Synthesis of sulfur-containing heterocyclic compounds by cyclo-condensation of acetylenic derivatives of anthraquinone with sodium sulfide

Reaction of vic - alkynylchloro-and vic - chloro-(1-oxoalk-2-ynyl)-anthraquinones with Na 2 S in ethanol, with short heating, has been shown to afford anthrathiophenediones and anthrathiopyrantriones, respectively, generally in good yields. Under the same conditions, 1-alkynylanthraquinones also undergo cyclocondensation to give anthra[2,1-b ]thiophene-6,11-diones.


Introduction
Condensed heterocyclic derivatives of quinones are of interest as biologically active substances and technical materials.A variety of such nitrogen-and oxygen-containing heterocycles has been described.There is much less information about sulfur-containing heterocyclic quinoid compounds.At the same time, the introduction of sulfur-containing rings into the structure of compounds often determines their pharmacological properties, [1][2][3] reduces side-effects of drugs, 4 or improves the technical characteristics of materials. 5,6Thus, substituted benzo [b]thiophenes are estrogen-receptor modulators, thrombin inhibitors, anti-tumor and anti-inflammation agents. 1,2,7,8ome of them are currently in pharmaceutical use or development. 7,8n this connection, we considered it reasonable to study synthetic pathways to anthraquinones annelated by thiophene and other sulfur-containing rings.To our knowledge, general methods for the synthesis even of anthrathiophenediones have not been described.0][11][12][13][14][15][16][17][18] One would expect that the same "acetylenic" approach will turn out to be fruitful for the construction of an anthrathiophene system as well.
Recently, a method for synthesis of substituted benzo [b]thiophenes by cyclization of orthomethylthio-and orthobenzylthio(alkynyl)benzenes under the action of electrophilic agents was elaborated. 1,19,20However, its expansion to derivatives of anthraquinone is complicated by the limited availability of the corresponding sulfides.[23][24]

Results and Discussion
In anthraquinone, a chlorine atom, irrespective of its position, possesses a high nucleofugal lability. 25The triple bond in acetylenic derivatives of quinones has an enhanced electrophilicity and readily adds nucleophiles. 26When a halogen atom and an acetylenic substituent are arranged in the same ring of anthraquinone, they mutually activate each other.We supposed that the above chemical peculiarities of these anthraquinone derivatives would make it possible to annelate the anthraquinone nuclei with a thiophene ring by using vicalkynylchloroanthraquinones as key acetylenes and Na 2 S as the simplest cyclizing agent.

Scheme 1
The 1-alkynyl-2-chloroanthraquinones 3a-c bearing the halogen atom in position 2 were condensed with Na 2 S in the same way as the chloroacetylenes 1, and under the same conditions.The yields of the anthra[2,1-b]thiophene-6,11-diones 4a-c were 66-97 %.It is noteworthy that in the 1 H NMR spectra of the anthrathiophenediones 4 the signal of the proton in the βposition of the thiophene ring, which is brought together spatially with the carbonyl group, is shifted to a lower field relative to that of the similar proton in spectra of compounds 2 (∆ δ 1.3-1.4ppm).
Thus, the cyclocondensation of vic-alkynylchloroanthraquinones with Na 2 S is a simple and convenient method for synthesis of angularly fused anthrathiophenediones.
The 4H-anthra [1,2-b]pyran system provides the cyclic skeleton of the aglycones of the natural antitumor antibiotics of the kidamycin group and their biologically active analogs, which are obtained biochemically. 27,28The synthesized 7b,c,f-h are thio-analogs of these compounds.
In the synthesis of the kidamycin antibiotics there is a problem in the construction of the heterocycle bearing chemically sensitive substituents (alkenyl, epoxy, etc.). 27Our cyclocondensation, owing to its mild conditions, gives an opportunity to prepare anthrathiopyrantriones with such labile substituents.The preparation of the alkenylthiopyran 7h (a mixture of Zand Eisomers) from the labile ketone 5h, as well as of the cyclohexenylthiopyran 7f demonstrates the applicability of the developed method for the synthesis of thio-analogs of aglycones of anthrapyrane antibiotics.
The initial step of the cyclocondensation of vicacetylenic derivatives of chloroanthraquinones may be not only the substitution of the chlorine atom but also the addition of Na 2 S to the triple bond.However, the intramolecular addition of Na 2 S, or other S-nucleophiles to alkynylquinones has not been studied.To confirm the possibility of a cyclocondensation pathway beginning with the addition of the cyclizing agent, we carried out the reaction of the 1-alkynylanthraquinones 9b,c with Na 2 S under the conditions of the cyclocondensation.The acetylenes 9b,c were found to react with Na 2 S, but the reaction was not limited to the addition of this nucleophile, and was followed by cyclization of the primary adducts to result in the formation of anthra[2,1-b]thiophene-6,11-diones 4b,c prepared before from the chloroacetylenes 3b,c.The cyclization step of the process seems to be an intramolecular nucleophilic oxidative substitution of the hydrogen atom, the quinone being the oxidant.The yields of the anthrathiophenediones 4b,c were 95 %.Our study of the scope and peculiarities of this reaction is in progress.
In summary, we have shown that condensation of vicacetylenic derivatives of chloroanthraquinones with Na 2 S offers a synthetic pathway to anthraquinones annelated by thiophene and thiopyran rings.