RADICAL FLUOROALKYLATION USING PHOTOREDOX CATALYSIS TO ACCESS TRIFLUOROMETHYL COUMARINS AND DIFLUOROMETHYL INDOLES By MILES ANTHONY RUBINSKI A DISSERTATION PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORIDA 2018
2018 Miles Anthony Rubinski
To my family
4 ACKNOWLEDGMENTS I would like to thank my supervisor, Dr. William R. Dolbier, for taking me on as a graduate student and giving me the opportunity to better myself as a chemist. His guidance has been invaluable, and I know I could not have achieved my goals without his support and advice. I also want to thank my supervisory committee members for their help and consideration. Their suggestions have been vital to my experience as a graduate student. I am humbled by the support of my family, without which I surely could not have completed my journey. To all my labmates, especially Dr. Simon Lopez, thank you for your assistance and all of the productive disc ussions. Finally, I would like to thank my partner, Alison Nadelberg, for being an amazing fiance and friend. I started this graduate school journey for myself, but I finished it for us.
5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ................................ ................................ ................................ ............... 4 LIST OF TABLES ................................ ................................ ................................ ........................... 6 LIST OF FIGURE S ................................ ................................ ................................ ......................... 7 LIST OF ABBREVIATIONS ................................ ................................ ................................ .......... 9 ABSTRACT ................................ ................................ ................................ ................................ ... 10 CHAPTER 1 INTRODUCTION TO METHODOLOGIES FOR LATE STAGE Csp 2 TRI AND DIFLUOROMETHYL BOND FORMATION ................................ ................................ ...... 12 2 PHOTOREDOX MEDIATATED RADICAL TRIFLUOROMETHYLATION AND CYCLIZATION OF ARYL PROPIOLATES FOR THE SYNTHESIS OF 3 TRIFLUOROMETHYL COUMARINS ................................ ................................ ................ 22 2.1 Introduction to the Synthesis of 3 Trifluoromethyl Coumarins ................................ ....... 22 2.2 Results and Discussion ................................ ................................ ................................ ..... 25 2. 3 Proposed Mechanism and Conclusion ................................ ................................ .............. 29 2.4 Experimental ................................ ................................ ................................ ..................... 31 3 THROUGH SPACE 19 F 15 N COUPLINGS FOR THE ASSIGNMENT OF STEREOCHEMISTRY IN FLUBENZIMINE ................................ ................................ ...... 34 3.1 Introduction to Through Space Coupling and Flubenzimine ................................ ........... 34 3.2 Results and Discussion ................................ ................................ ................................ ..... 35 3.3 Experimental Section ................................ ................................ ................................ ........ 38 4 DIRECT ACCESS TO 2 CF 2 H INDOLES VIA PHOTOREDOX CATALYSIS ................. 40 4.1 Introduction to Targeted Fluoroalkylation of Indoles ................................ ...................... 40 4.2 Results and Discussion ................................ ................................ ................................ ..... 44 4.3 Mechanism and Conclusion ................................ ................................ .............................. 51 4.4 Experimental Data ................................ ................................ ................................ ............ 54 5 CONCLUSION ................................ ................................ ................................ ....................... 64 LIST OF REFERENC ES ................................ ................................ ................................ ............... 68 BIOGRAPHICAL SKETCH ................................ ................................ ................................ ......... 75
6 LIST OF TABLES Table page 2 1 Optimization of reaction conditions with CF 3 SO 2 Cl and phenyl 3 phenyl propiolate. ..... 26 4 1 Optimization of reaction conditions for the difluoromethylation of indoles. .................... 45 4 2 Mechanistic investigations. ................................ ................................ ................................ 53
