A HYDROGEN BONDING ORTHO-DIRECTING EFFECT FOR THE IRIDIUM CATALYZED BORYLATION OF NH(t-BOC) AROMATICS By Philipp C. Roosen A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE Chemistry 2011 ABSTRACT A HYDROGEN BONDING ORTHO-DIRECTING EFFECT FOR THE IRIDIUM CATALYZED BORYLATION OF NH(t-BOC) AROMATICS By Philipp C. Roosen The C–H borylation of aromatic substrates has evolved from a stoichiometric curiosity to a valuable methodology for the synthetic chemist. Understandings of regioselective activation and high functional group tolerance have been considerably praised. Most aromatic substituents, such as alkyl, esters, amides, nitriles, amines, protected phenols and others act as steric obstacles for the iridium catalyst to avoid. This avoidance of appending groups can be reversed into a directed borylation with monophosphine ligands. Alternatively, the SiMe2H group elicits an ortho-directing effect via oxidative addition to the metal center. Described herein is the investigation of a new means to direct borylation. The NH(tert-butoxycarbonyl) group is a unique directing group that under standard borylation conditions provides ortho-directed borylation. The NH(t-Boc) group operates by a hydrogen bonding interaction between the N–H and catalyst. This unique effect was examined for a range of aromatic substructures. Introductory attempts at improving selectivity involved increasing N–H acidity and a ligand screen. The obtained borylated anilines are useful precursors to 3,4-dihydroquinolin-2-one heterocycles. Meinen Eltern iii ACKNOWLEDGEMENTS I would like to thank my advisor Prof. Mitch Smith for all the support in my professional development and pursuits as a chemist. I am extremely grateful to him for having given me opportunities to independently build myself. His approaches, suggestions and guidance were not only invaluable to the project at hand, but are also transferable to future undertakings. My experience would not have been all it was if it were not for everyone involved in the Boron collaboration. A special thanks is extended to Prof. Rob Maleczka for his continuous contributions during group meetings and LAH quenching help. I cannot thank Sean, Appi, Bala, Jon, Britt, Behnaz, Hong-tu and Colin enough for being terrific lab mates. Prof. Dan Singleton is very much appreciated for fruitful discussions involving mechanistic aspects of the NH(t-Boc) directed borylation project. Thanks to Dan and Kermit for being dependable with any NMR questions. If it were not for Richard’s ability to solve x-ray structures, I would have had to tape all my crystals into this thesis. I very much appreciate all the work being put in behind the scenes. I would like to thank my parents, Aziza and Norbert for making the life-changing decision of coming and staying in the US. Although we were only going to reside temporarily, I am very happy it turned permanent. Thank you Kathleen for keeping me company. Thank you to all of my friends for having traveled alongside me. I could not have been successful without your love and adoration Michelle. Thank you for being the inspiration to better myself every day. iv TABLE OF CONTENTS LIST OF TABLES vi LIST OF FIGURES vii LIST OF ABBREVIATIONS AND SYMBOLS x CHAPTER ONE – INTRODUCTION General Introduction to Aromatic Functionalization Transition Metal Influenced C–H Functionalization Boration of Hydrocarbons 1 1 4 8 CHAPTER TWO – RESULTS AND DISCUSSIONS Directed Aromatic Functionalization Scope of the NH(t-Boc) Directing Effect Comparisons of Lithiation and NH(t-Boc) Borylation Mechanism of NH(t-Boc) Directed Borylation Broadening the Hydrogen Bonding Directed Borylation Further Application of ortho-BPin-NH(t-Boc)-Anilines Conclusions 17 17 23 27 31 43 52 55 CHAPTER THREE – EXPERIMENTAL METHODS 57 APPENDICES APPENDIX A: Single crystal X-Ray diffraction structures APPENDIX B: NMR Spectra 153 154 169 REFERENCES 222 v LIST OF TABLES Table 1. ortho-Borylation of N-(t-Boc)-anilines 24 Table 2. Unsuccessful Ir C–H borylations 26 Table 3. IR data confirming the presence of an intramolecular hydrogen bonding interaction in 3b 35 Table 4. Effect of substitutions on ortho-borylation 36 Table 5. Catalyst electronic parameters for the NH(t-Boc) directed borylation 38 Table 6. Solvent influence on selectivity 40 Table 7. N,N-ligand screening for ortho-directed borylation 45 vi LIST OF FIGURES Figure 1. Electrophilic aromatic substitution 2 Figure 2. Synthetic route to 3-bromo-5-chlorophenol from TNT 3 Figure 3. Directed ortho-metallation 4 Figure 4. Route to the first isolated C–H activated organometallic complex 5 Figure 5. Ru-catalyzed isomerization via intramolecular C–H activation 6 Figure 6. Photoinduced insertion of carbon monoxide into a C–H bond 7 Figure 7. Routes for the formation of aryl boronates 9 Figure 8. Thermodynamics of methane borylation 9 Figure 9. First thermal, catalytic borylation of hydrocarbons 10 Figure 10. Comparative borylation of aromatics using Ir and Rh catalysts 11 Figure 11. Preparation of active catalyst and catalytic cycle for aromatic borylation 13 Figure 12. Synthetic utility of aryl pinacol boronic esters 14 Figure 13. Further reactivity of halogens in the presence of Bin 15 Figure 14. Literature precedence for ortho-borylation 16 Figure 15. (a) General outline for synergistic metallation (b) Zincation of a benzamide using a synergistic metallation approach: Kondo, T.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc. 1999, 121, 3539-2540 18 Figure 16. Directed borylation of 2-BPin-benzofuran 19 Figure 17. Directed borylation of the 1,3-benzodioxole framework 20 Figure 18. Select literature examples for the borylation of substituted anilines 21 Figure 19. Borylation of N,N-di(t-Boc) and N-(t-Boc) protected 3-chloroaniline; *hexamethylbenzene as an internal standard on an average of two runs 22 Figure 20. Crude 500 MHz 1H NMR of the borylation of N-(t-Boc)-3-chloroaniline vii 22 Figure 21. Extent of ortho-borylation on unsubstituted N-(t-Boc)-aniline 23 Figure 22. Derivatization of N-(t-Boc)-ortho-BPin-aniline 27 Figure 23. DoM of N-(t-Boc)-anilines 28 Figure 24. Preparation of 6-methoxybenzoxazolinone (6a) via an aryne intermediate 31 Figure 25. Plausible transition states for the NH(t-Boc) directed borylation of anilines 32 Figure 26. (a) Kennedy, J. W. J; Hall, D. G. J. Organomet. Chem. 2003, 680, 263270 (b) Hudnall, T. W.; Bondi, J. F.; Gabbaï, F. P. Main Group Chem. 2006, 5, 319327 33 Figure 27. Protected ortho-BPin anilines. Hydrogen atoms have been omitted for clarity. Thermal ellipsoids are shown at 50% probability. Select bond lengths and angles are found in Appendix A. For interpretation of the references to color in this and all other figures, the reader is referred to the electronic version of this thesis. 34 Figure 28. Correlation of ortho-borylation selectivity with the pKa of the corresponding pyridinium 39 Figure 29. C–D isotope effect for the NH(t-Boc) directed ortho-borylation; a average of two runs with 83% and 90% NMR yield b see experimental methods for details 41 Figure 30. Hydrogen bonding in Wulff aziridination 42 Figure 31. Hydrogen bonding in allylic substitution reactions 42 Figure 32. Hydrogen bonding in epoxidation reaction 43 Figure 33. Hydrogen bonding in ring opening cross metathesis 43 Figure 34. Synthesis of silica-SMAP (10g) 46 Figure 35. Application of phosphine ligands to the NH(t-Boc) directed borylation 48 Figure 36. Proposed transition states for the bis-ortho-directed borylation using silica-SMAP-[Ir] 49 Figure 37. Borylation of N-arylsulfonamides 50 Figure 38. Borylation of N-arylcarbamates 51 Figure 39. Biologically active molecules containing a 3,4-dihydroquinolin-2-one moiety 52 viii Figure 40. Acid induced t-Boc deprotection 53 Figure 41. Rh-catalyzed conjugate addition on N-(t-Boc) protected aniline substrate 54 Figure 42. Route to 3,4-dihydroquinolin-2-ones via NH(t-Boc) directed Ir catalyzed borylation and Rh catalyzed conjugate addition 55 ix LIST OF ABBREVIATIONS AND SYMBOLS Å Ångstrom Ac acetyl BDE bond dissociation energy Bn benzyl Boc butoxycarbonyl BOX 2,2’-bisoxazoline brsm based on recovered starting material Bu butyl Cat catecholate cm-1 wavenumbers Cp cyclopentadienyl Cp* pentamethylcyclopentadienyl COD 1,5-cyclooctadiene COE cyclooctene Cy cyclohexyl dba dibenzylideneacetone DCE 1,2-dichloroethane DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMG directed metallating group dmpe 1,2-bis(dimethylphosphino)ethane x DMSO dimethylsulfoxide DoM directed ortho metallation dppe 1,2-bis(diphenylphosphino)ethane dtbpy 4,4’-di(tert-butyl)-2,2’-bipyridine E+ electrophile EAS electrophilic aromatic substitution EDG electron donating group EI electron ionization equiv. equivalents ESI electrospray ionization Et ethyl ! hapticity, denotes how many contiguous atoms of a ligand bind to a metal EWG electron withdrawing group FDA United States Food and Drug Administration FG functional group FID flame ionization detection GC gas chromatography gCOSY gradient-select correlated spectroscopy HIV-1 NNRTI human immunodeficiency virus type 1 non-nucleoside reverse transcriptase inhibitor HRMS high-resolution mass spectrometry Ind indenyl IR infrared xi kcal mol-1 kilocalorie per mole kH / k D rate of protiated versus rate of deuterated KIE kinetic isotope effect " wavelength lit literature [M] metal [M]+ molecular ion peak m meta Me methyl Mes mesityl mM millimolar mmol millimole MOM methoxymethyl ether mp melting point MS molecular sieves MTBE methyl tert-butylether n- normal- NAS nucleophilic aromatic substitution NHC N-heterocyclic carbene NMR nuclear magnetic resonance NPhth phthalimide nOe nuclear Overhauser effect o ortho xii p para P(ArF)3 tris[3,5-bis(trifluoromethyl)phenyl]phosphine Ph phenyl Pin pinacolate pKa acid dissociation constant at logarithmic scale ppm parts per million Pr propyl (R)-tol-BINAP (R)-2,2’-bis(di-p-tolylphosphino)-1,1’-binaphthyl R remaining attachments Rf retention factor RT room temperature sec- secondary- SMAP silicon constrained monodentate phosphine t- tertiary- Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMS trimethylsilyl TNT 2,4,6-trinitrotoluene TON turnover number xiii CHAPTER ONE – INTRODUCTION General Introduction to Aromatic Functionalization Aromatic hydrocarbons are of keen interest to the modern consumer. As part of the exponential advancement in science and technology over the past 70 years, aromatics have been on the forefront as a dynamic molecular architecture. They are used to enhance octane fuel ratings, are found in countless polymeric materials, support agricultural development, are used as solvents for a variety of applications and appear in innumerable biologically active molecules and synthetic pharmaceuticals. The frequent appearance of the aromatic nucleus in commercial goods requires the production of materials in both quantity and quality.1 A major source of aromatics is the process of catalytic reforming. This method currently supplies benzene, toluene and xylenes as raw aromatics.2 These require further derivatization to meet particular specifications, thereby placing great interest on investigating the chemistry of the aromatic. Since benzene, toluene and xylenes are the generically produced aromatics, a key requirement for diversifying these compounds is selectively substituting a C–H bond for a bond of higher functionality. When compared to C–X bonds, the aromatic C–H bond does not have the luxury of high acidity, low bond dissociation energy or high polarity. Converse to these physical characteristics, chemists have been able to manipulate the aromatic core by a number of different methods. These can generally be categorized as (1) aromatic substitution (2) deprotonation and (3) transition metal influenced C–H rupture. 1 A mixing of two Kekulé structures via !-electron delocalization provides aromatics an intrinsic stability. The breaking of the aromatic #-system as a means of reactivity is described as aromatic substitution. In contrast to olefins, the breaking of #bonds in aromatics involves a thermodynamic penalty for disrupting aromaticity. EAS3 and NAS4 subsidize this thermodynamic mountain by rearomatizing the ring for product formation, figure 1. EDG EDG H E E+ EDG E+ EDG – H+ E EWG EDG E H E EWG H E EWG – H+ E Figure 1. Electropilic aromatic substitution The electronic properties of the aromatic dictate the regioselective functionalization of addition reactions. This is pertinent to both electrophilic and nucleophilic methods. Distinct patterns for the addition of electrophiles to monosubstituted benzenes were identified early.5,6 Electron donating substituents such as ring activating alkyls, phenols and anilines or ring deactivating halogens, provide ortho/para-substituted products while electron withdrawing substituents, like nitro and carbonyls provide meta-substituted products, figure 1.7 The combined electronic influence of all substitutions governs the site(s) of reactivity for polysubstituted aromatics. This can have profound consequences for the preparation of certain 2 substitution patterns. For example, the all meta placement of ortho/para directors requires tenacious effort when using aromatic substitution, figure 2.8 NO2 O2N Me OMe 1. Na2Cr2O7 NO2 2. HOAc 3. KOCN O2N OMe 1. Na2S NO2 2. NaNO2 3. CuBr O2N Br TNT OMe O2N Br 1. Sn, HCl 2. H2SO4 3. NaNO2 4. CuCl OH Cl Br Figure 2. Synthetic route to 3-bromo-5-chlorophenol from TNT Although aromatic C–H bonds are considerably weak acids (pKa of benzene = 37),9 they may still be deprotonated with strong base. This was first realized with the isolation of benzoic acid upon the carbonation of heated ethyl,10 iso-amyl or iso-butyl11 sodium and benzene solutions. Gilman and Young12 opened the discipline of DoM by describing the deprotonation of the benzene nucleus ortho to oxygen in dibenzofuran with lithium and sodium alkyls, figure 3. Wittig, Pockels and Dröge isolated orthomethoxy-triphenylcarbinol in 68% yield after the addition of benzophenone to a mixture of anisole and phenyl lithium and introduced the concept of the DMG.13 Since then, DoM has been applied to a variety of functional groups and remains on the cutting edge of organic synthesis.14,15 3 O O R[M] [M] 1. CO2 (s) CO2H 2. HCl – RH [M] = Li, Na OMe O PhLi – PhH OMe 58% yield for [M] = Na Ph2CO Li OMe OH Ph Ph 68% yield Figure 3. Directed ortho-metallation D oM has made a tremendous impact on aromatic chemistry. The site of deprotonation is predicted by the power of the DMG and electronics of the ring.14 If placed correctly on the aromatic DMG’s can create an enhanced, mutual site of metallation, however placement may also create competition for the base to afford product mixtures. If the difference in directing ability is large enough between DMG’s, only one will undergo complete DoM. The vast number of electrophiles allows access to diverse structures from a single source. Drawbacks of the DoM methodology include a narrowed functional group tolerance, the use of cryogenic temperatures and the need for a stoichiometric amount of base. Transition Metal C–H Functionalization The direct formation and functionalization of organometallics from hydrocarbon precursors has received a great deal of attention.16-25 The overall process is summarized as taking a C–H bond to a C–FG bond (FG = functional group) with the assistance of a transition metal. Two main modes have been described: inner-sphere and outer-sphere.26 An inner-sphere mechanism, also referred to as “organometallic”18 interaction involves 4 the formation of a discreet C–[M] ([M] = metal) bond that is turned over to the C–FG via external or coordinating reagent. An outer-sphere, “coordination”18 mechanism refers to ligand-influenced reactivity, as in carbenoid, oxo- and imino- species. Although this manifold may still involve action of the metal center, the functionalizing reagent is ligated to the metal. Both of these mechanisms involve C–H activation. C–H activation is referred to as the process of transferring a hydrocarbon onto a metal via interaction only with the bond in question. The first irrefutable C–H activation event was reported by Chatt and Davidson27 in 1965 by reacting (dmpe)2RuCl2 with benzene, naphthalene, anthracene and phenanthrene aromatic hydrocarbons and elemental sodium, figure 4. The ruthenium atom was inserted into the sterically most accessible C–H bond. These complexes were shown to be in equilibrium with their respective ! 2-aryl coordinated counterpart, illustrating a prototypical subsequent reaction of C–H activated complexes: C–H bond forming reductive elimination. PMe2 Cl 2 Na Me2P Ru Cl Me2P – 2 NaCl PMe2 PMe2 Me2P Ru PMe2 Me2P C10H8 PMe2 H Me2P Ru Me2P PMe2 Figure 4. Route to the first isolated C–H activated organometallic complex A change in perspective came as observations of C–H activation through H/D exchange,28,29 intramolecular cyclometallation30 and activated hydrocarbons31-33 became more prominent. These results began to shift the idea that C–H activations were difficult to finding practical methods of functionalizing the obtained organometallic, preferably in a catalytic manner. 5 One of the first productive progressions was the reaction between Cp2NbH3, Et3Al and benzene to afford PhAlEt2 by Tebbe.29,34 Further illumination on mechanism, generality and improvement of this system was not published. Another interesting report was the isomerization of 2-isocyano-m-xylene to 7-methyl indole using catalytic (dmpe)2Ru(2-napthyl)(H), figure 5.35 The mechanistic proposal involves elimination of HR (R = H or napthyl) to form the active catalyst, isocyanate coordination, cyclometallation, 1,1-insertion, isomerization and reductive elimination. Me PMe2 H Me2P Ru N Me2P H PMe2 H N PMe2 Me Me2P Ru PMe2 CN Me Me2P 140 °C Me Me2P PMe2 H Ru N Me2P H Me PMe2 PMe2 Me – HR PMe2 H Me2P Ru R Me2P PMe2 R = H or napthyl Me2P PMe2 H Ru N Me2P PMe2 Me Me2P Ru CN Me2P PMe2 Me Me2P PMe2 H Ru CN Me Me2P PMe2 Figure 5. Ru-catalyzed isomerization via intramolecular C–H activation A crucial development for transition metal C–H activated species is to increase the complexity of organics via intermolecular coupling, preferably in a catalytic manner. Pioneering achievements wed silyl hydrides with arenes using Vaska’s complex,36 Vaska’s rhodium analogue37 and Pt2(dba)3.38 Concurrently, IrH3(CO)(dppe) was found 6 to catalyze the insertion of carbon monoxide into the C–H bond of benzene to form benzaldehyde upon photo-irradiation, figure 6.39,40 The amount of benzaldehyde prepared is not kinetically determined, but rather is limited to a thermodynamic equilibrium. The observation of secondary products, such as benzyl alcohol did not allow for a confident assignment of the equilibrium constant. O PPh2 Ph2P H Ir H CO h! PPh2 H Ph2P Ir H OC O CO – H2 PPh2 H Ph2P Ir H OC H PPh2 H Ph2P Ir H CO PPh2 H Ph2P Ir H O Figure 6. Photoinduced insertion of carbon monoxide into a C–H bond In 1998 Berry and coworkers reported a dehydrogenative coupling of triethylsilane with aromatics using low stoichiometric quantities of Cp*Rh(R1) and (!6C6Me6)Ru(R1) [R1 = (H)2(SiEt3)2 or R1 = (Cl)2].41 The site of silation is not dependent upon electronic factors of the aromatic but instead determined purely by sterics. The silation of toluene and trifluoromethylbenzene provided a statistical distribution between the meta and para positions, while o- and m-xylene afforded single products. Although functional group tolerance was limited, the chemistry showed the real possibility of 7 selectively functionalizing a C–H bond complementary to aromatic substitution and DoM. Boration of Hydrocarbons Organoboranes have found wide application in synthetic chemistry. These compounds can be easily transformed into a variety of functional groups, have had successful employment in inducing reactivity and are themselves synthetic targets, useful for fluorescence,42 molecular transport43 and therapeutics.44 The use of organoboranes in synthetic chemistry has been recognized with a Nobel Prize to H. C. Brown in 1979 for work on “developing boron-containing compounds into important reagents in organic synthesis” and Akira Suzuki in 2010 for using organoboranes in “palladium-catalyzed cross-couplings in organic synthesis.” Organoboron reactivity usually involves the boron atom. As a neutral trivalent species boron does not fulfill the octet rule, relaying Lewis acidity. The degree of acidity is dependent on its substituents, i.e. EWG’s increase acidity while EDG’s reduce acidity. Popular boron functionalities, especially in organometallic chemistry are the boronic acid, R–B(OH)2 and boronic ester, R–B(OR)2. These groups provide a marked stability towards oxygen and air, thereby easing handling and allowing for storage under ambient conditions. This most likely has to do with oxygen’s ability to #-donate to the boron. Focus will be geared towards aryl boronates. Three paths can be imagined for the preparation of aryl boronic acids and esters, figure 7. First, metallation of an aryl halide forms a reactive nucleophile that is subsequently quenched with a boron source. Secondly, an aryl halide can be taken 8 directly to the boronate via a cross-coupling protocol.45 Aryl diazonium salts46 and amines47 can also be used to prepare boronates. The most atom economical method however, is access directly from a hydrocarbon. This can be achieved by using transition metals in both stoichiometric and substoichiometric fashion.48 cat. Pd, B2Pin2, KOAc H RO Mg [X] X MgX O B O – ROMgX O B O H–B(OR)2 – H2 Figure 7. Routes for the formation of aryl boronates The calculated thermodynamics of the conversion from hydrocarbon to organoborane are essentially thermoneutral, figure 8.49-51 This transformation is therefore a feasible process, requiring a kinetic solution. H3C H BDE = 105.0 O H B O O H3C B O 111.3 113.0 H H 104.2 !H = –0.9 kcal mol-1 H3C H BDE = 105.0 O H B O O H3C B O 110.8 111.6 H H 104.2 !H = 0.0 kcal mol-1 Figure 8. Thermodynamics of methane borylation In 1995, Hartwig reported the use of stoichiometric Cp(OC)2FeBCat, (OC)5MnBCat and (OC)5ReBCat for the photolytic borylation of arenes and olefins.52 9 The regioselective borylation of monosubstituted arenes followed a steric trend with only meta and para products being observed. Two dynamic reports appeared in 199953 and 200054 noting borylation of benzene and alkanes under catalytic, thermal conditions. Iverson and Smith53 observed 3 TON for the borylation of benzene with Cp*Ir(PMe3)(H)(BPin) using HBPin at 150 °C, figure 9. This result confirmed the possibility of catalytic arene functionalization with boron reagents. Hartwig and coworkers54 used Cp*Rh(! 4-C6Me6) to regioselectively borylate benzene and the terminal position of alkanes, using catalyst loadings as low as 0.5 mol%, figure 9. H + HBPin Me Me Me 17 mol% Me Ir Me H Me3P BPin BPin (150 °C, 120 h) + H2 53% yield R H + B2Pin2 Me Me Me Me Me Rh cat. Me Me Me Me Me Me R BPin + HBPin (150 °C) R = Ph R = octyl 92% NMR yield 88% NMR yield Figure 9. First thermal, catalytic borylations of hydrocarbons Marked differences in selectivity were found for the borylation of arenes between Cp*Ir(PMe3)(H)(BPin) and Cp*Rh(!4-C6Me6), figure 10.55 Both catalysts borylated at the sterically most available position on m-xylene and m-bis(trifluoromethyl)benzene to 10 afford all meta situated products. The selectivity between hydrocarbon and fluorocarbon activation was assessed with pentafluorobenzene, for which the rhodium species was less discriminating than the iridium catalyst. The borylation of m-xylene afforded more benzylic borylation with the rhodium than the iridium system. A mixture of unreacted starting material, chlorobenzene, m-BPin-chlorobenzene and m-BPin-m-dichlorobenzene were found as major products upon the treatment of m-dichlorobenzene with Cp*Rh(!4C6Me6) and HBPin, further highlighting halogen incompatibility.56 The rhodium borylation catalyst is observably less selective between hydrocarbon and halogen activation and between arene and benzylic activation than the iridium species. F F F + F HBPin [M] F (150 °C) F F BPin F F 81% 41% [M] = Cp*Ir(PMe3)(H)(BPin) [M] = Cp*Rh(!4-C6Me6) + F4 F 96 84 : : Me Me + HBPin [M] 60% 73% [M] = Cp*Ir(PMe3)(H)(BPin) [M] = Cp*Rh(!4-C6Me6) 4 16 + Me Me H PinB BPin (150 °C) BPin Me 97 88 : : 3 12 Figure 10. Comparative borylation of aromatics using Ir and Rh catalysts With greater regio- and chemoselective aromatic borylation for the iridium catalyst, further studies were performed to improve activity. Smith and coworkers57 examined the possibility that an active catalyst was formed upon thermolysis of Cp*Ir(PMe3)(H)(BPin) in HBPin via Cp* dissociation. Donor ligands, such as PMe3 11 were found to be required for catalysis. Reacting (! 6-mesitylene)Ir(BPin)3, PMe3 and HBPin was successful in dramatically increasing TON. The use of an IrI source, a bisphosphine ligand and HBPin lead to effective catalytic borylation of various aromatics with steric selectivity.57 Hartwig and coworkers58 reported an analogous reaction concurrently, using an IrI source, 2,2’-bipyridine and B2Pin2. Of considerable note is that both systems proved compatible with all halogen functionalities. Both experimental57-59 and computational60 efforts lead to identifying the active catalytic species and cycle, figure 11. The action of HBPin and a bidendate ligand upon an IrI source affords the 16e– (L2)Ir(BPin)3. This species activates an aromatic hydrocarbon to form an IrV intermediate. Subsequent release of the functionalized organic molecule affords an IrIII monohydride. The trisboryl (L2)Ir(BPin)3 is regenerated by action of R1BPin and elimination of R1H (R1 = BPin or H). A number of different chelating ligands, for example bisphosphine,57 substituted bipyridine,61 1,10phenthroline,58 bisoxazoline,62 2-pyridylimine63 and NHC’s64 have been used to catalyze the borylation. Initial kinetic and mechanistic studies were performed on (L2)Ir(BPin)3(COE) where L2 = bipyridine. This species however is only a precatalyst, requiring COE dissociation to enter the catalytic cycle. Access to the 16e– (L2)Ir(BPin)3 is achievable for bisphosphine ligands. The isolation of complexes found in the catalytic cycle allows for direct insight into the C–H cleavage step.65,66 12 Ir Ir Cl Ir 2 [Ir(COD)Cl]2 (Ind)Ir(COD) Me O 2 [Ir(OMe)COD]2 L HBPin L Ar H L L BPin BPin Ir BPin ! COE + COE L L BPin BPin Ir BPin H R1 L L = P P or N N BPin BPin L Ir BPin L H Ar BPin BPin L Ir H BPin L R1 L L Ar BPin BPin BPin Ir H R1 BPin R1 = H or BPin Figure 11. Preparation of active catalyst and catalytic cycle for aromatic borylation The borylation regioselectivity is of considerable interest. The site of functionalization is typically set not by electronics, but by sterics. This provides complementary regioselectivities to EAS and DoM for certain substituents patterns. Smith and coworkers set up competition experiments between a nitrile substituent and other groups at the para position to determine preferential borylation based on size.67 The synthetic utility of these boronates is versatile, figure 12. The well recognized and Nobel prize winning Suzuki-Miyaura coupling reaction68 is only one application of aryl boronic esters. These compounds can also be developed further to form carbon halogen,69,70 oxygen,71-74 nitrogen,72,75 nitrile,76 aryl57,77 and other carbon-carbon7880 bonds. Deborylation in the presence of heavy water affords the deuterio labeled aromatic. In addition to being able to manipulate the BPin, effort has been placed into 13 pursuing C–halogen couplings while keeping the BPin intact, figure 13. Many of these transformations can be accomplished in one-pot.73,81 The straight-forward access to functionality through an iridium catalyzed borylation can be seen in the application of total syntheses: rhazinicine (2008),82 SM-130686 (2009),83 (+)-complanadine (2010),84 (–)-taiwaniaquinone H (2011)85 and (–)-tainwaniaquinol B (2011)85. The iridium borylation allowed for concomitant Suzuki coupling, oxidation or bromination to move towards the molecule of interest. OH D H CN Ir C–H X BPin borylation X = F, Cl, Br B CO2R B = B(OH)2, BF3K aryl NH3Cl NHR SR Figure 12. Synthetic utility of aryl pinacol boronic esters 14 (R)2N (R)2N BPin OH R RS X BPin X H R R Ir C–H borylation RC R BPin R BPin R (RO)2B BPin R Figure 13. Further reactivity of halogens in the presence of a BPin The regiochemistry of activation using iridium C–H borylation has been described to be highly sensitive to sterics. The borylation ortho to substituents by means different from steric constraints can however also occur. This has been accomplished in four cases, figure 14. Diborylation of indole provides substitution first at the 2-position and then at the 7-position.86 Three other methods have been reported that use an inner-sphere chelation to induce ortho-borylation.87-89 The oxidative addition of a Si–H bond to the iridium catalyst is faster than a C–H bond. This enables silanes to act as a directing group that places the ortho-hydrogen in proximity to the metal. This concept has been applied to borylating protected phenols, anilines and N-heterocycles.78,89 Mono-dentate phosphines like triaryl-, tricyclohexyl-, tri-t-butyl-, trimethylphosphine and others serve as ligands to direct the borylation ortho to benzoates. These ligands show variation in yield and selectivity. Two ligands that have a showing a high degree of effectiveness are silica-SMAP88 and P(ArF)387. 