DISCOVERY AND THE DEVELOPMENT OF BISMUTH SALT MEDIATED CATALYTIC DEBORYLATION AND ALLIED STUDIES By Fangyi Shen A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of 2015 ABSTRACT DISCOVERY AND THE DEVELOPMENT OF BISMUTH SALT MEDIATED CATALYTIC DEBORYLATION AND ALLIED STUDIES By Fangyi Shen A rylboronate esters are vers atile synthetic building blocks. Iridium catalyzed C H activation/borylation reactions are a green way of making such building blocks as these reactions often obviate the need for prior funct ionalization (e.g. halogenation ), the use of pyrophoric reagents, cryogenic conditions, et c. I nstall ation of multiple boron substit uents about the starting arene and then Ir catalyzed selective deborylation of the individual borons can allow for the formation of an even greater diversit y of borylated building blocks. The regioselectivity of Ir - catalyzed borylation is usually driven by sterics, however heterocycles are known to borylated at positions that exhibit heightened C - H acidity through the influence of the heteroatom. The regioselective borylation attained with a tryptophan derivative has been utilized in the development of a novel convergent route to the TMC - 95 core. While pursuing a model synthesis of this natural product, the ability of bismuth salts to catalyze deborylations was discovered. These bismuth salts mediated method s can be h ighly selective in the in the deborylation of di and triborylated indoles. Furthermore, bismuths compounds are safe and less expensive as compared to the Ir - catalysts that facilitated deborylation. N umerous screening experiments on both substrates and other metal salts afforded a better understanding of how th ese novel deborylation s can be applied in various synthetic settings and provided insight into possible mechanism s. iii To Yue and Mei iv ACKNOWLEDGEMENTS Dr . Robert E. Maleczka Jr Dr . Milton R. Smith, III Dr . Babak Boham Dr . Kevin Walker Dr. William D. Wulff Dr . Luis Sanchez Steve Polious v TABLE OF CONTENTS LIST OF TABLES ................................ ................................ ................................ ......................... vi LIST OF FIGURES ................................ ................................ ................................ ...................... vii Chapter 1. Introduction of Ir catalyzed borylation /deborylation ................................ ................... 1 1.1. Significance ................................ ................................ ................................ ...................... 1 1.2. Highlig hts of Ir - catalyzed aromatic C - H activation/borylation ................................ ....... 2 1.3. Iridium catalyzed deborylation ................................ ................................ ......................... 4 REFERENCE S ................................ ................................ ................................ ............................ 7 Chapter 2. Model studies for the synthesis of the TMC - 95 core ................................ .................... 9 2.1. Target choice and significance ................................ ................................ ......................... 9 2.2. General analysis of the reported synthesis of TMC - 95 compounds ................................ 9 2.3. Our synthetic approach to the TMC - 95 core ................................ ................................ .. 13 2.4. Results and discussion ................................ ................................ ................................ .... 13 REFERENCE S ................................ ................................ ................................ .......................... 18 Chapter 3. Bismuth acetate as a green (and sometimes pink) catalyst for the selective protonation of substituted indoles ................................ ................................ ................................ .................... 21 3.1. Prior art ................................ ................................ ................................ ............................... 21 3.2. Discovery and development of bismuth mediated deborylation ................................ ........ 22 3.3. Results and discussion ................................ ................................ ................................ ........ 24 3.4. The source of MeOH is another significant factor in Bi - catalyzed deborylation .............. 38 3.5. Possible impact of the trace amount HOAC in bismuth mediated deborylation ............... 40 3.6. Summary ................................ ................................ ................................ ............................ 41 REFERENCE S ................................ ................................ ................................ .......................... 43 Chapter 4 . Deborylation/Deuteration mediated by silver oxide and copper chloride .................. 46 4.1. Introduction ................................ ................................ ................................ ........................ 46 4.2. Results of Copper chloride and Silver oxide mediated Deborylation/Deuteration ............ 49 4.3. Conclusions ................................ ................................ ................................ ........................ 51 REFERENCE S ................................ ................................ ................................ .......................... 52 Chapter 5 . Experimental details and characterization data ................................ .......................... 54 5.1. General Methods ................................ ................................ ................................ ................ 54 5.2. Experimental details for Chapter 2 ................................ ................................ ..................... 55 5.3. Experimental details for Chapter 3 ................................ ................................ ..................... 60 5.4. Experimental details for Chapter 4 ................................ ................................ ..................... 75 vi LIST OF TABLES Table 1 . Synthesis of monoborylated compounds via diborylation/deborylation .......................... 5 Table 2. High throughput experiments on 3 - methyl 2,7 - bisborylatedindole deborylation ........... 23 Table 3. Ir - catalyzed borylation of indoles ................................ ................................ ................... 26 Table 4. Bi(OAc) 3 catalyzed protodeboronations ................................ ................................ ......... 30 Table 5. Deborylation on arenes ................................ ................................ ................................ ... 36 Table 6. Condition established from MSU and Merck ................................ ................................ . 38 Table 7. Parameters controlling experiments ................................ ................................ ................ 39 Table 8. Selective deuterodeborylation reactions a ................................ ................................ ........ 48 Table 9. Deuteration protocol for synthesizing deuterated aromatics ................................ .......... 49 Table 10. Deuteration protocol for s ynthesizing deuterated aromatics ................................ ........ 50 vii LIST OF FIGURES Figure 1. Suzuki cross - coupling reaction ................................ ................................ ........................ 1 Figure 2. Preparing the aryl boronic ester ................................ ................................ ....................... 1 Figure 3. Example of a C H activation/borylation ................................ ................................ ......... 2 Figure 4. Synthetic utility of borylated arenes ................................ ................................ ................ 2 Figure 5. Synthesis 3 - Bromo - 5 - chlorophenol via traditional route ................................ ................ 3 Figure 6. Synthesis 3 - Bromo - 5 - chlorophenol via our method. ................................ ...................... 3 Figure 7. Discovery of Ir catalyzed deborylation during the borylation of trichlorobenzene ........ 4 Figure 8. Putative mechanism of Ir - catalyzed borylation/deborylation ................................ .......... 5 Figure 9. Ir - catalyzed borylations and deborylation on protected tryptophan ................................ 6 Figure 10. TMC - 95 nature products ................................ ................................ ............................... 9 Figure 11. Retro synthetic pattern ................................ ................................ ................................ . 10 Figure 12. Ring Closure by macrolactamization ................................ ................................ .......... 11 Figure 13. Ring closure by cross coupling reactions ................................ ................................ .... 12 Figure 14. Retro synthetic design of our approach ................................ ................................ ....... 13 Figure 15 Protection of L - tryptophan ................................ ................................ ............................ 14 Figure 16. Preparation of a 7 - pinacolboryl - L - tryptophan derivative ................................ ............ 14 Figure 17. BiCl 3 - mediated deprotection of a 7 - pinacolboryl - L - tryptophan derivative ................. 15 Figure 18 Preparation of the tyrosine unit for the synthesis of the TMC - 95 core ........................ 15 Figure 19. Preparation of a tyrosine - asparagine dipeptide ................................ ........................... 16 Figure 20. Preparation of a tripeptide and followed with the Suzuki coupling reaction .............. 17 Figure 21. Prior art ................................ ................................ ................................ ........................ 21 Figure 22 Discovery of Bi catalyzed protodeboronations ................................ ............................ 22 viii Figure 23. Deborylation feedback from high throughput screening ................................ ............. 23 Figure 24. Study on the relative rate of deborylations ................................ ................................ .. 24 Figure 25. Aiming to borylated all position on the substrates has indole moiety ......................... 24 Figure 26. Bi(OAc) 3 catalyzed protodeboronation of 3 - 1 ................................ ............................ 25 Figure 27. Changing the sequence of protodeboronation ................................ ............................. 31 Figure 28 The protecting Boc group changed the sequence of deborylation ............................... 33 Figure 29. Figure of preparing the heterocyclic bismuth triamide ................................ ............... 34 Figure 30. Putativ e transition states of Bi - catalyzed deborylation ................................ ............... 34 Figure 31. Proposed transition structure of 2 - substituted indole during the de borylation ............ 37 Figure 32 Exploring the potential role of HOAc ................................ ................................ .......... 40 Figure 33. Proposed transition structure of 2 - substituted indole during the deborylation ............ 47 Figure 34. Potential application (isotopic labeling and regioselective synthesis) ........................ 