References
1a
Bhattacharyya S.
Curr. Med. Chem.
2001,
8:
1383
1b
Lou B.
Drug Discovery Today
2001,
6:
1288
1c
Sammelson RE.
Kurth MJ.
Chem. Rev.
2001,
101:
137
1d
Baldwin JJ.
Comb. Chem. Mol. Diversity Drug Discovery
1998,
181
2a
Munoz B.
Chen C.
McDonald IA.
Biotechnology
2000,
71:
78
2b
Chen C.
Munoz B.
Tetrahedron Lett.
1999,
40:
3491
2c
Chen C.
Munoz B.
Tetrahedron Lett.
1998,
39:
6781
2d
Chen C.
Munoz B.
Tetrahedron Lett.
1998,
39:
3401
2e
Chen C.
McDonald IA.
Munoz B.
Tetrahedron Lett.
1998,
39:
217
3a
Pin J.-F.
Curr. Drug Targets: CNS Neurol. Disord.
2002,
1(3):
297
3b
Varney MA.
Cosford ND.
Jachec C.
Rao SP.
Sacaan A.
Lin F.-F.
Bleicher LS.
Santori EM.
Flor PJ.
Allgeier H.
Gasparini F.
Kuhn R.
Hess SD.
Velicelebi G.
Johnson EC.
J. Pharmacol. Exp. Ther.
1999,
290:
170
3c
Gasparini F.
Lingenhohl K.
Stoehr N.
Flor PJ.
Heinrich M.
Vranesic I.
Biollaz M.
Allgeier H.
Hechendorn R.
Urwyler S.
Varney MA.
Johnson EC.
Hess SD.
Rao SP.
Sacaan AI.
Santori EM.
Velicelebi G.
Kuhn R.
Neuropharmacology
1999,
38:
1493
4
Benzyl 6-methyl-2-(phenylethynyl)pyridine-1(2
H
)-carboxylate (
4b): 1H NMR (3:1 THF
d8
/CD3OD): δ = 7.43-7.25 (10 H, m), 5.98-5.93 (1 H, m), 5.89-5.87 (1 H, d), 5.75-5.70 (1 H, m) 5.54-5.52 (1 H, m), 5.25-5.16 (2 H, m), 2.17 (3 H, s). 13C NMR (3:1 THF
d8
/CD3OD): δ = 154.55, 137.49, 136.16, 132.69, 129.51, 129.51, 129.36, 129.32, 129.20, 124.31, 124.05, 120.70, 112.79, 87.72, 83.34, 68.85, 45.78, 22.17. ESMS (M + Na+): 352.
5
Resin-bound Benzyl 6-methyl-2-(phenylethynyl)pyri-dine-1(2
H
)-carboxylate (
4a): IR (KBr): 2221, 1714 cm-1.
Resin-bound Benzyl 2-(phenylethynyl)pyridine-1(2
H
)-carboxylate (
4d): IR (KBr): 2231, 1724 cm-1.
Resin-bound Benzyl 4-methoxy-2-(phenylethynyl)pyri-dine-1(2
H
)-carboxylate (
4e): IR (KBr): 2241, 1724, 1662 cm-1.
Resin-bound Benzyl 4-hydroxy-2-(phenylethynyl)pyri-dine-1(2
H
)-carboxylate (
4f): IR (KBr): 2221, 1734, 1683, 1605 cm-1.
Resin-bound Benzyl 3-methoxy-2-(phenylethynyl)pyri-dine-1(2
H
)-carboxylate (
4h): IR (KBr): 2221, 1716, 1660 cm-1.
Resin-bound Benzyl 6-methyl-2-prop-1-ynylpyridine-1(2
H
)-carboxylate (
4k): IR (KBr): 2240, 1719 cm-1.
6
General Procedure for Synthesis of Ethenylpyridine; 2-Methyl-6-[(
E
)-2-phenylethenyl]pyridine (
6a): To 2-picoline (118 mg, 1.5 equiv) was added phenylethynyl-magnesium bromide (0.5 M in THF, 10 mL, 5 equiv). The resulting solution was added to resin-bound chloroformate (1 g, 1 mmol/g) in polypropylene tube fitted with a frit. The tube was capped and the reaction was agitated for 15 min. The resin was filtered and washed with THF, THF/H2O 1:1, THF, MeOH, CH2Cl2 and THF. The resin was re-suspended in THF and NaOMe (4.4 M in MeOH, 0.23 mL, 1 equiv) was added. The resulting suspension was agitated for 3 h. The resin was filtered and washed with THF (3 ×). The combined filtrates were concentrated. Prep-TLC purification gave (E)-2-methyl-6-(2-phenylethen-1-yl)pyridine (6a) in 32% yield. The yield was 46% from the corresponding solution phase reaction. Compound 6a was converted to the HCl salt. 1H NMR (CD3OD): δ = 8.37-8.32 (1 H, t), 8.19-8.16 (1 H, d), 7.76-7.73 (2 H, m), 7.68-7.65 (1 H, d), 7.52-7.47 (3 H, m), 7.39-7.34 (1 H, d), 2.79 (3 H, s). 13C NMR (CD3OD): δ = 154.14, 151.44, 146.72, 142.34, 135.79, 131.71, 130.12, 129.29, 121.21, 121.79, 118.63, 19.65. ESMS (M + H+): 196. HRMS (MALDI) calcd for C14H13N (M + H) 196.1121. Found: 196.1125.