7 LIST OF FIGURES Figure page 1 1 Biologically active compounds with a fluoroalkyl group. ................................ ................. 13 1 2 Common trifluoromethylation sources. ................................ ................................ ............. 14 1 3 Common routes to form aromatic C CF 3 bonds. ................................ ............................... 15 1 4 Examples of tandem catalysis and reagent compatability with ph otoredox. ..................... 17 1 5 General photoredox mechanistic pathways. ................................ ................................ ...... 18 1 6 Common sources or precursor to the difluoromethyl group. ................................ ............. 20 1 7 Fluoroalkylated bioactive structures synthesized by the Dolbier research group. ............. 21 2 1 Strate gies for accessing 3 trifluoromethyl coumarins, positions numbered. ..................... 24 2 2 Substrate scope of para substituted phenylpropiolates. Yields calculated using trifluorotoluene as internal standard in the 19 F NMR. ................................ ....................... 27 2 3 Expanded sub strate scope of para substituted phenylpropiolates, products not isolated. Yields calculated using trifluorotoluene as internal standard in the 19 F NMR. ................................ ................................ ................................ ................................ 28 2 4 Meta substituted 3 phenylpropiolate affords a single regioisomer. Yields calculated using trifluorotoluene as internal standard in the 19 F NMR ................................ .............. 29 2 5 Plausible photocatalytic mechanism for the formation of 3 CF3 coumarins. ................... 30 2 5 Synthesis of 3 phenyl aryl propiolates. ................................ ................................ .............. 32 3 1 Ambiguous Flubenzimine structu re with position numbering. ................................ .......... 35 3 2 Possible configurations for flubenzimine. ................................ ................................ ......... 36 3 3 1 H, 19 F 13 C and 15 N chemical shifts assignment in Flubenzimine. ................................ ... 37 4 1 Representative pharmaceutical indole derivatives. Adapted from Ref. 50. ....................... 41 4 2 Methodologies to synthesize CF2R indoles. ................................ ................................ .... 43 4 3 Photocatalysts tested. ................................ ................................ ................................ ......... 46 4 4 Substrate scope 3 substituted indoles. Crude yields were calculated using 19 F NMR with trifluorotoluene as an internal standard. Isolated yields in parentheses. ................... 48
8 4 5 Substrates tested with differing substituents on the benzo portion of indole. Crude yields calculated using 19 F NMR and trifluorotoluene as an internal standard. Isolated yields in parentheses. ................................ ................................ ............................ 49 4 6 N protected indole example. Crude yields calculated using 19 F NMR and trifluorotoluene as an internal standard. Isolated y ields in parentheses. ............................ 51 4 7 Other substrates screened. Crude yields calculated using 19 F NMR and trifluorotoluene as an internal standard. ................................ ................................ ............. 51 4 8 Plausible mechanism for the photoredox difluoromethylation of indoles. ........................ 52 4 9 Synthesis of fac Ir(ppy) 3 ................................ ................................ ................................ ... 55 4 10 Synthesis of difluoromethyl phosphonoum bromide ................................ ......................... 57 4 11 Synthesis of aryl acetaldehydes. ................................ ................................ ........................ 57 4 12 Synthesis of indole substrates. ................................ ................................ ........................... 58 4 13 Representative 1 H NMR spectrum of 3 (4 chlorophenyl) 2 (difluoromethyl) 1 H indole. ................................ ................................ ................................ ................................ 