51 1 Chapter 1. Introduction of Ir catalyzed borylation /deborylation 1.1. Significance According to Roughley and Jordan in 2011, 1 - coupling reaction is the single most numerous reaction within the C C bond forming group, accounting for 40% of all such . Thus for cross - couplings ( Figure 1) and other organoboron transformations, the synthesis of aryl and heteroarylboronic esters is an important operation for pharmaceutical chemists . 2 Figure 1 . Suzuki cross - coupling reaction Often , the synthesis of these compounds is carried out from Grignard or lithium species generated via metal - halogen exchange or from halide - containing precursors via Miyaura coupling ( Figure 2 ). These and related methods suffer from the need for halogenated starting materials , pyrophoric bases and/or cryogenic temper atures . 3 Figure 2 . Preparing the aryl boronic ester 2 Chemists have recently developed ways to avoid these unfavorable conditions when preparing aryl and heteroarylboronic esters. In 1999, the Smith group demonstrated a n Ir - catalyzed arene C - H activation/borylation p r o cess that operates thermally and proceeds without the need for stoichiometric bases or additives ( Figure 3 ) . 4 Figure 3 . Example of a C H activation/borylation 1.2. Highlights of Ir - catalyzed aromatic C - H activation/borylation Iridium catalyzed C H activation/borylations not only allow for the direct replace ment of an aromatic hydrogen with a boronic ester , but also tolerate numourous functional groups . The products can be read ily employed in other transformations, such as cyanations , Suzuki coupling s , oxidations, halogenations, etc. (Figure 4). 5 Figure 4 . Synthetic utility of borylated arenes It is notable that the iridium cata lyzed C H activation/borylation regioselectivity is directed by sterics, as opposed to electronics, complementing electrophilic aromatic substitution and 3 functional group - directed metalation. Synthetic utilization of this characteristic allows access to structures t hat are often inaccessible via traditional routes. 3 - Bromo - 5 - chlorophenol highlights the challenges of using classical chemistry to prepare a contra electronically substituted benzene (Figure 5 enol was by Hodgson and Wignall who use d ten steps and started with TNT ! 6 Figure 5 . Synthesis 3 - Bromo - 5 - chlorophenol via traditional route By utilizing the key feature s of C - H activation/borylation method , namely the ability to select for speci fic hydrogens and to follow the borylation with other reactions (e.g. oxidations) in a one - pot fashion, 3 - b romo - 5 - chlorophenol was obtained in two steps and in 79% yield from commercially available 1,3 - bromo chlorobenzene (F igure 6 ). 7 Figure 6 . Synthesis 3 - Bromo - 5 - chlorophenol via our method. Given the selectivity and atom economy (H 2 is the only stoichiometric byproduct) of these reactions , iridium catalyzed C H activation/borylations also represen t an example of green chemistry. Another green aspect of the method is that it can eliminate the need for halogenated TNT 4 starting materials , which can lower the expense of preparation or avoid its potential harmful to biological organisms. 1.3. Iridium catalyzed deborylation Figure 7 . Dis covery of Ir catalyzed deborylation during the borylation of trichlorobenzene 5 Figure 8 . Putative mechanism of Ir - catalyzed borylation/deborylation It is possible to install more than one BPin into a substrate. For example, when exposed to excess B 2 Pin 2 indole substrates borylate at the 2 - position quickly, afterwards a second BPin is then installed at the 7 - position. Investigation into the Ir - catalyzed deborylation of such diborylated during the Ir - catalyzed - catalyzed deborylation. 8 Table 1 . Synthesis of monoborylated compound s via diborylation/deborylation 6 Thus, the diborylation/deborylation sequence shown in Figure 8 can afford 7 - borylated protected tryptophan, which complements the regioselectivity of mono - borylating the tryptophan starting material. 8 A t ryptophan - based building block prepared in this manner has been utilized in model studies toward the devel opment of a novel convergent route to the TMC - 95 core. A discussion of these efforts is described in next chapter. Figure 9 . Ir - catalyzed borylations and deborylation on protected tryptophan 7 REFERENC E S 8 REFERENCES 1. Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011 , 54 , 3451 3479 . 2. For a review of the Suzuki reaction see: Miyaura, N. and Suzuki, A. Chem. Rev. 1995 , 95 , 2457 2483 . 3. J. W. Clary, T. J. Rettenmaier, R. Snelling, W. Bryks, J. Banwell, W. T. Wipke, J. Org. Chem. , 2011 , 76 , 9602 4. Cho, J. - Y.; Tse, M. K.; Holmes, D.; Maleczka, R. E., Jr.; Smith, M. R., III Science 2002 , 295 , 305 . 5. (a) Mkhalid, I. A. I.; Barnard, J. H.; Marde r, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010 , 110 , 890 931. (b) Shi, F. Synthetic Applications of Iridium - Catalyzed Aromatic C H Borylation. PhD Thesis, Michigan State University, East Lansing, 2007 . 6. Hodgson, H. H.; Wignall, J. S. J. Chem. Soc. 1926 , 2077 . 7. Maleczka, R. E., Jr.; Shi, F.; Holmes, D.; Smith, M. R., III J. Am. Chem. Soc. 2003 , 125 , 7792 7793 . 8. Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.; Miller, S. L.; Maleczka, R. E., Jr.; Smith, M. R., III J. Org. Chem. 2 015 , 80 , 8341 8353. 9 Chapter 2. Model studies for the synthesis of the TMC - 95 core 2.1. Target choice and significance The isolation of TMC - 95A D (Figure 10) , a novel family of fungal metabolites with a distinctive cyclic peptide structure, from a ferment ation broth was reported in 2000. 1 Their intriguing structure was accompanied by remarkable activity and selectivity as proteasome inhibitors. 2 Such bioactivity makes them promising agents for the treatment of immune and other diseases. 3 Figure 10 . TMC - 95 nature products Owing to such properties, a number of groups embarked on efforts to synthesize TMC - 95 A and its analogs. Such synthetic efforts were aimed at furthering the understanding of these molecules biological activity, but also used TMC 95 as a vehicle to advance new chemical methods. Similarly, we viewed TMC - Ir - catalyzed C - H activation/borylation/deborylation chemistry through its use as a tool to access 2.2. General analysis of the reported synthesis of TMC - 95 compounds The distinctive cyclic peptide structure of TMC 95A is composed of a highly oxidized L - tr yptophan, (Z) - 1 - propenylamine, L - tyrosine, L - asparagine and 3 - methyl - 2 - oxopentanoic moiety. Two major retro synthetic disconnections were evident for this macro cycle (Figure 11 ). One of the disconnections is at the aryl - aryl linkage, which in the forward s ynthetic sense could be formed by 10 a Suzuki cross - coupling. The other disconnection is through one of the two cyclic amide bonds. In practice, disconnection of the Trp - Asp amide bond leads to a more convergent synthesis. Either formation of the biaryl bond or the Trp - Asp bond could be used to join the major fragments or close the ring. Thus, one could imagine a Suzuki ring closure of compound A or macrolactamization of compound B . Figure 11 . Retro synthetic pattern To date, 4 5 6 have successfully synthesized TMC - 95. In all three cases they built a dipeptide chain similar to compound B first (Figure 12 ) and then closed the ring by macrolactamization. 11 Figure 12 . Ring Closure by macrolactamization - mediated amidation that afforded a 36% yield of the macrocycle. This cycloamidation pathway has been used by most of the research groups in their subsequent TMC - 95 syntheses (Figure 1 2 ). 12 Besides the total syntheses, there have been a considerable number of reports on the preparation of TMC - 95 analogs, particularly coming from the Moroder 7 and Vidal groups 8 analog, he noticed even with a racemic mixture at the C3 chiral center of the oxidole, which resulted from the oxidation of the indole moiety, only the exact 3 S cyclic stereoisomer was formed (Figure 2 - 2). Figure 13 . Ring closure by cross coupling reactions Vidal also replaced the highly oxidized tryptophan, but this action led to rather disappointingly fact low yields during nickel catalyzed intramolecular Negishi cross - couplings (Figure 13 ). This finding is consistent with what Moroder inferred, t hat a sp 3 c enter is needed at the indole 3 - position to ensure a successful ring closure. 13 2.3. Our synthetic approach to the TMC - 95 core Our TMC - 95 core synthesis also substitutes the highly oxidized tryptophan with a tryptophan. In 3 hybridized C3 oxidole structure is lack ing in our synthesis (Figure 14 ). However, we thought to test if switching the reactant partners in the Suzuki - cross coupling partners would offer different results. Specially, we wanted to examine the cross c oupling of a 7 - BPin - Trp and a halide bearing tyrosine. An efficient route to intermediate 2 - 2 , which contains an L - tryptophan - based structure with a reactive pinacolboryl functional group at the 7 - position would provide access to a cyclic tripeptide 2 - 1 through Suzuki coupling. Figure 14 . Retro synthetic design of our approach 2.4. Results and discussion Synthesis of 7 - pinacolboryl - L - tryptophan methyl ester ( 2 - 7 ). One of the building blocks for 2 - 2 was the N - Boc methyl ester of tryptophan 2 - 4 , which was converted to its 7 - BPin derivative 2 - 7 14 for a subsequent peptide coupling step. To start the synthesis of 2 - 7 both the amine and carboxylic acid groups were protected as a Boc carbamate and methyl ester, respectively (Figure 15). i ) a) 2.5 equiv SOCl 2 , MeOH, 94%; 9 b) NaCO 3 , Boc 2 O, 80%. 10 Figure 15 Protection of L - tryptophan Now with compound 2 - 4 fully protected we were ready to apply our key borylation/deborylation sequence (Figure 16 ). First diborylation of 2 - 4 gave BPins at the 2 and 7 positions, then 7 - borylated protected tryptophan 2 - 6 was obtained by deborylation which followed the rule of the first boron on during the Ir - catalyzed borylation being the first boron off in the Ir - ca talyzed deborylation. The overall yield in these was 55% 11 , which gave the functionalized building block for TMC - 95 biaryl formation. i ) 2 equiv B 2 Pin 2 , 3 mol% [Ir(OMe)(COD)] 2 , 6 mol% d t bpy, 0.28 equiv HBPin, THF, r.t. 24 h, 70%; ii ) 1.5 mol% [Ir(OMe)CO D] 2 , MeOH/CH 2 Cl 2 (2:1), 50 °C, 2 h, 55% of 6 and 28 % of 5 Figure 16 . Preparation of a 7 - pinacolboryl - L - tryptophan derivative A key step in the reaction sequence to 2 - 1 required N - Boc deprotection of an early - stage precursor 2 - 6 . While TFA is the most commonly used reagent for Boc deprotection in peptide chemistry. 12 Attempts at converting 2 - 6 into 2 - 7 by treatment with TFA resulted in non - specific cleavage of the methyl ester and release of the BPin group. Efforts to control the r ate of TFA addition and 15 keeping the reaction temperature low did not alleniate this problem. Thus, Lewis acid BiCl 3 , a milder Boc deprotection reagent, was tested at various concentrations in reactions containing 2 - 6 . Stoichiometric amounts of BiCl 3 gave t he best conversion to 2 - 7 , in contrast to the catalytic quantities employed in the original report. 13 Under these conditions Boc deprotection of 2 - 6 with BiCl 3 provided 2 - 7 in 133% crude yield (Figure 17 ). The preparation of building block 2 - 7 , containing a BPin group at C - 7 and a free amine, encouraged the development of a route to dipeptide 2 - 11 . i ) 1.2 equiv BiCl 3 , CH 3 CN/H 2 O (50:1), 60 ºC, 2 h, quantitative (used crude in following step) Figure 17 . BiCl 3 - mediated deprotection of a 7 - pinacolboryl - L - tryptophan derivative Synthesis of Dipeptide ( 2 - 11 ). To acquire dipeptide 2 - 11 , L - tyrosine 2 - 8 was converted to its arylbromo derivative by acetic acid - catalyzed bromination. 