M. Deetz, J. Malerich, A. Beatty
Nov 9, 2004
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ChemInform
Abstract
2-Fluoro substituted benzoyl chlorides undergo cyclocondensation with 2-amino-N-heterocycles to form 4(3H)-quinazolinones. The reaction proceeds in moderate yields with different combinations of benzoyl chlorides and 2-amino-N-heterocycles. The products generally precipitate from the reaction mixture and require no further purification. Two tetrafluoro quinazolinones were found to be moderately active against a number of tumor cell lines. © 2001 Elsevier Science Ltd. All rights reserved. It has been more than a century since the initial studies on 4(3H)-quinazolinones, and they are well known as biologically active compounds. It has also been long recognized that incorporation of fluorine atoms into a molecular skeleton can significantly alter a compound’s biological activity. While there exist numerous methods for the synthesis of 4(3H)-quinazolinones and their derivatives, there are few general methods that easily produce fluorinated analogs. Herein, we report the synthesis of 4(3H)-quinazolinone derivatives, 1, using a simple, one-step reaction that generally requires no purification. The structural scope of the reaction is broad and allows quick access to quinazolinones bearing a range of peripheral functionality. The structure of the products, 1, were elucidated using multinuclear NMR spectroscopy, mass spectrometry, and X-ray crystallography. Evidence that quinazolinone 1a was its linear 4(3H)-isomer was gained from a fluorine decoupled C NMR spectrum. The C signal corresponding to the carbonyl carbon, C4, exists as a doublet with JCH=3.0 Hz. This is indicative of coupling through three bonds, a condition that is met by the linear 4(3H)-quinazolinone, 1a, but not with an alternative angular 4(1H)-quinazolinone, 3a, which would have resulted if the amine nitrogen reacted first with the acid chloride. Definitive evidence for the 4(3H)-isomer was gained by an X-ray crystal structure of the benzothiazole derivative, 1k (Fig. 1). The generality of the reaction was probed by reacting various 2-amino-Nheterocycles with 2-fluorobenzoyl chlorides. The general procedure involves treatment of a dichloromethane solution of 2-amino-N-heterocycle and i-Pr2EtN with acyl chloride at room temperature. The quinazolinone precipitates immediately, is collected by filtration and normally requires no further purification. The results are shown in Table 1. Examination of Table 1 shows that as the number of fluorines on the benzoyl chloride decreases, the isolated yields of cyclized product also decreases. Introduction of a nitro group at the 5-position leads to more efficient ring closure (compare entries 4 and 5), which is consistent with the ability of a para-nitro group to promote nucleophilic aromatic substitution. In most cases the major by-product is the corresponding amide 2 (Scheme 1). In the case of pentafluorobenzenesulfonyl chloride (entry 6), reaction with 2-aminopyrimidine yielded solely the corresponding sulfonamide with no evidence of cyclized product. Entries 7–11 in Table 1 show that Figure 1. X-Ray crystal structure of 1k. * Corresponding author. 0040-4039/01/$ see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0040 -4039 (01 )00096 -X M. J. Deetz et al. / Tetrahedron Letters 42 (2001) 1851–1854 1852 the cyclocondensation reaction can tolerate a number of other 2-amino-N-heterocycles. To confirm that 2,3 fusion takes place with all of these systems, the F NMR chemical shifts of the cyclized products were compared with those of the known linear 4(3H)-quinazolinone, 1k (Table 2). The close correlation is consistent with the linear product in all cases. The probable reaction mechanism is initial nucleophilic attack of the ring nitrogen on the benzoyl chloride followed by intramolecular nucleophilic aromatic substitution of the 2-fluoro substituent. It is known that in 2-aminopyrimidine, the ring nitrogen is the most nucleophilic atom. Treatment of 1a with methanol and butylamine, as model nucleophiles, results in ring-opened products, 4 (Table 3). This formal amide bond scission occurs