On the Acylation of 1,6-Diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles ^†

Abstract

Here, 1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles, prepared by the reaction of cyanoacethydrazide with arylmethylene malononitriles, react with 1-cyanoacetyl-3,5-dimethylpyrazole and chloroacetyl chloride to give corresponding cyanoacetamides and chloroacetamides. The reaction with phthalic anhydride proceeds under harsh conditions to give 4,7-dioxo-4,7-dihydropyrido[1′,2′:2,3][1,2,4]triazolo[5,1-a]isoindole- 1,3-dicarbonitriles.

1. Introduction

In 1981, 1,6-Diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles 1 were first prepared by Soto and colleagues through the reaction of cyanoacethydrazide 2 with two eq. arylmethylene malononitriles 3 [1] (Scheme 1). The reaction also may be performed in a multicomponent mode, using corresponding aldehyde, malononitrile and cyanoacethydrazide 2. The 1,6-diaminopyridines 1 are highly functionalized, promising reagents that can be used to build various nitrogen-bridged polyheterocyclic systems (for a review, see [2]). A survey of the literature revealed a lack of information on the reaction of 1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles 1 with functionalized acylating agents such as 1-cyanoacetyl-3,5-dimethylpyrazole, chloroacetyl chloride and phthalic anhydride. Consequently, we decided to fill this gap by performing the aforementioned reactions ourselves.

2. Results and Discussion

First, we prepared a series of the starting compounds 1. We confirmed the observation of Soto and colleagues [1] that high yields of compounds 1 may be achieved only when arylmethylene malononitriles 3 are taken in at least two-fold excess with respect to cyanoacethydrazide 2. Thus, the true oxidant in the reaction is arylmethylene malononitrile 3, not atmospheric oxygen.

In 1957, 1-Cyanoacetyl-3,5-dimethylpyrazole 4 (3-(3,5-dimethyl-1H-pyrazol-1-yl)-3-oxopropanenitrile, cyanoacetylpyrazole) was introduced into synthetic practice by Ried and Meyer [3] and, since then, it has established itself as a highly effective cyanoacetylating agent—more powerful than ethyl cyanoacetate and less impractical, stabler and more convenient than cyanoacetyl chloride. As of 2020, the chemical properties of 1-cyanoacetyl-3,5-dimethylpyrazole 4 have been covered in several review papers [4,5,6]. It has been prepared by a reaction of cyanoacethydrazide 2 with acetylacetone in aqueous HCl by a reported procedure [7] (Scheme 2):

When 1,6-diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitriles 1 were treated with 1-cyanoacetyl-3,5-dimethylpyrazole 4 in hot AcOH, corresponding cyanoacetamides 5 were isolated in fair yields (Scheme 3). Similar results were observed in the reaction of 1 with chloroacetyl chloride—the products were corresponding chloroacetamides 6. Compounds 5 and 6 can be considered as promising reagents for heterocyclic synthesis.

The reaction of 1,6-diaminopyridines 1 with phthalic anhydride proceeds in quite a different manner. Thus, when treated with an excess of phthalic anhydride in boiling DMF (dimethylformamide), derivatives of the new polyheterocyclic system—4,7-dioxo-4,7-dihydropyrido[1′,2′:2,3][1,2,4]triazolo[5,1-a]isoindole-1,3-dicarbonitrile 7—were isolated (Scheme 4). Presumably, the reaction started as simple acylation followed by cascade condensation to phthalimide and finally to polycyclic structure 7.

3. Experimental

Preparation of Compounds 5 and 6

First, 1,6-Diamino-2-oxo-1,2-dihydropyridine-3,5-dicarbonitrile 1 and 1.5 eq. 1-cyanoacetyl-3,5-dimethylpyrazole 4 were heated under reflux in a minimal amount of glacial AcOH. The reaction was monitored by TLC (thin-layer chromatography). After total consumption of 1, the reaction refluxed for 5 min, and the product was allowed to cool and left to stand overnight. A yellowish solid was separated, filtered off and washed with EtOH to give pure cyanoacetamides 5. A similar procedure as reported with chloroacetyl chloride afforded chloroacetamides 6.