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ipso substitutions of aryl boronic acids and aryltrifluoroborates

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ipso substitutions of aryl boronic acids and aryltrifluoroborates

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Content IPSO SUBSTITUTIONS OF ARYL BORONIC ACIDS AND ARYLTRIFLUOROBORATES by Christoph Thiebes A Thesis Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree MASTER OF SCIENCE (Chemistry) December 1997 Copyright 1997 Christoph Thiebes Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. UMI Number: 1427991 INFORMATION TO USERS The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleed-through, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion. ® UMI UMI Microform 1427991 Copyright 2005 by ProQuest Information and Learning Company. All rights reserved. This microform edition is protected against unauthorized copying under Title 17, United States Code. ProQuest Information and Learning Company 300 North Zeeb Road P.O. Box 1346 Ann Arbor, Ml 48106-1346 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Meiner Familie ii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Acknowledgments I am indebted to my advisor, Professor Dr. G. K. Surya Prakash for his continuous support and encouragement during my stay at the Loker Hydrocarbon Research Institute. His personal attention was invaluable. I am also grateful to Professor Dr. George A. Olah for being generous with his time when I needed it. I have learned a great deal from our discussions. I also wish to thank all members of the Olah and Prakash groups and the Loker Hydrocarbon Research Institute for their warm reception and support, but especially Professor Dr. William P. Weber, Professor Dr. Gregorz Mloston, Professor Dr. Istvan Palinko, Professor Dr. Shinji Masuda, Professor Dr. Nicos A. Petasis, Dr. Akihisa Saitoh, Dr. Juergen Wiedemann, Dr. Thomas Heiner, Dr. Arwed Burrichter, Dr. Andrei K. Yudin, Dr. Robert Anizfeld, Emily C. Tongco, Anjana Mitra, Eric Marinez and Michael Bradley for their support. Special thanks to Mohammed M. Hafez for many inspiring discussions and for being a friend. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Support by the Konrad- Adenauer-Foundation, Germany, the College of Letters, Arts and Sciences and a H. Moulton fellowship granted by the Loker Hydrocarbon Research Institute is gratefully acknowledged. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table of Contents IPSO SUBSTITUTIONS OF ARYL BORONIC ACIDS AND ARYLTRIFLUOROBORATES Chapter 1: General Introduction 1 1.1 Aryl Boronic Acids 1 1.1.1 Properties and Applications of Aryl Boronic Acids 1 1.1.2 Preparation of Aryl Boronic Acids 2 1.2 Properties and Preparation of Aryltrifluoroborates 4 1.3 Ipso Substitution of Aryl Boronic Acids and Aryltrifluoroborates- 5 Possible Application in Organic Synthesis 1.3.1 Historical Background: Ipso Substitution Reactions 5 of Substituted Arenes 1.3.2 Synthetic Applications of Ipso Substitution of Aryl 7 Boronic Acids and Aryltrifluoroborates 1.4 References 9 Chapter 2: Regioselective Halogenation of Aryl Boronic Acids and 11 Aryltrifluoroborates 2.1 Introduction 11 2.2 Halogenation of Arenes - Synthetic Approaches 12 2.3 Regioselective Halogenation of Aryl Boronic Acids 14 with A-Halosuccinimides 2.3.1 Bromination of Aryl Boronic Acids with Y-Bromosuccinimide 15 V Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.3.2 Iodination of Aryl Boronic Acids with TV-Iodosuccinimide 19 2.3.3 Bromination and Iodination of Esters of Aryl Boronic Acids 24 with JV-Halosuccinimides 2.4 Regioselective Fluorination of Aryltrifluoroborates and Aryl 25 Boronic Acids with Electrophilic Fluorinating Reagents of the N-F Class 2.4.1 Fluorination of Aryltrifluoroborates with Selectfluor™ 26 2.4.2 Attempted Fluorination of Aryltrifluoroborates 29 with W -Fluoropyridinium Triflate 2.5 Conclusion and Outlook 31 2.6 References 33 Chapter 3: Nitration and Nitrosation of Aryl Boronic Acids 35 and Aryltrifluoroborates 3.1 Introduction 35 3.2 Nitration of Aryl Boronic Acids and Aryltrifluoroborates 36 3.2.1 Nitration of Aryltrifluoroborates with Nitric Acid 36 3.2.2 Nitration of Aryltrifluoroborates with Nitronium 39 T etrafluoroborate 3.2.3.Nitration of Aryl Boronic Acids with Acetyl Nitrate and 42 Trifluoroacetyl Nitrate 3.2.4 Nitration of Alkenyl Boronic Acids 46 3.3 Nitrosation of Aryl Boronic Acids and Aryltrifluoroborates 48 3.4 Conclusion and Outlook 49 3.5 References 51 vi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 4: Reactions of Aryl Boronic Acids and Aryltrifluoroborates 52 with Various Carbon and Nitrogen Electrophiles 4.1 Reactions with Carbon Electrophiles 52 4.1.1 Attempted Aryltrifluoroborate Mannich Reaction 52 4.1.2 Attempted Alkylation and Acylation of Potassium 54 Phenyltrifluroborate 4.2 Attempted Preparation of Aryl Azides from Aryltrifluoroborates 56 4.3 Conclusion 57 4.4 References 58 Chapter 5: Experimental Part 59 5.1 General Aspects of Preparative Work 59 5.1.1 Chemicals Used 59 5.1.2 Product Purification 61 5.1.3 Product Characterization 62 5.2 Halogenation Reactions 63 5.2.1 Bromination of Aryl Boronic Acids with A-halosuccinimides 63 5.2.2 Attempted Bromination of 3-Nitrophenylboronic Acid with 63 other Electrophilic Brominating Reagents 5.2.3 Iodination of Aryl Boronic Acids 63 5.2.4 Iodination and Bromination of 2-Phenyl-1,3,2-dioxaborinane 64 5.2.5 Fluorination Reactions 65 5.3 Nitration and Nitrosation Reactions 66 5.3.1 Nitration of Aryltrifluoroborates with Nitric Acid 66 vii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.3.2 Nitration of Aryltrifluoroborates with Nitronium 66 T etrafluoroborate 5.3.3 Nitration of Aryl Boronic acids with Acetyl and Trifluoro- 66 acetylnitrate 5.3.3 Attempted Nitrosation of Aryltrifluoroborates with 67 Nitrosonium Tetrafluoroborate 5.4 Mischievous Reactions 68 5.4.1 Attempted Potassium Aryltrifluoroborate Mannich Reaction 68 5.4.2 Attempted Alkylation and Acylation of Potassium 68 Phenyltrifluoroborate viii Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. List of Schemes Scheme 1.1 The Suzuki Reaction 2 Scheme 1.2 Synthetic Routes to Aryl Boronic Acids and 3 Aryltrifluoroborates Scheme 1.3 Boroxine Formation 3 Scheme 1.4 Tpso-Desilylation 5 Scheme 1.5 Preparation of Fluoroarenes from Aryl Boronic Acids 6 Scheme 1.6 Possible Applications of the Ipso Substitution Reactions 8 of Aryl Boronic Acids and Aryltrifluoroborates Scheme 2.1 The Schiemann Reaction 12 Scheme 2.2 The Sandmeyer Reaction 13 Scheme 2.3 Bromination of Arylboronic Acids with iV-Bromosuccinimide 15 Scheme 2.4 Iodination of Methoxyphenylboronic Acids 21 Scheme 2.5 Radioactive Labeling with a two-phase system 24 Scheme 2.6 Iodination of Arylboronic Esters 25 Scheme 2.7 Electrophilic Fluorination of Aryltrifluoroborates 26 Scheme 2.8 Mechanistic Pathways for the Fluorination of Organic 29 Nucleophiles with N-F Class Reagents Scheme 2.9 One-Pot Synthesis of Symmetric Biaryls from 31 Aryl Boronic Acids Scheme 3.1 Formation of the Nitronium Ion 36 Scheme 3.2 Nitration of Aryltrifluoroborates with Nitric Acid 37 Scheme 3.3 Nitration of Aryltrifluoroborates with Nitronium 40 T etrafluoroborate ix Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Scheme 3.4 Scheme 3.5 Scheme 4.1 Scheme 4.2 Preparation of Nitroalkenes from Acetylenes Attempted Nitrosation of Aryltrifluoroborates and Aryl Boronic Acids with Nitrosonium Tetrafluoroborate The Aryltrifluoroborate Mannich Reaction Reaction of Aryltrifluoroborates with Electrophiles Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. List of Tables Table 2.1 Bromination of Aryl Boronic Acids with A-Bromosuccinimide 16 Table 2.2 Iodination of Aryl Boronic Acids with A-Iodosuccinimide 20 Table 2.3 Fluorination of Aryl Boronic Acids and 28 Aryltrifluoroborates with Selctfluor™ Table 2.4 Attempted Fluorination with A-Fluoropyridinium Triflate 30 Table 3.1 Nitration of Potassium Aryltrifluoroborates with Nitric Acid 3 8 Table 3.2 Nitration of Potassium Aryltrifluoroborates with Nitronium 41 T etrafluoroborate Table 3.3. Nitration of Aryl Boronic Acids with Acetyl Nitrate 44 Table 3.4. Nitration of Aryl Boronic Acids with Trifluoroacetyl Nitrate 46 Table 3.5 Nitration of Potassium Aryltrifluoroborates and Aryl Boronic 49 Acids with Nitronium Tetrafluroborate Table 4.1 Reaction of Potassium Aryltrifluoroborates with 53 Eschenmoser’s Salt Table 4.2 Attempted Preparation of 4-Methoxyphenylbenzylamines 54 Table 4.3 Attempted Alkylation and Acylation of Potassium 56 Phenyltrifluoroborate Table 5.1 Reagents and Solvents 61 xi Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Abstract Reactions of aryl boronic acids and potassium aryltrifluoroborates with electrophiles were investigated. It was found that these compounds undergo ipso substitution in certain cases. Aryl boronic acids react with jV-iodosuccinimide (NIS) and /V-bromosuccinimde (NBS) to afford iodo- and bromoarenes in good to excellent yields. The reaction is highly regioselective and yields, only the ipso substituted product. Esters of arylboronic acids react similarly, but are less reactive. NIS can be generated in situ from sodium iodide and A-chlorosuccinimide, providing a new method for the radioactive labeling of arenes. Aryltrifluoroborates react with Selectfluor™ to give fluoroarenes in low yields. Aryltrifluoroborates undergo ipso substitution with nitronium ion to give the corresponding nitroarenes in low yield. Aryl boronic acids undergo ipso nitration when reacted with trifluoroacteyl nitrate. The yields are low to moderate. Aryl boronic acids and aryltrifluoroborates did not react with carbon electrophiles without the use of Lewis acid catalysts. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 1. General Introduction Aryl boronic acids and aryltrifluoroborates are readily available and comparatively stable organometallic compounds that have a wide range of applications in organic synthesis. It has been found recently, that they also undergo electrophilic aromatic ipso substitution.1 This thesis investigates their reactivity towards various electrophiles and possible synthetic applications of such reactions. 1.1 Aryl Boronic Acids 1.1.1 Properties and Applications of Aryl Boronic Acids The parent compound of aryl boronic acids, phenylboronic acid, has been first prepared by Michaelis and Becker in 1880.2 Like boric acid itself, it was expected to have mild antiseptic activity and it was found that various aryl boronic acids are toxic towards microorganisms while being relatively harmless towards higher animals.3 The majority of aryl boronic acids are high melting, air-stable, crystalline compounds, which can be distinguished from other boron containing compounds by their chemical shift against an external standard of BF3 in U B NMR-spectra. Phenylboronic acid has found use in organic synthesis as a reagent for the protection of diols and as a template in stereocontrolled Diels-Alder reactions.4 ,5 Recently, Petasis and Zavialov reported a three-component synthesis of P,y-unsaturated a-aminoacids from alkenyl boronic acids, amines and a-ketoacids.6 The authors report that the reaction also works for aryl boronic acids to afford arylglycine derivatives. The 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. most widely used reaction of aryl boronic acids is the palladium-catalyzed Suzuki synthesis of asymmetric biaryls (Scheme 1.1). The reaction also works for the coupling of aryl boronic acids and vinyl halides and triflates, providing a new and convenient approach to the formation of carbon-carbon bonds under very mild conditions.7 OH Ar'-X Ar— ------------------- ► Ar-Af 0H Pd (0) / base X = Br, I Scheme 1.1 : The Suzuki Reaction 1.1.2 Preparation of Aryl Boronic Acids There are a wide variety of synthetic approaches to aryl boronic acids (Scheme 1.2).8 The first preparation of phenylboronic acid involved hydrolysis of phenylborondichloride obtained from the reaction of diphenylmerucry and BC13 .2 Recently, arylmagnesium bromides and aryllithium compounds have become the most important sources of aryl boronic acids. Aryllithium compounds can be conveniently prepared by halogen-metal exchange from haloarenes and n-butyllithium or by direct metalation of substituted aromatics with t-butyllithium.9 They can be reacted with various trivalent boron electrophiles such as trialkoxyborates, trihaloboranes, diborane, or BH3 -etherates. Acidic hydrolysis yields aryl boronic acids, which can be recrystallized from water or pentane-tetrahydrofuran. