| dc.description.abstract | The thesis entitled “Synthetic Investigations on Steroids — Studies in Dehydrogenation of 6?Methoxy?1?tetralone and Synthesis of Heterocyclic Analogues of Equilenin” is divided into four chapters.
Chapter I
A review of the synthesis of steroids having heteroatoms (viz., oxygen, nitrogen, and sulfur) as part of the steroidal skeleton.
Chapter II
After briefly describing earlier work on the synthesis of equilenin and its heterocyclic analogues, the objectives and the planning of the present investigations are discussed.
Chapter III
This chapter deals with the dehydrogenation of 6?methoxy?1?tetralone (1) with various dehydrogenating agents with a view to preparing 6?methoxy?1?naphthol (2), a useful intermediate for the synthesis of 11?oxa equilenin and other 11?oxa?15,16?diaza steroids.
Since the available methods for its preparation were not satisfactory, autoxidation of tetralone 1 using potassium tert?butoxide in an atmosphere of oxygen was studied. Instead of the expected naphthol 2, a high?melting yellow crystalline solid was obtained and, with the help of IR and UV spectral data, this was shown to be 2?hydroxy?6?methoxy?1,4?naphthoquinone (3). Further studies showed that this constitutes a general reaction for the preparation of 2?hydroxy?1,4?quinone derivatives. The mechanism of this reaction is discussed.
Dehydrogenation of tetralone 1 with 30% Pd/C gave the desired naphthol 2 in ~60% yield, but this method was unsatisfactory for handling large amounts. A similar reaction with palladium black in xylene gave only a poor yield of 2. Since a large number of compounds have been dehydrogenated successfully with quinones, dehydrogenation of tetralone 1 with chloranil was studied; however, the expected naphthol 2 could not be obtained. When the more powerful dehydrogenating agent, tetrachloro?1,2?benzoquinone (4), was used, no naphthol 2 was detected; instead, a greenish?yellow crystalline solid was obtained.
The following data—(i) presence of chlorine, (ii) molecular formula C??H?O?Cl? (M? ion at m/z 416; ^35Cl pattern), and (iii) formation of tetrachlorocatechol on pyrolysis—suggested that this solid could be an adduct of tetralone 1 and quinone 4. Furthermore, depending on the conditions employed for hydrogenation, the adduct gave either a mixture of a phenolic product (?80%) and a ketone, or a mixture of the same phenolic product and an alcohol.
On the basis of UV, IR, and NMR spectral data, the adduct was shown to be 2,2?(tetrachloro?o?phenylene dioxy)?3,4?dehydro?6?methoxy?1?tetralone (5) (Chart A). The structures 6, 7, and 8 were assigned for the ketone, alcohol, and phenol, respectively. Mass spectral fragmentation patterns of these compounds lent additional support to the assigned structures.
A mechanism involving a dehydrogenation–addition sequence via the naphthoxide radical has been proposed for the formation of the adduct (Chart A). According to this mechanism, naphthol 2 and the hydrogenolysis product 8 should furnish the same adduct 5 when treated with quinone 4. In fact, both compounds readily furnished the same adduct 5 under these conditions, thus confirming the mechanism.
The desired naphthol 2 was finally prepared by bromination of tetralone 1, followed by dehydrobromination with either calcium carbonate or a mixture of lithium bromide and lithium carbonate in dimethylformamide.
Chapter IV
This chapter is divided into two sections.
Section A
Describes the synthesis of 8?methoxy?3?cyano?3?methylbenz(h)chroman?4?one (13b) and its attempted conversion to 11?oxa equilenin methyl ether (Chart B).
Michael addition of naphthol 2 to acrylonitrile, followed by Hoesch cyclization of the resulting nitrile, gave chromanone 10 in very good yield. Formylation of 10 furnished the hydroxymethylene derivative 11 in excellent yield. This was converted to the isoxazole 12 by heating with hydroxylamine hydrochloride. Reported conditions for isomerization and methylation of isoxazoles were not applicable here; however, by following a modified procedure, the cyanomethyl chromanone 13 could be obtained in 55–60% yield.
The Stobbe condensation of 13a with dimethyl succinate, carried out with a view to building the D?ring, was not successful; instead, 1?hydroxy?2?naphthoic acid, a base?catalyzed ring?cleavage product, was obtained as the main product. Several unsuccessful attempts to effect the above condensation under a variety of conditions are described.
Section B
Describes the synthesis of 11?oxa?15,16?diaza equilenin derivatives. For this purpose, the synthesis of tricyclic keto ester 15 was undertaken.
Condensation of chromanone 10 with dimethyl oxalate readily yielded the corresponding glyoxylate 14, which, on heating with soft glass powder, gave the keto ester 18. Incidentally, direct carboxylation of 10 with diethyl carbonate was not successful. Several attempts to methylate keto ester 18 to get 15 were unsuccessful; instead, in all cases, the base?catalyzed ring?cleavage product (1?hydroxy?2?naphthoic acid) was isolated as the sole product.
However, the required tricyclic keto ester 15 was prepared in excellent yield by methanolysis of the nitrile 13 with methanol and hydrogen chloride. 11?Oxa?15,16?diaza equilenin derivative 16 was obtained by heating keto ester 15 with an ethanolic solution of hydrazine hydrate dried over CaO for two weeks. A few attempts to reduce the C=N in 16 were unsuccessful.
A few pyrazole analogues of 11?oxa equilenin (19 and 20) were prepared by condensing the corresponding ??diketones 17 with hydrazine hydrate. Condensation of glyoxylate 17 with hydroxylamine hydrochloride furnished the isoxazole analogues of 11?oxa equilenin. Thus, a route to the synthesis of several heterocyclic analogues of equilenin was accomplished. Of the many compounds tested, none showed significant biological activity; however, isoxazole 12b exhibited weak but definite antidepressant activity.
Appendix (Publications)
“A general method of preparation of substituted 2?hydroxy?1,4?quinones”,
T. R. Kasturi and T. Arunachalam, Canadian Journal of Chemistry, 44, 1066 (1966).
“Studies in dehydrogenation of 6?methoxy?1?tetralone — structure of a novel product formed with tetrachloro?1,2?benzoquinone”,
T. R. Kasturi and T. Arunachalam, Canadian Journal of Chemistry (1968) (In Press). | |