14 The resulting compound was N - Boc protected and then the phenol hydroxyl group was protected as a TBS ether to afford 2 - 9 in 70% yield (Figure 18 ). 15 i ) a) Br 2 , HBr/AcOH, r.t. 89%; b) Boc 2 O, t BuOH/H2O, pH 9, r.t. 89%; c) TBSCl, imidazole, then K 2 CO 3 , H 2 O,r.t. 70% of 9 Figure 18 Preparation of the tyrosine unit for the synthesis of the TMC - 95 core 16 Compound 2 - 9 was a ctivated to its hydroxysuccinimide ester 2 - 10 and coupled to L - asparagine monohydrate in one step. This method precluded the need to protect and subsequently deprotect L - - 2 - 11 in 79% yield (Figure 19 ). 16 Thus, the resulting dipeptide 2 - 11 , with its free carboxylic acid group, was already poised for the formation of the tripeptide 2 - 2 . i ) N - hydroxysuccinimide, DCC, DCM, r.t. 4 h; ii ) L - asparagine, NaHCO 3 , dioxane, water, 79% 2 - 11 Figure 19 . Preparation of a tyrosine - asparagine dipeptide Synthesis of Tripeptide ( 2 - 2 ) and Its Ring - Closure . Dipeptide 2 - 11 was further coupled with 2 - 7 (Figure 2 - 8) to afford the first model tripeptide 2 - 2 in 68% yield (Figure 20 ) . 17 i ) a) EDC, HOBT, NEt 3 , THF, 0 °C to r.t. 68%; b) cataXium A, Pd 2 dba 3 , CuCl, K 2 CO 3 , dioxane/H 2 O, at 60 °C Figure 20 . Preparation of a tripeptide and followed with the Suzuki coupling reaction With an ample supply of 2 - 1 , high throughput screening of coupling conditions were explored to find an operative catalyst and reaction conditions. After 268 experiments stoichiometric CuCl, ca talytic Pd 2 dba 3 , and cataXium ligand emerged as the first successful coupling conditions for the formation of 2 - 2 . 17 The coupling occurred in 30% yield and was accompanied by an undesired isomer. Optimization of these conditions for the selective formation of 2 - 6 and its oxidation to afford the TMC - 95 core are currently underway. 18 REFERENCE S 19 REFERENCES 1. (a) Kohno, J.; Koguchi, Y.; Nishio, M.; Nakao, K.; Kuroda, M.; Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000 , 65 , 990 995. (b) Koguchi, Y.; Kohno, J.; Nishio, M.; Takahashi, K.; Okuda, T.; Ohnuki, T.; Komatsubara, S. J. Antibiot. 2000 , 53 , 10 5 109. 2. Moore, B. S.; Eustaquio, A. S.; McGlinchey, R. P. Curr. Opin. Chem. Biol. 2008 , 12 , 434 440. 3. Coste, A.; Couty, F.; Evano, G. C. R. Chim. 2008 , 11 , 1544 1573 . 4. (a) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001 , 40 , 1967 1970. (b) Lin, S.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2002 , 41 , 512 515. (c) Lin, S.; Yang, Z. - Q.; Kwok, B. H. B.; Koldobskiy, M.; Crews, C. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2004 , 126 , 6347 6355. 5. ( a) Inoue, M.; Furuyama, H.; Sakazaki , H.; Hirama, M. Org. Lett. 2001 , 3 , 2863 2865. (b ) Inoue, M.; Sakazaki, H.; Furuyama, H.; Hirama, M. Angew. Chem., Int. Ed. 2003 , 42 , 2654 2657. 6. (a) Albrecht, B. K.; Williams, R. M. Org. Lett. 2002 , 5 , 197 200. (b ) Albrecht, B. K.; Williams, R. M. Proc. Natl. Acad. Sci. U. S. A. 2004 , 101 , 11949 11954 . 7. (a) Kaiser, M.; Milbradt, A.; Moroder, L. Lett. Pept. Sci. 2002 , 9 , 65 70. (b) Kaiser, M.; Groll, M.; Renner, C.; Huber, R.; Moroder, L. Angew. Chem., Int. Ed. 2002 , 41 , 780 783. (c) Kaiser, M.; Siciliano, C.; Assfalg - Machleidt, I.; Groll, M.; Milbradt, A. G.; Moroder, L. Org. Lett. 2003 , 5 , 3435 3437. (d) Kaiser, M.; Milbradt, A. G.; Siciliano, C.; Assfalg - Machleidt, I.; Machleidt, W.; Groll, M.; Renner, C.; Moroder, L. Chem. Biodiv. 2004 , 1 , 161 173. (e) Kaiser, M.; Groll, M.; Siciliano, C.; Assfalg - Machleidt, I.; Weyher, E.; Kohno, J.; Milbradt, A. G.; Renner, C.; Huber, R.; Moroder, L. ChemBioChem 2004 , 5 , 1256 M.; Kaiser, M.; Weyher, E.; Mo roder, L. Chem. Biol. 2006 , 13 , 607 614. 8. (a ) Berthelot, A.; Piguel, S.; Le Dour, G.; Vidal, J. J. Org. Chem. 2003 , 68 , 9835 9838. (b ) Basse, N.; Piguel, S.; Papapostolou, D.; Ferrier - Berthelot, A.; Richy, N.; Pagano, M.; Sarthou, P.; Sobczak - Thépot, J.; R eboud - Ravaux, M.; Vidal, J. J. Med. Chem. 2007 , 50 , 2842 2850. 9. David, R. A.; Abhisek, B. J. Org. Chem. 200 6 , 5 7 , 10181 - 10189 . 10. David, C.; Russell C. B.; Brent, R. C. Tetrahedron . 200 1 , 7 1 , 7106 7109. 11. Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.; Miller, S. L.; Maleczka, R. E., Jr.; Smith, M. R., III J. Org. Chem. 2015 , 80 , 8341 8353. 12. Jacobsen, O.; Klaveness, J.; Petter O. O.; Amiry - Moghaddam, M. R.; Rongved, P. Org. Biomol. Che m . 2009 , 7 , 1599 1611 . 20 13. Procedure adapted from Navath, R. S.; Pabbisetty, K. B.; Hu, L. Tetrahedron Lett. 2006 , 47 , 389 393. 14. Prieto, M.; Mayor, S.; Rodriguez, K.; Lloyd - Williams, P.; Giralt, E. J. Org. Chem. 2007 , 72 , 1047 1050 . 15. Marimganti, S.; Wieneke, R.; Geyer, A.; Maier, M. E. Eur. J. Org. Chem. 2007 , 2779 2790 . 16. Mitchell, A. R.; Kent, S. B. H.; Chu, I. C.; Merrifield, R. B. Analy. Chem . 1978 , 50 , 637 - 640. 21 Chapter 3. Bismuth acetate as a green (and sometimes pink) catalyst for the selective protonation of substituted indoles 3.1. Prior art Figure 21 . Prior art Recent ly, Movassaghi and co - workers 6 showed that the 2,7 - diborylation of tryptophans, tryptamines, and 3 - alkylindoles could be followed by in situ palladium - catalyzed C2 - protodeboronation to selectively afford the C7 - products ( Figure 2 1). While at first glance this tactic may not seem "green" owing to the loss of atom economy, from a strategic perspective such a borylation/protodeboronation sequence enables a streamlined approach to 7 - borylated indoles that are otherwise difficult to access without additional steps and/or prefunctionaliz a tion . 7 We too had observed selective deborylation s of a number of dibo rylated heterocycles, including several 2,7 - diborylated indoles ( Figure 2 1). 8 Our protodeboronation s were Ir - catalyzed , and for some systems could be performed by simply ex posing the crude borylation mixt ure to protic material. 22 Perhaps most usefully , we no ted that for diborylated indoles, azaindoles, thiophenes, and benzthiophenes the - catal yzed borylation was the first Bpin off in the Ir - catalyzed protode boronation . 3.2. Discovery and development of bismuth mediated deborylat ion Figure 22 Discovery of Bi catalyzed protodeboronations 23 Table 2 . High throug hput experiments on 3 - methyl 2, 7 - bisborylatedindole deborylation Feedback of the high throughput screening showed that only few metal salts responded positively, including as Bi(OTf) 3 , Bi(OAc) 3 , CuCl and AgO 2 . Notably, not all Ag, Cu, Bi and Ir salts worked, for example even BiCl 3 proved to be a fairly poor deborylating reagent and only gave trace amounts of product. Ag 2 O and CuCl gave fast deborylations, but removed both the BPins from substrates. Figure 23 . Deborylation feedback from high throughput screening 24 Having screened a series of metal salts against one substrate, we next screened a series of substrates against the Cu, Ag, Bi and Ir salts that emerged from the first screening (Figure 24 ). Bi(OAc) 3 showed selectivity heteroatom. In contrast, arenes or heterocycles where the boron was remote to the heteroatom, required Ir or Ag salts for facile deborylation. Finally, when boron was on the aryl moiety of the substrates explored, deborylation was the quickest with Ag, deborylation did not occur with Bi, and was slow wi th Ir. Figure 24 . Study on the relative rate of deborylations 3.3. Results and discussion These data gave us some sense what catergory of substrate responds best to different deborylation conditions. We thought to use the obsever ed differential reactivity to selectively deborylate di - or triborylate indoles with the aim of generating indoles with BPins at different positions ( Figure 25 ). Figure 25 . Aiming to borylated all position on the substrates has i ndole moiety 25 Figure 26 . Bi(OAc) 3 catalyzed protodeboronation of 3 - 1 26 Table 3 . Ir - catalyzed borylation of indoles a Isolated yields. b Borylations ran with 2.0 equiv B 2 pin 2 , 0.5 mol % [Ir(OMe)COD] 2 , 1 mol % d t bpy , at 80 °C. b Borylations ran as described above, but with 1 .0 equiv B 2 pin 2 . d Substrate stirred in neat HBpin (4 equiv) at rt for 1 h before being subjected to the borylation conditions. e Borylation ran with 2.0 equiv B 2 pin 2 , 3 mol % [Ir(OMe)COD] 2 , 6 mol % d t bpy , at 80 °C. 27 28 29 30 Table 4 . Bi(OAc) 3 catalyzed protodeboronations a Isolated yields. b Ratio determined by 1 H - NMR of the crude reaction mixture. c See Supporting Information for details. 31 Figure 27 . Changing the sequence of protodeboronation 32 Our conclusions on the order of deborylation obviously rests on the strength of our structural assignments of the various indoles illustrated in Figure 28 . The regio - chemical assignments of compounds 3 - 20 , 3 - 21 , 3 - 26 and 3 - 27 were made as follows. For compound 3 - 21 , H 2 and H 3 couple with the NH and each other and therefore afford the two doublet of doublets observed at 7.27 ppm and 6 .98 ppm. The NMR signal for the remaining proton H 5 would only be split by the C - 6 fluorine. The doublet observed at 7.33 ppm is consistent with such a proton. Thus we have assigned compound 3 - 21 as having its two BPins at carbons 4 and 7. Subjecting compo und 3 - 21 to the deborylation conditions result in the protiodeborylation of one of its BPins. The proton NMR of this compound ( 3 - 20 ) showed a new doublet of doublets at 7.14 ppm with the signal for H 7 also as a double of doublets. These coupling patterns f or H 5 and H 7 are consistent with both being ortho to fluorine and meta to each other. Therefore we have assigned compound 3 - 20 as having a BPin at C - 4. Were the BPin at C - 7 the coupling pattern would be different with larger J values expected for the H 5 doublet of doublets. In fact such a doublet of doublets is observed at 7.46 ppm (dd, J = 10.3, 2.5 Hz) in the NMR of compound 3 - 20 . The proton NMR of 3 - 26 is comprised of three doublets. The doublet at 7.41 ppm and 7.01 ppm are clearly coupled to each oth er and were therefore assigned as protons H 2 and H 3 . Again H 5 appears as a doublet with J coupling that is consistent with a proton ortho to fluorine. When compound 3 - 26 is mono debory - deuterated to afford compound 3 - 27 H 3 shifts upfield to 6.50 ppm, a che mical shift that is similar to that which is observed for Boc protected 6 - fluoroindole. Furthermore, two doublets are observed, the doublet at 7.42 ppm has J values of 3.4 Hz, and while the doublet of doublets at 6.95 ppm has J values of 9.3 Hz which this coupling pattern is consistent with one proton that ortho coupled to fluorine (H 5 ). Hence, we are confident in the structures of compounds 3 - 20 , 3 - 21 , 3 - 26 and 3 - 27 and the conclusion that the corresponding deborylations proceeds following the first on fir st off rule. 33 Figure 28 The protecting Boc group chang ed the sequence of deborylation 34 - 2 and C - 7 of indoles, and it not being very effective at deborylating a C - 4 BPin, we proposed a mechanistic explanation based on these - type heterocyclic bismuth triamide are known and are prepared by the ligand exchange reaction of Bi(NMe 2 ) 3 with tris(aminoethyl)amines (Figure 29 ) . 