Reactivity of 4 H -3,1-benzoxazin-4-ones towards nitrogen and carbon nucleophilic reagents: applications to the synthesis of new heterocycles

6,8-Dibromo-(4 H )-3,1-benzoxazinone 1a was synthesized and allowed to react with some nitrogen nucleophiles namely, hydroxylamine hydrochloride


Introduction
2][3][4][5][6][7] One of the most important features in (4H)-3,1-benzoxazinones chemistry is their use as key starting materials for further transformations.They are indeed useful intermediates in organic synthesis affording through reaction with nitrogen nucleophiles 4(3H)quinazolinones.With the aim of extending information on the reactivity of 4H-3,1-benzoxazinones and also synthesizing from them new heterocyclic systems, potentially with biological activity [8][9][10][11][12] and in continuation of our work on the behaviour of stable benzoxazinones 13 towards nitrogen and carbon nucleophiles, other derivatives were obtained via the interaction of acetic anhydride and/or isobutyroyl chloride with anthranilic acid derivatives.The electronically unsaturated character of unstable benzoxazinones which are (4H)-3,1-benzoxazinones bearing saturated substituents such as CH 3 , CH 2 COCH 3 , CH 2 CN and CH 2 CH 2 CO 2 H at position 2 [14][15][16][17] renders their synthesis difficult because they are not satisfactorily stable rings.Our contribution to solve this problem includes the construction of bulky substituents involving strong conjugation power to obtain stable benzoxazinones. 13,18erein, we report the synthesis of 2-substituted (4H)-3,1-benzoxazinones 1a and b via the reaction of freshly distilled acetic anhydride 19 and/or isobutyroyl chloride in dry pyridine 20