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. ^ // BY, R. H+,H 20 h +, h 2o 1. Mg/ Et 20 2. BY 3 3.H +,H 20 * B(OH)2 1. n-BuLi/ Et 20 2. BY 3 3.H+,H 20 k h f2/ h 2 o b f3 k 1. n-Buli/ Et 20 2. BY 3 3. KHF2,H 20 1. M g/ Et 20 2. BY 3 3. KHF2,H 20 X = Q , Br, I Y=OR,Br,Cl Scheme 1.2: Synthetic Routes to Aryl Boronic Acids and Aryltrifluoroborates Other methods involve hydrolysis of triarylboranes and aryldihaloboranes. For reactions investigated during the preparation of this thesis, aryl boronic acids, unless commercially available, were prepared by the reaction of aryllithium compounds with triisopropylborate. Ar /OH - 3 H20 p ~ \ Ar— B — Ar— B O OH + 3 H20 o - B / Ar Scheme 1.3 : Boroxine Formation 3 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Most aryl boronic acids undergo dehydration1 0 to form cyclic trimeric anhydrides (boroxines), thus it is difficult to obtain the acids free from traces of anhydride. Since their reactivity is similar and there is equilibration between the two species (Scheme 1.3),' this is not a major problem for the reactions investigated in this thesis. However, the yields are sometimes subject to uncertainty because of the different molecular weights. 1.2 Properties and Preparation of Aryltrifluoroborates Although the preparation of aryl trifluoroborates has been reported in 1967, there have been only isolated reports on the investigation of their reactions until recently.1 1 The most thorough study on their preparation and properties has been reported by Vedjes et al. in 1995.1 2 Aryltrifluoroborates have been used for in situ preparation of arylborondifluorides and in palladium catalyzed coupling reactions.1 2 ,1 3 Potassium aryltrifluoroborates have been found to be the most stable, while ion exchange with Mg2 + and Li+ results in a fast decomposition with formation of LiF and MgF2 , indicating that lithium and magnesium aryltrifluoroborates are relatively unstable.1 2 Therefore, for this thesis, only the reactions of potassium aryltrifluoroborates have been investigated. All substrates have been prepared according to a procedure by Vedjes et al. by reaction of commercially available aryl boronic acids with aqueous KHF2 in methanol. Alternative routes would involve quenching the intermediate product of the reaction of the aryllithium compound and BY3 with aqueous KHF2 . Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1.3 Ipso Substitution of Aryl Boronic Acids and Aryltrifluoroborates - Possible Application in Organic Synthesis 1.3.1 Historical Background: Ipso Substitution Reactions of Substituted Arenes Although the effect of various substituents in terms of their ability to direct electrophilic aromatic substitution to the ortho, para, or meta position of the substituent has been investigated extensively, the third possibility, the substitution of the substituent itself, known as ipso substitution, has not received much attention. The prefix ipso was introduced by Perkin and Skinner1 4 ® to describe an attack of a reagent at a substituted position. Synthetic applications of electrophilic ipso substitution reactions of arenes are rare, but various systems have been studied. The most common reactions are desulfonation, decarboxylation, dehydroxylation and dealkylation. Substitution is afforded by electrophiles such as nitronium ion, acetic anhydride and halogens.1 4 Another example of electrophilic aromatic ipso substitution is the ipso desilylation of arylsilanes, which undergo cleavage of the aryl-silicon bond when reacted with electrophiles such as sulfur trioxide, acetyl chloride, bromine, iodine and iodine monochloride (Scheme 1.4). Scheme 1.4: Ipso-Desilylation Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. These reactions have been the subject of extensive mechanistic studies.1 5 Probably, the reaction involves intermediates of type (1), which would explain why the ipso attack is favored: In (la) and (lb) there is a favorable interaction between the positive charge and the carbon-silicon bond. la lb lb Two applications of ipso substitution of aryl boronic acids have been reported recently, but in neither case involved a direct substitution. It was found that aryl azides can be prepared from aryl-lead triacetates and sodium azide. The aryl-lead triacetates were prepared in situ from the corresponding aryl boronic acids.1 6 For the preparation of fluoroarenes by reaction with cesium fluoroxysulphate (CFS), the aryl boronic acids had to be transformed into the corresponding diethanolamine ester (Scheme 1.5).1 7 H (HOCHsC H ^ H M s R \ = = / OH C6H5 Me / heat R \ = / o ^ ) C F S ■ £ \ - t MeCN R ' x / Scheme 1.5 : Preparation of Fluoroarenes from Aryl Boronic Acids 6 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The well-established Sandmeyer reaction and various examples of nucleophilic aromatic substitution reactions yield in ipso substitution products. However, since these reactions follow significantly different mechanisms, they are not discussed here.1 4 b 1 8 For the ipso substitution reactions of aryl boronic acids and aryl trifluoroborates various mechanisms could be thought of, however an extensive mechanistic study is well beyond the scope of this thesis. A brief survey of possible mechanisms will be given in chapter 6. 1.3.2 Synthetic Applications of Ipso Substitution of Aryl Boronic Acids and Aryltrifluoroborates Both alkenyl boronic acids and alkenyl trifluoroborates have been found to undergo ipso substitution upon reaction with electrophilic halogen sources, providing a new approach for the preparation of vinyl halides under mild conditions.1 9 These results prompted me to investigate the reactivity of aryl boronic acids with various electrophiles. The functionalization of arenes by electrophilic aromatic substitution is always subject to the formation of isomers of the desired products, resulting in lower yields and the need for product separation. The inherent regioselectivity of ipso substitution reactions and the expected enhanced reactivity towards electrophilic substitution of the carbon-boron bond showed a great potential for synthetic application, therefore an investigation seemed to be promising. The goal of my work described in this thesis was Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. therefore to demonstrate the synthetic utility of the ipso substitution reactions of aryl boronic acids and aryltrifluoroborates. Scheme 1.6 shows some viable reactions. The reaction conditions are described in detail in the corresponding chapters. COR' F Scheme 1.6: Possible Applications of the Ipso Substitution Reactions of Aryl Boronic Acids and Aryltrifluoroborates Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 1.4 References (1) Yudin, A. K. Dissertation, University of Southern California, Los Angeles, 1996 (2) Michaelis, A.; Becker, P. Ber. 1880,13, 58 (3) Seaman, W.; Johnson, J. R. J. Am. Chem. Soc. 1931, 53, 711 (4) Sugihara, J. M.; Bowman C. M. J. Am. Chem. Soc. 1958, 80,2443 (5) Narasaka, K.; Shimada, S.; Osoda, K.; Iwasawa, N. Synthesis 1991,1171 (6) Petasis, N. A.; Zavialov, I. A. J. Am. Chem. Soc. 1997,110,445 (7) For a review of the Suzuki reaction, see Miyaura, N.; Suzuki, A. Chem. Rev. 1995,95,2457 (8) Koster, R. in Houben-Weyl, 4th ed., Vol. E13a; Koster, R., Ed.; Thieme: Stuttgart, 1982; p. 617 (9) Snieckus, V. Chem. Rev. 1990, 90, 879 (10) Michaelis, A.; Becker, P. Ber. 1882,15,182 (11) a) Chambers, R. D.; Chivers, T. J. Chem. Soc. 1965, 3933 b) Thierig, D.; Umland, F. Naturwissenschaften 1967,54, 563 (12) Vedjes, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020 (13) Wright, S. W.; Hageman, D. L.; Me Clure, L. D. J. Org. Chem. 1994, 59, 6095 (14) a) Perrin, C. L.; Skinner, G. A. J. Am. Chem. Soc. 1971, 93, 3389 b) Traynham, J. G. J. Chem. Education 1983, 60, 937 c) Fischer, A.; Henderson, G. N.; RayMahasai, S. Can. J. Chem. 1987, 65, 1233 (15) Eabom, C.; Bott, R. W. in: Organometallic Compounds o f the Group IV Elements, Vol. 1, Part 1, MacDiarmid, A. G., Ed.; Marcel Dekker, Inc.: New York, 1968, p. 407 (16) Huber, M.; Pinhey, J. T.; J. Chem. Soc., Perkin Trans. 1 1990, 721 9 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (17) Clough, J. M.; Diorazio, L. J.; Widdowson, D. A. Synlett 1990, 761 (18) Sandmeyer, T. Ber. 1884,1633 (19) a) Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 56 b) Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash, G. K. S.; Olah, G. A. Synlett 1997, 5,606 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 2: Regioselective Halogenation of Arvl Boronic Acids and Aryltrifluoroborates 2.1 Introduction Electrophilic aromatic halogenation reactions play an important role in organic synthesis, since haloarenes have a wide range of applications.1 Bromoarenes and iodoarenes serve as aryl group donors in a number of metal- catalyzed coupling reactions and provide a convenient access to aryllithium compounds by halogen-metal exchange. In addition, radioactive labeling by iodination of biologically active aromatic compounds is an important method in radiology.2 Furthermore, iodoarenes have been shown to undergo photochemical dissociation readily and are therefore used in photochemistry. The scope of applications of fluoroarenes has been expanding since organofluorine compounds became the focus of extensive research due to their medicinal applications.3 Their enhanced therapeutic activity, first reported by Fried in 1954 is rationalized by the unique physiochemical properties of the fluorine- carbon bond.4 Due to this increasing importance, organofluorine chemistry has witnessed a steady growth during the past decades. Regarding the wide range of applications of haloarenes, a method that provides regioselective halogenation of aromatics under mild conditions even against the influence of directing groups is very desirable. This part of my thesis deals with reactions involving organoboron compounds that result in such transformations. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.2 Halogenation of Arenes - Synthetic Approaches The great importance of haloarenes in synthetic organic chemistry and industry has resulted in a great number of publications that deal with the introduction of halogens into aromatic compounds. Direct electrophilic aromatic halogenation is by far the most important method for the preparation of haloarenes. The reaction conditions necessary for performing these reactions depend strongly on the reactivity of the aromatic substrate and the halogen electrophile. Chlorine and bromine are usually reactive towards aromatics, yielding different substitution products depending on the presence of directing groups in the molecule. Lewis acid catalysis is used in many cases to achieve reasonable rates of reaction. However, selectivity is often low for these reactions and varies greatly with the nature of the substrate. Ring activation often results in an undesirable polysubstitution.1 Neat fluorine gas reacts with most substrates in an uncontrolled maimer, but fluorination can often be carried out with a mixture of fluorine and inert gases.5 An important method for the introduction of fluorine onto aromatics is the Schiemann reaction, involving aryldiazonium tetrafluoroborates, which are converted to the Scheme 2.1: The Schiemann Reaction Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. corresponding fluoroarenes upon heating. The reaction works also with diazonium hexafluorophosphates.6 Other reagents that deliver electrophilic fluorine differ greatly in reactivity and structure, but have in common that they are difficult to prepare and handle. These reagents include xenon difluoride, trifluoromethyl hypofluoride and trifluoroacetyl hypofluoride.7 Recently, many electrophilic fluorination reagents of the N-F class have been developed.8 These are neutral compounds with R2 N-F structure, quaternary ammonium (R3 NF+ A ) salts or fluoroarylsulfonamides, which offer better selectivity and safer handling than the compounds described above. Iodination is thermodynamically less favored due to the low carbon-iodine bond strength and the reaction of aromatics with iodine often leads to an equilibrium that can be shifted by oxidative removal of iodide.9 ,1 0 More reactive iodinating reagents like IC1 have been used successfully to achieve direct iodination.1 1 A regioselective method for the introduction of iodine onto aromatic rings is the reaction of arylthallium(III) compounds with potassium iodide.1 2 In most cases, however, iodine is introduced via the aryldiazonium salt (Sandmeyer-reaction) that can be prepared by diazotation of aromatic amines (Scheme 2.2).1 3 4 r Scheme 2.2: The Sandmeyer Reaction 13 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.3 Regioselective Halogenation of Aryl Boronic Acids with A-Halosuccinimides In 1973 Brown et al reported the reaction of alkenyl boronic acids with bromine in basic solution to give vinyl bromides.1 4 The fact that inversion of configuration is observed has been rationalized by a mechanism involving trans- addition of the bromine followed by anti-elimination of boron and bromide. Interestingly, the same reaction with iodine leads exclusively to retention of configuration.1 5 Recently, Petasis et al. reported the synthesis of geometrically pure vinyl halides with retention of configuration from alkenyl boronic acids and 7V-halosuccinimides.1 6 The reactions are carried out in acetonitrile at room temperature, thus avoiding the more severe conditions that were employed by Brown and his coworkers. The mechanism proposed differs from the one described by Brown, and the transformation yields geometrically pure products in all cases. This is believed to be an indication for activation of the boronic acid leaving group by the imido-oxygen of the halosuccinimide in a direct- displacement mechanism. N -Bromosuccinimide N -Iodosuccinimide Since direct halogenation of arenes with Af-halosuccinimides is only feasible at strongly activated positions, it was expected that polyhalogenation would not be a major problem. 