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DOI: 10.1055/s-0030-1258041
Synthesis of Orthogonally Protected Angular Nitrogen Polyheterocycles via CpCo-Catalyzed Pyridine Formation
Publikationsverlauf
Publikationsdatum:
12. August 2010 (online)
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Abstract
Unprecedented nitrogen polyheterocycles have been prepared by means of intramolecular Co-catalyzed [2+2+2] cycloaddition of two alkynes to one nitrile. They exhibit two nitrogen-containing rings fused in an angular fashion to one pyridine unit. Several relative positions of the nitrogen atoms have been studied, giving rise to eight different new scaffolds. In order to allow selective functionalization of the two amino groups, orthogonal protecting groups (PG¹ and PG²) were introduced prior to cyclization. Eleven combinations of seven different protecting groups (Bn, COCF3, Cbz, Boc, Ts, SO2-2-py, Ns) were tested, most of them being perfectly tolerated under the cyclization conditions.
Key words
alkyne - cobalt - cycloaddition - nitrile - pyridine
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Procedure for [2+2+2] Cycloadditions
To a refluxing solution of the starting material in xylenes (c 0.1 M) under argon was added 5 mol% of cyclopentadienyledicarbonyl cobalt, and the mixture was irradiated (visible light) using a 300 W halogen lamp until completion of the reaction (TLC monitoring). After removal of the volatiles under reduced pressure, the crude mixture was purified by flash chromatography (gradient mixtures of PE and EtOAc), affording the corresponding tricyclic pyridines.
Compound 2f: ¹H NMR (400 MHz, C6D6, 70 ˚C): δ = 2.84 (t, J = 6.0 Hz, 2 H), 3.46 (br s, 2 H), 4.18 (s, 2 H), 4.24 (br s,2 H), 4.44 (br s, 2 H), 5.30 (s, 2 H), 7.20-7.31 (m, 3 H), 7.45 (d, J = 7.6 Hz, 2 H), 8.14 (s, 1 H). ¹³C NMR (100 MHz, C6D6): δ = 31.0-32.2 (CH2), 41.2-42.1 (CH2), 42.8-43.4 (CH2), 49.5-49.9 (CH2), 50.4-50.7 (CH2), 67.3 (CH2), 117.03 (q, J = 286 Hz, CF3), 121.7-121.9 (C), 128.4 (CH), 128.5 (CH), 128.8 (CH), 131.3-131.7 (C), 137.4 (C), 142.3-142.9 (m, CH), 143.1-143.4 (C), 151.5-151.6 (C), 155.5 (q, J = 36 Hz, C). ¹9F NMR (376 MHz, CDCl3): δ = -69.7. IR (neat): 3089, 3064, 3033, 2949, 2864, 1689, 1138, 730 cm-¹. Mp 144.1 ˚C. HRMS: m/z calcd for C20H19O3N3F3: 406.1370; found: 406.13727.
Compound 2i: ¹H NMR (400 MHz, CDCl3): δ = 1.46 (s, 9 H), 2.78 (br s, 2 H), 3.17 (br s, 2 H), 3.59 (br s, 4 H), 4.69-4.72 (2 s, 2 H), 4.78 (br s, 2 H), 5.20 (s, 2 H), 7.28-7.41 (m, 5 H), 8.22-8.28 (2 s, 1 H). ¹³C NMR (100 MHz, CDCl3): δ = 28.5 (CH3), 28.7 (CH2), 31.3-31.8 (m, CH2), 40.1-45.9 (m, 2 CH2), 50.7-51.2 (CH2), 51.3-51.8 (CH2), 67.3-67.4 (CH2), 80.1 (C), 128.0 (CH), 128.3 (CH), 128.6 (CH), 130.5-131.4 (m, 2 C), 136.6 (C), 140.8-140.9 (CH), 145.6-145.9 (m, 2 C), 154.7-155.0 (C), 159.7 (C). IR (neat): 2974, 1692, 1414 cm-¹. Mp 154.1 ˚C. HRMS: m/z calcd for C24H30O4N3: 424.22308; found: 424.22297.
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References and Notes
Excellent yields of Mitsunobu reactions in the presence of the 2-nitrobenzenesulfonyl group have been reported, see ref. 8b.
23It is worthy of note that attempts to cyclize monoprotected diyne nitriles such as 16, 23, or 31 failed.
26Also we cannot exclude catalyst deactivation by the Ns group.