SYNTHESIS AND REACTIONS OF NOVEL HETEROARYLZIRCONOCENE REAGENTS by Caleb F. Harris June, 2012 Director of Thesis: Dr. Shouquan Huo Major Department: Chemistry The cross-coupling of metallated heteroaromatic species with aryl and heteroaryl halides is a powerful and highly desirable transformation in both the synthesis of pharmaceutical compounds as well as materials development. However, current methodology in this area has some limitations, particularly with organometallic reagents derived from 2-halopyridines, 2- haloquinolines, and other similar heteroaromatic compounds. Suzuki cross-coupling reactions of 2-pyridyl boronic acids or esters are often reported to be low yielding due to protodeborylation. In particular, the preparation of the corresponding heteroaromatic boronic reagents is often associated with low yields. Although Negishi cross-coupling reactions are often reported to be high yielding, the generation of heteroaromatic organozinc reagents require the use of expensive and user unfriendly Rieke® Zinc. The Stille reaction is the least desirable because of the highly toxic tin waste streams generated. Zirconium is a non-toxic, inexpensive, and abundant metal that exists primarily in the Zr(IV) oxidation state and its application in organic synthesis has been extensively studied. However, the preparation of heteroaromatic zirconocene reagents and their application in organic synthesis have not been reported. In 1986, Negishi reported the generation of a Zr(II) species, in situ, by reacting Cp2Zr(IV)Cl2 with 2 equivalents of n-BuLi followed by a ?-H abstraction process. We anticipated that the oxidative addition of a heteroaromatic halide to the Negishi reagent, “Cp2Zr(II)”, would generate the desired heteroaromatic zirconocene reagents. These novel reagents were successfully generated and used in palladium-catalyzed cross-coupling reactions. SYNTHESIS AND REACTIONS OF NOVEL HETEROARYLZIRCONOCENE REAGENTS A Thesis Presented To The Faculty of the Department of Chemistry East Carolina University In Partial Fulfillment Of the Requirements for the Degree Master of Science by Caleb F. Harris June, 2012 © Caleb F. Harris, 2012 SYNTHESIS AND REACTIONS OF NOVEL HETEROARYLZIRCONOCENE REAGENTS by Caleb F. Harris June, 2012 APPROVED BY: DIRECTOR OF THESIS:________________________________________________________ Shouquan Huo, PhD COMMITTEE MEMBER: _______________________________________________________ Brian Love, PhD COMMITTEE MEMBER: _______________________________________________________ Libero Bartolotti, PhD COMMITTEE MEMBER: _______________________________________________________ Colin Burns, PhD COMMITTEE MEMBER: _______________________________________________________ Baohong Zhang, PhD CHAIR OF THE DEPARTMENT OF CHEMISTRY:__________________________________ Rickey Hicks, PhD DEAN OF THE GRADUATE SCHOOL:____________________________________________ Paul J. Gemperline, PhD TABLE OF CONTENTS LIST OF FIGURES ....................................................................................................................... vi LIST OF SCHEMES..................................................................................................................... vii LIST OF TABLES ....................................................................................................................... viii LIST OF SYMBOLS/ABBREVIATIONS .................................................................................... ix CHAPTER 1: INTRODUCTION ...................................................................................................1 CHAPTER 2: BACKGROUND .....................................................................................................4 2.1 Heteroaryl Organometallic Reagents .............................................................................4 2.1.1 Heteroaryl Organozinc Reagents ....................................................................5 2.1.2 Heteroaryl Organoboron Reagents .................................................................6 2.1.3 Heteroaryl Organosilicon Reagents ................................................................7 2.1.4 Heteroaryl Organotin Reagents .......................................................................9 2.2 Palladium-Catalyzed Cross-Coupling of Heteroaryl Organometallic Reagents ............9 2.2.1 Negishi Reaction ...........................................................................................11 2.2.2 Suzuki Reaction ............................................................................................12 2.2.3 Hiyama Reaction ...........................................................................................12 2.2.4 Stille Reaction ...............................................................................................13 2.3 Negishi Reagent, Cp2ZrBu2 .........................................................................................14 2.3.1 Oxidative Addition of Vinyl Halides to the Negishi Reagent .....................15 2.3.2 Oxidative Addition of Vinyl Ethers to the Negishi Reagent .......................16 2.3.3 Oxidative Addition of Vinyl Sulfides/Sulfoxides/Sulfones to the Negishi Reagent ...........................................................................................16 2.3.4 Dehalogenation of Aryl Halides by Zirconocene ........................................17 CHAPTER 3: GENERATION OF HETEROARYLZIRCONOCENE REAGENTS..................19 3.1 Oxidative Addition of Heteroaryl Halides to the Negishi Reagent .............................19 3.1.1 Temperature ..................................................................................................19 3.1.2 Solvent .........................................................................................................20 3.1.3 Deuterium Studies ........................................................................................22 CHAPTER 4: PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF HETEROAROMATICZIRCONOCENE REAGENTS ........................................25 4.1 Transmetallation .........................................................................................................25 4.2 Functional Group Tolerance ........................................................................................27 4.3 Cross-Coupling Reactions of Various Heteroarylzirconocenes .................................29 4.4 Evaluation of the Cross-Coupling Reactions of Other Heteroarylzirconocenes .........30 CHAPTER 5: CONCLUSION .....................................................................................................32 CHAPTER 6: EXPERIMENTAL.................................................................................................33 6.1 General Procedure ........................................................................................................33 6.2 Deuterolysis Experimental Procedure..........................................................................38 6.3 1H and 13C NMR Spectra of Cross-Coupling Products ..............................................40 6.4 1H NMR Spectrum of 2-Deuterated Quinoline ...........................................................50 6.5 1H NMR Spectrum of 1-Deuterated Isoquinoline .......................................................51 6.6 1H NMR Spectrum of 5-Deuterated 2,2’-Bithiophene ...............................................52 CHAPTER 7: BIBLIOGRAPHY .................................................................................................53 LIST OF FIGURES Figure 1: Schematic representation of C^N*N, N^C*N, and