15 H N [Ir(OMe)COD]2 dtbpy BPin HBPin (60 °C, 4 h) SiMe2H [Ir(COD)Cl]2 dtbpy HBPin / B2Pin2 THF (80 °C, 2 h) OMe [Ir(OMe)COD]2 silica-SMAP B2Pin2 hexanes (RT, 2 h) BPin BPin N Ir SiMe2 H N O OMe 5 equiv. B2Pin2 octane (80 °C, 16 h) SiMe2H BPin 49% yield H PinB Ir O PinB OMe O P H PinB Ir O PinB F3C P F3C F3C OMe BPin Si SiMe3 O O Si Si O O O O O O SiO2 PinB [Ir(OMe)COD]2 P(ArF)3 BPin 90% yield PinB O H N 89% yield OMe O CF3 CF3 CF3 OMe BPin 95% GC yield Figure 14. Literature precedence for ortho-borylation This thesis describes the ortho-borylation of aniline substrates by a new mechanism. In contrast to the chelation method of activation described above, NH(t-Boc) aromatics undergo ortho-borylation via a hydrogen bonding mechanism. 16 CHAPTER 2 – RESULTS AND DISCUSSIONS Directed Aromatic Functionalization Directing groups focus the reactivity of a reagent to a specific position. This appending group determines the regiochemistry of functionalization in a chelating, steric or electronic manner. Chelating directed functionalizations are the focus here. The most prominent directed aromatic functionalization is the deprotonation of an ortho hydrogen.14,15 Both electronic acidifying effects and Lewis basic chelate directing groups are able to induce reactivity.90 For more powerful DMG’s, a heteroatom such as oxygen or nitrogen coordinates, influences reactivity and stabilizes the metal species. Organo-alkali metal and metal amides, such as butyl lithiums and lithium amides have emerged as favorites for synthetic chemists.14,15 The organometal species intermediate is not restricted to that of the alkali metal series. Synergistic reactivity of ate complexes91,92 allows for DoM with aluminum,93 cadmium,94 cobalt,95 copper,96 indium,97 iron,98 lanthanum,99 magnesium,100 manganese,101 zinc102 and zirconium.103 The obtained carbon-metal bond is polarized towards carbon, allowing for nucleophilic trapping with electrophiles, figure 15. Lewis basic groups also direct catalytic transition metal processes. Directing groups have influenced catalytic C–C coupling at the ortho position,20,104 ligand directed oxidations105 and even arylation at the meta position.106 An increase in Lewis acidity of a metal or basicity of the directing groups typically enhances performance. 17 (a) [M]R [M] = Li, Na, K [M' ]Rn DMG [M' ] [M][M' ]RRn O (b) Me Me N Li Me Me Me Me N Me Me Me THF Li O N N(i-Pr)2 Me Me Me Me THF Li THF DMG E DMG [M' ] = Al, Mg, Zn, etc. Zn(t-Bu)2 E+ Zn t-Bu — t-BuH Me Me Me Me Zn t-Bu (i-Pr)2N THF Li O N Me Me Zn t-Bu (i-Pr)2N O I2 N(i-Pr)2 I 95% yield Figure 15. (a) General outline for synergistic metallation (b) Zincation of a benzamide using a synergistic metallation approach: Kondo, Y.; Shilai, M.; Uchiyama, M.; Sakamoto, T. J. Am. Chem. Soc. 1999, 121, 3539-2540 In contrast to the aforementioned methodologies, the iridium C–H borylation chemistry with bidentate ligands does not undergo ortho-directed functionalization with esters, amides, ethers and other moieties that are frequently used in DoM or directed transition metal catalysis. Although a handful of reports have emerged challenging steric control,86-89 steric control is still praised as a hallmark of iridium C–H borylation.48 Described herein is the discovery and investigation of a chelate directing effect under standard iridium catalyzed aromatic C–H borylation. Although iridium borylation typically minimizes steric interactions, distinct patterns of borylation due to electronic effects have been observed for indole and 18 benzofuran.86 The oxygen in benzofuran has a clear impact in determining the regiochemistry of borylation as 6- and 7-borylation are most prominent, figure 16. O BPin O Ir C–H BPin Borylation (3% 3-BPin-benzofuran) PinB BPin O BPin 65 : 17 (18% divided between 4 other diborylated isomers) Figure 16. Directed borylation of 2-BPin-benzofuran An enhanced directing effect was found for 1,3-benzodioxole, which provides selectivity of >20 : 1 for the ortho-position, figure 16. Computational and experimental studies rationalized this as an affinity for the more acidic proton. Oxygen’s induced acidifying effect on the ortho hydrogen is masked by sterics in the case of 1,2dimethoxybenzene, but surfaces for 1,3-benzodioxole.62 This is presumably also the case for the selectivities observed in benzofuran, figure 16. The 5-chloro (1c) and 5-bromo (1d) substituted 1,3-benzodioxoles afforded selective borylation ortho to the heterocycle, but away from the substituent, figure 17. Unexpectedly, N-(t-Boc)-5-amino-1,3-benzodioxole (1e) provided 3 isomeric monoborylated products. 19 O O 1 mol% [Ir(OMe)COD]2 2 mol% Ligand O 1 equiv. HBPin C6H12 (RT, 41 h) O O BPin 1a 5 equiv. O PinB 1b Ligand = dtbpy, 47% yield (95 : 5) Ligand = BOX, 39% yield (99 : 1) Cl O O 1 mol% [Ir(OMe)COD]2 2 mol% dtbpy Cl 1.2 equiv. HBPin C6H12(RT, 48 h) O O BPin 1c 91% yield Br O O 1 mol% [Ir(OMe)COD]2 2 mol% dtbpy 1.5 equiv. HBPin C6H12 (50 °C, 13 h) Br O O BPin 1d 88% yield H N O O t-BuO O 1e 1 mol% [Ir(OMe)COD]2 2 mol% dtbpy 1.2 equiv. HBPin C6H12 (RT, 48 h) 3 mono-BPin products Figure 17. Directed borylation of the 1,3-benzodioxole framework So far, the borylation chemistry has been applied to only a limited number of Nsubstituted anilines. Anilines have not been widely explored as substrates for iridium C–H borylation. N-Acetyl,67 N,N-dimethyl67,74 and N,N-di-(t-Boc)83 anilines reflect functionalization at the sterically most accessible site, figure 18. After having two years of research invested into the project, a report appeared commenting on the borylation of an N-(t-Boc) aniline substrate in a footnote: “For reasons currently unappreciated, N-tertbutoxycarbonyl 3-methoxyaniline led to mixtures of unidentified products.”107 20 O Me Me NH N Me BPin CN Me BPin Cl N Me t-Boc N t-Boc PinB BPin F3C BPin CN Figure 18. Select literature examples for the borylation of substituted anilines Borylation of mono-t-Boc protected substrates had been examined previously for N-heterocycles. N-(t-Boc)-indole and N-(t-Boc)-pyrrole borylate at the 3-position, as opposed to unprotected indole and pyrrole which borylate at the 2-position.108 As this in conjunction with an N,N-di-t-Boc protected aniline demonstrates definitive steric control of the t-Boc group, two cases were examined. The mono-t-Boc protection of 3-chloroaniline occurs readily in the presence of tBoc2O. A catalytic amount of base was used to prepare the di-(t-Boc) protected compound. N,N-di-(t-Boc)-3-chloroaniline (2a) underwent smooth borylation at the most accessible site, via steric direction of the chloride and N(t-Boc)2, figure 19. The product (2b) was isolated in 91% yield as a colorless crystalline solid. In contrast, the borylation of a N-(t-Boc)-3-chloroaniline (2c) provided two different regioisomeric products in a 68 to 32 ratio, figure 19. The predicted all meta aryl boronate (2e) was found to be the minor isomer to an ortho borylated product (2d), figure 20. These two compounds were separated by column chromatography and the regiochemistry determined by 1H Jcoupling constants and nOe experiments (see experimental methods for details). 21 t-Boc N t-Boc 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 0.6 equiv. B2Pin2 MTBE (50 °C, 36 h) Cl 2a t-Boc NH 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy t-Boc 2c N t-Boc BPin Cl 2b 91% yield t-Boc NH NH BPin 0.2 equiv. HBPin 1 equiv. B2Pin2 MTBE (50 °C, 20 h) Cl t-Boc Cl Cl 2d 50% yield 98% and >98% NMR yield BPin 2e 25% yield 68 : 32 * Figure 19. Borylation of N,N-di-(t-Boc) and N-(t-Boc) protected 3-chloroaniline; *hexamethylbenzene as an internal standard on an average of two runs t-Boc t-Boc NH NH BPin Cl BPin Cl 2d 2e 2d 2d 2d 2e 2d 2e 2e Figure 20. Crude 500 MHz 1H NMR of the borylation of N-(t-Boc)-3-chloroaniline The NH(t-Boc) group managed to direct the C–H activation event and subsequent borylation ortho to itself. The catalyst avoids coming in proximity with the chloride and borylates at the more available ortho-position. This result stands in stark opposition to the view that the iridium borylation chemistry is a sterically defined methodology, in which 22 the catalyst avoids appendages of size. Detailed herein is an account of the scope, mechanism and utility of the observed directing effect. Scope of the NH(t-Boc) Directing Effect Submitting N-(t-Boc)-3-chloroaniline (2c) to iridium catalyzed borylation afforded an unexpected ortho-borylated major product. The strength of the directing effect was examined with the parent N-(t-Boc)-aniline (3a). Comparing the crude 1H NMR spectrum of the borylation with the chemical shifts of the known isomers allowed the assignment of an 8.7 : 2.0 : 1.0 (o : m : p) product distribution, figure 21. t-Boc NH 1 mol% [Ir(OMe)COD]2 2 mol% dtbpy 0.2 equiv. HBPin 0.5 equiv. B2Pin2 C6H12 (RT, 24 h) 3a t-Boc t-Boc NH t-Boc NH NH BPin BPin BPin 3b 8.7 3d : 2.0 : 1.0 Figure 21. Extent of ortho-borylation on unsubstituted N-(t-Boc)-aniline The isomer mixtures in the case of N-(t-Boc)-aniline (3a) and N-(t-Boc)-3chloroaniline (2c) compromise the synthetic utility of this new directing effect. Attention was therefore turned to para-substituted N-(t-Boc)-anilines to provide regiocontrolled borylation ortho to the NH(t-Boc) group, table 1. All substrates were prepared by reacting the free aniline with t-Boc2O. The N-(t-Boc)-anilines were then reacted with a pregenerated (dtbpy)Ir(BPin)3(COE)59 catalyst system. NMR and single crystal X-ray diffraction experiments were used to determine the regiochemistry of the isolated products. 23 Table 1. ortho-Borylation of N-(t-Boc)-anilines t-Boc R1 Entry NH R2 t-Boc NH BPin 5 t-Boc t-Boc 6 NH t-Boc 24 : 76 4i 30 h 68% e t-Boc NH Me BPin F 4q 36 h h 40% 10 t-Boc NH NH 9 BPin Me : 91 F O 7 t-Boc NH BPin BPin O N Me Me 4t c 16 h h,i 44% 4k 24 h 70% f 4c 18 h 79% NH CN BPin Cl t-Boc NH BPin Cl BPin 3 9 F Cl 4a 12 h b 78% t-Boc Product (time, yield a) t-Boc NH BPin F R2 Entry PinB OH 2 R1 Product (time, yield a) HN NH BPin 0.2 equiv. HBPin, B2Pin2 MTBE (50 °C) Product Entry (time, yield a) 1 t-Boc 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 11 t-Boc NH BPin Cl Br OMe 4e c 22 h 89% 4 t-Boc 4m c 24 h 95% 8 NH t-Boc 4g c 1 h d 68% O N Me NH BPin F3C O Me BPin CF3 Cl 4w 28 h 62% OMe 4o 24 h g 83% a Yields refer to isolated material for single run b 1.1 equiv. HBPin added to substrate prior to catalyst exposure c See Appendix A for crystal data d Cyclohexane, 120 °C e Yield is representative of major isomer f Isolated as an 8:92 mixture g RT h 3 equiv. substrate; Yield based on boron i THF, 80 °C. 24 Several compounds in table 1 warrant further discussion. Entry 1 shows that phenols are viable substrates after an in situ protection as a borate ester by excess pinacolborane. In addition, halogen tolerance, a hallmark of iridium catalyzed C–H borylation, provides boronates that possess alternative synthetic handles for further manipulations. The small size of fluorine does not allow for full discrimination between the two ortho-positions, entry 5. The major product however is complementary to the site of lithiation.109 Although the borylation ortho to fluorine is facile, the NH(t-Boc) directing effect overrides this tendency when placed in competition, entry 6. A complete reversal in regiochemistry is observed when comparing the borylation of N-acetyl-4aminobenzonitrile, figure 18 to N-(t-Boc)-4-aminobenzonitrile of table 1, entry 9. The two N,N-dimethyl-O-aryl carbamates examined do not direct borylation, entries 10, 11. The site of borylation for N-(t-Boc) protected 3,4-disubstituted anilines is at the most available ortho site, entries 7, 8, 11. Not all compounds reacted as expected using dtbpy as a ligand. The compounds that provided no reaction are included in table 2, entries 1-3. The inertness of the two 3,5disubstituted substrates is most likely due to steric encumbrance of the aromatic protons. The ortho-methyl group of table 2 entry 2 may inhibit the conformation required for a successful directing effect. Attempts at inducing reactivity through changes in temperature, ligand and solvent were unsuccessful. Other compounds did not hold constitution during the reaction and gave complex NMR and TLC analyses. Although some of these compounds may have borylated, no products were isolated for table 2, entries 4-11. Entry 4 required the use of THF as a solvent to ensure solubility and produced insoluble and unidentified material. Entry 5 25 showed low conversion to multiple products that did not elute from silica gel. Entries 6 and 7 provided more peaks in the 19F NMR than could be accounted for with mono and diborylation. The pyridine substrates of entries 8-10 did not lead to identifiable products and isolation was unsuccessful. The furan of entry 11 lead to what appears to be diborylation in combination with other products. Table 2. Unsuccessful Ir C–H borylations Entry Substrates inert to Ir C–H borylation 1 t-Boc Entry 4 Substrates that did not provide isolable products t-Boc NH Me t-Boc Me 5 NH NH N 9 5b t-Boc NH 5e Me 6 N t-Boc NH N Me 10 NH t-Boc NH F 5c Cl t-Boc NH O t-Boc NH Me t-Boc Substrates that did not provide isolable products 5d Me Me 3 8 NH 5a 2 Entry 5f Cl OH 7 t-Boc OMe NH 11 F 5g O 5h N t-Boc NH O OMe All substrates were examined with (dtbpy)Ir(BPin)3(COE) in MTBE at 50 °C before being subjected to other conditions 26 5j An important boron functionality that has found wide application is the potassium trifluoroborate salt (–BF3K).110 Conversion of pinacol boronic esters to this boronate derivative is readily accomplished with KHF2 and has been used in conjunction with iridium C–H borylation.75 The conversion of N-(t-Boc)-4-cyano-2-BPin-aniline to a BF3K salt allowed for an improved isolation when compared to the pinacol boronic ester, figure 22. The intermediate pinacol boronic ester was isolated as the minor component of a mixture with starting benzonitrile and the mixture subjected to KHF2. The increased yield is likely due to simple washing of the product salt versus column chromatography of the pinacol boronic ester. Overexposure to KHF2 lead to t-Boc deprotection. t-Boc 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy NH t-Boc BPin 0.2 equiv. HBPin 0.4 equiv. B2Pin2 MTBE (50 °C, 36 h) CN CN 4p 3 equiv. t-Boc NH 4q t-Boc NH BPin CN NH 3.4 equiv. KHF2 THF, H2O (RT, 10 min) BF3K CN 4r 51% yield 4q Figure 22. Derivatization of N-(t-Boc)-ortho-BPin-aniline Comparisons of Lithiation and NH(t-Boc) Borylation The NH(t-Boc) group is a known DMG.111 This group upon the addition of two equivalents of organolithium induces ortho-lithiation. A strong base such as t-BuLi is 27 typically required, however, the use of sec-BuLi or n-BuLi may suffice on electronically favorable substrates. The location of lithiation is dependent on the other substituents. The NH(t-Boc) group has a higher affinity for metallation than DMG’s like halogens, OMe112 and OMOM113 and is therefore categorized as a strong director alongside O-aryl carbamates and benzamides.15 Asymmetric substrates bearing two ortho-hydrogens will undergo metallation with the most acidic proton. This relative difference in acidity is determined by the meta-substituent, figure 23.114 Notable exceptions however involve electron withdrawing meta-substituents of considerable size, which thereby sterically block access to the proton, figure 23.115 t-Boc NH 1. t-BuLi 2. I2 MeO t-Boc NH I MeO 55% yield t-Boc F3C NH t-Boc 1. t-BuLi 2. CBr4 NH Br F3C 77% yield Figure 23. DoM of N-(t-Boc)-anilines Marder and Snieckus have begun to evaluate the complementarity between iridium borylation and DoM.107 This study used OMe, OMOM, SO2NEt2, benzamides and O-arylcarbamate DMG’s. The site of functionalization between NH(t-Boc) directed iridium borylation and the DoM methodology show similarity and complementarity. Substrates of table 1, entries 2, 4 are known to lithiate at the same site that the iridium chemistry affords 28 borylation.116 The starting material of entries 1, 8, 9 can be predicted, based on the DMG hierarchy, to lithiate at the same position as borylation. The lithiation of trifluoromethyl substituted aromatics displays fickle behavior.117 The selection of base is extremely important and can dramatically affect the site of metallation. The lithiation of N-(t-Boc)trifluoromethylanilines has not been extensively surveyed. Preliminary results show avoidance of the CF3 group, figure 23.115 The borylation of N-(t-Boc)-3-trifluoromethyl4-methoxyaniline (4n) can thereby be predicted to be identical to the borylation. The screening of bases may allow metallation to shift to alternative sites. Other aromatics provide complementary results between iridium borylation and lithiation. Aryl bromides will preferably undergo lithium-halogen exchange rather than DoM with the NH(t-Boc) group when exposed to an alkyl lithium.118 The iridium borylation chemistry however, tolerates aryl bromides and selectively functionalizes the ortho-C–H bond (4e). The borylation of N-(t-Boc)-4-chloro-3-fluoroaniline (4h) affords a major product that is complementary to that formed via lithiation. The lithiation of N-(tBoc)-4-chloro-3-fluoroaniline (4h) between the NH(t-Boc) and fluorine has been used in process chemistry to prepare an intermediate for an HIV-1 NNRTI candidate.109 Since O -aryl carbamates are stronger directors than their N-aryl carbamate counterpart, lithiation would be expected ortho to the oxygen on a substrate bearing both carbamates. The borylation chemistry however affords exclusive functionalization ortho to the NH(tBoc), entries 10, 11. DoM typically goes ortho to halogens, whereas halogens for iridium borylations act as steric obstacles, entry 11. One substrate was chosen to further assess this divergent reactivity. 29 N-(t-Boc)-3-chloro-4-methoxyaniline (4l) reacted with only one equivalent of nBuLi with and without TMEDA. The use of a stronger base was required to deprotonate the aromatic proton. Interestingly, the starting material was not obtained after quenching with water. Instead, the intermediate aryl lithium underwent LiCl expulsion to form an aryne that cyclized with the appending carbamate, figure 24. Hydrolysis afforded 6methoxybenzoxazolinone (6a). 6-Methoxybenzoxazolinone (6a) has been isolated from wheat, rye, maize and other sources. It has been linked to a number of biological activities such as insect resistance, antidiabetic potential and reproductive activity.119-122 The product is most commonly obtained in small amounts from natural sources or synthesis. The most common approach uses a CO unit like phosgene, bis(trichloromethyl)carbonate, urea and others, together with the unisolable 2-amino-5-methoxyphenol, obtained from 3methoxyphenol after nitration and reduction.123,124 Without optimization of the t-Boc protection or lithiation step, 6-methoxybenzoxazolinone (6a) was prepared in 46% yield over two steps from commercial materials. This marks the shortest synthesis of 6methoxybenzoxazolinone (6a) from commercial materials. 30 t-Boc NH2 Cl OMe 1.2 equiv. t-Boc2O EtOAc (RT, overnight, N2) NH Cl OMe 4l 86% yield t-Boc NH 2.3 equiv. sec-BuLi 2.3 equiv. TMEDA THF (–78 °C, 45 min) Cl OMe t-Boc N Ot-Bu Li O N Li Li – LiCl Cl OMe t-BuO O N Li OMe OMe 4l t-BuO O t-BuO N H2O O O N (–78 °C) Li OMe HCl / H2O O NH CH2Cl2 (RT, 31 h) OMe OMe 6a 53% yield Figure 24. Preparation of 6-methoxybenzoxazolinone (6a) via an aryne intermediate Lithiation ortho to halogens is a previously described method of preparing arynes. These have been reported to cyclize into benzoxazolinones using carbamates and benzoxazoles using amides, however, not for the preparation of 6methoxybenzoxazolinone (6a).125,126 Worth mentioning is that very careful temperature control has been successful in minimizing aryne formation.109,127 Mechanism of NH(t-Boc) Directed Borylation The mechanism of NH(t-Boc) directed borylation is proposed to involve hydrogen bonding of the N–H. This conjecture is supported by varying the NH(t-Boc) components, screening ligands and surveying solvents. 31 The hydrogen bond has been one of the most pervasive and flexible bonding modes. Its strength falls in the range of <1 to >50 kcal mol-1.128 This bonding has been employed to explain stark changes in physical properties, the stabilization of biological macromolecules and chemical reactivity. Hydrogen bonding in synthetic chemistry has been applied in organocatalysis, supramolecular assembly, transition metal catalysis and organometallics. The use of hydrogen bonding in catalysis is probably most well known in organocatalysis. Organocatalysts such as the ureas, amino acids and alcohols influence reactivity through hydrogen bond donation.129 Transition metal hydrogen bonding is also known. For example, hydrogen transfer complexes, such as Shvo’s catalyst react along hydrogen bonding pathways.130 The NH(t-Boc) directing effect could conceivably function by one of three proposed mechanisms, figure 25. The first involves N–H activation: an inner-sphere mechanism similar to the silane directed borylation described by Hartwig.89 The second involves carbonyl coordination to the boron center. The third is a hydrogen bonding interaction between the NH(t-Boc) group and the iridium catalyst. t-Bu t-Bu BPin N PinB H t-Bu N Ir N t-Boc (1) BPin N t-Bu N O Me PinB B Me O O Me Me N H Ot-Bu Ir H (2) t-Bu BPin t-Bu N N Ir B O Me Me H O H Me N Me t-BuO O PinB (3) Figure 25. Plausible transition states for the NH(t-Boc) directed borylation of anilines Proposed mechanism (1) can be eliminated by examining the borylation of Ndeuterio-N-(t-Boc)-3-chloroaniline (8a), table 4. This reaction forms the N-deuterio 32 borylated products. Neither DBPin nor scrambling of the carbamate was found. If this mechanism were operable, DBPin would be formed and the activated aromatic hydrogen would be incorporated into the carbamate. Analogous interactions to those in mechanisms (2) and (3) are found in the solid state, figure 26.131,132 The amide functionality can, depending on its electronics, form a Lewis acid-base adduct between carbonyl and boron or be involved in hydrogen bonding. Predicting the intramolecular interaction between the NH(t-Boc) group and an orthoBPin is however precarious, as the ethereal oxygen of the t-Boc may act as #–donating into the carbonyl or $-withdrawing from the N–H. These actions would predict a carbonyl coordination and hydrogen bonding interaction respectively. Authentic compounds were therefore prepared and examined in the solid state. N(1) F(3) B(1) O(2) F(1) O(1) O(3) F(2) O(3) O(1) (a) N(1) B(1) O(2) (b) Figure 26. (a) Kennedy, J. W. J.; Hall, D. G. J. Organomet. Chem. 2003, 680, 263-270 (b) Hudnall, T. W.; Bondi, J. F.; Gabbaï, F. P. Main Group Chem. 2006, 5, 319-327 33 O(1) O(3) O(2) O(3) O(2) N(1) N(1) B(1) O(1) B(1) O(4) 7a 3b Figure 27. Protected ortho-BPin anilines. Hydrogen atoms have been omitted for clarity. Thermal ellipsoids are shown at 50% probability. Select bond lengths and angles are found in Appendix A. For interpretation of the references to color in this and all other figures, the reader is referred to the electronic version of this thesis. Evidence for mechanism (3) is found in the solid state structure of N-(t-Boc)ortho-BPin-aniline (3b). A hydrogen bonding interaction, rather than a carbonyl coordination to the boron center is observed, figure 27. Solution state IR spectroscopy confirmed the presence of hydrogen bonding. The N–H stretch is 36-66 cm-1 lower for N-(t-Boc)-ortho-BPin-aniline (3b) when compared to N-(t-Boc)-para-BPin-aniline, table 3. This trend was observed in all examined solvents, but not as a thin film. This is most likely due to the presence of intermolecular hydrogen bonding networks. The analogous amide (7a) forms, as would be expected from increased carbonyl basicity, a Lewis acidbase adduct with the boron atom. Both the hydrogen bonding coordination and carbonyl to boron coordination are not artifacts of crystal packing forces as is revealed by their respective 11B NMR shifts. The compound 3b shows a resonance at % 30.4 ppm, while 7a shows a resonance at % 34 25.7 ppm. The upfield shift of 7a is attributed to the tetravalency of boron, while a resonance at % ~30 ppm is considered normal for aryl-BPin compounds. Table 3. IR data confirming the presence of an intramolecular hydrogen bonding interaction in 3b t-Boc t-Boc NH NH BPin 3b BPin IR Method N–H Stretch (cm-1) C=O Stretch (cm-1) N–H Stretch (cm-1) C=O Stretch (cm-1) thin film C6H6 (100 mM) C6H6 (10 mM) C6H6 (0.5 mM) pentane (10 mM) CH2Cl2 (10 mM) acetone (10 mM) 3373 3375 3375 3376 3385 3368 3370 1732 1736 1732 1733 1741 1725 – 3331 3411 3412 3416 3451 3427 3413 1732 1736 1736 1735 1746 1729 – 35 Table 4. Effect of substitutions on ortho-borylation t-Boc N X t-Boc 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy X = H 2c a 1 equiv. B2Pin2 1 equiv. B2Pin2 X = D 8a t-Boc Cl 20 h 17 h 98% NMR Yield >98% NMR Yield b 0.2 equiv. HBPin B2Pin2, MTBE (50 °C) Cl N BPin 68 : 32 68 : 32 b Y Cl BPin B2Pin2 (equiv.) Y X Cl 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy Y Entry X BPin 0.2 equiv. HBPin B2Pin2, MTBE (50 °C) Cl N Time Yield c Product 1 17 h 95% 8c O 1 N Me 8b O 8d 0.6 24 h 88% 8e O t-BuO 8f 1 24 h 50% d 8g NH 8h 2.5 48 h 52% e 8i O 2 t-BuO O 3 t-BuHN O 4 t-BuH2C a Data from figure 19 b Average of two runs c Yields refers to isolated material for single run d Only other observed product was 3-chlorophenol e Only other observed product was reduction to the secondary amine A number of derivatives were prepared and examined in order to discern mechanisms (2) from (3), table 4. The methylated N-(t-Boc) aniline substrate (8b) in entry 1 affords no ortho selectivity as expected if hydrogen bonding were involved. However, this does not distinguish between (2) and (3) because methyl substitution will perturb the carbamate geometry, potentially inhibiting a pathway via coordination to the 36 boron. The carbonate of entry 2 (8d) does not direct borylation. This would be obvious if hydrogen bonding were involved, however it does not rule out coordination since the basicity of the carbonyl has also been diminished. For entry 3 (8f), the NH and O groups are transposed relative to the NH(t-Boc) group. Again, all ortho selectivity is lost. Moving the NH would increase the ring size of the cyclic transition state for a hydrogen bonding mechanism by two atoms altering the activation energy relative to (3) and compromise selectivity. In contrast, it is hard to rationalize the loss of ortho selectivity in entry 3 (8f) when invoking mechanism (2) because this transposition increases carbonyl basicity,133 thereby strengthening a coordinating interaction. The amide substrate in entry 4 (8h) examines the effect of replacing the O with CH2. Again, all ortho selectivity is lost. Since amidic carbonyls are more basic than carbamic carbonyls,133 an enhanced O to B coordination would stimulate the directing effect. Proposed mechanism (2) cannot be responsible for the selectivity perturbations observed in table 4 when compared to the NH(t-Boc) group. Although the amide substrate in entry 4 (8h) could potentially participate in a hydrogen bonding mechanism, the acidity of the amide N–H bond is lower than that of the carbamate.134 The urea derivative (8j) was prepared, but suffered from low conversions and unidentified products. Based on the opposing electronic requirements between the hydrogen bonding and carbonyl coordination mechanisms, mechanisms (2) and (3) were conclusively discerned through ligand variation. The availability of 4,4’-disubstituted-2,2’-bipyridines either commercially or by synthesis allowed for a comprehensive analysis of the electronic requirements, table 5. Most ligands provided high conversions. 