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Synlett 2010(15): 2314-2318  
DOI: 10.1055/s-0030-1258041
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Yves Micloa, Pierre Garciaa, Yannick Evannob, Pascal Georgeb, Mireille Sevrinb, Max Malacria*a, Vincent Gandon*a, Corinne Aubert*a
a UPMC Univ Paris 06, IPCM UMR 7201, FR2769, 4 Place Jussieu, 75252 Paris Cedex 05, France, Fax: +33(1)44277360; e-Mail: vincent.gandon@u-psud.fr; corinne.aubert@upmc.fr;
b Sanofi-Aventis R&D, CNS Research Department, 31 Avenue Paul Vaillant-Couturier, 92220 Bagneux, France
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Publication History

Received 1 July 2010
Publication Date:
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.
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    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.