The Journal of Organic Chemistry
Article
The characterization data for 3-hydroxypyridines 2a−d,f−l,p,u,w,z
have been reported previously.17 The characterizations of other 3-
hydroxypyridines are reported below.
Hz, J = 11.3 Hz, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.24 (dd, J = 17.6 Hz, J
= 2.3 Hz, 1H), 5.42 (dd, J = 11.4 Hz, J = 2.1 Hz, 1H), 2.41 (s, 3H).
13C (75 MHz, CDCl3): δ 151.1, 149.1, 143.4, 132.8, 125.3, 124.3,
118.8, 22.7. HRMS (ESI+): calcd for C8H10NO: 136.0762, found
136.0757.
6-Benzyl-2-methylpyridin-3-ol (2e). 136 mg, 0.70 mmol, 58%. Pale
brown solid. Mp: 198−200 °C. IR (neat): 3059, 2927, 2460,
1
1729,1575, 1484, 1456, 1347, 1284, 1262. H (300 MHz, MeOD-
6-Methyl-2-(4-(3-phenylpropoxy)benzyl)pyridine-3-ol (2s). Com-
pound 2s was prepared according to the procedure described above
except for the purification step. The crude solid was first purified by
chromatography on silica gel and then triturated first with a mixture of
AcOEt/pentane 1:1 (2 mL) and then with diethyl ether (4 mL). 164
mg, 0.49 mmol, 41%. White solid. Mp: 150−152 °C. IR (neat): 3023,
2939, 2860, 2486, 1606, 1576, 1516, 1347, 1280, 1238, 1172, 1118,
d4): δ 7.32−7.15 (m, 5H), 7.07 (d, J = 8.4 Hz, 1H), 6.93 (d, J = 8.4 Hz,
1H), 4.01 (s, 2H), 2.41 (s, 3H). 13C (75 MHz, MeOD-d4): δ 151.6,
151.3, 146.7, 141.4, 129.8, 129.4, 127.2, 123.9, 123.0, 43.4, 18.2.
HRMS (ESI+): calcd for C13H14NO 200.1075, found 200.1075.
Methyl 12-(5-Hydroxy-6-methylpyridin-2-yl)dodecanoate (2m).
201 mg, 0.63 mmol, 52%. Pale yellow solid. 1H (300 MHz, CDCl3): δ
7.00 (d, J = 8.1 Hz, 1H), 6.85 (d, J = 8.1 Hz, 1H), 3.67 (s, 3H), 2.67 (t,
J = 7.8 Hz, 2H), 2.48 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H), 1.67−1.54 (m,
4H), 1.29−1.23 (m, 14H). 13C (75 MHz, CDCl3): δ 174.4, 150.9,
150.6, 145.8, 123.2, 121.0, 51.4, 36.4, 34.0, 30.5, 29.5, 29.4, 29.4, 29.3,
29.2, 29.1, 24.9, 17.9. The 1H NMR spectrum was in accordance with
literature data.14a
1
1033. H (300 MHz, MeOD-d4): δ 7.27−7.11 (m, 7H), 7.09 (d, J =
8.1 Hz, 1H), 6.95 (d, J = 8.4 Hz, 1H), 6.76 (d, J = 8.7 Hz, 2H), 4.02 (s,
2H), 3.90 (t, J = 6.3 Hz, 2H), 2.77 (t, J = 7.5 Hz, 2H), 2.40 (s, 3H),
2.07−1.98 (m, 2H). 13C (75 MHz, MeOD-d4) δ 158.7, 151.0, 149.2,
148.7, 142.9, 133.1, 130.6, 129.5, 129.3, 126.8, 124.7, 123.4, 115.2,
67.9, 37.8, 33.1, 32.2, 22.5. HRMS (ESI+): calcd for C22H24NO2
334.1807, found 334.1794.