4,4’- 37 Bis(cyano)-2,2’-bipyridine was prepared,135 but was not included in the table because it provided trace conversion and unreliable selectivity values. The pKa of 4-cyanopyridinium is 1.86. Table 5. Catalyst electronic parameters for the NH(t-Boc) directed borylation R1 t-Boc NH R1 t-Boc 4 mol% N N 2c NH BPin 2 mol% [Ir(OMe)COD]2 0.2 equiv. HBPin 1 equiv. B2Pin2 MTBE (50 °C, 20 h) Cl t-Boc NH Cl Cl 2d BPin 2e Entry R1 NMR Yield a 2d : 2e a pKa b 1 NMe2 97% 76 : 24 9.71 2 OMe >98% 62 : 38 6.62 3 t-Bu 98% 68 : 32 5.99 4 Ph 94% 62 : 38 5.55 5 H 98% 61 : 39 5.22 6 Br 31% 45 : 55 3.75 7 CO2Me 68% 48 : 52 3.26 8 CF3 52% 38 : 62 2.63 a Determined from 500 MHz 1H NMR with hexamethylbenzene as an internal standard on an average of two runs b pKa of the corresponding 4R1-pyridinium (a) Schofield, K. "Hetero-Aromatic Nitrogen Compounds", Plenum Press, New York, 1967 p 146 (b) Taagepera, M.; Henderson, W. G.; Brownlee, R. T. C.; Beauchamp, J. L.; Holtz, D.; Taft, R. W. J. Am. Chem. Soc. 1972, 94, 1369-1370 The selectivity between ortho and m e t a-borylation was correlated to the electronics of the iridium catalyst by taking into account the basicity of the ligand, figure 38 28. A clear relationship between ligand donation and ortho-selectivity exists with a strong R2 = 0.94. 4 3.5 ortho / meta ortho / meta NMe2 R2 2 0.94 = 3 R = 0.94 2.5 t-Bu 2 Ph 1.5 CO2Me 1 OMe H Br 0.5 CF3 0 2 4 6 8 10 pKa of pKa of 4-R1-pyridinium 1 -pyridinium Figure 28. Correlation of ortho-borylation selectivity with the pKa of the corresponding pyridinium Figure 28 shows a positive correlation between the electron richness of a ligand and ortho-borylation. This means that the more electron rich catalyst interacts more strongly with the NH(t-Boc) directing group. The exact opposite trend would be expected if a carbonyl coordination mechanism were involved for ortho-borylation. In that case, the carbonyl would be attracted to a more Lewis acidic catalyst. The clear trend in figure 28 directly opposes such a mechanism. It is apparent that a Lewis basic site on the catalyst interacts with a Lewis acidic site on the NH(t-Boc) group to induce ortho borylation. The only such site is the N–H. A third piece of evidence for a hydrogen bonding mechanism is realized from a solvent screening, table 6. If a hydrogen bonding mechanism is responsible for orthoborylation, then a coordinating solvent should disrupt the opportunity of N–H to catalyst 39 interaction. Experimentally, THF was found to afford less ortho-borylation while cyclohexane enhanced ortho-borylation relative to MTBE. This corresponds well with cyclohexanes inability to hydrogen bond strongly and THF, as a mildly basic solvent to competitively coordinate the N–H. Table 6. Solvent influence on selectivity t-Boc N t-Boc 2 mol% [Ir(OMe)COD]2 4 mol% Ligand t-Boc 2c t-Boc t-Boc N t-Boc BPin 0.2 equiv. HBPin 1 equiv. B2Pin2 solvent (50 °C) Cl N Cl Cl 2d BPin 2e Solvent Time NMR Yield a 2d : 2e a 1 THF 15 h 97% 49 : 51 2 MTBE 20 h 98% 68 : 32 3 cyclohexane 15 h 95% 77 : 23 Entry a Determined from 500 or 600 MHz 1H NMR on an average of two runs The kinetics of the reaction were probed to gain more mechanistic insight. N-(tBoc)-2-deuterio-5-chloroaniline (9a) was prepared by deuteriodeborylation and reborylated, figure 29. A kH / kD of 4.1 ± 0.1 is large enough to indicate C–H activation as the rate-limiting step and therefore also the selectivity determining step. Based on these results, there is no rate-limiting hydrogen bonding precoordination. KIE’s for benzene,59 1,2-dichlorobenzene59 and indole136 have been measured as 5.0 ± 0.4, 2.0 ± 0.4 and 2.03 ± 0.5 respectively, using dtbpy as ligand. 40 t-Boc BPin Cl 2d t-Boc 1. CD3OD / CH2Cl2 (1 : 1) (RT, 12 h) 2. Evaporate solvent under N2 flow t-Boc 3. 5 mol% [Ir(OMe)COD]2 (55 °C, 3 h) + 10 mol% [Ir(OMe)COD]2 (55 °C, 5 h) CD3OD / CH2Cl2 (2 : 1) NH Cl 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy NH D t-Boc 9a kH kD D 9a 45% yield, 94% D t-Boc NH NH BPin 0.4 equiv. HBPin 1 equiv. B2Pin2 MTBE (50 °C, 20 h) Cl NH Cl D Cl BPin 38 : 62 a %ortho(HH) / %meta(HH) = 68 / 32 = %ortho(DH) / %meta(DH) = 4.1 ± 0.1 b 38 / 62 Figure 29. C–D isotope effect for the NH(t-Boc) directed ortho-borylation; a average of two runs with 83% and 90% NMR yield b see experimental methods for details As has been shown through analyzing derivatives of the NH(t-Boc), a screening of the electronic parameters of the catalyst and solvent effects, the ortho directing effect of the NH(t-Boc) is explained by a hydrogen bonding interaction. This is not the first example of hydrogen bonding interactions influencing a drastic change in the selectivity of a reaction. Four examples have been selected from the literature that exemplify a change in diastereoselectivity, regioselectivity, and reaction rate due to the presence of hydrogen bonding interactions during catalysis. The Wulff aziridination reaction using ethyl diazoacetate provides cis-aziridines with high diastereoselectivity. The use of 2° diazoacetamides however inverts the distereoselectivity to trans-aziridines.137 The calculated transition state of the phenyl diazoacetamide addition to the imine reveals a hydrogen bonding interaction of the amide with the boroxinate catalyst. Although this reversal in selectivity has not been 41 conclusively attributed to the additional hydrogen bonding, such an interaction is certainly valuable, figure 30.138 O R N Ph Ph Ph R1 N2 OPh O B B O O O B H OPh R N O N R N O Ph cis R R1 R trans 1 Major when R1 = OEt Ph O Ph Major when R1 = NHPh Figure 30. Hydrogen bonding in Wulff aziridination The addition of nucleophiles to palladium-allyl complexes typically occurs at the less substituted carbon to afford linear products. Hydrogen bonding between a moiety on the allyl and nucleophile can however direct the addition proximal, figure 31.139 O Ph Ph N [(allyl)PdCl]2 (R)-tol-BINAP Me O OCO2Me Ph Ph [(allyl)PdCl]2 (R)-tol-BINAP O N O H Ph Ph N Me NPhth NH O O O O only regioisomer O Ph Ph NPhth NH O NH 95% regioselective O O Ph Ph N H N O [Pd] Figure 31. Hydrogen bonding in allylic substitution reactions A t-butyl alkynyl wielding ruthenium porphyrin provides little regioselective discrimination in olefin epoxidation, figure 32. However, incorporating a chiral amide onto the ruthenium porphyrin complex allows for regio- and enantioselective epoxidation via hydrogen bonding coordination.140 42 Ph O H NH cat. [Ru] O O NH O NH C6H6 (25 °C) t-Bu-alkynyl [Ru] catalyst chiral [Ru] catalyst N N O Mes Ru Mes O N N H O 62 91 : : ON H H N O H 38 9 Figure 32. Hydrogen bonding in epoxidation reaction The higher reactivity of allylic alcohols towards olefin metathesis has been broadly documented.141 By taking advantage of a proposed hydrogen bonding interaction, Hoveyda and coworkers were able to influence the diastereoselective ring opening, cross metathesis of cyclopropenes.142 In addition, the hydrogen bonding stabilization has a dramatic effect on the reaction rate, figure 33. Ph Me Ph Ph R cat. [Ru] toluene (22 °C) Ph Me R = Me 18 h 56% conversion R = OMe 18 h 51% conversion R = OH 5 min >98% conversion R Ph Me Ph 9 : 91 21 : 79 96 : 4 R MesN NMes H H Cl Ru Cl O Ph H Me Ph Figure 33. Hydrogen bonding in ring opening cross metathesis Broadening the Hydrogen Bonding Directed Borylation Incomplete selectivity for the NH(t-Boc) hydrogen bonding directed borylation stresses the importance of optimization. Attempts at enhancing a hydrogen bonding 43 directing effect included microwave conditions, examining ligands and searching for an NH(t-Boc) surrogate with a more powerful hydrogen bonding ability. The borylation reaction has been shown to proceed significantly faster in a microwave reactor with MTBE as a solvent.143 Microwave was therefore a possibility for improving reaction time along with potentially an influence on selectivity. N-(t-Boc)3-chloroaniline (2c) was borylated at 80 °C in MTBE under microwave irradiation. The conversion did not improve dramatically and selectivity was unchanged. The reaction required an excess of 3 hours to achieve high conversion. Other N-(t-Boc)-aniline substrates were not examined. A sample of bidentate ligands was evaluated for promoting the hydrogen bonding directing effect, table 7. Since 1,10-phenanthroline is a more basic ligand than 2,2’bipyridine (pKa of conjugate acid = 4.95 and 4.41144 or 5.16 and 3.62,145 respectively), the phenanthroline ligand would be expected to afford more ortho-borylation. However, this is not the case for 1,10-phenanthroline and 2,2’-bipyridine give 56 : 44 (2d : 2e), table 7 and 61 : 39 (2d : 2e), table 5 respectively. Although the bite angles of these ligands are similar when uncoordinated,146 this may change during coordination or between ground and transition states. The bipyridines are more flexible than the phenanthrolines, allowing the bipyridines to support possible secondary stabilizations for ortho-directed borylations. The more electron rich 3,4,7,8-tetramethyl-1,10phenanthroline increased the selectivity for ortho-borylation as expected when compared to the unsubstituted and less electron rich parent 1,10-phenanthroline. While the selectivity was slightly improved, a change in bite angle of the ligand has a disastrous effect on conversion, table 7, entry 3. A small screen of BOX ligands 44 showed a trend for more ortho-selectivity with a bulky ligand. This is clearly an electronic effect as previous results indicate bulky BOX ligands to enhance steric discrimination.147 Table 7. N,N-Ligand screening for ortho-directed borylation t-Boc 2 mol% [Ir(OMe)COD]2 4 mol% Ligand NH t-Boc 2c Entry 2 R1 N N O O N 2d : 2e a R1 = H 84% 56 : 44 Me 96% 66 : 34 12% 71 : 29 R2 = H 29% 58 : 42 Bn 30% 68 : 32 N R2 N 5 2e NMR Yield a R1 N BPin Cl 2d R1 R1 3 4 Cl Ligand 1 NH BPin 0.2 equiv. HBPin 1 equiv. B2Pin2 MTBE (50 °C, 20 h) Cl t-Boc NH R2 a Determined from 500 MHz 1H NMR with hexamethylbenzene as an internal standard as an average of two runs The reactivity of phosphine based catalyst systems with the NH(t-Boc) was also examined. Since two monophosphine compounds have been used to induce orthoborylation bearing DMG’s, their relationship with NH(t-Boc) was evaluated. Bisphosphinoethane ligands like dppe and dmpe are commercially available while P(ArF)3148 and silica-SMAP (10g)149,150 were prepared according to the literature procedure, figure 34. 45 BnBr 1.5 equiv. P(OEt)3 1.2-2 equiv. LiAlH4 O P OEt Bn OEt (RT ! 140 °C) 10a 93% yield (lit !95% yield) 3.3 equiv. PhSiCl3 10b 85-88% yield (lit 48-68% yield) ex situ HBr, cat. (PhCO2)2 MgBr Si Ph THF (RT, 14 h) BnPH2 1.5 equiv. TMSCl Et2O (–78 ! RT, 4-6 h) Br toluene (RT, 5 days) Br 10c 85-86% yield (lit 81-85% yield) BnPH2 1.1 equiv. BH3•THF 10d 35% yield (lit 86% yield) H3B Bn P 1.8-2 equiv. 10d BnPH2•BH3 THF (2 °C, 5-23 h) 4 equiv. NaH, THF (0 °C ! 2 °C, 20 h) Si Ph Br 10e 44-62% yield (lit 71% yield) 10b 1. 8 equiv. 1-octene DME (100 °C, 5 days) H3B Bn P Si Ph 10e Si Ph Br Br P 8 equiv. TfOH 2. 2 equiv. LiAlH4 THF (RT, 22 h) Si Ph C6H6 (RT, 9 h) 10f 27% yield (lit 51% yield) P H P Si OTf OTf 1. SiO2 C6H6 (80 °C, 15 h) 2. xs TMS-imidazole (60 °C, 11 h) Si SiMe3 O O Si Si O O O O O O SiO2 Silica-SMAP 10g Figure 34. Synthesis of silica-SMAP (10g) 46 H P Si OTf OTf The two bisphosphine ligands were unable to provide the selectivity of the dinitrogen ligands and provided heavy decomposition, figure 35. The use of P(ArF)3 lead to decomposition under literature conditions87 and no reaction under conditions used in table 1. Silica-SMAP (10g) has been shown to promote directed borylation with a number of different directing groups,88 including O-aryl carbamates.151 As no reports have appeared in the literature thus far in conjunction with N-aryl carbamates, the directing power of silica-SMAP (10g) was examined for the NH(t-Boc) group. The borylation of N-(t-Boc)-3-chloroaniline (2c) using silica-SMAP (10g) afforded three products, figure 35. All positions ortho to a substituent were functionalized. In addition to the NH(t-Boc) group directing borylation, the chloride substituent was found to be a competitive directing group as well. Borylation at the mutual meta position, as for the dinitrogen ligands was not observed. The most curious product arises from borylation at the mutual ortho-position (11a). This may be explained by a bis-ortho directing effect. The chloride is proposed to interact with the iridium center, while the NH(t-Boc) forms a hydrogen bonding interaction, figure 36. In the case of the substrate examined, silica-SMAP (10g) is not more selective than the dinitrogen ligands. The NH(t-Boc) group is not a strong enough director to ensure a regiopure product. The bis-ortho directing effect of the NH(t-Boc) and chloride competes with the single-ortho directing effect of the NH(t-Boc). 47 t-Boc NH t-Boc Conditions NH BPin Cl Cl 2c 4 mol% (Ind)Ir(COD) dppe Entry 1 Entry 2 equiv. HBPin C6H12 (100 °C, 14 h, closed) ! Decomposition 2 Desired 4 mol% (Ind)Ir(COD) dmpe 2 mol% [Ir(OMe)COD]2 P(ArF)3 Entry 2 equiv. HBPin 5 C6H12 (130 °C, 14 h, closed) ! Decomposition 6 1.1 equiv. B2Pin2 n-octane (80 °C, 16 h) ! Decomposition 0.75 equiv. B2Pin2 C6H12 (100 °C, 24 h, closed) ! No Reaction 4 7 3 equiv. HBPin (100 °C, 24 h, closed) ! Decomposition 3 0.2 equiv. HBPin 1.0 equiv. B2Pin2 MTBE (50 °C, 20 h) ! No Reaction 0.2 equiv. HBPin 1.0 equiv. B2Pin2 MTBE (80 °C, 20 h, closed) ! No Reaction 1 equiv. B2Pin2 0.2 equiv. HBPin 4 n-octane (100 °C, 20 h) ! Decomposition t-Boc NH 2 mol% [Ir(OMe)COD]2 silica-SMAP (10g) 1.1 equiv. B2Pin2 C6H12 (50 °C, 10 h) Cl t-Boc NH HN BPin t-Boc Cl Cl 2d 68 NH PinB Cl 2c t-Boc BPin 11a : 20 11c : 12 Figure 35. Application of phosphine ligands to the NH(t-Boc) directed borylation 48 PinB H PinB Ir Cl Me O B Me H O P N Ot-Bu Me Me O Si SiMe3 O O Si Si O O O O O O SiO2 HN t-Boc PinB Cl Figure 36. Proposed transition state for the bis-ortho-directed borylation using silica-SMAP-[Ir] An alternative method of optimizing the hydrogen bonding directing effect is to increase the N–H acidity. Sulfonamides are more acidic than carbamates. The borylation of both a methanesulfonamide (12a) and trifluoromethanesulfonamide (12c) however did not afford any directed borylation, figure 37. Instead, sterically defined borylation occurred. N–BPin bond formation was observed by 1H and 11B NMR during the course of the reactions. The iridium catalyst most likely catalyzes this since a 1 : 1 mixture of starting material and HBPin was found to be stable at 50 °C in CDCl3 for 3 hours with both sulfonamides. This mirrors catalytic N–B bond formation for N arylmethanesulfonamide and HBCat in the presence of Wilkinson’s catalyst.152 49 O O S Me NH Cl 12a O O S F3C NH Cl 12c 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 1 equiv. HBPin 0.75 equiv. B2Pin2 Et2O (RT, 28 h) 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy O O S BPin Me N Cl O O S Me NH BPin Cl BPin 12b 68% yield O O S BPin F3C N 1 equiv. HBPin 0.75 equiv. B2Pin2 Et2O (RT, 18 h) Cl 6h BPin O O S F3C NH Cl BPin 12d 82% yield Figure 37. Borylation of N-arylsulfonamides Attempts were made at expanding the directed borylation with different carbamate alkoxy substituents, figure 38. The bulky t-butyl group may interfere with the directing effect. It was therefore reasonable to predict that replacement with a methyl group (13a) will offer higher selectivity. This was however not the case as selectivity was roughly the same as for the NH(t-Boc) group. Replacement of the t-butoxy with a hexafluoroisopropoxy substituent will have a pronounced inductive effect on the N–H acidity. The borylation of this substrate (13d) was unsuccessful, leading to a number of unidentified products along with unreacted starting material. (Hexfluoroisopropoxy)pinacol boronate was observed by 1H and 19F NMR, indicating that the starting material suffered from decomposition under the reaction conditions. Another substrate that was examined wielded an electron deficient phenoxy substituent (13e). This compound did not survive the borylation conditions and decomposed rapidly. 50 O MeO NH 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy MeO 13a F3C O F3C O NH NH MeO Cl 13b 40% yield 55% brsm various catalyst loadings HBPin and B2Pin2 Et2O, MTBE and THF RT to 80 °C Cl 13d NH BPin 1 equiv. HBPin 0.75 equiv. B2Pin2 MTBE (50 °C, 20 h) Cl O O Cl BPin 13c 8% yield 11% brsm 66 : 34 unidentified products Cl 5 mol% [Ir(OMe)COD]2 10 mol% dtbpy O Cl O Cl 13e NH 1 equiv. HBPin 0.75 equiv. B2Pin2 Et2O (RT, 18 h) unidentified products Figure 38. Borylation of N-arylcarbamates Attempts at expanding the NH(t-Boc) directed borylation to better hydrogen bond donor groups has so far been unsuccessful. These findings place the NH(t-Boc) into a unique class of DMG’s that is able to direct iridium catalyzed borylation ortho using commonly found conditions. This ensures that no competitive borylation occurs between directing groups, as is the case for DoM. 51 Further Application of NH(t-Boc)-ortho-BPin-Anilines Anilines are valuable building blocks that have been used extensively for the synthesis of products of interest. The NH(t-Boc) directed borylation is thereby a new means of accessing aniline based intermediates. Transforming anilines to heterocycles has been the focus of extensive investigation. Methods to indoles153 and quinolines154 are among the most vibrant. A recent study evaluated the rhodium catalyzed conjugate addition of ortho-BPin-anilines to unsaturated esters as a method of preparing 2,3-dihydroquinolin-2-ones.155 This structure is found in a number of natural and biologically active compounds. Select examples include the natural product meloscine,156,157 cilostazol,158 the active component of Pletal® and a highly active HIV-1 NNTRI analogue of efavirenz,159 figure 39. O HN O O HN H N meloscine HN O CF3 O HN N N N N Cl N O O CF3 Cl cilostazol: Active efavirenz: FDA Effective HIV-1 NNRTI component of Pletal! approved component of analogue of efavirenz ATRIPLATM Figure 39. Biologically active molecules containing a 3,4tetrahydroquinolin-2-one moiety Fusing the NH(t-Boc) directed borylation with rhodium catalyzed conjugate addition for accessing this important biologically active motive will have a profound impact on the value of NH(t-Boc) directed borylation. While only two aromatic 52 substrates were used as examples in this study, the hydrogen bonding directed borylation allows access to a number of structurally different ortho-borylated anilines. The caveat is that the borylation chemistry accesses only ortho borylated N-(t-Boc)-anilines, while the heterocycle synthesis was evaluated on free anilines. Attempts at removing the t-Boc group via heating at 180 °C, as was successful for the deprotection of N-(t-Boc) heterocycles,108 was unsuccessful for ortho-borylated aniline derivatives. Luckily, acid treatment cleaves the t-Boc group with retention of the boronate to provide compounds available for heterocycle synthesis, figure 40. This works on both ortho and meta substituted anilines. t-Boc NH2 NH BPin TFA / CH2Cl2 (1 : 1) BPin (0 °C ! RT, 0.5 h) CF3 CF3 4g t-Boc 14a 91% yield NH2 NH BPin TFA / CH2Cl2 (1 : 1) (0 °C ! RT, 1h) Cl O O N Me Me 4w t-Boc Cl O Me BPin O N Me 14b 93% yield N Me HN TFA / CH2Cl2 (1 : 1) Me (0 °C ! RT, 1 h) Cl BPin Cl 8c BPin 14c 66% yield Figure 40. Acid induced t-Boc deprotection 53 This t-Boc deprotection step adds an additional isolation towards preparing the dihydroquinolinone. Although going directly from the N-(t-Boc)-aniline to the N-(t-Boc)2,3-dihydroquinolin-2-one would be advantageous, no cyclization was observed under the reaction conditions, figure 41. A four step, two-pot process was thereby developed to streamline the heterocycle synthesis via iridium C–H borylation, rhodium catalyzed conjugate addition, deprotection and cyclization, figure 42. Modifications to the literature procedure include using a 1 : 1 stoichiometric ratio of arene to acrylate. This allows for higher consumption of the more valuable aromatic starting material. t-Boc NH BPin Br 5 mol% [Rh(COD)Cl]2, 2.0 equiv. KOH 0.5 equiv. H2C=CHCO2Me t-Boc 1,4-dioxane / H2O (14 : 1) (100 °C, 8 h) 4e NH CO2Me Br 15a 50% yield Figure 41. Rh-catalyzed conjugate addition on N-(t-Boc) protected aniline substrate At the time these were the first examples of combining iridium borylation and rhodium catalyzed addition to unsaturated esters. Since this study was undertaken two reports of tandem iridium catalyzed borylation and rhodium catalyzed conjugate additions appeared in the literature.79,160 Tandem borylation and rhodium catalyzed 1,2addition to imines was reported in 2008 by Boebel and Hartwig.80 54 t-Boc t-Boc NH NH Ir C–H R1 Borylation a R2 [Rh(COD)Cl]2 methyl acrylate BPin R1 t-Boc KOH 1,4-dioxane / H2O (100 °C, 4 h) R2 R1 NH CO2Me R2 O NH2•TFA (0 °C ! RT, 2 h) R1 CO2Me R2 O 1,4-dioxane / H2O (0 °C ! 100 °C, 2 h) O HN OMe 16a 72% yield b R1 O HN R2 O HN Me Cl HN 5 equiv. KOH TFA, CH2Cl2 HN Br F Br 16b 57% yield 16c 50% yield 16d 38% yield a See experimental methods for details. Conditions reflect those in table 1 for details b Yield based on purified boronate ester 4m Figure 42. Route to 3,4-dihydroquinolin-2-ones via NH(t-Boc) directed Ir catalyzed borylation and Rh catalyzed conjugate addition Conclusions The NH(t-Boc) group has been shown to have a unique directing ability for iridium catalyzed C–H borylation. The chemistry allows for complementary products when compared to metallation. Not only is the regiochemistry different from metallation, but the chemoselectivity is also wider. The hydrogen bonding mechanism opens a new realm of directed borylation and potentially more broadly to transition metal catalyzed processes. The silica-SMAP ligand was prepared and roused a bis-ortho-directed borylation involving the NH(t-Boc) as a hydrogen bond donor and chloride as a chelate to 55 the iridium center. Anilines hold an important place in synthesis, thereby providing much potential for the prepared ortho-borylated substrates. This is especially relevant to the synthesis of heterocyclic scaffolds. Strengthening the coordinating power of hydrogen bonding has been attempted by varying the stoichiometric directing group. An improvement of the hydrogen bonding directed borylation that has not been pursued but has promises to be fruitful is the rational design of ligands incorporating Lewis basic sites. Ligand design will allow for improved selectivity using catalytic amounts of director. 56 CHAPTER THREE – EXPERIMENTAL METHODS All commercially available chemicals were used as received unless otherwise indicated. HBPin and B2Pin2 were generously supplied by BASF. Bis(!4-1,5cyclooctadiene)-di-µ-methoxy-diiridium(I) [Ir(OMe)COD]2 was prepared per literature procedure.161 (! 5-Indenyl) (!4-1,5-cyclooctadiene) iridium(I) (Ind)Ir(COD) was prepared per literature procedure.162 Bis(! 4-1,5-cyclooctadiene)-di-µ-chlorodirhodium(I) [Rh(COD)Cl]2 was prepared per literature procedure.163 MTBE, THF, toluene, cyclohexane and diethyl ether were refluxed over sodium/benzophenone ketyl, distilled and degassed. Dichloromethane as a reaction solvent was obtained from a dry still packed with activated alumina. DMSO was distilled twice from CaH2 and stored over activated molecular sieves in a glovebox. DMF was distilled from CaH2 and stored over activated molecular sieves in a glovebox. 1,3-Benzodioxole was distilled under reduced pressure. 4-Chloro-1,3-benzodioxole was distilled and passed through a short pad of alumina in a glovebox. 5-Bromo-1,3-benzodioxole was passed through a short pad of alumina in a glovebox. 5-Amino-1,3-benzodioxole was distilled under reduced pressure. KOAc was dried at 160 °C under high vacuum. Br2 was distilled from Ba(OH)2 and KBr through a Vigreaux column, then dried over sulfuric acid immediately before use. TMEDA was distilled from KOH. LiAlH4 was purified to a white solid in a glovebox by stirring with diethyl ether, filtering and removing all volatiles in vacuo (Caution: grey residue still contains active hydride and purified LiAlH4 is extremely pyrophoric). TMSCl was distilled from CaH2 before use. Column chromatography was 57 performed on Silicycle SiliaFlash® P60 silica gel. Thin layer chromatography was performed on 0.25 mm thick aluminum-backed silica gel plates purchased from Silicycle and visualized with ultraviolet light (" = 254 nm). Sublimations were conducted at the given temperature and pressure with a water-cooled cold finger unless otherwise indicated. 1H and 13C NMR spectra were recorded on an Inova-600 spectrometer (599.81 and 150.84 MHz respectively), Varian VXR-500 spectrometer (499.96 and 125.73 MHz respectively), Varian UnityPlus-500 spectrometer (499.74 and 125.67 MHz respectively) or Varian VXR-300 spectrometer (300.11 and 75.47 MHz respectively) and referenced to residual solvent signals. 11B, 19F and 31P spectra were recorded on an Inova-600 spectrometer (192.45 MHz for 11B), Varian UnityPlus-500 spectrometer (160.35 MHz for 11B and 202.29 MHz for 31P) or a Varian VXR-300 spectrometer (96.18, 282.08 and 121.42 MHz respectively) and were referenced to either neat boron trifluoride etherate (BF3•OEt2), neat trichlorofluoromethane (CFCl3) or 85% H3PO4 as the external standard. The boron bearing carbon atom was not observed due to quadrupolar relaxation. All coupling constants are apparent J values measured at the indicated field strengths (s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, bs = broad singlet). HRMS were obtained at the Michigan State University Mass Spectrometry Service Center using a Waters GCT Premier instrument run on EI direct probe or a Waters QTOF Ultima instrument run on ESI. Infrared spectroscopy was obtained at Michigan State University using an FT-IR Mattson spectrometer. Melting points were measured on a MEL-TEMP© capillary melting apparatus and stand uncorrected. 58 General Procedure for preparing N-t-Boc protected anilines 164 A flask was charged with a stir bar, substrate, 1 mL water per 1 mmol substrate and t-Boc2O. After stirring for the given time, ethyl acetate and 1,4-dioxane were added and the solution was acidified with saturated KHSO4 in water at 0 °C. After extracting three times with ethyl acetate, the organic phase was washed with concentrated brine, dried over MgSO4 and concentrated in vacuo. This solid was loaded onto a filter frit and washed three times with a minimal amount of cold hexanes. The remaining solid was dried under high vacuum. General Procedure for iridium C–H borylations In a glovebox, a solution of 30 µL (0.2 mmol) HBPin and 13.1 mg (0.02 mmol) [Ir(OMe)COD]2 in minimal MTBE was added to 10.7 mg (0.04 mmol) dtbpy. The solution was subsequently transferred to an air free flask equipped with a stir bar, B2Pin2, 1.0 mmol substrate and MTBE. The entire procedure was conducted using 2.0 mL MTBE. The reaction was allowed to proceed at 50 °C under a N2 atmosphere connected to a mercury bubbler for the time noted. General Procedure for rhodium catalyzed conjugate additions 155 A single neck round bottom flask was charged with a stir bar, aryl pinacol boronic ester, [Rh(COD)Cl]2, 1,4-dioxane and water under a N2 atmosphere. After the addition of methyl acrylate and freshly crushed KOH, the flask was fitted with a Friederich condenser and heated at 100 °C under N2. All volatiles were removed in vacuo after 4 59 hours of reaction time. The contents of this flask were diluted with dichloromethane and cooled to 0 °C under a N2 atmosphere. Following the dropwise addition of trifluoroacetic acid the flask was warmed to room temperature and stirred for 2 hours before all volatiles were removed in vacuo. The crude reaction mixture was diluted with 1,4-dioxane and water under a N2 atmosphere and cooled to 0 °C. After the complete addition of KOH the flask was fitted with a Friederich condenser and heated under N2 at 100 °C. The reaction was cooled to room temperature, quenched with 1M HCl in water, extracted three times with dichloromethane and washed with 0.5M NaOH in water. The organic phase was washed with saturated brine, dried over MgSO4 and concentrated in vacuo. This crude product was passed through a short pad of silica gel with ethyl acetate as the eluent and all solvent removed in vacuo. Precipitating the product from minimal dichloromethane or ethyl acetate with pentane afforded product after filtration. 