Benha University Faculty of Science Chemistry Department Synthesis and Reactions of Some Heterocyclic compounds of Expected Biological Activity A thesis Submitted in partial fulfillment of the requirements of master degree in chemistry Submitted by Esraa Azmy Abd El-Wahab (Bachelor of Science in Chemistry) Submitted To Chemistry Department - Faculty of Science -BenhaUniversity Supervised by Prof. Dr. Prof. Dr. Ashraf Abd El-Hamid Wasfy Mohamed Abo El-Ela Radwan Professor of Organic Chemistry Professor of Applied Chemistry Chemistry Department Faculty of Engineering Faculty of Science Shoubra Benha University Benha University Dr. Dr. Ali Abd El-Maboud Ali Manal Mahmoud El-Hefnawy Ass. Professor of Organic Chemistry Lecture of Organic Chemistry Chemistry Department Faculty of Engineering Faculty of Science Shoubra Benha University Benha University 2011 ِاللَّه مُ ضْ َف ٌَ اكَ وَ ىُ َهعْ َت ٍْ كُ َت ىْ َن ايَ كَ ًَ ههعَ وَ َتًَ كْ حِ نْ اوَ بَ اَتكِ نْ ا كَ يْ َهعَ ُاللَّه لَ زَ َْ َأوَ ﴿ ﴾ اًً يظِ عَ كَ يْ َهعَ ىيظعنا اللَّ قذص )١١١( هيآ ءاسُنا ةرىس DEDICATION To My Husband Benha University Faculty of Science Chemistry Department Title: Synthesis and Reactions of Some Heterocyclic compounds of Expected Biological Activity Student name: Esraa Azmy Abd El-Wahab Supervisors: Thesis advisors Thesis approved Prof. Dr. Ashraf Abdel-Hamid Wasfy Prof. Dr. Mohamed Abo El-Ela Radwan Dr. Ali Abd El-Maboud Ali Dr. Manal Mahmoud El-Hefnawy Prof. Dr. Shafei Galal Donia Head of Chemistry Department PRE-MASTER COURSES Beside the work carried out in this thesis the candidate has attended Post- graduate courses in organic chemistry Covering the following topics: 1. Physical organic chemistry 2. Heterocyclic chemistry 3. Analytical organic chemistry 4. Organic spectroscopy 5. Applied organic chemistry 6. Selected courses 7. English language Prof. Dr. Shafei Galal Donia Head of Chemistry Department ABSTRACT N-(2-(4-chlorophenyl)-1-(4-oxo-4H-benzo[d][1,3]oxazin-2-yl)vinyl)-2-(1,3- dioxoisoindolin-2-yl)acetamide 2 was synthesized by treatment of anthranilic acid with (Z)-2-((4-(4-chlorobenzylidene)-5-oxo-4,5-dihydrooxazol-2- yl)methyl)isoindoline-1,3-dione 1 in boiling butanol. The reactions of 2 with nitrogen and carbon nucleophiles and with carbon electrophiles was investigated. ACKNOWLEDGMENTS First and foremost thanks to ALLAH, the most compassionate and the most merciful. I would like also to thanks Prof. Dr. Ashraf Abd El-Hamid Wasfy, Professor of Organic Chemistry, Faculty of Science, Benha University for his supervision, useful guidance, encouragement and facilities he offered me throughout the progress of this work. I would like also to express my sincere thanks and deepest gratitude appreciation to Dr. Ali Abd El-Maboud Ali, Ass.Professor of Organic Chemistry, Faculty of Science, Benha Universityfor his guiding the work during experimental measurements, supervision and continuous help. I am extremely grateful to Prof.Dr. Mohamed Abo El-Ela Radwan, Professor of Applied Chemistry, Faculty of Engineering, Benha University for his kind supervision. Deep thanks to Dr.Manal Mahmoud El-Hefnawy, Lecture of Organic Chemistry, Faculty of Engineering, Benha University for her supervision and encouragement. I would like to thank my parents, my brothers for their endless support, encouragement and love. I am so indebted to my husband he has been, always, my pillar and my guiding light. Without the love and support of my husband, I would not have finished this work. Thank you, my husband, for everything. Finally, my thanks also extend to all the staff members and my colleagues in faculty of Engineering and Faculty of Science, Benha University for their cooperation and encouragement during this work. TABLE OF CONTENTS 1. SUMMARY .................................................................................................. i 2. AIM OF THE WORK ................................................................................. iii 3. INTRODUCTION ....................................................................................... 1 1. Importance of 4H-3,1-benzoxazin-4-ones ....................................................................................... 1 1.1 Pharmaceutical applications of 4H-3,1-benzoxazin-4-ones ...................................................... 1 1.2 Industrial applications ............................................................................................................... 3 2. Synthesis of 4H-3,1-benzoxazin-4-ones .......................................................................................... 3 2.1 From anthranilic acids ............................................................................................................... 3 2.1.1 Via the action of acid chlorides on anthranilic acid ........................................................... 3 2.1.2 Via the action of acid anhydrides on anthranilic acid ....................................................... 8 2.1.3 Via reaction of anthranilic acid with aromatic carboxylic acid ........................................ 11 2.1.4 Reaction of substituted anthranilic acid with Boc-protected amino acids ...................... 12 2.1.5 Reaction of substituted anthranilic acid with 2,2-dihydro fluoroalkanoic acid ............... 13 2.1.6 Synthesis of Bis(411)-3,1-benzoxazin-4-one derivatives :- .............................................. 13 2.1.7 From interaction of anthranilic acid with heterocyclic compounds ................................ 14 2.1.7.1 From 4-arylidene-2-aryl-oxazoIin-5-one ................................................................... 14 2.1.7.2 From iminodithiazole ................................................................................................ 14 2.1.7.3 From (4H)-3,2-benzoxazin-4-one .............................................................................. 