14 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.3.1 Bromination of Aryl Boronic Acids with 7V-Bromosuccinimide When non-activated boronic acids like phenylboronic acid or 4- chlorophenylboronic acid were reacted with N-bromosuccinimide (NBS) under the reaction conditions applied on alkenyl boronic acids, rates and yields of reaction were lower than those reported for the alkenyl boronic acids, reflecting the lower reactivity of the aryl boronic acids toward electrophiles. Full conversion was not achieved even after 72 hours and the isolated yields ranged between 27 % and 40%. For the optimization of the procedure, three parameters had to be considered: the solvent, the reaction temperature and the numbers of equivalents of AT-bromosuccinimide used. Solvents for this reaction have to be of high polarity to provide sufficient solubility of the aryl boronic acids. At low temperatures, the solvent with the best solubility seems to be acetonitrile. Nitromethane was also tried, but did not result in better yields than for the reaction in acetonitrile. Enhanced rates were observed for most substrates, when the reaction temperature was raised to 81 °C by refluxing the reaction mixture. The reactions were completed after 1.5 to 12 hours and the yields increased to 50-60%. Scheme 2.3: Bromination of Aryl Boronic Acids with N -Bromosuccinimide 15 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The optimal yields however, were achieved when the amount of N- bromosuccinimide was raised to 2 equivalents. Probably the excess of NBS enhanced the rate of reaction thus the competing thermal decomposition of the boronic acids was minimized. Since NBS is a relatively inexpensive reagent and the excess can be removed easily, this is not a major problem. Table 3.1 lists the substrates that have been studied. Table 2.1 Bromination of Aryl Boronic Acids with 7V-Bromosuccinimide Entry Ar N [eq.]a Temperature [°C] Time M Yield [%]b 17 Y = H 2.0 81 14 57 18 Y = 3-C1 2.0 81 8 59 19 Y = 4-C1 2.0 81 8 65 20 Y = 3-Br 2.0 81 8 81 21 Y = 4-Br 2.0 81 8 71 22 Y = 4-OCH, 2.0 81 1.5 82 23 Y = 3-N02 2.0 81 24 19 a Equivalents of NBS used ^ isolated yields Surprisingly, the parent compound, phenylboronic acid, gives a lower yield than the deactivated bromo- and chlorophenylboronic acids. This may be rationalized considering that the commercially available phenylboronic acid may contain significant amounts of the less reactive tricyclic anhydride or by an increased tendency towards decomposition at elevated temperatures.1 7 In all cases of non- or deactivated aryl boronic acids only the ipso substitution product was observed, indicating that the reaction was very regioselective. In the cases of 16 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4-bromo- and 4-chlorophenylboronic acids, no ortho substituted product was observed, while the bromination of bromobenzene and chlorobenzene is reported to give mainly the para and ortho product.1 The high yield for the bromination of 4-methoxyphenylboronic acid indicates that the ipso attack is more favored than attack at the activated ortho position. However, it has to be noted, that substitution at any other position than ipso could only be observed, if there is ipso substitution either before or after the substitution, because otherwise, the resulting disubstituted aryl boronic acids were discarded during workup. The yields and reaction times of this reaction follow the expected trend regarding the presence of activating and deactivating groups on the aromatic ring of the aryl boronic acids. Deactivated 3-nitrophenylboronic acids gave only 19 % of the desired product, while the very reactive 4-methoxyphenylboronic acid gave the highest yield (82 %). For highly activated aryl boronic acids a problem arises when the energy of activation for substitution at positions different than the boronic acid functionality becomes equal or lower than that for ipso substitution. For example, it was not possible under various reaction conditions that were tried, to obtain 3-bromothiophene in a clean way from 3-thiophenylboronic acid. Analysis of the products of this reaction by NMR- spectroscopy and GC/MS indicates that besides 3-bromothiophene and 2,3- dibromothiophene, the major product is 2,3,5-tribromothiophene, independent of the reaction temperature and the equivalents of NBS used. To improve yields for deactivated substrates other approaches were tried. Aryltrifluoroborates, which are expected to be more reactive towards electrophiles than 17 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. the aryl boronic acids were tested for their behavior under the same conditions, but it was found that the 4-haloaryltrifluoroborates gave even lower yields than the corresponding aryl boronic acids and the deactivated potassium 3-(a,a,a- trifluoromethyl)phenyltrifluoroborate gave only traces of product even after 12 hours of reflux with 2 equivalents of NBS in acetonitrile. These facts also indicate that there is activation of the boronic acid functionality by the imido oxygen of NBS as was proposed by Petasis and coworkers. In a second approach to improve the yield for the deactivated substrates, other sources of electrophilic bromine were tested. Due to its structural resemblance to NBS, l,3-dibromo-5,5-dimethylhydantoin was expected to be a promising alternative. Br Br 2,4,4,6-Tetrabromocyclohexadienone > S :" O —Br O 13-Dibromo-5^-<finiethyihydantoin This reagent is used in radical bromination reactions and serves as an economic alternative to NBS in industrial applications.1 8 Another source of strongly electrophilic 18 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. bromine is 2,4,4,6-tetrabromocyclohexadienone. It has been employed in various applications where bromination with other reagents was not feasible.1 9 Unfortunately, none of these attempts were successful in enhancing the yield for the deactivated 3-nitrophenylboronic acid. Both reagents were reacted with 3- nitrophenylboronic acid and phenylboronic acid at various temperatures, but in no case product formation was observed. 2.3.2 Iodination of Aryl Boronic acids with jV-Iodosuccinimide The investigation of the iodination of aryl boronic acids gave results that were close to those expected from the bromination reactions, but yields for the iodination were in general better and the reaction rates were higher. These observations indicate that N- Iodosuccinimide (NIS) is a stronger electrophile towards aryl boronic acids than NBS. The results of this investigation are presented in Table 2.2 and in Scheme 2.5 along with the reaction conditions. In general, the same conditions were applied as for the bromination with NBS, only that it was not necessary to increase the amount of NIS needed to more than 1.5 equivalents. For strongly activated aryl boronic acids, where disubstitution was expected, the reactions were carried out at room temperature and only one equivalent of NIS was used. It seems that NIS is a better-behaved electrophile than NBS, since in only one case disubstitution could not be avoided. For 2- and 3-thiophenylboronic acid no disubstituted products were observed at room temperature and with one equivalent of NIS. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 2.2 Iodination of Aryl Boronic Acids with A-Iodosuccinimide Entry Ar Method3 Equivalents NISb Temperature [°C] Time [h ] Yield la lb 2 3a 3b 4a 4b 5 6 a 6 b 7 8 9 1 0 a 1 0b 11 1 2a 12b 13 & Y = H Y = 2-CH3 Y = 3-C1 Y = 4-C1 Y = 3-Br Y = 4-Br Y = 2 -OCH3 Y = 3 -OCH3 Y = 4 -OCH3 Y =4-CHCH2 Y = 3-N02 Y = 4-CHO h 3 c o A B A A B A B A A B A A A A B A A B 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.0 1.0 1.5 1.0 1.0 2.0 1.2 1.2 1.0 81 81 81 81 81 81 81 81 81 81 RT RT 81 RT RT 81 81 81 RT 14 14 6 6 6 6 6 6 6 6 14 14 1.5 14 14 24 14 14 14 61 58 72 76 82 90 86 77 88 85 89 46d 90 78 75 25 94 91 84 H3CO 14 S' 1.0 RT 14 72 15 16 1.0 1.0 RT RT 14 14 71 83 3 For Method A commercially available (Aldrich) NIS was used, for B NIS was prepared in situ from NCS and Nal; ^Equivalents of NIS used; c isolated yields; d 26% yield of 3,4-diiodoanisole 20 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. B(OH) 2 OCH, 1.5 equiv. NIS 81 °C / 1.5h 90% OCH, B(OH)2 6 * 3 1.0 equiv. NIS RT / 14h OCH, 89% B(OH)2 OCH, OCH, OCH, 1.0 equiv. NIS RT / 14h \ y ~ ] 8(011)2 OCH 46% 23% 1.0 equiv. NIS RT / 14h [ I T 84 % OCH 1.5 equiv. NIS 81 °C / 16h 40-50 % OCH3 Scheme 2.4: Iodination of Methoxyphenylboronic Acids The reaction of activated 4-methoxyphenylboronic acid with 1.5 equivalents of NIS at 81 °C proceeded fast and gave clean para substituted product in excellent yield 21 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (Scheme 2.4). When the same reaction was carried out with 3-methoxyphenylboronic acid however, the overall yields were lower and 3,4-diiodoanisol was formed as a byproduct (29% of 59% total yield). Attempts to reduce the formation of the diiodinated product by lowering the reaction temperature to 25 °C and avoiding an excess of NIS were successful, but diiodination could not be avoided completely (23% of 69% total yield). Experimental data gathered in this investigation indicates that only the para methoxy positions of methoxyphenylboronic acids are sufficiently activated to allow significant polyhalogenation. In a control experiment, anisole was reacted with NIS and NBS under the same conditions as 4-methoxyphenylboronic acid and in both cases approximately 50% of the para product were isolated. Reaction times however had to be extended substantially to achieve full conversion of anisole. No traces of ortho substituted anisole were found, indicating that for the reaction with NIS there were some steric problems for ortho substitution. In the case of 2-methoxyphenylboronic acid and 2,6-dimethoxy- phenylboronic acid, only ipso substitution is observed. Apparently, the effect of the activation of the boron-carbon bond in ortho position to both methoxy groups and the steric hindrance of the second methoxy group in each para position of the other methoxy-group was sufficient to prevent the competitive substitution in the corresponding para positions. In the case of 4-methoxyphenylboronic acids the two effects - ring activation and enhanced tendency of the carbon-boron bond towards electrophilic substitution - result in a fast and clean ipso substitution. Interesting from a synthetic point of view is the clean conversion of 2-tolylboronic acid into 2- 22 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. iodotoluene in good yield and the formation of 4-iodobenzaldehyde in excellent yield from 4-formylphenylboronic acid. In both cases, the substitution does not follow the influence of the directing groups present in the molecule. For toluene, mainly para substitution would be expected for direct electrophilic aromatic halogenation and the same behavior was observed for the synthesis of iodotoluene via tolylthallium ditrifluoroacetates (o:m:p: 9:4:87) and other approaches.1 1 For benzaldehyde, the meta substituted arene is expected to be the major product of direct halogenation.1 The new method for the preparation could be applied to radioactive labeling, since it converts aryl boronic acids in high yields and under mild conditions into the corresponding iodoarenes. However, radioactive iodine is commercially available only in the form of molecular iodine or sodium iodide. Therefore, the reactions were carried out with N-iodosuccinimide that was generated in situ from sodium iodide and N- chlorosuccinimide (NCS) in an equimolar ratio. Preliminary results showed that the chlorination of aryl boronic acids with NCS is very slow and that even after a base is added to activate the boronic acid leaving group, only traces of the corresponding chloroarenes are formed. Also, the formation of NIS from NCS and sodium iodide in acetonitrile is very fast and can be monitored by the precipitation of the sodium chloride and the fading of the red color of iodine that is formed as an intermediate. Therefore, a competing chlorination of the aryl boronic acids was not expected. The results of the reaction of aryl boronic acids with in situ generated NIS are shown in Table 2.2. (Method B). In all cases the yields are the same as for method A, within the range of experimental error. As entry 10b shows, excess sodium iodide does not have to be employed. 