7
2-Ethyl-6-[(
E
)-2-phenylethenyl]pyridine (
6c): 1H NMR (CDCl3): δ = 7.76 (1 H, t), 7.79-7.74 (3 H, m), 7.55-7.32 (5 H, m), 7.16-7.13 (1 H, d), 3.06-2.99 (2 H, q), 1.41-1.36 (3 H, t). 13C NMR (CDCl3): δ = 162.14, 154.06, 138.88, 136.13, 134.79, 128.94, 128.83, 127.50, 125.67, 121.02, 119.09, 30.10, 13.91. ESMS (M + H+): 210. HRMS (MALDI) calcd for C14H13N (M + H): 210.1279. Found: 210.1256.
2-[(
E
)-2-phenylethenyl]pyridine (
E
-6d): 1H NMR (CDCl3): δ = 8.61-8.60 (1 H, d), 7.68-7.57 (4 H, m), 7.40-7.25 (4 H, m), 7.20-7.12 (2 H, m). 13C NMR (CDCl3): δ = 155.62, 149.72, 136.65 (2 C, overlap) 132.74, 128.79, 128.41, 127.95, 127.16, 122.20, 122.14. ESMS (M + H+) 182. HRMS (MALDI) calcd for C13H11N (M + H): 182.0967. Found: 182.0960.
2-[(
Z
)-2-phenylethenyl]pyridine (
Z
-6d): 1H NMR (CDCl3): δ = 8.59-8.57 (1 H, d), 7.46-7.40 (1 H, t), 7.27-7.20 (5 H, m), 7.17-7.15 (1 H, d), 7.10-7.06 (1 H, m), 6.86-6.82 (1 H, d), 6.71-6.67 (1 H, d). 13C NMR (CDCl3): δ = 156.36, 149.59, 136.66, 135.71, 133.31, 130.52, 128.92, 128.35, 127.65, 123.91, 121.83. ESMS (M + H+): 182.
4-Methoxy-2-[(
E
)-2-phenylethenyl]pyridine (
E
-6e): 1H NMR (CDCl3): δ = 8.39-8.37 (1 H, d), 7.65-7.60 (1 H, d), 7.55-7.52 (2 H, d), 7.35-7.32 (2 H, t), 7.27-7.24 (1 H, t), 7.10-7.05 (1 H, d), 6.82-6.81 (1 H, d), 6.61-6.59 (1 H, m), 3.73 (3 H, s). 13C NMR (CDCl3): δ = 166.18, 157.06, 150.81, 136.55, 132.80, 128.76, 128.39, 127.94, 127.15, 108.39, 108.15, 55.06. ESMS (M + H+): 212. Anal. Calcd for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.20; H, 6.08; N, 6.60.
4-Methoxy-2-[(
Z
)-2-phenylethenyl]pyridine (
Z
-6e): 1H NMR (CDCl3) δ = 8.39-8.37 (1 H, d), 7.29-7.23 (5 H, m), 6.85-6.81 (1 H, d), 6.68-6.61 (3 H, m), 3.55 (3 H, s). 13C NMR (CDCl3): δ = 165.62, 158.08, 150.94, 137.08, 133.74, 131.03, 129.27, 128.72, 128.01, 109.53, 109.40, 55.17. ESMS (M + H+): 212.
4-Hydroxy-2-[(
E
)-2-phenylethenyl]pyridine [
E
-6f): 1H NMR (CD3OD): δ = 7.78-7.75 (1 H, d), 7.62-7.59 (2 H, d), 7.44-7.33 (4 H, m), 7.02-6.96 (1 H, d), 6.65-6.64 (1 H, d), 6.42-6.39 (1 H, dd). 13C NMR (CD3OD) δ = 181.75, 149.20, 140.10, 136.74, 136.54, 130.63, 130.08, 128.50, 121.61, 116.63, 115.30. ESMS (M + H+): 198. HRMS (MALDI) calcd for C13H11NO (M + H): 198.0913. Found: 198.0916.
4-Methyl-2-[(
E
)-2-phenylethenyl]pyridine [
E
-6g): 1H NMR (CDCl3) δ = 8.51-8.49 (1 H, d), 7.60-7.55 (1 H, d), 7.53-7.50 (2 H, d), 7.40-7.35 (3 H, m), 7.15-7.13 (1 H, d), 6.82-6.81 (1 H,d), 6.61-6.59 (1 H, m), 2.15 (3 H, s). ESMS (M + H+): 196. HRMS (MALDI) calcd for C14H13N (M + H): 196.1121. Found: 196.1125.
4-Methyl-2-[(
Z
)-2-phenylethenyl]pyridine [
Z
-6g): 1H NMR (CDCl3) δ = 8.57-8.55 (1 H, d), 7.29-7.23 (5 H, m), 6.85-6.81 (1 H, d), 6.75-6.71 (1 H, d), 6.68-6.61 (2 H, m), 2.12 (3 H, s). ESMS (M + H+): 196. HRMS (MALDI) calcd for C14H13N (M + H): 196.1121. Found: 196.1121.