2 2 Figure 29 . Figure of preparing the heterocy clic bismuth triamide The structure of this product was characterized by X - ray crystallography, and the distance of Bi and the central coordinating N (3.021 Å) was found to be much s horter than the calculated van der Waals radii of Bi and N atoms (3.94 Å), but longer than a covalent Bi - N bond (2.180 to 2.189 Å in Bi(NMe 2 ) 3 ). 2 3 This infers that Bi - N coordination may be possible during the Bi - mediated deborylation. Hence we propose the transition states illustrated in Figure 30 . Figure 30 . Putative transition states of Bi - catalyzed deborylation 35 To test this mechanism, more substrates were subjected to Bi - mediated deborylation. As shown in Table 5 , Bi failed to deborylate halide containing arene 3 - 28 where neither of those two boron containing materials bare nearby heteroatoms. 36 Table 5 . Deborylation on arenes Comparing compounds 3 - 29 - a and 3 - 29 - b , bismuth cannot deborylate the remote BPin in 3 - 29 - a , but can deborylate the BPin in compound 3 - 29 - b . This is consistence with hypothesis that deborylation is facilitated by an adjacent N atom. We also examined nitriles, which have a nitrogen 37 atom but where the sp hybridization would make coordination of th e type illustrated in Figure 29 difficult to ach ive. However, 2 - BPin benzonitrile 3 - 30 - b gave the deborylated product in 30% yield after 21 h. Meanwhile, 4 - BPin benzonitrile 3 - 3 0 - a was unreactive. Thus, our hypothesis of nearby heteroatoms being a requirement of fast deborylation was only pointly suppor ted by experiments. The exact mechnism still remains as open question. We also wanted to explore if the presence of other heteroatom containing substituents would facilitate deborylation. Subjecting compound 3 - 32 to deborylation conditions resulted in 50% yield of the deborylated product. Thus, oxygen can facilitate deborylation; however, its ability to do so appears diminished as evidence by the need for the 24 h reaction time needed to deborylate 3 - 32 vs. 5 h for 3 - 31 . Figure 31 . Proposed transition struc ture of 2 - substituted indole during the deborylation Hence through these observations we proposed the the transition structure of 2 - substituted indole during the deborylation in Figure 31 . The substitution group on the 2 position hindered the 38 coordination between NH and Bi makes an efficient and a clean Bi - mediated deborylation hard to achive. 3.4. The source of MeOH is another significant factor in Bi - catalyzed deborylation 39 Table 7 . Parameters controlling experiments Although not quantified we suspect that common impurities in ACS grade MeOH such as formaldehyde and/ or material that may have leached from the plastic container can slow the reaction. In the case of the THF the difference between the distilled and sure sealed THF is less obvious, but the freshly distilled THF should be the most anhydrous. Thus it is possible that trace 40 lation. Again these results point to Bi(OAc) 3 mediated deborylations as being highly dependent upon the quality of the MeOH and somewhat THF dependant. 3.5. Possible impact of the trace amount HOAC in bismuth mediated deborylation Figure 32 Exploring the potential role of HOAc Although the mechanism of these Bi(OAc) 3 mediated deboronations remains to be established , the above examples point to an interaction with the indole nitrogen as being important to achieving se lectivity and gaining reactivity. Given Movassaghi and co - workers' Pd - catalyzed C2 protodeboronation of indoles with HOAc as the proton source, 6 we questioned if HOAc, either residual in the Bi(OAc) 3 or in situ generated, was playing a part in our bismuth - catalyzed protodeboronations. Towards this end, we examined the reactivity of diborylated 3 - 10 with 0.6 equiv of HOAc, which would correspond to the theoretical amount of acetic acid available from 20 mol % of Bi(OAc) 3 ( Figure 3 2 ). Under these conditions no protodebor nation was observed. Increasing the amount of HOAc to 40 equiv had no effect as again only starting 3 - 10 was observed after 5 h at 80 °C. The next set of experiments was performed with free 3 - 3 - 3 - 41 3.6. Summary In conclusion, bismuth a cetate i s a safe , shelf stable, inexpensive , and operationally simple alternative to Ir and Pd for the catalytic proto de boronations of indoles. Whereas the conditions for deboronations with Ir 8 and Pd 6 call for an inert atmosphere, Bi - catalyzed deboronatio ns can be run under air. Furthermore, while reaction times are dependent on the grade of methanol employed, solvents need not be distilled or degassed. In general , sequential deboronations with 42 by tuning the C H borylation and deboronation conditions one can access a variety of boron substitution patterns from a single starting indole. Furthermore, it is also easy to consider using deuterated protic materials in the deborylation so as to afford noval deuterated product. A description of such a process is presented in the next chapter. 43 REFERENCE S 44 REFERENCES 1. Zhichkin, P. E.; Krasutsky, S. G.; Beer, C. M.; Rennells, W. M.; Lee, S. H.; Xiong, J. M. Synthesis 2011 , 1604 1608. 2. Reck, F.; Zhou, F.; Eyermann, C. J.; Kem, G.; Carcanague, D.; Ioannidis, G.; Illingwo rth, R.; Poon, G.; Gravestock, M. B. J. Med. Chem. 2007 , 50 , 4868 4881. 3. (a) Mkhalid, I. A. I.; Barnard, J. H.; Marder, T. B.; Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010 , 110 , 890 931. (b) Preshlock, S. M.; Ghaffari, B.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith M. R., III J. Am. Chem. Soc . 2013 , 135 , 7572 7582. 4. (a) Vanchura, B. A., II; Preshlock, S. M.; Roosen, P. C. Kallepalli, V. A.; Staples, R. J.; Maleczka, R. E., Jr.; Singleton, D. A.; Smith, M. R., III Chem. Commun. 2010 , 46 , 7724 7726. (b) Tajuddin, H.; Harrisson, P.; Bitterlich, B.; Collings, J. C.; Sim, N.; Batsanov, A. S.; Cheung, M. S.; Kawamorita, S.; Maxwell, A. C.; Shukla, L.; Morris, J.; Lin, Z.; Marder, T. B.; Steel, P. G. Chem. Sci. 2012 , 3 , 3505 3514. 5. For representative examples see: (a) Takagi, J.; Sato, K.; Hartwig, J. F.; Ishiyama, T.; Miyaura, N. Tetrahedron Lett. 2002 , 43 , 5649 5651. (b) I shiyama, T.; Takagi, J.; Hartwig, J. F.; Miyaura, N. Angew. Chem., Int. Ed. 2002 , 41 , 3056 3058 . (c) Ishiyama, T.; Takagi, J.; Nobuta, Y.; Miyaura, N. Org. Synth. 2005, 82, 126 133, (d) Paul, S.; Chotana, G. A.; Holmes, D.; Reichle, R. C.; Maleczka, R. E., Jr.; Smith, M. R., III J. Chem. Soc. 2006 , 128 , 15552 15553. (e) Meyer, F. - M.; Liras, S.; Guzman - Perez, A.; Perreault, C.; Bian, J.; James, K. Org. Lett . 2010 , 12 , 3870 3873. (f) Homer, J. A.; Sperry, J. Tetrahedron Lett. 2014 , 55 , 5798 5800 . 6. Loach, R. P.; Fenton, O. S.; Amaike, K.; Siegel, D. S.; Ozkal, E.; Movassaghi, M. J. Org. Chem. 2014 , 79 , 11254 - 11263. 7. For a recent selective synthesis of a monoborylated indaxole by selective deborylation of a diborylated indazole using KOH see Sadler, S. A.; Hones, A. C.; Roberts, B.; Blakemore, D.; Marder, T. B.; Steel, P. G. J. Org. Chem. 2015 , 80 , 5308 5314. 8. Kallepal li, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.; Miller, S. L.; Maleczka, R. E., Jr.; Smith, M. R., III J. Org. Chem. 2015 , 80 , 8341 8353. 9. Procedure adapted from Navath, R. S.; Pabbisetty, K. B.; Hu, L. Tetrahedron Lett. 2006 , 47 , 389 393. 10. Mohan, R. Nat. Chem. 2010 , 2 , 336. 11. The details of these and other screening experiments will be presented elsewhere. 45 12. Indole and 6 - fluoroindol could be converted to their triborylated analogues in a single step, but the overall yields and combined catalys t loads required were better if diborylated 6 and 9 were isolated and then converted to 7 and 10 . See the Supporting Information for additional details. 13. Kallepalli, V. A. ; Shi, F.; Paul, S.; Onyeozili, E. N.; S. L.; Maleczka, R. E., Jr.; Smith, M. R., III J. Org. Chem. 2009 , 74 , 9199 9201. 14. Preshlock, S. M.; Plattner, D. L.; Maligres, P. E.; Krska, S. W.; Maleczka, R. E., Jr.; Smith M. R., III Angew. Chem., Int. Ed. 2013 , 52 , 12915 12919. 15. For the 3,5 - diborylation of 7 - azaindole see reference 8. 16. Ir - catlayzed borylation of 3 - borylated - N - Boc - indole afforded an ~1:1 mixture of 3,5 - and 3,6 - bisborylated - N - Boc - indole. 17. For a selective Ir - catalyzed C H borylation of a fully protected tryptophan and N - TIP S protected indoles see: Feng, Y.; Holte, D.; Zoller, J.; Umemiya, S.; Simke, L. R.; Baran, P. S. J. Am. Chem. Soc. 2015 , 137 , 10160 10163. 18. 10% Deuterium incorporation was initially observed at C3. Washing with H 2 O reprotonated this carbon. 19. The percent deuterium incorporation was determined by integration of the 1 H - NMR spectrum. 20. Guella, G.; Ascenzi, D.; Franceschi, P.; Tosi, P. Rapid Commun. Mass Spectrom. 2007 , 21 , 3337 3344. 21. Perera. D.; Shen F.Y.; Shane W. K.; Robert E. M. Jr.; Milton R. S . III. Unpublished results 22. Shimada, S. Curr. Org . Chem. 20 11 , 1 5 , 601 620 . 23. Neville, W. C.; John, C. R.; George, E.; Marjorie, F.; David C. R. G.; Norman, H. N. C. Inorg. Chem. 1991 , 30 , 4680 - 4682. 46 Chapter 4 . Deborylation/Deuteration mediated by silver oxide and copper chloride 4.1. Introduction 47 Figure 33 . Proposed transition structure of 2 - substituted indole during the deborylation With these conditions in hand, substrates were screened against this one - pot C - H Borylation/deuteration protocol (Ta ble 8 ). 6 The overall reactions were clean , producing the deuterated arenes as the only aromatic products in high yields and with greater than 95% deuterium incorporation. Even under relatively forcing borylati on/deborylation conditions, functional groups such as halogens, nitriles, amines and ethers were tolerated. 4 8 Table 8 . Selective deuterodeborylation reactions a a All reactions were run with 2 mmol of organoboronate. b Isolated yields. c Determined by integration of 13 C NMR spectra; see SI for details for method of calculation. d ~4% 4 - deuterated product was observed due to ~4% 4 - borylated isomer in the starting material. e Owing to product volatility, solvent impurities we re present.4.2. Results of Copper chloride and Silve oxide mediated Deborylation/Deuteriation 49 4.2. Results of Copper chloride and Silver oxide mediated Deborylation/Deuteration Table 9 . Deuteration protocol for synthesizing deuter ated aromatics 50 Table 10 . D euteration protocol for sy nthesizing deuterated aromatics a Isolated yields. b Crude yields. 51 In Table 10 , we show that Ag - catalyzed deborylation can be utilized to isotopically label arenes. The overall reactions were clean, producing the deuterated arenes as the only aromatic products in high yields and with greater t han 94% deuterium incorporation. F unctional groups such as halogens, nitriles, amines and ethers were tolerated. Compare the resul ts to Ir borylation/Deuteration. 4.3. Conclusions Figure 34 . Potential application (isotopic labeling and regioselective synthesis) 52 REFERENCE S 53 REFERENCES 1. Isotope Effects in Chemistry and Biology ; Kohen, A.; Limbach, H. - H., Eds.; CRC Press: Boca Raton, 2006 2. Atzrodt, J.; Derdau, V.; Fey, T.; Zimmermann, J. Angew. Chem. - Int. Edit. 2007 , 46 , 7744. 3. Golden, J. T.; Andersen, R. A.; Bergman, R. G. J. Am. Chem. Soc. 2001 , 123 , 5837. 4. Grainger, R.; Nikmal, A.; Cornella, J.; Larrosa, I. Org. Biomol. Chem. 2012 , 10 , 3172. 5. (a) Crabtree, R. H.; Holt, E. M.; Lavin, M.; Morehouse, S. M. Inorg. Chem. 1985 , 24 , 19 86 . (b) Beak, P.; Brown, R. A. J. Org. Chem. 1982 , 47 , 34. 