An access to some functionalized azocine derivatives

Article abstract of DOI:10.1016/S0040-4039(00)01008-X

The syntheses, from readily accessible 3-alkyl-4-methoxy-l,3,4,5-tetrahydropyridine 1, of functionalized 1,6,7,8-tetrahydroazocine 7 and 1,2,7,8-tetrahydroazocine 9 are reported. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01008-X

Tetrahedron Letters 41 (2000) 6067±6069
An access to some functionalized azocine derivatives
Laurent Gil,a,* Rossimiriam Pereira de Freitas Gil,b Daniela Cristina dos Santosb
and Christian Marazanoc
a
Â
Departamento de Quõmica, Instituto de CieÃncias Exatas e Biologicas, UFOP, Brazil
Â
Departamento de Quõmica, Instituto de CieÃncias Exatas, UFMG, Brazil
b
Â
cInstitut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette, France
Received 30 March 2000; accepted 14 June 2000
Abstract
The syntheses, from readily accessible 3-alkyl-4-methoxy-1,3,4,5-tetrahydropyridine 1, of functionalized
1,6,7,8-tetrahydroazocine 7 and 1,2,7,8-tetrahydroazocine 9 are reported. # 2000 Published by Elsevier
Science Ltd.
Keywords: azocines; nitrogen heterocycles.
Eight-membered nitrogen heterocycles constitute an important class of compounds, especially
in view of their pharmacological properties.1 These derivatives are generally dicult to obtain2
and, accordingly, relatively few methods are available for their preparation. This is especially the
case of highly functionalized derivatives or derivatives suitable for further chemoselective reactions.
We recently reported3 that tetrahydropyridines 1 (Scheme 1, R1 and R2=alkyl group) are good
precursors of 3-alkyl 1,6-dihydropyridines 2 which were too unstable to be isolated, but could be
trapped with common dienophiles to produce isoquinuclidine derivatives 3. As a continuation of
our studies concerning the reactivity of derivatives 1, we now report that the reaction of these
reactive intermediates with ethyl propiolate gave highly functionalized azocines heterocycles 4 in
high yield.
Dihydropyridinium salt 5 (Scheme 2) was obtained from the corresponding pyridinium salt
following well-established procedures.4 The reaction of salt 5 with sodium methoxide in methanol
gave adduct 1a in good yield.3 Adduct 1a, when treated with ethyl propiolate in re¯uxing aceto-
nitrile, gave the functionalized 1,6,7,8-tetrahydroazocine5 7 in 90% yield. It is believed that
azocine formation involves an initial [2+2] cycloaddition3,6 reaction between the enamine 1a to
give the cyclobutene intermediate 6, followed by an electrocyclic ring opening to give the azocine
system.
* Corresponding author. Fax: +55 031 551 1707; e-mail: laurent@iceb.ufop.br
0040-4039/00/$ - see front matter # 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01008-X

6068
Scheme 1.
Scheme 2.
Azocine 7 was treated with 1 equivalent of methanesulfonic acid to give, presumably, an
iminium salt (8, not isolated). Reduction of this salt with NaBH4 in methanol ®nally gave 1,2,7,8-
tetrahydroazocine 9.
Further studies to extend this approach to other azocines are currently in progress.
Acknowledgements
We thank FAPEMIG-MG and CAPES, Brazil for ®nancial support.

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References
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2. For previous related approaches, see: Lallemand, M.-C.; Chiadmi, M.; Tomas, A.; Kunesch, N.; Husson, H.-P.
Tetrahedron Lett. 1995, 36, 2053±-2056, and references cited therein.
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4. Grierson, D. S.; Harris, M.; Husson, H. P. J. Am. Chem. Soc. 1980, 102, 1064±1082.
5. Selected data for 7: mp 112ꢀC (ether±heptane); IR (cm^1) 2981, 2931, 1685, 1605, 1577, 1453, 1421, 1364, 1291,
1251, 1196; 1H NMR (CDCl3, 200 MHz) ꢀ 1.03 (1H, m), 1.29 (3H, t, J=7.1 Hz), 1.57 (1H, tt, J=12.6, 5 Hz), 1.64
(3H, d, J=1.6, 1.8 Hz), 2.85 (1H, m), 3.24 (3H, s), 3.60 (1H, m), 4.00±4.40 (3H, m), 4.20 (2H, q, J=7.1 Hz), 6.28
(1H, m), 7.23±7.40 (5H, m), 7.61 (1H, s); 13C NMR (CDCl3, 50.32 MHz) ꢀ 14.74, 16.82, 21.12, 44.98, 57.07, 59.82,
61.51, 79.21, 95.26, 122.39, 127.78, 128.18, 128.93, 131.33, 136.61, 148.99, 169.88; HRMS calcd for C19H25NO3:
315.1835; found: 315.1842; anal. calcd for C19H25NO3: C, 72.35; H, 7.99; N, 4.44; O, 15.22; found: C, 72.07; H,
8.24; N, 4.53; O, 15.03.
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