Thermal reaction of 3a H ,5 H -thiazolo[5,4-c ]quinoline-2,4-diones – an easy pathway to 4-amino-1 H -quinolin-2-ones and novel 6 H -thiazolo[3,4-c ]quinazoline-3,5-diones

S-(3-Alkyl/aryl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)thiocarbamates 3 were thermally reacted to form 4-hydroxy-1 H -quinolin-2-ones 1 . Under the same reaction conditions, 3a-alkyl/aryl-[1,3]thiazolo[5,4-c ]quinoline-2,4(3a H ,5 H )-diones 4 reacted to yield one of two different types of products, depending on the nature of substituent at the 5 position. Substitution with an alkyl or aryl group produced 4-amino-3-alkyl/aryl-1 H -quinolin-2-ones 5 , whereas the N-5 unsubstituted analogues rearranged to form novel 6 H -thiazolo[3,4-c ]quinazoline-3,5-diones 6 in high yields. The reaction mechanisms for the above transformations are discussed. All new products were characterized by NMR, MS and IR spectra. The structure of 1-butyl-9-methyl-6 H - thiazolo[3,4-c ]quinazoline-3,5-dione 6b was confirmed by single-crystal X-ray diffraction analysis.


Results and Discussion
The starting materials, thiocarbamates 3 and thiazoloquinolones 4, were prepared by tandem hydration/cyclodehydration of thiocyanates 2 according to the general procedure described previously (Scheme 1).We conducted semi-micro experiments to screen for the optimal temperature at which to perform the transformations of compounds 3 and 4. The compounds were heated neat in a melting point apparatus, and the resulting material was analyzed by TLC.Most of the compounds underwent relatively clean conversions in the range of approximately 150-250 °C, whereas at higher temperatures, decomposition to complex mixtures of products occurred.Based on this information, we decided to run the thermal reactions on a preparative scale in refluxing pxylene (138 °C) or cyclohexylbenzene (240 °C).
Thermal reactions of thiocarbamates 3 were conducted in boiling cyclohexylbenzene (Method E).As indicated in Table 1, the starting material was consumed within 5-30 min.5][6] Instead, 4-hydroxy-2H-quinolin-2-ones 1 (Scheme 1, Table 1) were isolated, the formation of which could be explained by S-C bond cleavage, as shown in Scheme 2. We were unable to detect the HNCOS fragment, but since elemental sulfur was isolated as a by-product from the reaction of 3e, its decomposition to sulfur and isocyanic acid may be inferred.As the transformation of thiocarbamates 3 to 4-hydroxy-2H-quinolin-2-ones 1 is of no interest from the synthetic point of view, further work focused on thiazoloquinolinediones 4.  Initial thermal experiments with compounds 4 were conducted in boiling p-xylene (Method D, Table 1, Entries 9, 13, and 17).Because the reaction times were very long and the yields of products were low, we changed the solvent to boiling cyclohexylbenzene (Method E).The thermal reaction of compounds 4 yielded one of two different types of products, depending on the nature of N-5 substituents.In those examples where N-5 substituents were alkyl or aryl groups (4e-h), the reaction products were 4-amino-1H-quinolin-2-ones 5 (Scheme 1, Table 1).Proton and carbon NMR spectra of 5 were similar to those of the corresponding 4-hydroxy-2quinolones 1, with the amino group resonance appearing at approximately δ 6 ppm.In the electron-impact mass spectra of 3a-butyl derivatives 5 (R 2 = Bu), the base peaks corresponded to m/z [M -42] + , and the other peaks of subsequent intensities corresponded to m/z [M -15] + , [M -43] + , and [M -71] + .The base peaks for 3a-phenyl-substituted compounds 5 corresponded to m/z of the [M -1] + ion.
We found that 4-amino-2H-quinolin-2-ones 5 could alternatively be prepared from thiazoloquinolinediones 4 via reduction with zinc in acetic acid (Table 2, Scheme 1, Method F), and both procedures described herein represent new pathways to access compounds of type 5.

Substituents
Reaction time (min) A proposed reaction mechanism that could account for the formation of 5e-h from 4e-h is depicted in Scheme 3. We believe that the C-S bond initially splits in a manner analogous to the decomposition of thiocarbamates 3, as described earlier.Elimination of a sulfur atom from the intermediate A leads to the isocyanate B, which, in turn, transforms to 5 during the isolation workup.This mechanism is supported by the fact that elemental sulfur was isolated as a reaction by-product from the thermal transformation of 4e.The proposed mechanism is at least partly supported by the isolation of side-product 7f from the thermal reaction of 4f (Table 1, Entry 16).Its formation can be rationalized by an intramolecular acylation of the phenyl ring in intermediate B.
Scheme 3. Proposed reaction mechanism for the thermal rearrangement of 4 to 5.
Interestingly, the N-5 unsubstituted thiazoloquinolinediones 4a-d behave differently and do not lead to 4-aminoquinolinones 5.The 13 C NMR spectra of the thermal reaction products show no signals in the region of 77-78 ppm, which corresponds to the region of the sp 3 hybridized carbon atom C-3a in compounds 4. In fact, both the 1 H and 13 C NMR spectra of these products were very similar to those of 2,6-dihydro-imidazo[1,5-c]quinazoline-3,5-diones 4 strongly indicating that the products were thiazolo[3,4-c]quinazoline-3,5-diones 6.In mass spectra, compounds 6 bearing a butyl group at position 3 exhibited base peaks at m/z values corresponding to [M -43] + , and other significant peaks correspond to the ions [M -42] + and [M -71] + .In the case of 6b, the structure was confirmed by single-crystal X-ray diffraction (Figure 1).Crystals of 6b ⋅ DMSO-d 6 were grown by slow evaporation of the solution of 6b in DMSO-d 6 in a stream of nitrogen at 23 °C.and furo[2,3-c]quinoline-2,4(3aH,5H)-diones. 8,9To the best of our knowledge, no compounds of type 6 have been heretofore described in the literature.

Experimental Section
General Procedures.Melting points were determined on a Kofler block or Gallencamp apparatus.IR (KBr) spectra were recorded on a Mattson 3000 Spectrometer.NMR spectra were recorded on a Bruker DPX-300 spectrometer in the respective solvents.Chemical shifts are given on the δ scale (ppm) and are referred to internal TMS.Mass spectra were obtained on a VG-Analytical AutospecQ instrument.Column chromatography was carried out on silica gel (Merck, grade 60, 70-230 mesh) using benzene and then successive mixtures of benzene-ethyl acetate (from the rations of 99:1 to 8:2) as eluent.The course of reaction and also the purity of substances were monitored by TLC (elution systems benzene-ethyl acetate 4:1, and chloroformethanol 9:1 and/or 19:1) on Alugram ® SIL G/UV 254 foils (Macherey-Nagel).Elemental analyses (CHN) were performed with EA 1108 Elemental Analyzer (Fisons Instrument).-h) were prepared from 4-hydroxy-quinoline-2(1H)-ones (1a-h) by general procedure described in the literature. 1

Scheme 4 .
Scheme 4. Proposed reaction mechanism for the rearrangement of 4 to 6.

Table 1 .
Thermal reactions of compounds 3 and 4 (Methods D and E)