6. Kallepalli, V. A.; Gore, K. A.; Shi, F.; Sanchez, L.; Chotana, G. A.; Miller, S. L.; Maleczka, R. E., Jr.; Smith, M. R., III J. Org. Chem. 2015 , 80 , 8341 8353. 54 Chapter 5 . Experimental details and characterization data 5.1. General Methods Unless otherwise stated, the reported yields refer to chromatographically and s pectroscopically pure compounds . Pinacolborane (HBPin) and B 2 pin 2 were generously supplied by BoroPharm and used as received. Bis( 4 - 1,5 - cyclooctadiene) - di - µ - methoxy - diiridium(I) ([Ir(OMe)(cod)] 2 ), was prepared per the literature procedures. 1 4,4 - Di - t - butyl - 2,2 - bipyridine (dtbpy) was purchased from Aldrich. IrCl 3 2 O) x was purch ased from Pressure Chemical Co. . 2 , 7 - bis(BPin ) - N - Boc - L - tryptophan methyl ester was prepared according to the literature procedure. 2 All substrates were purified by column chromatography . For all Ir - catalyzed reactions, tetrahydrofuran (THF) was obtained fr om a dry still packed with activated alumina and degassed before use. For all Bi - catalyzed deboronations, THF was reagent grade and used as received. Acetonitrile (MeCN), triethylamine (NEt 3 ), and dichloromethane (DCM) were reagent grade . In addition, some of the solvents were degassed by a F ree ze - Pump - T haw method. Silica gel was purchased from EMD (230 - 400 Mesh). Reactions were monitored by thin layer chromatography on precoated silica gel plates ( Merck ) , using UV light or phosphomolybdic acid stain for visualization. Column chromatography was performed on 60 Å silica gel (230 400 mesh). NMR spectra were recorded on Varian VXR - 500, Varian Unity - 500 - Plus (499.74 MHz for 1 H and 125.67 MHz for 13 C) spectrometer. 1 H and 13 C chemical shifts (in ppm) were r eferenced to the residual protonated or natural abundance solvent signals: CDCl 3 ( 7.26 for 1 H and 77.0 for 13 C) . 11 B spectra were recorded at 160.32 MHz. All coupling constants are apparent J values measured at the indicated field strengths. Melting poin ts were recorded on a MEL - TEMP ® capillary melting point apparatus (Barnstead|Thermolyne , Dubuque, IA ) and are uncorrected . High - resolution mass spectrum was acquired at the MSU Mass 55 Spectrometry facility usin g a Waters GCT Premier GC/TOF instrument (in ESI mode) (Waters Milford, MA ) . Low - resolution mass spectra were performed at the Molecular Metabolism and Disease Collaborative Mass Spectrometry Core facility at MSU on a Thermo Scientific LTQ - Orbitap Velos using the Ion Trap analyzer in positive ioniza tion mode by nano - ESI. 5.2. Experimental details for Chapter 2 2,7 - bis(Bpin) - Boc - L - tryptophan methyl ester (2 - 5). In a glove box, the starting material Boc - L - tryptophan methyl ester 2 - 4 (318 mg, 1.0 mmol, 1 equiv) and B 2 Pin 2 (508 mg, 2.0 mmol, 2 equiv) was weighed in a 20 mL vial. Two separate test tubes were charged with [Ir(OMe)(COD)] 2 (20 mg, 0.03 mmol, 6 mol % Ir) and d t bpy (16 mg, 0.06 mmol, 6 mol %). HBPin (40 mL, 0.28 mmol, 0.28 equiv) along with 1 mL of THF was added to the [Ir(OMe)(COD)] 2 test tube . THF (1 mL) was added to the d t bpy test tube in order to dissolve the dtbpy. The d t bpy solution was then mixed with the [Ir(OMe)(COD)] 2 and HBPin mixture. After mixing for one minute, the resulting solution was transferred to the 20 mL reaction vial conta ining indole substrate and B 2 Pin 2 . Additional THF (3 mL) was used to wash the test tubes and the washings were transferred to the reaction vial. The reaction vial was stirred at room temperature inside the glove box for 20 h. At this point the volatile mat erials were removed and the crude material was purified via a gradient column (10% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) on silica gel. The product was isolated as a white solid (359 mg, 63% yield, mp 88 - 94 °C). Regiochemistry of the diboryla ted product was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 a ), 7.78 - 7.76 (d, J=7.9 Hz, 1H, H b /H d ), 7.70 - 7.69 (d, J=6.8 Hz, 1H, H b /H d ), 7.13 - 7.10 (t, J=7.8 Hz, 1H, H c ), 5.99 - 5.97 (d, J=6.7 Hz, 1H, NH), 4.34 - 4.30 (m, 1H, CH), 3 .70 (s, 3H, CH 3 of Me), 3.43 - 3.30 (m, 2H, CH 2 ), 1.41 (br s, 6H, 2 CH 3 of BPin), 1.39 (br s, 18H, 6 CH 3 of BPin), 1.34 (br s, 9H, CH 3 of t Bu); 13 C NMR { 1 H} (CDCl 3 56 (CH), 122.9 (C), 119.2 (CH), 84.3 (C), 83.8 (C), 79.2 (C), 55.3 (CH), 52.1 (CH 3 ), 28.3 (3 CH 3 of t Bu), 27.2 (CH 2 ), 25.0 (4 CH 3 of BPin), 24.9 (2 CH 3 of BPin), 24.6 (2 CH 3 of BPin); 11 B NMR (CDCl 3 - IR (neat) max : 3453, 3391, 3056, 2980, 2934, 1754, 1719, 1551, 1514, 1497, 1441, 1416, 1391, 1368, 1337, 1294, 1207, 1167, 1136, 1101, 853, 683 cm 1 ; 20 D+15.2(c 0.4, CH 2 Cl 2 ) 7 - Bpin - Boc - L - tryptophan methyl ester (2 - 6) . To an air - free flask containing a degassed solution of 2, 7 - bis(Bpin) - Boc - L - tryptopha n methyl ester 2 - 5 (172.0 mg, 0.302 mmol) in methanol (1.0 mL) and dichloromethane (0.5 mL) was added in one portion [Ir(OMe)COD] 2 (3.0 mg, 0.004 mmol). The flask was purged and refilled with nitrogen three times and the resulting mixture was heated in oil bath at 55 °C for 3 hours. The reaction mixture was then filtered through a short plug of silica gel eluting with dichloromethane to remove the iridium residue. The crude material was concentrated by rot vap, and purified by column chromatography eluting with 20% ethylacetate/hexanes (R f = 0.4) furnished the product as a white solid (73.3 mg, 0.165 mmol, 55% yield, mp 177 - 179 °C). 1 H NMR (CDCl 3 , 500 MHz) 9.12 (s, 1 H), 7.66 (d, J = 8.1 Hz, 1 H), 7.63 (d, J = 7.1 Hz, 1 H), 7.11 (dd, J = 7.8, 7.1 Hz, 1 H), 7.04 (s, 1 H), 5.05 (d, J = 7.8 Hz, 1 H), 4.63 4.61 (m, 1 H), 3.66 (s, 3 H), 3.29 (d, J = 4.9 Hz, 2 H), 1.41 (s, 9 H), 1.37 (s, 12 H); 13 C NMR (CDCl 3 , 75 MHz) 172.7, 155.2, 141.3, 129.5, 126.6, 122.7, 122.3, 119.1, 109.6, 83.8, 79 .7, 54.2, 52.2, 28.3, 27.9, 24.9; 11 B NMR (CDCl 3 , 96 MHz) 30.6; FT - IR (neat) max : 3453, 2981, 2919, 2853, 2252, 1742, 1708, 1599, 1492, 1437, 1373, 1331, 1167, 1135, 799, 735 cm - 1 ; [ ] 20 D +39.3 ( c 1.0, CHCl 3 ); HRMS (ESI+): (m/z) calculated for [C 23 H 34 BN 2 O 6 ] + 445.2510, found 445.2519. 7 - BPin - L - tryptophan methyl ester (2 - 7). 7 - Bpin - Boc - L - tryptophan methyl ester 2 - 6 (330 mg, 0.75 mmol) was suspended in Acetonitrile (10 ml) and water (0.2 ml), and then the containing flask was sealed and placed in an oil bath at 60 ºC in order to provide a homogenous solution. A second 57 portion BiCl 3 (284 mg, 0.9 mmol) was added into the flask, the mixture was stirred at that temperature for 30 min. And an additional BiCl 3 (284 mg, 0.9 mmol) was added and the mixture was stirred for a further 15 min. The reaction was monitored by TLC. Volatile solvent were removed on a rotary evaporator. The crude material was suspended in MeOH (5 ml) and placed on a celite bed followed by washing with MeOH (twice with 3 times the volume of solvent). The filtrate was dried over anhydrous MgSO 4 , after filtration and solvent removal gave product 2 - 7, acetonitrile and presumably inorganic salts (350 mg, 1 mmol, 133 % yield) . Regiochemistry of th e crude product was assigned by NMR spectroscopy. 1 H NMR (CD 3 - 7.66 (d, J = 7.9 Hz, 1H), 7.54 - 7.52 (d, J = 7.0 Hz, 1H), 7.34 (s, 1H), 7.11 - 7.04 (t, J = 7.3 Hz, 1H), 4.38 (s, J = 5.8, 1H), 3.73 (s, 3H), 3.51 - 3.39 (m, 2H), 1.42 - 1.31 (m, 9H) , 1.19 (d, J = 9.9 Hz, 3H); 13 C NMR (CD 3 (CH), 119.91 (CH), 107.29 (C), 85.1 (2 C), 54.72 (CH), 53.64 (OCH 3 ), 31.1 (CH 3 of BPin), 28.83 (CH 3 of BPin), 27.33 (CH 2 ), 25.2 (2 CH 3 o f BPin); 11 B NMR (CD 3 HRMS (E S I) : m/z calculated for C 18 H 26 BN 2 O 4 [ M+H] + 345.1986 , found 345.1992 . This crude material was used directly in the following step without further purification and assuming a quantitative yield. (S) - O - TBS - N - Boc - 3 - bromotyrosine (2 - 9 ) . To a solution of ( S ) - N - Boc - 3 - bromotyrosine (1.30 g, 3.61 mmol) in DMF (15 mL) were successively added imidazole (0.74 g, 10.83 mmol) and TBSCl (1.20 g, 7.94 mmol). The resulting solution was stirred at room temperatur e overnight. The reaction mixture was then treated with water (15 mL), stirred for 30 min, and extracted with diethyl ether (3 × 30 mL). Combined ether layers were successively washed with 1N aqueous HCl (20 mL), saturated aqueous NaHCO 3 (20 mL), water (20 mL), and brine (20 mL). Once dried over Na 2 SO 4 , the organic extract was concentrated in vacuo . The resulting yellowish oil was redissolved in THF 58 (10 mL), treated with potassium carbonate 1 M in water (11 mL, 11 mmol), and stirred at room temperature for 1 hour. The mixture was acidified to pH 3 by addition of 1M aqueous HCl and then extracted with ethyl acetate (3 × 10 mL). The combined ethyl acetate layers were dried with Na 2 SO 4 , filtered, and concentrated in vacuo . The residue was purified by flash chro matography eluting with hexanes/EtOAc/HOAc 8:1.9:0.1 to provide ( S ) - O - TBS - N - Boc - 3 - bromotyrosine 2 - 9 as a slightly yellowish oil that became a foam under high vacuum and hardened upon standing to form a white solid (1.20 g, 2.53 mmol, 70% yield), mp 116 118 ºC; R f = 0.35 (hexanes/EtOAc/HOAc 8:1.9:0.1); [ ] 20 D +14.5 ° ( c 0.54, CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 ) 7.32 (apparent s, 1 H), 6.97 (dd, J = 8.1, 2.0 Hz, 1 H), 6.77 (d, J = 8.1 Hz, 1 H), 4.95 (d, J = 7.7 Hz, 1 H), 4.52 (m, 1 H), 3.11 (dd, J = 13.7, 4.4 Hz, 1 H), 2.94 (dd, J = 13.7, 6.3 Hz, 1 H), 1.41 (s, 9 H), 1.01 (s, 9 H), 0.21 (s, 6 H) ; 13 C NMR ( 12 5 MHz, CDCl 3 129.1, 120.1, 115.3, 80.5, 54.3, 36.6, 28.3, 25.7, 18.3, 4.2; IR (neat) max 3307, 2957, 293 0, 2859, 1684, 1654, 1496, 1395, 1366, 1289, 1255, 1167, 1046 cm 1 ; HRMS (E S I) : m/z calculated for C 20 H 33 NO 5 BrSi [ M+H] + 474.1311 , found 474.1313. Preparation of dipeptide (2 - 1 1 ) : To a stirring solution of 2 - 9 (0.996 g, 2.1 mmol) and N - hydroxysuccinimide (0.302 g, 2.63 mmol) in DME (21 mL) at 0 °C was added DCC (0.542 g, 2.63 mmol) in one portion. The containing flask was sealed and the reaction mixture was stirred at 0 ºC overnight. The resulting suspension was filtered and the solid ( urea) was rinsed with cold DME (3 × 5 mL). The filtrate together with the rinses was concentrated in vacuo , redisolved in dioxane (9 mL), and cooled to about 10 °C. To this solution was added a solution of L - asparagine (1.67 g, 12.60 mmol) and sodium bicar bonate (1.06 g, 12.60 mmol) in water (6 mL) in small portions. 59 After 1 h of vigorous stirring, most of the dioxane was removed under vacuum and the remaining aqueous phase was acidified to pH 3.5 and extracted three times with EtOAc. The combined extracts were washed with water and brine, dried over MgSO 4 , and evaporated to yield a white foam that was subjected to flash chromatography eluting with hexanes/EtOAc/HOAc 8:1.9:0.1 to afford dipeptide 2 - 1 1 (972 mg, 1.651 mmol, 79% yield) as a white solid, mp 147 147.5 ºC; R f = 0.21 (hexanes/EtOAc/HOAc 8:1.9:0.1); [ ] 20 D +16.5 ° ( c 0.4 9 , CH 2 Cl 2 ); 1 H NMR (500 MHz, CDCl 3 8.01 (br, 1 H), 7.31 (s, 1H), 6.99 (br, 1 H), 6.95 (d, J = 8.0 Hz, 1 H), 6.70 (dd, J = 8.0, 3.0 Hz, 1 H), 5.69 (br, 1H), 5.56 (br, 1H), 4.71 (m, 1 H), 4.40 (m, 1H), 3.06 (apparent d, J = 13.5 Hz, 1 H), 2.92 2.69 (m, 3 H), 1.26 (s, 9 H), 0.98 (s, 9 H), 0.16 (s, 6 H); 13 C NMR ( 12 5 MHz, CDCl 3 0, 129.2, 120.0, 115.1, 80.4, 55.6, 50.2, 37.3, 37.0, 28.3, 25.7, 18.3, 4.2; IR (neat) max 3449, 3297, 3055, 2957, 2857, 1734, 1669, 1604, 1495, 1473, 1437, 1372, 1329, 1292, 1254, 1205, 1167, 1047 cm 1 ; HRMS (E S I) : m/z calculated for C 24 H 39 N 3 O 7 BrSi [ M+H] + 588.1741 , found 588.1742. Tripeptide (2 - 2): To a stirred slurry of crude 7 - BPin - L - tryptophan methyl ester 2 - 7 (assumed to contain 49.3 mg, 0.142 mmol, 1.2 equiv) and dipeptide 2 - 10 (70.2 mg, 0.119 mmol) in THF (6 mL) were added EDC (45.8 mg, 0.239 mmol) and HOBT (36.6 mg, 0.239 mmol). The mixture was stirred and cooled to 0 °C under nitrogen atmosphere. Triethyla mine (166 µL, 1.194 mmol) was added in one portion via syringe and the mixture was allowed to slowly warm to room temperature and stirred for 24 h. The reaction mixture was concentrated in vacuo , adsorbed onto a minimum amount of silica gel, dried under hi gh vacuum, and directly subjected to column chromatography eluting with ether and then ether/EtOAc (1:1 to 0:1) to afford tripeptide 2 - 2 (63.1 60 mg, 0.069 mmol, 58% yield) as an off - white slightly orange solid, mp 131.5 133.5 ºC ; R f = 0.32 (EtOAc); [ ] 20 D +2 0 .5 ° ( c 0.21, CH 2 Cl 2 ); 1 H NMR ( 5 00 MHz, CDCl 3 9.22 (s, 1H), 7.76 (br d, J = 8.