Ethyl 3-(3-Hydroxypyridin-2-yl)propanoate (2n). The compound
was prepared according to the procedure described above except for
the purification step. The crude solid was first purified by
chromatography on silica gel and then triturated. 131 mg, 0.67
mmol, 56%. White solid. Mp: 102−104 °C. IR (neat): 3272, 2930,
1729, 1636, 1575, 1457, 1448, 1365, 1281, 1172, 1110. 1H (300 MHz,
CDCl3): δ 8.12 (dd, J = 4.8 Hz, J = 1.5 Hz, 1H), 7.21 (dd, J = 8.1 Hz, J
= 1.5 Hz, 1H), 7.07 (dd, J = 8.1 Hz, J = 4.5 Hz, 1H), 4.16 (q, J = 7.1
Hz, 2H), 3.10−3.05 (m, 2H), 2.89−2.84 (m, 2H), 1.24 (t, J = 7.1 Hz,
3H), 1H (300 MHz, MeOD-d4): δ 7.90 (dd, J = 4.8 Hz, J = 1.5 Hz,
1H), 7.18−7.07 (m, 2H), 4.11 (q, J = 7.1 Hz, 2H), 3.08 (t, J = 7.8 Hz,
2H), 2.69 (t, J = 7.8 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H). 13C (75 MHz,
MeOD-d4): δ 174.8, 153.4, 149.1, 139.9, 124.0, 123.5, 61.5, 33.2, 28.4,
14.4. The 1H NMR spectrum was in accordance with literature data.36
2-(3-Hydroxypropyl)pyridin-3-ol (2y). The compound was pre-
pared according to the procedure described above except for the
purification step. The crude solid was only purified by chromatography
on silica gel. 50 mg, 0.33 mmol, 27%. Pale yellow oil. IR (neat): 3133,
2940, 2871, 2346, 1577, 1455, 1289, 1170, 1017. 1H (300 MHz,
MeOD-d4) δ 7.90 (dd, J = 4.7,1.4 Hz, 1H), 7.18−7.07 (m, 2H), 3.59
(t, J = 6.8 Hz, 2H), 2.85 (t, J = 7.7 Hz, 2H), 1.89 (quin, J = 7.2 Hz,
2H). 13C (75 MHz, MeOD-d4) δ 153.5, 150.8, 139.6, 123.7, 123.6,
62.7, 32.3, 29.5. HRMS (ESI+): calcd for C8H12NO2 154.0868, found
154.0875.
Methyl 6-(3-Hydroxy-6-methylpyridin-2-yl)hexanoate (2o). Com-
pound 2o was prepared according to the procedure described above
except for the purification step. The crude solid was first purified by
chromatography on silica gel and then triturated. 119 mg, 0.50 mmol,
42%. Pale yellow solid. Mp: 88−90 °C. IR (neat): 2946, 2921, 2855,
1733, 1570, 1497, 1467, 1436, 1424, 1370, 1327, 1273. 1H (300 MHz,
MeOD-d4): δ 7.05 (d, J = 8.4 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 3.64
(s, 3H), 2.75 (t, J = 7.7 Hz, 2H), 2.39 (s, 3H), 2.32 (t, J = 7.4 Hz, 2H),
1.70−1.60 (m, 4H), 1.44−1.35 (m, 2H). 13C (75 MHz, MeOD-d4): δ
175.8, 151.0, 150.3, 148.3, 124.3, 122.9, 51.9, 34.6, 32.7, 30.0, 29.5,
25.8, 22.5. HRMS (ESI+): calcd for C13H20NO3 238.1443, found
238.1435.
1-(3-Hydroxy-6-propylpyridin-2-yl)heptan-3-one (2q). 168 mg,
0.67 mmol, 56%. Yellow solid. Mp: 144−146 °C. IR (neat): 2958,
2931, 2862, 2474, 1830, 1708, 1575, 1432, 1363, 1272. 1H (200 MHz,
MeOD-d4): δ 7.09 (d, J = 8.2 Hz, 1H), 6.95 (d, J = 8.2 Hz, 1H), 3.05−
2.98 (m, 2H), 2.86−2.77 (m, 2H), 2.63 (t, J = 7.6 Hz, 2H), 2.53 (t, J =
7.3 Hz, 2H), 1.73−1.38 (m, 4H), 1.27−1.24 (m, 2H), 0.98−0.89 (m,
6H). 13C (50 MHz, MeOD-d4): δ 213.4, 152.6, 151.1, 148.4, 124.3,
122.7, 43.1, 41.6, 39.5, 27.3, 27.0, 24.6, 23.3, 14.2, 14.0. HRMS (ESI+):
calcd for C15H24NO2 250.1807, found 250.1807.
6-Methyl-2-vinylpyridin-3-ol (2r). Compound 2r was prepared
according to the procedure described above except for the purification
step. The crude product was directly purified by chromatography on
silica gel (100% AcOEt) to give the desired product as a pale yellow
solid (81 mg, 0.60 mmol, 50%). Mp: 172−174 °C. IR (neat): 3023,
2921, 2848, 2493, 1865, 1733, 1576, 1492, 1401, 1274, 1250. 1H (300
MHz, MeOD-d4): δ 7.10 (d, J = 8.4 Hz, 1H), 7.08−6.96 (dd, J = 17.6
2-(3-Methoxypropyl)-6-methylpyridin-3-ol (2t). 108 mg, 0.60
mmol, 50%. White solid. Mp: 150−152 °C. IR (neat): 2919, 2818,
1
1575, 1502, 1421, 1367, 1264, 1279, 1202. H (300 MHz, CDCl3): δ
7.52 (b, 1H), 7.07 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 8.1 Hz, 1H), 3.43
(s, 3H), 3.39 (t, J = 5.9 Hz, 2H), 2.91 (t, J = 6.6 Hz, 2H), 2.45 (s, 3H),
2.02 (quin, J = 6.2 Hz, 2H). 13C (75 MHz, CDCl3): δ 149.7, 148.5,
147.9, 124.1, 122.2, 71.4, 58.5, 28.3, 28.2, 23.0. HRMS (ESI+): calcd
for C10H16NO2 182.1181, found 182.1181.
