Synthesis of 2,4,5-Trisubstituted Pyrimidines from Baylis-Hillman Adducts and Amidines

Abstract

The pyrimidine moiety is one of the most widespread heterocycles in biologically occurring compounds, such as nucleic acids and vitamin B1, and is an important constituent of numerous drug molecules in many therapeutic areas. Although various procedures for the synthesis of pyrimidine derivatives have been developed, it is convenient to synthesize substituted pyrimidines by the reaction of amidine or guanidine derivatives with a variety of 1,3-dielectrophilic three-carbon units such as α,β-unsaturated carbonyl compounds. During the continuous studies on the chemical transformation of Baylis-Hillman adducts our recent interest was focused on the synthesis of oxygen and nitrogen-containing heterocyclic compounds. In addition, we were interested in the reaction of Baylis-Hillman adducts and 1,3-dinucleophile like as 1,3-dinitroalkanes and dimethyl 1,3acetonedicarboxylate. In these respects we presumed that we could synthesize trisubstituted pyrimidine derivatives 3 by using some amidine derivatives 2 as shown in Scheme 1. In the reaction, Baylis-Hillman acetates 1 act as 1,3dielectrophilic component and amidine derivatives 2 served the role of 1,3-dinucleophile. The reaction of the Baylis-Hillman acetate 1a and benzamidine hydrochloride (2a) in tert-butanol in the presence of K2CO3 produced desired compound 3a in 91% isolated yield (entry 1 in Table 1). Similarly we prepared 2,4,5-trisubstituted pyrimidines 3b-h in 27-92% yields from the reaction of Baylis-Hillman acetates 1a-f and amidine derivatives 2a and 2b, and the results are summarized in Table 1. As shown in Table 1, the reaction of acetamidine hydrochloride (2b) gave relatively lower yields than the cases of 2a (see entries 1&2, entries 6&7) presumably due to low solubility of 2b in tert-butanol. The Baylis-Hillman acetates containing ester moiety (entries 1-5) or acetyl group (entries 6 and 7) showed moderate to good reactivity, however, nitrile-containing substrate 1f showed very low reactivity (entry 8). The reaction of 1a and 1,3-diphenyl guanidine (2c) gave the corresponding 2-aminopyrimidine derivative 3i in moderate yield (entry 9). Initially we examined the reaction of BaylisHillman adduct itself and benzamidine hydrochloride (2a), however, we could not obtain the desired product 3a directly. In summary, we synthesized some 2,4,5-trisubstituted pyrimidines from the reaction of Baylis-Hillman acetates and amidine derivatives in a one-pot reaction in moderate yields.