2-Oxiranecarbonitriles in the synthesis of linked quinono heterocyclic derivatives

Alkyl protected equivalents of hydroquinono-2-oxiranecarbonitriles 3 were prepared and applied in the synthesis of thiazolinone 5 and 7 , thiazole 8 and oxathiole 9 derivatives directly linked to the precursor of the quinonic part of the molecule. The synthesis of 2-[(1,4-naphthoquinolyl)amino]thiazole derivatives 11 is also reported.


Introduction
The importance of 2,2-dicyanooxiranes and 2-cyano-2-alkoxycarbonyloxiranes as intermediates in organic synthesis has been extensively investigated. 1Because of their multifunctional structure they proved to be versatile reagents in the synthesis of a large variety of carbocyclic, heterocyclic or acyclic derivatives.In general, nucleophilic reagents can react with 2cyanooxiranes regioselectively: they can attack the oxirane ring, cyano or alkoxycarbonyl functional group to give either ring opened products, new functionalised oxiranes or different heterocycles.Ring opening can be achieved with a variety of heteroatomic nucleophiles and their attack is followed by hydrogen cyanide elimination to give through non stable cyanohydrine and cyanoformyl intermediates among others also α-ketoesters or α-ketoamides (pyruvamides) 2,3 .In acidic conditions with halohydric acids α-haloketone analogues are formed.The bielectrophilic nature of 2-cyanooxiranes and their α-haloketone derivatives enables formation of a variety of heterocyclic compounds of pharmaceutical interest such as thiazoles, 4,5 dithioles, 6 imidazoles, 7 1,3-oxathioles, 8 1,3-oxaselenoles 9 and condensed imidazolo and thiazolo derivatives. 10n the other hand, quinonic compounds are ubiquitous in nature 11 and implicated in numerous cellular functions involving mechanisms of electron and hydrogen transfers. 12Some natural or synthetic quinonic derivatives are widely used as drugs for treatment of human cancer 13,14 or antibacterial drugs 15 , they also exhibit antimalarial 16 and antifungal 17 activity.Aminoquinones represent as well an important group of biologically active compounds involved in enzyme inhibition, DNA cross-linking, antibacterial, antifungal and anticancer activity. 18The need for a variety of quinonic compounds and libraries of such materials for different biological testing prompted us to plan the synthesis of multifunctional starting material from which a large variety of quinonic derivatives might be prepared.
In this publication we present the synthesis of several alkyl protected equivalents of hydroquinono-2-oxiranecarbonitrile and their further transformation into heterocyclic derivatives directly linked to the precursor of the quinonic part of the molecule.The synthesis of aminoquinonic derivatives is also reported.

Results and Discussion
2-Oxiranecarbonitrile reagents 3 were prepared in a two-step procedure outlined in Scheme 1.We chose starting 2,5-dimethoxy-or 3,4,5-trimethoxy-benzaldehyde 1 as alkyl protected equivalent of quinonic part of the molecule.According to the Knoevenagel procedure 19 it reacted with malononitrile derivatives in the presence of catalytic amount of piperidine.Styryl derivatives 2 were formed in high yields after condensation at room temperature. 1H NMR analysis of a crude product obtained in the reaction between 2,5-dimethoxybenzaldehyde 1a and ethyl cyanoacetate revealed formation of only one geometric isomer, according to the crystal structure determination, 20 E-styryl isomer 2c.Our result is in accordance with literature data. 19n the second step alkenes 2 were treated with an aqueous solution of sodium hypochlorite causing oxidation of the double bond and yielding oxiranes 3. Due to electron donating methoxy substituents on the phenyl ring reaction is highly pH sensitive.With variation of pH of the reaction medium and concentration of sodium hypochlorite solution two different products were obtained from 2-[(2,5-dimethoxyphenyl)methylen]malononitrile 2a.Selective formation of oxirane ring proceeded in a reaction medium with pH 8-9 (compounds 3a, 3b) and 3% solution of sodium hypochloride.This is in contrast to the previously published synthesis of 3-aryl substituted oxiranes with electron withdrawing groups attached on the phenyl ring, needing acidic medium for their formation. 21,22In acidic medium oxidation of the double bond was accompanied with electrophilic aromatic chlorination yielding compund 3c.Three methoxy substituents facilitate accompanying electrophilic aromatic chlorination even in basic medium (pH > 9).2-Cyanooxiranes 3 were further applied in the preparation of the heterocyclic compounds directly linked to the precursor of the qouinonic part of the molecule.In the reactions with thiourea derivatives presented in Scheme 2 and 3 the bielectrophilic nature of cyanooxiranes was exploited.

