Synthesis of some 2-imidoylimino-2,3-dihydro-thiazolo[4,5-d ]pyrimidines

The paper is concerned with chemistry of thiazolo[4,5-d ]pyrimidine derivatives bearing a 1,3-diazapropenylidene fragment at position 2 and an oxygen or a mobile chlorine atom at position 7. These compounds are obtained in three steps: (i) cycloaddition of malononitrile to available 1,2,4-thiadiazol-5(2 H )-imines to form N -(4-amino-5-cyanothiazol-2(3 H )-ylidene)amidines; (ii) their acylation or condensation with DMF dimethyl acetal followed by; (iii) pyrimidine ring closure.


Introduction
Goerdeler and co-workers developed a convenient approach to synthesis of 1,2,4-thiadiazol-5(2H)-imines A, whose central feature is ability to take part in ring cleavage [3+2]cycloadditions, where the structural element N=C-S serves as a quasi-1,3-dipolar reactant. 1n the 2000s we found that compounds A interact with malononitrile to give adducts B, which were involved in further heterocyclizations. 2The present paper is devoted to chemistry of a series of thiazolo [4,5-d]pyrimidines C bearing at position 2 a 1,3-diazapropenylidene fragment.We focused our attention on these species because the related 1,2-diazapropenylidene compounds D were found to show remarkable anti-inflammatory and antibacterial activities. 3

Results and Discussion
First and foremost, we synthesized some new key thiazole derivatives 5 starting from imidoyl chlorides 1 through carbamothioyl amidines 2, 1,2,4-thiadiazolium salts 3, and 1,2,4-thiadiazol-5(2H)-imines 4 (Scheme 1).Compounds 5 form as the result of the cycloaddition of malononitrile to bases 4 followed by a ring transformation with the participation of an active methylene group. 4In this synthesis the free isolated bases 4a,b were used but unstable 4c was applied in situ.

Scheme 1
Acylation of compounds 5 with acetic anhydride as well as benzoyl and p-nitrobenzoyl chlorides was performed in boiling pyridine (Scheme 2).In so doing the acetylation product 6a was isolated in 74% yield but 6b and 6c were not because they underwent the pyrimidine ring closure to give thiazolo [4,5-d]pyrimidine derivatives 7b,c.Interestingly, compound 7a can also be obtained, albeit in low yield, if one heats 5a in net acetic anhydride without adding pyridine.Another way to 7a is treatment of 6a with gaseous hydrogen chloride.Structures of compounds 7 were confirmed by 1 H NMR and IR spectroscopy and they are consistent with the well-known cyclization products of o-acylaminonitriles.

Scheme 3
This method of the pyrimidine ring formation by an intramolecular reaction of an amidine and a cyano groups was put into practice recently. 7It enabled us to get compounds 10 containing an aromatic pyrimidine ring with a reactive chlorine atom, which can be easily replaced by nucleophiles to produce corresponding N-, O-, and S-substituted thiazolo [4,5-d]pyrimidines 11.
Noteworthy, 1 H NMR spectroscopy of compounds 7, 10, 11 shown that in a solution they exist as mixtures of stereoisomers (signals of 7a,b, 11a, 11c are broadened, 7c, 10b, 11bduplicated).These stereoisomers can result from restricted syn-anti isomerization at nitrogen atoms as well as rotation around a single C-N bond in the side 1,3-diazapropenylidene fragment.In temperature dependent 1 H NMR the coalescence of signals was observed at 70-90 ºC (Supplementary Material).

Experimental Section
General.Melting points were determined on a capillary tube apparatus (bellow 250 ºC) and on a Fisher-Johns apparatus (above 250 ºC).IR spectra were taken on a Specord 71 IR spectrophotometer.NMR spectra were recorded in CDCl 3 or DMSO-d 6 on a Varian VXR 300, Varian Unity Plus 400, and a Bruker Avance DRX 500 spectrometer, TMS was used as the internal standard.Because of poor solubility of most compounds 7 and 11 in mentioned solvents, their 13 C NMR spectra were not obtained.Mass spectra were recorded on a Bruker Autoflex MALDI-TOF instrument.Combustion elemental analyses were performed by hand.All chemicals were supplied by Enamine (Kiev, Ukraine) and used without further purification.