N-(4-(3-Hydroxy-6-methylpyridin-2-yl)butyl)acetamide (2v).
Compound 2v was prepared according to the procedure described
above except for the purification step. The crude solid was first purified
by chromatography on silica gel and then triturated first with a mixture
of AcOEt/pentane 1:1 (2 mL) then with diethyl ether (4 mL). 106
mg, 0.48 mmol, 40%. White solid. Mp: 126−128 °C. IR (neat): 3277,
3068, 2929, 2868, 2580, 1633, 1554, 1498, 1428, 1371, 1275, 1175,
1
1127, 1062. H (300 MHz, MeOD-d4): δ 7.06 (d, J = 8.1 Hz, 1H),
6.93 (d, J = 8.1 Hz, 1H), 3.20 (t, J = 6.9 Hz, 2H), 2.78 (t, J = 7.5 Hz,
2H), 2.40 (s, 3H), 1.93 (s, 3H), 1.73−1.62 (m, 2H), 1.60−1.50 (m,
2H). 13C (75 MHz, MeOD-d4): δ 173.1, 151.0, 150.0, 148.4, 124.4,
123.0, 40.3, 32.4, 30.1, 27.3, 22.5. HRMS (ESI+): calcd for
C12H19N2O2 223.1447, found 223.1438.
Methyl 6-(3-Hydroxy-6-methylpyridin-2-yl)hexanoate (2x). Com-
pound 2x was prepared according to the procedure described above
except for the purification step. The crude solid was first purified by
chromatography on silica gel (EtOH/AcOEt/NH4OH 10/89/1) and
then triturated. 80 mg, 0.28 mmol, 23%. White solid. Mp: 96−98 °C.
IR (neat): 3030, 2933, 2855, 2818, 2764, 1570, 1491, 1455, 1430,
1
1346, 1273. H (300 MHz, MeOD-d4): δ 7.26−7.16 (m, 4H), 7.13−
7.08 (m, 2H), 6.98 (d, J = 8.4 Hz, 1H), 4.11 (s, 2H), 2.71 (t, J = 7.5
Hz, 2H), 2.33 (t, J = 7.8 Hz, 2H), 2.20 (s, 6H), 1.72−1.61 (m, 2H),
1.55−1.45 (m, 2H). 13C (75 MHz, MeOD-d4): δ 152.6, 151.4, 149.0,
141.1, 129.7, 129.1, 126.8, 124.6, 122.9, 60.3, 45.2, 38.7, 37.3, 29.3,
27.6. HRMS (ESI+): calcd for C18H25N2O: 285.1967, found 285.1965.
One-Pot Procedure for the Synthesis of 3-Hydroxypyr-
idines. To the corresponding triflate (1.2 mmol) in acetonitrile (0.92
mL, 15 equiv) or in the functionalized nitrile (4.5 mmol, 5 equiv)
under inert atmosphere in a microwave vial, equipped with a magnetic
stirrer bar, was added trimethylsilyl trifluoromethanesulfonate (22 μL,
0.12 mmol, 0.1 equiv). The vial was sealed, and the reaction was
performed in a microwave during 3 min (holding time) at 130 °C with
a maximum power of 100 W. Then, triethylamine (0.73 mL, 5.4 mmol,
4.5 equiv) and acrylic acid (160 μL, 2.4 mmol, 2 equiv) were
successively added to the reaction mixture under inert atmosphere.
The vial was quickly sealed, and the reaction was performed in a
microwave during 60 min (holding time) at 150 °C with a power of
300 W. The solution was quenched with satd aq NaHCO3 (10 mL)
and extracted with AcOEt (2 × 20 mL). The organic phases were
washed with a phosphate buffer (pH = 5.80, 8 mL) and brine (5 mL),
dried over MgSO4, and concentrated under reduced pressure. The
crude solid product was finally purified by chromatography on silica
gel (cake, CH2Cl2 100%, then AcOEt 100%, and finally AcOEt/EtOH
1316
dx.doi.org/10.1021/jo402729a | J. Org. Chem. 2014, 79, 1303−1319