Synthesis of Orthogonally Protected Angular Nitrogen Polyheterocycles via CpCo-Catalyzed Pyridine Formation

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 (PG^¹ and PG^²) 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

References and Notes

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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.
  Compound 2k: ^¹H NMR (400 MHz, CDCl₃): δ = 2.52-2.59 (m, 4 H), 2.68-2.73 (m, 2 H), 3.08-3.10 (m, 2 H), 3.55 (s, 2 H), 4.56 (s, 1 H), 4.61 (s, 1 H), 4.67 (s, 1 H), 4.69 (s, 1 H), 5.12 (s, 2 H), 7.15-7.30 (m, 11 H), 8.10-8.15 (2 s, 1 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 30.7-30.8 (CH₂), 39.3 (CH₂), 50.7-51.1-51.2-51.6 (mixture of slow interconverting rota-mers) (2 CH₂), 53.7 (CH₂), 54.2 (CH₂), 63.5 (CH₂), 67.3 (CH₂), 127.2 (CH), 128.0 (CH), 128.2 (CH), 128.4 (CH), 128.6 (CH), 129.1 (CH), 130.1-131.1 (C), 131.4-131.6 (C), 136.7 (C), 138.5 (C), 140.5-140.8 (CH), 144.5-144.8 (C), 154.8 (C), 161.1-161.2 (C). IR (neat): 2942, 1703, 1412 cm^-¹. HRMS: m/z calcd for C₂₃H₂₈O₂N₃: 414.21760; found 414.21754.

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21

Excellent yields of Mitsunobu reactions in the presence of the 2-nitrobenzenesulfonyl group have been reported, see ref. 8b.

23

It is worthy of note that attempts to cyclize monoprotected diyne nitriles such as 16, 23, or 31 failed.

26

Also we cannot exclude catalyst deactivation by the Ns group.