59 4 14 Representative 13 C NMR spectrum of 3 (4 chlorophenyl) 2 (difluoromethyl) 1 H indole. ................................ ................................ ................................ ................................ 59 4 15 Representative 19 F NMR spectrum of 3 (4 chlorophenyl) 2 (difluoromethyl) 1 H indole. ................................ ................................ ................................ ................................ 60 5 1 4 CF 2 R coumarins as a target using fluoroalkyl radicals generated by photoredox. ......... 65 5 2 Pharmaceutically relevant indoles containing a methyl group in the 2 position. .............. 65 5 3 2 CF 2 H Indomethacin derivative. ................................ ................................ ...................... 66
9 LIST OF ABBREVIATIO NS DABCO 1,4 diazabicyclo[2.2.2]octane d ap 2,8 bis(4 methoxyphenyl) 1,9 phenanthroline DAST Diethylaminosulfur trifluoride DCC dicyclohexylcarbodiimide DCE 1,2 dichloroethane DFMS Difluoromethanesulfinate DMF Dimethylformamide DMPU 1,3 dimethyl 3,4,5,6 tetrahydro 2 pyrimidinone DMSO Dimethyl sulfoxide Eq. Stoichiometric equivalent f ac Ir(ppy) 3 Tris[2 phenylpyridinato C2,N]iridium(III) HAT Hydrogen atom transfer hv Irradiated with light LED Light emitting diode Mes Mesitylene mL Milliliter mmol Millimole Ni Nickel NMR Nuclear Magnetic Resonance phen 1,10 phenanthroline rt Room temperature SET Single electron transfer THF Tetrahydrofuran
10 Abstract of Dissertation Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy RADICAL FLUOROALKYLATION USING PHOTOREDOX CATALYSIS TO ACCESS TRIFLUOROMETHYL COUMARINS AND DIFLUOROMETHYL INDOLES By Miles Rubinski December 2018 Chair: William R. Dolbier, Jr. Major: Chemistry Our group has developed a variety of methodologies to access difluoromethylated structures. The majority of the work was accomplished with CF 2 HSO 2 Cl as a source of difluoromethyl radical. By utilizing photo redox catalysis, transformation s that previously required significant amounts of expensive reagents, and harsh conditions, could now be performed using low catalyst loading, mild conditions, and a readily synthesized and affordable difluoromethyl source. I n hopes of expanding the substrate scope for the pairing of photoredox catalysis and fluoroalkylation, new structures were targeted and different fluoroalkyl sources were tested. The investigation of the trifluoromethylation of internal alkynoates was cond ucted for the synthesis of 3 trifluoromethyl coumarins using photoredox catalysis. The methodology allowed access to the target compounds, albeit in low to modest yields. The reactions were conducted using Cu(dap) 2 Cl, and CF 3 SO 2 Cl in acetonitrile at elevat ed temperatures. A visible light mediated approach to radical difluoromethylation of 3 and 3,5 substituted indoles was investigated using a readily synthesized difluoromethyl source, CF 2 HPPh 3 Br. Direct difluorom ethylation of indoles in the 2 nd position is a rare feat in the literature. The reactions
11 were conducted at room temperature, using Ir(ppy) 3 as photocatalyst in acetone, to afford the 2 difluoromethyl indoles in low to moderate yields. Through space 19 F 15 N couplings revealed the configuration of Flubenzimine, with the CF 3 group on N4 pointing towards the lone pair of N5. The 19 F 15 N coupling constants were measured at natural abundance using a spin state selective indirect detection pulse sequence. As 15 N l abelled proteins are routinely synthesized for NMR studies, through space 19 F 15 N couplings have the potential to probe the stereochemistry of these proteins by 19 F labelling of some amino acids, or can reveal the site of docking of fluorine containing d rugs.
12 CHAPTER 1 INTRODUCTION TO METHODOLOGI ES FOR LATE STAGE Csp 2 TRI AND DIFLUOROMETHYL BOND FORMATION Fluorinated organic compounds have proven to be vital to modern society, with their prevalence in pharmaceuticals, materials and agrochemicals increa sing over the last two decades. Properties such as lipophilicity and bioavailability are enhanced in drugs that contain fluorine when compared to the nonfluorinated equivalent. 1 These enhancements are related to the highly polarized C F bond, which can hav e desirable steric implications, hydrogen bonding capabilities, and increased metabolic stability from oxidative processes. 2 As a result of these properties, significant effort has produced modern techniques to access targeted bioactive structures containi ng fluorinated alkyl substituents. 