Synthesis of 6,7,8,9-tetrahydropyrido[2,3-b]indolizine and 3,4-dihydro-2H-pyrido[2′,3′:4,5]pyrrolo[2,1-b][1,3]oxazine derivatives as new melatonin receptor ligands

Article abstract of DOI:10.1016/S0040-4039(01)02359-0

The synthesis of new tricyclic azaindolic analogs of the hormone melatonin is described. Treatment of 1-(4-bromobutyl)pyrrolo[3,2-b]pyridine derivative with tributyltin hydride and AIBN results in radical cyclisation to give the 6,7,8,9-tetrahydropyrido[2,3-b]indolizine ring system. A new synthetic approach of pyridopyrrolo[2,1-b][1,3]oxazine moiety is shown to be accomplished readily from 1-(3-bromopropyl)-2-oxopyrrolopyridine derivative with sodium hydride in N,N-dimethylformamide.

Full text of DOI:10.1016/S0040-4039(01)02359-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1205–1208
Synthesis of 6,7,8,9-tetrahydropyrido[2,3-b]indolizine and
3,4-dihydro-2H-pyrido[2%,3%:4,5]pyrrolo[2,1-b][1,3]oxazine
derivatives as new melatonin receptor ligands
Herve´ Van de Poe¨l,a Ge´rald Guillaumeta and Marie-Claude Viaud-Massuardb,*
aInstitut de Chimie Organique et Analytique associe´ au CNRS, Universite´ d’Orle´ans BP 6759, 45067 Orle´ans Cedex 2, France
bEA 3247 Laboratoire de Chimie Organique, UFR des Sciences Pharmaceutiques, Universite´ de Tours, 31 Avenue de Monge,
37200 Tours, France
Received 28 September 2001; accepted 10 December 2001
Abstract—The synthesis of new tricyclic azaindolic analogs of the hormone melatonin is described. Treatment of 1-(4-bromo-
butyl)pyrrolo[3,2-b]pyridine derivative with tributyltin hydride and AIBN results in radical cyclisation to give the 6,7,8,9-tetra-
hydropyrido[2,3-b]indolizine ring system. A new synthetic approach of pyridopyrrolo[2,1-b][1,3]oxazine moiety is shown to be
accomplished readily from 1-(3-bromopropyl)-2-oxopyrrolopyridine derivative with sodium hydride in N,N-dimethylformamide.
© 2002 Published by Elsevier Science Ltd.
Melatonin (N-acetyl-5-methoxytryptamine) is the prin-
cipal hormone of the mammalian pineal gland and is
released following a circadian rhythm with highest lev-
els during the night.1 In humans it has been suggested
that melatonin have a variety of clinical uses in jet lag,2
seasonal depression3 and delayed sleep phase syn-
drome.4 A number of reports have appeared describing
effects of melatonin on the immune system5 which
suggests that melatonin has also immunomodulatory
properties and might be useful as a coadjuvant in
cancer therapy.6
efforts have now been directed towards the synthesis of
tricyclic analogs obtained from azaindole moiety by
introducing an alkyl or alkoxy chain in position 2
linked to N-1 position, while keeping the methoxy
group and the ethylamido chain present in melatonin
itself. We report here the synthesis of N-[2-(2-methoxy-
6,7,8,9 - tetrahydropyrido[2,3 - b]indolizin - 10 - yl)ethyl]-
acetamide 1a and N-[2-(8-methoxy-3,4-dihydro-2H-
pyrido-[2%,3%:4,5]pyrrolo[2,1-b][1,3]oxazin-10-yl)ethyl]-
acetamide 1b.
In view of our work on the synthesis of the tricyclic
ring system, we were attracted by recent reports of
radical cyclisations onto the indole 2-position.
The important contribution for receptor binding by
2-substituents has been further investigated on the
indole series and confirmed on a series of bioisosteric
ligands.7 Recently, in our research group, the synthesis
of azaindole bioisoteres has been reported8 and our
5-Methoxy-1H-pyrrolo[3,2-b]pyridine 2 was prepared
by the method of Makosza et al.,9 which consists of the
* Corresponding author. Tel.: 33 247 36 72 27; fax: 33 247 36 72 29; e-mail: mcviaud@univ-tours.fr
0040-4039/02/$ - see front matter © 2002 Published by Elsevier Science Ltd.
PII: S0040-4039(01)02359-0