CN
Simple stirring of 2,2-dicyanooxirane reagents 3a and 3d with thioureas 4a, 4b and 4c in acetonitrile at room temperature gave thiazolinone derivatives 5 in yields ranging between 36 % and 70 % for purified products.The structure of products was determined by IR, 1 H NMR, 13 C NMR, mass spectra and elemental analysis and comparison with previously published results. 5 1  NMR and 13 C NMR spectra of thiazolinones 5a-d in the solution of DMSO-d 6 revealed only one set of signals suggesting existence of only one tautomeric form under this condition.A peak in 1 H NMR appearing as singlet at δ between 5.3-6.0 ppm for the cyclic sp 3 CH structural element and a signal at δ 172.7-181.0ppm for carbonyl group in 13 C NMR suggest existence of thiazolinone tautomeric form 5A in DMSO-d 6 solution.The C=O absorption band observed between 1680-1720 cm -1 in IR (KBr) spectra indicates the same tautomeric form 5A also in the solid state.Structure of the compound 5a was confirmed by X-ray analysis determined 2aminothiazolinone form in the solid state (Figure 1). 23On the contrary, 1 H NMR and 13 C NMR spectra for the compounds 5e and 5f, in solution in DMSO-d 6 indicate equilibrium between thiazolinone 5A and 4-hydroxythiazole 5B tautomeric forms.In the 1 H NMR spectra of both compounds two sets of signals were observed for all the protons exept for cyclic CH structural element at the position 5 which appears as a singlet at δ 5.3-5.5 ppm and OH at δ 11.7-11.9ppm.The ratio between tautomeric forms 5A and 5B in the compound 5e is 1.3:1 and 5f 1.7:1.
Treatment of 2,2-dicyanooxirane 3a with thiohydantoin in acetonitrile at room temperature yielded imidazo[2,1-b]thiazol-3,6-dione derivative 7.This results from heterocyclisation of the more nucleophilic nitrogen atom with cyanoformyl intermediate 6. 1 H NMR and 13 C NMR spectral analysis of the product is in good agreement with literature data. 5,24 CN 2-Cyano-2-oxiranecarboxylate 3b is less reactive than corresponding 2,2-dicyanooxirane analogues.Reaction between compound 3b and thiourea 4a proceeded at reflux in acetonitrile and afforded 2-aminothiazole 8 in 49 % yield.The structure of the product was confirmed by Xray diffraction study. 23nvestigating the synthesis of new quinono-heterocyclic systems we used also synthetic strategy described by Breslow et al. for the preparation of 1,3-oxathiole derivatives. 25We performed a reaction between 2,2-oxiranedicarbonitrile reagents (3a, 3d) and potassium thiocyanate in acetic anhydride at room temperature and isolated 2-acetylimino-1,3-oxathiole derivatives 9 as confirmed by spectroscopic methods and C, H, N microanalysis (Scheme 4).The reaction presumably proceeds through thiocyanate attack on position 3, ring-opening to cyanhydrin intermediate A, formation of oxathiolane intermediate B which is finally trapped by Ac 2 O to yield 1,3-oxathioles 9. 8

Scheme 4
The prepared di-and trimethoxyphenyl heterocyclic systems 5, 7, 8 and 9 are now the subject of our further study focusing on the development of a method for the efficient dealkylation and transformation into connected quinono-heterocyclic systems.
As aminoquinonic compounds too present considerable interest 18 we studied also the synthesis of heterocyclic compounds connected to quinono subsistent through an amino spacer group.Aminothiazole derivatives 5a and 8 were treated with 2,3-dichloro-1,4-naphthoquinone 10 in solution in DMF and presence of one equivalent of potassium carbonate (Scheme 5).Reaction resulted in the substitution of one chlorine atom and afforded 2-[(3-chloro-1,4naphthoquinolyl)amino]-1,3-thiazoles 11 in reasonable yields.It is interesting to note that the compound 11b undergoes a dramatic change of color with a change of the pH of medium.While it exhibits red color in the acidic medium it changes to deep blue color in the basic medium.This is probably due to formation of a highly conjugated resonance-stabilized anionic form 12B. 26,27 In the case of compound 11a such phenomena were not observed.In conclusion, we developed a simple synthetic approach towards linked quinonoheterocyclic systems.We prepared a series of alkyl protected equivalents of hydroquinono-2oxiranecarbonitriles which proved to be versatile reagents for the synthesis of thiazoline, thiazole and oxathiole derivatives.Transformation of di-and trimethoxyphenyl substituted heterocycles systems into connected quinono-heterocyclic systems is under investigation.As extension of our study we also prepared naphthoquinolylamino-1,3-thiazole derivatives where heterocyclic core is connected to quinono subsistent through an amino spacer group.

Experimental Section
General Procedures.Melting points were determined with Kofler hot stage apparatus.The 1 H NMR spectra were recorded on a Bruker Avance DPX 300 (300 MHz) spectrometer with CDCl 3 and DMSO-d 6 as solvents and TMS as internal standard. 13C NMR spectra were obtained on a Bruker AM 300 spectrometer at 75 MHz with CDCl 3 and DMSO-d 6 as solvents and TMS as internal standard.Mass spectra were performed on an Autospec Q spectrometer.The microanalyses for C, H and N were obtained on a Perkin-Elmer Analyser 2400.IR spectra were determined with Perkin-Elmer 225 or 1420 spectrometer.All starting materials were commercially available (in most cases from Fluka).