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Behaviour of 1,3-disubstituted-
4,5,6,7-tetrahydrobenzo[c]thiophen-4-ones in the Fischer indole synthesis

Laurent Martarello, Delphine Joseph, Damien Prim and Gilbert Kirsch

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


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


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


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.


  1. J. K. Dalton, S. Demerac, B.E. Elmes, J.W. Loder, J.M. Swan, T. Telei, Aust. J. Chem. 1967, 2715; G. H. Svoboda, G. A. Poore, M.L. Montfort, J. Pharm. Sci., 1968, 1720
  2. L. Chunchaprasert, K.A. Nagaraja Rao, P.V.R. Shannon, J. Chem. Soc. Perkin Trans. 1, 1992, 1779; L. Chunchaprasert, P.V.R. Shannon, J. Chem. Soc. Perkin Trans. 1, 1994, 1765; D. Joseph, L. Martarello, G. Kirsch, J. Chem. Research (M), 1995, 2001; D. Joseph, L. Martarello, G. Kirsch, J. Chem. Research (M), 1995, 2557; L. Martarello, D. Joseph, G. Kirsch, J. Chem. Soc. Perkin Trans. 1, 1995, 2941; L. Martarello, D. Joseph, G. Kirsch, Heterocycles, 1996, 367
  3. W. Steinkopf, I. Poulsson, O. Herdey, Ann., 1938, 128 D. Prim, G. Kirsch, Synth. Commun., 1995, 2449
  4. NG. Buu-Hoï, NG. Hoan, NG. H. Khôi, Recl. Trav. Chim. Pays-Bas, 1950, 1053