The Journal of Organic Chemistry
Article
Hz, 1H), 7.21 (dd, J = 7.7, 4.7 Hz, 1H), 3.81−3.54 (m, 2H), 3.21−3.11
(m, 1H), 2.94−2.69 (m, 5H), 2.60 (ddd, J = 12.9, 9.3, 5.7 Hz, 1H),
2.51−2.43 (m, 1H), 2.40−2.32 (m, 1H), 1.46 (s, 9H), 1.03 (d, J = 5.9
Hz, 3H); 13C{1H} NMR (176 MHz, CDCl3) δ = 154.6, 150.1, 147.6,
136.1, 135.7, 123.2, 79.6, 54.9, 54.2, 51.2−48.9 (m, 2C), 44.8−42.8 (m,
1C), 29.8, 28.4, 14.9 (br s, 1C); LC-MS (HpH): 1.01 min (306) ([M +
60% yield) as a pale yellow oil. IR (neat): 2968, 2935, 2873, 2805, 1575,
1478, 1422, 1066 cm−1; 1H NMR (400 MHz, CDCl3) δ = 8.50−8.43
(m, 2H), 7.53 (dt, J = 8.0, 1.9 Hz, 1H), 7.21 (dd, J = 8.0, 5.1 Hz, 1H),
2.80−2.73 (m, 2H), 2.73−2.67 (m, 2H), 2.62 (q, J = 7.1 Hz, 4H), 1.06
(t, J = 7.1 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ = 150.2, 147.4,
136.1, 136.1, 123.2, 54.5, 46.9, 30.9, 11.9; LC-MS (HpH): 0.81 min
(179) ([M + H]+, 98%); HRMS (ESI) m/z: [M + H]+ calcd for
C11H19N2+ 179.1543; found 179.1549.
+
H]+, 100%); HRMS (ESI) m/z: [M + H]+ calcd for C17H28N3O2
306.2176; found 306.2180.
1-Methyl-4-(2-(pyridin-3-yl)ethyl)piperazine (3c). Prepared ac-
cording to general procedure D using 3-(chloromethyl)pyridine
hydrochloride (115 mg, 0.70 mmol, 1.0 equiv) and potassium 1-
methyl-4-(trifluoroboratomethyl)piperazine (231 mg, 1.05 mmol, 1.5
equiv) and stirring at reflux for 24 h. Flash chromatography on silica
(15−100% methanol in acetone) afforded the title compound (109 mg,
0.531 mmol, 76% yield) as a pale yellow oil. IR (neat): 2939, 2876,
2802, 1576, 1459, 1284, 1164, 1011 cm−1; 1H NMR (400 MHz,
CDCl3) δ = 8.50−8.40 (m, 2H), 7.51 (dt, J = 7.8, 2.0 Hz, 1H), 7.19 (dd,
J = 7.8, 4.9 Hz, 1H), 2.83−2.74 (m, 2H), 2.65−2.39 (m, 10H), 2.29 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ = 150.1, 147.5, 136.0, 135.7,
123.2, 59.7, 55.1, 53.1, 46.0, 30.7; LC-MS (HpH): 0.58 min (206) ([M
tert-Butyl (2-(Pyridin-3-yl)ethyl)carbamate (3h). Prepared accord-
ing to general procedure D using 3-(chloromethyl)pyridine hydro-
chloride (115 mg, 0.70 mmol, 1.0 equiv) and potassium (((tert-
butoxycarbonyl)amino)methyl)trifluoroborate (249 mg, 1.05 mmol,
1.5 equiv) and stirring at reflux for 3 h. Flash chromatography on silica
(0−40% acetone in chloroform) afforded the title compound (85 mg,
0.382 mmol, 55% yield) as a colorless oil. Analytical data are consistent
with the literature.8 IR (neat): 3338, 2976, 2932, 1692, 1525, 1169
cm−1; 1H NMR (400 MHz, CDCl3) δ = 8.46−8.41 (m, 2H), 7.54−7.48
(m, 1H), 7.21 (ddd, J = 7.8, 4.9, 1.0 Hz, 1H), 4.73 (br s, 1H), 3.36 (q, J =
6.6 Hz, 2H), 2.79 (t, J = 7.1 Hz, 2H), 1.41 (s, 9H); 13C{1H} NMR (101
MHz, CDCl3) δ = 155.8, 150.1, 147.8, 136.2, 134.4, 123.4, 79.3, 41.4,
33.4, 28.3; LC-MS (HpH): 0.85 min (223) ([M + H]+, 100%).
