Synthesis of some New Fused Pyrimidine Compounds

Biginelli reaction is a one-pot reaction which is used to prepare some of fused pyrimidine (2Amino-4-aryl-7, 7dimethyl-1, 4, 5, 6, 7, 8-hexahydro quinazoline-5-one) (A1-6) by the action of dimedone, guanidenium hydrochloride and some substituted benzaldehyde in presence of Lewis acid represented by boric acid (20% mole). These compounds were used later as precursors to prepare a superim type of schiff bases represented by compounds (2-Amino-4-aryl-5-hydrazono-7, 7-dimethyl-1, 4, 5, 6, 7, 8-hexahydro quinazoline) (B1-6). The assigned structure of the prepared compounds was corroborated by available physical and spectral methods.


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INTRODUCTION Three component one-pot condensation reaction has been emerged as a useful method in organic synthesis because the combination of three components to generate a new product in a single step is extremely economical among the multicomponent reaction (Huang et al.,2005;Orru and Groen, 2009;Ryabukhin et al., 2010) and efficient (Sun et al., 2008;Abdel hamid et al., 2011).
Additionally, this type of reaction received a great deals of attention in medical chemistry for various reasons, it's put on speed, diversity and efficiency in the drug discovery process (Müller, 2011).
In this presentation, Biginelli reaction was used to prepare a special type of fused pyrimidine derivatives starting from 1,3-cycloketone represented by dimedone, guanidenium hydrochloride and substituted benzaldehyde in presence of boric acid (20% mole).

EXPERIMENTAL
Melting points (M.P.) were measured on Electrothermal SMP30-Stuart melting point apparatus and were uncorrected. Infrared (FT-IR) spectra were recorded as (KBr) disk using a Bruker, FT-IR, spectrophotometer Tensor 27. Ultraviolet (U.V) spectra were performed on Shimadzu UV-visible Spectrophotometer UV-1660 PC using methanol as a solvent. Thin layer chromatography (TLC) was carried out on silica gel (120 mesh) coated plates (2х10) cm, activated for one hour at (110-120°C) before use and the plates were developed with iodine vapor.

RESULTS AND DISCUSSION
In order to optimize the reaction conditions, we firstly used triethyl amine as a base to prepare compounds (A 1-6 ) and then repeated this reaction under acidic condition according to Biginelli reaction condition by using boric acid (20% mole). This change in reaction condition from basic to acidic proved that the two methods give the same products (A 1-6 ) as shown in equation (1) Definitely, the acidic condition gave a higher yield than the basic condition, therefore the acidic conditions were adopted to prepare the required compounds (A 1-6 ) (Meshram et al., 2012;Tu et al., 2003). Furthermore, the reaction mechanism in basic conditions is completely different from that in acidic conditions. The reaction mechanism in basic conditions proceed through an ordinary nucleophilic attack of dimedone anion to the carbonyl carbon to afford α,β-unsaturated compound (2-benzylidene-5,5-dimethylcyclohexane-1,3-dione) which then in turn underwent nucleophilic addition reaction with guanidinuim hydrochloride to obtained 1-((2-hydroxy-4,4-dimethyl-6oxocyclohex-1-enyl)(aryl) methyl) guanidine. Finally, intramolecular cycloaddition reaction will occur followed by losing of water molecule to form compound (A 1-6 ), (Singh, 2011).
Whereas, in acidic condition, mechanistically, it is reasonable to assume that the reaction was proceeded firstly via protonation of the carbonyl group then it will undergo nucleophilic attack with guanidinium hydrochloride to afford the intermediate (I) which upon reaction with the enolated form of dimedone yielded the intermediate (II). Finally, intramolecular cycloaddition reaction takes place by the action of amino group on the carbonyl group to give the intermediate (III) followed by losing of water molecule to yield the corresponding compounds (A 1-6 ) as shown in scheme (1), (Hügel, 2009;Wang et al., 2010;Loto et al., 2012). The structures of compounds (A 1-6 ) were confirmed by spectral methods represented by FT-IR and U.V. spectra as shown in Table (1). In FT-IR spectra all compounds show absorption bands at (3309-3338 cm -1 ), (3112-3240 cm -1 ), (1651-1670 cm -1 ), (1595-1624 cm -1 ) and (1547-1612 cm -1 ) due to NH 2 , NH , C=O, C=C (cyclic) and C=N (cyclic) functional groups respectively. Whereas, the U.V. spectra showed absorption bands at λ max (236-296 nm) due to the cyclic system and to the n→π* transition (Finar,1977;Parikh, 1974).
Actually, our target in this work is not only to prepare new Biginelli products but to prove the ability of Biginelli products to act as a good synthon in organic synthesis. Thus, starting from this point and because the Biginelli products (A 1-6 ) having a carbonyl group in position 5, the latter used as good synthon to prepare hydrazones represented by compounds (B 1-6 ) by the action of hydrazine hydrate (80%) in presence of glacial acetic acid and sodium acetate. It is worth noting that, the use of acetic acid and sodium acetate together in this reaction is to keep the reaction under acidic medium (PH 3.7-5.6) (Dawson et al., 1986). The condensation reaction was found to proceed according to equation (2) The more plausible mechanism for this reaction was summarized in scheme (2). (Schmid,1996;Clayden et al., 2001).
Finally, ethyl acetate: benzene, (2:8) was used as a suitable solvent system in R f thin layer chromatography measurements (Singh, 2011) to provide a suitable explanation about the formation of compounds (A 1-6 ) and (B 1-6 ) as shown in Tables (1) and (2) respectively.