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 1 H), 7.59 (d, J = 7.0 Hz, 1 H), 7.46 (br d, J = 6.5 Hz, 1 H), 7.27 (d, J = 2.0 Hz, 1 H), 7.11 (s, 1 H), 7.09 (dd, J = 8.0, 7.0 Hz, 1 H), 6.89 (dd, J = 8.5, 2.0 Hz, 1 H), 6.74 (d, J = 8.5 Hz, 1 H), 5.95 (br, 1 H), 5.52 (br, 1 H), 4.96 (br d, J = 7.5 Hz, 1 H), 4.76 (m, 1 H), 4.73 (m, 1 H), 4.26 (m, 1 H), 3.60 (s, 3 H), 3.27 (apparent d, J = 6.0 Hz, 2 H), 2.92 (dd, J = 14 .0, 5.0 Hz, 1 H), 2.82 (m, 1 H), 2.79 (dd, J = 16.0, 4.0 Hz, 1 H), 2.46 (dd, J = 16.0, 6.5 Hz, 1 H), 1.37 (s, 9 H), 1.35 (s, 12 H), 1.00 (s, 9 H), 0.20 (s, 6 H); 13 C NMR ( 12 5 MHz, CDCl 3 173.4, 171.9, 171.4, 170.2, 155.5, 151.5, 141.2, 134.0, 130.5, 129. 4, 129.0, 126.2, 123.3, 122.0, 120.1, 119.0, 115.3, 109.0, 83.8, 80.5, 55.6, 53.2, 52.4, 49.6, 36.5, 36.45, 28.2, 27.3, 25.7, 25.0, max 3397, 2956, 2916, 2849, 1577, 1540, 1459, 1419, 1355 cm 1 ; HRMS (E S I) : m/z calculated for C 42 H 62 B N 5 O 10 SiBr [ M+H] + 914.3542 , found 914.3549 . 5.3. Experimental details for Chapter 3 General procedure for borylation with [Ir(OMe)(COD)] 2 and d t bpy. In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged with the substrate (1mmol). Two separate test tubes were charged with [Ir(OMe)(COD)] 2 (1 mol% Ir) and d t bpy (1 mol%). When B 2 pin 2 was used as the borylating agent, HBPin ( 2.8 x Ir mol%) was used to generate active catalyst . THF (2 × 200 µL) was added to the d t bpy containing test tube in order to dissolve the dtbpy. The dtbpy solution was then mixed with the [Ir(OMe)(cod)] 2 and HBPin mixture. After mixing for one minute, the res ulting solution was transferred to the vial . Additional THF (3 200 µL) was used to wash the test tubes and the washings were transferred to the vial . The vial was s ealed , brought out of the glove box and the reaction was carried out at the specified temperature. After completion 61 of the reaction, the volatile materials were removed on a rotary evaporator followed by removing the dark brown red color from the crude material with a silica plug. The crude material was purified by column chromatography. General procedure for deborylation with Bi(OAc) 3 and MeOH. A vial equipped with a magnetic stirring bar was charged with substrate (1 mmol, 1 equiv) and Bi(OAc) 3 (0.2 mmol, 20 mol %). Solvent mixture MeOH and THF (4 mL) was added to the vial. The vial was sealed and the reaction was carried out at the 80 °C. The reaction was monitored by TLC. After completion of the reaction, the crude material was passed through a plug of celite and washed three times by ethy l acetate. After the volatile materials were removed on a rotary evaporator the crude material was purified by column chromatography. General procedure for deborylation with [Ir(OMe)(COD)] 2 with a magnetic stirring bar was charged with substrate (1.0 mmol, 1.0 equiv) and [Ir(OMe)(COD)] 2 (methanol/dichloromethane 2:1, 5 m L) was degassed by a Freeze - Pump - Thaw method then added was sealed and the reaction was carried out at the 60 °C. The reaction was monitored by TLC, after comple tion of the reaction; the volatile materials were removed on a rotary evaporator. The crude material was pur ified by column chromatography. 7 - Bpin - Boc - L - tryptophan methyl ester (3 - 2) . The general procedure was applied to 2, 7 - bis(Bpin) - Boc - L - tryptophan met hyl ester 3 - 1 ( 39 mg, 0. 068 mmol) and Bi(OAc) 3 (5.3 mg, 0.0137 mmol, 20 mol%) with solvent mixture MeOH /THF (0.34 mL /0.27 mL) at 80 °C for 7 h. The crude material was concentrated and purified by column ( 20 % ethyl acetate/hexanes) on silica gel. The prod uct 62 was isolated as white solid ( 27 mg, 90 %). Regiochemistry of the crude product was assigned by NMR spectroscopy. 1 H NMR (CD 3 J = 7.8 Hz, 1H), 7.64 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 7.6 Hz, 1H), 7.06 (s, 1H), 5.06 (d, J = 7.8, 1H), 4.64 (m, 1H), 3.67 (s, 3H), 3.31 (d, J = 4.9, 2H), 1.43 (s, 9H), 1.39 (s, 12H); 13 C NMR (CD 3 155.2, 141.3, 129.5, 126.6, 122.7, 122.3, 119.1, 109.6, 83.8, 79.7, 54.2, 52.2, 28.3, 27. 9, 25.0. The spectral data were in accordance with literature. 3 7 - BPin - L - tryptophan methyl ester (3 - 3) : 7 - Bpin - Boc - L - tryptophan methyl ester 3 - 2 (330 mg, 0.75 mmol, 1 equiv) was suspended in acetonitrile (10 ml) and water (0.2 ml), and then the containing flask was sealed and placed in an oil bath at 60 ºC in order to provide a homogenous solution. BiCl 3 (142 mg, 0.45 mmol, 0.6 equiv) was added into the flask, the mixture was stirred at that temperature for 30 min. And an additional BiCl 3 (142 mg, 0.45 mmol , 0.6 equiv) was added and the mixture was stirred for a further 30 min. The reaction was monitored by TLC. Volatile solvent were removed on a rotary evaporator. The crude material was suspended in MeOH (5 ml) and placed on a celite bed followed by washing with MeOH (twice with 3 times the volume of solvent). The filtrate was dried over anhydrous MgSO 4 , after filtration and solvent removal gave product and presumably inorganic salts (350 mg, 1 mmol, 133 % yield) . Regiochemistry of the crude product was assig ned by NMR spectroscopy. 1 H NMR (CD 3 J = 7.8 Hz, 1H), 7.51 (d, J = 6.9 Hz, 1H), 7.31 (s, 1H), 7.05 (t, J = 7.3 Hz, 1H), 4.37 (m, 1H), 3.71 (s, 3H), 3.42 (m, 2H), 1.35 (s, 9H), 1.16 (d, J = 9.8 Hz, 3H); 13 C NMR (CD 3 7 (C=O), 142.4, 130.3, 127.4, 126.2, 122.7, 119.9, 107.3, 85.1, 54.7 , 53.7, 31.1, 28.8, 27.33, 25.2; 11 B NMR (CD 3 m/z calculated for C 18 H 26 BN 2 O 4 [ M+H] + 345.1986, found 345.1992. 63 2,7 - bis(BPin) - indole (3 - 6). The borylation step was carried out neat with indole 3 - 5 (585 mg, 5 mmol, 1 equiv), B 2 Pin 2 [Ir(OMe)(COD)] 2 (17 mg, 0.025 mmol, 1 mol % Ir) and d t bpy (13 mg, 0.05 mmol, 1 mol %) at 80 °C for 48 h and work ed up as described in the general procedure. The crude material was concentrated and purified by column (10% ethyl acetate/hexanes) on silica gel. The product was isolated as a white solid (1.9 g, 77%, mp 147 °C). Regiochemistry of the borylated products w as assigned by NMR spectroscopy. 1 H NMR (CDCl 3 J = 7.8 Hz, 1H), 7.72 (dd, J = 6.9, 1.0 Hz, 1H), 7.12 (m, 2H), 1.42 (s, 12 H, 4 C H 3 of BPin), 1.38 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) , 125.3, 119.5, 113.9, 84.1(2 C), 83.9 (2 C), 25.1 (4 CH 3 of BPin), 24.9 (4 CH 3 of BPin). The spectral data were in accordance with literature. 4 2,4,7 - tri(BPin) - indole (3 - 7). The borylation step was carried out neat with 2,7 - bis(BPin) - indole 3 - 6 (554 mg, 1 .5 mmol, 1 equiv), B 2 Pin 2 0.28 equiv), [Ir(OMe)(COD)] 2 (5 mg, 0.015 mmol, 1 mol % Ir) and d t bpy (4 mg, 0.015 mmol, 1 mol %) at 80 °C for 12 h and worked up as described in the general procedure. The cr ude material was purified by silica gel chromatography (10% ethyl acetate/hexanes) on silica gel to afford the product as white powder (713 mg, 96%). Alternative procedure, 2,4,7 - tri(BPin) - indole (3 - 7). In a glove box, a 20 mL vial, equipped with a magneti c stirring bar, was charged with indole 3 - 5 (585 mg, 5 mmol, 1 equiv) and B 2 Pin 2 (3.81 g, 10 mmol, 3 equiv). Two separate test tubes were charged with [Ir(OMe)(COD)] 2 (100 mg, 0.15 mmol, 6 mol % Ir) and d t mmol, 0.28 equiv) was added to the [Ir(OMe)(COD)] 2 test tube. THF (2 mL) was added to the d t bpy containing test tube in order to dissolve the d t bpy. The d t bpy solution was then mixed with the [Ir(OMe)(COD)] 2 64 and HBPin mixture. After mixing for 1 min, the resulting solution was transferred to the vial containing the indole substrate. Additional THF (3 mL) was used to wash the test tubes and the washings were transferred to the vial. The vial was well sealed, br ought out of the glove box and stirred at 70 °C. After 48 h, the reaction was stopped followed by removing the dark brown red color from the reaction solution with silica bed. The crude material was concentrated and purified by column (10% ethyl acetate/he xanes) on silica gel. The product was isolated as a white solid (1.5 g, 60%, mp 255°C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 J = 6.9 Hz, 1H), 7.62 (d, J = 6.9 Hz, 1H) , 7.59 (d, J = 2.1 Hz, 1H), 1.42 (s, 12 H, 4 C H 3 of BPin), 1.39 (s, 24 H, 4 C H 3 of BPin), 1.39 (s, 24 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) 84.0(2 C), 83.9 (2 C), 83.5 (2 C), 25.0 (8 CH 3 of BPin), 24.9 (4 CH 3 of B Pin); 11 B NMR (CDCl 3 , - IR (neat) max : 3461, 2979, 1538, 1372, 1327, 1292, 1137, 973, 855, 693 cm - 1 ; LRMS (ESI): m/z calculated for C 26 H 41 B 3 NO 6 [ M+H] + 496.31 , found 496.3. 2,7 - di(BPin) - 6 - fluoroindole (3 - 9). The borylation step was carried out neat with 6 - fluoroindole 3 - 8 (675 mg, 5 mmol, 1 equiv), B 2 Pin 2 equiv), [Ir(OMe)(COD)] 2 (17 mg, 0.05 mmol, 1 mol % Ir) and d t bpy (13 mg, 0.05 mmol, 1 mol%) at 80 °C for 24 h and worked u p as described in the general procedure. The crude material was concentrated and purified by column (5% ethyl acetate/hexanes) on silica gel. The product was afforded as a foamy solid (1.59 g, 82%, mp 117 - 119 °C). Regiochemistry of the borylated products w as assigned by NMR spectroscopy. 1 H NMR (CDCl 3 J = 8.3, 5.4 Hz, 1H), 7.10 (d, J = 2.0 Hz, 1H), 6.86 (dd, J = 10.3, 8.8 Hz, 1H), 1.44 (s, 12H, 4 C H 3 of BPin), 1.38 (s, 12H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) J = 247 Hz), 143.1 (d, J = 13.4 Hz), 126.2 (d, J = 11.4 Hz), 123.9, 113.7, 108.7 (d, J = 27.7 Hz), 84.0 (2 C), 65 83.8 (2 C), 24.9 (4 CH 3 of BPin), 24.7 (4 CH 3 of BPin); 11 B NMR (CDCl 3 - IR (neat) max : 3445, 2980, 1569, 1540, 1 387, 1418, 1288, 1235, 1166, 1020, 966, 852, 701 cm - 1 ; LRMS (ESI): m/z calculated for C 20 H 29 B 2 FNO 4 [ M+H] + 387.22 , found 388.3. 