Behaviour of 1,3-disubstituted-
4,5,6,7-tetrahydrobenzo[c]thiophen-4-ones in the Fischer indole synthesis
Laboratoire de Chimie Organique
Groupe de Synthèses Organique et Hétérocyclique
Faculté des Sciences, Université de Metz
Ile du Saulcy, 57045 Metz Cedex, France
Graphical abstract
Introduction
Since the discovery of enhanced anticancer activity in
9-hydroxyellipticine compared to ellipticine itself,1 many
compounds have been synthetised to study the effects of different substituents
at other positions or of replacement of the pyridine ring by other heterocyclic
rings on their biological properties.2
In order to obtain new derivatives and analogues of pyrido-cabazoles for
phamacological evaluation, we have decided to replace the pyridine ring by a
thiophene ring to prepare thieno-carbazoles 1 (Scheme 1).
Scheme 1
1a R1= R2= Me, R3= H; 1b R1= R2= Me, R3= OMe; 1c R1= SMe, R2=CO2Et, R3= H; 1d R1= SMe, R2= CO2Et, R3= OMe; 1e R1= SMe R3= H;
1f R1= SMe, R2= H, R3= OMe
Among all the possibilities, the simplest method to obtain compouds
1 appeared to be using a Fischer indole synthesis on
1,3-disubstituted-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one derivatives
2, readilly accessible by known methods (3) (Scheme 2).
Scheme 2
2a R1= R2= Me; 2b R1= SMe, R2= CO2Et;
2c R1= SMe, R2= H
Chemistry
The Fischer indole synthesis, as a one-step procedure, applied to
the thiophene 2a in refluxing acetic acid with phenylhydrazine
hydrochloride did not lead to the expected thieno[a]carbazole 4
described by Buu-Hoï4 but gave the isomeric structure
3 which resulted from a double bond shift from the thiophene nucleus
(Scheme 3).
Scheme 3 Reagents and conditions i: Ph-NHNH3Cl, MeCO2H, reflux, 3 h
The thiophene 2a reacted with para-methoxyphenylhydrazine
hydrochloride in acetic acid to give mainly resinification. The sole isolable
products were obtained as a mixture of compounds 5 and 6 with low yield (Scheme 4). Using other cyclisation conditions (MeOH-HCl), the same
products as before have been isolated but the yield had increased to 56%
(Scheme 4).
Scheme 4 Reagents and conditions i: p-H3CO-Ph-NHNH3Cl, MeCO2H, reflux;
ii: p-MeCO-Ph-NHNH3Cl, MeOH-HCl (100:1), 70 celsius
Compound 5 in a refluxing solution of MeOH-HCl didn't led to 6
but stayed unchanged.
Two other ketones from the same type (2b and 2c) have been used
in the Fischer indole synthesis (Scheme 5). No isomerization has been observed
in any instance, the expected dihydrothieno[a]carbazoles (7 to
10) have been isolated with good yields. The aromatisation of
dihydrogenated compounds by DDQ in benzene led to aromatic compounds 1c to 1d.
Scheme 5 Reagents and conditions i: p-R3-Ph-NHNH3Cl, MeCO2H, reflux; ii:
DDQ, benzene, reflux.
The non-isomerisation of the double bonds in 7 and 8 may be
explained by the presence on the thiophene nucleus of an electron-donating and
an electron-withdrawing group. The presence of only one electron-donating group
did not favour the isomerisation. Only in the case of two methyl groups on the
thiophene, did isomerisation occur each time.
Explanations for this phenomenon are welcome to Gilbert Kirsch
Experimental
General procedure for the Fischer indole synthesis in acetic
acid:
To a well stirred solution of substituted phenylhydrazine hydrochloride
(4.6 mol) in glacial acetic acid (15 ml) at 80 celsius was added dropwise a
solution of the ketone (4.2 mol) in glacial acetic acid. The mixture was heated
at reflux for 3 h and after cooling, added in small portions to cold water
(200 ml) with stirring. Filtration of the solid gave crude product which was
purified by chromatography on silica gel.
General procedure for the Fischer indole synthesis in CH3OH-HCl:
A mixture of substituted phenylhydrazine hydrochloride (4.6 mol) and
the ketone (4.2 mol) in 50 ml of CH3OH/HCl (100:1 v/v) was heated at 70 celsius for 24 h. The solvent was evapored under vaccum and the crude products were purified by chromatography on silica gel.
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