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H. Van de Poe¨l et al. / Tetrahedron Letters 43 (2002) 1205–1208
cyanomethylation of 5-nitro-2-methoxypyridine via
vicarious nucleophilic substitution of hydrogen, fol-
lowed by catalytic hydrogenation using palladium on
charcoal. Alkylation of the 5-methoxy-1H-pyrrolo[3,2-b]-
pyridine 2 with the 1,4-dibromobutane using sodium
hydride in N,N-dimethylformamide gave the corre-
sponding 1-(4-bromobutyl)-5-methoxy-1,3-dihydro-2H-
pyrrolo[3,2-b]pyridin-2-one 3 in 79%. Formylation of
the latter under Vilsmeier–Haack conditions provided
the desired substrate for the radical cyclisation in 91%.
The cyclisation reaction was carried out by slow addi-
tion of tributyltin hydride and azobisisobutyronitrile to
compound 4 in refluxing toluene and furnished the
expected tricyclic ring system in 65% yield. Moody and
Norton10 have shown radical cyclisation of alkyl radi-
cals to the 2-position of indole-3-carbaldehydes. Our
synthetic approach was based on the formation of the
6,7,8,9-tetrahydropyrido[3,2-b]indolizine moiety by
intramolecular radical cyclisation from 5-methoxy-4-
azaindole 2, as shown in Scheme 1.
N-Alkylation of 2 with sodium hydride and 1-benzy-
loxy-3-bromopropane in N,N-dimethylformamide gave
the required 1-[3-(benzyloxy)propyl]pyrrolopyridine 8
in 95% yield, which was then converted to the 2-oxo-
pyrrolopyridinederivative. First, wefocusedontheoxida-
tion of pyrrolo-[3,2-b]pyridine following the procedure
described by Marfat12 for the conversion of 7-azaindole
to 7-azaoxindole. Unfortunately, treatment of 8 with
3–4 equivalents of pyridinium bromide perbromide
(PBPB) in tert-butyl alcohol furnished only the dibro-
mide 9 in 94%. A solution to this problem was achieved
with the oxidative method reported by Robinson et
al.13 Oxidative bromination of 8 with 4 equivalents of
bromine in tert-butyl alcohol and water provided 25%
of dibromide 10 and 50% of tribromide 11 (Scheme 3).
Treatment of the mixture 10 and 11 with an excess of
zinc in acetic acid followed by cleavage of the benzyl
ether by hydrogenation gave the alcohol 14 in 61%
from 8. Transformation of 14 into the corresponding
bromide14 was then accomplished using carbon tetra-
To develop new tricyclic melatonin analogs, we wanted
to verify the effect on binding caused by incorporating
the oxygen atom within a six-membered ring as in 7. To
our knowledge the only reported methods for the elab-
oration of the pyridopyrrolo[2,1-b][1,3]oxazine skeleton
consists of the treatment of a pyrrolopyridine-3-car-
boxylate derivative with N-chlorosuccinimide and 3-
bromopropanol in chloroform, followed by cyclisation
with potassium carbonate in acetone without prior
isolation of the intermediate halo ether.11 We now
describe a novel synthetic approach to the pyrido
pyrrolo[2,1-b][1,3]oxazine ring system which was pre-
pared by an intramolecular cyclisation via an O-alkyla-
tion of 1-(3-bromopropyl)-2-oxopyrrolopyridine 6 with
sodium hydride in N,N-dimethylformamide (Scheme 2)
to provide 7 in 75% yield.
bromide
and
1,2-bis(diphenylphosphino)ethane
(DIPHOS) in methylene chloride followed by treatment
with sodium hydride in N,N-dimethylformamide to
provide the pyrido[2%,3%:4,5]pyrrolo[2,1-b][1,3]oxazine
ring system in 75% yield. Formylation of compound 7
was accomplished by reaction with phosphorus oxy-
chloride in N,N-dimethylformamide to yield the desired
aldehyde 15 in 86% (Scheme 4).
The target derivatives 1a and 1b were prepared accord-
ing to the route shown in Scheme 5.8 The formyl
derivatives 5 and 15 were condensed with nitromethane
in the presence of a catalytic amount of ammonium
acetate to afford the expected nitrovinyl products 16a
and 16b by a Henry reaction. Reduction of the a,b-
Scheme 1.
Scheme 2.

