N NH Me O 1 N NH CH2Cl O 3 NCS 2 N N CH2 O 4 N N O N Ar O O TEA N O O Ar 5a–e 8a–e N N O N Ar O O 9a–c PhNO2 a b c d e Ar = Ph Ar = C6H4Me- p Ar = C6H4Cl- p Ar = C6H4OMe- p Ar = C6H4NO2- p – + 234 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 234–235 J. Chem. Research (M), 1997, 1560–1575 Dipolar Cycloaddition Reactions with Quinazolinones: a New Synthesis of Azoloquinazolinone Derivatives Sami S. Ghabrial* and Mayssoune Y. Zaki National Organization for Drug Control and Research (NODCAR), P.O.Box 29, Cairo, A.R. Egypt Several new pyrroloquinazolinone derivatives are synthesised via a novel route involving the action of dipolarophiles on the diionic species generated in situ from the reaction of N-chlorosuccinimide with 2-methylquinazolin-4-one and subsequent treatment with triethylamine. Quinazolin-4-one (1) and its annelated azolo derivatives have been found to exhibit antibacterial activity against a variety of organisms, e.g. tuberculostatic activity.1,2 Moreover, the pyrrole moiety is also reported to be an active and essential component in a number of drugs and pharmaceutical preparations controlling infections of bacteria, protozoa and viruses, besides being analgesic and hypnotic.3-10 The incorporation of the two moieties increases the biological activity of both and thus it was of value to synthesise a number of new heterocyclic derivatives having both these moieties in the same molecules.A novel synthesis was developed which involved the use of N-chlorosuccinimide (NCS; 2) as chlorinating agent.In continuation our efforts towards the synthesis of biologically active fused heterocycles,1,2,3 we found that4,5 2-methyl quinazoline (1) reacted with N-chlorosuccinimide (2) to yield 2-chloromethylquinazoline (3) in situ which was separated and the structure confirmed on the basis of its analytical and spectral data [1H NMR 4.56 (s, 2 H, CH2Cl), 7.53–8.15 (m, 4 H, ArH’s) and 12.02 (brs, 1 H, NH)]. Compound 3 was then treated with triethylamine (TEA) to afford the zwitterionic 4 created by the loss of HCl.This zwitterionic species 4 was used as the starting material for the present study and its reactions with some N-arylmaleimides 5, 3-aryl- 2-cyanothioacrylamides 6 and w-nitrostyrenes 7 resulted in the formation of several new azoloquinazolinones required for medicinal studies. A mixture of 1, N-phenylmoleimide (5a) and the equivalent amount of TEA in dry chloroform was stirred for 1 h afforded a product of molecular formula C19H13N3O3 which corresponded to the addition of one molecule of 1 to one molecule of 5a followed by HCl elimination.The IR spectrum of this reaction product showed the presence of sat. CH2 and CH (2980 cmµ1), CO (1680) and C�N (1630) in addition to the (·CO·NAr·CO·) group as two widely separated bands at 1790 and 1710 cmµ1. The 1H NMR spectrum revealed signals for pyrrolidine-CH2, pyrrolidine H-3 and pyrrolidine H-4 in addition to aromatic protons in their expected positions (cf.Experimental, see full text). Based on the above data, this reaction product was formulated as the 3a,11a-dihydro-11H-pyrrolo[3p,4p:4,5]pyrrolo[ 2,1-b]quinazoline-1,3,5-trione derivative 8a. The formation of 8a in this reaction was assumed to proceed via the initial reaction of 1 with 2 to yield in situ the non-isolable 2-chloromethylquinazolinone 3. This reacts with TEA to yield the zwitterionic species 4 which then reacts with 5a via a dipolar cycloaddition reaction to yield isolable 8a.This reaction constitutes a simple and easy one pot reaction leading to a fused heterocyclic derivative which is otherwise difficult to obtain. Similarly, compound 4 reacted with each of the N-arylmaleimides 5b–e to give the corresponding pyrrolo-pyrroloquinazolinone derivatives 8b–e respectively. The structures of 8b–e were also established on the