Straightforward synthesis of quinazolin-4(3H)-ones via visible light-induced condensation cyclization

A green, simple and efficient method is developed for the synthesis of quinazolin-4(3H)-ones via visible light-induced condensation cyclization of 2-aminobenzamides and aldehydes under visible light irradiation. The reaction proceeds using fluorescein as a photocatalyst in the presence of TBHP without the need for a metal catalyst. In addition, this reaction tolerates a broad scope of substrates and could afford a variety of desirable products in good to excellent yields. Thus, the present synthetic method provides a straightforward strategy for the synthesis of quinazolin-4(3H)-ones.

Visible light was used as a readily available and renewable clean energy source for the green and metal catalyst free synthesis of quinazolin-4(3H)-ones. High and excellent yields of the desired products were obtained with good functional group tolerance.

In recent years, synthesis of nitrogen-containing heterocycles has drawn considerable attention due to their widespread occurrence in natural and synthetic organic molecules.¹ Among them, quinazolin-4(3H)-ones are common core structures found in a large number of natural products and synthetic drugs showing a broad range of biological and therapeutic activities (Fig. 1). For example, Pegamine, isolated from Peganum harmala, exhibits cytotoxic activity.² Afloqualone is a centrally acting muscle relaxant useful in the management of various conditions, including cerebral palsy, cervical spondylosis, and multiple sclerosis.³ Bouchardatine could significantly reduce lipid accumulation, and mainly inhibited early differentiation of adipocytes through proliferation inhibition and cell cycle arrest in a dose-dependent manner.⁴ Idelalisib have been shown to exhibit a broad spectrum of antimicrobial, antitumor, antifungal and cytotoxic activities.⁵ Ispinesib is one of the most potent kinesin spindle protein (KSP) inhibitors and is currently in clinical trials for cancer treatment.⁶ Sclerotigenin, isolated from organic extracts of the sclerotia of penicillium sclerotigenum, is responsible for most of the antiinsectan activity against crop pests.⁷ Besides, a number of quinazolin-4(3H)-ones have been synthesized to provide synthetic drugs and to design more effective medicines.^8,9Open in a separate windowFig. 1Representing natural and synthetic molecules containing quinazolin-4(3H)-one moieties.Owing to their pharmacological importance, considerable attention has been devoted to the development of simple and efficient methods for their construction (Scheme 1). Typically, quinazolin-4(3H)-ones are synthesized by acid or base-catalyzed condensation of amides with alcohols/aldehydes.^10,11 In some cases, an excess of hazardous oxidants, for instance KMnO₄, I₂, and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), are employed in the reaction, which are significant limitations in this method.^12–14 Over the past decades, various metal-based catalysts such as copper-catalyzed cyclization of 2-halobenzoic acids with amidines, palladium-catalyzed benzylic C–H amidation with benzyl alcohols and vanadium-catalyzed redox condensation of benzamides with alcohols or aldehydes have been reported for the synthesis of quinazolin-4(3H)-ones.^15–17 Although these approaches result in an excellent formation of the product, most of them are suffering from its own limitations such as corrosive or non-benign acid/base catalyst, hazardous oxidants, precious metal-based catalysts, complexity in work-up and relatively harsher reaction conditions. Therefore, development of a green, simple and efficient synthetic approach for the preparation of quinazolin-4(3H)-ones from inexpensive and easily available starting materials under relatively mild conditions is desirable.Open in a separate windowScheme 1Our work for synthesis of quinazolin-4(3H)-ones.Visible light-induced reaction, which is widely recognized as an attractive “green synthesis pathway” in organic synthesis, has become a fast-developing research area in the past decades.^18–21 In spite of simple operation and mild reaction conditions, the common transition metals (e.g., iridium and ruthenium) employed as photocatalysts are usually expensive, toxic and not easily available. Nevertheless, organic dyes, which have shown similar photocatalytic activity in some reactions, could be more attractive candidates than the common transition metals, because they are usually relatively cheap, less toxic and accessible.²² In particular, fluorescein has been very recently studied as photocatalyst due to its cheap and commercially available characteristics.²³In this study, we focus our attention on developing a straightforward method to prepare quinazolin-4(3H)-ones with 2-aminobenzamides and aldehydes using fluorescein as photocatalyst via visible light-induced condensation cyclization, in which the synthesis of quinazolin-4(3H)-ones would proceed in good to excellent yields under mild conditions without the need for metal catalyst (Scheme 1). This method lays a solid foundation for the synthesis of quinazolin-4(3H)-ones. Moreover, this visible light-induced strategy has great potential in the synthesis of other types of useful organic molecules.At the initial stage of investigation, 2-aminobenzamide (1a) and benzaldehyde (2a) were chosen as the model substrates under blue LED irradiation, and a series of reaction conditions including photocatalysts, oxidants, solvents and reaction time were optimized. Initially, the reaction was performed in the presence of 10 mol% fluorescein as photocatalyst and the desired product, 2-phenylquinazolin-4(3H)-one (3aa), was obtained in 89% yield (