Multicomponent, Solvent-Free Synthesis of 4-Substituted Aminopyrido[2,3-d]pyrimidines Derivatives ^†

Abstract

4-substituted aminopyrido [2,3-d]pyrimidines derivatives 1a–f were synthesized via the multicomponent reaction of 2-aminopyridines, triethyl orthoformate, and diverse primary amines under solvent-free conditions. The present work creates a variety of fluorescent heterocyclic compounds in a short time and with good yields. The structures of all synthesized compounds were established by IR, ¹H, and ¹³C NMR analysis.

1. Introduction

Pyrido[2,3-d]pyrimidines are one of the most interesting nitrogen heterocycles and play a vital role in progressive drug design and discovery [1]. They also have various biological activities such as antitumor [2], antipyretic [3], antihypertensive [4], antifungal [5], antibacterial [6], and anti-inflammatory activities [7]. More specifically, pyrido[2,3-d] pyrimidines have been shown to be effective against dihydrofolate reductases (DHFR) [8], tyrosine kinases, and adenosine kinase [9]. Moreover, the synthesis of these fused heterocyclic compounds provides an interesting challenge in medicinal chemistry [10,11,12].

Continuing our research in the field of new heterocyclic compounds of biological interest [13,14,15], we previously reported the synthesis of functionalized pyrido[2,3-d]pyrimidines [16] (Figure 1). Encouraged by these results, we decided to extend this methodology to the synthesis of new pyrido [2,3-d] pyrimidines via a multi-component reaction under solvent-free conditions.

2. Results and Discussion

In our current studies on the synthesis of 4-substituted aminopyrido [2,3-d] pyrimidines, we reported a simple and new multicomponent reaction in eco-friendly economical and environmental conditions.

Recently, multi-component reactions (MCRs) have become a promising approach to achieve such molecular diversity and complexity [17]. In this work, we present a new efficient method for the synthesis of aminopyrido [2,3-d] pyrimidines derivatives from 3 -cyano-2-aminopyridine under solvent-free conditions.

Synthesis of 4-Aminopyrido[2,3-d]pyrimidines Derivatives

The 4-aminopyrido [2,3-d] pyrimidines 1a–f were easily obtained via a one-pot reaction of 3-cyano-2-aminopyridines, triethyl orthoformate, and diverse primary amines. The mixture was heated for 3h without a solvent to obtain compounds 1a–f in good yields (61–85%). The primary amines used were benzylamine, butylamine, propylamine, hexylamine, phenylethylamine, and tryptamine (

Table 1. Synthesis of 4-aminopyrido[2,3-d]pyrimidines derivatives.

Product	Primary Amine	Yield (%)
1a	Benzylamine	85
1b	Butylamine	79
1c	Butylamine	71
1d	Cyclohexylamine	69
1e	Phenylethylamine	65
1f	Tryptamine	61

).

The structures of the compounds 1a–f were confirmed by spectral analysis. The IR spectra (KBr, ν_max, cm⁻¹) showed the absence of NH₂ and CN as well as the appearance of (C=C) at 1542–1559 cm⁻¹, (C=N) at 1669–1690 cm⁻¹, and NH at 3462–3540 cm⁻¹.

¹H NMR (CDCl₃, δ, ppm) showed the appearance of OCH₃ stretch at δ_H 3.86–3.88 ppm and NH stretch at δ_H 5.17–5.79 ppm, as well as H_pyrid stretch at δ_H 7.09–7.36 ppm and H_pyrimid stretch at δ_H 7.76–8.65 ppm.

3. The Proposed Mechanism for the Formation of 4-Aminopyrido[2,3-d]pyrimidines

1a–f 

The proposed mechanism for the formation of 4-aminopyrido[2,3-d] pyrimidines 1a–f is described in Figure 2.

The reaction begins with the formation of intermediate I followed by nucleophilic addition of the “NH₂” group of 2-aminopyridines on the double bond to form intermediate II. After rearrangement and 1,2-aza-Michael addition between the primary amine and the “CN” group of product III, intermediate IV is obtained. The latter undergoes a rearrangement and a 1,2-aza-Michael addition intramolecularly to form product V. Finally, an aromatization step to obtain the desired 4-aminopyrido[2,3-d]pyrimidines.

4. Experimental Procedure

General procedure for the synthesis of 4-aminopyrido[2,3-d]pyrimidines 1a–f:

The products 1a–f were obtained by the reaction between 10 mmol of 3-cyano-2-aminopyridine, 10 mmol of primary amine, and 10 mmol of triethyl orthoformate. The mixture was heated for 3h at 100 °C. After the completion of the reaction (TLC), the residue was purified by column chromatography over silica gel using a mixture of nhexane–EtOAc (5:5) as the eluent. All the desired compounds were obtained as a white solid [16].

5. Conclusions

In conclusion, we have successfully developed a new route for the synthesis of 4-substituted aminopyrido[2,3-d]pyrimidines derivatives via a multi-component reaction under solvent-free conditions with good yields. This new MCR provides a general and efficient strategy for the construction of structurally diverse fused pyridopyrimidines skeleton.