3 Continued effort has pushed chemists to find unique methodologies to install a select series of fluoroalkyl groups, as direct fluorination has drawbacks related to hazardous reagents being needed, harsh conditions, and p oor substrate scope. 4 More specifically, strategies for the synthesis of fluoroalkyl groups directly bonded to aroma tic or heteroaromatic motifs have been a remarkably active area of research, as this sort of structure is highly prevalent in bioactive orga nic compounds (Figure 1 1). The majority of recent publications regarding fluoroalk ylation are related to the trifluoromethyl (CF 3 ) and difluoromethyl (CF 2 H) groups. 3 Insertion of either group, with respect to derivatives of bioactive structures, has largely resolved into several late stage functionalization strategies that can be summarized as optimizations of direct CF 2 R aryl bond formation via C H or C X activation, or cyclization by incorporation of the desired fluoroalkyl unit into an appropriate substrate. While many fluoroalkylation strategies exist, especially for the formation of Csp 3 CF 2 R and X CF 3 bonds from alkenes and heteroatoms, continued effort is neede d for developing late stage methodologies for regioselective CF 2 R aryl and hetero aryl bonds. 5 Unfortunately, not all
13 Figure 1 1 Biologically active compounds with a fluoroalkyl group. strategies that are available for t rifluoromethylation are suitable for difluoromethylation due to the properties and availability of reagents, as well and the stability and reactivity of the various intermediates generated to realize fluoroalkylation. 6 As a result, inventing methods to ins tall either group in structures of interest is highly valuable, especially when done in a late stage step. Arguably the most efficient approach to form aromatic or heteroaromatic C CF 2 R bonds is via photoredox catalysis, and the various permutations inhere nt to this methodology. Late stage functionalization has two general advantages, especially with fluoroalkyl reagents, compared to early stage fluoroalkylation revolving around fluorinated building blocks. Specifically, fluoroalkylating and fluorinating re agents are expensive, and can require specialized equipment. 7 As a result, late stage fluoroalkylation, particularly in order to make fluoroalkylated arenes and heteroarenes, is much more efficient as previously established
14 biologically active structures c an first be synthesized using known methodologies, and the desired fluorinated moiety can then be installed on a much smaller scale. Late stage functionalization is also compatible with parallel synthetic approaches like convergent synthesis, where a relat ively advanced fluoroalkylated subunit can first be functionalized, then used near the end of the main route for improved atom economy. 8 A variety of trifluoromethylating reagent s have been developed in the past several decades, in order to realize direct trifluoromethylation (Figure 1 2 ). Prior to direct aryl trifluoromethylation, benzylic methyl groups were fully chlorinated and the carbon chloride bonds were then treated with inorganic fluoride sources to access trifluoromethyl toluene derivatives, a pr ocess that is now known as the Swarts reaction (Figure 1 3 path a). 9 Since then, Figure 1 2 Common trifluoromethylation sources. approaches to form Csp 2 CF 3 bonds stem from the Ruppert Prakash reagent (TMS CF 3 1 a ), which can act as a source of trifluoromethyl anion when treated with stoichiometric copper(I) and a fluor ide salt with aryl iodides as substrate (Figure 1 3 path b). 10 Catalytic Csp 2 X activation methods using TMS CF 3 as well as Umemoto ( 1 d ) and Togni reagents I and II ( 1 b and 1 c respectively) were developed with varying copper and palladium catalysts plus ligand
15 combinations, and boronic acids were found to have practical generality for most CF 3 sources (Figure 1 3 path c). 11 Significant explorat CF 3 resulted in a myriad of synthetic option s that all rely on these isola ble species. 12 Grushin and coworkers developed fluoroform ( CF 3 H) has a precursor to various CF 3 metal complexes to react with aryl hal ides, a particularly environmentally friendly approach. 13 Sandmeyer chemistry has also been employed on aniline derivatives for the synthesis of aromatic CF 3 compounds. 14 Figure 1 3 Common routes to form aromatic C CF 3 bonds. C H activation is relatively limited with respect to CF 3 aryl bond formation because of regioselectivity issues, with substrates typically requiring some directing group. 15 Aryl C H or C X activation strategies can be accomplished by generating the trifluoromethyl radical with Ag CF 3 ( 1 j ), 15a trifluoromethylsulfonyl chloride ( CF 3 SO 2 Cl, 1 e ), 16a Langlois reagent