N^N*C-coordinated platinum complexes .......................................................................................................2 Figure 2: Retrosynthetic analysis of desired ligands ......................................................................3 Figure 3: General palladium-catalyzed cross-coupling mechanism ............................................10 Figure 4: Negishi cross-coupling mechanism of heteroaromatic organozinc halides .................11 Figure 5: Suzuki cross-coupling mechanism of heteroaromatic organoborates ..........................12 Figure 6: Hiyama cross-coupling mechanism of heteroaromatic organosilates ..........................13 Figure 7: Stille cross-coupling mechanism of heteroaromatic organostannanes .........................14 Figure 8: Possible isomers of alkenylzirconocene .......................................................................15 Figure 9: Results of temperature changes on the rate of oxidative addition ................................20 Figure 10: NMR spectrum of 2-quinolylzirconocene deuterolysis product ................................22 Figure 11: NMR spectrum of 1-isoquinolylzirconocene deuterolysis product ............................23 Figure 12: NMR spectrum of 2,2’-bithiophen-5-ylzirconocene deuterolysis product ................24 Figure 13: Proposed heteroarylzirconocene cross-coupling mechanism .....................................27 LIST OF SCHEMES Scheme 1: Synthesis of 2-quinolylzinc chloride via Rieke’s method ............................................6 Scheme 2: Synthesis of aryl boronic acid via lithium-halogen exchange .....................................7 Scheme 3: Selective silylation of ortho-xylene .............................................................................8 Scheme 4: Generation of the Negishi reagent ..............................................................................15 Scheme 5: Takahashi’s proposed mechanism for the oxidative addition of vinyl halides to the Negishi reagent ....................................................................................................16 Scheme 6: Proposed mechanism for the oxidative addition of unactivated enol ethers to the Negishi reagent ....................................................................................................16 Scheme 7: Proposed mechanism involving a 5-member metallacycle ........................................17 Scheme 8: Dehalogenation reaction .............................................................................................18 Scheme 9: Proposed dehalogenation mechanism ........................................................................18 Scheme 10: Possible mechanisms of the oxidative addition to the Negishi reagent ...................19 LIST OF TABLES Table 1: Effect of solvent conditions on deuterium incorporation ..............................................21 Table 2: Screening of metal halides .............................................................................................26 Table 3: Functional group tolerance ............................................................................................28 Table 4: Other nitrogen containing heteroarylzirconocene coupling yields ................................29 Table 5: Coupling results of thiophene derivatives .....................................................................30 Table 6: Overall generation and cross-coupling results of various heteroarylzirconocene derivatives .....................................................................................................................31 LIST OF SYMBOLS/ABBREVIATIONS °C Degrees Centigrade ® Registered Trademark ?n n-chelated AcOD Deuterated Acetic Acid BTMSA Bis(trimethylsilyl)acetylene cod 1,5-Cyclooctadiene Cp Cyclopentadiene Csp2 sp2-hybridized Carbon D Deuterium DMA Dimethylacetamide DMAE Dimethylethanolamine DME 1,2-Dimethoxyethane DMF Dimethylformamide DPPF 1,1'-Bis(diphenylphosphino) ferrocene GC Gas Chromatography h Hours HetAr Heteroaryl L Ligand (unless denoted otherwise) LTMP Lithium 2,2,6,6-tetramethylpiperidide m Minutes NaOtBu Sodium tert-butoxide NMR Nuclear Magnetic Resonance OTf Triflate THF Tetrahydrofuran TLC Thin Layer Chromatography r.t. Room Temperature CHAPTER 1: INTRODUCTION Recently, we have reported a new class of tridentate cyclometallated platinum complexes featuring a five-six-membered metallacycle, which include the coordination patterns of (C^N*N)PtL and (N^C*N)PtL, where C^N or N^C represents a bidentate coordination to the metal center through a five-membered metallacyle, N*N and C*N represent a bidentate coordination to the metal center through a six-membered metallacyle, and L represents an anionic monodentate ligand such as a halide or acetylide.1 More specifically, an amine linker was used to extend the more conventional five-membered metallacyle into a six-membered ring. Those complexes have generally displayed high photoluminescence quantum yields and some of them are among the brightest phosphorescent emitters currently reported. The photoluminescence quantum efficiencies of the C^N*N and N^C*N-coordinated platinum complexes are comparable to or higher than those of C^N^N and N^C^N-coordinated complexes.2 One explanation for the better emission efficiency has been proposed based on the geometric change of the coordination from a fused five-five-membered metallacyle to a less strained five-six-membered ring. As a result, the square planer geometry of the platinum (II) complexes could be achieved through the increase of the biting angle from 160o in the C^N^N and N^C^N-coordinated complexes to greater than 170o typically found in the C^N*N and N^C*N-coordinated platinum complexes.3 Such explanation has also been proposed for other complexes, particularly for the complexes with a fused six-six-membered metallacycle. More recently, both beneficial and adverse effects of a geometrical change from five-five-membered to six-six-membered ring were reported on the tridentate platinum complexes.4 2 In order to substantiate the effect of changing the geometry from a five-five to a five-six- membered metallacyle on the emission efficiency, it is necessary to consider all three possible coordination patterns of cyclometallated platinum complexes. In particular, those that form a five-six-membered metallacycle through coordination to one carbon and two nitrogen coordinating atoms. Specifically, C^N*N, N^C*N, and N^N*C-coordinated complexes, as shown in Figure 1. X= carbon or nitrogen, L = mono anionic ligand Figure 1. Schematic representation of C^N*N, N^C*N, and N^N*C-coordinated platinum complexes During the course of these investigations, it became necessary to begin designing the ligands for the N^N*C, as well as N^N^C complexes. Of the initial series of ligands that were proposed, two involved a 2,2’ C-C bond between a quinoline and pyridine ring, 1 & 4 (Figure 2). The most convenient retrosynthetic analytical method of the compounds necessitated the use of a 3 2-quinolyl organometallic reagent to participate in the palladium-catalyzed cross-coupling reaction with 2 and 5 to generate both 1 and 4, respectively (Figure 2). (a*) Pd catalyzed, M = Zn, B, Sn. (b) Pd(dba)2 (2%), DPPF (2%), NaOtBu (1.2 equiv), toluene, reflux. (c) 1. nBuLi-LiDMAE, hexane , 0 °C. 2. CBr4, hexane, -78 oC Figure 2. Retrosynthetic analysis of desired ligands To our surprise, it was found that such heteroaromatic organometallic reagents were very much underdeveloped. The most intensively studied are 2-pyridylmetal reagents based on Sn5, Zn6, and