Green and Eco-Friendly Multicomponent Synthesis of 2-Hydroxypyridines Under Free Solvent Conditions ^†

Abstract

2-Hydroxypyridines (or commonly named 2-pyridones) are widespread nitrogen heterocycles in natural and synthetic products and their applications in biological, pharmaceutical and agrochemical compounds are becoming increasingly important. Therefore, several procedures have been described in the literature for the preparation of this heterocyclic framework. Among them, multicomponent reactions are the currently practiced method in synthetic organic chemistry, where reduced reaction times, high yields, and ease of product isolation are the main benefits of this method. In order to study the effect of the aforementioned method under greener medium, we herein describe a novel one-pot route for the design of 4,6-diaryl-3-cyano-2-pyridone derivatives under free solvent conditions. The three-component condensation of alkenes, ketones, and ammonium acetate efficiently resulted in the target heterocycles, with higher yields within a short time reaction compared to the classical method.

1. Introduction

2-Pyridones and their derivatives are widely found in bioactive natural products and therapeutical molecules. Their broad ranging biological activities comprise antibacterial [1], antiviral [2], anti-asthmatic agents [3], antifungal [4], anticancer [5], anti-inflammatory [6] and antidiabetic effects [7]. They have been useful scaffolds for synthesizing pharmacological compounds due to their attractive structural and biological features. Examples for substantial active pyridone containing drugs are shown in Figure 1 [8].

Multicomponent reactions (MCRs) are considered as a powerful method in developing a green synthetic strategy. They are known to selectively form make a unique product selectively via three or more components in only one step [9]. Moreover, MCRs form one of the most efficient tools in new chemical synthesis, with a high atom economy, rapid and easy implementation, environmentally friendly, and various target-oriented synthesis [10]. In addition, the use of organic synthesis under free solvent conditions is one of the fundamental objectives of green chemistry. These reactions are easy to perform and tend to proceed effectively and cleanly; therefore, they have rapidly gained attention and significance [11].

The development of an easy and effective procedure for the synthesis of 2-Hydroxpyridines is an active field of study, and there is still room for improvement in introducing milder reaction conditions and better product yields [12]. Encouraged by these facts and in view if our continuous efforts to apply green synthesis and especially solventless conditions to the preparation of heterocycles [13,14,15,16,17,18,19], we report a simple and convenient three-component reaction for the preparation of 4,6-diaryl-3-cyano-2-pyridone derivatives (Figure 2).

2. Results and Discussion

The present study was carried out using a solvent-free method on the multi-component condensation of alkenes (1) with ketones (2) and ammonium acetate (3), with the aim of synthesizing 4,6-substituted aryl-3-cyano-2-pyridones (4).

The reagents were mixed and heated under dry conditions. The progress of the reaction was monitored by TLC and, after completion, the crude product was washed with ethanol and diethyl ether to obtain the corresponding products. The results of the reaction are listed in

Table 1. Synthesis of 2-pyridone derivatives.

Product	1	2	3
R1	4-F	2-Cl	4-F
R2	3,4-diMe	4-OMe	4-Me
Yield (%)	60	46	62

Reaction conditions: Alkenes (0.01 mol), ketones (0.01 mol) and ammonium acetate (0.01 mol) under free solvent conditions.

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3. Experimental Procedure

A mixture of aromatic alkenes (0.01 mol), aromatic ketones (0.01 mol) and ammonium acetate (0.01 mol) was heated up to 80 °C without any solvent. Once the reaction was completed as indicated by TLC (3–6 h), the crude product was cooled to room temperature and washed a few times with diethyl ether and ethanol. The product was then filtered to afford the corresponding heterocycle.

Product 3: Yield: 62%; white solid; m.p. > 266 °C; IR (KBr): 3845(N-H); 3393(C-H_arom); 2212 (CN); 1643 (C=O) and 1513(C=C).

4. Conclusions

In this paper, we have reported a novel and simple synthesis of 2-pyridones based on the condensation of three components in a single reaction under solvent-free and green chemistry conditions. This procedure includes some advantages like a short time reaction, higher yields, benign reaction conditions, and an ecofriendly method.