60 2-(benzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1a) O O 1 mol% [Ir(OMe)COD]2 2 mol% BOX O B O O 0.5 equiv. B2Pin2 C6H12 (70 °C, 24 h, N2) O OB O O 1a 5 equiv. O 1b In a glovebox, an air free flask fitted with a stir bar, 127 mg (0.5 mmol) B2Pin2 and 575 µL (5.0 mmol) 1,3-benzodioxole. A solution of 6.6 mg (0.01 mmol) [Ir(OMe)COD]2, 3.3 mg (0.02 mmol) 2,2’-bisoxazoline in 2.0 mL cyclohexane was then added to the air free flask and stirred at 70 °C under N2. After 24 hours the solution was transferred to a 20 mL scintillation vial, the air free flask rinsed with methanol and all volatiles removed in vacuo. The obtained liquid was passed through a short pad of silica-gel with dichloromethane as the eluent. Vacuum transfer (0.01 mmHg, 40 °C) into a –78 °C cold bath yielded 315 mg 1,3-benzodioxole (52% recovery). Sublimation removed 1b (0.01 mmHg, 50 °C) leaving behind 63 mg 1a as a white solid (25% yield, mp = 88 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.19 (dd, J = 7.8, J = 1.5, 1H), 6.87 (dd, J = 3 7.6, J = 1.2, 1H), 6.80 (t, J = 7.8, 1H), 5.99 (s, 2H), 1.34 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.54, 146.89, 127.83, 121.03, 111.11, 100.79, 83.84, 24.80; 11B NMR (96 MHz, BF3•OEt2 = 0 ppm) % 30.3; FT-IR(thin film): 3076, 2998, 2975, 2926, 1638, 1492, 1441, 1407, 1390, 1370, 1351, 1320, 1268, 1248, 1199, 1164, 1142, 1128, 1058, 1028, 1002, 973, 944, 921, 852, 839, 778, 739, 690, 672, 484, 452 cm-1; HRMS calcd. for C13H17BO4 [M]+ 248.1220, found 248.1223. X-ray quality crystals were obtained via sublimation at room temperature and pressure in a 20 mL scintillation vial. 61 2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1b) O 1.2 equiv. n-BuLi O Br 1.1 equiv. i-PrOBPin Et2O (–78 °C ! RT, 14 h, N2) O OB O 1b O A solution of 240 µL (2.0 mmol) 5-bromo-1,3-benzodioxole in 5 mL diethyl ether was cooled to –78 °C under a N2 atmosphere. After a dropwise addition of 1 mL (2.4 mmol) 2.4M n-BuLi in hexanes the flask was stirred for 15 min. The cold bath was removed and 0.5 mL (2.2 mmol) neat isopropyl pinacol borate was added. The reaction was stirred for 14 hours, then quenched with water and acidified with 2M HCl in water. The mixture was extracted three times with diethyl ether. The organic layers were collected, washed with saturated brine, dried over MgSO4 and concentrated in vacuo. The crude oil was purified by gradient column chromatography from 1 : 5 (dichloromethane / hexanes) to afford 97 mg 5-bromo-1,3-benzodioxole as a colorless liquid (24% recovery, Rf = 0.78) to 1 : 1 (dichloromethane / hexanes) to provide 227 mg 1b as a white solid (46%, mp = 44 °C, lit165 mp = 42 °C, Rf = 0.41). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.35 (d, J = 7.8, 1H), 7.23 (s, 1H), 6.81 (d, J 3 = 7.8, 1H), 5.92 (s, 2H), 1.31 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 150.12, 147.15, 129.67, 113.89, 108.21, 100.66, 83.62, 24.78; 11B NMR (192 MHz, BF3•OEt2 = 0 ppm) % 30.4; FT-IR(thin film): 3067, 2978, 2930, 2886, 1617, 1505, 1470, 1436, 1356, 1342, 1304, 1271, 1251, 1237, 1154, 1108, 1056, 1040, 963, 936, 906, 880, 62 855, 816, 791, 733, 722, 679, 568, 489, 443 cm-1; HRMS calcd. for C13H17BO4 [M]+ 248.1220, found 248.1222. 2-(benzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1a) and 2(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1b) O O 1 mol% [Ir(OMe)COD]2 2 mol% dtbpy O B O O 1 equiv. HBPin C6H12 (RT, 41 h, N2) O OB O O 5 equiv. 1a O 1b In a glovebox, a solution of 6.6 mg (0.01 mmol) [Ir(OMe)COD]2 and 145 µL (1.0 mmol) HBPin was added to 5.8 mg (0.02 mmol) dtbpy in 2.0 mL cyclohexane. This mixture was added to a 20 mL scintillation vial fitted with a stir bar and 503 µL (5.0 mmol) 1,3benzodioxole. After 41 hours at room temperature the product distribution was 95 : 5 (1a / 1b) as measured by GC/FID. The solution was evaporated and the obtained liquid passed through a short pad of silica-gel with dichloromethane as the eluent. Removal of all volatiles, including 1,3-benzodioxole afforded 117 mg of a 95 : 5 (1a / 1b) mixture as a colorless solid (47% yield, mp = 72-76 °C). 63 2-(benzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1a) and 2(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1b) O O 1 mol% [Ir(OMe)COD]2 2 mol% BOX O B O OB O O 1 equiv. HBPin C6H12 (RT, 41 h, N2) O O O 5 equiv. 1a 1b In a glovebox, a solution of 6.6 mg (0.01 mmol) [Ir(OMe)COD]2 and 145 µL (1.0 mmol) HBPin was added to 2.8 mg (0.02 mmol) 2,2’-bisoxazoline in 2.0 mL cyclohexane. This mixture was added to a 20 mL scintillation vial fitted with a stir bar and 503 µL (5.0 mmol) 1,3-benzodioxole. After 41 hours at room temperature the product distribution was 99 : 1 (1a / 1b). The solution was evaporated and the obtained liquid passed through a short pad of silica-gel with dichloromethane as the eluent. Removal of all volatiles, including 1,3-benzodioxole afforded 97 mg of a 99 : 1 (1a / 1b) mixture as a colorless solid (39% yield, mp = 76-80 °C). 2-(6-chlorobenzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1c) Cl O O 1 mol% [Ir(OMe)COD]2 2 mol% dtbpy Cl O O 1.2 equiv. HBPin C6H12 (RT, 48 h, N2) O B O 1c In a glovebox, a solution of 174 µL (1.2 mmol) HBPin and 6.6 mg (0.01 mmol) [Ir(OMe)COD]2 in minimal cyclohexane was added to a test tube containing 5.3 mg (0.02 mmol) dtbpy. This solution was subsequently transferred to a 20 mL scintillation vial fitted with a stir bar and 117 µ L (1.0 mmol) 5-chloro-1,3-benzodioxole in 64 cyclohexane. The entire procedure was conducted using 2.0 mL cyclohexane. After 48 hours of stirring at room temperature the reaction was quenched with a small amount of methanol and all volatiles removed in vacuo. The crude product was passed through a pad of silica-gel with dichloromethane as the eluent to provide 256 mg 1c as white flakes (91% yield, mp = 114 °C, Rf = 0.75). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.15 (d, J = 2.2, 1H), 6.84 (d, J = 2.2, 1H), 3 6.02 (s, 2H), 1.33 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 151.52, 147.96, 126.87, 125.90, 111.82, 101.85, 84.22, 24.79; 11B NMR (96 MHz, BF3•OEt2 = 0 ppm) % 29.8; FT-IR(thin film): 2987, 2905, 1630, 1588, 1488, 1461, 1432, 1383, 1366, 1322, 1302, 1273, 1234, 1159, 1151, 1137, 1044, 973, 933, 873, 851, 873, 851, 843, 745, 713, 670, 442 cm-1; HRMS calcd. for C13H16ClBO4 [M]+ 282.0830, found 282.0831. 2-(6-bromobenzo[d][1,3]dioxol-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1d) Br O O 1 mol% [Ir(OMe)COD]2 2 mol% dtbpy Br O O 1.5 equiv. HBPin C6H12 (50 °C, 13 h, N2) O B O 1d In a glovebox, a solution of 28 µL (0.19 mmol) HBPin and 6.6 mg (0.01 mmol) [Ir(OMe)COD]2 in minimal cyclohexane was added to a test tube containing 5.3 mg (0.02 mmol) dtbpy. This solution was subsequently transferred to an air free flask fitted with a stir bar, 120 µL (1.0 mmol) 5-bromo-1,3-benzodioxole and 190 µL (1.31 mmol) HBPin in cyclohexane. The entire procedure was conducted using 2.0 mL cyclohexane. 65 After 13 hours under N2 atmosphere at 50 °C the solution was transferred to a 20 mL scintillation vial, the air free flask rinsed with methanol and all volatiles removed in vacuo. The crude product was passed through a pad of silica-gel with dichloromethane as the eluent to provide 286 mg 1d as a white solid (88% yield, mp = 132-134 °C, Rf = 0.79). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.30 (d, J = 2.0, 1H), 6.97 (d, J = 2.0, 1H), 3 6.01 (s, 2H), 1.33 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 152.02, 148.12, 129.86, 114.43, 112.77, 101.78, 24.77; 11B NMR (192 MHz, BF3•OEt2 = 0 ppm) % 29.4; FT-IR(thin film): 2982, 2908, 1457, 1428, 1364, 1322, 1272, 1233, 1195, 1136, 1063, 1042, 972, 931, 860, 847, 745, 693, 668 cm-1; HRMS calcd. for C13H16BrBO4 [M]+ 326.0325, found 326.0330. N-(tert-butoxycarbonyl)-5-amino-1,3-benzodioxole (1e) O O NH2 1.1 equiv. Boc2O H2O (RT, 1 h, open) O O O O NH 1e The general procedure was applied using 138 mg (1 mmol) 5-amino-1,3-benzodioxole, 2 mL water and 240 mg (1.1 mmol) t-Boc2O for 1 hour to provide 222 mg 1e as a white solid (94% yield, mp = 80-82 °C, lit166 mp = 80-82°C). 1H NMR (300 MHz, CDCl = 7.24 ppm): % 7.04 (s, 1H), 6.69 (d, J = 8.1, 1H), 6.63 (dd, 3 J = 8.3, J = 2.2, 1H), 6.32 (s, 1H), 5.90 (s, 2H), 1.48 (s, 9H); 13C NMR (151 MHz, 66 CDCl3 = 77 ppm): % 152.99, 147.79, 143.34, 132.63, 111.70, 107.95, 101.72, 101.03, 80.29, 28.27; FT-IR(thin film): 3329, 3077, 2978, 2895, 2276, 1701, 1636, 1636, 1617, 1532, 1493, 1449, 1433, 1392, 1367, 1341, 1273, 1244, 1165, 1103, 1040, 955, 933, 883, 854, 818, 801, 771, 741, 715, 646, 609, 552, 460, 439 cm-1; HRMS calcd. for C12H15NO4 [M]+ 237.1001, found 237.1011. N,N-di-(tert-butoxycarbonyl)-3-chloroaniline (2a) Cl NH2 2.4 equiv. Boc2O 0.01 equiv. DMAP CH2Cl2 (RT, 48 h, N2) O Cl O N O O 2a A solution containing 2.01 g (15.8 mmol) 3-chloroaniline, 19 mg (0.2 mmol) N,Ndimethyl-4-aminopyridine and 8.24 g (37.8 mmol) t-Boc2O in 10 mL dichloromethane was stirred via magnetic stirbar. After 48 hours, the solution was mixed with 1,4-dioxane, acidified with saturated KHSO4 in water at 0 °C, extracted with dichloromethane, washed with saturated brine, dried over MgSO4 and volatiles evaporated in vacuo to afford a colorless oil. Once this oil crystallized, residual t-Boc2O was sublimed out (0.02 mmHg, 25 °C). Then the solid was further sublimed (0.02 mmHg, 50 °C) to afford 2.80 g 2a as white needles (55% yield, mp = 76 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.27–7.24 (m, 2H), 7.15–7.14 (m, 1H), 3 7.03–7.01 (m, 1H), 1.41 (s, 18H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 151.43, 67 140.39, 133.98, 129.53, 128.37, 127.62, 126.30, 83.10, 27.88; FT-IR(thin film): 3000, 2974, 2944, 2880, 1735, 1702, 1586, 1475, 1366, 1273, 1239, 1160, 1125, 1075, 1044, 1023, 876, 842, 806, 773, 681 cm-1; HRMS calcd. for C16H22ClNO4 [M]+ 327.1237, found 327.1239. N,N-di(tert-butoxycarbonyl)-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (2b) O Cl 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy O N O O 0.2 equiv. HBPin 0.6 equiv. B2Pin2 MTBE (50 °C, 36 h, N2) 2a O O N Cl O O O B O 2b The general procedure was applied using 152 mg (0.6 mmol) B2Pin2, 327 mg (1.0 mmol) 2a for 36 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent (Rf = 0.57) to afford a colorless oil which crystallized upon standing for several days. The colorless crystals were loaded onto a filter frit and washed with a minimal amount of –78 °C pentane to afford 410 mg 2b as colorless crystals (91% yield, mp = 122-124 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.68 (dd, J = 2.0, J = 0.7, 1H), 7.44 (dd, J = 3 2.0, J = 0.7, 1H), 7.22 (t, J = 2.0, 1H), 1.41 (s, 18H), 1.31 (s, 12H); 13C NMR (126 MHz, 68 CDCl3 = 77 ppm): % 151.57, 139.88, 133.72, 133.60, 132.40, 131.01, 84.27, 83.06, 27.91, 24.842; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.2; FT-IR(thin film): 2980, 2934, 1794, 1752, 1729, 1716, 1572, 1470, 1455, 1419, 1391, 1369, 1355, 1328, 1272, 1242, 1149, 1118, 964, 887, 868, 851, 782, 715, 702, 490, 438, 424 cm-1; HRMS calcd. for C22H33BClNO6 [M]+ 453.2089, found 453.2091. N-(tert-butoxycarbonyl)-3-chloroaniline (2c) Cl NH2 1.2 equiv. Boc2O O Cl O NH EtOAc (RT, 13 h, open) 2c A solution of 10.00 g (78.4 mmol) 3-chloroaniline and 20.53 g (94.1 mmol) t-Boc2O in 15 mL ethyl acetate was stirred by magnetic stirbar open to air. All volatiles were removed after 13 hours to provide a pink solid that was washed three times with hexanes. The solid was collected and the procedure repeated on the filtrate. This provided 16.50 g 2c as a white solid (93% yield, mp = 82-84 °C, lit167 mp = 83 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.50 (s, 1H), 7.18–7.12 (m, 2H), 6.99–6.96 3 (m, 1H), 6.54 (bs, 1H), 1.50 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.42, 139.56, 134.69, 129.85, 122.97, 118.51, 116.39, 80.96, 28.25; FT-IR(thin film): 3320, 2978, 1709, 1603, 1537, 1480, 1449, 1426, 1404, 1390, 1287, 1244, 1159, 1078, 1059, 853, 772, 739, 691, 681 cm-1; HRMS calcd. for C11H14ClNO2 [M]+ 227.0713, found 227.0715. 69 N-(tert-butoxycarbonyl)-5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (2d) and N - (tert-butoxycarbonyl)-5-chloro-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (2e) O O NH Cl 2c 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy O NH Cl 0.2 equiv. HBPin 1 equiv. B2Pin2 MTBE (50 °C, 20 h, N2) O O B O O 2d O NH Cl O B O 2e The general procedure was applied using 254 mg (1.0 mmol) B2Pin2 and 227 mg (1.0 mmol) 2c for 20 hours. The reaction was transferred to a 20 mL scintillation vial with dichloromethane. A small amount of methanol was added and all volatiles were removed in vacuo. A silica gel column was run using 1 : 1 (dichloromethane / hexanes) as the eluent to afford 176 mg 2d as a white solid (50% yield, mp 108-110 °C, Rf = 0.46) and 90 mg 2e as a white solid (25% yield, mp = 130-132 °C, Rf = 0.12). Compound 2d 1H NMR (600 MHz, CDCl = 7.24 ppm): % 8.69 (s, 1H), 8.27 (s, 1H), 7.60 (d, J = 8.1, 3 1H), 6.93 (dd, J = 8.1, J = 2.0, 1H), 1.51 (s, 9H), 1.34 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 152.79, 146.32, 139.03, 137.13, 121.71, 117.62, 84.39, 80.22, 28.30, 24.84; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.3; FT-IR(thin film): 3365, 2979, 2933, 1733, 1605, 1574, 1524, 1419, 1381, 1351, 1315, 1276, 1233, 1161, 1125, 1098, 1069, 1046, 1026, 962, 934, 854, 815, 768, 744, 668 cm-1; HRMS calcd. for C17H25BClNO4 [M]+ 353.1565, found 353.1563. 70 Compound 2e 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.73 (s, 1H), 7.41 (d, J = 1.2, 1H), 7.40 (d, J 3 = 2.0, 1H), 6.50 (bs, 1H), 1.49 (s, 9H), 1.30 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 152.43, 139.09, 134.59, 128.90, 122.40, 121.21, 84.18, 80.87, 28.27, 24.83; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.2; FT-IR(thin film): 3333, 2978, 2932, 1733, 1708, 1602, 1579, 1540, 1455, 1432, 1355, 1325, 1269, 1244, 1159, 1144, 1117, 1064, 994, 966, 870, 857, 773, 716, 703, 667 cm-1; HRMS calcd. for C17H25BClNO4 [M]+ 353.1565, found 353.1566. N-(tert-butoxycarbonyl)-aniline (3a) 1.1 equiv. Boc2O NH2 H2O (RT, 1 h, open) O O NH 3a The general procedure was applied using 0.49 g (5 mmol) aniline, 6 mL water and 1.20 g (5.5 mmol) t-Boc2O for 1 h to provide 1.00 g 3a as a white solid (99% yield, mp = 134136 °C, lit164 mp = 132-133 °C). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.34 (d, J = 7.8, 2H), 7.27 (t, J = 7.33, 2H), 3 7.01 (dt, J = 7.3, J = 1.2, 1H), 6.50 (bs, 1H), 1.51 (s, 9H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 152.73, 138.31, 128.92, 122.97, 118.50, 80.44, 28.31; FT-IR(thin film): 3316, 3051, 3040, 2982, 1690, 1597, 1530, 1503, 1487, 1440, 1391, 1367, 1315, 1280, 1245, 71 1148, 1082, 1055, 1022, 909, 896, 828, 776, 746, 694 cm-1; HRMS calcd. for C11H15NO2 [M]+ 193.1103, found 193.1096. N-(tert-butoxycarbonyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3b) O NH2 B O O O 1.4 equiv. Boc2O NH EtOAc (RT, 4 days, open) B O O 3b A solution of 1.05 g (4.8 mmol) 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline and 1.46 g (6.7 mmol) t-Boc2O in ethyl acetate was stirred for 4 days at room temperature. All volatiles were removed in vacuo to provide an off-white solid. Crystallization from minimal dichloromethane and pentane provided 0.98 g 3b as a white solid (64% yield, mp = 94-96 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.66 (bs, 1H), 8.16 (d, J = 8.3, 1H), 7.70 (dd, 3 J = 7.3, J = 1.7, 1H), 7.40 (dt, J = 7.8, J = 8.6, J = 1.7, 1H), 6.96 (t, J = 7.3, J = 8.1, 1H), 1.51 (s, 9H), 1.34 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 153.13, 145.29, 136.14, 132.74, 121.50, 117.63, 84.17, 79.71, 28.36, 24.85; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.4; FT-IR(thin film): 3373, 3065, 2981, 2931, 1732, 1610, 1582, 1534, 1474, 1453, 1380, 1354, 1320, 1293, 1270, 1235, 1161, 1123, 1079, 1045, 1023, 962, 860, 840, 769, 752, 673, 529 cm-1; HRMS calcd. for C17H26NO4 [M]+ 319.1955, found 319.1955. 72 N-(tert-butoxycarbonyl)-3-bromoaniline (3c) Br NH2 1.1 equiv. Boc2O O Br O NH H2O (RT, 24 h, open) 3c The general procedure was applied using 1.80 g (10.5 mmol) 3-bromoaniline, 12 mL water and 2.42 g (11.1 mmol) t-Boc2O for 24 h to provide 2.60 g 3c as an off-white solid (92% yield, mp = 86-88 °C, lit168 mp = 85-86 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.26–7.23 (m, 1H), 7.15–7.14 (m, 2H), 7.01 3 (d, J = 7.8, 1H), 4.98 (bs, 1H), 1.37 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.09, 151.49, 134.39, 129.86, 125.28, 122.34, 120.07, 50.97, 28.73; FT-IR(thin film): 3331, 3068, 3055, 2967, 2934, 2875, 1718, 1686, 1588, 1537, 1475, 1458, 1427, 1393, 1366, 1279, 1258, 1212, 1152, 1087, 1068, 1050, 1022, 1000, 927, 897, 881, 867, 793, 769, 736, 689, 673, 650, 559, 460, 440 cm-1; HRMS calcd. for C11H14BrNO2 [M]+ 271.0208, found 271.0214. N-(tert-butoxycarbonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3d) O Br O NH 5 mol% (dppf)PdCl2•CH2Cl2 2.4 equiv. KOAc 1 equiv. B2Pin2 DMSO (100 °C, 13 h, N2) 3c O OB O O NH 3d In a glovebox, 272 mg (1 mmol) 3c, 254 mg (1 mmol) B2Pin2, 236 mg (2.4 mmol) KOAc, 36 mg (0.05 mmol) (dppf)PdCl2•CH2Cl2 and 3 mL DMSO were added to a 25 73 mL Schlenk flask. The flask was fitted with a reflux condenser and heated at 100 °C under N2. After 13 hours the contents were diluted with benzene and washed several times with water. The organic layer was dried over MgSO4. The obtained oil was purified by gradient chromatography with 1 : 1 (dichloromethane / hexanes) to dichloromethane to afford 73 mg 3d as a colorless solid (23% yield, mp = 110-112 °C). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.61–7.59 (m, 2H), 7.45 (d, J = 7.3, 1H), 3 7.28 (d, J = 7.8, 1H), 6.54 (bs, 1H), 1.48 (s, 9H), 1.30 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 152.77, 137.79, 129.33, 128.41, 124.62, 121.58, 83.79, 80.29, 28.28, 13.80; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.3; FT-IR(thin film): 3334, 3052, 2979, 2936, 1720, 1608, 1586, 1539, 1488, 1430, 1402,1321, 1275, 1240, 1154, 1111, 1077, 1059, 1029, 996, 965, 889, 872, 852, 796, 772, 733, 708, 673, 648, 606, 578, 539, 457 cm-1; HRMS calcd. for C17H26BNO4 [M]+ 319.1955, found 319.1959. N-(tert-butoxycarbonyl)-4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenol (4a) 169 O O NH HO O 1. 1.1 equiv. HBPin 2. 2 mol% [Ir(OMe)COD]2, 4 mol% dtbpy 0.2 equiv. HBPin, 1.5 equiv. B2Pin2 MTBE (50 °C, 12 h, N2) O NH B O O HO 4a An air free flask was charged with a stir bar and 209 mg (1.0 mmol) N-(tertbutoxycarbonyl)-4-aminophenol. The addition of 160 µL (1.1 mmol) HBPin produced vigorous bubbling. A mixture of 13.2 mg (0.02 mmol) [Ir(COD)OMe]2 and 30 µL (0.2 74 mmol) HBPin was added to 10.8 mg (0.04 mmol) dtbpy. This was added to the air free flask with 2 mL MTBE, 381 mg (1.5 mmol) B2Pin2 and allowed to react under N2 at 50 °C for 12 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and methanol, then removing all volatiles in vacuo. A column was run with 40 : 60 (ethyl acetate / hexanes) to provide 262 mg 4a as a white solid (78% yield, mp = 109-111 °C, Rf = 0.57). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.40 (s, 1H), 7.99 (d, J = 8.6, 1H), 7.14 (d, J 3 = 2.9, 1H), 6.90 (dd, J = 8.8, J = 2.9, 1H), 4.70 (s, 1H), 1.49 (s, 9H), 1.33 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 153.54, 150.36, 138.23, 121.81, 119.69 (2 C’s), 84.21, 79.74, 28.38, 24.81; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.3; FTIR(thin film): 3383, 2980, 2932, 1731, 1630, 1593, 1493, 1449, 1370, 1306, 1244, 1163, 1123, 1076, 1034, 966, 891, 855, 822, 735, 693, 633; HRMS(ESI+) calcd. for C17H27BNO5 [M+H]+ 336.1982, found 336.1985. N-(tert-butoxycarbonyl)-4-chloroaniline (4b) NH2 Cl O 1.1 equiv. Boc2O H2O (RT, 24 h, open) O NH Cl 4b The general procedure was applied using 5.00 g (39.2 mmol) 4-chloroaniline, 40 mL water and 9.41 g (43.1 mmol) t-Boc2O for 24 hours to provide 6.56 g 4b as a white solid (74% yield, mp = 98-100 °C, lit167 mp = 105-106 °C). The hexane washings were concentrated to approximately 5 mL and cooled to –30 °C to yield 1.60 g 4b as white 75 needles (18% yield, mp = 98 °C, lit167 mp = 105-106 °C; combined crops = 8.16 g, 91% yield). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.28 (d, J = 8.8, 2H), 7.22 (d, J = 9.0, 2H), 3 6.47 (bs, 1H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.56, 136.95, 128.92, 127.94, 119.71, 80.84, 28.29; FT-IR(thin film): 3366, 2988, 1696, 1591, 1522, 1495, 1451, 1401, 1364, 1306, 1269, 1240, 1179, 1165, 818, 772, 758, 617 cm-1; HRMS calcd. for C11H14ClNO2 [M]+ 227.0713, found 227.0719. N-(tert-butoxycarbonyl)-4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (4c) O O NH Cl 4b O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 0.75 equiv. B2Pin2 MTBE (50 °C, 18 h, N2) O NH Cl 4c B O O The general procedure was applied using 191 mg (0.75 mmol) B2Pin2 and 227 mg (1.0 mmol) 4b for 18 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with minimal dichloromethane as the eluent (Rf = 0.67). After removing all volatiles in vacuo, the residual starting material was sublimed (0.02 mmHg, 50 °C) leaving behind 278 mg 4c as a white solid (79% yield, mp = 106-108 °C). 76 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.60 (bs, 1H), 8.13 (d, J = 9.0, 1H), 7.64 (d, 3 J = 2.7, 1H), 7.33 (dd, J = 9.0, J = 2.9, 1H), 1.50 (s, 9H), 1.34 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.93, 143.74, 135.41, 132.42, 126.66, 119.09, 84.57, 80.06, 28.31, 24.82; 11B (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.2; FT-IR(thin film): 3405, 2979, 2932, 1733, 1605, 1579, 1524, 1470, 1408, 1393, 1374, 1345, 1313, 1257, 1235, 1162, 1134, 1110, 1077, 1046, 1029, 963, 869, 848, 829, 744, 690, 667, 530, 440 cm-1; HRMS calcd. for C17H25BClNO4 [M]+ 353.1565, found 353.1566. N-(tert-butoxycarbonyl)-4-bromoaniline (4d) NH2 Br O 1.1 equiv. Boc2O H2O (RT, 24 h, open) O NH Br 4d The general procedure was applied using 3.46 g (20.1 mmol) 4-bromoaniline, 22 mL water and 4.85 g (22.2 mmol) t-Boc2O for 24 hours to provide 5.40 g 4d as a white solid (98% yield, mp = 104 °C, lit164 mp = 102 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.35 (d, J = 8.8, 2H), 7.23 (d, J = 9.0, 2H), 3 6.56 (bs, 1H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.52, 137.46, 131.80, 120.06, 115.37, 80.82, 28.26; FT-IR(thin film): 3367, 3000, 2982, 2933, 2899, 1695, 1591, 1520, 1491, 1413, 1394, 1366, 1306, 1267, 1238, 1178, 1160, 1070, 1055, 1008, 815, 763, 631, 613, 498 cm-1; HRMS calcd. for C11H14BrNO2 [M]+ 271.0208, found 271.0211. 77 N-(tert-butoxycarbonyl)-4-bromo-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (4e) O O NH Br 4d O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 0.75 equiv. B2Pin2 MTBE (50 °C, 22 h, N2) O NH Br 4e B O O The general procedure was applied using 192 mg (0.75 mmol) B2Pin2 and 273 mg (1.0 mmol) 4d for 22 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent to afford 354 mg 4e as a white solid (89% yield, mp = 120122 °C, Rf = 0.68). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.60 (bs, 1H), 8.08 (d, J = 8.8, 1H), 7.78 (d, 3 J = 2.4, 1H), 7.47 (dd, J = 8.8, J = 2.7, 1H), 1.50 (s, 9H), 1.34 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.88, 144.23, 138.35, 135.33, 119.46, 114.27, 84.58, 80.10, 28.31, 24.82; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.6; FT-IR(thin film): 3371, 2978, 2932, 1733, 1603, 1574, 1522, 1469, 1405, 1370, 1313, 1229, 1136, 1080, 1047, 1025, 962, 902, 863, 828, 770, 743, 680, 638, 527, 442 cm-1; HRMS calcd. for C17H25BBrNO4 [M]+ 397.1060, found 397.1061. X-Ray quality crystals were grown from pentane at –20 °C. 78 N-(tert-butoxycarbonyl)-4-trifluoromethylaniline (4f) 170 NH2 F F F O 1 equiv. Boc2O 1,4-dioxane 6 M NaOH / H2O (RT, 15 h, N2) O NH F F F 4f The literature procedure was followed as described.171 A flask was charged with a stirbar, 0.97 g (6.0 mmol) 4-trifluoromethylaniline and 6 mL 1,4-dioxane. Upon mixing, 6 mL 1M NaOH in water was added to the flask. After the addition of 1.31 g (6.0 mmol) t-Boc2O the mixture was stirred at room temperature for 15 hours. The contents were poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over Na2SO4 and volatiles removed in vacuo. The obtained solid was loaded onto a filter frit and washed with hexanes to provide 0.58 g 4f as a white fluffy solid (37% yield, mp = 118-120 °C, lit171 mp = 115-117 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.51 (d, J = 8.8, 2H), 7.45 (d, J = 8.8, 2H), 3 6.64 (bs, 1H), 1.51 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.29 (s), 141.53 (d, J = 1.4), 126.25 (q, J = 3.7), 124.81 (q, J = 32.7), 124.23 (q, J = 271.1), 117.88 (s), 81.27 (s), 28.25 (s); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –62.10; FT-IR(thin film): 3364, 3012, 2986, 2940, 1703, 1617, 1596, 1528, 1507, 1445, 1410, 1395, 1372, 1334, 1317, 1274, 1237, 1158, 1108, 1071, 1024, 1016, 905, 838, 767, 632, 614, 505, 464 cm-1; HRMS calcd. for C12H14F3NO2 [M]+ 261.0977, found 261.0978. 79 N-(tert-butoxycarbonyl)-4-trifluoromethyl-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (4g) O O NH F F F 4f O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 0.55 equiv. B2Pin2 C6H12 (120 °C, 1 h, closed) O NH F F F 4g B O O In a glovebox, a solution of 29 µL (0.2 mmol) HBPin and 13.1 mg (0.02 mmol) [Ir(OMe)COD]2 in minimal cyclohexane was added to 10.7 mg (0.04 mmol) dtbpy. The solution was subsequently transferred to an air free equipped with a stir bar, 139 mg (0.55 mmol) B2Pin2 and 263 mg (1.0 mmol) 4f with cyclohexane. The entire procedure was conducted using 2.0 mL cyclohexane. The reaction was allowed to proceed at 120 °C in a closed system for 1 hour. Isolation involved cooling to room temperature, transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent (Rf = 0.73). The residual starting material was sublimed (0.02 mmHg, 80 °C) leaving behind 317 mg 4g as a white solid (82% yield, mp = 108-110 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.82 (bs, 1H), 8.30 (d, J = 8.8, 1H), 7.94 (d, 3 J = 2.0, 1H), 7.61 (dd, J = 8.8, J = 2.2, 1H), 1.51, (s, 9H), 1.36 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.75 (s), 148.18 (s), 133.21 (d, J = 3.7), 129.54 (d, J = 3.2), 124.38 (q, J = 271.6), 123.37 (q, J = 32.2), 117.28 (s), 84.72 (s), 80.44 (s), 28.25 (s), 24.81 (s); 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.6; 19F NMR (282 80 MHz, CDCl3, CFCl3 = 0 ppm): % &62.01; FT-IR(thin film): 3367, 2980, 2934, 1738, 1620, 1594, 1539, 1430, 1362, 1270, 1238, 1162, 1144, 1120, 1079, 1047, 1025, 964, 867, 848, 758, 682, 638, 606 cm-1; HRMS calcd. for C18H25BF3NO4 [M]+ 387.1829, found 387.1827. X-Ray quality crystals were grown from pentane at –20 °C. N-(tert-butoxycarbonyl)-4-chloro-3-fluoroaniline (4h) F Cl 1.1 equiv. Boc2O NH2 H2O (RT, 18 h, open) O O F NH Cl 4h The general procedure was applied using 3.00 g (20.6 mmol) 4-chloro-3-fluoroaniline, 20 mL water and 4.95 g (22.7 mmol) t-Boc2O for 18 hours to provide 4.87 g 4h as a white solid (97% yield, mp = 98-100 °C, lit109 mp = 103-104 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.41 (d, J = 9.5, 1H), 7.25–7.22 (m, 1H), 3 6.93–6.91 (m, 1H), 6.51 (bs, 1H), 1.50 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 158.18 (d, J = 246.7), 152.24 (s), 138.54 (s), 138.46 (s), 130.38 (s), 114.39 (s), 107.01 (d, J = 26.2), 81.30 (s), 28.24 (s); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –113.74 (dd, J = 10.7, J = 7.6); FT-IR(thin film): 3431, 3325, 3098, 2981, 2936, 1724, 1598, 1524, 1499, 1426, 1407, 1394, 1368, 1281, 1236, 1151, 1068, 1027, 977, 948, 867, 811, 722, 728, 666, 611, 554, 450, 429, 419 cm-1; HRMS calcd. for C11H13ClFNO2 [M]+ 245.0619, found 245.0625. 