The Journal of Organic Chemistry
ARTICLE
5-[3-(2-Bromoethyl)pyrrolidin-3-yl]pyridin-2-ol Hydro-
bromide (10). The title compound was obtained in quantitative yield
(9.12 g) as a brown powder from 9 according to general procedure E: 1H
NMR (400 MHz, D2O) δ 7.92 (d, J = 8.9 Hz, 1 H), 7.69 (s, 1 H), 6.86 (d,
J = 9.0 Hz, 1 H), 3.75 (d, J = 11.8 Hz, 1 H), 3.57 (m, 2 H), 3.43 (m, 1 H),
3.33 (m, 1 H), 3.22 (m, 1 H), 2.56 (m, 1 H), 2.40 (m, 3 H); J-MOD 13C
NMR (100 MHz, DMSO-d6) δ 161.4, 141.1, 133.3, 119.5, 119.1, 52.8,
48.0, 43.2, 40.7, 33.7, 29.1;massspectrum (free base) ESI+ m/z 271.0437
[C11H16BrN2O (M + 1) requires 271.0441]; mp 218ꢀ220 °C.
5-(1-Azabicyclo[3.3.1]non-5-yl)pyridin-2-ol (16). The title
compound was obtained in 61% yield (4.5 g) as an orange powder from
15 according to general procedure F: 1H NMR (400 MHz, DMSO-d6) δ
11.31 (br s, 1 H), 7.54 (dd, J = 9.6, 2.6 Hz, 1 H), 6.98 (d, J = 2.3 Hz, 1 H),
6.29 (d, J = 9.6 Hz, 1 H), 2.91 (m, 4 H), 2.86 (s, 2 H), 2.02 (m, 4 H), 1.64
(m, 2 H), 1.43 (m, 2 H); J-MOD 13C NMR (100 MHz, DMSO-d6) δ
161.4, 139.4, 129.7, 126.9, 119.8, 57.8, 51.2 (2 C), 35.4 (2 C), 29.6, 23.2
(2 C); IR (CHCl3; cmꢀ1) 3387 (weak), 2993, 2932, 2853, 1662, 1619,
1547, 1464, 1085, 881, 838; mass spectrum CI+ m/z 219.1498
[C13H19N2O (M + 1) requires 219.1497]; mp 191ꢀ192 °C.
5-(1-Azabicyclo[2.2.1]hept-4-yl)pyridin-2-ol (11). The title
compound was obtained in 74% yield (3.63 g) as a brown powder from
10 according to general procedure F: 1H NMR (400 MHz, DMSO-d6) δ
11.42 (br s, 1 H), 7.49 (dd, J = 9.4, 2.7 Hz, 1 H), 7.12 (d, J = 2.5 Hz, 1 H),
6.30 (d, J = 9.4 Hz, 1 H), 2.86 (m, 2 H), 2.55 (m, 2 H), 2.43 (s, 2 H) 1.64
(m, 2 H), 1.44 (m, 2 H); 13C NMR (100 MHz, DMSO-d6) δ 161.7,
141.0, 131.3, 119.7, 119.0, 63.2, 55.0 (2 C), 49.8, 36.6 (2 C); IR
(CH2Cl2, cmꢀ1) 3386, 3037; 2957, 2930, 1679, 1662, 1624, 1545,
1469, 1313, 1237, 1002, 961; mp 170ꢀ172 °C; mass spectrum ESI+ m/z
191.1174 [C11H15N2O (M + 1) requires 191.1184].
3-Cyano-3-pyridin-3-ylpentanedioic Acid Diethyl Ester
(18). The title compound was obtained in 84% yield (17 g) as a brown
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oil from 17 according to general procedure A: H NMR (400 MHz,
DMSO-d6) δ 8.76 (dd, J = 2.5, 0.6 Hz, 1 H), 8.52 (dd, J = 4.7, 1.5 Hz,
1 H), 7.95 (ddd, J = 8.1, 2.5, 1.5 Hz, 1 H), 7.43 (ddd, J = 8.1, 4.8, 0.7 Hz,
1 H), 3.95 (qd, J = 7.1, 2.2 Hz, 4 H), 3.39 (d, J = 16.7 Hz, 2 H), 3.29 (d,
J = 16.7 Hz, 2 H), 1.03 (t, J = 7.1 Hz, 6 H); J-MOD 13C NMR (100 MHz,
DMSO-d6) δ 168.2 (2 C), 148.9, 147.4, 133.8, 133.2, 123.3, 120.0, 60.4
(2 C), 42.5 (2 C), 39.4, 13.8 (2 C); mass spectrum CI+ m/z 291.1335
[C15H19N2O4 (M + 1) requires 291.1344].
