4.8 Hz, 1H), 8.91−9.04 (m,
1H); 13C NMR (101 MHz, CDCl3) δ 22.2, 27.0, 38.9, 48.7, 50.4, 61.8,
70.7, 113.8, 123.5, 127.5, 128.5, 129.0, 129.6, 133.9, 137.9, 139.6,
146.5, 147.9, 148.8, 177.5; IR (DCM) ν 3061, 2972, 2931, 1736, 1277,
1128, 1032, 966 cm−1; HRMS (ESI-TOF) calcd for C24H29N4O2
405.2285 [M + H]+ m/z, found 405.2285.
(6-Benzyl-3-(1H-indol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (16). Using Method A; the
reaction was heated to 80 °C for 30 min. Isolated 16 as a white solid,
1
mp 82.4 °C (313 mg, 71%). H NMR (400 MHz, CDCl3) δ 1.15 (s,
9H), 2.80 (t, J = 5.3 Hz, 2H), 2.87 (t, J = 5.3 Hz, 2H), 3.66 (s, 2H),
3.78 (s, 2H), 5.91 (s, 2H), 6.55 (ddd, J = 3.0, 2.0, 0.9 Hz, 1H), 7.14−
7.2 (m, 1H), 7.25−7.44 (m, 6H), 7.63 (dd, J = 8.5, 1.6 Hz, 1H), 7.92−
7.99 (m, 1H), 8.29 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 22.7,
27.0, 38.9, 48.8, 50.5, 61.8, 70.9, 103.1, 111.2, 113.2, 119.2, 121.5,
124.6, 125.5, 127.3, 128.1, 128.5, 129.0, 135.6, 138.1, 139.0, 150.7,
177.7; IR (DCM) ν 3409, 3239, 2973, 2931, 1735, 1444, 1276, 1126,
1110, 1029, 966 cm−1; HRMS (ESI-TOF) calcd for C27H31N4O2 [M +
H]+ m/z 443.2442, found 443.2441.
(6-Benzyl-3-(1-methyl-1H-pyrazol-4-yl)-4,5,6,7-tetrahydro-
1H-pyrazolo[3,4-c]pyridin-1-yl)methyl Pivalate (17). Using
Method A; the reaction was heated to 80 °C for 2 h. Isolated 17
(267 mg, 66%) as a white solid.
Using Method B; from 6 (520 mg, 1.09 mmol), XPhos precatalyst
18 (68.8 mg, 0.09 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-
(6-Benzyl-3-(thiophen-3-yl)-4,5,6,7-tetrahydro-1H-pyrazolo-
[3,4-c]pyridin-1-yl)methyl Pivalate (23). Using Method B; XPhos
precatalyst 18 (35 mg, 8 mol %). The reaction was stirred at rt for 20
min and isolated 23 as a white solid, mp 134.1−135.7 °C (200 mg,
1
89%). H NMR (400 MHz, CDCl3) δ 1.15 (s, 9H), 2.71−2.88 (m,
4H), 3.63 (s, 2H), 3.77 (s, 2H), 5.88 (s, 2H), 7.27−7.42 (m, 6H),
7686
dx.doi.org/10.1021/jo5012015 | J. Org. Chem. 2014, 79, 7682−7688