N-Methyl-N-(pyridin-3-yl-methyl)cyclohexanamine (3j). Prepared
according to general procedure D using 3-(chloromethyl)pyridine
hydrochloride (115 mg, 0.70 mmol, 1.0 equiv) and potassium N-
cyclohexyl-aminomethyltrifluoroborate (230 mg, 1.05 mmol, 1.5
equiv) and stirring at reflux for 24 h. Flash chromatography on silica
(70−100% EtOAc (+1% NEt3) in cyclohexane) afforded the title
compound (28 mg, 0.137 mmol, 20% yield) as a pale yellow oil. IR
(neat): 2932, 2853, 2780, 2762, 1575, 1423, 1114 cm−1; 1H NMR (600
MHz, CDCl3) δ = 8.52 (d, J = 1.5 Hz, 1H), 8.50−8.47 (m, 1H), 7.69 (br
d, J = 7.3 Hz, 1H), 7.25 (dd, J = 7.7, 4.8 Hz, 1H), 3.58 (s, 2H), 2.49−
2.39 (m, 1H), 2.19 (s, 3H), 1.90−1.77 (m, 4H), 1.68−1.57 (m, 1H),
1.37−1.19 (m, 4H), 1.10 (qt, J = 12.6, 3.6 Hz, 1H); 13C{1H} NMR
(151 MHz, CDCl3) δ = 150.2, 148.3, 136.5, 135.5 (br s), 123.3, 62.6,
55.0, 37.5, 28.5, 26.3, 25.9; LC-MS (HpH): 1.09 min (205) ([M + H]+,
+
+ H]+, 99%); HRMS (ESI) m/z: [M + H]+ calcd for C12H20N3
206.1652; found 206.1655.
4-(2-(Pyridin-3-yl)ethyl)thiomorpholine (3d). Prepared according
to general procedure D using 3-(chloromethyl)pyridine hydrochloride
(115 mg, 0.70 mmol, 1.0 equiv) and potassium (thiomorpholin-4-yl-
methyl)trifluoroborate (234 mg, 1.05 mmol, 1.5 equiv) and stirring at
reflux for 24 h. Flash chromatography on silica (30−100% acetone in
chloroform) afforded the title compound (52 mg, 0.250 mmol, 36%
yield) as a pale yellow oil. IR (neat): 2910, 2809, 2769, 1575, 1423,
1
1282, 1119 cm−1; H NMR (400 MHz, CDCl3) δ = 8.48−8.44 (m,
2H), 7.51 (dt, J = 7.7, 2.1 Hz, 1H), 7.21 (ddd, J = 7.7, 4.9, 1.0 Hz, 1H),
2.82−2.75 (m, 6H), 2.72−2.67 (m, 4H), 2.66−2.60 (m, 2H); 13C{1H}
NMR (101 MHz, CDCl3) δ = 150.1, 147.6, 136.1, 135.6, 123.2, 60.4,
54.9, 30.3, 28.0; LC-MS (HpH): 0.78 min (209) ([M + H]+, 100%);
HRMS (ESI) m/z: [M + H]+ calcd for C11H17N2S+ 209.1107; found
209.1112.
+
96%); HRMS (ESI) m/z: [M + H]+ calcd for C13H21N2 205.1699;
4-(2-(Pyridin-3-yl)ethyl)morpholine (3e). Prepared according to
general procedure D using 3-(chloromethyl)pyridine hydrochloride
(115 mg, 0.70 mmol, 1.0 equiv) and potassium (morpholin-4-
yl)methyltrifluoroborate (217 mg, 1.05 mmol, 1.5 equiv) and stirring
at reflux for 22 h. Flash chromatography on silica (30−100% acetone in
chloroform) afforded the title compound (69 mg, 0.359 mmol, 51%
yield) as a colorless oil. IR (neat): 2953, 2854, 2808, 1575, 1115 cm−1;
1H NMR (400 MHz, CDCl3) δ = 8.51−8.44 (m, 2H), 7.54 (dt, J = 7.8,
2.0 Hz, 1H), 7.22 (ddd, J = 7.8, 4.9, 1.0 Hz, 1H), 3.75 (t, J = 4.4 Hz,
4H), 2.86−2.78 (m, 2H), 2.65−2.59 (m, 2H), 2.54 (t, J = 4.4 Hz, 4H);
13C{1H} NMR (101 MHz, CDCl3) δ = 150.1, 147.7, 136.1, 135.4,
123.3, 66.9, 60.0, 53.6, 30.3; LC-MS (HpH): 0.61 min (193) ([M +
H]+, 98%); HRMS (ESI) m/z: [M + H]+ calcd for C11H17N2O+
193.1335; found 193.1336.
found 205.1706.
N-Methyl-2-phenyl-N-(pyridin-3-yl-methyl)ethan-1-amine (3l).