3-Methoxy-2-[(
E
)-2-phenylethenyl]pyridine (
E
-6h): 1H NMR (CDCl3) δ = 8.22-8.20 (1 H, m), 7.80-7.75 (1 H, d), 7.64-7.61 (2 H,m), 7.62-7.57 (1 H, d), 7.38-7.33 (2 H, t), 7.29-24 (1 H, t), 7.14-7.12 (2 H, m), 3.86 (3 H, s). 13C NMR (CDCl3) δ = 153.09, 145.29, 141.15, 137.33, 132.69, 128.68, 128.12, 127.28, 122.81, 121.72, 117.76, 55.43. ESMS (M + H+): 212. HRMS (MALDI) calcd for C14H13NO (M + H): 212.7010. Found: 212.1074. Anal. Calcd for C14H13NO: C, 79.59; H, 6.20; N, 6.63. Found: C, 79.20; H, 6.09; N, 6.38.
3-Methoxy-2-[(
Z
)-2-phenylethenyl]pyridine (
Z
-6h): 1H NMR (CDCl3) δ = 8.14-8.12 (1 H, dd), 7.24-7.12 (7 H, m), 6.81-6.77 (1 H, d), 6.74-6.70 (1 H, d), 3.66 (3 H, s). 13C NMR (CDCl3) δ = 153.39, 146.50, 140.89, 137.10, 133.73, 128.95, 127.84, 127.44, 125.16, 123.14, 117.54, 55.22. ESMS (M + H+): 212.
3-Methyl-2-[(
E
)-2-phenylethenyl]pyridine (
E
-6i): 1H NMR (CD3OD) δ = 8.32-8.33 (1 H, d), 7.62-7.57 (4 H, m), 7.43-7.27 (4 H, m), 7.18-7.14 (1 H, m), 2.43 (3 H, s). 13C NMR (CDCl3) δ = 153.67, 146.52, 139.00, 137.08, 134.27, 131.93, 128.74, 128.46, 127.13, 123.72, 122.52, 17.83. ESMS (M + H+): 196. HRMS (MALDI) calcd for C14H13N (M + H): 196.1121. Found: 196.1116. Anal. Calcd for C14H13NO: C, 86.12; H, 6.71; N, 7.17. Found: C, 86.24; H, 6.87; N, 7.17.
3-Methyl-2-[(
Z
)-2-phenylethenyl]pyridine (
Z
-6i): 1H NMR (CD3OD) δ = 8.44-8.42 (1 H, dd), 7.45-7.42 (1 H, dd), 7.15-7.08 (4 H, m), 7.05-7.01 (2 H, m), 6.80-6.76 (1 H, d), 6.70-6.66 (1 H, d), 2.10 (3 H, s). 13C NMR (CDCl3) δ = 156.67, 146.84, 139.68, 137.41, 134.39, 133.20, 129.42, 129.03, 128.38, 128.10, 123.58, 18.32. ESMS (M + H+): 196.
2-Methyl-6-vinylpyridine (
6j): 1H NMR (CD3OD) δ = 8.33-8.28 (1 H, t), 8.02-8.00 (1 H, d), 7.67-7.65 (1 H, d), 6.95-6.86 (1 H, dd), 6.50-6.44 (1 H, d), 5.96-5.93 (1 H, d), 2.68 (3 H, s). 13C NMR (CDCl3) δ = 155.00, 151.20, 147.50, 128.96, 128.27, 127.57, 122.06, 19.62. GCMS (EI): 119.
2-Methyl-6-[(1
E
)-prop-1-enyl]pyridine (
E
-6k): 1H NMR (CD3OD) δ = 8.38, 8.32 (1 H, t), 8.05-8.02 (1 H, d), 7.70-7.67 (1 H, d), 7.24-7.16 (1 H, m), 6.77-6.72 (1 H, d), 2.78 (3 H, s), 2.09 (3 H, d). 13C NMR (CDCl3) δ = 154.18, 151.85, 147.10, 143.45, 126.24, 123.13, 121.60, 19.56, 19.40. GCMS (EI): 133.
2-Methyl-6-[(1
Z
)-prop-1-enyl]pyridine (
Z
-6k): 1H NMR (CD3OD) δ = 8.47, 8.42 (1 H, t), 7.94-7.91 (1 H, d), 7.79-7.76 (1 H, d), 6.70-6.66 (1 H, d), 6.62-56 (1 H, m), 2.81 (3 H, s), 2.07 (3 H, d). 13C NMR (CDCl3) δ = 158.56, 155.05, 147.21, 141.50, 126.63, 125.45, 121.66, 19.71, 15.50. GCMS (EI): 133.
8 An isoxazolinocyclobutenone to isoxazolocyclobutanone isomerization both in solution and solid-phase was reported, see: Cheng W.-C.
Wong M.
Olmstead MM.
Kurth MJ.
Org. Lett.
2002,
4(3):
741