1,7-Electrocyclisations of stabilised azomethine ylides

Article abstract of DOI:10.1016/S0040-4039(02)02676-X

Ester-stabilised α,β:γ,δ-unsaturated azomethine ylides 9 were generated by the deprotonation method from isoquinolinium salts 8. 1,7-Electrocyclisation of these dipoles followed by a 1,5-hydrogen shift, gives tetrahydro[5,6]azepino[2,1-a]isoquinolines 10.

Full text of DOI:10.1016/S0040-4039(02)02676-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 793–794
1,7-Electrocyclisations of stabilised azomethine ylides
´
Miklo´s Nyerges,* Andrea Vira´nyi, Aron Pinte´r and La´szlo´ To
3
ke
Research Group of the Hungarian Academy of Sciences, Department of Organic Chemical Technology,
Technical University of Budapest, H-1521 Budapest P.O.B. 91, Hungary
Received 3 September 2002; revised 6 November 2002; accepted 22 November 2002
Abstract—Ester-stabilised a,b:g,d-unsaturated azomethine ylides 9 were generated by the deprotonation method from isoquinolin-
ium salts 8. 1,7-Electrocyclisation of these dipoles followed by a 1,5-hydrogen shift, gives tetrahydro[5,6]azepino[2,1-
a]isoquinolines 10. © 2003 Elsevier Science Ltd. All rights reserved.
The 1,3-dipolar cycloaddition reaction is one of the
most simple approaches for the construction of five
membered heterocyclic rings.1 There are, however,
many other synthetically useful reactions of these
dipoles, including the 1,5- and 1,7-electrocyclic2,3 ring
closure of appropriately substituted dipolar systems.
Recently, we4 and others5 published the first examples
of the 1,7-electrocyclisation of non-stabilised azome-
thine ylides with a,b:g,d-unsaturation.
unsaturated, ester-stabilised azomethine ylides 1 (E=
CO2Et). The former dipoles react via a 1,7-electrocycli-
sation,6 followed by a [1,5]-hydrogen shift to give
dihydrobenzazepines 2, whilst the latter give other
products (3 or 4) via novel rearrangements (Scheme
1).7,8 As a continuation of these studies we have now
examined the reactivity of some a,b:g,d-unsaturated,
ester-stabilised azomethine ylides 9 generated by depro-
tonation of imminium salts 8. The synthesis of precur-
sors was carried out according to the Bischler–
Napieralski procedure9 by cyclisation of amide 6 in the
presence of POCl3 that resulted in the formation of
3,4-dihydroisoquinolines 7. Subsequent reaction with
bromoalkyl derivatives in anhydrous ether gave the
quaternary salts 8a–d (Scheme 2).
During these and further studies we have found signifi-
cant differences between the reactivity of a,b:g,d-unsat-
urated, non-stabilised ylides 1 (E=H) and a,b:g,d-
Reacting the isoquinolinium salts 8a–d with triethyl-
amine at ambient temperature, in dry ethanol leads to
the formation of 8-substituted-2,3-dimethoxy-13-
phenyl-5,6,8,14a-tetrahydro[5,6]azepino[2,1-a]isoquino-
lines 11a–d via azomethine ylide intermediates 9a–d.
Compounds could be isolated by a simple filtration in
moderate to good yields. In this reaction the azome-
thine ylides were produced by dehydrohalogenation of
the isoquinolinium salts,10 which leads via a 1,7-electro-
cyclisation reaction to the azepine 10 and finally by a
[1,5]-hydrogen shift to the products 11a–d. The stereo-
chemistry of tetracycles 11a–d was deduced by NOE
studies (Scheme 3).
In summary, we have demonstrated the first 1,7-electro-
cyclisation of electron-withdrawing group stabilised
azomethine ylides (11a and 11c), while the explored
reaction sequence provides a useful route to the tetra-
hydro[5,6]azepino[2,1-a]isoquinoline ring system.
Scheme 1.
* Corresponding author. Fax: (+361)463-3648; e-mail: mnyerges@
mail.bme.hu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02676-X

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M. Nyerges et al. / Tetrahedron Letters 44 (2003) 793–794
Scheme 2. Reagents and conditions: (i) Ph2CꢀCHCOCl, NaOH, Et2O, H2O, rt (88%); (ii) POCl3, toluene, reflux (72%); (iii)
RCH2Br, Et2O, rt (95–100%).
Scheme 3. Reagents and conditions: (i) Et3N, EtOH, rt.
Acknowledgements
5. Marx, K.; Eberbach, W. Tetrahedron 1997, 53, 14687.
6. Arany, A.; Bendell, D.; Groundwater, P. W.; Garnett,
I.; Nyerges, M. J. Chem. Soc., Perkin Trans. 1 1999,
2605.
7. (a) Groundwater, P. W.; Sharif, T.; Arany, A.; Hibbs, D.
E.; Hursthouse, M. B.; Nyerges, M. Tetrahedron Lett.
1998, 38, 1433; (b) Groundwater, P. W.; Sharif, T.;
Arany, A.; Hibbs, D. E.; Hurthouse, M. B.; Garnett, I.;
Nyerges, M. J. Chem. Soc., Perkin Trans. 1 1998, 2837.
8. Nyerges, M.; Arany, A.; Fejes, I.; Groundwater, P. W.;
This work was financially supported by the National
Found for Science and Research, Hungary (OTKA
Project No. T 032221). N.M. thanks the Ministry of
Education for a Gyo¨rgy Be´ke´sy fellowship.
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