B7. It was this fact that prompted us to investigate alternative methods for the generation of heteroaryl organometallic reagents. Specifically, the development of a novel series based around zirconium was desired because of its relativity low cost, abundant availability, and low toxicity. CHAPTER 2: BACKGROUND 2.1 Heteroaryl Organometallic Reagents The palladium-catalyzed cross-coupling of metallated heteroaromatic species (i.e. Negishi, Suzuki, and Stille reactions) with aryl and heteroaryl halides is a powerful and highly desirable transformation in both the synthesis of pharmaceutical compounds, as well as materials development. However, current methodology in this area has some limitations, particularly with organometallic reagents derived from 2-halopyridines, 2-haloquinolines, and other similar heteroaromatic compounds. Owing to the intrinsic reactivity of heteroaromatic compounds based upon pyridine, quinoline, isoquinoline, and pyrimidine; their organometallic reagents are not common. For example, commonly used organolithium and organomagnesium reagents can react with these heteroaromatic reagents via nucleophillic attack, causing the generation of these heteroaromatic lithium and magnesium reagents to be problematic or impossible. On the other hand, organozinc and organoboron compounds are relatively more stable as a result of the high covalent character of the carbon-zinc or carbon-boron bond.8 However, the preparation of the zinc reagents require expensive and user unfriendly Rieke® zinc. Heteroaromatic boronic acid reagents can be prepared from diboranes which, however, are also expensive and the instability of pyridylboronic acids is frequently reported. Lastly, any type of heteroaromatic tin reagent would involve the issue of the toxicity. Obviously, this is a very underdeveloped area of chemistry that could potentially benefit synthetic laboratories everywhere if a safe, convenient, and affordable method of generating heteroaryl organometallic moieties was established. 5 2.1.1 Heteroaryl Organozinc Reagents The Negishi reaction is a powerful and commonly used palladium-catalyzed cross- coupling reaction of organozinc reagents with organohalides or triflates.9 The most common method for preparing organozinc reagents is the in situ generation of organolithium or magnesium reagents from organohalides, followed by transmetallation to zinc. The most common source of zinc in these types of reactions is typically ZnCl2. 10 Other methods include the oxidative addition of organohalides to Zn(0) in order to produce the corresponding organozinc reagents.11 This approach is more advantageous than the metallation-transmetalation method using organolithium/magnesium reagents and ZnCl2 because of higher functional group tolerance. It is often necessary to employ catalytic amounts of NaI and zinc that has been activated via sequential treatment with 1,2-dibromoethane and chlorotrimethylsilane to facilitate the conversion of alkyl halides to alkylzinc reagents.12 Huo, however, has developed a much more convenient method for the generation of alkylzinc reagents from alkyl halides using zinc activated with I2 in DMA. 13 Rieke’s method has shown to be the most promising method of generating heteroaryl organozinc reagents in moderate to high yield.14 His method involves stirring 0.46 equivalents of a heteroaromatic halide to Rieke® zinc in either THF or DME for typically 12-24 hours. Once the heteroaryl halide has been consumed, the stirring is stopped, allowing all unreacted zinc to settle to the bottom of the reaction vessel and the homogenous solution is transferred via cannula into another reaction flask for cross-coupling, continuously under inert atmospheric conditions (Scheme 1).15 6 Scheme 1. Synthesis of 2-quinolylzinc chloride via Rieke’s method Not only is this method inconvenient, the cost of Rieke® zinc is very high, currently priced at $330 for a 5g suspension in THF.16 This makes the development of a different type of heteroaryl organometallic reagent very attractive. 2.1.2 Heteroaryl Organoboron Reagents The Suzuki-Miyaura reaction, using aryl boronic acids, has emerged as one of the most popular methods to obtain functionalized biaryl compounds. Aryl boronic acids and their esters are generally thermally stable and insensitive to air and moisture.17 As a consequence, boronic acids are much easier to handle than other commonly used organometallic cross-coupling reagents. These organoborane reagents contain strong covalent carbon-boron bonds and are compatible with a wide range of functional groups,18 allowing a number of highly functionalized boron derivatives to be prepared by various synthetic methods including: hydroboration, transmetallation, and cross-coupling.19 The preparation of aryl boronic reagents can be achieved by a lithium-halogen exchange followed by transmetallation of the resulting aryllithiums with organoboron compounds, generally in high yields (Scheme 2). However, this method is not as successful when applied to heteroaryl compounds, which readily undergo nucleophilic attack from the heteroaryl organolithium reagent generated in situ. 7 Scheme 2. Synthesis of aryl boronic acid via lithium-halogen exchange The most intensively studied heteroaryl organoborane derivative is based upon the 2- pyridyl moiety.7 Although these reagents have been heavily investigated, 2-pyridyl boronic acids remain notoriously unstable, thus precluding their effective utilization.20 Although there have been a large number of 2-substituted aryl borates developed, such as trifluoroborate salts,21 trialkoxy or trihydroxyborate salts,22 diethanolamine adducts,23 sterically bulky boronic esters,24 and boroxines,25 it still remains a great challenge to develop air-stable and chemically pure heteroaryl organoborane building blocks.26 2.1.3 Heteroaryl Organosilicon Reagents In general, organosilicon reagents are stable enough to be employed for a variety of uses. Typically, silicon-based compounds are inert, easily prepared, and are much less reactive than other compounds containing carbon-metal/pseudometal bonds, due to the low polarity of the C-Si bond. Because of this, the C-Si bond is very similar to the C-C in many aspects, consequently allowing these reagents to be tolerant of a wide variety of functional groups as well as varying reaction conditions. This allows these compounds to be used in a number of various synthetic manipulations.27 Trialkyl(aryl)silanes, specifically, are quite stable and readily generated. In the presence of a fluoride ion, these aryl organosilicon reagents undergo palladium-catalyzed cross-coupling reactions in the same general fashion as an arylmetal reagent.28 The direct silylation of aromatic compounds are typically carried out with 1,2-di-tert-butyl-1,1,2,2-tetrafluorodisilane which serves as a silyating reagent in the presence of an iridium catalyst. Ortho-xylene, for example, 8 has been shown to participate in selective, Ir-catalyzed silylation at the aromatic C-H bond to give 8 in high yields (Scheme 3).29 Scheme 3. Selective silylation of ortho-xylene The current methods of generating heteroaryl silanes, however, are not as straightforward. Again, as is the trend, the most heavily studied heteroaryl silane is based upon the 2-pyridyl moiety. Good to excellent yields have been obtained for the Hiyama coupling of 2- trimethylsilylpyridine with a range of aryl and heteroaryl halides, however the synthesis of 2- trimethylsilylpyridine remains a problem.30 Typically, the synthesis of 2-trimethylsilylpyridine is carried out by halogen-metal exchange followed by treatment with chlorotrimethylsilane.31 Since, however, this method is not suitable for base-sensitive substrates or compounds susceptible to nucleophilic attack, it has forced many groups to attempt find viable alternatives to this method. A method using metal-catalyzed coupling of heteroaryl halides with a silane source is very desirable. Unfortunately, all reported attempts to generate 2-trimethylsilylpyridine via palladium-catalyzed C-Si cross-coupling reactions have resulted in the formation of the symmetrical homocoupled 2,2’-bipyridine byproduct and only trace amount of the desired silane.30 There is a reported method of generating 2-triethoxysilylpyridine using a bis(acetonitrile)(1,5-cyclooctadiene) rhodium(I) tetrafluoroborate catalyzed cross-coupling reaction of 2-bromopyridine with triethoxysilane,32 however no examples of the reagent actually being used in a cross-coupling reaction are known. Therefore, the generation of heteroaryl 9 silanes remains the biggest hindrance in this area since, once generated, they have demonstrated the ability to readily participate in Hiyama coupling reactions. 