81 N-(tert-butoxycarbonyl)-4-chloro-5-fluoro-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (4i) and N-(tert-butoxycarbonyl)-4-chloro-3-fluoro-2(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (B) O F O O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy F 4h B O O Cl 0.2 equiv. HBPin 1.5 equiv. B2Pin2 MTBE (50 °C, 30 h, N2) O NH NH Cl O 4i F B O H N O O Cl B The general procedure was applied using 381 mg (1.5 mmol) B2Pin2 and 245 mg (1.0 mmol) 4h for 30 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude product consisted of 76 : 24 (4i / B) and was fractioned through neutral Al2O3 (III) with 1 : 3 (dichloromethane / hexanes) as the eluent to provide 251 mg 4i as a white solid (68% yield, mp = 120-122 °C). Compound 4i 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.69 (bs, 1H), 8.10 (d, J = 12.5, 1H), 7.68 (d, 3 J = 8.8, 1H), 1.50 (s, 9H), 1.34 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 160.70 (d, J = 250.4), 152.64 (s), 145.65 (d, J = 11.1), 137.61 (s), 113.33 (d, J = 17.5), 106.34 (d, J = 27.2), 84.64 (s), 80.50 (s), 28.27 (s), 24.82 (s); 11B (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.0; 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –108.01 (t, J = 12.1); FT-IR(thin film): 3366, 3126, 2980, 2933, 1734, 1591, 1530, 1473, 1452, 1419, 1382, 1353, 1319, 1283, 1242, 1160, 1139, 1092, 1063, 1004, 961, 906, 890, 860, 82 828, 771, 734, 689, 672, 622, 597, 439 cm-1; HRMS calcd. for C17H24BFClNO4 [M]+ 371.1471, found 371.1480. Compound B 1H (500 MHz, CDCl = 7.24 ppm): % 8.79 (bs, 1H), 7.92 (d, J = 9.0, 1H), 7.35 (t, J = 8.8, 3 J = 8.6, 1H), 1.49 (s, 9H), 1.36 (s, 12H); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –102.7 (d, J = 9.2). N-(tert-butoxycarbonyl)-4-fluoro-3-methylaniline (4j) NH2 F O 1.2 equiv. Boc2O H2O (RT, 3 dys, open) O NH F 4j The general procedure was applied using 10.00 g (80 mmol) 4-fluoro-3-methylaniline, 85 mL water and 20.93 g (96 mmol) t-Boc2O for 3 days to provide 16.76 g 4j as a fluffy white solid (93% yield, mp = 76-78 °C). TLC analysis with dichloromethane as the eluent (Rf = 0.68) showed complete conversion of 4-fluoro-3-methylaniline after 3 hours. 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.23 (s, 1H), 7.05–7.02 (m, 1H), 6.88 (t, J = 3 9.0, 1H), 6.34 (s, 1H), 2.22 (d, J = 2.0, 3H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 157.35 (d, J = 240.2), 152.94 (s), 133.90 (d, J = 2.6), 125.23 (d, J = 18.6), 121.74 (s), 117.54 (s), 115.06 (d, J = 23.8), 80.48 (s), 28.31 (s), 14.63 (d, J = 3.6); 19F NMR (282 MHz, CFCl3 = 0 ppm): % –124.59; FT-IR(thin film): 3322, 3079, 2978, 2932, 1698, 1623, 1603, 1531, 1506, 1454, 1412, 1368, 1315, 1283, 1243, 1214, 1153, 1114, 83 1018, 1031, 1004, 884, 816, 771, 764, 719, 576, 546 cm-1; HRMS calcd. for C12H16FNO2 [M]+ 225.1165, found 225.1169. N-(tert-butoxycarbonyl)-4-fluoro-5-methyl-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (4k) and N-(tert-butoxycarbonyl)-4-fluoro-5-methyl-3(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (B) O O NH F 4j O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy O O NH NH BO O F 0.2 equiv. HBPin 1.2 equiv. B2Pin2 MTBE (50 °C, 24 h, N2) 4k O F O B O B The general procedure was applied using 305 mg (1.2 mmol) B2Pin2, 225 mg (1 mmol) 4j for 24 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane, quenching with a small amount of methanol and removing all volatiles in vacuo to provide a 91 : 9 (4k / B) mixture. The crude solid was passed through a pad of silica gel with dichloromethane as the eluent. This solid was further purified by crystallization from minimal chloroform and 1 mL pentane at –80 °C to afford 244 mg 92 : 8 (4k / B) as a white solid (70% yield, mp = 108116 °C). Column chromatography on 99 mg using 10 : 1 (ethyl acetate / hexanes) as the eluent afforded 75 mg 4k as a white solid (76% yield based on 99 mg mixture, mp = 124126 °C, Rf = 0.41) while B was fractioned with impurities. 84 Compound 4k 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.50 (s, 1H), 8.01 (d, J = 6.6, 1H), 7.27 (d, J 3 = 9.8, 1H), 2.26 (d, J = 1.7, 3H), 1.50 (s, 9H), 1.33 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 156.36 (d, J = 239.9), 153.23 (s), 140.99 (s), 129.67 (d, J = 17.8), 121.17 (d, J = 21.9), 120.70 (s), 84.32 (s), 79.75 (s), 28.35 (s), 24.82 (s), 15.16 (d, J = 3.5); 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 29.9; 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % &127.06 (t, J = 8.6, J = 6.9); FT-IR(thin film): 3357, 3042, 2979, 2926, 1723, 1652, 1582, 1540, 1420, 1370, 1350, 1311, 1292, 1254, 1170, 1139, 1067, 1009, 961, 893, 854, 836, 763, 738, 687 cm-1; HRMS calcd. for C18H27BFNO4 [M]+ 351.2017, found 351.2011. Compound B 1H NMR (600 MHz, CDCl = 7.24 ppm): % ): % 7.50 (s, 1H), 7.27–7.25 (m, 1H), 3 6.39–3.38 (m, 1H), 2.22 (d, J = 2.0, 3H), 1.48 (s, 9H), 1.32 (s, 12H); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % &114.0. N-(tert-butoxycarbonyl)-2-chloro-4-aminoanisole (4l) Cl O NH2 1.2 equiv. Boc2O EtOAc (RT, overnight, open) O Cl O O NH 4l A solution of 4.00 g (25.3 mmol) 3-chloro-4-methoxyaniline and 6.62 g (30.3 mmol) tBoc2O in ethyl acetate was stirred overnight. All volatiles were removed in vacuo to 85 provide an off-white solid. The collected product was loaded onto a filter frit and washed three times with hexanes to provide 5.64 g 4l as a white solid (86% yield, mp = 88-90 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.44 (s, 1H), 7.15 (d, J = 7.3, 1H), 6.82 (d, J 3 = 9.0, 1H), 6.36 (bs, 1H), 3.83 (s, 3H), 1.48 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.83, 151.11, 132.03, 122.65, 121.31, 118.23, 112.46, 80.64, 56.45, 28.31; FTIR(thin film): 3328, 3002, 2978, 2934, 2841, 1698, 1590, 1502, 1454, 1442, 1393, 1367, 1279, 1255, 1239, 1161, 1062, 1023, 937, 836, 809, 735 cm-1; HRMS calcd. for C12H16ClNO3 [M]+ 257.0819, found 257.0816. N-(tert-butoxycarbonyl)-5-chloro-4-methoxy-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (4m) O Cl O O NH 4l 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 1.5 equiv. B2Pin2 MTBE (50 °C, 24 h, N2) O O NH Cl O 4m B O O The general procedure was applied using 382 mg (1.5 mmol) B2Pin2, 385 mg (1.0 mmol) 4l for 24 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent to afford 365 mg 4m as an off-white solid (95% yield, mp = 130 °C, Rf = 0.39). 86 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.49 (s, 1H), 8.27 (s, 1H), 7.20 (s, 1H), 3.87 3 (s, 3H), 1.50 (s, 9H), 1.34 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.99, 149.62, 139.37, 127.20, 120.07, 118.49, 84.44, 79.91, 56.46, 28.33, 24.82; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.5; FT-IR(thin film): 3370, 3112, 2977, 2938, 2835, 1727, 1604, 1586, 1520, 1467, 1401, 1351, 1305, 1265, 1232, 1200, 1162, 1090, 1057, 956, 855, 743, 428, 408 cm-1; HRMS calcd. for C28H27BClNO5 [M]+ 383.1671, found 383.1674. X-Ray quality crystals were grown from pentane at –20 °C. N-(tert-butoxycarbonyl)-4-methoxy-3-trifluoromethylaniline (4n) 170 F F F NH2 O 1.2 equiv. Boc2O THF (reflux, overnight, N2) F F F O O NH O 4n A flask containing 2.0 g (10 mmol) 4-methoxy-3-trifluoromethylaniline, 2.51 g (12 mmol) t-Boc2O and 8 mL THF was refluxed overnight. All volatiles were removed and the crude brown oil was purified via column chromatography using 9 : 1 (ethyl acetate / hexanes) as the eluent to afford 2.8 g 4n as a white solid (92% yield, mp = 138-139 °C, Rf = 0.29). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.53 (s, 1H), 7.49 (s, 1H), 6.91 (d, J = 8.8, 3 1H), 6.47 (s, 1H), 3.84 (s, 3H), 1.49 (s, 9H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 153.35 (s), 152.96 (s), 131.08 (s), 123.75 (s), 123.33 (q, J = 272.7), 118.94 (q, J = 31.1), 118.26 (s), 112.75 (s), 80.77 (s), 56.26 (s), 28.28 (s); 19F NMR (282 MHz, CDCl3, 87 CFCl3 = 0 ppm): % –62.63; FT-IR(thin film): 3322, 3005, 2980, 2936, 1699, 1510, 1464, 1429, 1394, 1369, 1327, 1278, 1239, 1162, 1135, 1055, 1025, 940, 895, 868, 820, 729, 542 cm-1; HRMS calcd. for C13H16F3NO3 [M]+ 291.10966, found 291.1082. N-(tert-butoxycarbonyl)-4-methoxy-5-trifluoromethyl-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (4o) F F F O O NH O 4n 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 0.75 equiv. B2Pin2 MTBE (RT, 24 h, N2) F F O F O NH O 4o B O O In a glovebox, a solution of 7 µL (0.05 mmol) HBPin and 3.2 mg (0.005 mmol) [Ir(OMe)COD]2 in minimal MTBE was added to 2.6 mg (0.01 mmol) dtbpy. The solution was subsequently transferred to a 5 mL scintillation vial equipped with a stir bar, 46 mg (0.18 mmol) B2Pin2 and 70 mg (0.24 mmol) 4n. The entire procedure was conducted using 0.7 mL MTBE. The reaction proceeded at room temperature for 24 hours. Isolation involved adding a drop of methanol to the vial before removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent to afford 83 mg 4o as a white solid (83% yield, mp = 126128 °C, Rf = 0.29). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 8.49 (s, 1H), 8.41 (s, 1H), 7.29 (s, 1H), 3.87 3 (s, 3H), 1.50 (s, 9H), 1.36 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 153.10 (s), 151.57 (d, J = 1.7), 138.43 (s), 123.39 (q, J = 273.3), 122.16 (q, J = 31.1), 118.90 (s), 88 117.07 (bs), 84.76 (s), 80.11 (s), 56.33 (s), 28.33 (s) 24.84; 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –62.78; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.0; FT-IR(thin film): 3373, 2979, 2934, 2881, 1729, 1589, 1534, 1453, 1420, 1392, 1360, 1327, 1300, 1273, 1258, 1230, 1157, 1138, 1088, 1053, 971, 954, 906, 855, 836, 766, 731, 665 cm-1; HRMS calcd. for C19H27BF3NO5 [M]+ 417.1934, found 417.1943. N-(tert-butoxycarbonyl)-4-aminobenzonitrile (4p) NH2 N O 1.2 equiv. Boc2O 0.1 equiv. I2 THF (70 °C, 49 h, N2) O NH N 4p A modified literature procedure was followed.172 A solution of 4.91 g (42.5 mmol) 4aminobenzonitrile, 1.05 g (4.2 mmol) I2 and 10.87 g (49.8 mmol) t-Boc2O in 6 mL THF was stirred for 49 hours at 70 °C under N2. After the addition of an additional 9.06 g (42.5mmol) t-Boc2O and a total of 4 days at 70 °C under N2 the contents were diluted with diethyl ether. The organic layer was washed with saturated Na2S2O3 in water, washed twice with 2M HCl in water, washed with saturated brine, dried over MgSO4 and all volatiles removed in vacuo to provide a yellow liquid. After the addition of 20 mL 1 : 1 (diethyl ether / pentane) all volatiles were removed to afford a yellow solid. This crude solid was loaded onto a filter frit and washed extensively with pentane to provide a yellow-tinged solid (mp = 106-112 °C, lit173 mp = 120-120.5 °C). The yellow-tinged solid was sublimed (120 °C, 0.001 mmHg) to afford 4.20 g 4p as a white solid (46% yield, mp = 116-118 °C, lit173 mp = 120-120.5 °C). This solid was then passed through a 89 pad of silica-gel with dichloromethane as the eluent to yield 3.5 g 4p a white solid (38% yield, mp = 118-120 °C, lit173 mp = 120-120.5°C, Rf = 0.53). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.55 (d, J = 8.8, 2H), 7.46 (d, J = 8.8, 2H), 3 6.67 (bs, 1H), 1.50 (s, 9H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 151.90, 142.53, 133.29, 119.01, 118.06, 105.81, 81.71, 28.21; FT-IR(thin film): 3328, 2979, 2933, 2225, 1732, 1710, 1607, 1590, 1523, 1411, 1370, 1318, 1233, 1156, 1056, 1027, 900, 838, 772, 701 cm-1; HRMS calcd. for C12H14N2O2 [M]+ 218.1055, found 218.1053. N-(tert-butoxycarbonyl)-4-amino-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)benzonitrile (4q) O O NH N 3 equiv. 4p O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 0.4 equiv. B2Pin2 MTBE (50 °C, 37 h, N2) O NH B O O N 4q In a glovebox, a solution of 30 µL (0.2 mmol) HBPin and 13.1 mg (0.02 mmol) [Ir(OMe)COD]2 in minimal MTBE was added to 10.8 mg (0.02 mmol) dtbpy. The solution was subsequently transferred to an air free equipped with a stir bar, 103 mg (0.4 mmol) B2Pin2 and 654 mg (2.0 mmol) 4p in MTBE. The entire procedure was conducted using 2.0 mL MTBE. The reaction proceeded at 50 °C under N2 for 37 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed 90 through a short pad of silica gel with dichloromethane as the eluent and all volatiles removed in vacuo. This recovered solid was washed with copious amounts of cyclohexane and concentrated. Cyclohexane was found to best solubalize 4q in the presence of 4p when compared to room temperature and –78 °C hexanes, pentane and cyclopentane. Column chromatography of the residual white solid, containing a mixture of starting material and borylated product with Florisil® using 1 : 9 (ethyl acetate / hexanes) afforded 136 mg 4q (40% yield, mp = 118 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.86 (bs, 1H), 8.32 (d, J = 8.8, 1H), 7.98 (d, 3 J = 2.2, 1H), 7.63 (dd, J = 8.8, J = 2.2, 1H), 1.51 (s, 9H), 1.35 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.43, 148.85, 140.51, 136.17, 119.13, 117.57, 104.68, 84.9, 80.88, 28.22, 24.83; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.5; FTIR(thin film): 3354, 2980, 2932, 2221, 1735, 1609, 1585, 1529, 1480, 1414, 1397, 1362, 1321, 1250, 1165, 1139, 1078, 1050, 1030, 979, 966, 914, 891, 850, 832, 768, 748, 693, 563 cm-1; HRMS calcd. for C18H25BN2O4 [M]+ 344.1907, found 344.1910. Potassium (N-(tert-butoxycarbonyl)-2-amino-5-cyanophenyl) trifluoroborate (4r) O O NH N 3 equiv. 4p 1. 2 mol% [Ir(OMe)COD]2, 4 mol% dtbpy 0.2 equiv. HBPin, 0.4 equiv. B2Pin2 MTBE (50 °C, 36 h, N2) 2. 3.4 equiv. KHF2 THF, H2O (RT, 10 min, N2) O O NH N 4r K F B F F In a glovebox, a solution of 15 µ L (0.1 mmol) HBPin and 6.6 mg (0.01 mmol) [Ir(OMe)COD]2 in minimal MTBE was added to 5.3 mg (0.02 mmol) dtbpy. The 91 solution was subsequently transferred to an air free equipped with a stir bar, 52 mg (0.2 mmol) B2Pin2 and 327 mg (1.5 mmol) 4p in MTBE. The entire procedure was conducted using 2.0 mL MTBE. The reaction proceeded at 50 °C under N2 for 36 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. This recovered solid was washed with copious amounts of cyclohexane and concentrated. Cyclohexane was found to best solubalize 4q in the presence of 4p when compared to room temperature and –78 °C hexanes, pentane and cyclopentane. The residual white solid, containing a mixture of starting material and borylated product, was treated with 136 mg (1.7 mmol) KHF2 in 350 µL THF and 210 µL water for 10 min. After all volatiles were removed in vacuo, the remaining solid was extracted with acetone. Concentrating the solution provided a solid that was washed with hexanes and chloroform to afford 90 mg 4r as a white solid (51% yield, mp > 230 °C). 1H NMR (500 MHz, acetone-d = 2.05 ppm): % 8.44 (bs, 1H), 8.19 (d, J = 8.5, 1H), 7.66 6 (d, J = 2.0, 1H), 7.40 (dd, J = 8.6, J = 2.2, 1H), 1.49 (s, 9H); 13C NMR (126 MHz, acetone-d6 = 206 ppm): % 153.20, 146.76, 136.87, 130.93, 120.90, 116.79, 104.13, 79.76, 28.19; 11B NMR (96 MHz, acetone-d6, BF3•OEt2 = 0 ppm): % 3.4; 19F NMR (282 MHz, acetone-d6, CFCl3 = 0 ppm): % –139.15; FT-IR(thin film): 3393, 3020, 2985, 2935, 2229, 1724, 1581, 1517, 1392, 1366, 1312, 1245, 1212, 1156, 1119, 1052, 1024, 943, 937, 899, 847, 819, 598 cm-1; HRMS calcd. for C12H13BF3N2O2 [M-K]– 285.1022, found 285.1025. 92 O-(N’,N’-dimethylcarbamoyl)-N-(tert-butoxycarbonyl)-4-aminophenol (4s) 170 O O NH HO O 2.8 equiv. Me2NCOCl 3 equiv. pyridine (50 °C, 5 h, N2) NH O N O O 4s A flask was charged with a stirbar, 1.51 g (7.2 mmol) N-(tert-butoxycarbonyl)-4aminophenol and 1.7 mL (21.6 mmol) pyridine under a N2 atmosphere. After the addition of 1.9 mL (20.2 mmol) N,N-dimethylcarbamoyl chloride the mixture was heated at 50 °C for 5 hours. The contents were diluted with ethyl acetate, washed with 1M HCl in water and the organic layer dried over MgSO4. Crystallization from 3 : 1 (ethyl acetate / hexanes) afforded 1.33 g 4s as a white solid (66% yield, mp = 178-180 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.29 (d, J = 8.6, 2H), 6.99 (d, J = 8.8, 2H), 3 6.56 (bs, 1H), 3.06 (s, 3H), 2.98 (s, 3H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 155.09, 152.79, 146.87, 135.48, 122.07, 119.37, 80.39, 36.68, 36.39, 28.32; FTIR(thin film): 3297, 3131, 3053, 2979, 2932, 1706, 1606, 1535, 1513, 1490, 1458, 1407, 1369, 1309, 1239, 1207, 1163, 1108, 1050, 1017, 873, 873, 825, 757, 746, 694, 600, 525 cm-1; HRMS calcd. for C14H20N2O4 [M]+ 280.1423, found 280.1429. 93 N-(tert-butoxycarbonyl)-O-(N’,N’-dimethylcarbamoyl)-4-amino-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4t) O NH O N O O 3 equiv. 4s O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 0.4 equiv. B2Pin2 THF (80 °C, 16 h, closed) NH O N O O 4t B O O In a glovebox, a solution of 15 µ L (0.1 mmol) HBPin and 6.6 mg (0.01 mmol) [Ir(OMe)COD]2 in minimal THF was added to 5.3 mg (0.02 mmol) dtbpy. The solution was subsequently transferred to an air free flask equipped with a stir bar, 51 mg (0.2 mmol) B2Pin2 and 610 mg (1.5 mmol) 4s in THF. The entire procedure was conducted using 2.0 mL THF. The reaction was allowed to proceed at 80 °C in a closed system for 16 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent (Rf = 0.07). The recovered solid was washed with copious amounts of cyclohexane, concentrated to approximately 4 mL and cooled. The precipitated starting material was filtered and washed sparingly with cold cyclohexane. The filtrate was pumped down and the remaining solid crystallized from pentane at –80 °C overnight to afford 89 mg 4t as white needles (44% yield, mp = 126-128 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 8.59 (bs, 1H), 8.15 (d, J = 9.0, 1H), 7.41 (d, 3 J = 2.9, 1H), 7.13 (dd, J = 9.0, J = 2.9, 1H), 3.04 (s, 3H), 2.96 (s, 3H), 1.50 (s, 9H), 1.32 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 155.21, 153.08, 145.61, 142.44, 94 128.61, 126.04, 118.60, 84.33, 79.73, 36.64, 36.35, 28.34, 24.83; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.5; FT-IR(thin film): 3382, 2979, 2933, 1728, 1615, 1592, 1533, 1476, 1455, 1425, 1387, 1347, 1329, 1198, 1158, 1072, 1048, 1023, 965, 915, 854, 822, 791, 770, 743, 678, 547 cm-1; HRMS calcd. for C20H31BN2O6 [M]+ 406.2275, found 406.2275. X-Ray quality crystals were grown from pentane at –20 °C. N-(tert-butoxycarbonyl)-2-chloro-4-aminophenol (4u) Cl HO NH2 1.1 equiv. Boc2O H2O (RT, 22 h, open) O Cl HO O NH 4u The general procedure was applied using 5.00 g (34.8 mmol) 2-chloro-4-aminophenol, 40 mL water and 8.40 g (38.5 mmol) t-Boc2O for 22 hours to provide 7.98 g 4u as a white solid (99% yield, mp = 90-92 °C, lit174 mp = 77-79 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.51, (s, 1H), 6.99 (dd, J = 8.6, J = 2.4, 1H), 3 6.89 (d, J = 8.8, 1H), 6.35 (bs, 1H), 5.40, (s, 1H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.91, 147.40, 131.82, 119.91, 119.39, 116.16, 80.75, 28.31; FTIR(thin film): 3341, 3038, 2979, 2934, 1692, 1596, 1515, 1455, 1413, 1394, 1368, 1280, 1241, 1147, 1060, 1015, 938, 871, 816, 774, 746, 689, 588 cm-1; HRMS calcd. for C11H14ClNO2 [M]+ 243.0662, found 243.0669. 95 O-(N’,N’-dimethylcarbamoyl)-N-(tert-butoxycarbonyl)-2-chloro-4-aminophenol (4v) 170 O Cl HO O NH 4u O 1.3 equiv. Me2NCOCl pyridine (70 °C, 25 h, N2) O Cl O N NH O 4v A flask was charged with a stirbar and 2.00 g (8.2 mmol) 4u in pyridine under a N2 atmosphere. After the addition of 1.0 mL (10.7 mmol) N,N-dimethylcarbamoyl chloride the mixture was heated at 70 °C for 25 hours. The contents were diluted with ethyl acetate, washed with 1M HCl in water and the organic layer dried over MgSO4. Impurities were removed by washing the product with hexanes to afford 1.94 g 4v as a white solid (75% yield, mp = 162 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.50, (s, 1H), 7.02–6.96 (m, 3H), 3.10 (s, 3 3H), 3.00 (s, 3H), 1.47 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 154.26, 152.63, 142.49, 136.75, 126.98, 123.75, 119.82, 117.56, 80.44, 36.81, 36.46, 28.23; FTIR(thin film): 3429, 3321, 3055, 2986, 1718, 1606, 1518, 1456, 1392, 1265, 1209, 1155, 1059, 910, 875, 823, 740, 706 cm-1; HRMS(ESI+) calcd. for C14H19ClN2O4 [M+H]+ 315.1115, found 315.1118. 96 O-(N’,N’-dimethylcarbamoyl)-N-(tert-butoxycarbonyl)-2-chloro-5-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-4-aminophenol (4w) O Cl O N O NH O 4v O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 1.5 equiv. B2Pin2 MTBE (50 °C, 28 h, N2) NH Cl O N O O 4w B O O The general procedure was applied using 381 mg (1.5 mmol) B2Pin2, 314 mg (1.0 mmol) 4v for 28 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent twice to afford 272 mg 4w as a white solid (62% yield, mp = 140-142 °C, Rf = 0.26). 1H NMR (300 MHz, CDCl = 7.24 ppm): % 8.62 (s, 1H), 8.34 (s, 1H), 7.48 (s, 1H), 3.09 3 (s, 3H), 2.99 (s, 3H), 1.50 (s, 9H), 1.32 (s, 12H); 13C NMR (75 MHz, CDCl3 = 77 ppm): % 154.20, 152.77, 143.13, 141.69, 131.59, 130.60, 119.05, 84.51, 80.18, 36.80, 36.45, 28.28, 24.82; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 29.9; FT-IR(thin film): 3365, 2977, 2933, 1731, 1609, 1579, 1522, 1470, 1411, 1382, 1345, 1309, 1249, 1155, 1089, 1057, 973, 955, 908, 853, 839, 791, 752, 684, 669, 600, 503, 436 cm-1; HRMS calcd. for C20H30BClN2O6 [M]+ 340.1885, found 340.1895. 97 N-(tert-butoxycarbonyl)-3,5-dimethylaniline (5a) NH2 O 1.2 equiv. Boc2O O NH H2O (RT, 4 h, open) 5a The general procedure was applied using 1.82 g (15.0 mmol) 3,5-dimethylaniline, 15 mL water and 3.99 g (18.3 mmol) t-Boc2O for 4 hours to provide 2.82 g 5a as a white solid (85% yield, mp = 90 °C, lit175 mp = 93 °C). 1H NMR (300 MHz, CDCl = 7.24 ppm): % 6.98 (s, 2H), 6.66 (s, 1H), 6.38 (bs, 1H), 2.26 3 (s, 6H), 1.50 (s, 9H); 13C NMR (75 MHz, CDCl3 = 77 ppm): % 152.78, 138.64, 138.14, 124.75, 116.22, 80.29, 28.33, 21.34; FT-IR(neat): 3332, 2005, 2977, 2977, 2921, 2874, 1700, 1612, 1539, 1475, 1454, 1428, 1391, 1366, 1329, 1277, 1236, 1160, 1081, 1037, 1007, 936, 874, 840, 772, 688, 641, 512 cm-1; HRMS calcd. for C13H19NO2 [M]+ 221.1416, found 221.1416. N-(tert-butoxycarbonyl)-2,4-dimethylaniline (5b) NH2 1.2 equiv. Boc2O EtOAc (RT, 2 h, open) O O NH 5b A solution of 10.0 g (82.5 mmol) 2,4-dimethylaniline and 21.6 g (99.0 mmol) t-Boc2O in 20 mL ethyl acetate was stirred for 2 hours. All volatiles were removed in vacuo providing an off-white solid. The collected product was loaded onto a filter frit and washed three times with pentane to provide 13.80 g 5b as a white solid (76% yield, mp = 98 92 °C, lit164 mp = 90 °C). The filtrate was reduced in volume and crystallized at –30 °C to provide 1.65 g 5b as white needles (9% yield, mp = 92 °C, lit164 mp = 90 °C; combined yield = 85%). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.58 (s, 1H), 6.98–6.95 (m, 2H), 6.15 (bs, 3 1H), 2.26 (s, 3H), 2.19 (s, 3H), 1.50 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 153.27, 133.61, 133.36, 130.95, 127.83, 127.20, 121.48, 80.16, 28.34, 20.68, 17.62; FTIR(neat): 3319, 2976, 2919, 2862, 1693, 1593, 1521, 1441, 1391, 1366, 1307, 1240, 1162, 1050, 1025, 898, 813, 769, 556, 520, 446 cm-1; HRMS calcd. for C13H19NO2 [M]+ 221.1416, found 221.1414. N-(tert-butoxycarbonyl)-3,5-dichloroaniline (5c) NH2 Cl Cl O 1.1 equiv. Boc2O Cl O NH THF (70 °C, 36 h, N2) Cl 5c A solution of 7.00 g (43.2 mmol) 3,5-dichloroaniline and 10.37 g (47.5 mmol) t-Boc2O in THF was stirred for 36 hours at 70 °C under N2. All volatiles were removed in vacuo providing a light brown solid. Crystallization from boiling hexanes provided 5.10 g 5c as white needles (45% yield, mp = 104-106 °C). The remaining liquid was partitioned between ethyl acetate and 1M HCl in water. The organic layer was washed three times with 1M HCl in water, saturated brine and dried over MgSO4. The collected oil was dissolved in hexanes and crystallized at –30 °C to provide 3.87 g 5c as white needles 99 (34% yield, mp = 104-106 °C) The filtrate was reduced in vacuo and crystallized from hexanes at –30 °C to provide and additional 0.59 g 5c (5% yield, mp = 104-106 °C; combined crops = 9.56 g, 84% yield). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.29 (s, 2H), 6.98 (d, J = 2.4, 1H), 6.63 (bs, 3 1H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.16, 140.28, 135.17, 122.84, 116.61, 81.49, 28.19; FT-IR(neat): 3418, 3321, 3179, 3117, 2991, 2933, 1735, 1588, 1450, 1408, 1368, 1305, 1268, 1250, 1222, 1169, 1114, 1067, 993, 943, 864, 824, 809, 760, 671 cm-1; HRMS calcd. for C11H13Cl2NO2 [M]+ 261.0323, found 261.0325. N-(t-Boc)-N’-acetyl-p-phenylenediamine (5d) 170 NH2 O N H O 5 mol% Zn(ClO2)2•6H2O 1.3 equiv. Boc2O t-BuOH (30 °C, 20 h, open) O NH O N H 5d A solution of 5.0 g (33.3 mmol) 4-aminoacetanilide, 9.45 g (43.3 mmol) t-Boc2O, 0.62 g (1.67 mmol) Zn(ClO4)2•6H2O and 50 mL t-BuOH was stirred for 20 hours at 30 °C. All volatiles were removed in vacuo and the crude solid was partitioned between dichloromethane and brine. The organic layer was concentrated and the crude solid washed with diethyl ether / hexanes to afford 2.03 g 5d as a white solid (23% yield, dec. = 188 °C). 100 1H NMR (500 MHz, DMSO-d = 2.49 ppm): % 9.79 (s, 1H), 9.21 (s, 1H), 7.42 (d, J = 6 8.6, 2H), 7.33 (d, J = 7.8, 2H), 1.99 (s, 3H), 1.45 (s, 9H); 13C NMR (126 MHz, DMSOd6 = 39.5 ppm): % 167.76, 152.79, 134.71, 133.84, 119.44, 118.44, 78.74, 28.11, 23.79; FT-IR(neat): 3325, 2968, 2924, 1693, 1658, 1608, 1540, 1521, 1402, 1366, 1308, 1262, 1240, 1161, 1113, 1056, 11018, 858, 812, 654, 596, 515 cm-1; HRMS(ESI+) calcd. for C13H19N2O3 [M+H]+ 251.1396, found 251.1400. N-(tert-butoxycarbonyl)-N’,N’-dimethyl-p-phenylenediamine (5e) NH2 N O 1.1 equiv. Boc2O EtOAc (RT, 20 min, open) O NH N 5e A solution of 2.00 g (14.7 mmol) N,N-dimethyl-p-phenylenediamine, 3.55 g (16.2 mmol) t-Boc2O and 5 mL ethyl acetate was stirred for 20 min. All volatiles were removed in vacuo and the crude solid was washed three times with hexanes to afford 3.11 g 5e as a white solid (92% yield, mp = 98-100 °C, lit176 mp = 89-90 °C). 1H NMR (300 MHz, CDCl = 7.24 ppm): % 7.17 (d, J = 8.3, 2H), 6.68 (d, J = 8.6, 2H), 3 6.23 (bs, 1H), 2.87 (s, 6H), 1.48 (s, 9H); 13C NMR (75 MHz, CDCl3 = 7.24 ppm): % 153.41, 147.47, 128.34, 120.87, 113.48, 79.88, 41.09, 28.35 ; FT-IR(thin film): 3328, 2977, 2900, 2860, 1693, 1592, 1524, 1502, 1451, 1366, 1320, 1240, 1160, 1053, 946, 902, 818, 775, 703, 526 cm-1; HRMS calcd. for C13H20N2O2 [M]+ 236.1525, found 236.1531. 101 N-(tert-butoxycarbonyl)-4-amino-3-fluorophenol (5f) F NH2 HO F 1.1 equiv. Boc2O EtOAc (RT, 2 h, open) O O NH HO 5f A solution of 3.00 g (23.5 mmol) 4-amino-3-fluorophenol, 5.64 g (25.9 mmol) t-Boc2O and 15 mL ethyl acetate was stirred for 2 hours. All volatiles were removed in vacuo and the crude solid was washed three times with pentane. This solid was sublimed (90 °C, 0.01 mmHg) to afford 4.76 g 5f as white needles (93% yield, mp = 90-92 °C). 1H NMR (300 MHz, CDCl = 7.24 ppm): % 7.51 (t, J = 8.8, 1H), 6.54–6.45 (m, 3H), 6.37 3 (bs, 1H), 1.49 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 154.26 (d, J = 244.4), 153.82 (s), 153.19 (d, J = 10.3), 123.71 (s), 118.44 (s), 111.31(d, J = 2.8), 103.38 (d, J = 22.7), 81.17 (s), 28.30 (s); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –127.4; FTIR(thin film): 3332, 2980, 2930, 1691, 1629, 1603, 1527, 1453, 1393, 1368, 1294, 1250, 1159, 1108, 1056, 1027, 964, 845, 815, 769, 732, 623, 578, 467 cm-1; HRMS calcd. for C11H14FNO3 [M]+ 227.0958, found 217.0955. 102 N-(tert-butoxycarbonyl)-O-(methoxymethyl)-4-amino-4-fluorophenol (5g) F O O F 4 equiv. MOMCl NH HO 5f O O NH 1.2 equiv. Et3N THF (RT, 4 h, N2) O O 5g A solution of 2.27 g (10.0 mmol) 5f, 1.67 mL (12.0 mmol) triethylamine and 20 mL THF was placed under N2. After a slow addition of 3.0 mL (40.0 mmol) chloromethyl methyl ether at room temperature the solution was stirred for 4 hours. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate, washed with 0.7M KOH in water and washed with saturated brine. The organic layer was collected, dried over MgSO4 and all volatiles removed in vacuo. The obtained solid was sublimed (65 °C, 0.01 mmHg) to afford 0.94 g 5g as white needles (35% yield, mp = 42-44 °C). 1H NMR (300 MHz, CDCl = 7.24 ppm): % 7.86 (bs, 1H), 6.89–6.70 (m, 2H), 6.48 (bs, 3 1H), 5.09 (s, 2H), 3.44 (s, 3H), 1.49 (s, 9H); 13C NMR (75 MHz, CDCl3 = 7.24 ppm): % 153.10 (d, J = 10.6), 152.70 (d, J = 243.2), 152.70 (s), 121.43 (s), 120.89 (d, J = 11.1), 112.09 (d, J = 3.0), 104.05 (d, J = 22.7), 94.84 (s), 80.76 (s), 55.96 (s), 28.27 (s); 19F NMR (282 MHz, CDCl3 CFCl3 = 0 ppm): % –129.57; FT-IR(thin film): 3443, 3347, 2977, 2934, 2901, 2853, 1729, 1633, 1600, 1527, 1430, 1395, 1369, 1312, 1242, 1216, 1150, 1102, 1075, 1050, 1006, 942, 922, 847, 821, 769, 743, 715, 644, 540, 459 cm-1; HRMS calcd. for C13H18FNO4 [M]+ 271.1220, found 271.1220. 