23 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.3.3 Bromination and Iodination of Esters of Aryl Boronic Acids with N- Halosuccinimides Esters of aryl boronic acids are easily accessible from the corresponding acids and phenylboronic acid serves as protecting group for diols in organic synthesis.2 0 Since the aryl boronic esters offer advantages over aryl boronic acids in terms of solubility, stability, and ease of purification, it would be very desirable to expand the scope of the method for regioselective halogenation described above on them. Other applications of the new method could be expected. Deprotection of protected diols could be effected under non-acidic conditions. For the radioactive labeling of arenes a two-phase system can be envisioned. The aryl boronic esters of polymeric diols on a solid support (Scheme 2.5) could be reacted with the desired isotope of iodine in the form of sodium iodide and Af-chlorosuccinimide, thus after reaction only the liquid phase contains the radioactive material, which would then be very easy to isolate. Nal*/ NCS OH OH' Scheme 2.6: Radioactive Labeling with a Two-Phase System As it was expected, the reactivity of a stable aryl boronic ester towards electrophilic ipso substitution was found to be very low. Sterically hindered 2-phenyl- 1,3,2-dioxaborinane reacts with NIS slowly (Scheme 2.6), affording iodobenzene in only moderate yield (30 %). With NBS, after refluxing for 72 h in CH3 CN, only traces of 24 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. bromobenzene and dibromobenzene were detected. These results indicate that the reaction is generally feasible, but that the conditions and the nature of the alkoxy groups have to be selected very carefully in order to achieve higher yields. 2.4 Regioselective Fluorination of Aryltrifluoroborates and Aryl Boronic Acids with Electrophilic Fluorinating Reagents of the N-F Class Recently, Petasis, Prakash, Olah et al. reported the electrophilic fluorination of potassium alkenyl trifluoroborates with l-(chloromethyl)-4-fluoro-l,4- diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (SELECTFLUOR™).2 1 The authors found that the reaction also worked for alkenyl boronic acids, but resulted in disadvantageous side reactions. Yudin also reported, that potassium phenyltrifluoroborate was converted to fluorobenzene when reacted with l-(chloromethyl)-4-fluoro-l,4- diazabicyclo[2.2.2]octane bis(tetrafluoroborate), also known as SELECTFLUOR™ (F- TEDA-BF4 ) at room temperature.2 2 To introduce fluorine via aryltrifluoroborates seemed to be a promising approach since the direct fluorination of aromatics with electrophilic fluorinating reagents of the N-F class has been proven to be problematic and to be only feasible for activated substrates.2 3 A generally applicable method that would allow the NIS Scheme 2.6: Iodination of an Aryl Boronic Ester 25 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. regioselective introduction of fluorine onto aromatics under mild conditions would therefore be highly desirable. This part of my thesis deals with the investigation of the reaction of aryl boronic acids and aryltrifluoroborates with two commercially available electrophilic fluorinating reagents. Scheme 2.7: Electrophilic Fluorination of Aryltrifluoroborates 2.4.1 Fluorination of Aryltrifluoroborates with Selectfluor™ 1 -(Chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) was introduced as a new electrophilic fluorinating agent and has become a commercial product that is extensively employed in the pharmaceutical industry.2 4 ,2 5 Selectfluor™ is a relatively stable compound with high reactivity. It converts phenylmagnesium bromide to fluorobenzene and fluorinates various carbanions in good yields.2 5 Direct reactions with aromatics however, are limited to activated substrates like anisole or acetanilide and yield a mixture of ortho and para substituted product. Fluorination of xylenes yields in a substantial amount of difluorinated product.2 3 The enhanced reactivity of the carbon- boron bond towards electrophilic cleavage and the results for the reaction of alkenyl trifluoroborates with Selectfluor™ led me to the investigation of the reaction with aryltrifluoroborates. 26 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. F 1 -(Chloromethyl>4~fluoro-1,4-dazabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor™) The results of reaction of potassium phenyltrifluoroborate with Selectfluor™ as described by Yudin2 2 could not be reproduced. After 48 hours of stirring the reactants in acetonitrile, no traces of fluorobenzene could be detected by 1 9 F NMR-spectroscopy and GC/MS investigation. However, after refluxing the reaction mixture for 14 hours, the starting material had disappeared and traces of fluorobenzene were detected. Upon analysis of the GC/MS results it became apparent, that benzene (equal amount to that of fluorobenzene) was formed. For the reaction with the deactivated 3- bromophenyltrifluoroborate, 2.5 equivalents of Selectfluor™ were used. GC/MS investigation showed that besides traces of bromobenzene, three isomers of the fluorobromobenzene were the main products. The overall yield was very low and the isomer distribution (1:1:1) indicates that the products observed may have been formed from bromobenzene after protolytic deboronation. Similar results were obtained for other substrates (Table 2.3), including the corresponding aryl boronic acids, which were even less successful. As in the case of the aryltrifluoroborates, protodeboronation was observed. Since the reactions were conducted under non-acidic conditions, it is intriguing how the apparent protodeboronation of the aryltrifluoroborates takes place. 27 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 2.3: Fluorination of Aryl Boronic Acids and Aryltrifluoroborates with Selectfluor Starting Material Product Temperature Time Equivalents Yielda [°C] [ h ] Selectfluor™ [ % ] ■BF-iK HiCO Br RT 48 1.2 0 81 14 1.2 Traces 81 14 2.0 Traces RT 48 1.2 Traces 81 14 2.0 Traces RT 81 81 81 24 14 14 14 1.2 1.2 > 5 b 10b 2.0 Traces 2.5 Traces a) Traces found by GC/MS, isolated yield <5% b) Determined by 1 9 F NMR The mechanism of electrophilic fluorination of organic substrates with Selectfluor™ and related reagents is not fully understood at this time, although two possible pathways have been proposed (Scheme 2.8).8 The most straightforward mechanism suggests a direct nucleophilic attack on fluorine, resulting in the displacement of the NR2 ' group. An alternative pathway is a single-electron-transfer (SET) mechanism, involving the initial formation of a charge transfer complex. The formation of the 28 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. protodeboronated products under non-acidic conditions indicates that the substitution may follow a SET mechanism. The reactive phenyl radical abstracts a proton from another reactant or solvent molecule. SET- ReactionsReactions with Nucleophiles R2NF+ + Nu- [R2N-F+, Nif] ► R2N + Nu-F Nucleophilic Displacement at Fluorine R2N -F++Nu" [I^N--F--Nu] R2NF + Nu-F Scheme 2.8: Mechanistic Pathways for the Fluorination of Organic Nucleophiles with N-F Class Reagents 2.4.2 Attempted Fluorination of Aryltrifluoroborates with A-Fluoropyridinium Triflate The TV-fluoropyridinium salt system was introduced by Umemoto and coworkers in 1986 and has become a commercially available compound with many interesting properties.2 7 It has been shown that the reactivity of the compounds can be adapted to that of the substrate by choosing the appropriate counterion. Fluoropyridinium triflates have been found to be more reactive than the corresponding tetrafluoroborates and perchlorates.2 7 Phenol is fluorinated by fluoropyridinium triflates smoothly but without a good ortho-para selectivity.2 8 F o s o 2 c f3 N- Fluoropyridinium Triflate 29 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Since the results of the reactions with Selectfluor™ were unsatisfactory, fluoropyridinium triflate was tested as another electrophilic fluorinating reagent. Table 2.4: Attempted Fluorination with A-Fluoropyridinium Triflate Starting Material Equivalents of F+ Temperature [°C] Time Comment 1.2 RT 48 No reaction 1.2 81 14 No reaction ^>— B(OH) 2 1.2 81 14 No reaction h 3oo— bf3k 1.2 81 14 No reaction With various aryltrifluoroborates and with phenylboronic acid, the desired fluorinated product was not observed (Table 2.4). All the reactions were carried out in acetonitrile at both room temperature and under reflux. 2.5. Conclusion and Outlook It has been shown that the reaction of N- halosuccinimides with aryl boronic acids is a very convenient and effective new method for the mild preparation of iodo- and bromoarenes. The preparation of bromoarenes from aryl boronic acids may be inefficient in most cases, since aryl boronic acids themselves are often prepared from the corresponding bromoarenes. However, a number of substituted aryl boronic acids are 30 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 29 available by a direct metalation approach. In addition, the boronic acid functionality could serve as a protecting group for haloarenes, which can be easily removed under mild conditions by the reaction with jV-halosuccinimides. For example, it has been shown that iodobromoarenes undergo metal-catalyzed coupling reactions preferably under substitution at the iodo-carbon bond.3 0 This could be avoided, if the iodo position is protected by the boronic acid functionality during the coupling reaction, which could then subsequently be removed by reaction with NIS. The same could be assumed for asymmetrically substituted dibromoarenes. Another interesting feature of the preparation of iodo- and bromoarenes from arylboronic acids is that it may be applied in a one-pot synthesis of symmetric biaryls by a subsequent Pd(0)-catalyzed coupling of remaining aryl boronic acid with the aryl halide (Scheme 2.7). 1.) 0.5 equiv. NIS / MeCN R V = \ 2.) Pd(0) ^ y~ b( o h )2 Scheme 2.9: One-Pot Synthesis of Symmetric Biaryls from Aryl Boroic Acids The modification of the procedure that allows the in situ preparation of NIS from radioactive sodium iodide also offers a new method for introducing radioactive iodine onto aromatic rings under very mild conditions and in good yields. The new method avoids toxic thallium or mercury intermediates, strong oxidizing reagents and acidic conditions that are necessary for other methods.1 0 ,3 1 It can be said that the new method is convenient, practical and complementary to other known methods. 31 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Unfortunately, the fluorination reactions with Selectfluor™ and jV-pyridinium triflate did not prove to be as successful as they were expected to be, therefore, the selective preparation of fluoroarenes new methods have to be found. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 2.6 References (1) For a monograph see: de la Mare, P. B. D. Electrophilic Halogenation; Cambridge University Press: Cambridge, 1976 (2) a) Miyaura, N.; Suzuki A.; Chem. Rev. 1995,2457 b) Fanta, P. E. Chem. Rev. 1964, 613 c) Dewanjee, M. K. Radioiodination: Theory, Practice and Biomedical Applications; Kluwer Academic Publishers: Boston, 1992 (3) Filler, R.; Kobayashi, Y. Eds. Biomedicinal Aspect o f Fluorine Chemistry, Elsevier Biomedicinal Press: New York, 1982 (4) Fried, J.; Subo, E. F. J. Am. Chem. Soc. 1954,1455 (5) Cacace, F.; Giacomello, P.; Wolf A. P. J. Am. Chem. Soc. 1980,102,3511 (6) Newman, M. S.; Galt, R. H. B. J. Org. Chem. 1960,214 (7) a) Patrick, T. B.; Nadji S. J. J. Fluorine Chem. 1988,39,415 b) Middleton, W. J.; Bingham, E. M. J. Am. Chem. Soc. 1980,102,4845 c) Rozen, S.; Lerman, O.; J. Org. Chem. 1980, 45, 672 (8) Lai, G. S.; Pez, G. P., Syvret R. G. Chem. Rev. 1996,96,1737 and references therein (9) Baird Jr., W. C.; Surridge, J. H. J. Org. Chem. 1970, 35, 3436 (10) For a recent review on the preparation of iodoarenes see: Merkushev, E. B. Synthesis 1988, 923 (11) Funk, R. C.; Vollhardt, K. P. C. J. Chem. Soc. Chem. Commun. 1976, 833 (12) McKillop A.; Hunt, J. D.; Zelesko, M. J.; Fowler J. S.; Taylor E. C.; McGillivray G.; Kienzle F. J. Am. Chem. Soc. 1971, 93, 4941 (13) Sandmeyer, T. Ber. 1884,1633 (14) Brown, H. C.; Hamakoka,T.; Ravindran, N.; J. Am. Chem. Soc. 1973,95,6456 (15) Brown, H. C.; Hamakoka,T.; Ravindran, N.; J. Am. Chem. Soc. 1973, 95, 5786 (16) Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 56 33 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. (17) Michaelis, A.; Becker, P. Ber. 1882,15,182 (18) Gilow, H. M.; Burton, D. E. J. Org. Chem. 1981,46,2221 (19) Calo, V.; Ciminale, F.; Lopez, L.; Todesco, P. E. J. Chem Soc. (C) 1971, 3652 (20) Sugihara, J. M.; Bowman C. M. J. Am. Chem. Soc. 1958, 80,2443 (21) Petasis, N. A.; Yudin, A. K.; Zavialov, I. A.; Prakash, G. K. S.; Olah, G. A. Synlett 1997, 606 (22) Yudin, A. K. Dissertation, University of Southern California, Los Angeles, 1996 (23) Lai, G.S.; J. Org. Chem. 1993, 58,2791 (24) Banks, R. E. U.S. Patent. 5,086,178,1992 (25) a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lai, G. S.; Sharif, I.; Syvret, R. G. J. Chem. Soc. Chem. Commun. 1992, 595 b) Banks, E. R.; Lawrence, N. J.; Popplewell, A. L. J. Chem. Soc. Chem. Commun. 1994, 343 (26) a) Umemoto, T.; Tomita, K. Tetrahedron Lett. 1986, 37, 3271 b) Umemoto, T.; Tomita, K.; Kawada, K.; Tomizawa, G. U.S. Patent 4,996,320,1991 (27) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.; Kawada, K.; Tomita, K. J. Am. Chem. Soc. 1990,112, 8563 (28) Umemoto, T.; Kawada, K.; Tomita, K. Tetrahedron Lett. 1986, 37, 4465 (29) Snieckus, V. Chem. Rev. 1990, 90, 879 (30) Plevyak, J. E.; Dickerson, J. E.; Heck, R. F. J. Org. Chem. 1979, 44, 4078 (31) Olah, G. A.; Wang, Q.; Sandford, G.; Prakash, G. K. S. J. Org. Chem. 1993, 58, 3194 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 3: Nitration and Nitrosation of Arvl Boronic Acids and Aryltrifluoroborates 3.1 Introduction The nitration of arenes is one of the most widely studied electrophilic aromatic substitution reactions, since nitroarenes play an important role as final products or precursors to other synthetically or industrially interesting compounds.1 Reduction to the amino derivatives provides access to diazonium ions. Diazotation leads to an important class of dyes and allows the introduction of various functionalities in Sandmeyer-type reactions. Nevertheless, nitration is problematic in some cases. For example, the electron- withdrawing effect of the nitro group often prevents a polynitration. This may be favorable in most cases, but for the increasingly important class of highly energetic compounds, it would be desirable to add more than one nitro group on an aromatic ring selectively. Here lies the motive for the investigation of the nitration and nitrosation of aryltrifluoroborates and aryl boronic acids. As the results of the investigation of the reaction with TV-halosuccinimides indicate, these compounds undergo electrophilic substitution more easily than the corresponding arenes. Aryl boronic acids and aryltrifluoroborates could therefore provide a way to prepare nitroarenes from less activated precursors under milder conditions. Another important drawback in common nitration reaction of arenes is the lack of regioselectivity and a resulting need for product separation, which could be avoided by a regioselective reaction. 35 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The preparation of nitrosoarenes is more problematic and the direct nitrosation of arenes is feasible only in the cases of strongly activated compounds like phenols and tertiary amines.2 Thus, a new method for the direct nitrosation of arenes that employs the enhanced reactivity of aryltrifluoroborates would be very useful. 3.2 Nitration of Aryl Boronic Acids and Aryltrifluoroborates 3.2.1 Nitration of Aryltrifluoroborates with Nitric Acid Concentrated nitric acid (HN03 ) affects nitration of arenes. More effective, however, is a mixture of nitric acid and sulfuric acid. The mechanism of these reactions has been subject of intensive study, and it is widely acknowledged that the effective nitrating reagent is the nitronium (N02 + ) ion. It is formed by self-protonation of nitric acid, but it is present in higher concentrations in mixtures of nitric and sulfuric acid (Scheme 3.1). The formation of the nitronium ion has been shown to be the rate- determining step in many electrophilic aromatic nitration reactions.1 HN03 + 2Y? H30 + + N 02+ 2 HNO3 H2N 03 + + N 03' H2N 03+ -----► N 0 2++H20 Scheme 3.1: Formation of the Nitronium Ion It was investigated, if the aryltrifluoroborates would undergo regioselective (ipso) nitration and whether their reactivity towards the nitronium ion is higher than that of 36 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. other arenes. The nitric/sulfuric acid system was not tested on aryl boronic acids, because preliminary studies indicate, that they undergo nitration at other positions rather than at the ipso position under these conditions, although some nitrodeboronation was also observed in theses cases.3 BF3K Scheme 3.2: Nitration of Aryltrifluoroborates with Nitric Acid Various potassium aryltrifluoroborates were tested for their behavior towards the nitric/sulfuric acid system. It was found that the reaction conditions had to be carefully adjusted to the reactivity of the aryltrifluoroborates. Two major side reactions had to be considered. When the temperature or the concentration of the nitronium ion was too low to affect fast reaction, hydrolysis to the unreactive aryl boronic acids was observed. In the case of 4-chlorophenyltrifluoroborate which was reacted with 50 % (w/w) nitric acid (excess) for 5 hours at room temperature, 4-chlorophenylboronic acid was recovered nearly quantitatively. However, when the concentration of the nitronium ion or the temperature were to high, oxidative decomposition of the aryltrifluoroborate took place, indicated by the formation of a highly colored to black tarry residue. Attempts were made to find the optimized reaction conditions for various substrates, but as the results 37 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. presented in Table 3.1 indicate, it was not possible to obtain the desired products in good yields. Table 3.1: Nitration of Potassium Aryltrifluoroborates with Nitric Acid Starting Material Equivalents [HN03 ] Equivalents Temperature Time yieldb HNOj (w/w) H2 S04 [° Ci [h] [%] ^ // b f 3 k a 0 ,N BF3K -b f 3 k Excess 50% - RT 4 0 3 70% - 0 -R T a 3 Traces Excess 70% - 0 -R T 3 5% Excess 70% - RT 3 Traces Excess 50% RT 4 0 3 70% - 0 -R T 3 Traces Excess 70% RT 2 0 Excess 50% RT 4 0 3 70% - 0 -R T 3 7 Excess 70% - 0 -R T 3 14 Excess 70% - RT 3 Traces Excess 50% RT 4 0 Excess 70% - 0 -R T 3 19 Excess 70% - RT 3 Traces Excess 70% 0 -R T 4 Traces Excess 70% - RT 4 7 Excess 70% 2 RT 4 12 Excess 70% 10 RT 4 29 30 70% 40 RT 4 53 30 70% 40 0-RT 4 20 Excess 70% 0-RT 4 0 Excess 70% - RT 4 Traces Excess 70% - RT 4 Traces 30 70% 40 RT 4 Traces a) reaction mixture was stirred for lh at 0 °C and then warmed to room temperature b) isolated yields 38 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. It was found that the best results were obtained for deactivated substrates like 3- bromo- or 3-trifluoromethylphenylboronic acid. These seem to be stable enough towards oxidative decomposition under reaction conditions that favor nitration over hydrolysis of the trifluoroborate. Intriguingly, it was not possible to obtain the good yields for the 3- trifluoromethylphenyltrifluoroborate in the case of 3-nitrophenyltrifluoroborate. The reactions were mostly carried out with a large excess of nitric acid, since it was used as a solvent. When smaller amounts were used, the reaction mixture could not be stirred, which caused lower yields. Attempts were made to react the aryltrifluoroborates with nitric acid in acetonitrile, but here also the hydrolysis and the oxidation took place without major product formation. Another approach was to react the aryltrifluoroborates in a two-phase system, to protect the products from oxidation once they are formed. Therefore, the aryltrifluoroborates were dispersed in dichloromethane or ether and then the nitric acid was added. However, this did not result in enhanced yields. It seems that the oxidation products are formed mainly from the starting materials and not from the products. 3.2.2. Nitration of Aryltrifluoroborates with Nitronium Tetrafluoroborate Nitronium tetrafluoroborate (N02 BF4 ) is a strong source for the nitronium ion, and has been effectively used in the direct nitration of various arenes.4 It is also used as a mild oxidizing reagent. Yudin5 reported, that aryltrifluoroborates undergo ipso substitution when treated with nitronium tetrafluoroborate in acetonitrile (Scheme 3.3), Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. while Olah and coworkers found that the inactivated phenylboron dichloride can be nitrated with nitronium tetrafluoroborate without deboronation.6 Since oxidation is less problematic in the nitrations of arenes with nitronium tetrafluoroborate than with the conventional mixed acid system (HN03 /H2 S04 )4 , it seemed to be a promising alternative to this reagent. Advantageous is that the system is water free and the reagent itself is non-acidic, so that hydrolysis could be avoided, too. As the results presented in Table 3.2 indicate, the reaction did not offer a significant advantage over the mixed acid system. The main reason for this is that nitronium tetrafluoroborate oxidizes the aryltrifluoroborate faster than the nitration takes place. Even 3-trifluoromethylphenyltrifluoroborate, which was comparatively stable under the conditions for nitration with mixed acid systems, undergoes extensive oxidation, indicated by the formation of a black tarry residue, when the nitration is carried out above -40 °C. It could be anticipated that the reactions have to be carried out at lower temperatures to reduce oxidative decomposition, but the melting points of the solvents in which aryltrifluoroborate salts are soluble put a limit to the temperatures that could be employed. The substrates exhibit only limited solubility in both nitromethane (m.p. -28 N02BF4 R R Scheme 33: Nitration of Aryltrifluoroborates with Nitronium Tetrafluoroborate 40 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. °C) and acetonitrile (m.p. - 42 °C) close to their melting points. The reactions that were carried out in nitromethane did not result in better yields, since the reaction temperature had to be above -30 °C because of the high melting point of the solvent. Since there was no suitable alternative, acetonitrile was used as the solvent for these reactions. It was found that the yields are the best if to a solution of the aryltrifluoroborate in acetonitrile is dropped very slowly a solution of the nitronium salt in the same solvent, rather than reverse. Table 3.2: Nitration of Potassium Aryltrifluoroborates with Nitronium Tetrafluoroborate Starting Material Temperature [°C] Time [minutes] Yielda ) [%] o - b f 3 k -15 -40 20 50 Traces Traces y - b f 3 k -15 -40 20 50 Traces >5% O —b f 3k 0 -15 40 60 Traces 5 -40 60 17 f 3 c -40 120 14 Q — b f 3k 0 -15 40 60 Traces Traces r -40 60 Traces o 2 n a) isolated yields after column chromatography / distillation 41 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Since the nitration of aryltrifluoroborate salts with nitronium tetrafluoroborate was unsuccessful due to the high tendency of the substrates to undergo oxidative decomposition even at low temperatures, the transfer nitration with iV-nitropyridinium tetrafluoroborate9 was tested for the nitration of 3-trifluoromethylphenyltrifluoroborate, the substrate that gave the best results for the nitration with nitronium tetrafluoroborate. A'-Nitropyridinium Tetrafluoroborate It was found that oxidative decomposition is reduced significantly here, however, the conversion was very low at room temperature and when the system was heated, oxidation occurred once again, thus the reaction did not result in reasonable yields of the desired product. 