2,3,4,5,6,7,8,9-Octahydro-1H-pyrido[4,3-b]azepines. Synthesis and properties

Full text of DOI:10.1007/s11178-005-0357-x

Russian Journal of Organic Chemistry, Vol. 41, No. 9, 2005, pp. 1402–1403. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 9, 2005,
pp. 1430–1431.
Original Russian Text Copyright © 2005 by Grishina, Esipova, Terent’ev.
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COMMUNICATIONS
Dedicated to Full Member of the Russian Academy of Sciences
N.S. Zefirov on His 70th Anniversary
2,3,4,5,6,7,8,9-Octahydro-1H-pyrido[4,3-b]azepines.
Synthesis and Properties
G. V. Grishina, T. V. Esipova, and P. B. Terent’ev
Faculty of Chemistry, Lomonosov Moscow State University, Vorob’evy gory 1, Moscow, 119992 Russia
e-mail: galinagrishina@yandex.ru
Received June 7, 2005
The synthesis and chemical properties of 1,7-di-
substituted 2,3,4,5,6,7,8,9-octahydro-1H-pyrido[4,3-b]-
azepines were studied. These compounds belong to
a new heterocyclic system containing an endocyclic
enamine fragment. Compounds XIII–XV were synthe-
sized via a series of consecutive reactions including
lithiation of 4-iminopiperidines I–III with lithium
diethylamide, alkylation of lithium salts IV–VI with
1-bromo-4-chlorobutane, nucleophilic substitution of
the chlorine atom in 3-(4-chlorobutyl)imines VII–IX
by iodine, and intramolecular cyclization of 3-(4-iodo-
butyl)imines X–XII to target 1,7-disubstituted pyrido-
[4,3-b]azepinium salts XIII–XV by heating in boiling
acetonitrile. All these reactions were carried out
without isolation of intermediate products VII–XV.
us previously for the preparation of their six-mem-
bered analogs, 1,2,3,4,5,6,7,8-octahydro-1,6-naph-
thyridines [1].
However, no cyclization of intermediate VII (R =
Ph) to desired azepine XVI occurred under the condi-
tions optimal for the synthesis of 1,6-naphthyridines.
We succeeded in obtaining azepinium salt XIII only
via cyclization of the corresponding iodide X which
was prepared by nucleophilic substitution of the
chlorine atom in 1-benzyl-3-(4-chlorobutyl)-4-phenyl-
iminopiperidine (VII) by iodine on heating with NaI in
boiling acetonitrile. 6-Benzyl-1-phenyl-2,3,4,5,6,7,8,9-
octahydro-1H-pyrido[4,3-b]azepine (XVI) was iso-
lated by treatment of salt XIII with alkali. The struc-
ture of enamine XVI was determined on the basis of
the GC–MS data, MALDI spectra (using positive and
We planned to obtain seven-membered enamines
XVI–XVIII according to the procedure developed by
1
negative ion registration), and H and 13C NMR
R
R
R
R
N
N
N
N
Li+
Cl
I
LDA, THF, –35°C
Cl(CH2)4Br, –35°C
NaI, MeCN
N
N
N
N
CH2Ph
CH2Ph
CH2Ph
CH2Ph
I–III
IV–VI
VII–IX
X–XII
O
CH2Ph
CH2Ph
NHR
N
N
OH–
MeCN, Δ, 24 h
+
N
N
N
CH2Ph
R
R
XIII–XV
XVI–XVIII
XIX–XXI
I, IV, VII, X, XIII, XVI, XIX, R = Ph; II, V, VIII, XI, XIV, XVII, XX, R = p-MeC6H4;
III, VI, IX, XII, XV, XVIII, XXI, R = p-MeOC6H4.
1070-4280/05/4109-1402 © 2005 Pleiades Publishing, Inc.

2,3,4,5,6,7,8,9-OCTAHYDRO-1H-PYRIDO[4,3-b]AZEPINES.
1403
tion of previously unknown 1-substituted 3-(4-amino-
butyl)piperidin-4-ones XIX–XXI.
spectra. We also found that compound XVI undergoes
opening of the seven-membered ring during isolation
and chromatographic purification on silica gel to give
3-(4-phenylaminobutyl)-1-benzylpiperidin-4-one
(XIX). Analogous transformations of azepines XVII
(R = p-MeC6H4) and XVIII (R = p-MeOC6H4) into
δ-amino ketones XX and XXI occurred even at
a higher rate. Thus we revealed that newly synthesized
1,7-disubstituted 2,3,4,5,6,7,8,9-octahydro-1H-pyrido-
[4,3-b]azepines XVI–XVIII readily undergo hydrolyt-
ic cleavage of the seven-membered ring with forma-
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 05-03-32658a).
REFERENCE
1. Gaidarova, E.L., Borisenko, A.A., Chumakov, T.I., Mel’-
nikov, A.V., Orlov, I.S., and Grishina, G.V., Tetrahedron
Lett., 1998, vol. 39, No. 42, p. 7767.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 9 2005