H. Van de Poe¨l et al. / Tetrahedron Letters 43 (2002) 1205–1208
1207
Scheme 3.
Scheme 4.
Scheme 5.

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H. Van de Poe¨l et al. / Tetrahedron Letters 43 (2002) 1205–1208
unsaturated nitroalkenes to the desired saturated
amines was performed with sodium borohydride in a
mixture of chloroform and isopropanol in the presence
of silica gel, followed by hydrogenation over Raney
nickel. The ethylamino function was acylated with ace-
tic anhydride in a mixture of methylene chloride and
pyridine to furnish the target compounds 1a, 1b in 74
and 81% yields, respectively.
5. Liebmann, P. M.; Wo¨lfler, A.; Felsner, P.; Hofer, D.;
Schauenstein, K. Int. Arch. Allergy Immunol. 1997, 112,
203–211.
6. Lissoni, P.; Paolorossi, F.; Tancini, G.; Ardizzoia, A.;
Barni, S.; Brivio, F.; Maestroni, G. J. M.; Chilelli, M. Br.
J. Cancer 1996, 74, 1466–1468.
7. (a) Spadoni, G.; Stankov, B.; Duranti, A.; Biella, G.;
Lucini, V.; Salvatori, A.; Fraschini, F. J. Med. Chem.
1993, 36, 4069–4074; (b) Garratt, P. J.; Jones, R.; Rowe,
S. J.; Sugden, D. Bioorg. Med. Chem. Lett. 1994, 4,
1555–1558; (c) Garratt, P. J.; Jones, R.; Tocher, D. A.;
Sugden, D. J. Med. Chem. 1995, 38, 1132–1139.
8. Maze´as, D.; Guillaumet, G.; Viaud, M. C. Heterocycles
1999, 50, 1065–1080.
In summary, two types of tricyclic azaindolic analogs of
melatonin were investigated. Both reactions involved
5-methoxy-4-azaindole as common intermediates. The
synthesis of 6,7,8,9-tetrahydro-pyrido[2,3-b]indolizine
moiety was easily performed by intramolecular radical
cyclisation. We have now developed a new procedure
leading to the access of the pyridopyrrolo[2,1-b]-
[1,3]oxazine skeleton.
9. (a) Makosza, M.; Danikiewicz, W.; Wojciechowski, K.
Liebigs Ann. Chem. 1988, 203–208; (b) Makosza, M.
Synthesis 1991, 103–111.
10. (a) Moody, C. J.; Norton, C. L. Tetrahedron Lett. 1995,
36, 9051–9052; (b) Moody, C. J.; Norton, C. L. J. Chem.
Soc., Perkin Trans. 1 1997, 2639–2643.
Acknowledgements
11. (a) Gaster, L. M.; Joiner, G. F.; King, F. D.; Wyman, P.
A.; Sutton, J. M.; Bingham, S.; Ellis, E. S.; Sanger, G. J.;
Wardle, K. A. J. Med. Chem. 1995, 38, 4760–4763; (b)
Wyman, P. A.; Gaster, L. M.; King, F. D.; Sutton, J. M.;
Ellis, E. S.; Wardle, K. A.; Young, T. J. Bioorg. Med.
Chem. Lett. 1996, 4, 255–261; (c) King, F. D.; Gaster, L.
M.; Wyman, P. A.; Joiner, G. F. International Patent
Application WO 94/07859, 1994; Chem. Abstr. 1995,
121:157530n.
We are grateful to A.D.I.R. Company (Courbevoie,
France) for its multiform support.
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