Results and Discussion
With the aim of expanding the synthetic potential of the (4H) 3,1-benzoxazinones formed, we have studied the reaction of 1a with hydroxylamine hydrochloride.This is a simple and convenient route to the synthesis of 3-hydroxy-4(3H)-quinazolinone 2 which is a promising intermediate for diverse organic synthesis [ Scheme 1].Thus reactions of the latter compound with acetic anhydride and ethyl chloroacetate afforded 3-acetoxy-and 3ethoxycarbonylmethoxy-4(3H)-quinazolin-ones 3 and 4 respectively.Aminolysis of benzoxazinone 1a occurred when it was treated with 4-aminoacetophenone to yield 3-(4acetophenyl)-4(3H)-quinazolinone 5 via heteroring opening followed by ring closure. 21 variety of 2,3-disubstituted 4(3H)-quinazolinones containing a heterocyclic group in position 3 have been prepared from the reaction of 2-methyl and 2-phenyl-(4H)-3,1benzoxazinones with different heterocycles containing the amino functionality. 22Various quinazolinone dyes have been synthesized from coupling diazotized aminoquinazolinone with various coupling components and their dyeing effect on viscose rayon, silk and wool fibers has been assessed. 23The forementioned findings prompted the author to carry out the reaction of 1a with o-phenylenediamine to obtain 3-(2-aminophenyl)-4(3H)-quinazolinone 6 which could be diazotized and coupled.It is of interest to compare the previous result with the cyclocondensation of 2-aryl-(4H)-3,1benzoxazinones with o-phenylenediamine to give benzoimidazoquinazolines if the reaction is conducted in orthophosphoric acid at reflux temperature. 24Sulfanilamide and its derivatives have great antibacterial power and are widely used in medicine against "cocci infections".Consequently, we have tried to expand the applicability of sulfanilamides, and herein we report the synthesis of novel heterocycles of anticipated biological activity containing quinazolinone moiety incorporated sulfa drug residue.Thus, treatment of 4H-3,1-benzoxazinone 1a with sulfanilamide and/or sulfamethoxazole afforded 2,3-disubstituted 4(3H)-quinazolinones 7 and 8 respectively. 13,25Successful attempt to construct a third heterocyclic ring condensed with quinazoline was achieved via reaction of 1a with semicarboazide hydrochloride in refluxing dry pyridine to give triazolo[2,3-c]quinazoline 9. Reaction of (4H)-3,1-benzoxazin-4-one 1a with ethanolamine at refluxing temperature resulted in the hydroxyethylquinazolinone 10 which was utilized to alkylate some aromatic systems namely, phthalimide and 2-naphthol in acidic media to afford the respective quinazolinones 11 and 12.
According to our previous works, the reaction of hydrazine hydrate with 2-substituted 4H-3,1-benzoxazinones results in the formation of 3-aminoquinazolinone derivatives when the substituent at position-2 is bulky 13 or when the reaction is carried out in presence of anhydrous zinc chloride. 6Thus, when 4H-3,1-benzoxazinone 1b was allowed to react with hydrazine hydrate in boiling ethanol, it yielded the respective 3-amino-4(3H)-quinazolinone 13 and this agreed well with our reported finding [cf.Scheme 2].3-Aminoquinazolinone 13 could be used as versatile building blocks in the synthesis of new heterocyclic systems.Thus, the amino functionality of 3-amino-4(3H)-quinazolinone reacts with carbon electrophiles namely, chloroacetamide and aromatic aldehydes viz benzaldehdye, 4-methoxy-benzaldehyde and 4chlorobenzaldehyde to afford triazino[2,3-c]quinazoline 14 and 3-arylideneamino-4(3H)quinazolinones 15a-c respectively.The former compound was formed through 3carbamoylmethylamino-4(3H)-quinazolinone intermediate followed by ring closure, whereas the latter was formed by nucleophilic attack of the amino group on the electronically deficient carbonyl carbon atom of the aldehyde followed by dehydration, a process in which the driving force of removing the bad leaving hydroxyl group is the conjugation with the aromatic nucleus in the more thermodynamically stable compound 15a-c.It is of interest to investigate the behaviour of azomethines 15a-c which contain an activated C=N bond towards aliphatic and aromatic mercaptans.Cyclocondensation of 15c with 2-mercaptoacetic acid in the presence of few drops of piperidine gave the thiazolidin-4-one derivative 16. 26 The reaction proceeded via nucleophilic addition of sulfur to C=N followed by cyclization and a thiazole nucleus attached to N3 of quinazolinone derivative 16 was obtained.On the other hand, when azomethine 15c was allowed to react with thiophenol in the presence of piperidine as a basic catalyst, the adduct 17 was isolated.It has been reported that 2-phenyl-(4H)-3,1-benzoxazin-4-one underwent base-catalyzed ring opening with active methylene containing compounds e.g., ethyl acetoacetate, diethylmalonate and ethyl cyanoacetate in refluxing pyridine to afford ethyl o-benzamidobenzoylacetate. 28 In the present work, it has been found that hitherto unknown reaction of malononitrile with benzoxazinone 1a in presence of ethanolic sodium ethoxide resulted in 4-hydroxy-3cyanoquinoline derivative 18 [cf.Scheme 3].The o-hydroxynitrile 18 could be versatile in the synthesis of fused heterocycles utilizing its bifunctionality.Thus, when compound 18 reacted with phenyl isocyanate in the presence of triethylamine in refluxing benzene, it gave the oxazino [5,6-c] quinoline 19.[31][32][33] Thus, reaction of oxazinone 1a with ethereal solution of phenylmagnesium bromide and/or benzylmagnesium bromide yielded the unexpected carbinols 20 and 21 respectively.The reaction proceeded through attack of the Grignard's reagent on the carbonyl group of the oxazinone nucleus to give the o-acetamidobenzophenone or o-acetamidoacetophenone intermediate which was attacked by another molecule of the reagent to afford the corresponding carbinol.The isolation of one and the same product from two different routes; reaction of benzoxazinone 1a with phenylmagnesium bromide and/or dry benzene in presence of anhydrous aluminium chloride led us to assume that the addition of the second Grignard's molecule occurred at the carbonyl functionality adjacent to N-Mg bond [cf.Scheme 4].The behavior of 2-methyl-(4H)-3,1-benzoxazin-4-one 1a towards aromatic hydrocarbons namely, benzene, ethylbenzene, m-and p-xylenes under Friedel-Crafts reaction conditions was also studied.The present study revealed that the less bulky hydrocarbons viz benzene and ethylbenzene afforded two simultaneous products.The first is obtained due to attack of the acylating agent upon one molecule of the substrate hydrocarbon to give the respective benzophenone derivative 22 and 23 and the second resulted from the reaction of the acylating agent with two molecules of the hydrocarbon to afford the carbinols 20 and 24 respectively.When the reaction is carried out with more bulky hydrocarbons viz m-and p-xylenes, a sole product was isolated which was identified as the 2-acetamidobenzophenone derivatives 25 and 26.According to our speculation, the formation of one product in case of more bulk hydrocarbons is due to the bulk of the substrate hydrocarbon.Finally, when (4H)-3,1benzoxazin-4-one 1a, was allowed to react with barbituric and/or thiobarbituric acids in refluxing pyridine, 5-arylidene-barbituric and thiobarbituric acids 27a and b were obtained through fission of oxazinone nucleus.The product 27 was obtained from heteroring opening of the oxazinone nucleus followed by enolization.This seems to be reasonable owing to compound 27 is being thermodynamically stable via cinnamoyl resonance and hydrogen-bonding as well, while the keto form of compound 27 stabilizes by benzoyl resonance (stabilization by cinnamoyl resonance is higher than benzoyl resonance).synthesized compounds are given in Table 1. 13 C-NMR spectra of some synthesized compounds are listed in Table 2.
34,35elting points reported are uncorrected and were determined on a Stuart electric melting point apparatus.The IR spectra were measured on a Unicam 1200 Spectrophotometer using potassium bromide Wafer technique.Mass spectra were measured on Shimadzu GC-MS-QP 1000 EX instrument operating at 70 eV.The values of m/z of the fragments are written followed by (I r / %) percentage of relative intensity.The 1 H-and 13 C-NMR spectra were recorded in CDCl 3 or DMSO-d 6 solutions on Varian Gemini 200 MHz instrument.34,35TMS was used as internal standard with chemical shifts δ from downfield to upfield.TLC were performed on ready-to-use silica gel plates Merck 60.Satisfactory results were obtained for elemental analysis in Institut für Organische Chemie, Tubingen University, Tubingen, Germany: C ± 0.41%, H ± 0.29%, N ± 0.32%.Physical characteristics of the © ARKAT USA, Inc

Table 1 .
Physical characteristics of synthesized compounds