2.1.4 Heteroaryl Organotin Reagents Organotin (organostannane) reagents are one of the most studied types of organometallic reagents in the field of organometallic chemistry. These reagents undergo palladium-catalyzed coupling reactions (Stille reaction) efficiently and typically in very high yields with high tolerance for functional groups, making them worthy of mentioning here. However, not a lot of focus will be spent on this section due to the fact that organostananes are rapidly disappearing from organic synthesis. Although these reagents are historically successful in organic synthesis, they are extremely toxic and potentially harmful to both the handler and the environment,33 along with being expensive if commercially purchased. It is this toxicity that makes these reagents impractical for large-scale use. 2.2 Palladium-Catalyzed Cross-Coupling Reactions of Heteroaromatic Organometallics Palladium-catalyzed cross-coupling reactions of aryl or vinyl halides with heteroaryl organometallic reagents is one of the most frequently used methods for generating Csp2-Csp2 bonds between the two groups. A simplistic mechanism is shown below (Figure 3) demonstrating that the transformation typically begins with the oxidative addition of an aryl/vinyl halide 10 to a Pd(0) complex 9 to afford the intermediate 11. It is this organopalladium halide complex that undergoes transmetallation with the heteroaromatic organometallic reagent 12 to generate the diorganopalladium species 14. Finally, reductive elimination from 14 affords the desired cross-coupling product 7 and regenerates the the Pd(0) catalyst 9. 10 Figure 3. General palladium-catalyzed cross-coupling mechanism. In this catalytic cycle, the electronic and steric properties of both the heteroaromatic organometallic reagent and the cross-coupling partner affect the rates of these reactions. The overall structure of the palladium catalyst also plays a large role in kinetics of these reactions.34 The oxidative addition of the aryl/vinyl halide to Pd(0) has a halide reactivity order of: I > Br ? OTf > Cl. The rate of the transmetallation step is typically inhibited with increasing steric bulk of both the heteroaromatic reagent and the coupling partner, yet is often faster with increasing electron-richness of the organic fragments (R).35 The rate of reductive elimination is typically enhanced by increasing the bite angle of the ligands, forcing the heteroaryl and aryl/vinyl groups closer. This is typically performed by using a large monodentate phosphine ligand. Also, when one coupling partner is electron-withdrawing and the other is electron-donating, the elimination step has been observed to occur faster.36 The source of Pd(0) is typically introduced in one of two ways; either Pd(0) is added directly to the reaction mixture or Pd(II) is reduced in situ by an organometallic reagent to afford the Pd(0) species and some heteroaryl homocoupling product. This is why heteroaryl organometallic reagents are typically used in excess to the aryl/vinyl coupling partners. 11 Organometallic cross-coupling reactions are generally divided into subcategories based upon the choice of main-group metal.34 The four currently used heteroaromatic organometallic reagents, as noted in Chapter 2.1, and their palladium-catalyzed reactions are: heteroarylzincates (Negishi reaction), heteroarylboranes (Suzuki reaction), heteroarylsilanes (Hiyama reaction), and heteroarylstannanes (Stille reaction). Organostanyl and organozincate reagents transmetallate directly to palladium to generate the intermediate HetAr-Pd(II)-X 14, whereas organoboranes and organosilanes require the presence of some base or fluoride to facilitate the transmetallation due to the low polarity of the C-B or C-Si bond, respectively.37 2.2.1 Negishi Reaction The Negishi reaction is the palladium-catalyzed cross-coupling of organozinc reagents with organohalides or triflates.38 It is compatible with many functional groups including ketones, esters, amines, and nitriles. Although the competing ?-hydride elimination of the intermediate (heteroaryl)(alkyl)Pd(II) complex 16 (Figure 4) can lead to side products, there are many examples of Negishi couplings of alkylzinc reagents that indicate C-C bond-forming reductive elimination supersedes ?-hydride elimination side reactions.38 Figure 4. Negishi cross-coupling mechanism of heteroaromatic organozinc halides 12 2.2.2 Suzuki Reaction First published in 1979, the Suzuki reaction is one of the most frequently employed palladium-catalyzed C-C bond forming reactions and involves the cross-coupling of organoboron reagents with organohalides or triflates.39 One major advantage of the Suzuki reaction over others is that boron-containing side products of these reactions are typically removed with ease via an alkali workup. One of the main problems involved with the Suzuki reaction is that since the C-B bond is relatively non-polar, a fluoride ion or anion base 17 is necessary to generate a tetracoordinate borate complex 18 or transmetallation to palladium will not occur (Figure 5). This is a major hindrance when there is a desire to use base- or fluoride-sensitive substrates.34 Figure 5. Suzuki cross-coupling mechanism of heteroaromatic organoborates 2.2.3 Hiyama Reaction The Hiyama reaction is the palladium-catalyzed C-C bond forming reaction between aryl, heteroaryl, alkenyl, alkyl halides, or pseudohalides with organosilanes (Figure 6). Similar to the Suzuki reaction, transmetallation of an organosilicon reagent does not occur under normal Pd- catalyzed cross coupling conditions. This is because of the relatively nonpolar nature of the C- 13 Si bond which must be activated by either fluoride (typically some sort of salt such as TBAF or TASF in these reactions) or an anionic base to form a pentacoordinate silicate, which weakens the C-Si bond by enhancing the polarization.34 As with the Suzuki reaction, this reaction should be avoided when there is a desire to use base- or fluoride-sensitive substrates. Several heteroaryl halides have been cross-coupled with aryl or heteroaryl silicon reagents,40 although as stated previously in Chapter 2, the generation of heteroaryl silanes remains quite problematic. Figure 6. Hiyama cross-coupling mechanism of heteroaromatic organosilanes 2.2.4 Stille Reaction The Stille reaction is another C-C bond forming, palladium-catalyzed cross-coupling reaction between an electrophile and an organostannane (Figure 7).41 Although, perhaps regarded as the most versatile of all palladium-catalyzed cross-coupling reactions due to both the tolerance of a wide variety of functional groups and the ease in which most organostannanes are prepared, the fact-of-the-matter is that the toxicity of stannanes make this unsuitable for large-scale synthesis. 