3.2.3 Nitration of Aryl Boronic Acids with Acetyl Nitrate and Trifluoroacetyl Nitrate Since the nitration of the potassium aryltrifluoroborates was unsuccessful because of their instability towards oxidizing reagents, it was tried to find a method that allowed the regioselective nitration by ipso substitution of aryl boronic acids, which have been shown to be relatively stable towards strong oxidizers like fuming nitric acid.3 a This would also make the preparation of the aryltrifluoroborates from the aryl boronic acids unnecessary, which is desirable. 42 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Since there is some evidence that the regioselective iodination and bromination (Chapter 2) involves activation of the boronic acid functionality by the imido oxygen of the jV-halosuccinimide, it was expected that a nitrating reagent like acetyl nitrate, that has a neighboring oxygen capable of activating the boronic acids, could affect the desired conversion. There is considerable evidence, that in the nitrations of phenylboronic acid in acetic anhydride, there is coordination of boron by a solvent molecule, so that the meta directing effect of the boronic acid group is replaced by the ortho/para-directing effect of the negatively charged tetrahedral boron complex.8 Acetyl nitrate is a well established reagent for the nitration of arenes. In many cases it induces a very high ortho/para selectivity in favor of the ortho product.7 The reagent can be prepared from acetic anhydride and concentrated nitric acid and then be used without isolation. Other approaches include in situ preparation from silver nitrate and acetyl chloride in acetonitrile.9 0 The possibility of in situ preparation is important since acetyl nitrate is very instable and can decompose explosively when it is isolated. The reaction of aryl boronic acids with acetyl nitrate showed that once again, in order to achieve the desired conversions, the reaction temperature had to be raised to room temperature, leading to side reactions like extensive oxidation. As Table 3.3 shows, the reaction is most successful for the less deactivated substrates. Oxidation was observed O Acetyl Nitrate 43 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. only as a minor side reaction in most cases, however, only in the case of phenylboronic acid, were the formation of a black tarry residue was observed, a moderate yield of the desired product was observed. In this case it is possible that a preliminary protodeboronation and a subsequent nitration of benzene or the reverse could have taken place, since the reaction time was very long and the yield (38 %) is much higher than for other aryl boronic acids, which are more stable towards protodeboronation. For the 3- bromophenylboronic acid for example, only the ipso substitution product was observed. Table 3.3: Nitration of Aryl Boronic Acids with Acetyl Nitrate Starting Material Equivalents of Acetyl Nitrate” Temperature [°C] Time E h ] Yield" [%] B(OH) 2 1.5 1.5 3 RT 0 °C - RT 0-RT 10 5 24 7 Traces 38 a ---- — B(OH) 2 1.5 1.5 3 0-RT 0-RT 0-RT 3 5 12 Traces 5 7 I V -B (O H ) 2 3 3 0-RT 0-RT 3 12 9 11 b/ { V - B ( O H ) 2 3 RT 5 7 / f3c a) 1 mmol nitric acid / 2.7 mmol acetic anhydride7 bb) isolated yield 44 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. It seems that the acetyl nitrate system does not provide sufficient concentration of nitronium ion to effect the desired conversion, or that nitration takes place at other positions rather than ipso so that the products are nitrophenylboronic acids which were discarded during workup. Since acetyl nitrate does not seem to be reactive enough towards the aryl boronic acids, trifluoroacetyl nitrate was tested as a possible alternative. It can be prepared from ammonium nitrate and trifluoroacetic anhydride in situ. It was expected to be more reactive than acetyl nitrate and can be used under non-acidic conditions. The reagent has been introduced by Crivello and has very interesting properties.1 0 Many arenes are nitrated in good yield, but phenols are oxidized to quinonoid products. When aryl boronic acids were reacted with trifluoroacetyl nitrate, oxidative decomposition was a major side reaction again and the procedure given by Crivello had chlorophenylboronic acid, at room temperature, there was extensive oxidation so that the reaction temperature had to be lowered in order to obtain better yields. Nevertheless, trifluoroacetyl nitrate seems to be a better nitrating reagent for aryl boronic acids than acetyl nitrate, as the results presented in table 3.4 indicate. O Trifluoroacetyl Nitrate to be altered to take this into account. In the reaction of the 3-bromo- and the 4- 45 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3.4: Nitration of Aryl Boronic Acids with Trifluoroacetyl Nitrate Starting Material Equivalents of Temperature Trifluoroacetyl Nitratea ) [°C] Time [h] Yieldb ) [%] < ^ J ) — B(OH) 2 1.5 3 RT 0 -R T 5 6 Traces 20 a -----— B(OH) 2 1.5 3 0 -R T 0 -R T 6 6 17 29 \ ^ B(OH) 2 3 3 RT 0 - RT 3 3 <5 26 r J 3 0 - RT 12 31 Br a) limited by the amount of ammonium nitrate b) isolated yields 3.2.4 Nitration of Alkenyl Boronic Acids Although the reactions of alkenyl boronic acids were not subject of this thesis, it was tested, if the nitration works in their case. This would provide a novel approach to nitroalkenes from the corresponding acetylenes (Scheme 3.4), which are very important substrates in organic synthesis as Michael-acceptors and as dienophiles in Diels-Alder reactions. B(OH)2 Scheme 3.4: Preparation of Nitroalkenes from Acetylenes Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Since they are much more reactive than aryl boronic acids and very susceptible towards protodeboronation, mixed acid reagents and nitronium tetrafluoroborate were not considered to be good nitrating reagents for the alkenyl boronic acids. The formation of geometrically pure vinyl halides in the halogenation of alkenyl boronic acids with N- halosuccinimides indicates that the mechanism involves activation of the boronic acid functionality in a direct displacement mechanism.1 0 The results presented indicate that there might be activation of the boronic acid functionality in the nitration with acetyl nitrate and trifluoroacetyl nitrate as well. Therefore, the nitration of alkenyl boronic acids with these reagents could lead to geometrically pure nitroalkenes, which would make the method even more valuable. For this investigation, E-styrylboronic acid was regarded as the best substrate, considering stability and accessibility. When E-styrylboronic acid was reacted with acetyl nitrate under similar conditions than the aryl boronic acids, only traces of the desired product, B-nitrostyrene, could be observed along with a significant amount of styrene, the product of protodeboronation. It was therefore expected that the non-acidic trifluoroacetyl nitrate would be a better nitrating reagent. The nitration was carried out at -35 °C in acetonitrile to avoid decomposition of the substrate. Investigation of the reaction mixture after workup by GC/MS indicated that B-nitrostyrene was formed without formation of styrene and a 'H NMR spectrum indicated that the product was obtained in very high geometrical purity. Unfortunately, only a small amount of substrate was available thus a further investigation was not possible. 47 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3.3 Nitrosation of Aryl Boronic Acids and Aryltrifluoroborates Results by Yudin indicate that aryltrifluoroborates undergo ipso substitution when they are reacted with nitrosonium tetrafluoroborate to affect nitrosoarenes.4 Since there was no experimental data available, the scope of this new reaction was investigated. B(OH)2 NOBF NOBF CH3CN Scheme 3.5:Attempted Nitrosation of Aryltrifluoroboratesand Aryl BoronicAcids with Nitrosonium Tetrafluoroborate Various aryltrifluoroborates were reacted with nitrosonium tetrafluoroborate (NOBF4 ) in acetonitrile. Although in every case the typical green color of nitrosoarenes appeared during reaction, no product could be detected by means of GC/MS analysis or thin-layer chromatography. Oxidative decomposition was less problematic for the reaction of nitrosonium tetrafluoroborate than for the reaction with nitronium tetrafluoroborate and could be mostly avoided, when the temperature of the reaction mixture did not exceed -25 °C. 48 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 3.5: Nitration of Potassium Aryltrifluoroborates and Aryl Boronic Acids with Nitrosonium T etrafluoroborate Starting Material Temperature [°C] Time [minutes] Comment O —b f 3k -15 -40 20 40 Black Tar Green Solution —BF3K -25 -35 20 60 Black Tar Green Solution —B(OH) 2 -20 -30 20 40 Black Tar Yellow Solution —b f 3 k -15 -40 20 50 Red Solution Green Solution 9 - f3c - b f 3 k -15 -40 20 50 Yellow Solution Green Solution 3.4 Conclusion and Outlook The nitration of aryl boronic acids and aryltrifluoroborates does not seem to be as successful for the regioselective preparation of nitroarenes as it was expected. Potassium aryltrifluoroborates do undergo nitration under ipso substitution and they are more reactive than the corresponding arenes. In the case of 3-bromophenyltrifluoroborate, in all cases where product could be obtained, it was the ipso substituted product, despite the directing influence of the substituent, thus the reaction can be considered to be 49 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. regioselective. Of the various reagents that were employed, none has the capability to affect the desired conversion in high yields. The mixed acid system has the advantage of being extremely inexpensive, the acetyl nitrate approach does not require the preparation of aryltrifluoroborates, thus these two systems seem to be the most suitable. Nitronium tetrafluoroborate gave worse results and is an expensive and very sensitive reagent, thus it is not the reagent of choice. The nitrosation was not successful, although the intermediate formation of the desired product can be suspected, considering the appearance of the green color of the reaction mixture. The most interesting result regarding synthetic utility is the possibility of the preparation of geometrically pure nitroalkenes from the corresponding alkenyl boronic acids. This reaction has a great potential for synthetic application and should be investigated in the future. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 3.5 References (1) a) Olah, G. A.; Malhorta, R.; Narang, S. C. Nitration - Methods and Mechanism; VCH: New York, 1989 b) K. Schofield, Aromatic Nitration; Cambridge University Press: Cambridge, 1980 (2) Williams, D. L. H. Nitrosation; Cambridge University Press: Cambridge, 1988, p. 58 (3) a) Ainley, A. D.; Challenger, F. J. Chem. Soc. 1930, 2171 b) Harvey, D. R.; Norman, R. O. C. J. Chem. Soc. 1962,3823 c) Seaman, W.; Johnson, J. R. J. Am. Chem. Soc. 1931, 53, 711 d) Gronowitz, S.; Ross, C. Acta Chem. Scand. 1975, 990 (4) Olah, G. A.; Prakash, G. K. S.; Wang Q.; Li, X. in Encyclopedia o f Reagents for Organic Synthesis; Paquette, L. A. Ed., Vol. 6, Wiley: Chichester, 1995 (5) Yudin, A. K. Dissertation, University of Southern California, Los Angeles, 1996 (6) Olah, G. A.; Piteau, M.; Laali, K.; Rao, C.; Farooq, O. J. Org. Chem. 1990, 55,46 (7) Dewar, M. J. S.; Mole, T. Urch, D. S.; Warford, E. W. T.; J. Chem. Soc. 1956, 3576 (8) Harvey, D. R.; Norman, R. O. C. J. Chem. Soc. 1962,3822 (9) a) Louw, R. in Encyclopedia o f Reagents fo r Organic Synthesis; Paquette, L. A. Ed., Vol. 1, Wiley: Chichester, 1995 b) Folsum, H. E.; Castrillon J. Synth. Commun. 1992, 22, 1799 c) Olah, G. A.; Lin, H. C.; Olah, J.; Narang, S. C. Proced. Nation. Acad. Sc. 1978, 75,1045 (10) Crivello J. V. J. Org. Chem. 1981,46,3056 (11) Petasis, N. A.; Zavialov, I. A. Tetrahedron Lett. 1996, 37, 56 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 4: Reactions of Arvl Boronic Acids and Aryltrifluoroborates with Various Carbon and Nitrogen Electrophiles This part of this thesis deals with the reaction of various electrophiles in ipso substitutions of aryl boronic acids and aryltrifluoroborates. The reactions investigated would provide a new method for the introduction of functional groups onto aromatic rings that usually do not undergo these reactions as readily as this was expected considering the enhanced susceptibility of the aryl-boron bond to electrophilic substitution. 