Synthesis of 6-Amino-5-cyano-1,4-disubstituted-2(1H)-Pyrimidinones via Copper-(I)-catalyzed Alkyne-azide ‘Click Chemistry’ and Their Reactivity

In this paper we present the room temperature synthesis of a novel serie of 1,4-disubstituted-1,2,3-triazoles 4a-l by employing the (3 + 2) cycloaddition reaction of pyrimidinones containing alkyne functions with different model azides in the presence of copper sulphate and sodium ascorbate. To obtain the final triazoles, we also synthesized the major precursors 6-amino-5-cyano-1,4-disubstituted-2(1H)-pyrimidinones 3a-r from ethyl 2,2-dicyanovinylcarbamate derivatives 2a-c and various primary aromatic amines containing an alkyne group. The triazoles were prepared in good to very good yields.

Structures of compounds 4a-l were established on the basis of their spectroscopic data. The IR absorption band corresponding to a terminal C≡C-H group was not observed around 3,271 cm −1 . The mass spectra showed the respective [M + H] + peaks. According to 1 H-NMR spectra of the 'click' products the terminal triple bonded proton signal (δH = 4.3 ppm) of the alkynes 3 disappeared and the newly formed triazole signal was observed at 8.5-9.5 ppm. The triazole ring formation was also identified from the 13 C-NMR spectra with the new signals of the ethylenic C atoms of the 1,2,3triazole moiety at δ = 120-122 ppm (CH ar-triazole ) and δ = 146-148 ppm (C q-triazole ).

X-ray crystal analysis of compounds 3b and 3g
To further confirm the structure of compounds 3, an X-ray crystallographic study of compounds 3b and 3g was carried out (Figures 2 and 3). Crystals were obtained by slow evaporation from methanol solution. Crystallographic data were collected at 180K with an Oxford-Diffraction XCALIBUR CCD Diffractometer equipped with a Cryojet cooler device from Oxford Instruments. Structures were solved by direct methods using SIR92 [20] and refined by full-matrix least-squares procedures on F using the programs of the PC version of CRYSTALS [21]. Atomic scattering factors were taken from the International Tables for X-ray Crystallography [22].  CCDC contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Conclusions
In summary, various 6-amino-5-cyano-1-(meta-or para-ethynylphenyl)-4-substituted-2(1H)pyrimidinones were synthesized and utilized as starting materials in the 'click' reaction to attach azido residues. Consequently, we have employed these, in house synthesized precursors, to prepare a new class of hybrid molecules 1,4-disubstituted-1,2,3-triazoles employing already known chemistry of (3 + 2) cycloaddition of azides and acetylenes in good to very good yields. All products that we have obtained were hitherto unknown. A number of them are presently under pharmacological screening.

Experimental
Commercially available reagent grade chemicals were used as received without additional purification. All reactions were followed by TLC (E. Merck Kieselgel 60 F-254), with detection by UV light at 254 nm. Column chromatography was performed on silica gel (60-200 mesh E. Merck). IR spectra were recorded on a Perkin-Elmer PARAGON 1000 FT-IR spectrometer. 1 H-and 13 C-NMR spectra were recorded on an AC Bruker spectrometer at 300 MHz ( 1 H) and 75 MHz ( 13 C) using (CD 3 ) 2 SO as solvent with (CD 3 ) 2 SO (δ H 2.5) or (CD 3 ) 2 SO (δ C 39.5). Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (0 ppm) as internal reference and the following multiplicity abbreviations were used: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; J in hertz. The mass spectra were recorded on an ion trap mass spectrometer (Finnigan LCQ Deca XP Max) using electrospray as an ionization source. Melting points were determined on an Electrothermal 9300 capillary melting point apparatus and are uncorrected. UV-visible spectra were recorded on a Specord 205 Analytikjena spectrophotometer. The purity of all compounds was determined by LC-PDA-MS methods and was found to be in the range between 96-99%.

General experimental procedure for preparation of 1,4-disubstituted-1,2,3-triazoles 4a-l
The mixture of alkyne 3 (1 mmol) and azides (1 mmol) was suspended in a mixture of THF/t-BuOH/H 2 O (3:1:1, v/v/v, 6/2/2 mL). Sodium ascorbate (89 mg, 0.45 equiv) was added followed by addition of CuSO 4 5H 2 O (16 mg, 0.1 equiv). The heterogeneous mixture was stirred vigorously for 2 days, at which time TLC showed complete conversion. The reaction mixture was concentrated under vacuum and the residue was treated with H 2 O (50 mL) and extracted with dichloromethane (3 × 15 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and evaporated under reduced pressure to give a crude mass. Column chromatography purification using ethyl acetate/dichloromethane as eluent gave the clicked product 4.  derivative A 3 . We thank Dr. Carine Duhayon for providing the X-ray crystal analysis. Hany Ibrahim and Pierre Perio for their help in the physico-chemical characterization of our compounds.