14 Figure 7. Stille cross-coupling mechanism of heteroaromatic organostannanes 2.3 The Negishi Reagent, Cp2ZrBu2 As suggested by the electronic configuration of zirconium, [Kr]4d25s2, the most common oxidative state for zirconium compounds is +4, although there are a large number of Zr(II) compounds as well.42 Considering the multitude of both Zr(II) and Zr(IV) compounds, approximately 75-80% of the currently well-characterized organozirconium compounds are zirconocene (Cp2Zr) derivatives, where Cp = ? 5-C5H5. Cp2ZrCl2 is one of the first organozirconium compounds reported in the literature43 and it is the source in which the majority zirconocene derivatives are typically derived. In 1986, Negishi reported the generation of a zirconium species that acts like 14-electron Zr(II), in situ, by reacting Cp2Zr(IV)Cl2 19 with 2 equivalents of n-BuLi. The dibutyl intermediate, Cp2Zr(IV)Bu2 20, undergoes a ?-H abstraction process at ambient temperature in which the zirconocene equivalent 21, a Cp2Zr(II) – butene, ?-coordination complex is produced (Scheme 4).44 15 Scheme 4. Generation of the Negishi reagent 2.3.1 Oxidative Addition of Vinyl Halides to the Negishi Reagent During the 1970’s, a number of alkenylzirconocene compounds emerged which were easily prepared by the hydrozirconation of alkynes.45 The hydrozirconation of terminal alkynes generated compound type 23, in situ, and in the presence of Cp2ZrHCl (Schwartz reagent), immediately isomerized to compound type 22 (Figure 8). Figure 8. Possible isomers of alkenylzirconocene In order to prepare a zirconocene type 23, Takahashi’s group investigated the oxidative addition reaction of 2-haloalkenes to the Negishi reagent 21.46 The reaction proved successful in generating a number of compounds of type 23 in high yields. Although at the time, there had been a few reported examples of oxidative addition to the Negishi reagent using alkyl halides and arenes,47 phosphorus compounds,48 silanes,49 and allyl ethers,50 this was the first report of the oxidative addition of alkenyl halides to the Negishi reagent. The proposed mechanism for this oxidative addition involved the formation of a 3-member zirconacycle followed by a ?- halide abstraction process as shown in Scheme 5. 16 Scheme 5. Takahashi’s proposed mechanism for the oxidative addition of vinyl halides to the Negishi reagent 2.3.2 Oxidative Addition of Vinyl Ethers to the Negishi Reagent Since the oxidative addition of halogenated alkene moieties to the Negishi reagent afforded functionalized alkenylzirconocenes via an oxidative addition - ?-elimination sequence, Marek reported an extension of this concept to include the formation of vinyl organozirconocene derivatives from unactivated enol ethers.51 As vinyl organometallic derivatives represent an important class of organometallic reagents for the creation of C-C bonds, there are a number of methods reported for the generation of these reagents. Typically, as previously shown, these reagents are generated from the corresponding halide as the starting material. However, the area involving the preparation of vinyl organometallic derivatives from unactivated enol ethers is still underdeveloped. Marek’s group reported that the oxidative addition of a multitude of enol ethers to the Negishi reagent, regardless of the initial stereochemistry, occurs readily and with greater than 99% steroselectivity, producing the E vinylzirconocene in high yields (Scheme 6). Scheme 6. Proposed mechanism for the oxidative addition of unactivated enol ethers to the Negishi reagent 2.3.3 Oxidative Addition of Vinyl Sulfides/Sulfoxides/Sulfones to the Negishi Reagent Until the early 2000’s, there had been no report of the direct transformation of vinyl sulfones into vinylic organometallic derivatives.52 In 2002, Marek reported the successful 17 oxidative addition of a variety of vinyl sulfides, vinyl sulfoxides, and vinyl sulfones to the Negishi reagent in high yields.53 As with the vinyl ethers, this reaction is very stereoselective, producing only the E isomer. Perhaps the most interesting finding reported by Marek, in the same work, is related to the mechanistic studies of these reactions. When the Negishi reagent was used as a precursor to the formation of these sulfonylzirconocene reagents, an attempt was made to characterize the intermediate by quenching the reaction with MeOD. Unfortunately, no intermediate was observed (Scheme 7). However, when an ethene-zirconocene complex 24 was used as the precursor, the deuterated product 26 was observed with greater than 95% D-incorporation, which indicates that, at least with the ethene-zirconocene complex, there is a 5-member metallacycle intermediate 25 formed as opposed to the 3-member metallacycle intermediate proposed in previous sections. Scheme 7. Proposed mechanism involving a 5-member metallacycle 2.3.4 Dehalogenation of Aryl Halides by Zirconocene Having demonstrated multiple reactions in which various substrates undergo oxidative addition to the Negishi reagent, particularly primary vinyl halides, it is easy to see why it was postulated that an aryl halide might undergo the same reaction. Interestingly, Takahashi reported 18 when his group attempted the oxidative addition of various aryl halides to the Negishi reagent, a dehalogenation reaction occurred instead, in very high yields (Scheme 8).54 Deuterolysis experiments were reported not to yield any trace of deuterium. Scheme 8. Dehalogenation reaction Takahashi suggested that a metal-halogen exchange could take place between an aryl halide such as bromobenzene and the dialkylzirconocene 27 to generate phenylbutylzirconocene 28 with the release of bromobutane. The ?-hydrogen abstraction from the butyl group of 28 would produce free benzene and the Negishi reagent 29 (Scheme 9). Scheme 9. Proposed dehalogenation mechanism CHAPTER 3: GENERATION OF HETEROARYLZIRCONOCENE REAGENTS 3.1 Oxidative Addition of Heteroaryl Halides to the Negishi Reagent Although aryl halides are simply dehalogenated in the presence of the Negishi reagent, it was postulated that perhaps a 2-halogenated heteroaryl compound could undergo an oxidative addition mechanism different from that of the aryl halide counterpart, possibly through coordination of the heteroatom to zirconocene. Interestingly, we found that after 2- chloroquinoline was reacted with the Negishi reagent in THF for 1 hour at 50 °C, quenching of the reaction mixture with AcOD produced quinoline with 70% D incorporation at the 2-position of the quinoline, which indicated the formation of 2-quinolylzirconocene chloride (Table 1). It is reasonable to assume that the coordination of the heteroatom to zirconium may facilitate the formation of a three-membered zirconacycle intermediate similar to that reported in Chapter 2 (Scheme 10). Scheme 10. Possible mechanism of the oxidative addition to the Negishi reagent 3.1.1 Temperature Since the synthesis of the Negishi reagent is a well-established procedure, focus was set upon the evaluation of both the temperature and solvent conditions of the reaction to optimize the generation of this 2-quinolylzirconocene chloride reagent. Initial studies concentrated upon the temperature of the oxidative addition step. This step was carried out at four different 20 temperatures ranging