A New Pathway to 3-Hetaryl-2-oxo2H-chromenes: On the Proposed Mechanisms for the Reaction of 3-Carbamoyl-2iminochromenes with Dinucleophiles. Molecules 2000

The present account summarizes the author's studies to elucidate the mechanisms of the recently reported rearrangements resulting from inter- and/or intramolecular reactions of 2-imino-2H-chromene-3-carboxamides with different dinucleophiles.


Introduction
The coumarin (2H-chromen-2-one) moiety is often found in natural products [1].In view of the ubiquity of this fragment in a variety of biologically active compounds, the synthesis of various 2Hchromen-2-one analogs is important in gauging their potential as a source of chemotherapeutics [2].As part of our investigations on the reactivity of 3-carbamoyl-2-imino-2H-chromenes [3], we recently introduced a new method for synthesis of 3-hetaryl-2-oxo-2H-chromenes [4].This method was based on the rearrangements of 2-imino-2H-chromene-3-carboxamides into 3-hetaryl-2-oxo-2H-chromenes under the action of dinucleophiles.In this account, results of our studies on clarification of the mechanism of the above-mentioned rearrangements are summarized and exemplified by utilizing anthranilic acid, its derivatives, and arylhydrazides as N-nucleophiles.In order to elucidate the mechanisms of the applied rearrangements, a model system approach based on isolation of stable reaction intermediates or their structural analogs was used.
A method for synthesis of 2-(arylimino)chromenes 19 was recently introduced in our laboratory and it was shown that a variety of 2-(aryl-or alkylimino)-substituted 2H-chromen-2-ones of type 19 could be prepared [3].This method is based on aminolysis of cyclic imido esters and is similar to the reaction of simple imidates with amines [16].This type of reactions should also be similar to the acid hydrolysis of 2-imino-2H-chromenes to 2H-chromen-2-ones which proceeds through the formation of the corresponding benzopyrylium salts [17,18].

Conclusion
The results obtained in the study of the rearrangements of 2-imino-2H-chromene-3-carboxamides with different N-nucleophiles clearly indicate that the reactions studied follow the mechanisms described in Schemes 1 and 5. Finally, this work opened a new avenue for the synthesis of a variety of new 3-hetaryl substituted 2-oxo-2H-chromene derivatives.

General
Melting points (°C) were measured on a Büchi melting point apparatus and are uncorrected.Thin layer chromatography (TLC) was performed on aluminum sheets precoated with silica gel (Merck, Kieselgel 60 F-254). 1 H-NMR spectra were recorded on Bruker WP-100 SY, Bruker DPX-250, Bruker AMX-400 or Varian WXR-400 spectrometers in DMSO-d 6 or DMSO-d 6 -CDCl 3 using TMS as an internal standard (chemical shifts in δ ppm).Mass spectra (MS) were obtained with Finnigan MAT-4615B spectrometer at an ionization potential of 70 eV.Combustion analyses of all compounds synthesized gave satisfactory microanalytical data.Infrared spectra (IR) were recorded in KBr pellets on Nicolet Protege 460 FT-IR or an IBM 486 computer-controlled Specord M-80 spectrometers.
Method C: A solution of 30 (309 mg, 1.0 mmol) in glacial (99.8%) acetic acid (5 mL) was refluxed for 30 min.The mixture was cooled, the yellow precipitate was filtered off, washed with water and recrystallized from DMF/BuOH to afford 201 mg (70%) of 7a.According to 1 H-NMR and IR spectral data as well as the melting points, the products obtained by Methods A, B and C are identical.
Amidines 16a,b were prepared from carbamoyliminochromenes 1a,b and 1-aminopyridone 15 [27] using the reaction conditions described in Method A for the synthesis of 12.

General procedures
Method A: A mixture of 1a or 1b (1.5 mmol) and anthranilic acid 2 (275 mg, 2 mmol) in aqueous (80%) acetic acid (10 mL) was refluxed for 2 h.After the reaction finished, the mixture was cooled and the precipitate was filtered off, washed with water and cold propan-2-ol (2 x 5 mL).The products obtained were recrystallized from an appropriate solvent.
Method B: To a well stirred solution of ethyl 2'-carboxymalonanilate (37) [23] (4 mmol) in ethanol (10 mL) was added an equivalent amount of salicylaldehydes 9a or 9b and a few drops of piperidine as a catalyst.The reaction mixture was stirred at room temperature for ca. 1 day and then poured into water.The products precipitated were filtered off and recrystallized from an appropriate solvent.