An efficient synthesis of 2,3,6,7-tetrasubstituted 4,6-dihydro-4-oxo-3 H -pyrrolo[3,4-d ]pyrimidin-7-carbonitrile derivatives

The iminophosphorane 3 , prepared by reaction of ethyl 4-amino-5-cyano-1-phenyl-1 H -pyrrole- 3-carboxylate ( 2 ) with triphenylphosphine, hexachloroethane and triethylamine, reacted with equimolar quantities of aromatic isocyanates to give carbodiimides 4 . Further reaction of carbodiimides 4 with various amines or phenols then gave 2,3,6,7-tetrasubstituted 4,6-dihydro-4-oxo-3 H -pyrrolo[3,4-d ]pyrimidin-7-carbonitrile derivatives 6 in satisfactory yields in the presence of a catalytic amount of sodium ethoxide or potassium carbonate


Introduction
Compounds possessing a pyrrolo [3,4-d]pyrimidine nucleus possess a broad range of biological activities and have been used as potent cystic fibrosis transmembrane conductance regulator inhibitors, 1 β-site APP-cleaving enzyme 1 inhibitors 2 and A3 adenosine receptor antagonists. 3 Recent reports have also shown that some pyrrolo [3,4-d]pyrimidine derivatives may be used as inhibitors of heat shock protein 90 which could inhibit multiple pathways in human cancers. 4-6 There are many methods for the synthesis of fused pyrrolo [3,4-d]pyrimidine derivatives.One of the generally used approach is elaboration of a pyrrolo ring onto the prefabricated pyrimidine ring which bearing reactive functionalities at C-4 and C-5, 7-9 another popularly used method involved the formation of a pyrimidine ring onto the 3-aminopyrrole intermediate. 10-15Although some pyrrolo [3,4-d]pyrimidine derivatives have been constructed, but the synthesis of 2,3,6,7tetrasubstituted 4,6-dihydro-4-oxo-3H-pyrrolo [3,4-d]pyrimidin-7-carbonitrile derivatives is rarely described.

Scheme 1
Iminophosphorane 3 reacted with equimolar quantities of aromatic isocyanates to form carbodiimides 4, which were allowed to further treated with amines to provide guanidine intermediates 5.In the presence of a catalytic amount of sodium ethoxide in ethanol at room temperature, intermediates 5 were easily converted into 2-amino-3-aryl-4-oxo-6-phenyl-4,6dihydro-3H-pyrrolo [3,4-d]pyrimidine-7-carbonitrile derivatives at room temperature in satisfactory yields (Scheme 2).The results are listed in Table 1 (entry 6a-6l).The cyclization reactions were achieved all in moderate to good yields whether the amines used were sterically bulky or not, and no isomers were formed such as those that have been observed in similar cases. 29-  The structures of 2-amino-3-aryl-4-oxo-6-phenyl-4,6-dihydro-3H-pyrrolo [3,4-d]pyrimidine-7-carbonitrile derivatives 6 were confirmed by their spectral data.For example, the IR spectra of 6a revealed the groups of CN and C=O absorption bands at 2215 and 1707 cm -1 , respectively.
The 1 H NMR spectrum of 6a shows two triplets at 3.15 and 3.46 ppm due to the NCH2 and OCH2, respectively.The signals attributable to the Ar-Hs and 5-H of the pyrrole ring are found at 7.18-7.57and 7.68 ppm as multiplet and singlet, respectively.The MS spectrum of 6a shows molecular ion peak at m/z 415 with 100% abundance.
In order to extend this method of preparation of 2,3,6,7-tetrasubstituted 4,6-dihydro-4-oxo-3H-pyrrolo [3,4-d]pyrimidin-7-carbonitrile derivatives, phenols were further used to react with carbodiimides 4. When carbodiimides 4 reacted with phenols, the presence of a catalytic amount of potassium carbonate brought about the reaction to give 6 (Y = OAr) directly in good yields.The results are listed in Table 1 (entries 6m-6o).It is reasonable to assume that the reactions of carbodiimides 4 with phenols take place through an original nucleophilic addition to give the intermediates 5, which subsequently cyclized to produce 2-aryloxy-3-aryl-4-oxo-6-phenyl-4,6dihydro-3H-pyrrolo [3,4-d]pyrimidine-7-carbonitrile 6 under the basic conditions.It is noteworthy that the molecules all contain a carbonitrile group, which has been shown to be of importance in the design of biologically active heterocycles. 32-37

Conclusions
In conclusion, we have developed a new and efficient way to prepare previously unreported 2,3,6,7-tetrasubstituted 4,6-dihydro-4-oxo-3H-pyrrolo [3,4-d]pyrimidin-7-carbonitrile derivatives via reaction of carbodiimides with a variety of amines and phenols.Because of the mild reaction conditions, satisfactory yields and versatile substituents, it may well serve as an efficient route to many biologically active derivatives of this nucleus substituted as indicated.