(5-Oxo-3-pyridin-3-ylpyrrolidin-3-yl)acetic Acid Ethyl
Ester (19). The title compound was obtained in 65% yield (9.5 g) as
an orange oil from 18 according to general procedure C: 1H NMR (400
MHz, DMSO-d6) δ 8.51 (dd, J = 2.4, 0.5 Hz, 1 H), 8.44 (dd, J = 4.7, 1.5
Hz, 1 H), 7.75 (br s, 1 H), 7.70 (ddd, J = 8.0, 2.4, 1.6 Hz, 1 H), 7.35 (ddd,
J = 8.0, 4.7, 0.7 Hz, 1 H), 3.85 (q, J = 7.1 Hz, 2 H), 3.68 (d, J = 10.1, 0.7
Hz, 1 H), 3.54 (d, J = 10.1 Hz, 1 H), 2.88 (d, J = 14.9 Hz, 1 H), 2.83 (d,
J = 14.9 Hz, 1 H), 2.69 (d, J = 16.2 Hz, 1 H), 2.60 (d, J = 16.2 Hz, 1 H),
0.96 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 174.8,
170.2, 147.7, 147.6, 139.7, 134.0, 123.2, 59.7, 51.4, 44.1, 44.0, 42.0, 13.8;
mass spectrum CI+ m/z 249.1239 [C13H17N2O3 (M + 1) requires
249.1239].
2-(3-Pyridin-3-yl-pyrrolidin-3-yl)ethanol (20). The title com-
pound was obtained in 94% yield (4.414 g) as a colorless oil from 19
according to general procedure D: 1H NMR (400 MHz, DMSO-d6) δ
8.55 (d, J = 2.1 Hz, 1 H), 8.44 (dd, J = 4.7, 1.4 Hz, 1 H), 8.31 (s, 1 H),
7.72 (dt, J = 8.2, 2.0 Hz, 1 H), 7.35 (dd, J = 7.9, 4.7 Hz, 1 H), 3.28 (d, J =
11.2, 1 H), 3.19 (d, J = 10.8 Hz, 1 H), 3.13 (m, 3 H), 2.94 (m, 1 H), 2.14
(m, 2 H), 1.87 (m, 2 H); J-MOD 13C NMR (100 MHz, DMSO-d6) δ
148.1, 147.4, 140.1, 134.4, 123.2, 57.6, 55.3, 47.7, 43.9, 41.8, 36.9; mass
spectrum CI+ m/z 193.1343 [C11H17N2O (M + 1) requires 193.1340].
3-[3-(2-Bromoethyl)pyrrolidin-3-yl]pyridine Hydrobro-
mide (21). The title compound was obtained in quantitative yield
(0.437 g) as a brown powder from 20 according to general procedure E:
1H NMR (400 MHz, DMSO-d6) δ 9.20 (br s, 2 H), 8.97 (d, J = 2.6 Hz,
1 H), 8.88 (d, J = 6.4 Hz, 1 H), 8.58 (d, J = 11.2 Hz, 1 H), 8.03 (dd, J =
10.9, 7.4 Hz, 1 H), 3.68 (m, 1 H), 3.58 (m, 1 H), 3.41 (m, 1 H), 3.25 (m,
3 H), 2.41 (m, 4 H); J-MOD 13C NMR (100 MHz, DMSO-d6) spectrum
was not exploitable due to degradation of the compound in DMSO during
the J-MOD experiment; mass spectrum (free base) ESI+ m/z 255.0488
[C11H16BrN2 (M + H) requires 255.0491]; mp 169ꢀ171 °C.
4-Cyano-4-(6-methoxypyridin-3-yl)heptanedioic Acid Di-
ethyl Ester (12). The title compound was obtained in 99% yield
(17.22 g) as a yellow oil from 6 according to general procedure B: 1H
NMR (400 MHz, CDCl3) δ 8.23 (d, J = 2.6 Hz, 1 H), 7.52 (dd, J = 8.7,
2.6 Hz, 1 H), 6.75 (d, J = 8.7 Hz, 1 H), 4.05 (m, 4 H), 3.92 (s, 3 H), 2.47
(m, 2 H), 2.33 (m, 2 H), 2.18 (m, 4 H), 1.19 (t, J = 7.2 Hz, 6 H); J-MOD
13C NMR (100 MHz, DMSO-d6) δ 171.2 (2 C), 163.4, 144.7, 136.9,
125.2, 120.7, 111.0, 60.1 (2 C), 53.3, 44.3, 34.2 (2 C), 30.0 (2 C), 13.9 (2
C); IR (film, cmꢀ1) 2978, 2937, 2902, 2837, 2239, 1733, 1602, 1568,
1495, 1460, 1380, 1291, 1260, 1190, 1023, 832; mass spectrum EI+ m/z
348.1683 [C18H24N2O5 (M+) requires 348.1685].