4.1 Reactions with Carbon Electrophiles 4.1.1 Attempted Aryltrifluoroborate Mannich Reaction The alkenyl boronic Mannich reaction has been reported by Petasis and coworkers in 1993. It is a new method for the synthesis of allylamines and its utility was demonstrated by the facile preparation of naftifme, an important antifimgal reagent.1 It was reported however, that the reaction did not work well for aryl boronic acids, to affect the corresponding benzylamines. It was therefore tested, whether the enhanced reactivity of the aryltrifluoroborates compared to the alkenyl boronic acids would result in better yield of the desired product. O R © R CH2NR2 Scheme 4.1: The Aryltrifluoroborate Mannich Reaction 52 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. In a first set of trials, several aryltrifluoroborates were reacted in acetonitrile with Eschemoser’s salt (TV,iV-dimethylmethyleneammonium iodide), a preformed mannich electrophile. CH2 i0 II 1 H3 C^©x CH3 Eschenmoser's Salt (IV,N-dmethylammonium iodide) Table 4.1: Reaction of Potassium Aryltrifluoroborates with Eschenmoser’s Salt Starting Material Solvent Temperature Time [°C] [h] c h 3 c n CHjCN CHjCN RT 81 81 6 6 24 No reaction No reaction No reaction Cl— bf3k CHjCN CHjCN RT 81 6 16 No reaction No reaction H3CO— ^ — BF3K CHjCN 81 16 No reaction However, as the results presented in Table 4.1 indicate the desired products are not formed under the various reaction conditions employed. These results were not surprising, because it was reported by Petasis et. al. that Eschenmoser’s salt does not react with alkenyl boronic acids, but that the reaction of secondary amines with alkenyl boronic acids in the presence of paraformaldehyde yields the desired allylamines. Therefore, several secondary amines were reacted with 4- 53 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. methoxyphenylaryltrifluoroborate, the substrate that was considered to be the most reactive. However, the desired products were not observed. Table 4.2: Attempted Preparation of 4-Methoxybenzylamines Starting Material Solvent Temperature [°C] Time [h] Yield [%] CH3 CN RT 6 No reaction 1,4-Dioxane 105 15 No reaction CHjCN 81 24 No reaction CHjCN RT 6 No reaction CHjCN 81 16 No reaction CHjCN 81 16 No reaction HN 'N ' H Obviously, the reactivity of the electrophiles and the aryltrifluoroborates are not high enough to effect the desired conversion. 4.1.2 Attempted Alkylation and Acylation of Potassium Phenyltrifluoroborate The alkylation and acylation of arenes belong to the class of Friedel-Crafts reactions, which have been studied extensively, because these reactions provide an important way of forming carbon-carbon bonds.2 However, these reactions usually require activation of the electrophile by a Lewis acid catalyst. The ipso substitution of aryltrifluoroborates with acylating and alkylating reagents seemed interesting because of various reasons. First, the enhanced reactivity of the aryltrifluoroborates towards 54 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. electrophilic substitution could provide a way of performing the desired transformations under milder conditions. Since the substitution of BF3 produces a strong Lewis acid catalyst, the use of an external catalyst would be unnecessary (Scheme 4.2). Also, the inherent regioselectivity of Ipso substitution reactions and the fact that substitution may be effected against the influence of directing groups, made the approach very promising. The first reaction that was tested, was the acylation of aryltrifluoroborates with acid chlorides and anhydrides. Acylation did not take place in these cases. The use of an external catalyst was not tried considering the ease of ring acylation under these conditions. As can be seen from Table 4.2. alkyl halides do not react to give the corresponding alkylbenzenes. Scheme 4.2: Reaction of Aryltrifluoroborates with Electrophiles 55 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 4.3: Attempted Alkylation and Acylation of Potassium Phenyltrifluoroborate Reagent Solvent Temperature [°C] Time M Yield [%] CHjCN CH3 CN 0 RT 6 15 No reaction No reaction Mel CHjCN CHjCN 0 RT 6 16 No reaction No reaction O x F3C CI CH3 CN RT 14 No reaction 0 0 AA CH3 CN RT 81 16 5 No reaction No reaction 0 0 f 3c ^ o ^ c f 3 CHjCN RT 81 16 5 No reaction No reaction 4.2 Attempted Preparation of Aryl Azides from Aryltrifluoroborates As preliminary results indicate, it is possible to obtain an equivalent of N3 + by reacting the azide anion with Selectfluor™,3 a new electrophilic fluorinating reagent (see 2.4.1). It was tested if electrophilic Ipso substitution of aryltrifluoroborates and arylboronic acids could be effected to provide a new method for the preparation of the important class of aryl azides. Therefore, phenylboronic acid and potassium phenyltrifluoroborate were reacted in acetonitrile with an equimolar solution of Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Selectfluor™ and sodium azide in acetonitrile, which had been stirred for 15 minutes. However, no product formation was observed in both cases. 4.3 Conclusion The reaction of aryltrifluoroborates with various carbon electrophiles was not successful. It may be necessary to use a catalyst to activate the electrophiles, but even in the case of the cationic Eschenmoser salt, no reaction occurred. Also, benzene is known to undergo Friedel-Crafts acylation with acid chlorides and anhydrides catalyzed by Lewis Acids at low temperatures, so that it will be difficult to adapt the reaction conditions for the aryltrifluoroborates to avoid ring substitution. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 4.4 References (1) Petasis, N. A.; Akritopoulou I. Tetrahedron Lett.1993, 34, 583 (2) Olah G. A., Ed. Friedel-Crafts and Related Reactions, Vol. 1-4; Wiley Interscience; New York, 1963 (3) a) Banks, R. E.; Mohialdin-Khaffaf, S. N.; Lai, G. S.; Sharif, I.; Syvret, R. G. J. Chem. Soc. Chem. Commun. 1992, 595 b) Banks, E. R.; Lawrence, N. J.; Popplewell, A. L. J. Chem. Soc. Chem. Commun. 1994, 343 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 5: Experimental Part 5.1 General Aspects of Preparative Work Reactions involving air- or moisture sensitive compounds were conducted in argon-filled Schlenk flasks, which contained a PTFE-coated magnetic stirring rod and were sealed with a rubber septum. The flasks were evacuated and heated. For addition or removal of solvents, liquid or dissolved reactants, PVC-syringes, equipped with steel needles were employed. Solids were added under argon flow after the septum was removed. Inverse addition of liquids was conducted with a double-ended needle. During the whole reaction, argon pressure remained slightly higher than atmospheric pressure (side joint of Schlenk type flask attached to argon filled balloon or argon tank). Reactions were monitored by gas chromatography/mass spectrometry (GC/MS), thin layer chromatography (TLC) or 1 9 F NMR spectroscopy. For TLC Merck 60 FR254 silica gel coated glass plates with UV indicator were used. For detection of compounds without UV indicators, the plates were developed in an iodine chamber, or by treatment with a potassium permanganate solution (4 % w/w). 5.1.1 Chemicals Used With the exception of 2-methoxyphenylboronic acid and 2,6-dimethoxyphenyl- boronic acid, which were obtained in a one-pot-synthesis from the corresponding bromo compounds, (see following procedure) aryl boronic acids were used as obtained from Aldrich Chemical Co. and used without further purification. 59 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Preparation o f 2-Methoxyphenylboronic Acid: To a solution of 9.35 g (50 mmol) of freshly distilled 2-bromoanisole in 200 ml dry diethylether in a flame dried Schlenk flask 20.4 ml (51 mmol) of a 2.5 M solution of n-butyllithium in diethylether were added over a period of 35 minutes at a temperature of -78 °C under an atmosphere of dry argon. After the addition was completed, the reaction mixture was stirred at -78 °C for one hour. Then a solution of 11.8 ml triisopropyl borate (51 mmol) in 200 ml diethyl ether was transferred to the reaction mixture by using a double-ended needle. The reaction mixture was allowed to warm to room temperature overnight and then quenched with 100 ml of 5% aqueous hydrogen chloride and left standing at room temperature for 5 hours. The organic phase was separated and the aqueous phase was extracted three times with 100 ml of diethyl ether. The combined organic phases were dried with MgS04 and the solvent was removed in vacuo. The resulting brown liquid was left standing for two days. The resulting white large crystals were filtered off and recrystallized two times from hot water, yielding a combined crop of 2.6 grams of white crystals (34.2 % of the theoretical yield). NMR (ppm, Acetone-d6 ): 'H: 3.927 (s, 3H), 6.94-7.09 (m, 2H), 7.38-7.46 (m, 1H), 7.81- 7.85 (m, 1H) nB : 28.201 All potassium aryltrifluoroborates were prepared by a method derived from Vedjes procedure (see chapter 1) from the commercially available arylboronic acids. Table 5.1 lists other reagents and solvents that were used as received unless stated otherwise. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Table 5.1: Reagents and Solvents Chemical Source (Method of Purification) Acetonitrile refluxed for 2 h over calcium hydride, stored over molecular sieve A 4 A/-Bromosuccinimide Aldrich Chemical Co. N-Chlorosuccinimide Aldrich Chemical Co. Dichloromethane Fisher Scientific Diethylether EM Science 1,4-Dioxane Mallinckrodt (refluxed for 2h over sodium) Ethyl Acetate Mallinckrodt Magnesium Sulfate, anhydrous Mallinckrodt Methanol Mallinckrodt A-Iodosuccinimide Aldrich Chemical Co. (or prepared in situ from NCS and Nal) Nitric Acid Mallinckrodt Nitromethane Fisher Scientific Nitronium tetrafluoroborate Aldrich Chemical Co. Nitrosonium Tetrafluoroborate Aldrich Chemical Co. Pentane Fisher Scientific (refluxed for 2h over P2 0 5 ) 2-Phenyl-1,3,2-dioxaborinane Aldrich Chemical Co. Selectfluor™ Air Products Sodium Bicarbonate Mallinckrodt Sodium Hydroxide Mallinckrodt Sodium Bisulfite Mallinckrodt Sodium Iodide Aldrich Chemical Co. Sulfuric Acid EM Science 5.1.2 Product Purification Products were purified by crystallization, distillation and column chromatography. Microdistillations were conducted using a Buchi GKR-251 microdistillation instrument. For column chromatography EM Science Grade 62 silica gel was used with the corresponding eluent. 6 1 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.1.3 Product Characterization Melting points were measured on a Mel-Temp II instrument (Mel Temp USA) and if available melting points of a mixture of the product and an authentic sample were taken to verify the identity of the product. The spectroscopic data of the products were compared to those of authentic samples or those taken from Aldrich Spectroscopic Library Handbook. *H and 1 3 C NMR spectra were taken in CDC13 or CD3 OD solutions on a Varian Unity 300 (300 MHz) instrument, 1 9 F NMR spectra were taken in CDC13 or CD3 OD solutions on a Varian VXR 200 (200MHz) instrument,1 1 B NMR spectra were taken in CDC13 or CD3 OD on a Bruker 270 MHz instrument. GC/MS data were obtained from a Hewlett Packard 5890 series mass spectrometer. 5.2 Halogenation Reactions 5.2.1 Bromination of Aryl Boronic Acids with A-Bromosuccinimide General Procedure for the Bromination with N-bromosuccinimide: Method A: To a solution of 1 mmol arylboronic acid in dry CH3 CN (5 ml) N- bromosuccinimide (Aldrich) was added and the mixture was stirred at the given temperature protected from air until completion of the reaction was confirmed by TLC (silica gel, hexanes : ethyl acetate =1 : 1). After the reaction was completed, the reaction mixture was extracted with pentane (3 x 50 ml) and the collected pentane extracts were washed with distilled water, aqueous NaHS03 (1 M), aqueous NaHC03 (1 M) and distilled water and finally dried over MgS04 . The residue obtained by evaporation of the solvent 62 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. in vacuo was further purified by column chromatography (silica gel / pentane). Evaporation of the eluent afforded the pure product. 