from -78 °C to 50 °C. The summarized results demonstrate that the oxidative addition of 2-chloroquinoline to the Negishi reagent occurs most readily at the elevated temperature of 50 °C (Figure 9). Figure 9. Results of temperature changes on the rate of oxidative addition 3.1.2 Solvent When a temperature capable of producing the oxidative addition product had been established, solvent conditions were evaluated in order to determine the ideal condition for the maximum generation of the 2-quinolylzirconocene reagent. Performing both the formation of the Negishi reagent and oxidative addition of 2-chloroquinoline in toluene resulted in less than desirable results, with 50% D-incorporation. When the reaction was run in DME, complete consumption of 2-chloroquinoline was never achieved. However, when the entire reaction was run in diethyl ether, a 78% D-incorporation was observed along with only a minimal amount of side product monitored on GC. Predicting that solubility issues might be experienced during potential cross-coupling reactions of this novel reagent, a mixture of THF and diethyl ether (v/v 1:1) was evaluated as the solvent system (Table 1). With this condition, D-incorporation of 21 AcOD quenched quinoline was the highest achieved at 80% (Figure 10), and this product was isolated in an 89% yield. Solvent Time D Incorporation (%) Toluene 60 min 50 THF 45 min 70 Ethyl Ether 90 min 78 THF: Ethyl Ether (1:1) 45 min 80 DME N/A N/A Table 1. Effect of solvent conditions on deuterium incorporation 22 3.1.3 Deuterium Studies Figure 10. NMR spectrum of 2-quinolylzirconocene deuterolysis product The successful generation of the 2-quinolylzirconocene chloride prompted further investigation into the development of other 2-halogenated heteroaromatic species, in order to establish the scope of this reaction. An attempt was next made to generate a 1- isoquinolylzirconocene reagent via the same method. The reaction of 1-chloroisoquinoline with the Negishi reagent, under the same conditions, proceeded smoothly. However, when deuterolysis was performed on the reaction, only a 25% D incorporation was observed at that position (Figure 11). 23 Figure 11. NMR spectrum of 1-isoquinolylzirconocene deuterolysis product Interestingly, an excellent result was observed upon deuterolysis of the product derived from 5-bromo-2,2’-bithiophene and the Negishi reagent. The NMR of the product indicated a 90% D incorporation at the 5- position (Figure 12). The mechanism for the oxidative addition may involve either a three or five-membered zirconacycle or both. 24 Figure 12. NMR spectrum of 2,2’-bithiophen-5-ylzirconocene deuterolysis product The drastic difference between the reactions, especially of 2-chloroquinoline and 1- chloroisoquinoline, as well as that of 5-bromo-2,2’-bithiophene, with the Negishi reagent is not well understood. 25 CHAPTER 4: PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF HETEROARYLZIRCONOCENE REAGENTS Organozirconium compounds have demonstrated their unique utilities in organic synthesis.42 Of those utilities, one is the participation of the reagents in palladium-catalyzed cross-couplings (Negishi reaction).55 With novel heteroaryl zirconocene reagents in hand, the investigation of their utility in palladium-catalyzed cross-coupling with both aryl- and heteroaryl halides was pursued. 4.1 Transmetallation In hopes that the reaction would proceed in the same manner as both the Stille and Negishi reactions (i.e. direct transmetallation from the organometallic reagent to the palladium catalyst), an attempt was made to couple the 2-quinolylzirconium reagent with ethyl 3- bromobenzoate in the presence of tetrakis(triphenylphosphine)palladium(0). The benzoate was used in 0.5 equivalent to the zirconocene reagent and the palladium catalyst was used in 0.5 mol % loading to the benzoate. After 48 hours at 50 °C, there was only a trace amount of the desired product observed and a large amount of the unreacted benzoate remained. After reviewing the literature, it was reported by Negishi that in certain catalytic reactions of this nature (those involving sterically hindered metal centers), the difficulty in coupling must be kinetic rather than thermodynamic, and that a single transmetallation process of high activation energy could be replaced by a double or multiple transmetallation processes of low kinetic barriers.56 Such a kinetically unfavorable transmetallation process could be facilitated by the use of one or more coordinatively unsaturated compounds of low steric hinderance containing metals whose electronegativity is comparable with that of zirconium. Of the number of systems that were screened by Negishi, both Zn(II) bromide and chloride were shown to 26 enhance the rate and increase the yields of the palladium-catalyzed coupling of alkenylzirconium derivatives with unsaturated organic halides to synthesize various olefins. This ideology was applied to the cross-coupling reaction of 2-quinolylzirconium reagent with ethyl 3-bromobenzoate, maintaining the conditions previously used, only this time with 1 equivalent of ZnBr2 added to the benzoate. After 48 hours, the reaction had proceeded further than without the presence of the Zn(II) salt, although it still did not reach completion and was quite sluggish. This prompted the screening of a number of metal halides in order to determine if we could enhance the rate and yield of the reaction. Both ZnBr2 and ZnCl2, as well as CuCl, CuBr·SMe2, and CuI were screened. To our delight, all three of the reactions containing the Cu(I) salts facilitated the reaction to completion within 42 hours, with CuCl being the most successful (Table 2), providing a 91% isolated yield of the desired product. Metal Time (h) Observation Zn(II)Br2 72 Low conversion; Sluggish Zn(II)Cl2 72 Low conversion; Sluggish Cu(I)Cl 22 Aryl Halide consumed Cu(I)Br·SMe2 22 Aryl Halide consumed Cu(I)I 45 Aryl Halide consumed Table 2. Screening of metal halides 27 Presumably, the transmetallation of 2-quinolylzirconocene chloride with CuCl affects the cross coupling of the novel heteroaryl reagents (Figure 13). The use of a catalytic amount of CuCl (10%) was not effective, implying that the role of CuCl may not just be limited to the transmetallation. Figure 13. Proposed heteroarylzirconocene cross-coupling mechanism 4.2 Functional Group Tolerance With an established procedure now in hand, the versatility of this reaction needed to be evaluated. Obviously the reaction was tolerant of the ester functionality in the benzoate, therefore aldehyde, ketone, nitrile, and amine functionalities were investigated as well. The results of all reactions demonstrated that ester, ketone, and nitrile functional groups were all well tolerated, with complete consumption of the functionalized aryl halide within 24 hours and high isolated yields of the desired product (Table 3). However, within 3 hours of adding 4- bromobenzaldehyde, there was complete consumption of the aldehyde reagent, although there was only a very small amount of desired product. There were, however, many other undesired products observed by both GC and TLC. The reaction with 3-bromoaniline tapered off after 28 about 40 hours, leaving a large amount of unreacted of the aryl halide. Again, TLC results showed the reaction was not very clean. Reactions were run in Et2O-THF (1:1) with 1.0 equivalent of heteroaryl halide, 1.2 equivalents of Cp2ZrBu2, 0.5 equivalent of CuCl, 2.5% of Pd(PPh3)4, and 0.5 equivalents of aryl halide. The temperature of the oil bath was set to 50 oC in all reactions. The reported yields are isolated yields. For