15 2.1.7.4 From 3- methyl-2-(ethoxycarbonylmethoxy) quinoxaline ........................................ 15 2.1.7.5 From 2-ethoxycarbonyl-4(3H)-quinazolin-4-one ...................................................... 15 2.1.7.6 From substituted coumarin ....................................................................................... 16 2.1.7.7 From hetero-ring opening of furanone derivatives .................................................. 17 2.1.7.8 From hetero-ring opening of 1,3-dioxin-4-one derivatives ...................................... 17 2.2 From N-acylanthranilic acid..................................................................................................... 17 2.2.1 Acetic anhydride as cyclizing agent .................................................................................. 17 2.2.2 Thionyl chloride as cyclizing agent ................................................................................... 18 2.2.3 Vilsmeier reagents as cyclizing agent ............................................................................... 18 2.2.4 Cyanuric chloride as cyclizing agent ................................................................................. 19 2.2.5 Dicyclohexylcarbodiimide as cyclizing agent .................................................................... 19 2.3 From 2-methyl-4H-3,1-benzoxazin-4-one ............................................................................... 20 2.4 From isatoic anhydrides .......................................................................................................... 21 2.4.1 Reaction of isatoic anhydride with acid anhyd rides ..................................................... 21 2.4.2 Reaction of isatoic anhydride with acid chlorides ......................................................... 22 2.4.3 Reaction of isatoic anhydride with phosphoryl- stabilized anions ............................... 23 2.5 Oxidation of indoles ............................................................................................................... 23 2.6 Miscellaneous .......................................................................................................................... 24 2.6.1 From β-(Triphenylphosphoranylidene)amino esters ...................................................... 24 2.6.2 From iminophosphorane .................................................................................................. 25 2.6.3 From N-benzenesulphonylanthranilic acid ...................................................................... 25 2.6.4 From thioamide derivatives ............................................................................................. 25 2.6.5 From electrochemical trichloroacetylanilides .................................................................. 25 2.6.6 CO Incorporation reaction using arynes ......................................................................... 26 2 2.6.7 From 2-(1H-1,2,3-benzotrizol-1-yl)phenylethanone ........................................................ 26 2.6.8 From heating of acetylanthranilic acid by microwave .................................................. 27 2.6.9 Thermolysis of 2-(3-benzoylthioureido)-4,5-dimethoxy benzoic acid ............................ 28 2.6.10 Thermally induced cyclization of ketenimines ............................................................... 28 2.6.11 From o-iodoaniline ......................................................................................................... 28 3. Reactions of 4H-3,1-benzoxazin-4-ones ........................................................................................ 30 3.1 Reactions with Hydrogen nucleophiles ................................................................................... 30 3.2 Reactions with Oxygen nucleophiles ....................................................................................... 30 3.3 Reactions with nitrogen nucleophiles ..................................................................................... 31 3.3.1 Ammonlysis ...................................................................................................................... 32 3.3.2 Hydrazinolysis ................................................................................................................... 33 3.3.2.1 Reactions with hydrazine hydrate ............................................................................. 33 3.3.2.2 Reaction with hvdrazine hydrate in presence of carbondisulphide ......................... 37 3.3.2.3 Reaction with subsitituted hydrazines ...................................................................... 38 3.3.2.4 Reactions with hydroxylamine hydrochloride .......................................................... 40 3.3.2.5 Reactions with thiosemicarbazide and aminoguanidines ......................................... 40 3.3.3 Aminolysis ........................................................................................................................ 41 3.3.3.1 Reactions with primary nonaromatic amines ........................................................... 41 3.3.3.2 Reactions with secondary amines ............................................................................. 43 3.3.3.3 Reactions with alkylamines ....................................................................................... 44 3.3.3.3.1 Reactions with benzylamine ............................................ 44 3.3.3.3.2 Reactions with phenylethylamine .................................... 45 3.3.3.4 Reactions with anilines .............................................................................................. 48 3.3.3.4.1 Reactions with p-bromoanilines ...................................... 49 3.3.3.4.2 Reactions with p-aminodiphenylamine ........................... 49