103 N-(t-Boc)-2-methoxy-5-aminopyridine (5h) 170 O N O 1.3 equiv. Boc2O NH2 1,4-dioxane (RT, 22 h, open) O NH O N 5h A solution of 2.0 g (16 mmol) 4-amino-2-methoxypyridine, 4.57 g (21 mmol) t-Boc2O and 8 mL 1,4-dioxane was stirred for 22 hours at room temperature. The contents were partitioned between dichloromethane and 1M HCl in water. The organic layer was washed with brine, dried over Na2SO4 and all volatiles removed in vacuo. Impurities were sublimed out (0.2 mmHg, 85 °C) to leave behind 0.86 g 5h as a white solid (24% yield, mp = 81 °C, lit177 mp = 84-85 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.97 (d, J = 2.9, 1H), 7.80 (s, 1H), 6.68 (d, J 3 = 9.0, 1H), 6.37 (s, 1H), 3.87 (s, 3H), 1.48 (s, 9H); 13C NMR (126 MHz, CDCl3 = 7.24 ppm): % 160.57, 153.19, 137.50, 131.46, 128.98, 110.56, 80.79, 53.48, 28.31; FT-IR(thin film): 3323, 3003, 2978, 2946, 1725, 1700, 1615, 1587, 1528, 1497, 1381, 1283, 1244, 1162, 1126, 1057, 1025, 901, 829, 802, 770, 733 cm-1; HRMS calcd. for C11H16N2O3 [M]+ 224.1161, found 224.1166. 104 2-furanyl acid chloride (5i) O O OH 2 equiv. SOCl2 O O Cl (80 °C, 2 h , open) 5i A literature procedure was followed as described.178 A flask charged with a stirbar, 5.0 g (45 mmol) 2-furoic acid and 6.5 mL (90 mmol) thionyl chloride was heated at 80 °C for 2 hours under a reflux condenser. Excess thionyl chloride was distilled at 80 °C. Further distillation at 79 °C under aspirator pressure afforded 4.81 g 5i as a colorless liquid (82% yield). 1H NMR (300 MHz, CDCl = 7.24p): % 7.73 (dd, J = 1.5, J = 0.7, 1H), 7.48 (dd, J = 3.7, 3 J = 0.7, 1H), 6.61 (dd, J = 3.7, J = 1.7, 1H); 13C NMR (75 MHz, CDCl3 = 7.24p): % 155.50, 149.75, 146.18, 124.56, 113.23; FT-IR(neat): 3478, 3141, 1769, 1634, 1559, 1459, 1388, 1259, 1233, 1160, 1080, 1025, 949, 886, 823, 775, 694, 579, 551 cm-1; HRMS calcd. for C5H3ClO2 [M]+ 129.9822, found 129.9828. N-(tert-butoxycarbonyl)-2-aminofuran (5j) O 1.2 equiv. NaN3 Cl O H N t-BuOH (25 °C ! 80 °C, 35 h , N2) 5i O O O 5j A literature procedure was followed as described.179 A round bottom flask was charged with a stir bar, 3.50 g (26.8 mmol) 5i, 2.09 g (32.2 mmol) sodium azide and 30 mL tertbutanol, then heated at 25 °C for 20 hours. After placing a protective shield in front of the 105 reaction flask, the solution was heated at 80 °C for 15 hours. All solvent was removed in vacuo and the crude solid purified via sublimation (90 °C at 0.05 mmHg) to afford 2.43 g 5j (50% yield, mp = 94-96 °C, lit179 mp = 98-99°C). 1H NMR (500 MHz, CDCl = 7.24p): % 7.04–7.03 (m, 1H), 6.63 (s, 1H), 6.32–6.30 (m, 3 1H), 6.01 (s, 1H), 1.48 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77p): % 151.86, 145.39, 136.08, 111.27, 95.16, 81.31, 28.18; FT-IR(thin film): 3240, 3154, 3071, 1983, 2923, 1690, 1610, 1557, 1523, 1473, 1369, 1284, 1257, 1211, 1160, 1073, 1057, 1004, 875, 793, 728, 647, 593 cm-1; HRMS calcd. for C9H13NO3 [M]+ 183.0895, found 183.0899. 6-methoxy-2-oxo-2,3-dihydrobenzoxazole (6a) O Cl O O NH 4l 1. 2.4 equiv TMEDA 2.4 equiv. sec-BuLi THF (–78 °C, 45 min, N2) 2. HCl / H2O CH2Cl2 (RT, 31 h, N2) O O O NH 6a A 25 mL round bottom flask was charged with a stir bar, 65 "L (0.44 mmol) TMEDA and 1.2 mL THF before being cooled to –78 °C under N2. The reaction was stirred for 5 minutes after the dropwise addition of 0.35 mL (0.44 mmol) 1.3M sec-BuLi in 92 : 8 (cyclohexane / hexane). While still at –78 °C, a solution of 50 mg (0.19 mmol) 4l in 0.8 mL THF was added dropwise and stirred for 45 minutes. After the addition of saturated NH4Cl in water the flask was warmed to room temperature, extracted with dichloromethane, dried over MgSO4 and all volatiles removed in vacuo. The obtained oil was redissolved in 5 mL 1 : 1 (dichloromethane / water) acidified with 3 drops 2M HCl 106 in water and stirred at room temperature for 31 hours. The product was extracted with dichloromethane, dried over MgSO4 and concentrated in vacuo. Trituration with minimal chloroform provided 17 mg 6a as colorless needles (53% yield, mp = 150 °C, lit123 mp = 154-155 °C). 1H NMR (500 MHz, acetone-d = 2.05 ppm): % 10.05 (s, 1H), 7.02 (d, J = 8.6, 1H), 6.90 6 (d, J = 2.4, 1H), 6.73 (dd, J = 8.6, J = 2.4, 1H), 3.79 (s, 3H); 13C NMR (126 MHz, acetone-d6 = 206 ppm): % 156.69, 155.23, 145.39, 124.37, 110.39, 109.79, 97.62, 56.06; FT-IR(thin film): 3086, 2983, 2876, 1777, 1737, 1500, 1452, 1316, 1209, 1183, 1137, 1095, 1022, 969, 940, 881, 844, 795, 775, 731, 708, 675, 601 cm-1; HRMS calcd. for C8H7N4O3 [M]+ 165.0426, found 165.0431. 3,3-dimethyl-N-(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)butanamide (7a) NH2 O BO 1 equiv. t-BuCH2COCl 1 equiv. Et3N Et2O (0 °C, 3 h, N2) HN O B O O 7a A stirring solution of 110 mg (0.50 mmol) 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline and 70 µL (0.50 mmol) triethylamine in 10 mL diethyl ether was prepared under a N2 atmosphere and cooled to 0 °C. The addition of 70 µL (0.50 mmol) 3,3dimethylbutyryl chloride via syringe was done dropwise. After stirring for 3 hours at 0 °C 107 all volatiles were removed in vacuo. The white powder was loaded onto a filter frit and washed with copious amounts of pentane then washed with chloroform. The chloroform was collected separately and passed through a pad of silica gel with chloroform as the eluent to afford 127 mg 7a as a white solid (80% yield, mp = 140-142 °C, Rf = 0.14). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 9.95 (bs, 1H), 8.14 (bs, 1H), 7.71 (dd, J = 3 7.3, J = 1.2, 1H), 7.34 (t, J = 7.3, 1H), 7.06 (t, J = 7.3, 1H), 2.00 (s, 3H), 1.350 (s, 12H), 1.04 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 170.55, 165.55, 135.40, 131.52, 123.58, 118.26, 83.36, 77.202, 31.35, 29.89, 25.24; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 25.7; FT-IR(thin film): 3380, 3261, 3189, 3019, 2989, 2963, 2913, 2873, 1633, 1600, 1581, 1559, 1480, 1446, 1382, 1369, 1315, 1279, 1218, 1173, 1154, 1118, 1054, 1000, 944, 875, 853, 759, 736, 699, 643, 539 cm-1; HRMS calcd. for C18H28BNO3 [M]+ 317.2162, found 317.2169. X-Ray quality crystals were grown from CHCl3 at 5 °C. N-(tert-butoxycarbonyl)-N-deuterio-3-chloroaniline (8a) O Cl O NH 2c 1. D2O / THF (40 °C, 18 h, N2) 2. Evaporate 3. D2O / THF (40 °C, 6 h, N2) O Cl O N D 8a A 100 mL Schlenk flask was washed with D2O and evaporated under N2 flow prior to use. The flask was charged with a stir bar, 2.04 g (8.8 mmol) 2c, 5 mL D2O and 5 mL THF, then heated to 40 °C. After 18 hours of stirring all volatiles were removed under N2 108 flow at 90 °C. The white solid was redissolved in 5 mL D2O and 5 mL THF and stirred at 40 °C for an additional 6 hours. All volatiles were removed under N2 flow at 90 °C. The remaining solid was sublimed (0.005 mmHg, 70 °C) to the side of the flask. The solid was scraped onto a filter frit in the glovebox, washed with a minimal amount of pentane and dried to afford 1.63 g 8a as a white solid (80% yield, >98% D-incorporation by NMR, mp = 82-84 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.50 (s, 1H), 7.18–7.12 (m, 2H), 6.99–6.97 3 (m, 1H), 1.50 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.56, 139.46, 134.72, 129.88, 122.97, 118.39, 116.26, 80.99, 28.27; FT-IR(neat): 2979, 2931, 2432, 1694, 1600, 1576, 1486, 1453, 1397, 1369, 1299, 1247, 1167, 1101, 1079, 1063, 1037, 998, 905, 852, 773, 708, 681 cm-1; HRMS calcd. for C111H132HClNO2 [M]+ 228.0776, found 228.0780. N-(tert-butoxycarbonyl)-N-methyl-3-chloroaniline (8b) O Cl O NH 2c O 3.9 equiv. NaH, 5.5 equiv. MeI Cl Et2O (0 °C ! RT, overnight, N2) O N 8b A flask was charged with a stirbar, 5 mL diethyl ether and 380 mg (1.7 mmol) 2c and cooled to 0 °C under a N2 atmosphere. The contents were stirred during the slow addition of 160 mg (6.7 mmol) NaH powder. Once no more gas evolution was observed 0.6 mL (9.4 mmol) methyl iodide was added and the contents stirred at room temperature overnight. The reaction was quenched with saturated NH4Cl in water, extracted with 109 diethyl ether, the organic layer washed with brine, dried over MgSO4 and concentrated in vacuo. After column chromatography with dichloromethane as the eluent (Rf = 0.65) the obtained liquid was taken into the glovebox and passed through a short pad of activated neutral alumina with diethyl ether to afford 400 mg 8b as a colorless liquid (99% yield). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.25–7.21 (m, 2H), 7.13–7.11 (m, 2H), 3.23 3 (s, 3H), 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 154.36, 144.97, 133.94, 129.42, 125.64, 125.37, 123.49, 80.79, 37.12, 28.29; FT-IR(thin film): 3057, 2975, 2927, 2855, 1705, 1615, 1594, 1577, 1482, 1457, 1434, 1391, 1364, 1352, 1305, 1253, 1153, 1120, 1091, 985, 865, 824, 777, 725, 694, 587, 418 cm-1; HRMS calcd. for C12H16ClNO2 [M]+ 241.0870, found 241.0870. N-(tert-butoxycarbonyl)-N-methyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (8c) O O Cl O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy O N Cl N 8b 0.2 equiv. HBPin 0.75 equiv. B2Pin2 MTBE (50 °C, 17 h, N2) O B O 8c The general procedure was applied using 191 mg (0.75 mmol) B2Pin2, 181 mg (0.75 mmol) 8b for 17 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane, quenching with a small amount of methanol and removing all volatiles in vacuo. The crude solid was passed 110 through a short pad of silica gel with dichloromethane as the eluent to afford a colorless oil that crystallized upon standing for several days to afford 262 mg 8c as colorless crystals (95% yield, mp = 64-66 °C, Rf = 0.72). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.55 (d, J = 1.2, 1H), 7.50 (d, J = 1.2, 1H), 3 7.33 (s, 1H), 3.23 (s, 3H), 1.43 (s, 9H), 1.32 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 154.37, 144.49, 133.64, 131.38, 129.18, 128.74, 84.23, 80.67, 37.12, 28.27, 24.83; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.2; FT-IR(thin film): 2978, 2931, 1706, 1569, 1560, 1506, 1472, 1458, 1425, 1353, 1293, 1269, 1250, 1145, 994, 964, 882, 849, 769, 704, 604 cm-1; HRMS calcd. for C18H27BClNO4 [M]+ 367.1722, found 367.1723. O-(tert-butoxycarbonyl)-3-chlorophenol (8d) 169 Cl OH 1.2 equiv. Boc2O 0.02 equiv. DMAP CH2Cl2 (RT, 13 h, N2) O Cl O O 8d The general procedure was applied using 2.0 g (15.6 mmol) 3-chlorophenol, 0.28 g (2.3 mmol) N,N-dimethyl-4-aminopyridine, 20 mL dichloromethane and 4.1 g (18.7 mmol) tBoc2O for 13 hours to provide 3.2 g 8d as a yellow liquid (91% yield). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.29–7.26 (m, 1H), 7.20–7.18 (m, 2H), 3 7.07–7.05 (m, 1H), 1.54 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 151.55, 111 151.38, 134.61, 130.08, 126.00, 121.974, 119.64, 84.02, 27.67; FT-IR(neat): 3076, 2982, 2934, 2882, 1761, 1591, 1476, 1430, 1395, 1370, 1277, 1255, 1220, 1096, 1091, 1070, 1049, 1020, 1001, 912, 847, 780, 742, 676, 597 cm-1; HRMS calcd. for C11H13ClO2 [M]+ 228.0553, found 228.0558. O-(tert-butoxycarbonyl)-5-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenol (8e) O O Cl O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy Cl O O O 8d 0.2 equiv. HBPin 0.6 equiv. B2Pin2 MTBE (50 °C, 24 h, N2) O B O 8e The general procedure was applied using 152 mg (0.6 mmol) B2Pin2, 228 mg (1.0 mmol) 8d for 24 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent (Rf = 0.68) to afford a colorless oil that crystallized upon standing for several days. The colorless crystals were loaded onto a filter frit and washed with a minimal amount of –78 °C pentane to afford 306 mg 8e as colorless crystals (88% yield, mp = 80 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.62 (dd, J = 2.0, J = 0.7, 1H), 7.45 (dd, J = 3 2.2, J = 0.7, 1H), 7.24 (t, J = 2.2, 1H), 1.53 (s, 9H), 1.31 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 151.52, 151.11, 134.28, 131.99, 125.46, 124.60, 84.35, 83.83, 27.67, 112 24.82; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 29.8; FT-IR(thin film): 3077, 2980, 2934, 1761, 1633, 1573, 1471, 1417, 1372, 1351, 1328, 1266, 1216, 1143, 1098, 1052, 965, 930, 865, 842, 782, 714, 701, 450, 425 cm-1; HRMS calcd. for C17H24BClO5 [M]+ 354.1405, found 354.1407. 3-chlorophenyl tert-butylcarbamate (8f) Cl OH 0.3 equiv. Et3N toluene (RT, 14 h, N2) H N O 1.1 equiv. t-BuNCO Cl O 8f A solution containing 3.00 g (23.3 mmol) 3-chlorophenol, 2.8 mL (25.0 mmol) tert-butyl isocyanate and 1 mL (7.2 mmol) triethylamine in 10 mL toluene was stirred via magnetic stirbar at room temperature under a N2 atmosphere. After 14 hours all volatiles were removed in vacuo and the remaining solid loaded onto a filter frit and washed with hexanes to afford 4.81 g 8f as a white solid (92% yield, mp = 96 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.27–7.24 (m, 2H), 7.15–7.14 (m, 1H), 3 7.03–7.01 (m, 1H), 5.01 (bs, 1H), 1.41 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 151.43, 140.39, 133.98, 129.53, 128.37, 127.62, 126.30, 83.10, 27.88; FT-IR(thin film): 3331, 3068, 3035, 3006, 2967, 2934, 2907, 2875, 1718, 1588, 1537, 1475, 1458, 1427, 1393, 1366, 1279, 1258, 1212, 1152, 1087, 1068, 1050, 1022, 1000, 927, 897, 881, 867, 793, 769, 689, 673, 650, 559, 460, 440 cm-1; HRMS calcd. for C11H14ClNO4 [M]+ 227.0713, found 227.0719. 113 3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl tert-butylcarbamate (8g) H N O H N O Cl O 8f 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 0.2 equiv. HBPin 1 equiv. B2Pin2 MTBE (50 °C, 24 h, N2) Cl O O B O 8g The general procedure was applied using 254 mg (1.0 mmol) B2Pin2, 227 mg (1.0 mmol) 8f for 24 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent to afford a colorless oil containing 8g and 3-chlorophenol (5:1). This mixture was diluted with ethyl acetate and washed with 2M NaOH in water until the aqueous layer was colorless. The organic layer was subsequently washed with saturated brine, dried over MgSO4 and concentrated in vacuo to afford 178 mg 8g as a white solid (50% yield, mp = 106-108 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.58 (d, J = 1.22, 1H), 7.40 (d, J = 1.5, 1H), 3 7.21 (t, J = 2.2, J = 2.0, 1H), 4.98 (s, 1H), 1.36 (s, 9H), 1.31 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.25, 151.03, 134.11, 131.35, 125.98, 125.15, 84.25, 50.293, 28.76, 24.823; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.5; FTIR(thin film): 3339, 2981, 2932, 1736, 1571, 1522, 1446, 1412, 1370, 1350, 1327, 1266, 114 1199, 1144, 1097, 1052, 1025, 965, 935, 914, 864, 844, 734, 702 cm-1; HRMS calcd. for C17H25BClNO4 [M]+ 353.1565, found 353.1565. N-(3-chlorophenyl)-3,3-dimethylbutanamide (8h) Cl NH2 1.2 equiv. t-BuCH2COCl 1.3 equiv. Et3N Et2O (0 °C ! RT, 2 h, N2) O Cl NH 8h A stirring solution of 1.57 g (12.3 mmol) 3-chloroaniline and 2.2 mL (15.8 mmol) triethylamine in 30 mL diethyl ether at 0 °C was prepared under a N2 atmosphere. The addition of 2.0 mL (14.4 mmol) 3,3-dimethylbutyryl chloride via syringe was done dropwise. After 2 hours at room temperature, the contents were poured into 10 mL water and the solution extracted three times with diethyl ether, washed with saturated brine, dried over MgSO4 and evaporated in vacuo. The off-white solid was loaded onto a filter frit and washed three times with hexanes to afford 2.66 g 8h as a white solid (96% yield, mp = 110-112 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.64 (bs, 1H), 7.61 (s, 1H), 7.31 (d, J = 7.3, 3 1H), 7.16 (t, J = 8.1, 1H), 7.02 (d, J = 7.8, 1H), 2.19 (s, 2H), 1.06 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 170.57, 139.01, 134.47, 129.81, 124.20, 120.22, 118.07, 51.31, 31.30, 29.74; FT-IR(thin film): 3280, 3249, 3182, 3118, 3072, 2962, 2925, 2900, 2867, 1656, 1590, 1532, 1442, 1417, 1367, 1333, 1268, 1253, 1235, 1200, 1133, 1092, 1077, 998, 925, 869, 792, 751, 688, 542, 430 cm-1; HRMS calcd. for C12H16ClNO [M]+ 225.0920, found 225.0918. 115 N-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3,3dimethylbutanamide (8i) O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy O Cl NH Cl NH 8h 0.2 equiv. HBPin 2.5 equiv. B2Pin2 MTBE (50 °C, 48 h, N2) O B O 8i The general procedure was applied using 635 mg (2.5 mmol) B2Pin2, 225 mg (1.0 mmol) 8h for 48 hours. Isolation involved transferring the solution to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude mixture was purified via column chromatography using dichloromethane as the eluent to afford 183 mg 8i as a white solid (52% yield, mp = 160-162 °C, Rf = 0.27). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.99 (s, 1H), 7.47 (d, J = 1.7, 1H), 7.45 (d, J 3 = 2.2, 1H), 7.17 (bs, 1H), 2.18 (s, 2H), 1.30 (s, 12H), 1.06 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 170.09, 138.54, 134.58, 130.10, 123.43, 122.75, 84.24, 51.62, 31.29, 29.79, 24.83; 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.6; FT-IR(thin film): 3306, 3124, 2977, 2869, 1672, 1629, 1578, 1543, 1468, 1353, 1266, 1232, 1143, 1116, 868, 715, 707 cm-1; HRMS calcd. for C18H27BClNO3 [M]+ 351.1773, found 351.1775. 116 1-(tert-butyl)-3-(3-chlorophenyl) urea (8j) Cl NH2 O 1.2 equiv. t-BuNCO 0.5 equiv. Et3N DCE (80 °C, 16 h, N2) Cl H N NH 8j A solution containing 2.55 g (20 mmol) 3-chloroaniline, 1.4 mL (10 mmol) triethylamine and 2.7 mL (24 mmol) tert-butyl isocyanate in 20 mL 1,2-dichloroethane was heated at 80 °C under a N2 atmosphere. After 16 hours all volatiles were removed in vacuo and the crude oil dissolved in ethyl acetate, washed with 1M HCl in water, 2M NaOH in water, saturated brine, dried over MgSO4 and concentrated in vacuo. Crystallization from boiling dichloromethane / pentane provided 1.87 g 8j as white needles (41% yield, mp = 146-148 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.35 (s, 1H), 7.13–7.07 (m, 2H), 6.94–6.91 3 (m, 2H), 5.11 (bs, 1H), 1.33 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 154.84, 140.40, 134.63, 129.91, 122.77, 119.70, 117.60, 50.79, 29.29; FT-IR(thin film): 3348, 3187, 3120, 2962, 2931, 2878, 1652, 1590, 1551, 1480, 1454, 1420, 1394, 1365, 1284, 1253, 1210, 1100, 1077, 1037, 996, 893, 876, 771, 680, 601, 461, 439 cm-1; HRMS calcd. for C11H15ClN2O [M]+ 226.0873, found 226.0871. 117 N-(tert-butoxycarbonyl)-2-deuterio-5-chloroaniline (9a) O O NH Cl BO O 2d 1. CD3OD / CH2Cl2 (1 : 1) (RT, 12 h, N2) 2. Evaporate solvent under N2 flow 3. 5 mol% [Ir(OMe)COD]2 (55 °C, 3 h, N2) + 10 mol% [Ir(OMe)COD]2 (55 °C, 5 h, N2) CD3OD / CH2Cl2 (2 : 1) O O NH Cl D 9a All glassware used in this reaction was washed with D2O and evaporated under N2 flow prior to use. A 25 mL 2-neck round bottom flask was fitted with a reflux condenser, stir bar, 72 mg (0.2 mmol) 2d, 0.7 mL CD3OD and 0.7 mL dichloromethane. All volatiles were removed under N2 flow after 12 hours of stirring. To this flask was added 6.8 mg (0.01 mmol) [Ir(OMe)COD]2, 1.4 mL CD3OD and 0.7 mL dichloromethane. TLC analysis using Dichloromethane as the eluent showed no reaction after 3 hours at 55 °C. An additional 13 mg (0.02 mmol) [Ir(OMe)COD]2 was added and the reaction heated at 55 °C for 5 hours. TLC analysis showed complete conversion and all volatiles were removed in vacuo. The brown solid was passed through a short pad of silica gel using dichloromethane as the eluent, taken into the glovebox and passed through a pipette of neutral alumina to afford 21 mg 9a as a tan solid (45% yield, 94% D-incorporation by mass spectroscopy, mp = 82-84 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.49 (s, 1H), 7.17 (d, J = 8.1, 1H), 6.98 (dd, 3 J = 7.3, J = 2.0, 1H), 6.52 (s, 1H), 1.50 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 152.40, 139.47, 134.67, 129.76, 122.97, 118.44, 80.98, 28.26; FT-IR(neat): 3410, 3329, 3063, 2979, 2931, 1731, 1701, 1590, 1522, 1473, 1414, 1393, 1368, 1300, 1273, 1246, 118 1159, 1094, 1054, 1027, 982, 929, 854, 826, 771, 623, 543 cm-1; HRMS calcd. for C111H122HClNO2 [M]+ 228.0776, found 228.0782. Borylation of N-(tert-butoxycarbonyl)-2-deuterio-5-chloroaniline O O NH Cl D 9a 5 mol% [Ir(OMe)COD]2 10 mol% dtbpy 0.4 equiv. HBPin 1 equiv. B2Pin2 MTBE (50 °C, 50 h, closed) O Cl O NH BO O O O NH Cl D O B O 2d In a glovebox, a stock solution was prepared by adding 15 µL (0.05 mmol) HBPin to 4 mg (0.006 mmol) [Ir(OMe)COD]2 and transferring the slurry to 3 mg (0.1 mmol) dtbpy and 31 mg (0.1 mmol) B2Pin2 using 250 µL MTBE. Two J-Young NMR tubes were each loaded with 70 µL stock solution. Another stock solution was prepared by adding 50 µL MTBE to 19 mg 9a and 18 µL (7 mg 9a) of this solution was added to each NMR tube. The NMR tubes were sealed and heated at 50 °C for 20 hours. A drop of methanol was added and all volatiles removed in vacuo. CDCl3 was added to the NMR tubes and the contents evaluated by 500 MHz 1H NMR. The KIE was evaluated as described below. 119 kH % ortho(HH) / % meta(HH) KIE = = kD % ortho(DH) / % meta(DH) kH [(67.7 / 32.3) + (67.5 / 32.5)] / 2 KIE(obs) = = kD(obs) 2.09 ± 0.01 = [(36.6 / 63.4) + (38.5 / 61.5)] / 2 = 3.5 ± 0.1 0.602 ± 0.035 Substrate has 94% deuterium incorporation. kH Therefore: kH = kD(obs) (0.06)kH + (0.94)kD kD(obs) = (0.06)kH + (0.94)kD kD(obs) – (0.06)kH kD = (0.602 ± 0.035) – (0.06)(2.09 ± 0.01) = = 0.507 ± 0.058 0.94 kH KIE = 0.94 2.09 ± 0.01 = kD = 4.1 ± 0.1 0.507 ± 0.058 Diethyl benzyl phosphonate (10a) 180 Br O P O O 1.5 equiv. P(OEt)3 (RT ! 140 °C, open) 10a A 500 mL round bottom flask was charged with a stir bar, 36 mL (303 mmol) benzyl bromide and 77 mL (449 mmol) triethyl phosphite before being fitted with a short path distillation apparatus. The solution was heated at 115 °C until all ethyl bromide distilled over, then the flask was heated to 140 °C to remove excess triethyl phosphite to leave behind 64 g 10a as a colorless liquid (93% yield). 120 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.29–7.28 (m, 4H), 7.23–7.22 (m, 1H), 3 4.02–3.94 (m, 4H), 3.13 (d, J = 21.7, 2H), 1.215 (t, J = 7.1, 6H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 131.53 (d, J = 8.9), 129.67 (d, J = 6.9), 128.40 (d, J = 2.8), 126.74 (d, J = 3.4), 61.99 (d, J = 6.9), 33.69 (d, J = 138.0), 16.24 (d, J = 6.2); 31P NMR (202 MHz, CDCl3, H3PO4 = 0 ppm): % 27.15; FT-IR(thin film): 3086, 3063, 3031, 2982, 2930, 2907, 2870, 1496, 1454, 1391, 1250, 1190, 1163, 1097, 1055, 1028, 961, 877, 843, 802, 772, 750, 698, 619, 587, 561, 530, 488, 445 cm-1; HRMS calcd. for C11H17O3P [M]+ 228.0915, found 228.0906. Benzyl phosphine (10b) 150,181,182 O P O O 10a 2 equiv. LiAlH4 1.5 equiv. TMSCl Et2O (–78 °C ! RT, 6 h, N2) PH2 10b In a glovebox, a 250 mL Schlenk flask was fitted with a stirbar, 60 mL diethyl ether and 3.64 grams (96.0 mmol) LiAlH4 before being sealing with a septum and fastened with copper wire. The flask was taken out of the glovebox and placed under N2 before being cooled to –78 °C. After the addition of 9 mL (78.8 mmol) TMSCl over the course of 10 min, the flask was stirred at –78 °C for 30 min. The addition of 10 mL (48.0 mmol) 10a was done dropwise over the course of 2 hours. After complete addition the flask was stirred at –78 °C for 3 hours and then gently warmed to room temperature (Caution: This reaction generates H2 which is accelerated during warming). A 31P NMR sample showed complete conversion at this point. Quenching was performed at 0 °C by the dropwise 121 addition of 10 mL degassed ethyl acetate, 140 mL degassed water and 5 mL degassed 15 wt% aqueous NaOH. The diethyl ether layer was canula transferred through MgSO4 into a 250 mL Schlenk flask. The water layer was washed three times with 60 mL portions of diethyl ether. The Schlenk flask was fitted with a distillation head and cooled to 0 °C. Diethyl ether was removed by cooling the collection flask to –78 °C and applying 1 mmHg pressure. After all diethyl ether was collected in the cold traps the collection flask was warmed to 0 °C while still at 1 mmHg. Warming the Schlenk flask to room temperature and cooling the collection flask to –78 °C at 0.005 mmHg afforded 5.32 grams 10b as a colorless liquid (88% yield). O P O O 10a 1.2 equiv. LiAlH4 1.5 equiv. TMSCl Et2O (–78 °C ! RT, 4 h, N2) PH2 10b The reaction was repeated with identical glassware and technique using 90 mL diethyl ether, 7.24 grams (115.1 mmol) LiAlH4 and 18 mL (141.8 mmol) TMSCl. The addition of 20 mL (95.9 mmol) 10a was done dropwise over the course of 5 hours. After complete addition the flask was stirred at –78 °C for 3 hours and then gently warmed to room temperature (Caution: H2 evolution is accelerated during warming). After cooling to 0 °C another 4 mL (19.2 mmol) 10a was added dropwise over the course of 20 min. LiAlH4 was quenched as above and purification was performed as above to afford 12.2 grams 10b as a colorless liquid (85% yield). For future note, it is recommended that the slow addition of 10a be performed at 0 °C instead of at –78 °C to adequately monitor the formation of H2. It is worth mentioning that 10b is air sensitive and pyrophoric. 122 1H NMR (300 MHz, CDCl = 7.24 ppm): % 7.53–7.37 (m, 5H), 3.25 (d, J = 194.4, 2H), 3 3.07 (m, 2H); 13C NMR (75 MHz, CDCl3 = 77 ppm): % 142.37 (s), 128.40 (s), 127.48 (d, J = 3.5), 125.49 (d, J = 2.5), 20.67 (d, J = 10.6); 31P NMR (121 MHz, CDCl3, H3PO4 = 0 ppm): % –120.8; FT-IR(in CDCl3): 3852, 3365, 3151, 3029, 2823, 2613, 1440, 2307, 2150, 1945, 1875, 1800, 1748, 1654, 1599, 1538, 1494, 1452, 1422, 1318, 1228, 1179, 1077, 1029, 929 cm-1. HRMS could not be obtained due to the instability of benzyl phosphine in air. Phenyl trivinylsilane (10c) 150 Cl Cl Cl Si 3.3 equiv. H2C=CHMgBr Si THF (RT, 14 h, N2) 10c A 2 L two-neck flask was fitted with a N2 inlet and a pressure equalizing addition funnel then filled with 760 mL (760 mmol) 1.0M vinyl magnesium bromide solution in THF. The slow addition of 36.9 mL (230 mmol) trichlorophenylsilane was performed via addition funnel at room temperature. A dropwise addition ensured controlled warming of the solution. This mixture was subsequently stirred for 14 hours, after which saturated NH4Cl in water was added slowly. The contents were filtered through Celite, dried with MgSO4 and transferred to a 200 mL 14/20 single-neck flask. Distillation under high vacuum into a flask cooled to 0 °C afforded 36.28 grams 10c as a colorless liquid (85%). 123 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.55–7.53 (m, 2H), 7.38–7.34 (m, 3H), 6.32 3 (dd, J = 20.0, J = 14.4, 3H), 6.19 (dd, J = 14.7, J = 3.9, 3H), 5.84 (dd, J = 20.0, J = 3.9, 3H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 135.90, 135.06, 134.44, 133.81, 129.41, 127.83; FT-IR(thin film): 3067, 3051, 3007, 2945, 1923, 1590, 1428, 1401, 1267, 1111, 1007, 958, 810, 716, 620, 549 cm-1; HRMS calcd. for C12H14Si [M]+ 186.0865, found 186.0861. Tris(2-bromoethyl)(phenyl)silane (10d) 150 Br Si 4.3 equiv. Br2, tetralin 0.08 equiv. (PhCO2)2 10c toluene (RT, 5 days, N2) Br Si Br 10d N2 in Br2 out tetralin tetralin aq. NaOH Glassware was set up as shown above using glass tubing and rubber stoppers. Hydrogen bromide was generated slowly by adding a total of 42 mL (815 mmol) Br2 to 44 mL tetralin. This was scrubbed with a second solution of tetralin before being passed through a solution of 11.00 g (186 mmol) 10c in 50 mL toluene with assistance from a dispersion frit and N2. A total of 3.58 g (14.8 mmol) benzoyl peroxide was added in small portions over the course of 5 days at room temperature. The reaction was monitored by 1H NMR. 124 Work up involved removing the toluene solution from the hydrogen bromide source and stirring the solution with saturated Na2S2O3 in water and saturated NaHCO3 in water for 2 hours. The water layer was extracted twice with diethyl ether. The organic layers were collected, washed with brine, dried over MgSO4 and concentrated in vacuo to afford a colorless oil that darkened upon standing. This oil was washed with ethanol (distilled from 3Å MS) and canula transferred into a round bottom flask. The solution was concentrated and crystallized at –20 °C to afford 7.01 g 10d as a light brown solid (28% yield, mp = 50-58 °C). This compound was recrystallized from hot ethanol (distilled from 3Å MS) to yield 3.98 g 10d as off-white needles (16% yield, mp = 62-64 °C, lit150 mp = 66.8-67.5 °C). Column chromatography was performed on the remaining material with hexanes as the eluent to afford impure 10d (Rf = 0.03). The impure 10d was dissolved in minimal dichloromethane at 50 °C, diluted with 20 mL hexanes and crystallized at –20 °C to afford 4.83 g 10d (19% yield, mp = 60-62 °C, lit150 mp = 66.8-67.5 °C, overall 35% yield). For future note, it is recommended that column chromatography be performed on the crude product prior to crystallization. 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.44–7.40 (m, 5H), 3.51–3.48 (m, 6H), 3 1.73–1.70 (m, 6H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 133.73, 131.78, 130.53, 128.67, 28.99, 19.17; FT-IR(thin film): 3070, 3043, 2961, 2897, 1486, 1425, 1253, 1151, 1112, 1025, 875, 733, 699, 599, 469, 431, 404 cm-1; HRMS calcd. for C12H17Br3Si [M]+ 425.8650, found 425.8695. 