Prepared according to general procedure D using 3-(chloromethyl)-
pyridine hydrochloride (115 mg, 0.70 mmol, 1.0 equiv) and potassium
N-benzyltrifluoroboratomethylamine (253 mg, 1.05 mmol, 1.5 equiv)
and stirring at reflux for 19 h. Flash chromatography on silica (10−80%
acetone in chloroform) afforded the title compound (61 mg, 0.270
mmol, 39% yield) as a pale yellow oil. IR (neat): 2946, 2790, 1576,
1453, 1425, 1122, 1048 cm−1; 1H NMR (400 MHz, CDCl3) δ = 8.54−
8.44 (m, 2H), 7.65−7.57 (m, 1H), 7.33−7.15 (m, 6H), 3.57 (s, 2H),
2.87−2.79 (m, 2H), 2.71−2.64 (m, 2H), 2.30 (s, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 150.27, 148.5, 140.3, 136.5, 134.4, 128.7, 128.3,
126.0, 123.3, 59.4, 59.0, 42.0, 33.9; LC-MS (HpH): 1.07 min (227)
+
([M + H]+, 100%); HRMS (ESI) m/z: [M + H]+ calcd for C15H19N2
3-(2-(Piperidin-1-yl)ethyl)pyridine (3f). Prepared according to
general procedure D using 3-(chloromethyl)pyridine hydrochloride
(115 mg, 0.70 mmol, 1.0 equiv) and potassium 1-
(trifluoroboratomethyl)piperidine (215 mg, 1.05 mmol, 1.5 equiv)
and stirring at reflux for 23 h. Flash chromatography on silica (10%
methanol in acetone) afforded the title compound (65 mg, 0.342 mmol,
49% yield) as a yellow oil. IR (neat): 2932, 2835, 2780, 2762, 1575,
227.1543; found 227.1551.
tert-Butyl 4-(2-(6-Methylpyridin-3-yl)ethyl)piperazine-1-carboxy-
late (3o). Prepared according to general procedure D using 5-
(chloromethyl)-2-methylpyridine hydrochloride (125 mg, 0.70 mmol,
1.0 equiv) and potassium 4-(trifluoroboratomethyl)piperazine-1-
carboxylic acid tert-butyl ester (321 mg, 1.05 mmol, 1.5 equiv) and
stirring at reflux for 3 h. Flash chromatography on silica (30−100%
acetone in chloroform) afforded the title compound (187 mg, 0.612
mmol, 87% yield) as a white solid. Mp (DCM/cyclohexane): 67−70
°C; IR (neat): 2974, 2929, 2809, 1690, 1418, 1244, 1167, 1120 cm−1;
1H NMR (400 MHz, CDCl3) δ = 8.29 (d, J = 2.3 Hz, 1H), 7.36 (dd, J =
7.8, 2.3 Hz, 1H), 7.02 (d, J = 7.8 Hz, 1H), 3.40 (t, J = 5.1 Hz, 4H), 2.73−
2.67 (m, 2H), 2.55−2.50 (m, 2H), 2.47 (s, 3H), 2.40 (t, J = 5.1 Hz, 4H),
1.41 (s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ = 155.9, 154.6,
149.1, 136.4, 132.2, 122.7, 79.5, 59.7, 52.8, 43.4 (br s), 30.1, 28.3, 23.8;
LC-MS (HpH): 1.01 min (306) ([M + H]+, 99%); HRMS (ESI) m/z:
[M + H]+ calcd for C17H28N3O2+ 306.2176; found 306.2183.
1
1423, 1114 cm−1; H NMR (400 MHz, CDCl3) δ = 8.48−8.41 (m,
2H), 7.51 (dt, J = 7.8, 2.0 Hz, 1H), 7.19 (dd, J = 7.8, 4.9 Hz, 1H), 2.82−
2.75 (m, 2H), 2.58−2.51 (m, 2H), 2.50−2.38 (m, 4H), 1.60 (quin, J =
5.6 Hz, 4H), 1.49−1.41 (m, 2H); 13C{1H} NMR (101 MHz, CDCl3) δ
= 150.1, 147.5, 136.0, 136.0, 123.2, 60.6, 54.5, 30.7, 26.0, 24.4; LC-MS
(HpH): 0.85 min (191) ([M + H]+, 95%); HRMS (ESI) m/z: [M +
H]+ calcd for C12H19N2+ 191.1543; found 191.1550.
N,N-Diethyl-2-(pyridin-3-yl)ethan-1-amine (3g). Prepared accord-
ing to general procedure D using 3-(chloromethyl)pyridine hydro-
chloride (115 mg, 0.70 mmol, 1.0 equiv) and potassium N,N-
diethyltrifluoroboratomethylamine (203 mg, 1.05 mmol, 1.5 equiv)
and stirring at reflux for 24 h. Flash chromatography on silica (15−80%
methanol in acetone) afforded the title compound (75 mg, 0.421 mmol,
tert-Butyl 4-(2-(5-Methylpyridin-3-yl)ethyl)piperazine-1-carboxy-
late (3p). Prepared according to general procedure D using 3-
(chloromethyl)-5-methylpyridine hydrochloride (125 mg, 0.70 mmol,
3595
J. Org. Chem. 2021, 86, 3583−3604