A New Approach to 7-Amino-4-oxo-4,5-dihydro-3H-pyrano[2,3-d]pyrimidine-6-carbonitriles ^†

Abstract

S-alkyl derivatives of thiobarbituric acid easily react with arylmethylene malononitriles in the presence of base to give new 7-amino-4-oxo-4,5-dihydro-3H-pyrano[2,3-d]pyrimidine-6-carbonitriles. The structure of products and the mechanism of formation are discussed.

1. Introduction

2-Amino-4H-Pyran-3-carbonitriles and related chromenes are of practical interest due to their wide range of biological activity and complexing capability [1,2,3]. One of the most useful methods to prepare these compounds is the reaction of 1,3-dicarbonyl compounds with arylmethylene malononitriles (Scheme 1).

Scheme 1. General approach to 2-amino-4H-pyrans.

Easily accessible S-alkyl derivatives of thiobarbitic acids 1 [4] have not been used in the reaction prior to our studies. Compounds 1 can be easily prepared by treating thiobarbitic acid 2 with 2-haloacetic acid derivatives in an aqueous dioxane or aqueous alcohol solution in the presence of bases (Na₂CO₃, NaOH) (Scheme 2).

Scheme 2. The preparation of compounds 1.

2. Results and Discussion

When active methylene pyrimidines 1 react with dinitriles 3 in boiling EtOH in the presence of catalytic amounts of base, previously undescribed 7-amino-4-oxo-4,5-dihydro-3H-pyrano[2,3-d]pyrimidine-6-carbonitriles 4 were isolated. The latter can be also prepared by multicomponent approach, using aldehydes, malononitrile and pyrimidines 1 as the starting reagents. This approach allows one to use aliphatic aldehydes since corresponding alkylidene malononitriles are hardly available. However, in this case the yields of target products 4 are low, probably due to the side reactions of aldol condensation with aliphatic aldehydes occurred in the presence of base. Compounds 1 are capable to react with anilines and triethyl orthoformate to form compounds 5 that were not described in the literature previously (Scheme 3).

Scheme 3. The preparation of compounds 4 and 5.

The mechanism of the reaction is shown in the Scheme 4. On the first stage, thiobarbitic acid derivatives 1 undergo a Michael reaction with activated alkenes 3 in boiling ethanol in the presence of morpholine to form non-isolable Michael adducts 6. The resulting Michael adducts under reaction conditions are easily isomerized to give anions 7. The latter undergo heterocyclization, leading to the formation of pyran six-membered ring. Finally, intermediate 8 after protonation afforded the target products 4.

Scheme 4. The plausible mechanism for the formation of bicyclic core of 4.

The structures of the key compounds were confirmed by X-ray studies (Figure 1 and Figure 2).

Figure 1. The structure of compound 1 (X = OEt).

Figure 2. The structure of compound 4 (X = OEt, R = 5-methylfur-2-yl).

3. Experimental

2-[(4-Hydroxy-6-oxo-1H-pyrimidin-2-yl)sulfanyl]acetamide (1, X = NH₂)

The compound was prepared according to a modified method reported in [5] as follows: 2.88 g (0.02 mol) of thiobarbituric acid 2, 0.8 g (0.02 mol) of sodium hydroxide and 30 mL of water were mixed together. The resulting cloudy orange solution was filtered through a paper filter. Then, 1.88 g (0.02 mol) of α-chloroacetamide was added to the clear filtrate. The solution was vigorously stirred for 30 min at a constant temperature of 50 °C and left to stand for three days. The precipitate formed was filtered off and washed with water and dried to constant weight. The resulting product 1 is a pale pink powder. The substance is insoluble in water, EtOH, AcOH, ethyl acetate, and well soluble in DMF when heated. The yield was 62%.

2-[(4-Hydroxy-6-oxo-1H-pyrimidin-2-yl)sulfanyl]acetic acid (1, X = OH)

The compound was prepared according to a modified method reported in [5] as follows: 0.96 g (0.024 mol) of sodium hydroxide and 3.46 g (0.024 mol) of thiobarbituric acid 2 were dissolved in 100 mL of water. The resulted solution had a pH value of 8. Furthermore, 0.96 g (0.024 mol) of sodium hydroxide was dissolved in 100 mL of water, then 2.27 g (0.024 mol) of monochloroacetic acid was added. To the prepared aqueous solution of sodium chloroacetate, sodium thiobarbiturate solution was added dropwise through a paper filter. The reaction mixture was stirred for 15 min at a constant temperature of 50 °C, and left overnight. Then, diluted hydrochloric acid (10 mL of HCl + 20 mL of dist. H₂O) was added dropwise to the reaction mixture to adjust pH to 2. The precipitate was filtered off and dried to constant weight. The product was a colorless fine crystalline powder. The compound is poorly soluble in water and EtOH, but well soluble in DMF upon heating. The yield was 30%.

2-[(7-Amino-5-(4-chlorophenyl)-6-cyano-4-oxo-4,5-dihydro-3H-pyrano[2,3-d]pyrimidin-2-yl)thio]acetamide (4, R = 4-ClC₆H₄, X = NH₂)

A round-bottom flask was charged with 15 mL of EtOH, 0.28 g (0.002 mol) of 4-chlorobenzaldehyde, 0.13 g (0.002 mol) of malononitrile and one drop of base (triethylamine or morpholine). The mixture was stirred until completion of the reaction and the formation of a white precipitate of dinitrile 3. To the resulting suspension 2-[(4-hydroxy-6-oxo-1H-pyrimidin-2-yl)sulfanyl]acetamide 1 (0.2 g, 0.001 mol) and 3 drops of morpholine were added. The reaction mixture was heated under reflux until the reaction was completed (control by TLC, precipitation). The formed precipitate was filtered off and dried to a constant weight. The product 4 is light yellow powder. The substance is insoluble in water and EtOH, but well soluble in DMF when heated. The yield was 23%.