a detailed procedure, see Chapter 6: Experimental. Table 3. Functional group tolerance 29 4.3 Cross-Coupling Reactions of Various Heteroarylzirconocenes With such successful generation of the desired product using 4-bromobenzonitrile (95%), the cross-coupling reaction of it with 1-isoquinolylzirconocene chloride, 2-pyrazylzirconocene chloride, and 2-pyridylzirconocene bromide were performed with the same reaction conditions. Although the deuterolysis experiment was not performed on the oxidative addition reactions of 2-bromopyridine and 2-chloropyrazine, the moderate yields of the cross-coupling reactions may be due to relatively low yields of 2-pyrazylzirconocene chloride and 2-pyridylzirconocene bromide formation (Table 4). This is possibly a result of the competing dehalogenation mechanism as indicated by the low D-incorporation of the 1-isoquinolylzirconocene reagent reported in Chapter 3. Table 4. Other nitrogen containing heteroarylzirconocene coupling yields Having now established functional group tolerance and determining a partial scope of heteroarylzirconocene reagent generation, it was important to investigate the ability of the reagents to couple with heteroaryl halides as well. Since the generation of 2- 30 thiophenylzirconocene derivatives was the most successful of all heteroaryl halides examined in this work, it was chosen as the model in the coupling reactions. Pleasingly, the coupling reaction of 2-thiophenylzirconocene bromide with 2-chloroquinoline and 2-bromopyridine were successful and high yielding (Table 5). Also, 2,2’-bithiophenyl-5-zirconocene bromide and 4- bromobenzonitrile were coupled in high yield as well. Table 5. Coupling results of thiophene derivatives 4.4 Evaluation of the Cross-Coupling Reactions of Other Heteroarylzirconocenes The attempted generation of other heteroarykzirconocenes, in which no deuterium studies were performed included: 2-bromopyrimidine, 2-bromopyrazine, 2-chloropyridine, 2- bromopyridine, 2-bromothiazole, 2,3-dibromothiophene, 3-bromo-1-methyl-1H-indazole, and 2- bromo-1-methyl-1H-benzo[d]imidazole. Since no deuterium studies were performed, the successful generation of these reagents was based upon the cross-coupling result with 4- bromobenzonitrile, along with physical observation of the reaction vessel, TLC, and GC results. All of the aforementioned reagents were able to be split into four categories as summarized in Table 6. 31 Table 6. Overall generation and cross-coupling results of various heteroarylzirconocene derivatives The “Consumed; Decomposed” title indicates that all of the halogenated heteroaryl reagent was consumed upon addition to the Negishi reagent, however a substantial amount of black precipitate was observed. TLC showed multiple spots, of which, none were believed to correspond to the desired heteroaryl reagent. Attempted cross-coupling reactions resulted in no observable desired product. “Consumed; Low Yield” again means that all of the halogenated heteroaryl reagent was consumed, however during the oxidative addition step, other side products were observed as well by TLC and GC. The cross-coupling reaction resulted in low to moderate yields of the desired product. “Not Completely Consumed” simply means that not all of the heteroaryl halide was consumed even when the ratio of the Negishi reagent to halide was increased. No attempts at cross-coupling were made. Finally, the “High Yield” title indicated that there was complete consumption the halide precursor and a large amount of desirable cross- coupling product was produced. 32 CHAPTER 5: CONCLUSION In summary, the heteroarylzirconocene reagents were prepared through the oxidative addition of the heteroaromatic halides to the Negishi reagent. The reagents have been successfully used as excellent partners in the palladium catalyzed cross coupling reaction with a variety of functionalized aryl halides and heteroaryl halides. This is first report of the heteroaromatic zirconium reagents and their applications to the organic synthesis. The method provides an alternative solution to challenges in the preparation of heteroaromatic organometallic reagents and their utility in cross coupling reactions. To further advance this methodology, investigations may be necessary to elucidate the competing dehalogenation mechanism and suppress this unwanted process. 33 CHAPTER 6: EXPERIMENTAL 6.1 General Procedure All reactions were conducted under argon atmosphere and anhydrous conditions. Tetrahydrofuran (THF) and diethyl ether were distilled from sodium and benzophenone under argon before use. All other reagents were purchased from chemical companies and were used as received. Preparative chromatography was performed on silica gel 60 (0.063-0.200 mm). Thin layer chromatography was performed with silica gel 60 F254 plates. GC analysis was carried out on a Shimadzu 2010 gas chromatograph equipped with a Shimadzu SHRXI-5MS column. NMR spectra were measured on a Bruker 400 MHz or Varian Inova 500 MHz spectrometer. Spectra were taken in CDCl3 using tetramethylsilane (0 ppm) as standard for 1H NMR and 13C NMR chemical shifts. Methyl 4-(quinolin-2-yl)benzoate): General Procedure: To a dry, argon-flushed, 25 mL three-necked round-bottomed flask with a condenser and a magnetic stir bar was charged bis(cyclopentadienyl)zirconium(IV) dichloride (702 mg, 2.4 mmol), THF (3 mL), and ethyl ether (3 mL) and then cooled to -78o C in a dry ice/isopropanol bath. To the solution, 1.6 M n-BuLi (3.0 mL, 4.8 mmol) in hexanes was added dropwise and the reaction mixture was allowed to stir for 1 hr at -78o C. A solution of 2-chloroquinoline (327 mg, 2 mmol) in THF (1.5 mL) and ethyl ether (1.5 mL) prepared in a separate dry, argon-flushed, 25 mL round-bottomed flask was transferred via syringe to the reaction mixture at -78o C. After the addition, the dry ice bath was 34 removed and the reaction was heated to 50oC for approximately 45 minutes, until all 2- chloroquinoline was consumed as monitored by GC analysis of the reaction mixture. Then, methyl 4-bromobenzoate (215 mg, 1 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol;), and CuCl (99 mg, 1 mmol) were added all at once. The mixture was heated in an oil bath set to 50 oC for 48 hrs. The GC analysis showed that all methyl 4-bromobenzoate was consumed. The reaction was allowed to cool to room temperature and then quenched with H2O (10 mL). The reaction mixture was filtered and the filtrate was extracted with dichloromethane (3x 20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel with hexane and ethyl acetate (v/v 5:1) to yield a tan solid, 218 mg, 84%. 1H-NMR (CDCl3, 400 MHz) ?: 3.95 (s, 3H), 7.55 (t, J = 7.4 Hz, 1H), 7.74 (t, J = 7.3 Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.89 (d, J = 8.6 Hz, 1H), 8.18 (d, J = 8.4 Hz, 3H) , 8.24 (d, J = 7.2 Hz, 3H). 13C-NMR (CDCl3, 100 MHz) ?: 52.2, 119.0, 126.8, 127.5, 129.9, 130.1, 130.6, 137.0, 143.7, 148.3, 156.0, 166.9. Spectral data match those previously reported.57 Ethyl 3-(quinolin-2-yl)benzoate): This compound was synthesized by the cross coupling of ethyl 3-bromobenzoate with 2-quinolylzirconocene chloride according to the general procedure. The crude product was purified by column chromatography on silica gel with dichloromethane and hexane (v/v 10:1) to yield an yellow oil, 252 mg, 91%. 1H-NMR (CDCl3, 400 MHz) ?: 8.79–8.80 (m, 1H), 8.41–8.44 (m, 1H), 8.27 (d, J = 8.6 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 8.13–8.16 (m, 1H), 7.94 (d, J = 8.6 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.73–7.77 (m, 1H), 7.61 (t, J = 7.8 Hz, 1H), 7.54–7.58 (m, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.45 (t, J = 7.1 Hz, 35 3H). 