2,4,7 - tri(BPin) - 6 - fluoroindole (3 - 10). The borylation step was carried out neat with 2,7 - bis(BPin) - 6 - fluoroindole 3 - 9 (1.48 g, 3.82 mmol, 1 equiv), B 2 Pin 2 (970 mg, 3.82 mmol, 1 equiv), HBPin (160 2 (12.7 mg, 0.019 mmol, 1 mol % Ir) and d t bpy (10 mg, 0.038 mmol, 1 mol %) at 80 °C for 12 h and worked up as described in the general procedure. The crude material was purified by silica gel chromatography (10% ethyl acetate/hexanes) on silica gel to afford the product as white powder (1.82 g, 92%). Alternative procedure, 2,4,7 - tri(BPin) - 6 - fluoroindole (3 - 10). In a glove box, a 20 mL vial, equippe d with a magnetic stirring bar, was charged with 6 - fluoroindole 3 - 8 (675 mg, 5 mmol, 1 equiv) and B 2 Pin 2 (3.81 g, 15 mmol, 3 equiv). Two separate test tubes were charged with [Ir(OMe)(COD)] 2 (100 mg, 0.15 mmol, 6 mol % Ir) and d t bpy (80 mg, 0.3 mmol, 6 mol %). HBPin 2 test tube. THF (2 mL) was added to the d t bpy containing test tube in order to dissolve the d t bpy. The d t bpy solution was then mixed with the [Ir(OMe)(COD)] 2 and HBPin mixture. After mixing for 1 min, the resulting solution was transferred to the vial containing the indole substrate. Additional THF (3 mL) was used to wash the test tubes and the washings were transferred to the vial. The vial was well sealed, brought out of the glove b ox and stirred at 70 °C. After 24 h, the reaction was stopped followed by removing the dark brown red color from the reaction solution with silica bed. The crude material was concentrated and purified by column (10% ethyl acetate/hexanes) on silica gel. Th e product was crystallized out from MeOH as white crystals (1.59 g, 62%, mp 278°C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 66 (br s, 1H, NH), 7.54 (d, J = 2.1 Hz, 1H), 7.32 (d, J = 10.3 Hz, 1H ), 1.43 (s, 12H, 4 C H 3 of BPin), 1.38 (s, 24H, 8 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) J = 247 Hz), 142.7 (d, J = 12.4 Hz), 128.4, 115.7 (d, J = 25.8 Hz), 115.3, 84.0 (2 C), 83.9 (2 C), 83.8 (2 C), 25.0 (8 CH 3 of BPin), 24.8 (4 CH 3 of BPin); 11 B NMR (CDCl 3 - IR (neat) max : 3455, 2979, 1540, 1510, 1387, 1323, 1292, 1235, 1137, 1042, 966, 852, 702 cm - 1 ; LRMS (ESI): m/z calculated for C 26 H 40 B 3 FNO 6 [ M+H] + 514.30 , found 514.3. 4,7 - bis(BPin) - 2 - carboethoxy - indole (3 - 12). The bory lation step was carried out neat with 7 - BPin - 2 - fluoroindole 3 - 11 (189 mg, 1 mmol, 1 equiv), B 2 Pin 2 0.28 mmol, 0.28 equiv), [Ir(OMe)(COD)] 2 (3.3 mg, 0.01 mmol, 1 mol % Ir) and d t bpy (2.6 mg, 0.01 mmol, 1 mol %) at 8 0 °C for 12 h and worked up as described in the general procedure. The crude material was purified by silica gel chromatography (5% ethyl acetate/hexanes) on silica gel to afford the product as white powder (146 mg, 81%, mp 163 °C). Regiochemistry of the b orylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 (d, J = 6.9 Hz, 1H), 7.68 (d, J = 7.0 Hz, 1H), 7.67 (s, 1H), 4.4 5 (q, J = 7.1 Hz, 2 H, CH 2 CH 3 ), 1.46 (t, J = 7.1 Hz, 3 H, CH 2 CH 3 ), 1.41 (s, 12 H, 4 C H 3 of BPin), 1.41 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) 162.3 (C=O), 141.0, 131.7, 130.7, 128.1, 127.5, 110.0, 84.1 (2 C), 83.7 (2 C), 60.8 (CH 2 ), 24.9 (8 CH 3 of BPin), 14.4 (CH 3 ); 11 B NMR (CDCl 3 , 160 MHz): 31.3; FT - IR (neat) max : 3448, 297 8, 1721, 1512, 1385, 1347, 1292, 1136, 973, 855, 763, 695 cm - 1 ; LRMS (ESI): m/z calculated for C 23 H 34 B 2 NO 6 [ M+H] + 442.25 , found 442.3. 4,7 - bis(BPin) - 3 - methyl - indole (3 - 14). The borylation step was carried out neat with 2 - methylindole 3 - 13 (131 mg, 1 mmol, 1 equiv), B 2 Pin 2 0.28 mmol, 0.28 equiv), [Ir(OMe)(COD)] 2 (3.3 mg, 0.01 mmol, 1 mol % Ir) and d t bpy (2.6 mg, 0.01 mmol, 1 mol %) at 80 °C for 24 h and worked up as described in the general procedure. The 67 crude mater ial was purified by silica gel chromatography (20% ethyl acetate/hexanes) on silica gel to afford the product as white powder (271 mg, 71%, mp 353 °C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 6 (br s, 1H), 7.5 5 (d, J = 6.9 Hz, 1 H), 7.54 (d, J = 6.9 Hz, 1 H), 6.68 (s, 1H), 2.52 (s, 3 H), 1.40 (s, 12 H, 4 C H 3 of BPin), 1.38 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) 126.5, 101.7, 83.8 (2 C) , 83.3 (2 C) , 25.0 ( 8 CH 3 of BPin), 14.2 (CH 3 ); 11 B NMR (CDCl 3 , 160 MHz): 30.5; FT - IR (neat) max : 3449, 2976, 1610, 1511, 1372, 1332, 1304, 1167, 1136, 968, 856, 697 cm - 1 ; LRMS (ESI): m/z calculated for C 21 H 32 B 2 NO 4 [ M+H] + 384.24 , found 384.3. 3 , 5 - bis(BPin) - 6 - fluoro - indole (3 - 15). In a glove box, a 20 mL vial, equipped with a magnetic stirring bar . The 6 - fluoro indole 3 - 8 ( 54 mg, 0.4 mmol, 1 equiv) was stirred in HBPin (240 , 1.6 mmol, 4 equiv) at r.t. for 1 h followed by adding B 2 Pin 2 (2.54 g, 10 mmol, 2 equiv). Two separa te test tubes were charged with [Ir(OMe)(COD)] 2 (100 mg, 0.15 mmol, 6 mol % Ir) and d t bpy (80 [Ir(OMe)(COD)] 2 test tube. THF ( 1 mL) was added to the d t bpy containing test tube in order to dissolve the d t bpy. The d t bpy solution was then mixed with the [Ir(OMe)(COD)] 2 and HBPin mixture. After mixing for 1 min, the resulting solution was transferred to the vial containing the indole substrate. Additional THF ( 1 mL) was used to wash t he test tubes and the washings were transferred to the vial. The vial was well sealed, brought out of the glove box and stirred at 8 0 °C. After 5 h, the reaction was stopped followed by removing the dark brown red color from the reaction solution with sili ca bed. The crude material was concentrated and purified by column (30% ethyl acetate/hexanes) on silica gel. The product was isolated as a colorless oil ( 112 m g, 90 %). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 J = 5.4 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.02 (d, J 68 = 10.3 Hz, 1H), 1.38 (s, 12 H, 4 C H 3 of BPin); 1.37 (s, 12 H, 4 C H 3 of BPin) 13 C NMR (CDCl 3 , 125 MHz) 164.2 (d, J = 24 2 Hz) , 139.2 (d, J = 13.4 Hz) , 134.6 (d, J = 2 .9 Hz) , 130.9 (d, J = 9.5 Hz) , 127.7, 97.1 (d, J = 2 9.6 Hz) , 83.5 (2 C), 83.0 (2 C), 24.9 (4 CH 3 of BPin) , 24.8 (4 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 30.7; FT - IR (neat) max : 3423, 2980, 1625, 1475, 1373, 1145, 982, 851, 674 cm - 1 ; LRMS (ESI): m/z calculated for C 20 H 29 B 2 FNO 4 [ M+H] + 387.22 , found 388.3. 3 , 5 - bis(BPin) - N - Boc - indole (3 - 17). In a glove box, a 20 mL vial, equipped with a magnetic stirring bar, was charged with N - Boc - 6 - fluoro indole 3 - 16 ( 471 mg, 2 mmol, 1 equiv) and B 2 Pin 2 ( 1 g, 4 mmol, 2 equiv). Two separate test tubes were charged with [Ir(OMe)(COD)] 2 ( 40 mg, 0. 06 mmol, 6 mol % Ir) and d t bpy ( 32 mg, 0. 12 mmol, 6 mol %). HBPin ( 84 0.56 mmol, 0.28 equiv) was added to the [Ir(OMe)(COD)] 2 test tube. THF ( 1 mL) was added to the d t bpy containing test tube in order to dissolve the d t bpy. The d t bpy solution was then mixed with the [Ir(OMe)(COD)] 2 and HBPin mixture. After mixing for 1 min, the resulting solution was transferred to the vial containing the indole substrate. Additional TH F (3 mL) was used to wash the test tubes and the washings were transferred to the vial. The vial was well sealed, brought out of the glove box and stirred at 8 0 °C. After 3 h, the reaction was stopped followed by removing the dark brown red color from the reaction solution with silica bed. The crude material was concentrated and purified by column (10% ethyl acetate/hexanes) on silica gel. The product was isolated as a white solid ( 780 m g, 80 %, mp 1 63 °C). Regiochemistry of the borylated products was assigne d by NMR spectroscopy. 1 H NMR (CDCl 3 J = 5.9 Hz, 1H), 7.95 (s, 1H), 7.85 (d, J = 10.8 Hz, 1H), 1.65 (s, 9 H, 3 C H 3 of Boc), 1.39 (s, 12 H, 4 C H 3 of BPin); 1.38 (s, 12 H, 4 C H 3 of BPin) 13 C NMR (CDCl 3 , 125 MHz) 164.7 (d, J = 24 4 Hz) , 149.0, 135.6, 130.3 (d, J = 9.5 Hz) , 129.3, 102.0 (d, J = 31.5 Hz) , 84.3 (C), 83.7 (2 C), 83.5 (2 C), 28.1 ( 3 CH 3 of B oc ) , 24.9 ( 8 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 29.8; FT - IR (neat) max : 3447, 2978, 1740, 1636, 1559, 1443, 1363, 1322, 69 1255, 1139 , 1063, 853, 668 cm - 1 ; LRMS (ESI): m/z calculated for C 25 H 37 B 2 FNO 6 [ M+H] + 488.27 , found 488.3. 7 - BPin - indole (3 - 18). The general procedure was applied to 2,7 - bis(BPin) - indole 3 - 6 (36.9 mg, 0.1 mmol, 1 equiv) and Bi(OAc) 3 (7.72 mg, 0.02 mmol, 20 mol%) with solvent mixture MeOH /THF (0.5 mL /0.4 mL) at 80 °C for 17 h. The crude material was concentrated and purified by column (5% ethyl acetate/hexanes) on silica gel. The product was isolated as white solid (20 mg, 82%). Reg iochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 J = 7.9 Hz, 1 H), 7.68 (d, J = 7.0 Hz, 1 H), 7.28 (dd, J = 2.8 Hz, 1 H), 7.15 (dd, J = 7.5 Hz, 1 H), 6.57 (dd, J = 2.8 Hz, 1 H), 1 .41 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 (CH), 119.3 (CH), 102.0 (CH), 83.8 (2 C), 25.0 (4 CH 3 of BPin); 11 B NMR (CDCl 3 , 160 MHz): 30.8. The spectral data were in accordance with literatur e. 4 7 - BPin - indole - 2d (3 - 18 - d 1 ). A vial equipped with a magnetic stirring bar was charged with 2,7 - bis(BPin) - indole 3 - 6 (185 mg, 0.5 mmol, 1 equiv) and Bi(OAc) 3 (38.6 mg, 0.1 mmol, 0.2 equiv ) . Solvent mixture CD 3 OD was added to the vial. The vial was sealed and the reaction was carried out at the r.t. The reaction was monitored by TLC. After completion of the reaction, the crude material was passed through a plug of celite and washed three times by ethyl acetate. Af ter the volatile materials were removed on a rotary evaporator the crude material was purified by column chromatography eluting with 5% ethylacetate/hexanes. The product was isolated as a white solid (96 mg, 79%, mp 87 - 88 °C). Regiochemistry of the borylat ed products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 1 H), 7. 84 (d, J = 7.8 Hz, 1H), 7.74 (d, J = 6.9 Hz, 1H), 7.31 (t, J = 2.9 Hz, 0.13H), 7.20 (t, J = 7.8 Hz, 1H), 6.61 (d, J = 2.0 Hz, 1H); 13 C NMR (CDCl 3 129.2, 126.7, 124.2, 123.9 (t, J = 70 25.8 Hz) , 119.2, 101.9, 101.7, 83.8 (2 C), 25.0 (4 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 31.2; FT - IR (neat) max : 3457, 2977, 1592, 1503, 1367, 1314, 1130, 978, 845, 805, 753, 678 cm - 1 ; LRMS (ESI): m/z calculated for C 14 H 18 DBNO 2 [ M+H] + 245.15, found 245.1. Percent D incorporation (based on quantitative 1 H NMR): 92% 4,7 - bis(BPin) - indole (3 - 19). The general procedure was applied to 2,4,7 - tri(BPin) - indole 3 - 7 (100 mg, 0.2 mmol, 1 equiv) and Bi(OAc) 3 (15.4 mg, 0.04 mmol, 2 0 mol%) with solvent mixture MeOH /THF (1 mL /0.8 mL) at 80 °C for 17 h. The crude material was concentrated and purified by column (5% ethyl acetate/hexanes) on silica gel. The product was isolated as white solid (55.4 mg, 75%, mp 225°C). Regiochemistry o f the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 4 (d, J = 7.3 Hz, 1 H), 7.63 (d, J = 7.3 Hz, 1 H), 7.31 (t, J = 5.4, 2.9 Hz, 1 H), 7.03 (t, J = 4.9, 2.9 Hz, 1 H), 1.40 (d, J = 2.5 Hz, 24 H, 8 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) 9 (2 C) , 83.4 (2 C) , 25.0 (8 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 31.6; FT - IR (neat) max : 3426, 2978, 1400, 1325, 1137, 1067, 968, 856 cm - 1 ; LRMS (ESI): m/z calculated for C 20 H 30 B 2 NO 4 [ M+H] + 370.23, found 370.3. 4 - BPin - 6 - fluoro - indole (3 - 20). The general procedure was applied to 2,4,7 - tri(BPin) - 6 - fluoroindole 3 - 10 (513 mg, 1 mmol, 1 equiv) and Bi(OAc) 3 (77.2 mg, 0.2 mmol, 20 mol%) with solvent mixture MeOH /THF (10 mL /4 mL) at 80 °C for 15 h. The crude material was concentrated and purified by column ( 10 % ethyl acetate/hexanes) on silica gel. The product was isolated as white solid (205 mg, 80%, mp 114 °C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 J = 10.3, 2.5 Hz, 1 H), 7.18 (dd, J = 2.9 Hz, 1H), 7.14 (dd, J = 9.3, 1.5 Hz, 1H), 7.07 (dd, J = 2.5 Hz, 1H), 1.43 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 (d, J = 237 Hz), 135.3 (d, J = 11.5 Hz) , 71 129.1, 125.1 (d, J = 3.8 Hz) , 115.3 (d, J = 22.9 Hz) , 104.3, 100.3 (d, J = 25.8 Hz) , 83.7 (2 C), 24.9 (4 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 31.3; FT - IR (neat) max : 3344, 2979, 1612, 1384, 1264, 1137, 1064, 966, 849, 782, 682 cm - 1 ; LRMS (ESI): m/z calculated for C 14 H 18 BFNO 2 [ M+H] + 261.13, found 262.1. 