3-(60-Methoxy-6-oxo-1,4,5,6-tetrahydro-2H-[3,30]bipyridinyl-
3-yl)propionic Acid Ethyl Ester (13). The title compound was
obtained in 95% yield (10.7 g) as a colorless oil from 12 according to
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general procedure C: H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J =
2.5 Hz, 1 H), 7.72 (dd, J = 8.7, 2.5 Hz, 1 H), 7.49 (d, J = 2.2 Hz, 1 H), 6.80
(d, J = 8.7 Hz, 1 H), 3.92 (d, J = 7.1 Hz, 2 H), 3.84 (s, 3 H), 3.55 (d, J =
12.4 Hz, 1 H), 3.24 (d, J = 12.4 Hz, 1 H), 2.15 (m, 2 H), 1.90 (m, 6 H),
1.10 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, DMSO-d6) δ 172.5,
169.5, 162.2, 145.4, 137.8, 129.9, 110.2, 59.8, 54.9, 53.0, 37.6, 34.6, 30.6,
28.6, 28.1, 13.9; IR (CH2Cl2; cmꢀ1) 3396, 3044, 2979, 2946, 2870,
1727, 1665, 1603, 1491, 1375, 1295, 1219, 1186, 1023, 830; mass
spectrum EI+ m/z 306.1583 [C16H22N2O4 (M+) requires 306.1579].
3-(60-Methoxy-1,4,5,6-tetrahydro-2H-[3,30]bipyridinyl-3-
yl)propan-1-ol (14). The title compound was obtained in 97% yield
(8.5 g) as a pale yellow oil from 13 according to general procedure D. 1H
NMR (200 MHz, CDCl3) δ 8.07 (d, J = 2.5 Hz, 1 H), 7.50 (dd, J = 8.7,
2.6 Hz, 1 H), 6.70 (d, J = 8.7 Hz, 1 H), 3.89 (s, 3 H), 3.45 (t, J = 6.5 Hz,
2 H), 3.43 (s, 1 H), 3.19 (d, J = 12.8 Hz, 1 H), 2.83 (d, J = 12.8 Hz, 1 H),
2.76 (m, 2 H), 2.05 (m, 1 H), 1.65 (m, 5 H + H2O), 1.45 (m, 1 H), 1.19
(m, 2 H); J-MOD 13C NMR (100 MHz, DMSO-d6) δ 161.4, 145.3,
137.9, 134.3, 109.6, 61.3, 55.1, 52.8, 46.5, 38.3, 35.9, 34.6, 26.7, 22.4; IR
(film; cmꢀ1) 3281, 2935, 2852, 2816, 2729, 1601, 1569, 1498, 1454,
1378, 1280, 1256, 1168, 1129, 1057, 1022, 894, 823; mass spectrum CI+
m/z 251.1756 [C14H23N2O2 (M + 1) requires 251.1759].
30-(3-Bromopropyl)-10,20,30,40,50,60-hexahydro[3,30]bipyri-
dinyl-6-ol Hydrobromide (15). The title compound was obtained
in quantitative yield (12.9 g) as a brown powder from 14 according to
general procedure E: 1H NMR (400 MHz, D2O) δ 7.93 (d, J = 9.3 Hz,
1 H), 7.66 (s, 1 H), 6.85 (d, J = 9.5 Hz, 1 H), 3.68 (d, J = 13.2 Hz, 1 H),
3.44 (s, 2 H), 3.33 (d, J = 13.9 Hz, 1 H), 3.23 (m, 2 H), 2.35 (m, 1 H),
1.88 (m, 6 H), 1.54 (m, 1 H); J-MOD 13C NMR (100 MHz, DMSO-d6)
δ 161.1, 141.6, 134.2, 121.0, 118.7, 49.7, 43.4, 37.5, 37.3, 34.9, 29.6, 26.4,
18.4; mass spectrum (free base) ESI+ m/z 299.0755 [C13H19BrN2O
(M + 1) requires 299.0753]; mp 236ꢀ238 °C.
4-Pyridin-3-yl-1-azabicyclo[2.2.1]heptane (22). The title
compound was obtained in 66% yield (0.96 g) as a yellow oil from 21
according to general procedure F: 1H NMR (400 MHz, DMSO-d6) δ
8.57 (dd, J = 2.4, 0.8 Hz, 1 H), 8.42 (dd, J = 4.8, 1.6 Hz, 1 H), 7.74 (ddd,
J = 7.8, 2.3, 1.6 Hz, 1 H), 7.33 (ddd, J = 7.8, 4.7, 0.8 Hz, 1 H), 2.93 (m, 2
H), 2.62 (m, 4 H), 1.76 (m, 2 H), 1.64 (m, 2 H); 13C NMR (100 MHz,
DMSO-d6) δ 148.1, 147.3, 138.4, 134.6, 123.3, 63.2 (2 C), 55.0 (2 C),
51.2, 37.3 (2 C); mass spectrum EI+ m/z 174.1155 [C11H14N2 (M+)
requires 174.1157].
4-Cyano-4-pyridin-3-ylheptanedioic Acid Diethyl Ester
(23). The title compound was obtained in 92% yield (24.797 g) as a
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orange oil from 17 according to general procedure B: H NMR (400
MHz, CDCl3) δ 8.69 (d, J = 2.3 Hz, 1 H), 8.60 (dd, J = 4.7, 1.4 Hz, 1 H),
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dx.doi.org/10.1021/jo201501f |J. Org. Chem. 2011, 76, 8336–8346