5.2.2 Bromination of 3-Nitrophenylboronic Acid with other Electrophilic Brominating Reagents To a solution of 0.167g (1.0 mmol) of 3-nitrophenylboronic acid in 5 ml dry CH3 CN 0.343g (1.2 mmol) in a 25ml round-bottomed flask l,3-dibromo-5,5- dimethylhydantoin were added and the reaction mixture was stirred protected from air for 24 hours. Analysis by thin-layer chromatography (TLC) and GC/MS showed no sign of product formation. The flask was equipped with a reflux condenser with an attached drying tube containing calcium chloride and the reaction mixture was then heated to reflux for 6 hours and then cooled down. No product was observed by GC/MS and TLC. The corresponding reaction employing 2,4,4,6-Tetrabromo-2,5-cyclohexadienone was conducted under similar conditions did also not result in the formation of the desired product. 5.2.3 Iodination of Aryl Boronic Acids General Procedure for the Iodination with N-iodosuccinimide\ Method A: To a solution of 1 mmol arylboronic acid in dry CH3 CN (5 ml) N-iodosuccinimide (Aldrich) was added and the mixture was stirred at the given temperature protected from air and light until completion of the reaction was confirmed by TLC (silica gel, hexanes : ethyl acetate = 1 : 1). After the reaction was completed, the reaction mixture was extracted with pentane (3 x 50 ml) and the collected pentane extracts were washed with distilled water, 63 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. aqueous NaHS03 (1 M), aqueous NaHC03 (1 M) and distilled water and finally dried over MgS04 . The residue obtained by evaporation of the solvent in vacuo was further purified by column chromatography (silica gel / pentane). Evaporation of the eluent afforded the pure product. Method B {in situ preparation of NIS): To a suspension of 1 mmol arylboronic acid and n equivalents sodium iodide in dry CH3 CN (3 ml) a solution of n equivalents N- chlorosuccinimide in 2 ml of dry CH3 CN was added. The reaction and workup were carried out as described for method A. 5.2.4 Iodination and Bromination of 2-PhenyI-l,3,2-dioxaborinane To a solution of 0.166g (1.0 mmol) 2-phenyl-1,3,2-dioxaborinane in 5 ml dry acetonitrile 0.337g (1.5 mmol) of N-iodosuccinimide were added and then stirred under reflux protected from air and light for 80 hours. GC/MS investigation showed that the starting material had almost disappeared and that iodobenzene had been formed (M/e = 204 (M+ )). The reaction mixture was extracted with pentane (3 x 50 ml) and the collected pentane extracts were washed with distilled water, aqueous NaHS03 (1 M), aqueous NaHC03 ( l M ) and distilled water and finally dried over MgS04. The residue obtained by evaporation of the solvent in vacuo was further purified by column chromatography (silica gel / pentane). Evaporation of the eluent afforded the pure iodobenzene (60 mg / 29.4% th. yield). The reaction was repeated under similar conditions with A-bromosuccinimide. After 72 hours of reflux GC/MS investigation revealed that besides a large amount of 64 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. starting material, only traces of bromobenzene (M/e =158 (M+ )) and dibromobenzenes (M/e = 238 (M+ )) were present. 5.2.5 Fluorination Reactions General Procedure: To a solution of 1 mmol of the aryl boronic acid or the potassium aryltrifluoroborate in 5 ml dry acetonitrile Selectfluor™ was added and the corresponding mixture was stirred protected from air. The reaction was monitored by 1 9 F NMR spectroscopy. The solvent was evaporated and the residue was treated with 1 ml of 1 M NaOH solution. Extraction with ethyl acetate (3 x 30 ml) and evaporation gave the products in a crude yield of less then 5% th. yield. GC/MS investigation was conducted to verify formation of product. In the cases where the yields were determined by means of 1 9 F NMR spectroscopy, 1 mmol of a,a,a-trifluorotoluene was added to the reaction mixture prior to reaction as an internal standard. The yield was calculated using the signal integration results. The reactions with jV-pyridinium triflate were conducted in similarly, but here GC/MS and 1 9 F NMR investigation did not show any sign of product formation, so that isolation of products was unnecessary. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.3 Nitration and Nitrosation Reactions 5.3.1 Nitration of Aryltrifluoroborates with Nitric Acid General Procedure: To 1 mmol of the aryltrifluoroborate in a round-bottomed flask, nitric acid, or a mixture of nitric acid and sulfuric acid were added slowly. The mixture was stirred protected from air and then poured over ice. This mixture was extracted with ethyl ether (3 x 50 ml) and the organic phase was washed with sodium bicarbonate solution and water and was finally dried over magnesium sulfate. Evaporation of the solvent in vacuo yielded the crude product, which was purified by column chromatography or recrystallization. 5.3.2 Nitration of Aryltrifluoroborates with Nitrosonium Tetrafluoroborate General Procedure: To a stirred solution of 1 mmol of the aryltrifluoroborate in 5 ml dry acetonitrile in a Schlenk flask under an argon atmosphere, a solution of 1.1 mol nitrosonium tetrafluoroborate in dry acetonitrile was added slowly. The reaction mixture was stirred and then 2 ml of water was added. The mixture was extracted with ether (3 x 50 ml) and washed with sodium bicarbonate solution and water and dried over magnesium sulfate. The residue obtained after evaporation of the solvent was purified by column chromatography or recrystallization. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.3.3 Nitration of Aryl Boronic Acids with Acetyl and Trifluoroacetyl Nitrate General Procedure - Acetyl Nitrate: Acetyl nitrate was prepared by adding 3.8 ml of cold nitric acid (69 %) to 15 ml vigorously stirred freshly distilled acetic anhydride at 0° C. The reagent was cooled and used subsequently. To 1 mmol of aryl boronic acid in a round-bottomed flask acetyl nitrate was added slowly and the mixture was stirred. Then the reaction mixture was poured over ice and then extracted with ethyl ether (3 x 50 ml). Washing of the organic phase with sodium bicarbonate solution and water followed by drying over magnesium sulfate and evaporation in vacuo yielded a crude product that was purified by column chromatography. General Procedure - Trifluoroacetyl Nitrate: To a vigorously stirred suspension of 1 mmol arylboronic acid and ammonium nitrate in 2 ml dry acetonitrile, 2 ml of freshly distilled trifluoroacetic anhydride were added and the reaction mixture was stirred protected from air. Workup was conducted according to the procedure for acetyl nitrate. 5.3.4 Attempted Nitrosation of Aryltrifluoroborates with Nitrosonium T etrafluoroborate General Procedure: To a stirred solution of 1 mmol of the aryltrifluoroborate or aryl boronic acid in 5 ml dry acetonitrile in a Schlenk flask under an argon atmosphere, a solution of 1.1 mol nitrosonium tetrafluoroborate in dry acetonitrile was added slowly. The reaction mixture was stirred and then 2 ml of water was added to quench the reaction. The mixture was extracted with ether (3 x 50 ml) and washed with sodium bicarbonate solution and water and dried over magnesium sulfate. Investigation by thin-layer- chromatography and GC/MS did not show any trace of the desired product. 67 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. 5.4 Mischievous Reactions 5.4.1 Attempted Potassium Aryltrifluoroborate Mannich Reactions General Procedure: a) Reaction with Eschenmoser’s salt: To a stirred solution of 1 mmol of the aryltrifluoroborate in 5 ml dry acetonitrile in a Schlenk flask under an argon atmosphere, 0.204g (1.1 mol) N,7V-dimethylammonium iodide was added. The reaction mixture was stirred and then the reaction mixture was acidified with aqueous HC1. After removal of the solvent under reduced pressure, the residue was dissolved in 1 ml of water and treated with 5ml aqueous sodium hydroxide solution (25%) followed by extraction with ethyl ether (3 x 30ml). The organic phase was dried over potassium hydroxide. GC/MS and TLC investigation showed no trace of N, A-dimethylbenzylamine and the starting material could be recovered, b) Reaction with paraformaldehyde and secondary amines: A suspension of 1 mmol amine, 1 mmol paraformaldehyde and 1 mmol aryltrifluoroborate are refluxed in dioxane or acetonitrile. Workup was conducted according to a) and no traces of the corresponding amine could be detected by either GC/MS or TLC. 5.4.2 Attempted Alkylation and Acylation of Potassium Phenyltrifluoroborate To a solution of 0.184g potassium phenyltrifluoroborate in 5ml dry acetonitrile, 1.2 mmol of the alkylating or acylating reagent were added slowly. The reaction mixture was stirred and then quenched with water, followed by extraction with ethyl acetate (3 x 30 ml). The organic phase was washed with aqueous sodium bicarbonate solution and Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. water and dried over magnesium sulfate. GC/MS and TLC investigation showed no sign of product formation. 69 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. Chapter 6: Conclusion and Outlook In the thesis presented it has been shown that aryl boronic acids undergo ipso substitution with iV-halosuccinimides to afford the corresponding haloarenes in moderate to excellent yields. The new method presented is complementary to others and does not require harsh acidic reaction conditions, strong oxidizers or toxic metal salts. The possibility of radioactive labeling by a modification of the method greatly increases the utility of the method. Another possible application of the new method may be the palladium-catalyzed coupling of the haloarenes obtained from this reaction in situ with excess arylboronic acids. The mechanism of this reaction was not investigated, and the results presented do not provide adequate data for a discussion of a mechanism. Although the order of reactivity of the substituted aryl boronic acids, as reflected in the reaction times and yields, is close to that expected for the corresponding arenes in electrophilic aromatic substitution reactions, it is unlikely that this reaction follows a conventional addition- elimination pathway with a Wheeland-type intermediate and a rate-limiting attack on the substituted carbon. If such an intermediate is formed, the enhanced reactivity of the carbon-boron bond indicates that elimination is rate-limiting. It is very probable however, that there is significant activation of the boronic acid functionality by a solvent molecule or the imido-oxygen of the succinimide. The yields of the fluorination reactions of aryltrifluoroborates were not satisfactory, and there is considerable evidence, that radicals are involved in these reactions, which leads to an unfavorable formation of side products. 70 Reproduced with permission of the copyright owner. Further reproduction prohibited without permission. The results of the nitration of aryltrifluoroborates with nitronium tetrafluoroborates and mixed acid systems were also unsatisfactory, mainly due to side reactions that could not be avoided. The reaction of arylboronic acids with trifluoroacetyl nitrate gave better results. However, considering the high efforts and cost involved in preparing the aryl boronic acid precursors and the low yields, this method is unlikely to find an application in organic synthesis. If the method could be extended to alkenyl boronic acids however, it could provide an alternative route to the important class nitroalkenes. Investigation in this direction should be conducted in the future. Carbon electrophiles did not react with aryltrifluoroborates without the use of a catalyst, however, further investigation seems to be worthwhile, since a new method for regioselective acylation and alkylation would be very interesting in synthetic organic chemistry. Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.

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Asset Metadata

Creator Thiebes, Christoph (author)

Core Title ipso substitutions of aryl boronic acids and aryltrifluoroborates

School Graduate School

Degree Master of Science

Degree Program Chemistry

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag chemistry, organic,OAI-PMH Harvest

Language English

Contributor Digitized by ProQuest (provenance)

Advisor Prakash, G.K. Surya (committee chair), Olah, George A. (committee member)

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c16-44747

Unique identifier UC11338776

Identifier 1427991.pdf (filename),usctheses-c16-44747 (legacy record id)

Legacy Identifier 1427991.pdf

Dmrecord 44747

Document Type Thesis

Rights Thiebes, Christoph

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the au...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus, Los Angeles, California 90089, USA