Synthesis of novel heterocyclic fused pyrimidin-4-one derivatives from imino-1,2,3-dithiazoles

Extending the potential applications of 4,5-dichloro-1,2,3-dithiazolium chloride chemistry, we investigated the synthesis of original derivatives of thieno[2,3-d ]pyrimidin-4-one system by condensation of alkyl and aromatic diamines with 2-N -iminodithiazolothiophene derivatives. We continued our study for access to novel pyrazolo-and pyrido-fused pyrimidinones using the potential applications of Appel’s salt chemistry

For the reason given above, we have investigated the synthesis of novel thieno[2,3-d]pyrimidinone derivatives using the potential applications of Appel's salt chemistry.
Considering our previously published results 27,28 and those from Kim's group, 25,26 we decided to investigate the reaction of the new iminodithiazole with ethylenediamine and o-aminobenzylamine in order to access to original structures containing thieno [2,3-d]pyrimidin-4-one ring.We discovered that stirring imine with ethylene diamine in THF at low temperature allowed the rapid synthesis of the original heterocyclic skeleton (4) (10% yield) accompanied by a large amount of the cyanothioformamide (5) (63%).Considering the previous results published by our team, 27,28 the most plausible mechanism of the reaction implied existence of a key intermediate (VI) and a final nucleophilic attack of the primary amino group of ethylene diamine on the carbonitrile carbon to generate the cyclic amidine (Scheme 3).Pursuing our strategy, the iminodithiazole precursor (3) was heated under microwaves irradiation (at 120°) with o-aminobenzylamine and yielded 7% of new pentacyclic skeleton (6) and a mixture of two other products which were identified as the new 2-thiocarboxamidothiophene (7) (22%) and the known cyanothioformamide (5) (11%).
It should be noticed that the resulting product ( 6) was difficult to isolate and the yield was quite low (7%), showing the difficulty for the intermediate to cyclize.Herein, formation of the pentacylic core (6) suggested nucleophilic substitution of the cyano group of the intermediate (VII) by the o-aminobenzylamine (Scheme 4).Scheme 4. Synthesis of the novel pentacyclic thieno[2,3-d]pyrimidinone system (6).
In continuation of this work, we attempted to isolate the methyl 2-N-(4-chloro-5H-1,2,3-dithiazol-5ylidene)thiophene-3-carboxylate counterpart.To the best of our knowledge, the chemical behaviour of this iminodithiazole with amines has never been reported.
Furthermore, we have extended this methodology towards new polycyclic analogs, using ethyl 5-amino-1methyl-1H-pyrazole-4-carboxylate and methyl 2-aminopyridine-3-carboxylate as readily available heteroaromatic substrates.Corresponding imines (11) and (12) were obtained in dichloromethane at room temperature with respectively 68% and 51% yields.Under the same conditions reported to those employed above, treatment of imines with alkane and aromatic diamines led to new heterocyclic fused pyrimidinones (Scheme 6).The reaction of imines with ethylene diamine afforded the cyclized and stable products (13 and 14) 29,30 which result from the substitution of the cyano group by nucleophilic attack of the aliphatic amine of the intermediate (VIII) rather than the expected cyclic amidine described above.
Finally, only the tetracyclic compound (15) was identified in 24% yield when imine (11) reacted with oaminobenzylamine.Compound (12) containing pyrimidine core did not react with aromatic diamine to give the target tetracyclic product.

Conclusions
We described here a method which allows access to complex fused products starting from easily obtainable substrates in one step.We demonstrated that 5-(N-arylimino)-4-chloro-5H-1,2,3-dithiazole derivatives can be used as available building blocks for the rapid synthesis of various polycyclic molecules.The pharmacological targets of these original heterocycles remain to be established.

Experimental Section
General.All commercially available compounds were used as received without further purification.Silica gel 0.063-0.2mm (70-230 mesh) was used for all column chromatography.NMR spectra were recorded on a Jeol NMR LA400 spectrometer in chloroform-d or DMSO-d 6 at 400 MHz for 1 H NMR spectra and 100 MHz MHz for 13 C NMR spectra.Chemical shifts were reported in ppm and multiplicities were described as follows: bs, broad singlet; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet.Coupling constants 'J' were reported in Hz.IR spectra were recorded on a Perkin Elmer spectrum 100 FT-IR ATR spectrometer.Absorptions are given in wavenumbers (cm -1 ).Melting points were determined on a Kofler melting point apparatus.Mass spectra were measured with a Micro mass Q-TOF spectrometer.Microwave experiments were conducted in sealed vials (10 mL) with a Biotage Initiator microwave reactor (400 W, monomode system with a microwave power delivery system ranging from 5 to 400 W.) under air with magnetic stirring.Reaction temperature and pressure were determined using the built-in, on-line IR and pressure sensors.
6][27][28] Under an inert atmosphere (argon), dithiazolium salt 1 (0.208 g, 1 mmol) was added to a solution of amino ester (1 mmol) in dichloromethane (5 mL).Pyridine (2 mmol) was slowly added.The mixture was stirred until all of the amine had been consumed (tlc control).The mixture was warmed to room temperature and the reaction mixture filtered through acidic alumina and pour into ice water and the organic layer was separated and the aqueous phase extracted with dichloromethane.The crude product was purified by column chromatography using petroleum ether/DCM as the eluent.