A facile and efficient one-pot three-step protocol for synthesis of 6-aryl-7-oxo-5-aryoxy/alkoxy-1-( p -tolyl)-6,7-dihydro-1 H -pyrazolo[4,3-d ]pyrimidine-3-carbonitrile

A facile and efficient one-pot three-step approach to the synthesis of substituted 1 H - pyrazolo[4,3-d ]pyrimidin-7(6 H )-ones 4 from ethyl 3-cyano-1-( p -tolyl)-4-((triphenylphosphoran-ylidene)amino)-1 H -pyrazole-5-carboxylate 1 has been developed. In this method, treatment of phospazene 1 with arylisocyanates and followed by nucleophilic addition with phenols/alcohols in the presence of a catalytic amount of K 2 CO 3 /R 2 ONa in THF at room temperature gave the corresponding 6-aryl-7-oxo-5-aryoxy/alkoxy-1-( p -tolyl)-6,7-dihydro-1 H -pyrazolo[4,3-d ]- pyrimidine-3-carbonitrile 4 in satisfactory to good yields.

Over the past two decades, the aza-Wittig-mediated annulation strategy has been widely used for the synthesis of nitrogen-containing heterocyclic compounds. 16This method, which is called Eguchi aza-Wittig protocol, 17 is known as tandem aza-Wittig heterocumulene-mediated annelation, and is recently classified as reaction. 18Although annelation of ring systems with quinazolinones by means of an aza-Wittig reaction has been developed, 19 synthesis of pyrazolo [4,3-d]pyrimidin-7-ones by means of tandem aza-Wittig reactions of iminophosphorane with aryl isocyanates and nucleophiles has received less attention.In connection with our ongoing studies on fused nitrogen-containing heterocyclic construction synthesis and drug discovery project, we have focused on the synthesis of quinazolinones and other fused heterocyclic pyrimidinones.Previously, we reported an efficient approach to the synthesis of a new series of 6-aryl-3-cyano-5-alkylamino-1-p-tolyl-1H-pyrazolo [4,3-d]pyrimidin-7(6H)-ones 20 via iminophosphorane-mediated annulation involving in reactions of iminophosphorane with aromatic isocyanates, followed by nucleophilic addition with primary amines and secondary amines, respectively.Herein, we further employ this facile and efficient one-pot three-step process, via aza-Wittig/intermolecular nucleophilic addition/intramolecular cyclization, for the preparation of 6-aryl-7-oxo-5-aryoxy/alkoxy-1-(p-tolyl)-6,7-dihydro-1H-pyrazolo[4,3d]pyrimidine-3-carbonitriles 4. The syntheses as depicted in Scheme 1 rely on the following reactions: (a) reaction of aza ylide with isocyanate to give a carbodiimide, (b) addition of phenol /alcohol to the carbodiimide to generate a carbamimidate, and (c) lactamization of the latter with neighboring ethyl ester group to deliver fused pyrimidinones.Although all the three steps are frequently utilized for building a pyrimidinone nucleus, the reactions carried out in a one-pot operation leading to complex molecules are still attractive.This three-step synthesis in a one-pot process have economical and environmental advantages over the step by step synthesis in the procedure, isolation and purification steps, time, costs, and waste production.
It is notable that slight differences in yields of producing the title compounds 4a-l were observed when different phenols were used for the nucleophiles.Switching the phenyl group from an electronic withdrawing group (4-Br-phenyl, 4-Cl-phenyl and 2, 4-diCl-phenyl) to an electronic donating group (4-OCH3 phenyl and 4-CH3 phenyl) resulted in yield from 67% to 93% for compounds 4 in several cases.
Reagents and conditions: a. p-R 1 C6H4NCO, THF, 0-5 °C, 12 h; b.R 2 OH, K2CO3 or R 2 ONa THF, r.t., 6-12 h.Yield 67-93%.Encouraged by the aforementioned results and with the suitable reactions in hand, we next examined the feasibility of the protocol employing ethanol for example as nucleophiles in the annulation.Unfortunately, the one-pot reaction gave a complex mixture which mainly containing intermediate 3.However, when the reaction carried out in the presence of catalytic EtONa, it took place smoothly and the 5-alkoxy-6-aryl-7-oxo-1-(p-tolyl)-6,7-dihydro-1H-pyrazolo [4,3d]pyrimidine-3-carbonitrile 4m were obtained in satisfactory yields.The final yields are very low when alcohols containing more than three carbon atoms were used as nucleophiles in the annulation.
It is worth noting that the facile cyclization catalysts are K2CO3 and R 2 ONa, when phenols and alcohols are used, respectively.This can be rationalized in term of the more acidic NHOR 2 in the intermediate 3 when R 2 is alkyl.Structural elucidation of compounds 4 was accomplished from the analytical and IR, 1 H NMR and GC-MS spectral data.The mass spectra showed the expected molecular ion peaks or M + ±1 and M + ±2 peaks, and the IR spectra showed a strong bands at 1719-1736 cm -1 , attributed to the C=O groups, and a CN absorption at 2236-2341 cm -1 , while in the 1 HNMR spectra, the aromatic protons are found, as multiplets, at =7.89-7.69ppm.For example, the 1 H NMR spectra of the compound 4a show the signal of aromatic C-H at =7.57-7.00ppm as multiplet and -CH3 at =2.37 ppm and =2.39 ppm as a singlet.The IR spectra of 4a exhibit a strong stretching resonance peak at 1720 cm -1 which indicates the presence of a C=O bond, and medium strong sharp peak at 2239 cm -1 belonging to CN stretching resonance.The MS spectra of 4a show M + at m/z 433 with 100% abundance.

Experimental Section
General. 1 H NMR were recorded in CDCl3 on a Varian Mercury Plus 400 (400 MHz) spectrometer and resonance are given in ppm () relative to TMS.Mass spectra were obtained on a Finnigan trace MS spectrometer.Melting points were recorded on X-4 electrothermal melting point apparatus and were uncorrected.Elemental analyses were determined on a 2400 Perkin-Elmer elemental analysis instrument.

General procedure for synthesis of the carbodiimide (2)
To a solution of iminophosphorane 5 (1.59 g, 3.0 mmol) in anhydrous THF (10 mL) was added rapidly aryl isocyanate (3.0 mmol) at room temperature.The reaction mixture was left unstirred for 6-12 h at 0-5 o C to generate carbodiimides 2, which were used directly for next step without further purification.

Synthesis of the title compounds (4).
To the reaction mixture of 2 (3.0 mmol), was added phenol or alcohol (3.1 mmol) and a catalytic amount of K2CO3 or R 2 ONa at room temperature.
The reaction mixture was allowed to stir for 6-12 h, filtered, condensed and the crude residue was recrystallized with EtOH and CH2Cl2 to give 4 in 67-93 % yields