Novel synthesis of the pyrrolo[2,1-c][1,4]benzodiazocine ring system
via a Dieckmann condensation
Konstantina Koriatopoulou, Nikolaos Karousis, George Varvounis
*
Department of Chemistry, University of Ioannina, GR-451 10 Ioannina, Greece
article info
Article history:
Received 7 May 2008
Received in revised form 25 June 2008
Accepted 10 July 2008
Available online 15 July 2008
Keywords:
Pyrroles
Oxidation
Dieckmann condensation
Pyrrolobenzodiazocine
abstract
A novel four-step synthesis to the pyrrolo[2,1-c][1,4]benzodiazocine ring system is described. 1H-Pyrrole-
2-carbaldehyde was alkylated with ethyl or methyl bromoacetate and the resulting ethyl or methyl
(2-formyl-1H-pyrrol-1-yl)acetates oxidised with potassium permanganate to the corresponding 1-[(2-
ethoxy or methoxy)-2-oxoethyl]-1H-pyrrole-2-carboxylic acids. The latter was converted into their acid
chlorides by reaction with thionyl chloride and without isolation transformed into the respective methyl
2-({[1-(2-ethoxy or methoxy-2-oxoethyl)-1H-pyrrol-2-yl]carbonyl}amino)benzoates by reaction with
methyl anthranilate. Dieckmann condensation of methyl 2-({[1-(2-methoxy-2-oxoethyl)-1H-pyrrol-2-
yl]carbonyl}amino)benzoate provided the pyrrolo[2,1-c][1,4]benzodiazocine.
Ó 2008 Published by Elsevier Ltd.
1. Introduction
The addition of medium-sized rings containing two nitrogen
atoms as substituents in biologically active compounds is known
to increase the pharmaceutical potency of the compounds. One
example is the diazocine ring. The tethering of octahydro-1,4-diazo-
cines to guanidine has produced derivatives of superior anti-hy-
pertensive activity to that of guanidine.
1
Several methods have been
employed for the synthesis of 1,4-diazocines. Sarges and Tretter
2
treated methyl
b
-bromomethyl-cinnamate with N,N
0
-dimethyl-
ethylenediamine to give 1,4-dimethyl-2-phenylpiperidine-2-acetic
acid methyl ester, which, after hydrolysis to the corresponding acid
and treatment with triethylamine and dicyclohexylcarbodiimide,
was transformed into 1,4-dimethyl-7-phenyl-1,2,3,4-tetrahydro-
1,4-diazocin-5(8H)-one. The 7-naphthyl derivative was prepared
analogously. 1,4-Dibenzyl-octahydro[1,4]diazocine was prepared
by condensing N,N
0
-dibenzylethane-1,2-diamine with 1,3-dibromo-
propane.
3
The first aromatic 1,4-diazocine derivatives were
synthesised by Vogel and co-workers
4
in 1979. 3,8-Dioxatri-
cyclo[5.1.0.0
2,4
]octane was transformed into 3,8-bis(methylsul-
fonyl)-3,8-diazatri-cyclo[5.1.0.0
2,4
]oct-5-ene, which was thermally
ring expandedto 1,4-bis(methylsulfonyl)-1,4-dihydro-1,4-diazocine
and the methylsulfonyl groups removed with potassium in liquid
ammonia to give the 1,4-dihydro-1,4-diazocine. NMR spectroscopy
and X-ray crystallography used to prove the 10
p
electron aromatic
character of these compounds. 3,8-Diazatricyclo[5.1.0.0
2,4
]octanes
were prepared from cis-benzenetriimine by N,N
0
-disubstitution,
nitrosation and N
2
O-elimination reactions. Their [
p
2sþ
s
2sþ
s
2s]
cycloreversion to 1,4-dihydro-1,4-diazocines occurred at low
temperature.
5
Reduction of N,N
0
-[(1E,2E)-1,2-diphenylethane-1,2-
diylidene]dianiline with sodium to the corresponding dianion
followed by substitution of 1,4-dichlorobutane gave directly
1,2,3,4-tetraphenyl-1,4,5,-6,7,8-hexahydro-1,4-diazocine. Three more
tetraaryl derivatives were synthesised in this manner.
6
So far, three pyrrolobenzodiazocine ring systems are known.
Derivatives of 6,11-dihydropyrrolo[1,2-b][2,5]-benzodiazocine were
obtained by heating 1-{2-[(acyl-amino)methyl]benzyl}pyrroles
with phosphoryl chloride.
7
(2-Nitrophenyl)acetyl chloride, gener-
ated in situ from (2-nitrophenyl)acetic acid and thionyl chloride, was
reacted with proline or 3-hydroxyproline to give (4-unsubstituted
or 4-hydroxy)-1-[(2-nitrophenyl)acetyl]proline that was selectively
reduced to the aniline analogue. The latter was cyclised with dicyclo-
hexylcarbodiimide to give (2-unsubstituted or 2-hydroxy)-1,2,3,6,-
11,12a-hexahydropyrrolo[2,1-c][1,4]benzodiazocine-5,12-dione.
8
[(3-Acetyl or 3-propionyl)-2-methyl-5-(2-nitrophenyl)-1H-pyrrol-
1-yl]-acetic acid underwent catalytic hydrogenation and the
5-amino derivative was cyclised by thionyl chloride to give (2-acetyl
or 2-propionyl)-3-methyl-5,6-dihydropyrrolo[1,2-e][1,5]benzodi-
azocin-7(8H)-one.
9
2. Results and discussion
We have previously described the synthesis of 4,5-dihy-
dropyrrolo[1,2-b][2,5]benzodiazocin-6(11H)-imine or 6(11H)-one
*
Corresponding author. Tel.: þ30 26510 98 382; fax: þ30 26510 98 799.
E-mail address: gvarvoun@cc.uoi.gr (G. Varvounis).
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.07.029
Tetrahedron 64 (2008) 10009–10013