125 1-boranato-1-benzyl-4-(2-bromoethyl)-4-phenyl-1-phospha-4-silacylohexane (10e) 150 PH2 1.1 equiv. BH3•THF BH3 PH2 THF (2 °C, 23 h, N2) 2 equiv. 10d BH3 Br 4 equiv. NaH, THF (0 °C ! 2 °C, 20 h, N2) 10b P Si 10e A 25 mL Schlenk flask was charged with a stir bar, placed under a N2 atmosphere, loaded with 0.2 mL (0.28 g, 2.26 mmol) 10b and cooled to 2 °C with an Endocal refrigerated bath/circulator as measured by mercury thermometer. A syringe was used to add 2.6 mL 1.0M BH3•THF solution (2.6 mmol) dropwise onto the stirring 10b. This solution was stirred at 2 °C for 23 hours. A 100 mL Schlenk flask was charged with a stir bar and 1.95 g (4.54 mmol) 10c before being placed under a N2 atmosphere, cooled to 0 °C and diluted with 6 mL THF. While under a N2 atmosphere 0.22 g (9.06 mmol) NaH were added to the 100 mL Schlenk flask. The 10b borane adduct in THF was slowly transferred using a Teflon canula over the course of 15 min. The flask was moved into the Endocal cooling bath and stirred at 2 °C. After 20 hours the contents were quenched with saturated NH4Cl in water, diluted with water and extracted with two portions of diethyl ether. The organic layers were collected, washed with concentrated brine, dried over MgSO4 and concentrated in vacuo. The crude oil was purified via gradient silica gel chromatography using hexanes to 1 : 1 (dichloromethane / hexanes) as the eluent to afford 0.57 g 10e as a waxy solid (62% yield, Rf = 0.15). 126 PH2 1.1 equiv. BH3•THF BH3 PH2 10b P 4 equiv. NaH, THF (0 °C ! 2 °C, 20 h, N2) THF (2 °C, 5 h, N2) 1.8 equiv. 10d BH3 Si Br 10e The reaction was repeated with 0.8 mL (1.12 g, 9.1 mmol) 10b and 12.0 mL 1.0M BH3•THF solution (11.8 mmol) for 5 hours. A 250 mL Schlenk flask was charged with 7.04 g (16.4 mmol) 10c, 20 mL THF and 0.87 g (36.4 mmol) NaH. Transfer using a Teflon canula was done over the course of 45 min. After 20 hours the contents were quenched as described above and purified as above to afford 1.61 g 10e as a waxy solid (44% yield, Rf = 0.15) and 2.90 g 10d (41% recovery). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.49–7.23 (m, 9H), 7.11 (d, J = 7.1, 1H), 3 3.47–3.42 (m, 2H), 3.05 (dd, J = 76.2, J = 11.0, 2H), 1.98–1.18 (m, 10H), 0.54 (d, J = 116.0, 3H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 133.77–133.55 (m, 2C), 132.48 (d, J = 33.0), 131.89 (dd, J = 20.6, J = 6.9), 130.24–130.02 (m, 2C), 129.54–129.47 (m, 2C), 128.64–128.35 (m, 2C), 127.13–126.93 (m, 2C), 32.31 (dd, J = 122.9, J = 30.9), 30.02–29.62 (m, 2C), 19.79 (d, J = 241.0), 18.28–17.77 (m, 2C), 4.72 (d, J = 43.3); 31P NMR (202 MHz, CDCl3, H3PO4 = 0 ppm): % 14.23 (t, J = 100.7); 11B NMR (160 MHz, CDCl3, BF3•OEt2 = 0 ppm): % –41.1; FT-IR(thin film): 3084, 3065, 3027, 2920, 2893, 2367, 2244, 1600, 1494, 1453, 1425, 1250, 1156, 1114, 1057, 1027, 912, 853, 798, 765, 736, 700, 572, 491, 472 cm-1; HRMS calcd. for C19H27BBrPSi [M]+ 404.0896, found 404.0881. 127 4-phenyl-1-phospha-4-silabicyclo[2.2.2.]octane (10f) 150 P BH3 8 equiv. 1-octene P DME (100 °C, 5 days, N2) Si Br Si 10e Br P 2 equiv. LiAlH4 Si (RT, 22 h, N2) 10f A 100 mL Schlenk flask was charged with a stir bar, loaded with 1.61 g (3.97 mmol) 10e using 30 mL DME and sealed with a septum. The flask was placed under N2 and the addition of 5 mL (31.79 mmol) 1-octene was performed via syringe. The septum was exchanged for a reflux condenser and the contents heated at 100 °C for 5 days. The flask was cooled to room temperature, DME removed via canula and the remaining white solid washed with three portions of 1:1 diethyl ether / hexanes. All volatiles were removed under high vacuum. The flask was introduced into a glove box and diluted with 30 mL THF. The addition of 301 mg (7.95 mmol) LiAlH4 was done in small portions at room temperature. After 22 hours of stirring at room temperature the flask was sealed with a septum, fastened with copper wire and placed under N2. LiAlH4 was quenched dropwise with degassed water at 0 °C. Once all hydride was quenched, excess degassed water and degassed benzene were added. The solution was canula transferred through celite into a 250 mL Schlenk flask. The reaction vessel was washed four times with benzene. All volatiles were removed under high vacuum. The Schlenk flask was introduced into a glovebox and the obtained white solid was passed through a pipette of neutral alumina using benzene as the eluent. This solid was then sublimed (40 °C, 0.005 mmHg) to afford 223 mg 10f as white needles (27% yield, mp = 88-90 °C, lit150 mp = 90.5-90.7 °C). 128 Worth noting is that 10f is not air stable in solution as has been claimed in the literature.150,183 1H NMR (500 MHz, C D = 7.15 ppm): % 7.30–7.28 (m, 2H), 7.15–7.12 (m, 3H), 1.86 6 6 (q, J = 10.7, J = 7.6, 6H), 0.87–0.83 (m, 6H); 13C NMR (126 MHz, C6D6 = 128 ppm): % 136.49 (s), 134.26 (s), 129.67 (s), (2C underneath C6D6), 18.22 (d, J = 15.8), 4.57 (s); 31P NMR (202 MHz, CDCl , H PO = 0 ppm): % –59.11; FT-IR(thin film): 3063, 2933, 3 3 4 2920, 2893, 1424, 1412, 1127, 963, 842, 759, 729, 697, 649, 462 cm-1; HRMS(ESI+) calcd. for C12H18PSi [M+H]+ 221.0915, found 221.0911. Silica-SMAP (10g) 149 Si OO S F O F F H P P 8 equiv. TfOH C6H6 (RT, 9 h, N2) Si O O S O F F P SiO2 C6H6 (80 °C, 15 h, N2) F P Si O O Si Si O O O O O O SiO2 H Si O O Si Si O O O O O O SiO2 H P xs TMS-imidazole (60 °C, 11 h, N2) Si O Si O O O SiO2 Silica-SMAP Si O Si O O O A 25 mL Schlenk flask was charged with a stir bar, 40 mg (0.18 mmol) 10f and 3 mL benzene in a glovebox. All proceeding manipulations were performed in a glovebag 129 under N2. The contents were stirred at room temperature after the addition of 150 µL (1.7 mmol) trifluoromethanesulfonic acid. Silica gel was activated by refluxing 15 g Silicycle Siliaflash® P-60 40-63µm 230-400 mesh in 50 mL concentrated HCl for 4 hours, filtering the contents and washing with copious amounts of water and methanol. The silica gel was dried in vacuo at 160 °C and stored in a glovebox. After 11 hours of stirring, 330 mg activated silica gel was added to the reaction flask and the contents heated at 80 °C for 24 hours under a reflux condenser. The silica gel was filtered and washed with degassed benzene, degassed methanol, degassed water, degassed saturated NaHCO3 in water, degassed water, degassed methanol and degassed benzene before being dried in vacuo first at room temperature then at 90 °C in vacuo. The silica gel was transferred to a 25 mL Schlenk flask and diluted with 3 mL degassed 1trimethylsilylimidazole. The contents were heated at 60 °C under N2 for 24 hours. The silica gel was filtered and washed with degassed benzene and degassed methanol before being dried in vacuo first at room temperature then at 90 °C to afford 203 mg 10g. 130 N-(tert-butoxycarbonyl)-3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (11a) O O 2 mol% [Ir(OMe)COD]2 4 mol% silica-SMAP (10g) O Cl B O O 1.1 equiv. B2Pin2 C6H12 (50 °C, 10 h, N2) 2c O NH Cl NH Cl O B O H N O O 2d 11a O Cl OB O O NH 11c In a glovebox, a pressure tube was charged with a stir bar, 1 mg (0.0015 mmol) [Ir(OMe(COD]2, 39 mg 10g, 28 mg (0.11 mmol) B2Pin2, 23 mg (0.1 mmol) 2c and 150 µL cyclohexane. The pressure tube was sealed and heated at 50 °C for 10 hours in an oil bath. All volatiles were removed and contents analyzed by 500MHz 1H NMR giving 68 : 20 : 12 (2 d : 11a : 11c) at 89% conversion (no internal standard). Column chromatography was performed using dichloromethane as the eluent to afford 13 mg 2d (38% yield, Rf = 0.77) and 4 mg 11a (13% yield, Rf = 0.60). Compound 11a 1H NMR (600 MHz, CDCl = 7.24 ppm): % 8.29 (s, 1H), 7.91 (d, J = 8.3, 1H), 7.24 (t, J 3 = 9.3, J = 7.1, 1H), 6.99 (d, J = 7.8, 1H), 1.48 (s, 9H), 1.38 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 152.83, 145.13, 139.69, 132.11, 123.82, 117.29, 84.50, 80.12, 28.30, 24.72; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.3; FT-IR(thin 131 film): 3368, 2978, 2928, 2851, 1736, 1600, 1573, 1526, 1444, 1391, 1368, 1339, 1311, 1266, 1229, 1160, 1144, 1103, 1060, 962, 858, 822, 784, 757, 700, 670, 579, 579, 494 cm-1; HRMS calcd. for C17H25BClNO4 [M]+ 353.1565, found 353.1582. N-(tert-butoxycarbonyl)-4-bromo-3-chloroaniline (11b) Cl Br 1.3 equiv. Boc2O NH2 EtOAc (60 °C, 2 days) O Cl O NH Br 11b A solution of 2.30 g (11.1 mmol) 4-bromo-3-chloroaniline and 3.16 g (14.5 mmol) Boc2O in 15 mL ethyl acetate was heated at 60 °C for 2 days. The solution was cooled to room temperature and washed three times with 1M HCl in water. The organic layer was collected, washed with brine and dried over MgSO4. The collected product was loaded onto a filter frit and washed three times with pentane to provide 2.50 g 11b as a white solid (75% yield, mp = 108 °C). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.61 (s, 1H), 7.45 (d, J = 8.8, 1H), 7.05 (dd, 3 J = 8.8, J = 2.0, 1H), 6.48 (bs, 1H), 1.49 (s, 9H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 152.20, 138.62, 134.77, 133.62, 119.93, 117.84, 115.22, 81.33, 28.24; FTIR(thin film): 3414, 3326, 3170, 3098, 2979, 2933, 1731, 1702, 1585, 1513, 1472, 1456, 1375, 1298, 1273, 1241, 1159, 1116, 1059, 1020, 936, 859, 814, 773, 733, 691, 637, 577 cm-1; HRMS calcd. for C11H12BrClNO2 [M–H]– 303.9740, found 303.9736. 132 N-(tert-butoxycarbonyl)-3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (11c) O O NH Cl Br 11b O 10 mol% (dppf)PdCl2•CH2Cl2 3 equiv. KOAc Cl 1.1 equiv. B2Pin2 DMF (100 °C, 15 h, N2) O OB O NH 11c In a glovebox, 613 mg (2 mmol) 11b, 559 mg (2.2 mmol) B2Pin2, 589 mg (6 mmol) potassium acetate, 163 mg (0.2 mmol) (dppf)PdCl2•CH2Cl2 and 6 mL DMF were added to a 50 mL Schlenk flask. The flask was heated at 100 °C under a reflux condenser and N2. After 15 hours the contents were diluted with benzene and washed several times with water. The organic layer was dried over MgSO4 and all volatiles removed in vacuo. The obtained oil was purified by chromatography with dichloromethane as the eluent to afford 98 mg recovered 11b and 11c contaminated with B2Pin2. Crystallization from pentane afforded 300 mg 11c in two crops as a white solid (43% yield, mp = 120-124 °C). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.59 (d, J = 8.1, 1H), 7.47 (d, J = 1.5, 1H), 3 7.15 (dd, J = 8.1, J = 1.7, 1H), 6.57 (bs, 1H), 1.48 (s, 9H), 1.33 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 152.09, 141.61, 140.65, 137.39, 118.64, 115.28, 83.89, 81.08, 28.24, 24.76; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.5; FT-IR(thin film): 3333, 2978, 2932, 1733, 1709, 1603, 1581, 1516, 1493, 1383, 1351, 1319, 1273, 1234, 1156, 1142, 1110, 1055, 1033, 962, 855, 826, 772, 732, 691, 656, 621, 578 cm-1; HRMS(ESI+) calcd. for C17H26BClNO4 [M+H]+ 354.1643, found 354.1649. 133 N-(3-chlorophenyl)methanesulfonamide (12a) Cl NH2 1.6 equiv. MeSO2Cl pyridine CH2Cl2 (0!°C RT, 5 h, N2) Cl O O S NH 12a A stirring solution of 5.13 g (40.2 mmol) 3-chloroaniline and 15 mL pyridine in 20 mL dichloromethane was cooled to 0 °C under a N2 atmosphere. The addition of 5.0 mL (64.6 mmol) methanesulfonyl chloride via syringe was done dropwise. After 30 minutes the flask was taken out of the ice bath and stirred for 4.5 hours at room temperature. The reaction was quenched with 10 mL 2M HCl in water at 0 °C before being extracted twice with dichloromethane. The organic layers were washed with saturated brine, dried over MgSO4 and concentrated in vacuo. The off-white solid was dissolved in hot chloroform and cooled to 0 °C to afford 6.78 g 12a as white needles (81% yield, mp = 92-94 °C, lit184 mp = 93-95 °C). Worth noting is that these crystals rapidly discolor unless stored under vacuum or N2. 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.28–7.24 (m, 2H), 7.15–7.10 (m, 2H), 7.07 3 (bs, 1H), 3.04 (s, 3H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 138.00, 135.32, 130.69, 125.34, 120.30, 118.34, 39.56; FT-IR(thin film): 3251, 3018, 2931, 1594, 1478, 1418, 1390, 1318, 1250, 1223, 1151, 1091, 1080, 970, 926, 889, 758, 770, 699, 594, 552, 516 cm-1; HRMS calcd. for C7H8ClNO2S [M]+ 204.9964, found 204.9967. 134 N-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)methanesulfonamide (12b) Cl O O S NH 12a 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 1 equiv. HBPin 0.75 equiv. B2Pin2 Et2O (RT, 28 h, N2) O O S NH Cl O B O 12b In a glovebox, a solution of 145 µL (1 mmol) HBPin and 13.1 mg (0.02 mmol) [Ir(OMe)COD]2 in minimal diethyl ether was added to 10.8 mg (0.04 mmol) dtbpy. The solution was subsequently transferred to a 20 mL scintillation vial equipped with a stir bar, 191 mg (0.75 mmol) B2Pin2 and 205 mg (1 mmol) 12a in diethyl ether. The entire procedure was conducted using 2.0 mL diethyl ether. The reaction proceeded at room temperature for 28 hours. A sample illustrated an N-BPin bond by 11B NMR (% 24.5). Isolation involved rinsing the scintillation with dichloromethane and methanol before removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with ethyl acetate as the eluent. Starting material was precipitated out of chloroform with pentane at 0 °C. Crystallization from 1 : 1 (chloroform / pentane) at –80 °C afforded 225 mg 12b as a white solid (68% yield, mp = 136-138 °C). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.56 (d, J = 1.5, 1H), 7.42 (t, J = 2.0, 1H), 3 7.35 (d, J = 1.5, 1H), 6.43 (bs, 1H), 3.01 (s, 3H), 1.32 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 137.37, 135.25, 131.50, 124.41, 123.15, 84.50, 39.75, 24.83; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.1; FT-IR(thin film): 3273, 2978, 135 2929, 1599, 1574, 1486, 1422, 1391, 1354, 1329, 1272, 1215, 1156, 1144, 1115, 997, 976, 866, 843, 758, 738, 702, 665, 540, 514 cm-1; HRMS calcd. for C13H19BClNO4S [M]+ 331.0816, found 331.0812. N -(3-chlorophenyl)-1,1,1-trifluoromethanesulfonamide (12c) and N -(3chlorophenyl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (B) F Cl NH2 1 equiv. Tf2O Et3N, CH2Cl2 (0 °C ! RT, 15 h, N2) Cl O O S NH F F F F O O S F N O S O Cl F 12c B F F A stirring solution of 2.19 g (17.2 mmol) 3-chloroaniline and 3 mL triethylamine in 50 mL dichloromethane at 0 °C was prepared under a N2 atmosphere. The addition of 2.9 mL (17.2 mmol) trifluoromethanesulfonyl anhydride via syringe was done dropwise. After 30 minutes the flask was taken out of the ice bath and stirred for 15 hours at room temperature. The reaction was quenched with 10 mL 2M HCl in water at 0 °C before being extracted once with dichloromethane. The organic layer was washed with saturated brine, dried over MgSO4 and concentrated in vacuo to afford a colorless oil composed of 88 : 12 (12c / B). Silica gel chromatography using 1 : 10 (ethyl acetate / hexanes) as the eluent was performed to afford 2.33 g 12c as a white solid (52% yield, mp = 76-78 °C, lit185 mp = 76.5-77.6 °C, Rf = 0.32) and 0.56 g B as a white solid (8% yield, mp = 5860°C, Rf = 0.47). 136 Compound 12c 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.33–7.27 (m, 3H), 7.17–7.15 (m, 1H), 6.81 3 (bs, 1H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 135.35 (s), 134.84 (s), 130.67 (s), 127.77 (s), 123.40 (s), 121.29 (s), 119.63 (q, J = 322.7); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –75.56; FT-IR(thin film): 3261, 3082, 1594, 1478, 1458, 1414, 1360, 1233, 1201, 1190, 1169, 1139, 1078, 941, 887, 868, 788, 703, 678, 619, 566, 512 cm-1; HRMS calcd. for C7H5ClF3NO2S [M]+ 258.9682, found 258.9687. Compound B 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.57–7.55 (m, 1H), 7.45 (t, J = 8.1, 1H), 7.40 3 (t, J = 2.0, 1H), 7.31–7.30 (m, 1H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 135.64 (s), 132.72 (s), 132.53 (s), 131.10 (s), 130.72 (s), 129.28 (s), 119.36 (q, J = 325.0); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –70.74; FT-IR(thin film): 3098, 1584, 1471, 1447, 1421, 1221, 1125, 984, 954, 936, 901, 861, 730, 683, 670, 603 cm-1; HRMS calcd. for C8H4ClF6NO4S2 [M]+ 390.9174, found 390.9185. 137 N-(3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)phenyl)trifluoromethanesulfonamide (12d) Cl F F O O S F NH 12c 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy 1 equiv. HBPin 0.75 equiv. B2Pin2 Et2O (RT, 24 h, N2) F F O O S F NH Cl O B O 12d In a glovebox, a solution of 56 µ L (0.5 mmol) HBPin and 6.6 mg (0.01 mmol) [Ir(OMe)COD]2 in minimal diethyl ether was added to 5.4 mg (0.02 mmol) dtbpy. The solution was subsequently transferred to a 20 mL scintillation vial equipped with a stir bar, 95 mg (0.375 mmol) B2Pin2 and 130 mg (0.5 mmol) 12c in diethyl ether. The entire procedure was conducted using 2.0 mL diethyl ether. The reaction proceeded at room temperature for 24 hours. A sample illustrated an N-BPin bond by 11B NMR (% 24.4). Isolation involved rinsing the scintillation vial with dichloromethane and methanol before removing all volatiles in vacuo. The crude solid was passed through a short pad of silica gel with dichloromethane as the eluent to afford 157 mg 12d as a white solid (82% yield, mp = 88-90 °C, Rf = 0.57). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.58 (d, J = 1.5, 1H), 7.42 (t, J = 2.0, 1H), 3 7.35 (d, J = 1.5, 1H), 6.43 (bs, 1H), 3.01 (s, 3H), 1.32 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 135.10, 134.35, 133.69, 127.24, 125.92, 119.61 (q, J = 322.5), 84.67, 24.80; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.1; FT-IR(thin film): 3291, 3171, 1974, 2934, 1576, 1473, 1428, 1353, 1234, 1212, 1142, 998, 981, 962, 138 888, 867, 841, 701, 605, 510 cm-1; HRMS calcd. for C13H16BF3ClNO4S [M]+ 385.0534, found 385.0529. N-(methoxycarbonyl)-3-chloroaniline (13a) Cl NH2 1.3 equiv. ClCO2Me Et3N Et2O (0!°C ! RT, 2 h, N2) O Cl O NH 13a A stirring solution of 1.9 mL (15 mmol) 3-chloroaniline and 3 mL triethylamine in 30 mL diethyl ether at 0 °C was prepared under a N2 atmosphere. The addition of 2.2 mL (19 mmol) methyl chloroformate via syringe was done dropwise. After warming to room temperature, the contents were stirred for 2 hours. The reaction was quenched with water before being extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4 and concentrated in vacuo to afford a crude solid that was washed sparsely with diethyl ether to afford 2.96 g 13a as a white solid (89% yield, mp = 80-82 °C, lit186 mp = 84-85.5 °C). 1H NMR (300 MHz, CDCl = 7.24 ppm): % 7.48 (s, 1H), 7.20–7.19 (m, 2H), 7.03–7.01 3 (m, 1H), 6.62 (bs, 1H), 3.76 (s, 3H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 153.73, 139.03, 134.76, 130.00, 123.48, 118.70, 116.56, 52.50; FT-IR(thin film): 3350, 1709, 1609, 1591, 1557, 1486, 1434, 1404, 1385, 1316, 1257, 1232, 1100, 957, 883, 866, 777, 766, 682, 641, 619 cm-1; HRMS calcd. for C8H8ClNO2 [M]+ 185.0244, found 185.0251. 139 N-(methoxycarbonyl)-5-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (13b) and N-(methoxycarbonyl)-5-chloro-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (13c) O O 2 mol% [Ir(OMe)COD]2 4 mol% dtbpy O NH Cl NH Cl 13a 0.2 equiv. HBPin 0.75 equiv. B2Pin2 MTBE (50 °C, 16 h, N2) O O B O O 13b Cl O NH O B O 13c The general procedure was applied using 103 mg (0.41 mmol) B2Pin2 and 100 mg (0.54 mmol) 13a for 16 hours. The reaction was transferred to a 20 mL scintillation vial with dichloromethane. A small amount of methanol was added and all volatiles were removed in vacuo. A silica gel column was run using dichloromethane as the eluent to afford 25 mg recovered 13a, 68 mg 13b as a white solid (40% yield, 55% brsm, mp 164-166 °C, Rf = 0.36) and 12 mg 13c as a film (8% yield, 11% brsm, Rf = 0.11). Compound 13b 1H NMR (600 MHz, CDCl = 7.24 ppm): % 8.84 (s, 1H), 8.30 (s, 1H), 7.62 (d, J = 8.1, 3 1H), 6.96 (dd, J = 8.1, J = 2.0, 1H), 3.76 (s, 3H), 1.34 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 153.93, 145.84, 139.10, 137.22, 122.11, 117.65, 84.53, 52.18, 24.81; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.2; FT-IR(thin film): 3340, 2981, 2923, 2852, 1736, 1607, 1574, 1530, 1457, 1419, 1381, 1348, 1321, 1273, 1221, 1147, 1098, 1079, 1053, 963, 912, 856, 799, 743, 668 cm-1; HRMS calcd. for C14H19BClNO4 [M]+ 311.1096, found 311.1101. 140 Compound 13c 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.76 (s, 1H), 7.44 (s, 1H), 7.40 (s, 1H), 6.64 3 (s, 1H), 3.75 (s, 3H), 1.30 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 153.74, 138.56, 134.69, 129.39, 122.53, 121.37, 84.25, 52.47, 24.82; 11B NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.4; FT-IR(thin film): 3331, 2978, 2924, 2851, 1740, 1716, 1605, 1582, 1542, 1455, 1445, 1354, 1324, 1266, 1221, 1142, 1114, 1081, 967, 933, 866, 843, 770, 736, 702, 667 cm-1; HRMS calcd. for C14H19BClNO4 [M]+ 311.1096, found 311.1105. N-(1,1,1,3,3,3-hexafluoroisopropoxycarbonyl)-3-chloroaniline (13d) Cl 1.1 equiv. (CF3)2CHOH NCO C6H6 (RT, 18 h, N2) Cl O N H F F F O F F F 13d A solution of 4.00 g (26.1 mmol) 3-chlorophenyl isocyanate and 3.0 mL (28.7 mmol) 1,1,1,3,3,3-hexafluroisopropanol in 20 mL benzene was stirred at room temperature under a N2 atmosphere. All volatiles were removed in vacuo after 18 hours. The product was crystallized from hot pentane / chloroform to afford 5.95 g 13d as a white fluffy solid (71% yield, mp = 98 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.49 (bs, 1H), 7.26–7.20 (m, 2H), 7.12-7.10 3 (m, 1H), 6.97 (bs, 1H), 5.73 (septet, J = 6.1, 1H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 165.60 (s), 149.41 (s), 137.22 (s), 135.12 (s), 125.08 (s), 120.48 (q, J = 282.2), 141 119.28 (s), 117.13 (s), 67.71 (septet, J = 35.0); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –73.60; FT-IR(thin film): 3305, 3080, 2971, 1738, 1594, 1542, 1431, 1385, 1356, 1286, 1267, 1193, 1107, 1006, 923, 906, 892, 871, 785, 761, 721, 692, 674, 640 cm-1; HRMS calcd. for C10H6ClF6NO2 [M]+ 320.9991, found 320.9996. 3,5-dichlorophenyl (3-chlorophenyl)carbamate (13e), 1,3-bis(3-chlorophenyl)urea (B), and 1,3,5-tris(3-chlorophenyl)-1,3,5-triazinane-2,4,6-trione (C) Cl O OH 1.5 equiv. 3-ClC H NCO 6 4 Cl Cl NH Cl 0.1 equiv. Et3N toluene (RT, 16 h, N2) Cl Cl 13e H N O Cl O Cl Cl B N O NH N O N O C Cl A stirring solution of 0.71 g (4.3 mmol) 3,5-dichlorophenol and 0.1 mL (0.36 mmol) triethylamine in 20 mL toluene was prepared at room temperature under a N2 atmosphere in a 100 mL flask. The addition of 0.7 mL (1.0 g, 6.0 mmol) 3-chlorophenyl isocyanate was done dropwise. All volatiles were removed after 16 hours and the crude oil was dissolved in diethyl ether, washed three times with water, three times with 0.5M NaOH in water, three times with 0.5M HCl in water and once with concentrated brine. The organic layer was collected, dried over MgSO4 and concentrated in vacuo. The yellow oil was dissolved in chloroform and the solution filtered through a fine frit. The filtrate was collected, concentrated and the filtration repeated to afford 168 mg B as a white solid 142 (20% yield based on isocyanate, mp = 246 °C, lit187 mp = 241 °C). The filtrate was purified via silica column chromatography using 1 : 1 (dichloromethane / hexanes) as the eluent to afford 453 mg 13e as a white solid (22% yield based on isocyanate, mp = 116118 °C, Rf = 0.33) and 237 mg C as a white solid (35% yield based on isocyanate, mp = 220 °C, lit188 mp = 221 °C, Rf = 0.05). A spot at Rf = 0.11 was not isolated cleanly. Compound 13e 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.53 (bs, 1H), 7.26–7.24 (m, 3H), 7.14 (d, J 3 = 1.2, 2H), 7.12–7.10 (m, 1H), 6.98 (bs, 1H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 150.98, 150.25, 137.92, 135.24, 135.01, 130.23, 126.27, 124.49, 120.70, 118.99, 116.85; FT-IR(thin film): 3404, 3310, 3197, 3127, 3085, 1740, 1721, 1597, 1584, 1534, 1484, 1421, 1310, 1276, 1210, 1098, 1023, 999, 940, 892, 856, 809, 778, 711, 680, 685, 559, 521, 432 cm-1; HRMS calcd. for C13H8Cl3NO2 [M]+ 314.9621, found 314.9633. Compound B 1H NMR (500 MHz, DMSO-d = 2.49 ppm): % 8.97 (s, 2H), 7.70 (s, 2H), 7.31–7.25 (m, 6 4H), 7.02 (d, J = 7.6, 2H); 13C NMR (126 MHz, DMSO-d6 = 39.5 ppm): % 152.24, 140.99, 133.19, 130.41, 121.70, 117.74, 116.82; FT-IR(thin film): 3293, 3018, 1637, 1585, 1567, 1552, 1478, 1422, 1407, 1286, 1223, 1095, 1072, 872, 811, 789, 771, 687, 667, 644 cm-1; HRMS calcd. for C13H10Cl2N2O [M]+ 280.0170, found 280.0182. 143 Compound C 1H NMR (300 MHz, CDCl = 7.24 ppm): % 7.45–7.42 (m, 9H), 7.30–7.26 (m, 3H); 13C 3 NMR (75 MHz, CDCl3 = 77 ppm): % 147.90, 134.97, 134.10, 130.34, 129.93, 128.88, 126.71; FT-IR(thin film): 3082, 1714, 1589, 1478, 1411, 1226, 1075, 1035, 1003, 867, 782, 753, 740, 693, 680 cm-1; HRMS calcd. for C21H12Cl3N3O3 [M]+ 458.9944, found 458.9935. 4-trifluoromethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (14a) O O NH F F F 4g B O O TFA / CH2Cl2 (1 : 1) (0 °C ! RT, 30 min, N2) NH2 F F B O O F 14a A stirring solution of 50 mg (0.13 mmol) 4g in 2 mL dichloromethane was cooled to 0 °C. After a dropwise addition of 2 mL trifluoroacetic acid the flask was removed from the cold bath and stirred at room temperature for 30 min under a N2 atmosphere. Next, all volatiles were removed in vacuo, the residual oil redissolved in dichloromethane and washed once with 2 mL saturated NaHCO3 in water. The organic phase was washed with saturated brine, dried over MgSO4 and concentrated in vacuo to afford 34 mg 14a as a white solid (91% yield, mp = 112-114 °C, lit189 mp = 117-118 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.84 (d, J = 1.7, 1H), 7.39 (dd, J = 8.6, J = 3 2.2, 1H), 6.57 (d, J = 8.6, 1H), 5.04 (bs, 2H), 1.33 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 156.09 (s), 134.24 (q, J = 3.7), 129.50 (q, J = 3.7), 124.97 (q, J = 270.2), 144 118.51 (q, J = 32.7), 114.11 (s), 83.97 (s), 24.87 (s); 11B NMR (96 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.6; 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % –61.30; FT-IR(thin film): 3474, 3378, 3004, 2980, 1629, 1575, 1502, 1393, 1382, 1370, 1322, 1258, 1167, 1148, 1098, 1075, 833, 445, 433 cm-1; HRMS calcd. for C12H17BF3NO2 [M]+ 287.1304, found 287.1303. O-(N’,N’-dimethylcarbamoyl)-2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-4-aminophenol (14b) O Cl O N O NH O 4w B O O TFA / CH2Cl2 (1 : 1) Cl O N NH2 O B O O (0 °C ! RT, 1 h, N2) 14b A stirring solution of 50 mg (0.11 mmol) 4w in 1 mL dichloromethane was cooled to 0 °C. After a dropwise addition of 1 mL trifluoroacetic acid the flask was removed from the cold bath and stirred at room temperature for 1 hour under a N2 atmosphere. Next, all volatiles were removed in vacuo, the residual oil redissolved in dichloromethane and washed once with 2 mL saturated NaHCO3 in water. The organic phase was washed with saturated brine, dried over MgSO4 and all volatiles removed in vacuo to afford 36 mg 14b as a white solid (93% yield, mp = 150-152 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.34 (s, 1H), 6.60 (s, 1H), 4.42 (bs, 2H), 3.07 3 (s, 3H), 2.97 (s, 3H), 1.28 (s, 12H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 154.68, 151.77, 138.22, 131.26, 131.02, 115.52, 83.76, 36.73, 36.35, 29.62, 24.82; 11B NMR (96 145 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.6. FT-IR(thin film): 3478, 3373, 2978, 2929, 1724, 1606, 1487, 1422, 1385, 1355, 1309, 1271, 1245, 1201, 1168, 1142, 1068, 1019, 977, 954, 856, 755, 675 cm-1; HRMS calcd. for C15H22BClN2O4 [M]+ 340.1361, found 340.1366. N-methyl-3-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (14c) O O N Cl O B TFA / CH2Cl2 (1 : 1) (0 °C ! RT, 1 h, N2) O H N Cl 8c O B O 14c A stirring solution of 71 mg (0.19 mmol) 8c in 2 mL dichloromethane was cooled to 0 °C. After a dropwise addition of 2 mL trifluoroacetic acid the flask was removed from the cold bath and stirred at room temperature for 1 hour under a N2 atmosphere. Next, all volatiles were removed in vacuo, the residual oil redissolved in dichloromethane and washed once with 2 mL saturated NaHCO3 in water. The organic phase was washed with saturated brine and dried over MgSO4. The oil was passed through a short pad of silicagel with dichloromethane as the eluent (Rf = 0.45) to afford 34 mg 14c as a white solid (66% yield, mp = 80-82 °C). 