Карцев В.Г.Избранные методы с-за и модифик. гетероциклов т.1 , 2003

Table 1. Continued

Scheme 2

a: HCONMe2, POCl3, ∆, 80°C

b: HCONMe2, POCl3, Cl2CHCHCl2, ∆, 80°C

c: MeCONMe2, POCl3, ∆, 80°C

The validity of this new quinoline synthesis was further evaluated by performing the Vilsmeier reaction on bisketene-N,S-acetals 4, 6 and 8 with a view to synthesize planar tricyclic and tetracyclic heterocyclo fused quinolines (Scheme 3). Thus the biske- tene-N,S-acetal 4 from m-phenylenediamine gave corresponding angularly fused azaphenanthridine 5 in 48% yield, while corresponding linearly fused bisquinoline could not be isolated from the reaction mixture. Bisketene-N,S-acetal 6 from o-phenylenediamine however required drastic conditions (POCl3/DMA/TCE, 130°C), and the product isolated after workup was characterized as 2-methythio-9-hydroxy-4,7-diphenylphenanthroline 7 on the basis of its spectral and analytical data. In the absence of any activation at the site of cyclization with Vilsmeier reagent, intramolecular Combe's type cyclization of the enaminone functionality is the preferred cyclization mode to yield the observed product 7 [4]. Bisketene-N,S-acetal 8 from 1,5-diaminonaphthalene underwent smooth cyclization with Vilsmeier reagent to afford 2,8-bis(benzoyl)-3,9-bis(methylthio)quinolino[8,7-b]- quinoline 9 in 60% yield (Scheme 3).

Scheme 5

Quinolines 2a, c, i were next subjected to annelation reaction with hydrazine hydrate with a view to synthesize pyrazolo[3,4-b]quinolines 17a, c, i which are known to exhibit various biological activities such as antiviral, antimalarial and lowering of serum cholesterol [6]. Recently, 3-phenylpyrazolo[3,4-b]quinoline-4-one has been shown to display pH dependent fluorescent properties for extreme pH measurement [7]. Thus, reaction of 2c with hydrazine hydrate afforded hydrazone 18c in nearly quantitative yield. Hydrazone 18c failed to undergo cyclization to pyrazolo[3,4-b]quinoline 17c even after prolonged refluxing, which is presumably due to adoption of unfavorable E-configuration. However, pyrazoloquinolines 17a, c could be obtained directly from corresponding quinolines 2a, c in high yields by reacting them with hydrazine hydrate under microwave irradiation conditions [6]. Similarly, synthesis of corresponding tetracyclo-10H-benzo- [h]pyrazolo[3,4-b]quinoline 17i could be achieved from benzo[h]quinoline precursor 2i following a similar procedure (Scheme 6). Many of these pyrazolo-fused benzo[h]quinolines are shown to bind with DNA inhibiting topoisomerase I activity [8].

Initially formed o-benzoyl radical 19 undergoes radical translocation [9] by attack on the methylthio group to give radical intermediate 20 which, on loss of methyl radical, affords benzothiopyrano quinolines 18b and 18d in excellent yields.

Conclusions

We have developed a simple, highly efficient and regioselective synthesis of functionalized 2-methylthio-3-substituted quinolines through Vilsmeier cyclization of a variety of α-oxoketene-N,S-acetals. The 2-methylthio functionality in these quinolines has been further manipulated to afford either 2-alkyl/arylamino quinolines, pyrazolo[3,4-b]quino- lines and benzothiopyrano[b]quinolines through ring annelation with hydrazine hydrate or via radical cyclization.

References

1.(a) Junjappa H., Ila H., Asokan C.V., Tetrahedron 1990 46 5423, Tetrahedron Report No. 278; (b) Tominaga Y., J. Heterocycl. Chem. 1989 26 1167; (c) Ila H., Junjappa H., Mohanta P.K., in Progress in Heterocyclic Chemistry, Gribble G.W., Gilchrist T.L., Eds., Oxford: Pergamon Press, 2001, vol. 13, p. 1.

2.Mahato P.K., Venkatesh C., Syam Kumar U.K., Ila H., Junjappa H., J. Org. Chem. 2003 69 (in press).

3.Singh O.M., Junjappa H., Ila H., J. Chem. Soc. Perkin Trans. 1 1997 356.

4.Jones G., in Comprehensive Heterocyclic Chemistry II, Katritzky A.R., Rees C.W., Scriven E.F.V., Eds., Oxford: Pergamon Press, 1996, vol. 5, p. 167.

5.Kim D.W., Choi H.Y., Lee K.-J., Chi D.Y., Org. Lett. 2001 3 445.

6.Paul S., Gupta M., Gupta R., Loupy A., Tetrahedron Lett. 2001 42 3827.

7.Su M., Liu Y., Ma H., Ma Q., et al., Chem. Commun. 2001 960.

8.Kerry M.A., Boyd G.W., Mackay S.P., Meth-Cohn O., Platt L., J. Chem. Soc. Perkin Trans. 1 1999 2315.

9.Ooi, T., Furuya M., Sakai D., Hokke Y., Maruoka K., Synlett 2001 541.

–бромирование 1 бромом в ледяной уксусной кислоте позволяет получить 7-бромпроизводное 8 [3].

Схема 2

При взаимодействии 1 с P4S10 образуется трудноразделимая смесь продуктов. Реакция сопровождается сильным осмолением. В то же время, замещение амидного кислорода на серу легко осуществить в две стадии (схема 3):

1)синтез 4-хлорпроизводного 7,

2)реакция 7 с тиомочевинной в бутаноле (или изопропаноле) с последующим разложением изотиурониевой соли 9 без ее выделения дает тион 10 [5].

Схема 3

Конденсация лактонов 1 и 10 с ароматическими и гетероароматическими альдегидами в кипящем бутаноле в присутствии вторичных аминов приводит к образованию илиденпроизводных 11 с хорошими выходами [5, 6] (схема 4).