Solid Phase Synthesis of 1,2-Disubstituted Alkenes: A Novel Alkynyldihydropyridine to Alkenylpyridine Isomerization

Abstract

A series of 1,2-disubstituted pyridylalkenes have been prepared using a solid-phase resin approach. This approach takes advantage of a novel alkynyldihydropyridine to alkenylpyridine isomerization.

Key words

solid-phase synthesis - 1,2-disubstituted alkenes - alkynyldihydropyridine - alkenylpyridine - isomerization

References

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• 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 

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.