1H NMR (600 MHz, CDCl = 7.24 ppm): % 7.07 (d, J = 1.7, 1H), 6.88 (d, J = 2.4, 1H), 3 6.63 (d, J = 2.2, 1H), 3.49 (bs, 1H), 2.80 (s, 3H), 1.31 (s, 12H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 149.94, 134.77, 122.83, 116.96, 114.34, 83.92, 30.56, 24.78; 11B 146 NMR (192 MHz, CDCl3, BF3•OEt2 = 0 ppm): % 30.6; FT-IR(thin film): 3373, 3107, 2979, 2927, 2871, 1603, 1572, 1511, 1449, 1413, 1317, 1271, 1214, 1144, 1109, 1079, 985, 965, 910, 858, 845, 716, 703 cm-1; HRMS calcd. for C13H19BClNO2 [M]+ 267.1197, found 267.1204. Methyl 2-[N-(tert-butoxycarbonyl)-5-bromo-2-aniline] propanoate (15a) O O NH BO O Br 2 equiv. KOH, 1,4-dioxane / H2O (100 °C, 8 h, N2) O 5 mol% [Rh(COD)Cl]2 0.5 equiv. methyl acrylate 4e O NH O Br O 15a A two neck round bottom flask was charged with a stir bar, 50 mg (130 "mol) 4e, 3.2 mg (6.3 "mol) [Rh(COD)Cl]2, 1 mL 1,4-dioxane and 70 "L water under a N2 atmosphere. After the addition of 6 "L (63 "mol) methyl acrylate and 15 mg (252 "mol) freshly crushed KOH, the flask was fitted with a Friederich condenser and heated at 100 °C under N2. All volatiles were removed in vacuo after 8 hours of reaction time. The oil was taken up in chloroform and washed once with 1M HCl in water, washed with saturated brine and dried over MgSO4. After all volatiles were removed in vacuo, the residual oil was purified via preperative TLC using 97 : 3 (chloroform / hexanes) to afford 11.4 mg 15a as a white solid (50% yield, mp = 56-58 °C, Rf = 0.34). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.59 (d, J = 8.1, 1H), 7.28 (dd, J = 8.8, J = 3 2.2, 1H), 7.24 (s, 1H), 7.23 (d, J = 2.4, 1H), 3.66 (s, 3H), 2.82 (t, J = 6.8, 2H), 2.66 (t, J = 6.8, 2H), 1.50 (s, 9H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 173.87, 153.46, 147 135.31, 133.45, 132.11, 130.09, 124.88, 116.99, 80.50, 52.01, 34.41, 28.34, 25.20; FTIR(thin film): 3341, 2978, 2932, 1724, 1596, 1578, 1511, 1453, 1430, 1401, 1367, 1289, 1238, 1160, 1087, 1050, 1025, 906, 821, 821, 773, 643 cm-1; HRMS calcd. for C15H20BrNO4 [M]+ 357.0576, found 357.0579. 7-chloro-6-methoxy-3,4-dihydroquinolin-2-one (16a) O O NH Cl BO O O 4m 1. 5 mol% [Rh(COD)Cl]2, 2 equiv. KOH 1 equiv. methyl acrylate H2O / 1,4-dioxane (100 °C, 4 h, N2) 2. CH2Cl2 / F3CCO2H (0 °C ! RT, 2 h, N2) 3. 5 equiv. KOH, H2O / 1,4-dioxane (0 °C ! 100 °C, 2 h, N2) H N Cl O O 16a The general procedure was applied with 50.4 mg (0.13 mmol) 4m, 3.8 mg (0.0065 mmol) [Rh(COD)Cl]2, 1.0 mL 1,4-dioxane, 75 µL water, 12 µL (0.13 mmol) methyl acrylate and 14.9 mg (0.27 mmol) KOH. t-Boc deprotection was induced with 2.0 mL trifluoroacetic acid and 2.0 mL dichloromethane. Cyclization was promoted with 36.8 mg (0.65 mmol) KOH in 1.0 mL 1,4-dioxane and 75 µL water for 2 hours. Precipitation from minimal dichloromethane with pentane afforded 19.3 mg 16a as white needles (72% yield, mp = 210 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 9.14 (s, 1H), 6.87 (s, 1H), 6.72 (s, 1H), 3.84 3 (s, 3H), 2.92 (t, J = 7.1, 2H), 2.60 (t, J = 7.7, 2H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 171.64, 150.81, 131.23, 123.07, 121.12, 117.26, 112.25, 56.60, 30.43, 25.49; FTIR(thin film): 3193, 3069, 2965, 3898, 2847, 1715, 1691, 1625, 1505, 1461, 1440, 1396, 1369, 1312, 1253, 1220, 1195, 1159, 1054, 979, 956, 931, 866, 838, 813, 774, 750, 709, 148 637, 619, 588, 509, 472 cm-1; HRMS calcd. for C10H10ClNO2 [M]+ 211.0400, found 211.0397. 6-fluoro-7-methyl-3,4-dihydroquinolin-2-one (16b) O O NH F 4j 1. 1 mol% [Ir(OMe)COD]2, 2 mol% dtbpy 0.2 equiv. HBPin, 1.2 equiv. B2Pin2 MTBE (50 °C, 24 h, N2) 2. 3 mol% [Rh(COD)Cl]2, 2 equiv. KOH 1 equiv. methyl acrylate H2O / 1,4-dioxane (100 °C, 3 h, N2) 3. CH2Cl2 / F3CCO2H (0 °C ! RT, 2 h, N2) 4. 5 equiv. KOH, H2O / 1,4-dioxane (0 °C ! 100 °C, 2 h, N2) H N O F 16b The general procedure was applied using 305 mg (1.2 mmol) B2Pin2 and 225 mg (1.0 mmol) 4j for 24 hours. The crude reaction was transferred to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude mixture was passed through a short pad of silica gel with dichloromethane as the eluent. At this point, the regiochemical mixture of aryl pinacol boronic esters was subjected to the general procedure using 15 mg (0.03 mmol) [Rh(COD)Cl]2, 3.0 mL 1,4dioxane, 215 µL water, 90 µL (1.0 mmol) methyl acrylate and 112 mg (2.0 mmol) KOH. t-Boc deprotection was induced with 3.0 mL trifluoroacetic acid and 3.0 mL dichloromethane. Cyclization was promoted with 281 mg (5.0 mmol) KOH in 3.0 mL 1,4-dioxane and 215 µL water. Precipitation from dichloromethane with pentane afforded 103 mg 16b (57% yield, mp = 186-188 °C). 149 1H NMR (600 MHz, CDCl = 7.24 ppm): % 9.18 (bs, 1H), 6.79 (d, J = 9.5, 1H), 6.63 (d, 3 J = 6.6, 1H), 2.89 (t, J = 7.3, 2H), 2.59 (t, J = 7.8, 2H), 2.20 (s, 3H); 13C NMR (151 MHz, CDCl3 = 77 ppm): % 172.02 (s), 157.1 (d, J = 240.5), 133.03 (d, J = 2.9), 123.78 (d, J = 19.0), 122.45 (d, J = 8.1), 117.90 (d, J = 4.6), 114.43 (d, J = 24.2), 30.49 (s), 25.03 (s), 14.21 (d, J = 3.5); 19F NMR (282 MHz, CDCl3, CFCl3 = 0 ppm): % &124.75 (t, J = 8.6, J = 6.9); FT-IR(thin film): 3209, 3088, 2957, 2904, 1683, 1523, 1496, 1437, 1399, 1382, 1223, 1196, 1102, 1026, 1009, 883, 810, 768, 737, 643, 623, 599, 572, 509, 481, 449 cm-1; HRMS calcd. for C10H10FNO [M]+ 179.0746, found 179.0753. 6-bromo-3,4-dihydroquinolin-2-one (16c) O O NH Br 4d 1. 1 mol% [Ir(OMe)COD]2, 2 mol% dtbpy 0.025 equiv. HBPin, 0.68 equiv. B2Pin2 MTBE (50 °C, 22 h, N2) 2. 2 mol% [Rh(COD)Cl]2, 2 equiv. KOH 1 equiv. methyl acrylate H2O / 1,4-dioxane (100 °C, 3 h, N2) 3. CH2Cl2 / F3CCO2H (0 °C ! RT, 2 h, N2) 4. 5 equiv. KOH, H2O / 1,4-dioxane (0 °C ! 100 °C, 2 h, N2) H N O Br 16c In a glovebox, a solution of 26 mg (0.04 mmol) [Ir(OMe)COD]2 and 55 µL (0.1 mmol) HBPin was added to 21 mg (0.08 mmol) dtbpy using 1 mL MTBE. This mixture was added to an air free flask fitted with a stir bar, 695 mg (2.7 mmol) B2Pin2 and 1.08 g (4 mmol) 4d using 3 mL MTBE. After 22 hours at 50 °C the solution was evaporated and the obtained product passed through a short pad of silica-gel with dichloromethane as the eluent. The general procedure using 39 mg (0.08 mmol) [Rh(COD)Cl]2, 3.0 mL 1,4dioxane, 215 µL water, 357 µL (4 mmol) methyl acrylate and 445 mg (8 mmol) KOH. t150 Boc deprotection was induced with 3.0 mL trifluoroacetic acid and 3.0 mL dichloromethane. Cyclization was promoted with 1.14 g (20 mmol) KOH in 3.0 mL 1,4dioxane and 215 µL water. Precipitation from dichloromethane with pentane afforded 447 mg 16c as light green needles (50% yield, mp = 168 °C, lit190 mp = 168-169 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 9.42 (bs, 1H), 7.26–7.24 (m, 2H), 6.71 (d, J 3 = 8.1, 1H), 2.92 (t, J = 7.8, J = 7.3, 2H), 2.60 (t, J = 7.8, J = 7.3, 2H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 171.80, 136.44, 130.74, 130.36, 125.62, 117.06, 115.42, 30.29, 25.08; FT-IR(thin film): 3194, 3061, 2968, 2896, 1677, 1589, 1489, 1434, 1405, 1376, 1317, 1287, 1251, 1192, 1072, 1027, 926, 875, 814, 767, 686 cm-1; HRMS calcd. for C9H8BrNO [M]+ 224.9789, found 224.9786. 7-bromo-3,4-dihydroquinolin-2-one (16d) O Br O NH 3c 1. 2 mol% [Ir(OMe)COD]2, 4 mol% dtbpy 0.2 equiv. HBPin, 1 equiv. B2Pin2 MTBE (50 °C, 18 h, N2) 2. 5 mol% [Rh(COD)Cl]2, 2 equiv. KOH 1 equiv. methyl acrylate H2O / 1,4-dioxane (100 °C, 4 h, N2) 3. CH2Cl2 / F3CCO2H (0 °C ! RT, 2 h, N2) 4. 5 equiv. KOH, H2O / 1,4-dioxane (0 °C ! 100 °C, 2 h, N2) Br H N O 16d The general procedure was applied using 254 mg (1.0 mmol) B2Pin2 and 272 mg (1.0 mmol) 3c for 18 hours. The crude reaction was transferred to a 20 mL scintillation vial, rinsing the air free flask with dichloromethane and removing all volatiles in vacuo. The crude mixture was passed through a short pad of silica gel with dichloromethane as the 151 eluent. At this point, the regiochemical mixture of aryl pinacol boronic esters was subjected to the general procedure using 25 mg (0.05 mmol) [Rh(COD)Cl]2, 2.0 mL 1,4dioxane, 150 µL water, 90 µL (1.0 mmol) methyl acrylate and 112 mg (2.0 mmol) KOH. t-Boc deprotection was induced with 3.0 mL trifluoroacetic acid and 3.0 mL dichloromethane. Cyclization was promoted with 287 mg (5.1 mmol) KOH in 2.0 mL 1,4-dioxane and 150 µL water for 2 hours. Precipitation from minimal ethyl acetate with pentane afforded 85 mg 16d as white needles (38% yield, mp = 180-182 °C, lit191 mp = 181 °C). 1H NMR (500 MHz, CDCl = 7.24 ppm): % 7.98 (bs, 1H), 7.09 (d, J = 9.5, 1H), 7.00 (d, 3 J = 7.8, 1H), 6.50 (s, 1H), 2.91 (t, J = 7.8, 2H), 2.62 (t, J = 7.8, 2H); 13C NMR (126 MHz, CDCl3 = 77 ppm): % 172.29, 138.57, 129.24, 125.90, 122.48, 120.65, 118.39, 30.37, 24.83; FT-IR(thin film): 3177, 3069, 2963, 2892, 2844, 1694, 1603, 1588, 1485, 1436, 1393, 1371, 1326, 1278, 1237, 1194, 1075, 1030, 994, 935, 863, 797, 781, 756, 726, 689, 609, 576, 539, 473, 444 cm-1; HRMS calcd. for C9H8BrNO [M]+ 224.9789, found 224.9794. 152 APPENDICES 153 APPENDIX A Single crystal X-Ray diffraction structures 154 Appendix A. Summary of crystal data and structure refinement for 1a Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 67.96° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Largest diff. peak and hole 2-(benzo[d][1,3]dioxol-4-yl)-4,4,5,5tetramethyl-1,3,2-dioxaborolane (1a) C13 H17 B O4 248.08 173(2) K 1.54178 Å Monoclinic P 21/n a = 6.68900(10) Å a = 90°. b = 10.5454(2) Å b = 91.3070(10)°. c = 18.7996(3) Å g = 90°. 1325.74(4) Å3 4 1.243 Mg/m3 0.735 mm-1 528 0.42 x 0.27 x 0.22 mm3 4.71 to 67.96°. -7<=h<=8, -12<=k<=11, -22<=l<=22 8918 2366 [R(int) = 0.0314] 98.5 % Semi-empirical from equivalents 0.8561 and 0.7481 Full-matrix least-squares on F2 2366 / 0 / 167 1.037 R1 = 0.0420, wR2 = 0.1061 R1 = 0.0520, wR2 = 0.1135 0.185 and -0.218 e.Å-3 155 Appendix A (cont.). Summary of crystal data and structure refinement for 1a C(8) C(9) O(4) O(3) B(1) C(4) C(3) O(1) C(1) C(4) C(2) O(2) Selected bond lengths [Å] and angles [°] for 1a O(1)-C(3) O(1)-C(1) O(2)-C(2) O(2)-C(1) O(3)-B(1) O(4)-B(1) 1.3712(18) 1.4280(19) 1.374(2) 1.421(2) 1.364(2) 1.362(2) B(1)-C(4) C(2)-C(7) C(2)-C(3) C(3)-C(4) C(4)-C(5) C(8)-C(10) C(3)-O(1)-C(1) C(2)-O(2)-C(1) B(1)-O(3)-C(8) B(1)-O(4)-C(9) O(4)-B(1)-O(3) O(4)-B(1)-C(4) O(3)-B(1)-C(4) 105.84(12) 105.92(12) 106.98(12) 106.66(11) 113.93(13) 125.26(14) 120.81(14) O(2)-C(1)-O(1) O(2)-C(2)-C(3) O(1)-C(3)-C(4) O(1)-C(3)-C(2) C(3)-C(4)-B(1) C(5)-C(4)-B(1) 156 1.555(2) 1.366(2) 1.385(2) 1.380(2) 1.411(2) 1.520(2) 108.27(13) 109.67(14) 127.42(13) 109.65(13) 125.10(14) 120.49(14) Appendix A (cont.). Summary of crystal data and structure refinement for 3b Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 67.34° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Absolute structure parameter Largest diff. peak and hole N-(tert-butoxycarbonyl)-2-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3b) C17 H26 B N O4 319.20 173(2) K 1.54178 Å Monoclinic P 21 a = 9.3992(2) Å a = 90°. b = 10.5475(2) Å b = 116.3830(10)°. c = 10.2449(2) Å g = 90°. 3 909.87(3) Å 2 1.165 Mg/m3 0.654 mm-1 344 0.47 x 0.35 x 0.17 mm3 4.82 to 67.34°. -11<=h<=10, -12<=k<=12, -10<=l<=12 5886 2614 [R(int) = 0.0233] 98.8 % Semi-empirical from equivalents 0.8958 and 0.7481 Full-matrix least-squares on F2 2614 / 1 / 215 1.043 R1 = 0.0352, wR2 = 0.0882 R1 = 0.0368, wR2 = 0.0898 0.24(18) 0.175 and -0.232 e.Å-3 157 Appendix A (cont.). Summary of crystal data and structure refinement for 3b O(1) C(1) C(8) O(3) O(2) N(1) C(9) C(2) C(3) B(1) C(7) O(4) C(4) Selected bond lengths [Å] and angles [°] for 3b O(1)-C(1) O(2)-C(1) O(3)-B(1) O(4)-B(1) N(1)-C(1) C(1)-O(1)-C(14) B(1)-O(3)-C(8) B(1)-O(4)-C(9) C(1)-N(1)-C(2) O(3)-B(1)-O(4) O(3)-B(1)-C(3) O(4)-B(1)-C(3) O(2)-C(1)-O(1) O(2)-C(1)-N(1) 1.343(2) 1.211(2) 1.363(2) 1.365(2) 1.370(2) N(1)-C(2) B(1)-C(3) N(1)-H(1) N(1)H(1)-O(3) 121.45(14) 106.57(13) 106.50(13) 128.39(15) 113.60(16) 124.86(15) 121.54(15) 126.40(16) 126.36(16) O(1)-C(1)-N(1) C(7)-C(2)-N(1) N(1)-C(2)-C(3) C(4)-C(3)-B(1) C(2)-C(3)-B(1) O(3)-C(8)-C(11) O(3)-C(8)-C(10) O(4)-C(9)-C(12) O(4)-C(9)-C(8) 158 1.401(2) 1.560(3) 0.8800 2.093 107.23(15) 122.44(15) 117.64(14) 117.42(15) 124.64(15) 109.13(16) 106.47(16) 108.65(16) 102.10(13) Appendix A (cont.). Summary of crystal data and structure refinement for 4e Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 25.41° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Largest diff. peak and hole N-(tert-butoxycarbonyl)-4-bromo-2-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (4e) C17 H25 B Br N O4 398.10 173(2) K 0.71073 Å Monoclinic P 21/c a = 31.1629(7) Å a = 90°. b = 9.4125(2) Å b = 102.4030(10)°. c = 13.7729(2) Å g = 90°. 3 3945.59(13) Å 8 1.340 Mg/m3 2.102 mm-1 1648 0.45 x 0.13 x 0.12 mm3 1.34 to 25.41°. -37<=h<=34, -11<=k<=11, -15<=l<=16 22366 7260 [R(int) = 0.0683] 99.8 % Semi-empirical from equivalents 0.7806 and 0.4534 Full-matrix least-squares on F2 7260 / 0 / 447 0.981 R1 = 0.0603, wR2 = 0.1543 R1 = 0.1057, wR2 = 0.1865 0.841 and -0.781 e.Å-3 159 Appendix A (cont.). Summary of crystal data and structure refinement for 4e O(3B) O(1B) C(7B) O(4B) C(12B) N(1B) C(17B) B(1B) C(6B) C(1B) C(5B) O(2B) C(2B) C(4B) C(3B) Br(1B) Selected bond lengths [Å] and angles [°] for 4e Br(1B)-C(3B) O(1B)-B(1B) O(2B)-B(1B) O(3B)-C(7B) O(4B)-C(7B) 1.906(5) 1.371(6) 1.347(6) 1.344(6) 1.196(6) B(1B)-C(1B) N(1B)-C(7B) N(1B)-C(6B) N(1B)-H(1B) N(1B)H(1B)-O(1B) 1.559(7) 1.379(6) 1.399(6) 0.8800 2.059 B(1B)-O(1B)-C(12B) B(1B)-O(2B)-C(13B) C(7B)-O(3B)-C(8B) O(2B)-B(1B)-O(1B) O(2B)-B(1B)-C(1B) O(1B)-B(1B)-C(1B) C(7B)-N(1B)-C(6B) C(2B)-C(1B)-B(1B) 107.3(4) 108.2(4) 119.4(4) 113.6(4) 122.3(4) 124.1(4) 127.5(4) 116.7(4) C(6B)-C(1B)-B(1B) C(2B)-C(3B)-Br(1B) C(4B)-C(3B)-Br(1B) N(1B)-C(6B)-C(1B) N(1B)-C(6B)-C(5B) O(4B)-C(7B)-O(3B) O(4B)-C(7B)-N(1B) O(3B)-C(7B)-N(1B) 124.8(4) 120.6(4) 118.7(3) 118.2(4) 122.0(4) 127.1(5) 125.5(5) 107.4(4) 160 Appendix A (cont.). Summary of crystal data and structure refinement for 4g Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 25.00° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Largest diff. peak and hole N-(tert-butoxycarbonyl)-4-trifluoromethyl-2(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)aniline (4g) C18 H25 B F3 N O4 387.20 100(2) K 0.71073 Å Orthorhombic Pbca a = 10.6990(11) Å a = 90°. b = 18.0954(19) Å b = 90°. c = 20.924(2) Å g = 90°. 3 4050.9(7) Å 8 1.270 Mg/m3 0.105 mm-1 1632 0.30 x 0.29 x 0.16 mm3 1.95 to 27.49°. -13<=h<=11, -23<=k<=22, -27<=l<=26 32048 4646 [R(int) = 0.0497] 100.0 % Semi-empirical from equivalents 0.9838 and 0.9695 Full-matrix least-squares on F2 4646 / 0 / 251 1.037 R1 = 0.0424, wR2 = 0.0942 R1 = 0.0659, wR2 = 0.1051 0.349 and -0.323 e.Å-3 161 Appendix A (cont.). Summary of crystal data and structure refinement for 4g O(3) O(4) C(7) O(1) C(13) N(1) C(4) C(14) B(1) C(5) C(3) O(2) C(2) C(12) F(2) F(1) F(3) Selected bond lengths [Å] and angles [°] for 4g F(1)-C(12) F(2)-C(12) F(3)-C(12) O(1)-B(1) O(2)-B(1) O(3)-C(7) 1.3312(18) 1.3499(19) 1.3385(18) 1.3726(19) 1.3587(19) 1.3419(17) O(4)-C(7) B(1)-C(1) N(1)-C(7) N(1)-C(6) N(1)-H(1) N(1)H(1)-O(1) 1.2088(18) 1.559(2) 1.3701(18) 1.4035(18) 0.8800 2.115 B(1)-O(1)-C(13) B(1)-O(2)-C(14) C(7)-O(3)-C(8) O(2)-B(1)-O(1) O(2)-B(1)-C(1) O(1)-B(1)-C(1) C(7)-N(1)-C(6) 107.03(11) 106.81(11) 121.38(11) 113.75(13) 122.37(13) 123.87(13) 127.07(12) C(2)-C(1)-B(1) C(6)-C(1)-B(1) C(5)-C(6)-N(1) N(1)-C(6)-C(1) O(4)-C(7)-O(3) O(4)-C(7)-N(1) O(3)-C(7)-N(1) 117.28(13) 124.67(13) 122.38(13) 117.35(12) 126.50(13) 126.05(13) 107.45(12) 162 Appendix A (cont.). Summary of crystal data and structure refinement for 4m Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 67.50° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Largest diff. peak and hole N-(tert-butoxycarbonyl)-5-chloro-4methoxy-2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)aniline (4m) C18 H27 B Cl N O5 383.67 173(2) K 1.54178 Å Monoclinic P 21/n a = 10.43390(10) Å a = 90°. b = 10.3572(2) Å b = 90.1600(10)°. c = 18.9283(3) Å g = 90°. 3 2045.50(5) Å 4 1.246 Mg/m3 1.879 mm-1 816 0.28 x 0.24 x 0.13 mm3 4.83 to 71.70°. -8<=h<=12, -11<=k<=12, -22<=l<=23 15442 3707 [R(int) = 0.0360] 95.6 % Semi-empirical from equivalents 0.7895 and 0.6183 Full-matrix least-squares on F2 3707 / 0 / 243 1.043 R1 = 0.0422, wR2 = 0.1083 R1 = 0.0483, wR2 = 0.1120 0.329 and -0.483 e.Å-3 163 Appendix A (cont.). Summary of crystal data and structure refinement for 4m O(3) C(7) O(4) O(1) N(1) C(2) C(1) C(13) B(1) C(14) C(3) O(2) C(4) Cl(1) C(6) C(5) O(5) Selected bond lengths [Å] and angles [°] for 4m Cl(1)-C(4) O(1)-B(1) O(2)-B(1) O(3)-C(7) O(4)-C(7) O(5)-C(5) 1.7380(18) 1.373(3) 1.361(2) 1.348(2) 1.207(2) 1.362(2) O(5)-C(8) N(1)-C(7) N(1)-C(2) B(1)-C(1) N(1)-H(1) N(1)H(1)-O(1) 1.430(2) 1.367(2) 1.413(2) 1.558(3) 0.8800 2.187 B(1)-O(1)-C(13) B(1)-O(2)-C(14) C(7)-O(3)-C(9) C(5)-O(5)-C(8) C(7)-N(1)-C(2) O(2)-B(1)-O(1) O(2)-B(1)-C(1) O(1)-B(1)-C(1) 105.65(14) 106.76(15) 120.12(14) 117.05(14) 127.60(15) 113.88(16) 121.02(17) 125.08(17) C(6)-C(1)-B(1) C(2)-C(1)-B(1) C(3)-C(2)-N(1) C(1)-C(2)-N(1) O(4)-C(7)-O(3) O(4)-C(7)-N(1) O(3)-C(7)-N(1) 115.75(16) 125.54(17) 121.73(16) 118.59(15) 125.78(17) 125.97(18) 108.26(15) 164 Appendix A (cont.). Summary of crystal data and structure refinement for 4t Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 67.35° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Absolute structure parameter Largest diff. peak and hole N-(tert-butoxycarbonyl)-O-(N’,N’dimethylcarbamoyl)-4-amino-3-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (4t) C20 H31 B N2 O6 406.28 173(2) K 1.54178 Å Monoclinic P 21 a = 9.5289(5) Å a = 90°. b = 35.4913(19) Å b = 91.204(3)°. c = 13.1869(8) Å g = 90°. 3 4458.7(4) Å 8 1.210 Mg/m3 0.723 mm-1 1744 0.32 x 0.23 x 0.20 mm3 3.35 to 67.35°. -11<=h<=11, -41<=k<=42, -15<=l<=15 27443 14042 [R(int) = 0.0599] 96.5 % Semi-empirical from equivalents 0.8659 and 0.8005 Full-matrix least-squares on F2 14042 / 1 / 1082 1.036 R1 = 0.0782, wR2 = 0.2242 R1 = 0.0999, wR2 = 0.2409 0.3(3) 0.381 and -0.404 e.Å-3 165 Appendix A (cont.). Summary of crystal data and structure refinement for 4t C(16A) C(15A) O(2A) B(1A) C(2A) O(1A) O(3A) C(7A) O(6A) C(3A) N(1A) N(2A) O(5A) C(6A) C(5A) C(4A) O(4A) Selected bond lengths [Å] and angles [°] for 4t B(1A)-O(2A) B(1A)-O(1A) B(1A)-C(1A) O(1A)-C(15A) O(2A)-C(16A) O(3A)-C(7A) O(3A)-C(8A) O(4A)-C(7A) O(5A)-C(12A) 1.340(7) 1.390(7) 1.569(8) 1.485(6) 1.457(6) 1.341(7) 1.502(7) 1.209(7) 1.369(7) O(5A)-C(3A) O(6A)-C(12A) N(1A)-C(7A) N(1A)-C(6A) N(2A)-C(12A) N(2A)-C(14A) N(2A)-C(13A) N(1A)-H(1A) N(1A)H(1)-O(1A) 1.401(6) 1.240(7) 1.370(8) 1.399(7) 1.320(8) 1.448(7) 1.477(9) 0.8800 2.083 O(2A)-B(1A)-O(1A) O(2A)-B(1A)-C(1A) O(1A)-B(1A)-C(1A) B(1A)-O(1A)-C(15A) B(1A)-O(2A)-C(16A) C(7A)-O(3A)-C(8A) C(12A)-O(5A)-C(3A) C(7A)-N(1A)-C(6A) C(12A)-N(2A)-C(14A) O(4A)-C(7A)-N(1A) O(3A)-C(7A)-N(1A) C(11A)-C(8A)-O(3A) O(3A)-C(8A)-C(10A) O(3A)-C(8A)-C(9A) O(6A)-C(12A)-N(2A) O(6A)-C(12A)-O(5A) 112.9(5) 123.8(5) 123.3(5) 106.9(4) 109.0(4) 119.7(4) 117.1(5) 128.3(4) 121.3(6) 125.6(5) 107.2(4) 111.4(5) 108.8(5) 101.9(4) 125.3(5) 121.6(5) C(12A)-N(2A)-C(13A) C(14A)-N(2A)-C(13A) C(2A)-C(1A)-B(1A) C(6A)-C(1A)-B(1A) C(4A)-C(3A)-O(5A) C(2A)-C(3A)-O(5A) N(1A)-C(6A)-C(1A) N(1A)-C(6A)-C(5A) O(4A)-C(7A)-O(3A) N(2A)-C(12A)-O(5A) O(1A)-C(15A)-C(18A) O(1A)-C(15A)-C(17A) O(1A)-C(15A)-C(16A) O(2A)-C(16A)-C(20A) O(2A)-C(16A)-C(19A) O(2A)-C(16A)-C(15A) 122.9(5) 115.7(5) 116.1(5) 125.0(5) 119.6(5) 119.4(5) 118.8(4) 122.4(5) 127.2(6) 113.0(5) 105.9(5) 107.3(5) 101.9(4) 108.5(4) 106.4(4) 103.2(4) 166 Appendix A (cont.). Summary of crystal data and structure refinement for 7a•CHCl3 Identification code Empirical formula Formula weight Temperature Wavelength Crystal system Space group Unit cell dimensions Volume Z Density (calculated) Absorption coefficient F(000) Crystal size Theta range for data collection Index ranges Reflections collected Independent reflections Completeness to theta = 25.33° Absorption correction Max. and min. transmission Refinement method Data / restraints / parameters Goodness-of-fit on F2 Final R indices [I>2sigma(I)] R indices (all data) Absolute structure parameter Largest diff. peak and hole 3,3-dimethyl-N-(2-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)phenyl)butanamide (7a) C19 H29 B Cl3 N O3 436.59 173(2) K 0.71073 Å Orthorhombic P 21 21 21 a = 9.5268(11) Å a = 90°. b = 11.8725(13) Å b = 90°. c = 20.737(2) Å g = 90°. 2345.5(5) Å3 4 1.236 Mg/m3 0.408 mm-1 920 0.39 x 0.27 x 0.23 mm3 1.96 to 25.33°. -11<=h<=11, -14<=k<=14, -24<=l<=24 17213 4288 [R(int) = 0.0453] 100.0 % Semi-empirical from equivalents 0.9134 and 0.8570 Full-matrix least-squares on F2 4288 / 0 / 251 1.095 R1 = 0.0459, wR2 = 0.1155 R1 = 0.0543, wR2 = 0.1218 -0.04(8) 0.427 and -0.454 e.Å-3 167 Appendix A (cont.). Summary of crystal data and structure refinement for 7a•CHCl3 C(14) C(8) O(3) O(2) C(7) B(1) N(1) O(1) C(1) C(2) C(6) C(3) Selected bond lengths [Å] and angles [°] for 7a•CHCl3 O(1)-B(1) O(2)-B(1) O(3)-C(13) O(3)-B(1) N(1)-C(13) B(1)-O(1)-C(7) C(8)-O(2)-B(1) C(13)-O(3)-B(1) C(13)-N(1)-C(2) O(1)-B(1)-O(2) O(1)-B(1)-C(1) O(2)-B(1)-C(1) O(1)-B(1)-O(3) O(2)-B(1)-O(3) C(1)-B(1)-O(3) 1.433(3) 1.467(4) 1.279(3) 1.609(3) 1.304(3) N(1)-C(2) B(1)-C(1) C(1)-C(2) C(1)-C(6) C(2)-C(3) 108.7(2) 108.70(18) 125.2(2) 124.2(2) 105.7(2) 116.6(2) 116.1(2) 107.6(2) 103.5(2) 106.24(19) C(2)-C(1)-B(1) C(3)-C(2)-N(1) C(1)-C(2)-N(1) O(1)-C(7)-C(10) O(1)-C(7)-C(9) O(1)-C(7)-C(8) O(2)-C(8)-C(12) O(2)-C(8)-C(11) O(2)-C(8)-C(7) O(3)-C(13)-N(1) 168 1.418(3) 1.582(4) 1.403(3) 1.404(4) 1.387(4) 121.7(2) 117.6(2) 118.9(2) 108.2(2) 109.0(2) 101.88(19) 107.9(2) 109.0(2) 102.4(2) 123.0(2) APPENDIX B NMR Spectra 169 Appendix B (cont.). NMR spectra of 1c Cl O O O B O 500 MHz 1H NMR of 1c (CDCl3 = 7.24 ppm) Cl O O O B O 126 MHz 13C NMR of 1c (CDCl3 = 77 ppm) 170 Appendix B (cont.). NMR spectra of 1d Br O O O B O 600 MHz 1H NMR of 1d (CDCl3 = 7.24 ppm) Br O O O B O 151 MHz 13C NMR of 1d (CDCl3 = 77 ppm) 171 Appendix B (cont.). NMR spectra of 2b O O N O O BO O Cl 500 MHz 1H NMR of 2b (CDCl3 = 7.24 ppm) O O Cl O N O BO O 126 MHz 13C NMR of 2b (CDCl3 = 77 ppm) 172 Appendix B (cont.). NMR spectra of 2d O NH O B O O Cl 600 MHz 1H NMR of 2d (CDCl3 = 7.24 ppm) O O NH O B O Cl 151 MHz 13C NMR of 2d (CDCl3 = 77 ppm) 173 Appendix B (cont.). NMR spectra of 2d O O NH O B O Cl 600 MHz nOe NMR of 2d (CDCl3 = 7.24 ppm) O O NH O BO Cl 600 MHz nOe NMR of 2d (CDCl3 = 7.24 ppm) 174 Appendix B (cont.). NMR spectra of 2e O NH O BO O Cl 600 MHz 1H NMR of 2e (CDCl3 = 7.24 ppm) O O Cl NH BO O 151 MHz 13C NMR of 2e (CDCl3 = 77 ppm) 175 Appendix B (cont.). NMR spectra of 3d O NH O BO O 600 MHz 1H NMR of 3d (CDCl3 = 7.24 ppm) O O NH BO O 151 MHz 13C NMR of 3d (CDCl3 = 77 ppm) 176 Appendix B (cont.). NMR spectra of 4a O NH O BO O OH 500 MHz 1H NMR of 4a (CDCl3 = 7.24 ppm) O O NH O BO OH 126 MHz 13C NMR of 4a (CDCl3 = 77 ppm) 177 Appendix B (cont.). NMR spectra of 4a O O NH O B O OH 600 MHz nOe NMR of 4a (CDCl3 = 7.24 ppm) 178 Appendix B (cont.). NMR spectra of 4c O NH O BO O Cl 500 MHz 1H NMR of 4c (CDCl3 = 7.24 ppm) O O NH O BO Cl 126 MHz 13C NMR of 4c (CDCl3 = 77 ppm) 179 Appendix B (cont.). NMR spectra of 4c O O NH O B O Cl 500 MHz nOe NMR of 4c (CDCl3 = 7.24 ppm) O O NH O BO Cl 500 MHz nOe NMR of 4c (CDCl3 = 7.24 ppm) 180 Appendix B (cont.). NMR spectra of 4e O NH O BO O Br 500 MHz 1H NMR of 4e (CDCl3 = 7.24 ppm) O O NH O BO Br 126 MHz 13C NMR of 4e (CDCl3 = 77 ppm) 181 Appendix B (cont.). NMR spectra of 4g O NH O BO O F F F 500 MHz 1H NMR of 4g (CDCl3 = 7.24 ppm) O NH O BO O F F F 126 MHz 13C NMR of 4g (CDCl3 = 77 ppm) 182 Appendix B (cont.). NMR spectra of 4i O NH O BO O F Cl 500 MHz 1H NMR of 4i (CDCl3 = 7.24 ppm) O O NH O BO F Cl 126 MHz 13C NMR of 4i (CDCl3 = 77 ppm) 183 Appendix B (cont.). NMR spectra of 4k O NH O BO O F 500 MHz 1H NMR of 4k (CDCl3 = 7.24 ppm) O O NH O BO F 126 MHz 13C NMR of 4k (CDCl3 = 77 ppm) 184 Appendix B (cont.). NMR spectra of 4k O O NH O B O F 300 MHz nOe NMR of 4k (CDCl3 = 7.24 ppm) O O NH O BO F 300 MHz nOe NMR of 4k (CDCl3 = 7.24 ppm) 185 Appendix B (cont.). NMR spectra of 4m O NH O BO O Cl O 500 MHz 1H NMR of 4m (CDCl3 = 7.24 ppm) O O NH O BO Cl O 126 MHz 13C NMR of 4m (CDCl3 = 77 ppm) 186 Appendix B (cont.). NMR spectra of 4o O O F F NH O BO F O 600 MHz 1H NMR of 4o (CDCl3 = 7.24 ppm) O O F F NH O BO F O 151 MHz 13C NMR of 4o (CDCl3 = 77 ppm) 187 Appendix B (cont.). NMR spectra of 4q O NH O BO O N 500 MHz 1H NMR of 4q (CDCl3 = 7.24 ppm) O O NH O BO N 126 MHz 13C NMR of 4q (CDCl3 = 77 ppm) 188 Appendix B (cont.). NMR spectra of 4q O O NH O BO N 300 MHz nOe NMR of 4q (CDCl3 = 7.24 ppm) O O NH O BO N 300 MHz nOe NMR of 4q (CDCl3 = 7.24 ppm) 189 Appendix B (cont.). NMR spectra of 4r O O NH F F B F K N 500 MHz 1H NMR of 4r (acetone-d6 = 2.05 ppm) O O NH F F B F K N 126 MHz 13C NMR of 4r (acetone-d6 = 206 ppm) 190 Appendix B (cont.). NMR spectra of 4t O NH O BO O O O N 500 MHz 1H NMR of 4t (CDCl3 = 7.24 ppm) O O NH O BO O O N 126 MHz 13C NMR of 4t (CDCl3 = 77 ppm) 191 Appendix B (cont.). NMR spectra of 4w O NH O BO O Cl O O N 300 MHz 1H NMR of 4w (CDCl3 = 7.24 ppm) O O NH O BO Cl O O N 75 MHz 13C NMR of 4w (CDCl3 = 77 ppm) 192 Appendix B (cont.). NMR spectra of 7a HN O O B O 500 MHz 1H NMR of 7a (CDCl3 = 7.24 ppm) HN O O B O 126 MHz 13C NMR of 7a (CDCl3 = 77 ppm) 193 Appendix B (cont.). NMR spectra of 8c O N O BO O Cl 500 MHz 1H NMR of 8c (CDCl3 = 7.24 ppm) O O Cl N BO O 126 MHz 13C NMR of 8c (CDCl3 = 77 ppm) 194 Appendix B (cont.). NMR spectra of 8e O O O BO O Cl 500 MHz 1H NMR of 8e (CDCl3 = 7.24 ppm) O O Cl O BO O 126 MHz 13C NMR of 8e (CDCl3 = 77 ppm) 195 Appendix B (cont.). NMR spectra of 8g O N H O BO O Cl 500 MHz 1H NMR of 8g (CDCl3 = 7.24 ppm) O N H Cl O BO O 126 MHz 13C NMR of 8g (CDCl3 = 77 ppm) 196 Appendix B (cont.). NMR spectra of 8i O NH BO O Cl 500 MHz 1H NMR of 8i (CDCl3 = 7.24 ppm) O NH Cl BO O 126 MHz 13C NMR of 8i (CDCl3 = 77 ppm) 197 Appendix B (cont.). NMR spectra of 9a O NH O D Cl 500 MHz 1H NMR of 9a (CDCl3 = 7.24 ppm) O O NH D Cl 126 MHz 13C NMR of 9a (CDCl3 = 77 ppm) 198 Appendix B (cont.). NMR spectra of 10a O P O O 500 MHz 1H NMR of 10a (CDCl3 = 7.24 ppm) O P O O 126 MHz 13C NMR of 10a (CDCl3 = 77 ppm) 199 Appendix B (cont.). NMR spectra of 10a O P O O 202 MHz 31P NMR of 10a (H3PO4 = 0 ppm) 200 Appendix B (cont.). NMR spectra of 10b PH2 300 MHz 1H NMR of 10b (CDCl3 = 7.24 ppm) PH2 75 MHz 13C NMR of 10b (CDCl3 = 77 ppm) 201 Appendix B (cont.). NMR spectra of 10b PH2 121 MHz 31P NMR of 10b (H3PO4 = 0 ppm) 202 Appendix B (cont.). NMR spectra of 10c Si 500 MHz 1H NMR of 10c (CDCl3 = 7.24 ppm) Si 126 MHz 13C NMR of 10c (CDCl3 = 77 ppm) 203 Appendix B (cont.). NMR spectra of 10d Br Br Br Si 600 MHz 1H NMR of 10d (CDCl3 = 7.24 ppm) Br Br Si Br 151 MHz 13C NMR of 10d (CDCl3 = 77 ppm) 204 Appendix B (cont.). NMR spectra of 10e P BH3 Si Br 500 MHz 1H NMR of 10e (CDCl3 = 7.24 ppm) P Si BH3 Br 126 MHz 13C NMR of 10e (CDCl3 = 77 ppm) 205 Appendix B (cont.). NMR spectra of 10e P BH3 Si Br 202 MHz 31P NMR of 10e (H3PO4 = 0 ppm) P Si BH3 Br 160 MHz 11B NMR of 10e (BF3•OEt2 = 0 ppm) 206 Appendix B (cont.). NMR spectra of 10f P Si 500 MHz 1H NMR of 10f (C6D6 = 7.15 ppm) P Si 126 MHz 13C NMR of 10f (C6D6 = 128 ppm) 207 Appendix B (cont.). NMR spectra of 10f P Si 202 MHz 31P NMR of 10f (H3PO4 = 0 ppm) 208 Appendix B (cont.). NMR spectra of 11a O O HN OB O Cl 600 MHz 1H NMR of 11a (CDCl3 = 7.24 ppm) O O HN OB O Cl 151 MHz 13C NMR of 11a (CDCl3 = 77 ppm) 209 Appendix B (cont.). NMR spectra of 11a O O HN OB O Cl 600 MHz nOe NMR of 11a (CDCl3 = 7.24 ppm) O O HN OB O Cl 600 MHz nOe NMR of 11a (CDCl3 = 77 ppm) 210 Appendix B (cont.). NMR spectra of 11c O NH O Cl O B O 600 MHz 1H NMR of 11c (CDCl3 = 7.24 ppm) O NH O Cl O B O 151 MHz 13C NMR of 11c (CDCl3 = 77 ppm) 211 Appendix B (cont.). NMR spectra of 12b OO S NH BO O Cl 600 MHz 1H NMR of 12b (CDCl3 = 7.24 ppm) OO S NH Cl BO O 151 MHz 13C NMR of 12b (CDCl3 = 77 ppm) 212 Appendix B (cont.). NMR spectra of 12d F F O O S NH F BO O Cl 500 MHz 1H NMR of 12d (CDCl3 = 7.24 ppm) F F O O S NH F Cl BO O 126 MHz 13C NMR of 12d (CDCl3 = 77 ppm) 213 Appendix B (cont.). NMR spectra of 13b O NH O BO O Cl 600 MHz 1H NMR of 13b (CDCl3 = 7.24 ppm) O O NH O BO Cl 151 MHz 13C NMR of 13b (CDCl3 = 77 ppm) 214 Appendix B (cont.). NMR spectra of 13b O NH O BO O Cl 300 MHz nOe NMR of 13b (CDCl3 = 7.24 ppm) O O NH O BO Cl 300 MHz nOe NMR of 13b (CDCl3 = 7.24 ppm) 215 Appendix B (cont.). NMR spectra of 13c O NH O BO O Cl 600 MHz 1H NMR of 13c (CDCl3 = 7.24 ppm) O O Cl NH BO O 151 MHz 13C NMR of 13c (CDCl3 = 77 ppm) 216 Appendix B (cont.). NMR spectra of 14b NH2 O BO Cl O O N 500 MHz 1H NMR of 14b (CDCl3 = 7.24 ppm) NH2 O BO Cl O O N 126 MHz 13C NMR of 14b (CDCl3 = 77 ppm) 217 Appendix B (cont.). NMR spectra of 14c NH BO O Cl 600 MHz 1H NMR of 14c (CDCl3 = 7.24 ppm) NH Cl BO O 151 MHz 13C NMR of 14c (CDCl3 = 77 ppm) 218 Appendix B (cont.). NMR spectra of 15a O NH O O O Br 500 MHz 1H NMR of 15a (CDCl3 = 7.24 ppm) O O NH O O Br 126 MHz 13C NMR of 15a (CDCl3 = 77 ppm) 219 Appendix B (cont.). 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