Iowa State University Capstones, Theses and Retrospective Theses and Dissertations Dissertations 1957 Reactions of phenoxazine and some of its derivatives Leonard Oro Moore Iowa State College Follow this and additional works at: https://lib.dr.iastate.edu/rtd Part of the Organic Chemistry Commons Recommended Citation Moore, Leonard Oro, "Reactions of phenoxazine and some of its derivatives " (1957). Retrospective Theses and Dissertations. 1343. https://lib.dr.iastate.edu/rtd/1343 This Dissertation is brought to you for free and open access by the Iowa State University Capstones, Theses and Dissertations at Iowa State University Digital Repository. It has been accepted for inclusion in Retrospective Theses and Dissertations by an authorized administrator of Iowa State University Digital Repository. For more information, please contact [email protected]. REACTIONS OF PHENOXAZINE AND SOME OF ITS DERIVATIVES by Leonard Oro Moore A Dissertation Submitted to the Graduate Faculty in Partial Fulfillment of The Requirements for the Degree of DOCTOR OF PHILOSOPHY Major Subject: Organic Chemistry Approved: Signature was redacted for privacy. of Major Work Signature was redacted for privacy. Head of Mkjolr Department Signature was redacted for privacy. Dean of Graduate College Iowa State College 1957 il TABLE OF CONTENTS Page INTRODUCTION 1 HISTORICAL 4 Nomenclature 4 Preparation 5 Aminophenols with hydroxy compounds .... 6 Aminophenols with active halogen compounds. 9 Aminophenols with ortho-qulnones and ortho-hydroxyquinones 9 Phenols with nitroso compounds 12 Oxidative cyclizations 13 Reductive cyclizations 16 N-Substitution Reactions 19 Nuclear Substitution Reactions 21 Oxidation Reactions 23 Other Reactions 27 Physical Properties 29 Uses of Phenoxazine and Its Derivatives 32 Biological staining 33 Treatment of cancer 35 Treatment of tuberculosis 36 Naturally Occurring Phenoxazine Derivatives. 37 Boronic Acids. 39 EXPERIMENTAL 42 Nitration 42 Nitration of phenoxazine 42 Preparation of 3-nitro-10-ethylphenoxazine ( attempted) 43 Preparation of 3,7-dinltro-10- ethylphenoxazine 43 preparation of 3-nltro-10-acetylphenoxazine 44 Preparation of 3,7-dinitro-10- acetylphenoxazine 45 Bromination 45 Reaction of phenoxazine with N-cromosuccinimlde. 45 ill Reaction of phenoxazine with three moles of bromine 46 Reaction of phenoxazine with five moles of bromine 47 Reaction of phenoxazine with twelve moles of bromine 47 Reaction of 10-ethylphenoxazine with N-bromosuccinimide 48 Reaction of 10-ethylphenoxazine with two moles of N-bromosuccinimide 49 Reaction of 10-ethylphenoxazine with two moles of bromine 49 Reaction of 10-ethylphenoxazine with four moles of bromine 50 Reaction of 10-phenylphenoxazine with N-bromosuccinimide. , 51 Reaction of 10-acetylphenoxazine with N-bromo succinimide 51 At room temperature (attempted). ... 51 At reflux temperature with a catalyst (attempted) 52 Reaction of 10-acetylphenoxazine with two moles of bromine 53 Azo Coupling 54 Reaction of phenoxazine wit^ £- nitrobenzene diazonium chloride 54 Reaction of 10-ethylphenoxazine with £-ni trobenzene diazonium chloride .... 55 Reaction of 10-phenylphenoxazine with p-nitrocenzene diazonium chloride (attempted) 56 Metalation 56 General procedure 56 Reaction of phenoxazine with n-butyllithium 57 Reaction of 10-ethylphenoxazine with n-butyllithium 58 Reaction of 10-ethylphenoxazine with methyllithium 59 Reaction of 10-phenylphenoxazine with n-butyllithium 59 Reaction of 10-phenylphenoxazine with methyllithium 60 iv Reduction of Nitro Derivatives 61 Reduction of 3,7-dinltro-10-etviylpv'enoxezine 61 Reduction of 3-nltro-10-acetylphenoxazine . 61 Cleavage Reactions 62 Reaction of 10-ethylphenoxazine with hydriodic acid 62 Reaction of 10-ethylphenoxazine with li thlum 62 Reaction of dibromo-10-ethylphenoxazine with hydriodic acid 63 Method I (attempted) 63 Method II 64 Reaction of 10-phenylphenoxazine with hyariodic acid (attempted) 64 Reaction of 10-phenylphenoxazine with lithium (attempted) 65 Reduction of Onium Salts 65 Reduction by sodium bisulfite (attempted) . 65 Reduction by hydrogen (attempted) 66 Reduction b} stannous chloride and hydrochloric acid (attempted) 66 Reduction by lithium in ether (attempted) • 67 Reduction by lithium aluminum hydride in ether ( attempted) 67 Reduction by lithium aluminum hydride in t e t rahydro furan 67 Reduction by sodium borohydrioe and aluminum trichloride 69 Miscellaneous Reactions of Phenoxazine 69 Reaction of 3,7-dlbromop^enoxazonium bromide hydrobromide with ethyl magnesium cromide (attempted) 69 Hydrolysis of 3-nitro-lO-acetylphenoxazine. 70 Preparation of 3-nitro-10-ethylphenoxazine. 