Palladium-catalyzed synthesis of novel tetra-and penta-cyclic biologically active benzopyran-and pyridopyran-containing heterocyclic systems

Syntheses of novel tetra-and penta-cyclic benzopyran and pyridopyran derivatives, via direct intramolecular arylation of 2-iodophenoxymethylhetarenes and 3-(2-bromo-pyridin-3-yloxymethyl)-benzo[4,5]imidazo[2,1-b ]thiazole in the catalytic system Pd(OAc) 2 / Xantphos / Cs 2 CO 3 / Ag 2 CO 3 in toluene, and a one-pot bicatalytic method for 12 H - [1]benzopyrano[3′,4′:4,5]thiazolo[3,2-a ]benzimidazole directly from 3-chloro-methylbenzo[4,5]imidazo[2,1-b ]thiazole and 2-iodophenol, are described. This latter compound exhibits high cytotoxicity (MG-22A , 6 μg/mL) on the mouse hepatoma cancer cell line and low toxicity (LD 50 , 1058 mg/kg) on the mouse Swiss albino embryo fibroblasts 3T3.

7][18][19] Regioselective functionalization of the imidazole ring by transition metal-catalyzed C-N and C-C bond formation was reported in details by Rossi et al. 20 Interestingly, that the pyrano[3′,4′:4,5]imidazo [1,2-a]pyridin-1-one ring system has been constructed by Cu(I)catalyzed cross-coupling and heterocyclization reactions of halogenated imidazopyridinecarboxylic acids in the presence of terminal alkynes. 21][24] Furthermore, the synthesis of tetra-and penta-cyclic imidazolo-and thiazolo-benzopyran derivatives has not been investigated until now and so is the main aim of the present work.Beside this, selected stable compounds (4a, 10 and 13) were tested as cytotoxic agents.

Scheme 1
The influence of catalyst, ligand and additive on the intramolecular Heck-type cyclization was studied in detail.Initially, we examined direct intramolecular arylation of 2-iodophenoxymethylhetarene 3a using 10 mol.%Pd(PPh3)4 as catalyst and 2 eq.Cs2CO3 as base.No product was found under these conditions.The use of the system 10 mol.%Pd(OAc)2 / 20 mol.% Xantphos / Cs2CO3 (2 eq.) / toluene provided the polycycle 4a in a low (17%) yield with 55% conversion.The high activity of Ag2CO3 as an additive in Rh-catalyzed arylation of hetarenes was recently demonstrated. 25The addition of 0.5 eq.Ag2CO3 to the system Pd(OAc)2 (10 mol.%) / Xantphos (20 mol.%) / Cs2CO3 (2 eq.) / toluene furnished the desired product 4a in improved (69 %) yield with full conversion of the starting material 3a.All catalytic systems in the presence of Ag2CO3 were more active.

Scheme 2 Scheme 3 Scheme 4
The structure of compound 13 was confirmed by X-ray structural data.Needle like crystals of compound 13 suitable for intensity measurement were grown from chloroform.The entire molecule of polycycle 13 is essentially planar (Figure 1).The maximal deviation from the least squares mean plane drawn through all non-hydrogen atoms of the molecule is 0.398(2) Ǻ for the O5 atom.The molecule contains four condensed rings, the 1,3,4-thiadiazole (A), imidazole (B), pyran (C) and benzene (D).Rings A, B and D are planar within 0.002Ǻ, 0.002 Ǻ and 0.01Ǻ respectively.The pyran ring (C) adopts a twist-half-chair conformation where atoms C6, C6a, C10b and C10c form a strict plane (±0.005Ǻ), while the O5 and C4a atoms deviate from this plane by 0.564(4)Ǻ and 0.258(4)Ǻ respectively.The thiadiazolo-imidazole system (A+B) forms a dihedral angle of 9.5(1)º with the benzene ring (D).
Bond lengths in compound 13 are in good agreement with the crystal structure of methyl 2-chloro-8-oxo-6H,8H- [1]    2).Compound 4a exhibit high activity on the mouse hepatoma (MG-22A, 6 μg/mL) cancer cell line.However, on the human fibrosarcoma cell line this compound is essentially inactive.Polycyclic compound 10 exhibit middle activity on both cancer cell lines.Compound 13 is inactive on the MG-22A and HT-1080 cancer cell lines.Interestingly, that toxicity of compounds 4a, 10 and 13 (LD50, 1058-1487 mg/kg) detected on the mouse normal fibroblasts is not high.

Experimental Section
General. 1 H and 13 C NMR spectra were recorded on a Varian Mercury BB 400 MHz in CDCl3 using HMDSO as internal standard.LC-MS spectra were recorded on Alliance Waters 2695 instrument and Waters 3100 mass detector.Column chromatography was performed with silica gel 0,035-0,070 nm (Acros).X-Ray diffraction data was collected using Nonius KappaCCD single crystal diffractometer (Bruker AXS) (MoKα 1 -radiation, graphite monochromator).The structure was solved by SIR2004 28 and refined by SHELXL97 29 programs.Rms deviation of fitted atoms = 0.0066.3-Chloromethylbenzo [4,5] 3,4]thiadiazole (11) were obtained by the procedure described in article. 24All prepared compounds are new and were characterized by melting point, LC-MS, HRMS, 1 H NMR and 13 C NMR spectra.

Figure 1 .
Figure 1.View of the molecule 13 with atomic numbering and ring labels.

Table 1 .
Crystal data of the compound 13