13C-NMR (CDCl3, 100 MHz) ?: 14.4, 61.2, 118.9, 126.6, 127.3, 127.5, 128.6, 130.0, 130.3, 131.1, 131.9, 137.0, 140.0, 148.3, 156.3, 166.5. Spectral data match those previously reported.58 4-(quinolin-2-yl)benzonitrile: This compound was synthesized by the cross coupling of 4-bromobenzonitrile with 2-quinolylzirconocene chloride according to the general procedure. The crude product was purified by column chromatography on silica gel with hexane and ethyl acetate (v/v 3:1) to yield an off-white solid, 219 mg, 96%. 1H-NMR (CDCl3, 400 MHz) ?: 7.58 (t, J = 7.8 Hz, 1H), 7.75-7.82 (m, 3H), 7.87 (t, J = 8.6 Hz, 2H), 8.17 (d, J = 8.5 Hz, 1H), 8.27- 8.30 (m, 3H). 13C-NMR (CDCl3, 100 MHz) ?: 112.7, 118.6, 118.8, 127.2, 127.6, 128.1, 129.9, 130.2, 132.6, 137.3, 143.7, 148.3, 154.9. Spectral data match those previously reported.59 1-(4-(quinolin-2-yl)phenyl)ethanone: This compound was synthesized by the cross coupling of 1-(4-bromophenyl)ethanone with 2-quinolylzirconocene chloride according to the general procedure. The crude product was purified by column chromatography on silica gel with hexane and ethyl acetate (v/v 3:1) to yield a yellow solid, 210 mg, 85%. 1H-NMR (CDCl3, 400 MHz) ?: 2.67 (s, 3H), 7.54-7.58 (m, 1H), 7.74-7.78 (m, 1H), 7.85 (d, J = 8.1 Hz, 1H), 7.92 (d, J = 8.6 Hz, 1H), 8.10-8.13 (m, 2H), 8.19 (d, J = 8.5 Hz, 1H), 8.26-8.29 (m, 3H). 13C-NMR 36 (CDCl3, 100 MHz) ?: 26.8, 119.0, 126.8, 127.4, 127.5, 127.7, 128.9, 129.9, 129.9, 137.0, 137.4, 143.9, 148.3, 155.9, 197.9. Spectral data match those previously reported.57 4-(isoquinolin-1-yl)benzonitrile): This compound was synthesized by the cross coupling of 4-bromobenzonitrile with 1-isoquinolylzirconocene chloride according to the general procedure. The crude product was purified by column chromatography on silica gel with dichloromethane and ethyl acetate (v/v 1:0 to 50:1) to yield an off-white solid, 74 mg, 32%. 1H- NMR (CDCl3, 400 MHz) ?: 7.57-7.61 (m, 1H), 7.72-7.76 (m, 2H), 7.82-7.86 (m, 4H), 7.93 (d, J = 8.3Hz, 1H), 7.99 (d, J = 9.3Hz, 1H), 8.64 (d, J = 5.7 Hz, 1H). 13C-NMR (CDCl3, 100 MHz) ?: 112.4, 118.7, 120.9, 126.4, 126.6, 127.3, 127.8, 130.4, 130.7, 132.2, 136.9, 142.3, 144.0, 158.5. Spectral data match those previously reported.60 4-(pyridin-2-yl)benzonitrile: This compound was synthesized by the cross coupling of 4- bromobenzonitrile with 2-pyridylzirconocene chloride according to the general procedure. The crude product was purified by column chromatography on silica gel with hexane and ethyl acetate (v/v: 5:1 to 3:1) to yield a yellow solid, 101 mg, 56%. 1H-NMR (CDCl3, 400 MHz) ?: 7.31-7.34 (m, 1H), 7.76-7.84 (m, 4H), 8.12 (d, J = 8.2 Hz, 2H), 8.74 (d, J = 4.8 Hz, 1 H). 13C- NMR (CDCl3, 100 MHz) ?: 112.5, 118.8, 121.0, 123.3, 127.5, 132.6, 137.1, 143.5, 150.1, 155.2. Spectral data match those previously reported.61 37 4-(pyrazin-2-yl)benzonitrile: This compound was synthesized by the cross coupling of 4- bromobenzonitrile with 2-pyrazinylzirconocene chloride according to the general procedure. The crude product was purified by column chromatography on silica gel with hexane and ethyl acetate (v/v: 3:1 to 1:1) to yield an off-white solid, 89 mg, 49%. 1H-NMR (CDCl3, 400 MHz) ?: 7.82 (d, J = 8.6 Hz, 2H), 8.16 (d, J = 8.6Hz, 2H), 8.60 (d, J = 2.4 Hz, 1H), 8.70 (dd, J = 1.6 Hz, 2.4 Hz, 1H), 9.1 (d, J = 1.4 Hz, 1H). 13C-NMR (CDCl3, 100 MHz) ?: 113.5, 118.4, 127.5, 132.8, 140.5, 142.4, 144.2, 144.5, 150.7. Spectral data match those previously reported.62 2-(thiophen-2-yl)pyridine: This compound was synthesized by the cross coupling of 2- bromopyridine with 2-thiophenylzirconocene chloride according to the general procedure. The crude product was purified by column chromatography on silica gel with dichloromethane and hexane (v/v 3:1) to yield a white solid, 150 mg, 93%. 1H-NMR (CDCl3, 400 MHz) ?: 7.09-7.14 (m, 2H), 7.37-7.39 (m, 1H), 7.56-7.57 (m, 1H), 7.62-7.68 (m, 2H), 8.55 (d, J = 4.8 Hz, 1H). 13C- NMR (CDCl3, 100 MHz) ?: 118.8, 121.9, 124.5, 127.6, 128.0, 136.6, 144.9, 149.6, 152.6. Spectral data match those previously reported.61 2-(thiophen-2-yl)quinoline: This compound was synthesized by the cross coupling of 2- chloroquinoline with 2-thiophenylzirconocene chloride according to the general procedure. The 38 crude product was purified by column chromatography on silica gel with hexane and ethyl acetate (v/v 10:1) to yield a yellow solid, 173 mg, 82%. 1H NMR (400 MHz, CDCl3) ?: 7.14- 7.16 (m, 1H), 7.45-7.49 (m, 2H), 7.66-7.70 (m, 1H), 7.72-7.73 (m, 1H), 7.75-7.79 (m, 2H), 8.07- 8.13 (m, 2H). 13C-NMR (CDCl3, 100 MHz) ?: 117.6, 125.8, 126.1, 127.2, 127.5, 128.1, 128.6, 129.3, 129.8, 136.6, 145.4, 148.1, 152.3. Spectral data match those previously reported.63 4-([2,2'-bithiophen]-5-yl)benzonitrile: This compound was synthesized by the cross coupling of 4-bromobenzonitrile with 2,2’-bithiophen-5-ylzirconocene chloride according to the general procedure. The crude product was purified by column chromatography on silica gel with hexane and dichloromethane (v/v 3:1 to 1:1) to yield a yellow solid, 262 mg, 98%. 1H NMR (400 MHz, CDCl3) ?: 7.05 (dd, J = 3.6, 5.1 Hz, 1H), 7.18 (d, J = 3.8 Hz, 1H), 7.24 (dd, J = 1.1, 3.6 Hz, 1H), 7.27 (dd, J = 1.1, 5.1 Hz, 1H), 7.34 (d, J¼3.8 Hz, 1H), 7.63–7.68 (m, 4H). 13C- NMR (CDCl3, 100 MHz) ?: 110.46, 118.82, 124.33, 124.85, 125.20, 125.66, 125.85, 128.03, 132.75, 136.68, 138.28, 139.12, 140.36. Spectral data match those previously reported.64 6.2 Deuterolysis Experimental Procedure To a dry, argon-flushed, 25 mL three-necked round-bottomed flask with a condenser and a magnetic stir bar was charged bis(cyclopentadienyl)zirconium(IV) dichloride (702 mg, 2.4 mmol), THF (3 mL), and ethyl ether (3 mL) and then cooled to -78o C in a dry ice/isopropanol bath. To the solution, 1.6 M n-BuLi (3.0 mL, 4.8 mmol) in hexanes was added dropwise and the reaction mixture was allowed to stir for 1 hr at -78o C. A solution of 2-chloroquinoline (327 mg, 2 mmol) in THF (1.5 mL) and ethyl ether (1.5 mL) prepared in a separate dry, argon- flushed, 25 mL round-bottomed flask was transferred via syringe to the reaction mixture at -78o 39 C. After the addition, the dry ice bath was removed and the reaction was heated to 50oC for approximately 45 minutes, until all 2-chloroquinoline was consumed as monitored by GC analysis of the reaction mixture. The reaction mixture was allowed to cool to room temperature. AcOD (0.5 mL) of was added and the mixture was stirred at room temperature for 3 hours. After the usual work-up, the deuterated quinoline was isolated and purified by column chromatography on silica gel (CH2Cl2-EtOAc, v/v 10:1), 250 mg, 89%. 1H NMR analysis of the product showed an 80% D incorporation to the 2-position of quinoline (1H NMR spectrum, page 50). 40 6.3 1H and 13C NMR Spectra of Cross-Coupling Products Methyl 4-(quinolin-2-yl)benzoate CAS: 104967-52-4 41 Ethyl 3-(quinolin-2-yl)benzoate CAS: 1050421-21-0 42 4-(quinolin-2-yl)benzonitrile CAS: 181867-59-4 43 1-(4-(quinolin-2-yl)phenyl)ethanone CAS: 221910-24-3 44 4-(isoquinolin-1-yl)benzonitrile CAS: 494749-11-0 45 4-(pyridin-2-yl)benzonitrile CAS: 32111-34-5 46 4-(pyrazin-2-yl)benzonitrile CAS: 143526-42-5 47 2-(thiophen-2-yl)pyridine CAS: 3319-99-1 48 2-(thiophen-2-yl)quinoline CAS: 34243-33-9 49 4-([2,2'-bithiophen]-5-yl)benzonitrile CAS: 748789-05-1 50 6.4 1H NMR Spectrum of 2-Deuterated Quinoline 51 6.5 1H NMR Spectrum of 1-Deuterated Isoquinoline 52 6.6 1H NMR Spectrum of 5-Deuterated 2,2’-Bithiophene 53 CHAPTER 7: BIBLIOGRAPHY 1. 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