16 ( CF 3 SO 2 Na 1 f ), 16b or trifluoromethyl iodide ( CF 3 I, 1 h ) (Figure 1 2, path d). 16c Notably, a particularl y fruitful area of research is the pairing of photoredox catalysis and trifluoromethyl sources to access the trifluoromethyl radical. Heteroaromatic trifluoromethylation can be accomplished using similar strategies as listed above, with an emphasis on C H activation as the heterocycles tend to be more electron rich in certain position s allowing for a reduced emphasis on prefunctionalization in the form of a C X bond 17 Compared to Cu mediated routes, and transition metal catalyzed approaches, using photoredox provides access to the tri fluoromethyl radical using relatively mild conditions with rarely a need for additives, low catalyst loading, and is also compatible with a wide array of other catalyst types. Less prevalent than direct trifluo ro methylation of Csp 2 H or Csp 2 X bonds is a c yclization strategy for the late stage synthesis of a variety of aromatic and heteroaromatic compounds. Apart from the cyclization of substrates already containing the CF 3 group there are a limited number of examples related to the incorporation of the CF 3 group followed by inter or intramolecular cyclization One aspect of this strategy that is beneficial is the opportunity for regioselectivity in the construction of aromatic C CF 3 bonds when compared to a C H activation strategy, or the need for X bond As highlighted above, the pairing of photoredox catalysis and trifluoromethylation has been an active and fruitful area of research. Much of the current knowledge about photoredox is owed to separate reports by the groups o f Macmillan, Stephenson, and Yoon. 18 In particular, various combinations of transition metal catalysts with photoredox catalysts, hydrogen atom transfer reagents, which provide access to novel C H activation pathways, and series of cascade reactions have all been significant contributions. 19 A recent publication showcases the flexibility of photoredox catalysis, as Yi and coworkers demonstrated the merging of photoredox catalysis
17 and cobalt catalysis, to enable an oxidant free radical alkenylation (Figure 1 4). 19e Macmillan demonstrated an Ir photocatalyst, a Ni catalyst, and a hydrogen atom transfer reagent working together in three interconnected catalytic cycles to afford a wide array of ketones by pairing various aldehydes and aryl, vinyl, or alkyl bromides (Figure 1 4). 19f Figure 1 4. Examples of tandem catalysis and reagent compatability with photoredox. The general mechanism of photoredox catalysis has two main pathways, reductive quenching cycle and oxidative quenching cycle (Figure 1 5) 20 Thi s nomenclature is with respect
18 Figure 1 5 General photoredox mechanistic pathways. to the electron transfer and the catalyst in the final step of the mechanism. The excited state of the photocatalyst can act as a powerf ul reductant or oxidant depending on the catalyst and the
19 substrate being used, with photons providing the energy needed to switch from a mundane ground state into a highly versatile species. The general trend of redox potential is primarily dependent on t he metal center, followed by the ligands being relatively electron donating, which increases reductive potential, or withdrawing ligands which increases the ability of the catalyst to be reduced. 21 While strategies for trifluoromethylation were relatively widespread before photoredox catalysis garnered the attention of the organofluorine community, direct incorporation of the CF 2 H group benefitted immensely from the pairing, especially considering the hurdles encountered with alternative strategies. Strateg ies related to difluoromethylation have become an increasingly popular research endeavor, with publications increasing drastically within the last decade. 22 Initial methods involved using unstable reagent like sulfur tetrafluoride (SF 4 ) and diethylaminosul fur trifluoride (DAST) to deoxyfluorinate aldehydes and ketones to provide access to difluoroalkylated compounds. 23 Much of the interest in developing better methodologies is owed to the ability of the CF 2 H group to be a hydrogen bond donor, similar to an alcohol or an amine, while also increasing the lipophilici ty of bioactive compound s 24 Contrary to the high availability of commercially available trifluoromethylating reagents, CF 2 H sources, when available, are costly, while others must be synthesized (Fi gure 1 6) Alternatively, CF 2 H synthons are frequently used i n the form of ethyl bromodifluoro acetate ( 1 r ) or dimethyl bromodifluorophophonate with Cu or photoredox catalytic systems, which can be decarboxylated or dephosphorylated to give the CF 2 H group in a variety of structures as an additional step. 25, 26
