Synthesis of new furo[2,3-d ]pyrimidines and furo[3,2-e ][1,2,4]triazolo[1,5-c ]pyrimidines

2-Aminofuran-3-carbonitriles (1) reacted with triethylorthoformate (2a) or triethylorthoacetate (2b) to afford the corresponding imidates 3a,b . Reaction of 3a,b with semicarbazide hydrochloride gives the (4-imino-furo[2,3-d ]pyrimidine-3-yl)ureas 5a,b , which are in turn cyclized with dichlorotriphenylphosphorane to give the iminophosphoranes 6 . Hydrolysis of 6 leads to the 2-amino-furo[3,2-e ][1,2,4]triazolo[1,5-c ]pyrimidines 7a,b . Compound 7a can also be prepared by the reaction of 4-imino-furo[2,3-d ]pyrimidine 8, which prepared by hydrazinolysis of 3a , with cyanogen bromide or isothiuronium sulfate in alkaline medium. 2-Aryl-furo[3,2-e ][1,2,4]triazolo[1,5-c ]pyrimidines 12a,b were synthesized by the reaction of the substituted benzoic acid hydrazides 9a,b with 3a or 1 .


Results and Discussion
Treatment of 1 with triethylorthoformate 2a or triethylorthoacetate 2b in acetic anhydride at reflux afforded the corresponding imidates 3a and 3b respectively (Scheme 1).The IR spectra of compounds 3a,b showed a strong absorption band of the nitrile group at 2220 cm -1 but no absorption frequency in the NH region.The 1 H NMR spectra of product 3a,b were compatible with the proposed structure.For example, the CH proton of the imidate group in 3a appeared downfield at δ 8.9, where as a triplet (3H) at δ 1.25 and quartet (2H) at δ 4.30 were assigned to the methyl and methylene protons of the ethoxy group in the same functionality.The reaction of compounds 3a,b with semicarbazide hydrochloride in equimolar proportions in ethanol and in the presence of triethylamine gave the corresponding (4-imino-furo [2,3-d] Compounds 5a,b were readily cyclized to the corresponding iminophosphoranes 6 upon treatment with in situ prepared dichlorotriphenylphosphorane using a hexachloroethanetriphenylphosphine-triethylamine reagent 32,33 (Scheme 1).The molecular structures of the iminophosphoranes 6a,b were supported on the basis of elemental and spectral analyses which were found to be in good agreement with the assigned structures.
Hydrolysis of compound 6 leads to the 2-amino-furo[3,2-e][1,2,4]triazolo[1,5c]pyrimidines 7a,b (Scheme 1).The structure of 7a,b was deduced on the basis of analytical and spectral data.Thus, the appearance of intense absorption bands at 3480-3300 cm -1 and a broad signal for 2H at 5.65-5.85ppm for NH 2 in the IR and 1 H NMR spectra respectively.Furthermore, the fragmentation patterns of the mass spectra of 7a and 7b showing the molecular ion peak at m/z 387 (M + , 45%) and m/z 401 (M + , 55%), respectively, which were found to be in good agreement with the assigned structure.
Hydrazinolysis of compound 3a in ethanol at 40°C for one hour yielded the 3-amino-5,6di-(4-methoxyphenyl)-4-imino-3H,4H-furo [2,3-d]pyrimidine (8) (Scheme 1).The structure of compound 8 was determined on the basis of elemental analysis, spectral data and the chemical transformations outlined below.In addition, the structure of 7a was confirmed further by an alternative synthesis by the reaction of compound 8 with cyanogen bromide or isothiuronium sulfate in ethanol and in the presence of K 2 CO 3 or KOH, respectively (Scheme 1).Scheme 2 outlines the synthesis of 2-aryl-furotriazolopyrimidine (12a,b) from the reaction of the imidoesters 3a with the corresponding substituted benzoic acid hydrazides 9a,b in refluxing bromobenzene.Structures of 12a,b were based on the correct elemental analyses and spectral data.The reaction mechanism illustrated in Scheme 2 has been confirmed by the synthesis of the intermediate 10 and 11 in the reaction of the imidoester 3a with 9a under milder conditions.Thus, the amidrazone 10 was obtained by short-term reflux of an ethanolic solution of the imidoester 3a and 4-hydroxybenzoylhydrazine (9a) applied in equimolar amounts.The IR as well as the mass spectrum agreed with the proposed structure 10.Heating a dimethylformamide solution of the amidrazone 10 gives rise to 4-imino-furopyrimidine 11, the IR spectrum of which revealed the absence of CN and the presence of absorption bands at 1675, 3150 and 3306-3175 cm -1 corresponding to the CO, NH and OH, respectively.Also, the 1 H NMR spectrum of compound 11 revealed the presence of two signals at δ = 10.33, and 10.53 ppm due to two NH groups, in addition to the signals at δ = 8.85 and 10.87 ppm due to pyrimidine-CH and OH protons.The cyclization of 11 to 12a, via elimination of a molecule of water, proceeds upon reflux in bromobenzene for 8 hours.The structure of 2-aryl-furotriazolopyrimidine 12a was confirmed from its elemental and spectral analyses, which showed the molecular ion peak at m/z 464 (M + , 35%).Also, the IR spectrum of 12a revealed the absence of the characteristic stretching vibrations due to the NH and amidic carbonyl groups, which appear in the IR spectrum of compound 11.In addition, the 1 H NMR spectrum of 12a demonstrated characteristic singlet at δ 3.75 and 3.90 for the two-methoxy protons, a multiplet at δ 6.97-7.28 for phenyl protons, a sharp signal at δ 8.48 for the H-5 proton in the pyrimidine ring and broad signal at δ 11.08 for the hydroxyl proton.
Further confirmation of structure 12a was made via the synthesis of compound 14, prepared from the reaction of compound 1 with 9a.Subsequent refluxing of 14 in orthoester 2a smoothly converts it to the final product 12a (Scheme 2).The identity of the products of the cyclization of 14 with those obtained by the cyclization of 11 was confirmed by comparison of their IR and 1 H NMR spectra.

ARKAT
University of Hull, UK, performed elemental analyses.Compound 1 was prepared according to the method reported in the literature 9 .

Synthesis of imidates 3a,b.
A mixture of compound 1 (10 mmol) and triethylorthoformate 2a or triethylorthoacetate 2b (3 ml) in redistilled acetic anhydride (25 ml) was refluxed for 1 h.After cooling, the precipitated pale yellow crystalline product was filtered off and washed thoroughly with ethanol and recrystallized from ethanol to yield 3a,b as yellow crystals.

Conclusions
We have presented various methods for the synthesis of new furo [2,3-d] pyrimidine-3-yl)urea derivatives 5a,b (Scheme 1).The formation of 5 was rationalized in terms of the initial formation of the intermediate 4, the nucleophilic attack of the semicarbazide N-2 on the neighboring nitrile group forming the furo[2,3-d]pyrimidine 5.The structures of 5a,b were established by their correct analyses and compatible spectroscopic data.
yl]furan(14).A mixture of 1 (20 mmol) and 9 (24 mmol) in diphenyl ether (50 ml), was stirred at reflux temperature for 5 h.The mixture was allowed to cool to room temperature and n-Hexane (150 ml) was added.The precipitate was collected by filtration, washed with additional ARKAT n-