Polymer-assisted synthesis of ethyl 2-amino-4,6-diarylpyrimidine-5-carboxylates

Nine novel ethyl 2-amino-4,6-diarylpyrimidine-5-carboxylates have been synthesized in modest to good yields by a five-step procedure that involves building of the heterocyclic moiety on a solid support derived from Merrifield’s resin and final displacement with an amine

Among the pyrimidines 4, products bearing an amino group in position 2 (R 2 = -NRR') are poorly described in the literature probably because of the lack of straightforward synthetic methods.Indeed, the amino moiety can be introduced during the ring formation process with an appropriate guanidine (1, R 2 = -NRR') but the approach is of restricted interest because of the limited availability of substituted guanidines.The amino moiety can also be introduced by displacement of a good leaving group with an amine after construction of the heterocycle 3 or 4.However, to the best of our knowledge, that strategy has been seldom exploited to access the title compounds.In this paper we wish to report on the preparation of the target substances from alkyl 2-(alkylthio)pyrimidine-5-carboxylates bound to a solid support through the thio group, reasoning that an aminolysis reaction could effect the cleavage from the polymer while inducing the expected functionalities in position 2.

Results and Discussion
Our strategy (Scheme 2) started by the modification of the Merrifield's resin into 5 by reaction with thiourea.Condensation of 5 with a pre-formed 8 ethyl 3-aryl-2-benzoylpropenoate (6) gave the polymer-supported 1,4-dihydropyrimidine 7, which was oxidized by treatment with ceric ammonium nitrate 1a, 9 to afford 8.The formation of the polymer-bound compounds was followed on line by infrared spectroscopy.Disappearance 10 of the C-Cl band at 1264 cm -1 and appearance of a broad absorption 11 around 3435 cm -1 are indicative for the fixation of the thiourea.The presence of a carbonyl peak at 1680 cm -1 suggests the incorporation of the ester moiety (in 7) and that band is shifted to 1720-1730 cm -1 in the corresponding aromatic derivative (8).Inspection of the infrared spectra revealed that construction of the 1,4-dihydropyrimidine system on the polymer was the crucial step that determined the overall yield.We also observed that reacting together the solid 5, an aldehyde, and a β-ketoester (the Hideg modification 12 of the Biginelli synthesis) was a less attractive method, as formation of by-products in solution occurred more rapidly than the interaction with the solid reagent.
Disappointingly, we found that displacement of the alkylthio group in 8, by an amine, was a slow process.Therefore, we turned towards the concept described by Obrecht 11,13 who suggested transforming the alkylthio group into the more labile sulfone by treatment with metachloroperoxybenzoic acid.It was not possible to convert 7 into 9 directly, thus justifying the use of two oxidants.Finally, the cleavage from the resin was readily accomplished with various aliphatic or aromatic primary and secondary amines in boiling ethanol.Overall yields (not optimized), based on the chlorine content of the Merrifield's resin, ranged from 35 to 75 % as indicated in the Table.

Conclusions
In this paper we present our preliminary results on a simple strategy to access the title compounds.From these results, it can be anticipated that the sequence might be suitable for a combinatorial approach.Indeed substituents R 4 and R 6 could be independently modified, as well as the nature of the ester group (R 5 ).However, to reach that goal, each step remains to be carefully optimized, and particular attention must be dedicated to the construction of the 1,4dihydropyrimidine skeleton on the support, as, in our hands, that reaction appeared to be highly sensitive to small variations in the experimental conditions.

Experimental Section
General Procedures. 1 H and 13 C NMR spectra were obtained using a Bruker AMX-300 spectrometer (300 MHz for 1 H and 75 MHz for 13

Table .
Nature of the substituents in compounds 10 -18 and overall yields iii Scheme 2. Procedure used to prepare compounds 10 -18.