20 Figure 1 6. Common sources or precursor to the difluoromethyl group. More challenges are encountered in the case of transition metal catalyze d difluoromethylation. The established strategy of using transition metal catalyst s for cross coupling has limited applications, specifically with CuCF 2 H complexes being relatively unstable compared to Cu CF 3 6a Taking into consideration all of the limitat ions and drawbacks of the polar strategies for difluoromethylation, radical precursors are particularly attractive options, especially when generated via photoredox catalysis. Difluoromethyl triphenyl phosphonium bromide ( 1 o ) has seen recent development t owards Csp 3 CF 2 H bond formation, most examples relying on Cu catalysts to generate the radical. 27 Other recent examples have shown that CF 2 HPPh 3 Br is compatible in certain systems with photoredox. 28 Difluoromethane sulfonyl chloride ( 1 n ) has also enjoyed s ignificant use, pri marily with terminal alkenes, bo th activated and unactivated. 29 Baran group has employed a Zn complex ( 1 q ) in several impressive works where under oxidative conditons the difluoromethyl radical is generated, and CF 2 H arenes and heteroarenes can be accessed. 8 Further development towards late stage difluoromethylation with radical CF 2 H precursors is an important area of research to expand upon, especially as the regioselectivity can be altered depending on the generating of a CF 2 H radical, utilizing cross coupling methods, or employing a novel radical cascade approach. The Dolbier group has contributed a significant amount to this
21 area of research, primarily with photoredox catalysis pairing with CF 2 HSO 2 Cl to access Csp 3 CF 2 H bonds into derivatives of biologically relevant substructures, with several examples of Csp 2 CF 2 H formations be ing reported as well (Figure 1 7 ). Much of this work was inspired by the utilization of CF 3 radical sources, with certain affinities being realized for electron poor C C pi bonds because of the relative nucleophilicty of the CF 2 H radical in comparison. The incentive for developing methodologies for late stage fluoroalkylations via photoredox catalysis is amplified in the case of difluoromethylation, esp ecially when compared to trifluoromethylation. Both moieties are high priority group s for the installment into bioactive structures, including agrochemicals and pharmaceuticals. Methodologies that seek to optimize and ease the enabling of late stage fluoro alkylation, specifically with Csp 2 CF 2 R in aromatics and heteroaromatics in mind, remains a vital research endeavor. Generating fluoroalkyl radicals is the most direct and efficient way to realize the installment of these groups, and research pointed towar ds new methodologies is worthwhile. Figure 1 7 Fluoroalkylated bioactive structures synthesized by the Dolbier research group.
22 CHAPTER 2 PHOTOREDOX MED IAT ATED RADICAL TRIFLUOROMETHYLATION AND CYCLIZATION OF ARYL PROPIOLATES FOR THE SYNTHESIS OF 3 TRIFLUOROMETHYL COUMARINS 2.1 Introduction to the Synthesis of 3 Trifluoromethyl Coumarins Coumarins are a class of naturally occurring biologically active compound that have garnered the attention of the synthetic commun ity. Much of this interest is due to the coum arin substructure being used in therapies related to anti inflammatory, antitumor, antineurodegenerative, anticoagulant, antimicrobial, and anti HIV treatments. 30 Consequently, methods were developed to construc t a variety of coumarin derivatives, many of which were effectively generate the coumarin skeleton. 31 Of particular note are the strategies that take advantage of the in tramolecular cyclization pathway from substituted arylalkynoates to target coumarins with substituents in the 3 rd position. 