Mukaiyama’s reagent promoted C–N bond formation: a new method to synthesize 3-alkylquinazolin-4-ones Puminun Punthasee, Avassaya Vanitcha, Sumrit Wacharasindhu * Organic Synthesis Research Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok 10330, Thailand article info Article history: Received 14 September 2009 Revised 24 December 2009 Accepted 25 January 2010 Available online 1 February 2010 abstract A new approach to synthesize 3-alkylquinazolin-4-ones is developed. Treatment of quinazolin-4-ones with Mukaiyama’s reagent, a base and a primary amine nucleophile results in the formation of 3-alkyl- quinazolin-4-ones in moderate to good yields under mild conditions. Using this methodology, a one-step synthesis of the natural alkaloid, echinozolinone, is accomplished. Ó 2010 Elsevier Ltd. All rights reserved. Quinazolinones 1 and related quinazolines 2 are nitrogen-con- taining heterocycles that are common in nature. They possess a wide range of biological properties including antimalarial, anti- inflammatory, anti-cancer, and anticonvulsant amongst others. 1 For example, febrifugine (3), a quinazolinone isolated from the Chi- nese herb Dichroa febrifuga, is used as an antimalarial drug 2 while erlotinib (4), a quinazoline, has stimulated intense interest as a po- tent kinase inhibitor (Fig. 1). 3 In this Letter, we report a new meth- od to synthesize 3-alkylquinazolin-4-ones via a coupling reaction between quinazolin-4-one and a primary amine in the presence of Mukaiyama’s reagent. Retrosynthetically, the most common procedure to 3-alkylqui- nazolin-4-ones is N-alkylation at the 3 position of quinazolin-4- one with appropriate alkyl halides in the presence of a strong base. 4 These methods, however, require harsh conditions and pro- duce unavoidable elimination products from the alkyl halide in addition to non-selective O-alkylation. In the case of aminoquinaz- oline 2, strong and acidic reagents such as SOCl 2 , POCl 3 , and PCl 5 were used to activate the carbonyl of quinazolin-4-one prior to the addition of the corresponding amine. 5 In continuing attempts to develop robust synthetic methods for aminoquinazolines 2, we recently demonstrated an efficient ‘one-step’ synthesis of cyclic amidines using the phosphonium reagent, benzotriazol-1-yloxy-tris-(dimethylamino)phosphonium hexafluorophosphate (BOP 6); this amination was accomplished in high yield. 6 Nevertheless, this method is inconvenient for scale-up because the phosphonium reagent is expensive and has a high molecular weight resulting in atom inefficiency. Moreover, the by-product of the reaction is HMPA which is considered to be a carcinogenic substance. 7 In search of new activators, we reasoned that there was a possibility of using another amide-coupling agent. 8 Mukaiyama’s reagent, 2-chloro-1-methyl-pyridinium io- dide 7 would appear to be appropriate for the activation due to its high stability and low cost. 9 Surprisingly, the use of this activa- tor under our previous conditions led to the isolation of 3-butyl- quinazolin-4-one 9 as the sole product in 60% yield with 20% recovery of starting material and without detection of the expected amidine 8 (Scheme 1). The 1 H NMR data of 8 and 9 are clearly dis- tinguishable since the 2-H signal of 8 appears at 8.60 ppm while the same proton in 9 resonates at higher field (8.03 ppm) due to the aromaticity of the quinazoline ring. Moreover, the HMBC spec- trum of 9 confirmed the regioselectivity of this coupling reaction which occurred at N-3 instead of N-1. 10 To explore the scope of this new procedure, a panel of low cost amide bond-coupling agents was screened (Table 1). DCC gave a lower yield compared to Mukaiyama’s reagent while cyanuric chloride and 2,4-dichloro-6-methoxy[1,3,5]triazine (DCMT) re- sulted in decomposition and only trace amounts of the desired qui- nazolinones 9 were detected. This short survey revealed that Mukaiyama’s reagent was well-suited for this transformation. 11 0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2010.01.087 * Corresponding author. Tel.: +66 2 218 7634; fax:+66 2 218 7598. E-mail address: sumrit.w@chula.ac.th (S. Wacharasindhu). N N O O N H HO Febrifugine 3 N N HN O O MeO MeO erlotinib 4 N N O R 1 N N NHR 2 1 4 2 8 Figure 1. Representative 3-substituted-quinazolin-4-ones and a related quinazo- line. Tetrahedron Letters 51 (2010) 1713–1716 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet