Investigations of New Synthetic Routes to Cinnoline and Fused Cinnoline Derivatives by Martin Scobie B.Sc. Thesis presented for the degree of Doctor of Philosophy University of Edinburgh 1992 Declaration I declare that this thesis is my own composition, that the work of which it is a record has been carried out by myself and that it has not been submitted in any previous application for a higher degree. The thesis describes the results of research carried out in the Department of Chemistry, University of Edinburgh, under the supervision of Dr. G. Tennant between October 1986 and September 1989. Acknowledgements I would like to thank Dr. G. Tennant for his supervision and encouragement during the course of my research. I would like to thank the University of Edinburgh for the provision of laboratory and library facilities. I would also like to acknowledge the help and expertise of the technical staff of the Department of Chemistry, University of Edinburgh, notably Ms. H. Grant and Mr. J. Millar for the measurement of n.m.r. spectra, Ms. E. McDougall for the determination of microanalyses, Ms. E. Stevenson and Mr. A.T. Taylor for the measurement of mass spectra and Dr. A.J. Blake and Dr. R.O. Gould for crystallographic structural determinations. Finally, I am grateful to Dr. J.J.R. Kamal for his assistance with the preparation of this manuscript. "N.M.R. Spectroscopy" Dr. I.H. Sadler (University of Edinburgh). "Medicinal Chemistry" Prof. P.O. Sammes (Smith, Kline and French). "Elements of Cell Biology" Dr. J. Phillips (University of Edinburgh). "Introduction to Management" Several speakers (Dept. of Business Studies, University of Edinburgh). "Mass Spectrometry" Prof. K.R. Jennings (University of Warwick). "Current Topics in Organic Chemistry I and II" Several speakers (Dept. of Chemisiry,University of Edinburgh). "Catalysis and the Chemical Industry" Several speakers (I.C.I., Grangemouth). Departmental Seminars. Departmental Colloquia. ABSTRACT The subject matter of this thesis is concerned with the investigation of new synthetic mutes to cinnoline and fused cinnoline derivatives. A description of the results obtained in these studies is preceded in Chapter 1 by a survey of literature methods for the synthesis of cinnoline derivatives. Chapter 2 describes an investigation into the use of 2-nitroaroy1forminiidates as intermediates in the synthesis of 3,4-substituted cinnoline derivatives and in particular 2-amino-3-(2-nitroaryl)quinoxalines. The base-catalysed cycisation of the latter compounds, to afford quinoxalino[2,3 -Q]cinnoline fl-oxides is also reported and the scope of this method investigated. Chapter 3 describes the synthesis of 3-arnino-5-hydroxy-4-(2-nitroaryl)-2ff- pyrazole derivatives and their base-catalysed cyclisation to give 1-hydroxy-311- pyrazolo[3,4-Q]cinnoline j-oxides. The influence of substituent effects on the scope of this cycisation was also studied. Furthermore the oxidative ring-scission of the resulting hydroxypyrazolo[3,4-]cinnoline derivatives to afford cinnoline-4-carboxylic acid 1-s-oxides is also reported. Chapter 4 deals with studies on the synthesis and cycisation of 3-amino-4-(2- nitroaryl)isoxazol-5(2-ones. Base-induced cyclisation of the isoxazolone derivatives afforded isoxazolo[3,4-ç]cinnolinones which were converted to 3-aminocinnoline-4- carboxylic acid i-oxides by their reaction with hydrazine. CONTENTS PREFACE 1 CHAFFER ONE A Survey of Literature 5 Methods for the Synthesis of Cinnoline Derivatives CHAPTER TWO Investigation of 27 2-Nitrobenzoy1formimidate Derivatives as Synthetic Precursors of Cinnolines and Fused Cinnolines Experimental Section 83 23. CHAPTER THREE Studies of the Synthesis and 138 Ring-Scission Reactions of Pyrazo1o[3,4-Jcinnoline Derivatives Experimental Section 184a Itj CHAPTER FOUR Studies of the Synthesis and 233 Ring-Scission Reactions of Isoxazolo[3,4- Jcinnoline Derivatives Experimental Section 268 BIBLIOGRAPHY 304 PREFACE Inflammatory processes associated with membrane breakdown in the arthritic joint have been closely linked to the presence of radical species and in particular hydroxyl (H0 ), peroxy anion (Of) and hydroperoxy (H02 ) radicals 13 Once formed these species can react with many organic molecules commonly found in the cell environment such as fatty acids or amino acids and so promote the breakdown and eventual destruction of the cell. Since the number of oxy-radicals produced in vivo is likely to be high, chemotherapy by oxy-radical scavenging on a one to one basis is impractical. If however the scavenger system is capable of being regenerated via some reductive or oxidative process occuring in vivo then efficient scavenging will result by redox turnover. One such system is represented (Scheme 1) by -tocopherol (1) which has been shown to be capable of scavenging up to 120 singlet oxygen radicals before molecular breakdown occurs. The enzyme 5-lipoxygenase is known to catalyse (Scheme 1) the production of 5-hydroperoxyicosa-6,8,11,14-tetraenoic acid (3) from arachidonic acid (2). The hydroperoxide (3) is then enzymatically transformed eventually giving rise to the leukotriene derivatives LTC4 and LTD4. The inhibition of this process is beleived to be important in the amelioration of inflammation particularly in the treatment of asthma. Although inhibited by radical scavengers in general the enzyme 5-lipoxygenase is structurally related to several other imprtant enzymes such as 12-lipoxygenase, 15- lipoxygenase and cyclooxygenase 6 and so requires a specific inhibitor substrate. Some of the most promising specific 5-lipoxygenase inhibitors to date (Scheme 1) are the quinone derivatives (4), (5) and (6). Quinonoid structures therefore provide attractive targets as potential antiinflammatory drugs, both as regenerable radical scavengers and as specific 5- lipoxygenase inhibitors. Of particular interest are those quinonoid systems which are capable of undergoing potentially reversible redox processes through which efficient Me Me 1 o Me Me HO Me (1) C -_:=CO2H (i) 'O 2 C::.CO2H C'.H (2) (3) O=CO2H LTC4, LTD4 Ph (4) (5) Me (6) 5-li poxygenase hydroperoxidase Scheme 1 2 R 0 Xx. o - )!fI*T - 0 - 101 1 ' R 0 R 0 yOH -H20 N ~H20 OH (10) (8) [0/1 [Hl \\101 R 0 - OH p. (9) = benzenoid or heteroaromatic nucleus Scheme 2 radical scavenging could be effected. A previously undescribed example (Scheme 2) of this type of redox system is represented by the fused pyrad6jáne-3,4-quinones (8), their s-oxides (7) and the corresponding diosphenols (9) and (10). The following thesis is concerned with the investigation of novel synthetic routes to the previously undescribed cinnoline-3,4-quinones (8; V = benzenoid) and their N-oxides (7; ;: = benzenoid) and diosphenol derivatives[(9) and (10); Y!} = benzenoid], with a view to their evaluation as antlinflammatory agents. The results of these studies are discussed in chapters 2,3 and 4, and are preceeded in chapter 1 by a brief survey of the synthesis of cinnoline and its derivatives. 4 CHAPTER 1 A Survey of Literature Methods for the Synthesis of Cinnoline Derivatives A Survey of Literature Methods for the Synthesis of Cinnoline Derivatives The first recorded synthesis (Scheme 3) of a derivative of cinnoline (15) was reported by von Richter 10 in 1883. In an unsuccessful attempt to prepare the phenol (12) by diazotisation of 2-aniinophenylpropiolic acid (11), he found that the intermediate diazonium species (13) had been trapped to afford cinnolin-4( 111)-one 3- carboxylic acid (15). Cydisation is readily explained by initial hydration of the triple bond to give an enol intermediate (13) which is set up as shown to undergo cycisation to the cinnolinone (15). Although a substantial number of cinnoline derivatives have been prepared by the diaz.otative cyclisation of ortho-aminophenylacetylenes, a major drawback of this method is the relative difficulty, of obtaining the acetylenic starting materials. For this reason, the von Richter cinnoline synthesis has tended to have been superceded by other more versatile methods. In a cinnoline synthesis (Scheme 4) which is mechanistically similar to that of von Richter, 2-aminophenylethylene derivatives (16) are cyclised diazotatively to give 3,4-disubstituted cinnolines (19). The procedure known as the Widman- Stoermer cinnoline synthesis 11 is limited to the cyclisation of ortho- aminophenylethylene derivatives in which the benzylic position is occupied by a group capable of stabilising the carbocation intermediate (18). Of more general utility, is the Borsche synthesis 12,13 (Scheme 5) of functionalised cinnolin-4(lth-ones (24). In this procedure 2-aminoacetophenones [e.g. (20)] undergo diazotative cydisation which is readily explained in terms of an initial acid-catalysed enolisation [(20) -4 (21)] followed by diazotisation and subsequent nucleophilic attack by the enol side-chain on the resulting ortho- diazonium cation. Final tautomerism then completes the mechanistic sequence [(22) -* (23) -* (24)]. Yields in this type of reaction are usually best when concentrated acids are used and heating is avoided thus preventing the formation of phenols (20; OH for A complication which occasionally arises is the unwanted CO2H L (i) x NH2 OH (11) (12) H j%0 L.CO2H ( 13) N0 0 JL (CO2H N H H (14) (15) (i) NaNO2, HC1, H20, 0-5 0 . Scheme 3 OMe Me (i) Me :~~"D (16) (17) OMe OMe Me Me H (19) (18) (i) NaNO2, HC1, H20, 0-5 0 Scheme 4 8 YT (20) (21) H ) w,D H (23) (22) VV (24) (i) NaNO2, HC1 (conc.), room temp. Scheme 5 ;sJ CHO CHO LJL (25) (26) (ü) or (iii) HO H NO2 NO2 - H20 V IP [N ] (28) (27) NaNO2, HC1 (conc.), H20, 0-5 ° KOH, H20, EtOH, MeNO2. KOH, H20, room temp. Scheme 6 10 halogenation of the aryl ring when halogen acids are used as the acidic medium 14• However, the use of formic acid in these reactions is reported to avoid this complication 15• In a modification of the Borsche method first reported by Baumgarten 16 (Scheme 6) diazobenzaldehyde [derived from the corresponding amino compound (25)] is coupled with nitromethane giving a nitroformyihydrazone derivative (26).