70 Reaction of phenoxszinecarboxylic acid with methanol 71 Reaction of methyl phenoxazinecarboxylate with ethyl iodide 71 Method I (attempted) 71 Method II 72 V Preparation of (N-ethylamldo)-10- ethylphenoxazine 73 Reaction of 10-ethylphenoxazinecarboxyllc acid with methanol 73 Preparation of methyl x-nltro-10- ethylphenoxazinecarboxylate 73 Reaction of bromo-10-ethylphenoxazine with n-butyllithium 74 Reaction of lO-(jD-bromophenyl)phenoxazine with n-butyllithium 75 Preparation of Boronic Acids 76 preparation of phenoxazineboronlc acid (attempted) 76 Preparation of 10-ethylphenoxazineboronlc acid anhydride 77 Preparation of lO-phenylyhenoxazineboronic acid anhydride 78 Reaction of n-butyl borate with organometalllc compounds 79 General procedure 79 Reactions of boron trichloride with organomercury compounds 80 General procedure 80 Reaction of benzeneboronic acid with Indulin (attempted) 82 Reaction of benzeneboronic acid with Sudan Black B 82 Preparation of 5-(3-trifluoromethyl- phenylazo)-2-hydroxybenzeneboronic acid anhydride 84 Preparation of 5-(2,6-dlchloro-4- nltrophenylazo)-2-hydroxybenzeneboronic acid anhydride 85 Preparation of 5-(4-nltro-2-methyl- sulfonylphenylazo)-2-hydroxybenzene­ boronic acid 86 DISCUSSION 88 Nitration 88 Bromination 90 Azo Coupling 94 Metalatlon 95 Reduction of Nltro Derivatives 97 vl Cleavage Reactions 98 Preparation of Boronic Acids 99 Suggestions for Future Research 103 SUMMARY 106 ACKNOWLEDGMENT 108 1 INTRODUCTION Phenoxazine and its derivatives have not received a great deal of attention either theoretically or commercially. The only derivatives of commercial importance are a few dyes, 1 2 called the oxazlne dyes. ' The research on this compound has been closely related to these dyes and no general systematic study of substitution reactions has been made. This may be due in part to the ready oxidation of phenoxazine to phenox- azone. The ready oxidation to the oxazone has led to a series of reactions in which the 3-positlon is attacked by amines and by carbonyl compounds. A little work has been done on the nitration of 10-acetylphenoxazine and related compounds, and a few N~substituted compounds have been prepared. There has never been a general review of the properties of phenoxazine and Its derivatives, though short discussions have been included in several books. !k. Venkataraman, "The Chemistry of Synthetic Dyes, " Vol. II, Academic Press, Inc., New York, N. Y-, 1952, pp. 780-791. 2H. A. Lubs, ed., "The Chemistry of Synthetic Dyes and Pigments," Reinhold Publishing Corp., New York, N. Y., 1955, pp. 259-261. 3D. E. Pearson in R. C. Elderfield, "Heterocyclic Com­ pounds," Vol. VI, John Wiley and Sons, Inc., New York, N. Y«, 1957, pp. 684-705. ^A. A- Morton, "The Chemistry of Heterocyclic Compounds," McGraw-Hill Book Co., Inc., New York, N• Y-, 1946, pp. 478- 480- 2 This study has been undertaken to review tv>e known chem­ istry of phenoxazine and to study the relative directive lnflu ence of the nitrogen and the oxygen atoms of this compound, and the effect on the directive influence of the nitrogen caused by substituting the nitrogen with various groups such as ethyl, phenyl, and acetyl. Since some polynuclear heterocycles also are known to act as scintillators In radiation counters, a series of N-aryl phenoxazine compounds has been prepared which are being tested as solutes for these counters. Some of the oxazlne dyes, notably the Nile Blue dyes, are known to stain brain cancer tissue preferentially, and some decrease the rate of growth of tumors. An interest in this use of these compounds is closely related to the use of boron as a source of in vivo radiation, since it must be prin­ cipally in the carcinogenic tissue to be most useful. The methods of preparing boronic acids was studied in an effort to find a method of preparing a boron derivative of phenox­ azine, or ideally a Nile Blue dye, which might be useful in cancer chemotherapy. Because of the similarity of this compound to other heterocycles whose chemistry has been Investigated much more thoroughly, frequent recourse has been made to the literature . Newton Hayes, International Journal of Applied Radi­ ation and Isotopes, 1, 46 (1956). 3 concerning these heterocycles. These include carbazole, dlbenzofuran, phenothlazlne and phenoxathiln. 4 HISTORICAL The historical section of this dissertation includes a survey of the methods of preparation and the properties of phenoxazine and its known derivatives. The literature is covered completely through 1955, and the period between Jan­ uary 1956 and June 1957 is covered as completely as possible by survey of the more important and more accessible Journals and by a scrutiny of the heterocyclic section of Current Chemical Papers. This publication contains a classified world list of the new papers in pure chemistry. The chemistry of the boronic acids is considered only g since the appearance of the review