4,7 - bis(BPin) - 6 - fluoro - indole (3 - 21). The general procedure was applied to 2,4,7 - tri(BPin) - 6 - fluoroindole 3 - 10 (5 13 mg, 1 mmol, 1 equiv) and Bi(OAc) 3 (77.2 mg, 0.2 mmol, 20 mol%) with solvent mixture MeOH /THF (2.5 mL /4 mL) at 80 °C for 5 h. The crude material was concentrated and purified by column ( 5 % ethyl acetate/hexanes) on silica gel. The product was isolated as white solid (259 mg, 67%, mp 185°C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 J = 10.3 Hz, 1 H), 7.27 (dd, J = 2.9, 2 Hz, 1H), 6.98 (dd, J = 2.9, 2 Hz, 1H), 1.42 (s, 12 H, 4 C H 3 of BPin), 1.39 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 (d, J = 24 6 Hz) , 140.4, 128.1, 124.6 (d, J = 3.8 Hz) , 114.9 (d, J = 2 5.8 Hz) , 103.9, 83.9 (2 C), 83.8 (2 C), 25.0 ( 8 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 30.4; FT - IR (neat) max : 3125, 2923, 1559, 1401, 1256, 1139, 1063, 853 cm - 1 ; LRMS (ESI): m/z calculated for C 20 H 29 B 2 FNO 4 [ M+H] + 387.22 , found 38 8.3. Optimized procedure, 4 - BPin - 2 - carboethoxy - indole (3 - 22) . The deborylation step was carried out neat with 4,7 - bis(BPin) - 2 - ethyl ester - indole 3 - 12 ( 220.5 mg, 0. 5 mmol) ), [Ir(OMe)(COD)] 2 (1 0 mg, 0.0 3 mmol, 6 mol % Ir) in MeOH ( 800 2 0 mmol, 4 0 equiv) and THF ( 5 mL) at r.t. for 12 h and worked up as described in the general procedure. The crude mat erial was concentrated by rot vap, and purified by column chromatography eluting with 5 % ethylacetate/hexanes . The product was isolated as a white solid ( 85 m g, 54 %, mp 13 9 °C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 14 (br s, 1H), 7.7 0 ( m , 1H), 7.68 (d d , J = 6.9, 1 Hz, 1H), 7. 54 ( d , J = 8.3 Hz , 1H), 7. 34 (d d , J = 8.3, 7.3 Hz, 1H), 4.4 5 72 (q, J = 6.9 Hz, 2 H, CH 2 CH 3 ), 1.4 5 (t, J = 7. 3 Hz, 3 H, CH 2 CH 3 ), 1.41 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) 162.3 (C=O), 136.2, 131.7, 129.0, 127.6, 124.6 (C), 114.8, 110.5, 83.6 (2 C), 61.0 (CH 2 ), 24.9 (4 CH 3 of BPin), 14.4 (CH 3 ); 11 B NMR (CDCl 3 , 160 MHz): 30.8; FT - IR (neat) max : 3331, 2979, 1686, 1521, 1250, 1146, 1022, 980, 852, 769, 681 cm - 1 ; LRMS (ESI): m/z calculated for C 17 H 23 BNO 4 [ M+H] + 316.16, found 316.2. 4 - BPin - 2 - methyl - indole (3 - 23). The deborylation step was carried out neat with 4,7 - BPin - 2 - methylindole 3 - 14 (38 mg, 0.1 mmol, 1 equiv), [Ir(OMe)(COD)] 2 (1 mg, 0.003 mmol, 3 mol % Ir) in MeOH and DCM at 60 °C for 2 h and worked up as described in the general procedure. The crude material was purified by silica gel chromatography (5% ethyl acetate/hexanes) on silica gel to afford the product as white solid (20 mg, 74%, mp 157 160 °C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 1H), 7.58 (d, J = 6.9 Hz, 1 H), 7.38 (d, J = 7.8 Hz, 1 H), 7.11 (t, J = 7.8 Hz, 1 H), 6.71 (s, 1H), 2.47 (s, 3 H), 1. 39 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) 120.3, 113.0, 102.4, 83.3 (C), 25.0 (4 CH 3 of BPin), 13.8(CH 3 ); 11 B NMR (CDCl 3 30.9; FT - IR (neat) max : 3436, 2976, 1549, 1371, 1269, 1130, 1064, 973, 858, 637 cm - 1 ; LRMS (ESI): m/z calculated for C 15 H 21 BNO 2 [ M+H] + 258.16, found 258.2. 5 - BPin - 6 - fluoro - indole (3 - 24) . The deborylation step was carried out neat with 3 , 5 - bis(BPin) - 6 - fluoro - indole 3 - 15 ( 193 mg, 0. 5 mmol, 1 equiv), [Ir(OMe)(COD)] 2 ( 5 mg, 0.015 mmol, 3 mol % Ir) in MeOH and DCM at 60 °C for 2 h and worked up as described in the general procedure. The crude material was purified by silica gel chromatography (30% ethyl acetate/hexanes) on silica gel to afford the product as white solid ( 86 mg, 66%). Al ternative procedure, 5 - BPin - 6 - fluoro - indole (3 - 24) . The general procedure was applied to 3,5 - bis(BPin) - 6 - fluoro - indole 3 - 15 (77 mg, 0.2 mmol, 1 equiv) and Bi(OAc) 3 (15.4 mg, 0.04 mmol, 73 20 mol%) with solvent mixture MeOH /THF (0.8 mL /0.4 mL) at 80 °C for 3 h. The crude material was concentrated and purified by column (5% ethyl acetate/hexanes) on silica gel. The product was isolated as a white solid (46 mg, 88 %, mp 159 - 162°C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NM R (CDCl 3 (d, J = 5.4 Hz, 1H), 7.17 (dd, J = 3.4, 2.5 Hz, 1H), 7.04 (d, J = 10.3 Hz, 1H), 6.53 (dd, J = 2.5 Hz, 1H), 1.38 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) J = 242 Hz), 138.2 (d, J = 13.4 Hz), 1 29.6 (d, J = 10.5 Hz), 128.3, 124.7 (d, J = 3.8 Hz), 103.1, 97.1 (d, J = 29.6 Hz), 83.5 (2 C), 24.8 (4 CH 3 of BPin); 11 B NMR (CDCl 3 , 160 MHz): 30.7; FT - IR (neat) max : cm - 1 ; LRMS (ESI): m/z calculated for C 14 H 18 BFNO 2 [ M+H] + 261.13, found 262.1. Optimized procedure, 5 - BPin - N - Boc - indole (3 - 25). The deborylation step was carried out neat with 3 , 5 - bis(BPin) - N - Boc - indole 3 - 17 (1 95 mg, 0. 4 mmol), [Ir(OMe)(COD)] 2 ( 8 mg, 0.0 24 mmol, 6 mol % Ir) in MeOH ( 800 2 0 mmol, 5 0 equiv) and THF ( 4 mL) at r.t. for 10 h and worked up as described in the general procedure. The crude material was concentrated by rot vap, and purified by column chromatography eluting with 5 % ethylacetate/hexanes . The product was isolated as a colorless oil ( 67 m g, 47 %). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 7.93 (d, J = 5.9 Hz, 1H), 7. 82 ( br d, J = 8 .3 Hz, 1H), 7.5 3 (d, J = 2.9 Hz, 1H), 6 .5 3 (d, J = 3.9 Hz, 1H) , 1.6 6 (s, 9 H, 3 C H 3 of Boc), 1.3 8 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 , 125 MHz) 165.1 (d, J = 24 4 Hz) , 149.4, 129.1 (d, J = 9.5 Hz) , 126.6, 126.2 (d, J = 3.8 Hz) , 107.2, 102.2 (d, J = 31.5 Hz) , 84.1 (C), 83.7 (2 C), 28.1 ( 3 CH 3 of B oc ) , 24.8 ( 4 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 30.1; FT - IR (neat) max : 3443, 2979, 1737, 1622, 1446, 1359, 1257, 1143, 1085, 959, 860, 732 cm - 1 ; LRMS (ESI): m/z calculated for C 19 H 26 BFNO 4 [ M+H] + 362.19, found 362.3. 74 4,7 - bis(BPin) - 6 - fluoro - N - Boc - indole (3 - 26). A round bottom flask equipped with a magnetic stirring bar, a condenser and an additional funnel was charged with 4,7 - bis(BPin) - 6 - fluoro - indole 3 - 21 (217 mg, 0.56 mmol, 1 equiv), MeCN (1 mL) and NEt 3 (1.6 mL, 11.2mmol, 20 equiv) were injected into the flask followed with refluxing th e solution at 80 °C for 0.5 h. DMAP (137 mg, 1.12 mmol, 2 equiv) and Boc 2 O (2.4 g, 11.2 mmol, 20 equiv) were weighted together in one vial, after adding the MeCN (1 mL), allowing the mixture stirred at r.t. until it became a yellow homogenous solution. The n this solution was introduced to an additional funnel and allowed it flow at the rate of 1 drop/ 2 min to the round bottom flask, the reaction was refluxed at 80 °C for another 10 h. Until the reaction was judged to be complete by TLC, it was concentrated and p urification by column chromatography eluting with 5% acetones/heptanes . The product was isolated as white solid (250 mg, 80%, mp 1 58 °C). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 41 (d, J = 3 .4 Hz, 1 H), 7. 3 7 (d, J = 9.8 Hz, 1H), 7.01 (d, J = 3.9 Hz, 1H), 1. 6 2 (s, 9 H, 3 C H 3 of BPin), 1. 45 (s, 12 H, 4 C H 3 of BPin) , 1.3 7 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 (d, J = 2 37 Hz) , 150.1, 136.7, 131.0, 125.0 (d, J = 3.8 Hz) , 11 7.2 (d, J = 2 5.8 Hz) , 109.6, 84.0 (2 C), 83.9 (C), 83.8 (2 C), 28.2 ( 3 CH 3 of B oc ) , 25.6 ( 4 CH 3 of BPin) , 25.0 ( 4 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 29.1; FT - IR (neat) max : 3422, 2979, 1723, 1540, 1458, 1039, 1233, 1145, 935, 852, 769, 668 cm - 1 ; LRMS (ESI): m/z calculated for C 25 H 37 B 2 FNO 6 [ M+H] + 488.27, found 488.2. 7 - BPin - 6 - fluoro - N - Boc - indole - 4 - d (3 - 27). The deborylation step was carried out neat with 4,7 - bis(BPin) - 6 - fluoro - N - Boc - indole 3 - 26 (76 mg, 0.156 mmol, 1 equiv), [Ir(OMe)(COD)] 2 (0.78 m g, 0.00234 mmol, 1.5 mol% Ir) in CD 3 OD 253 r.t. for 10 h and worked up as described in the general procedure. The crude material was concentrated by rot vap, and purified by column chromatography eluting with 10% ethyl 75 acetate/hexanes. The product was isolated as a colorless oil (44 mg, 78%). Regiochemistry of the borylated products was assigned by NMR spectroscopy. 1 H NMR (CDCl 3 42 (d, J = 3 .4 Hz, 1 H), 6.95 (d, J = 9.3 Hz, 1H), 6.50 (d, J = 3.4 H z, 1H), 1. 6 2 (s, 9 H, 3 C H 3 of Boc), 1.4 7 (s, 12 H, 4 C H 3 of BPin); 13 C NMR (CDCl 3 (d, J = 2 37 Hz) , 150.0, 125.8, 125.0 (d, J = 3.8 Hz) , 110.7 (d, J = 2 7.7 Hz) , 107.7, 84.0 (3 C), 28.2 ( 3 CH 3 of B oc ) , 25.6 ( 4 CH 3 of BPin) ; 11 B NMR (CDCl 3 , 160 MHz): 28.4; FT - IR (neat) max : 3439, 2978, 1724, 1601, 1541, 1353, 1257, 1151, 1093, 984, 854, 736, 613 cm - 1 ; LRMS (ESI): m/z calculated for C 19 H 25 DBFNO 4 [ M+H] + 363.19, found 363.2. Percent D incorporation (based on quantitative 1 H NMR): 84% 5.4. Exp erimental details for Chapter 4 General Procedure for Preparation of Deuterated Aromatics To 1 mmol borylated arene were added 20 mol% Ag 2 O, 0.1 mL D 2 O and 0.5 mL dry THF. The flask was sealed and heated in an oil bath to 80 °C until the reaction was judged complete by TLC thin plate . Upon completion, the mixture was filtered through 1 mL silicon gel , dried over MgSO 4 and evaporated. Column chromatography ( 5% ethyl acetate/hexane) afforded the product. 1,2,3 - Trichlorobenzene - 5 - d . The deuteration step was then carried out at 80 °C for 1 h as described in the general procedure, after which the crude material was purified with a silica gel chromatography to afford 100 m g of the deuterated compound (55%) as a white solid . 1 H NMR (500 MHz, CDCl 3 ): 7.36 (t, J H - D = 1.1 Hz). The spectral data were in accordance with literature. 3 2,6 - Dichloropyridene - 4 - d. The deuteration step was then carried out at 80 °C for 1 h as described in the general procedure, after which the crude material was purified with a silica gel chromatography to afford 58 m g of the deuterated compound (40 %) as a white solid. 1 H NMR (500 MH z, CDCl 3 ): 7.25 (t, J H - D = 1.1 Hz). The spectral data were in accordance with literature. 3 76 3 - Chlorobenzotrifluoride - 5 - d . The deuteration step was then carried out at 80 °C for 2.5 h as described in the general procedure, after which the crude material wa s purified with a silica gel chromatography to afford 111 mg of the deuterated compound (78%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): 7.6 0 (br, 1 H), 7.54 7.48 (m, 2 H). The spectral data were in accordance with literature. 3 3 - Bromobenzonitrile - 5 - d . The deuteration step was then carried out at 80 °C for 3 h as described in the general procedure, after which the crude material was purified with a silica gel chromatography to afford 109 m g of the deuterated compound (60 %) as a w hite solid . 1 H NMR (500 MHz, CDCl 3 ): 7.78 (t, J = 1.6 Hz, 1 H), 7.73 (br, 1 H), 7.59 (br, 1 H). The spectral data were in accordance with literature. 3 3 - Chloroanisole - 5 - d . The deuteration step was then carried out at 80 °C for 2 h and worked up as described in the general procedure, after which the crude material was purified with a silica gel chromatography to afford 8 9 m g of the deuterated compound (62 %) as a colorless oil . 1 H NMR (300 MHz, CDCl 3 ): 6.91 (br, 1 H), 6.88 (t, J = 2.3 Hz, 1 H) , 6.77 (br, 1 H), 3.78 (s, 3 H). The spectral data were in accordance with literature. 3 1,2 - Dichlorobenzene - 4 - d . The deuteration step was then carried out at 80 °C for 3 h and worked up as described in the general procedure, after which the crude material was afford 135 mg of the deuterated compound (91%) as a colorless oil. 1 H NMR (300 MHz, CDCl 3 ): 7.41 - 7. 44 (m, 2 H), 7.16 - 7.20 (m, 1 H). The spectral data were in accordance with litera ture. 3