basis of correct elemental analysis and spectral data which were found to be in good agreement with the assigned structures.On the other hand, dehydrogenation of 8a–c using either chloranil or nitrobenzene resulted in the formation of the corresponding 11H-pyrrolo[3p,4p:4,5]pyrrolo[2,1-b]quinazoline- 1,3,5-trione derivatives 9a–c respectively. The structure *To receive any correspondence. Scheme 1 Scheme 2J. CHEM. RESEARCH (S), 1997 235 of 9a–c was confirmed by elemental analysis and spectral data.The IR spectra of compounds 9a–c showed the presence of CO (1890) and the (·CO·NAr·CO·) group (1780, 1710) in addition to sat. CH2 (2980) and C�N (1630 cmµ1). The 1H NMR spectra of compounds 9a,c revealed only signals for pyrroline-CH2 (d, 4.8) and aromatic protons (m, 7.2–8.0). No pyrrolidine H-3 or H-4 signals were detected in these spectra in accordance with the dehydrogenation reaction. The behaviour of 4 towards a variety of 3-aryl-2-cyanothioacrylamide derivatives 6a–e was also investigated. Thus, it was found that 1 and 4 reacted with 3-pmethoxyphenyl- 2-cyanothioacrylamide (6a) in the presence of TEA to yield a product with molecular formula C20H16N4SO2 which had an absorption band corresponding to the nitrile function in the IR spectrum.Moreover, pyrrolidine- CH and CH2 protons were detected by 1H NMR. Based on the above spectral data, the reaction product was formulated as the thiocarboxamido-3H-pyrrolo[2,1-b]quinazolin- 9-one derivative 10a.The reaction is assumed to proceed via the initial formation of 4 followed by cycloaddition to 6a to yield the product 10a. In a similar manner, each of 6b–e reacted with 1 and NCS in the presence of TEA to yield the corresponding 2,3-dihydropyrrolo[ 2,1-b]quinazolin-9(1H)-one derivatives 10b–e, respectively. The structures of 10b–e were also confirmed by elemental analysis and spectral data as for 10a. Evidence for the structures of 10a–e was provided by the action of sodium ethoxide.Thus, each of 10a–e reacted with boiling sodium ethoxide to give, after acidification, products corresponding to the loss of one molecule of HCN in each case. The IR spectra of these reaction products showed that the bands of the nitrile function were entirely absent. Accordingly, these reaction products were formulated as the thiocarboxamido- 3H-pyrrolo[2,1-b]quinazolin-9-one derivatives 11a–c, respectively. Moreover, the 1H NMR revealed pyrroline- CH2, aromatic and NH2 protons only.Furthermore, compound 1 and NCS in chloroform and TEA (i.e. 4) reacted with a variety of w-nitrostyrenes 7a–e. Thus 4 reacted with w-nitrostyrene 7a to yield the cycloadduct 12a. IR and 1H NMR spectra showed the structure to be the 2-nitro-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)- one derivative 12a. Analogously, each of 7b–e reacted with 4 to afford the 2-nitro-2,3-dihydropyrrolo[2,1-b]quinazolin- 9(1H)-ones 12b–e, respectively. Moreover, compounds 12a–c could also be dehydrogenated by the action of chloranil to give the corresponding 2-nitro-4H-pyrrolo[2,1-b]quinazolin-9-one derivatives 13a–c, respectively. 1H NMR revealed signals for pyrroline-CH2 and aromatic protons only. Techniques used: 1H NMR, FTIR, elemental analysis References: 14 Tables 1 and 2: Data for compounds 3, 8, 9, 10, 11, 12 and 13 Received, 19th March 1997; Accepted, 21st March 1997 Paper E/7/01931I References 1 A. O. Abdelhamid, F. A. Khalifa and S. S. Ghabrial, Phosphorus Sulfur Relat. Elem., 1988, 40, 41. 2 S. S. Ghabrial, Phosphorus Sulfur Silicon Relat. Elem., 1993, 84, 17. 3 S. S. Ghabrial and M. Y. Zaki, Indian J. Chem., 1994, 33, 855. 4 S. S. Ghabrial, I. Thomson and K. B. G. Torssell, Acta Chem. Scand., Ser. B, 1987, 41, 426. 5 S. S. Ghabrial and A. O. Abdelhamid, Arch Pharm., 1985, 320, 1281. 6 K. 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