Synthesis of fused heterocycles from 2-aryl-5-(chlorosulfonyl)-1,3-oxazole-4- carboxylates and α-aminoazoles involving the Smiles rearrangement

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Introduction
Among a variety of pharmaceutically promising amides of azolesulfonic acids, oxazolesulfonyl amides seem to us particularly interesting.These species have the weakly aromatic oxazole ring capable to hydrolytic cleavage, 1 which may be important for bioactivity associated with the enzyme inhibition.Thus, 1,3-oxazole-5-sulfonyl amide 1 (Fig. 1) is known to be a rare dual cyclooxygenase-2/5lipoxygenase inhibitor.Other promising representatives of 1,3-oxazole-5-sulfonyl amides are those bearing a pronounced electron-withdrawing substituent at position C(4), in particular, compounds 2 and 3 obtained recently from the corresponding 1,5-oxazole 5-sulfonyl chlorides in our laboratory. 3,4One of our research tasks was entering into the sulfonamide grouping of 2 and 3 an electron-deficient heterocyclic substituent R 2 , which increases the acidity of the N-H linkage making a molecule to be easier delivered to the target enzyme like that in the case of the sulfanilamide drugs. 5Recently we reported that the interaction of 4-cyano-1,3-oxazole-5-sulfonyl chlorides with 1H-pyrazol-5-amines and 1H-1,2,4-triazol-5-amine leads to unexpected substitution products, which, nevertheless, are useful for further heterocyclization. 6e aim of the present work was to investigate into products of interaction of 1,3-oxazole-5-sulfonyl chlorides having a methoxycarbonyl group at position C(4) with the aforementioned heterocyclic amines.

Scheme 1. Synthesis of compounds 7 and 8
Despite the fact that a very similar analogy was reported with this reaction, 6 its result requires careful consideration because both endo-and exocyclic aminoazole nitrogen atoms can take part.It is known, for example, that 3-metyl-1H-pyrazol-5-amine as well as 3-metyl-1H-1,2,4-triazol-5-amine react with aromatic sulfonyl chlorides to give mixtures of sulfonyl derivatives. 7,8Nevertheless, the reaction of 4 with 5 and 6 in the presence of triethylamine proceeded quite regioselectively with 76-84% yield of endo-substitution products 7 and 8.The fact that compounds 7 and 8 contain a primary amino group is confirmed by i) two characteristic IR absorption bands relevant to the asymmetric and symmetric N-H stretching from 3500-3200 cm -1 , ii) a two proton NMR singlet at 6.5 ppm (for 7) and within 7.8-7.5 ppm (for 8).X-ray crystal analysis of 7c and 8b was also carried out, which revealed their additional structural stabilization due to an intramolecular NH2•••O2S hydrogen bond (Fig. 2 and Fig. 3).As for the mechanism, anion-intermediates A-D are conceived, from which sequence A-C is a new example of the N -S Smiles rearrangement with the sulfur dioxide extrusion. 9oducts 9 and 10 were obtained in 60-75% yield and are very high melted and poorly soluble solids.Their structure was verified by the spectral data, among which it is worth mentioning the strong IR absorption in the region 1680-1720 cm -1 attributed to C=O bond vibration.This characteristic allows excluding the existence of 9 and 10 in the OH tautomer form in the solid state.However, they can exist in different NH tautomer forms (9, 9' and 10, 10', 10").X-ray diffraction study of compound 10c showed that the [1,3]oxazolo [5,4-d][1,2,4]triazolo[1,5-a]pyrimidin-9(5H)-one structure 10" takes place in a crystal (Fig. 4).We did not study the tautomerism in a solution.In the 1 H NMR spectra of 9 and 10 dissolved in DMSO-d6, the NH signal was not detected but multiplets analysis indicated the presence of the only tautomer.It should be noted that the elimination of MeOH is, apparently, a rate-determining stage of the transformation A→D.We found that if compounds 7b,c are heated with NaH in THF for only 30 min, the Smiles rearrangement products 11b,c are allowed to be isolated in 62-65% yield after acidifying the reaction mixture (Scheme 3, one of the two possible tautomers of 11 is shown).These later cyclize into 9b,c on further heating with NaH in THF.This observation along with the above crystallographic evidence supports the cyclocondensation pathway shown in Scheme 2 and doubts on the alternative possibility depicted in Scheme 4.

Scheme 4. An alternative cyclocondensation pathway
Theoretically anions A could eliminate MeOH to give 7 membered cyclic intermediates E.An analogy of this cyclization has been reported. 10Anions E could undergo ring contraction to give anions F. The protonation of the latter could lead to the angular regioisomers of tricyclic compounds 8 and 9, which in fact were not found during the experiment.

Conclusion
In conclusion, described in the article cyclocondensation reaction of esters 7 and 8 under the action of NaH the Smiles rearrangement with extrusion of SO2 does occur followed by the elimination of MeOH.This reaction sequence is a convenient approach to the synthesis of new "a" annulated [1,3]oxazolo [5,4-d]pyrimidine derivatives.

Instruments, Reagents, and Methods
Melting points were determined on a Fisher-Johns apparatus.IR spectra were recorded on a Vertex-70 spectrometer from KBr pellets. 1 H and 13 C NMR spectra were recorded on Varian Mercury 400 (400 and 100 MHz, respectively) and Bruker Avance DRX 500 (500 and 125 MHz, respectively) spectrometers in DMSO-d6. 13C NMR spectra were obtained for most new compounds, except for 9ac and 10a,b because of their poor solubility.LC-MS analysis was performed on an Agilent 1200 Series system equipped with a diode array and a G6130A mass-spectrometer (atmospheric pressure electrospray ionization).Combustion elemental analysis was performed in the Institute of Bioorganic Chemistry and Petrochemistry analytical laboratory.
Crystallographic measurements were performed on a Bruker Smart Apex II diffractometer operating in the  scan mode using Mo-K radiation with  = 0.71078 Å. Structures were solved by direct methods and refined by the full-matrix least-squares technique in the anisotropic approximation for non-hydrogen atoms using the Bruker SHELXTL program package. 11The carbon-linked hydrogen atoms were placed at calculated positions and refined as a "riding" model, the other hydrogen atoms were located in DF synthesis and refined isotropically.Crystallographic data (excluding structure factors) for the structures in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers CCDC1834792, CCDC1834794, and CCDC1834796.Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.Uk).

Experimental procedure and physical data for compounds 7 and 8
Compound 4 (4 mmol) was added to a solution of heterocyclic amine 5 or 6 (4 mmol) and Et3N (4 mmol) in anhydrous dioxane (15 mL), this composition was refluxed for 2 h.The resulting mixture was cooled to 20-25 °C, the precipitate was filtered off, and the filtrate was evaporated in vacuum.The residue was triturated with water to give a crude product which was separated, recrystallized from MeCN, and dried at 70-80 °C.

Experimental procedure and physical data for compounds 10
To a solution of compound 8 (1 mmol) in anhydrous THF (15 mL), 80 mg of 60% NaH (2 mmol) was added.The reaction mixture was stirred at 20-25 °C for 1 h then heated at 50-60 °C for 2 h, cooled to room temperature, diluted with water (20 mL), and acidified by the concd hydrochloric acid (0.2 mL).The precipitate formed was filtered off, recrystallized from DMF/MeCN (1:1), and dried at 70-80 °C to give the analytically pure product.