32 The proposed mechanism for this approach is thought to be consistent throughout the literature, with the primary difference being in what manner the initial radical is generated: oxidatively, reductively, or photocatalytically. Once the desired radical is generated and adds to the alpha carbon of the ester moiety the vinyl radical intermediate is fo rmed. Intramolecular aryl cyclization occurs to form a new radical ring intermediate being either a 6 endo or 5 exo annulation followed by ester migration. Ultimately, deprotonation and rearomatization yields the 3 substituted coumarin. Strategies for fluo roalk ylation of organic compounds have become a popular research endeavor. Much of this attention is related to the remarkable properties bestowed upon bioactive compounds containing even just a single fluorine atom when compared to their nonfluorinated co unterparts. 1 In particular, the trifluoromethyl group has enjoyed significant attention, owing to its ability to enhance factors such as increased membrane permeability by increasing
23 lipophilicity, as well as being metabolically stable. 3a h In fact, the tr ifluoromethyl group is present in several noteworthy pharmaceuticals. The install ation of the trifluoromethyl group into bioactive structures has a foundation in exploiting activated C X bonds in aromatic and heteroaromatic structures. Typically, these rea ction require high temperatures, high catalyst loading, or the use of hyper reagent, Langlois reagent, Rupert Prakash reagent, CF 3 SO 2 Cl, and others have all been employed to realize late stage f unctionalization of bioactive structures, especially to form Csp 2 CF 3 bonds in arenes and heteroarenes. 10 17 In particular, CF 3 SO 2 Cl was found to be compatible with Ru(bpy) 3 Cl 2 to potentially expand the substrate scope for trifluoromethylation, as C H bon ds can be targeted in certain aromatic systems. This methodology is worth exploring for the synthesis of coumarins, as alkynes have been shown to be suitable traps for the trifluoromethyl radical to construct a variety of intermediates and impressive bioac tive frameworks. 33 Photoredox is an increasingly popular approach to forge a collection of complex compounds, and trifluoromethylation is in a unique position to reap the benefits of this strategy. In the case of coumarins, taking advantage of a prefunctio nalized C X bond is difficult, especially in the 3 position where many different groups have been added in the literature. 32 The trifluoromethyl group in particular has been installed in a myriad of ways to make 3 CF 3 coumarin derivatives (Figure 2 1). Ini tial examples include employing bis(trifluoroacetyl)peroxide with coumarins, and also treating 3 carboxylic acid coumarins with sulfur tetrafluoride (SF 4 ) (path a and b Figure 2 1 ). 34, 35 CF 3 SO 2 Na, was used with by Cao et al. combined wi th Mn(III) catalyst and peroxide to directly trifluoromethylate the 3 position in coumarin derivatives as a form of late stage C H activation via the CF 3 radical under mild conditions with moderate yields (path c Figure 2 1 ). 36
24 reagent was also shown to generate the CF 3 radical in the prese nce of various Cu catalysts. I n 2014 this approach was found suitable for the trifluoromethylation and cyclization from aryl 3 phenylpropiolates (path d Figure 2 1 ). 37 After our experimentatio n with the trifluoromethyl radical, via CF 3 SO 2 Cl and photoredox catalysis in 2015, specifically with aryl 3 phenylpropiolates, a publication from the Xiong group in 2018 showed this approach to be highly efficient with para substituted aryl 3 phenylprop iolates as well as other substrates, but Figure 2 1. Strategies for accessing 3 trifluoromethyl coumarins positions numbered
25 using a Ru(bpy) 3 Cl 2 as the photocatalyst (path e). 38 Concomitantly, another photoredox mediate d approach was published by Cai et al. in 2018 that utilized Ir(ppy) 3 instead. 39 Interestingly, there was a discrepancy with the structures reported for the Cu catalyzed approach in 2014 as compared to the recent photoredox catalyzed approaches. However the structure was unambiguously confirmed by X ray analysis in 2018 indicating their proposed mechanism was highly probably. In this work, w e seek to demonstrate our early attempts at optimizing the cyclization of 2 1a to afford the product 2 2a via photor edox catalysis, and discuss the results observed as well as the process by which our results were obtained. 2.2 Results and Discussion Initial investigation of the methodology with the standard s ubstrate, phenyl 3 phenylpropiolate ( 2 1a ), were conducted at room temperature for 18 hours with CF 3 SO 2 Cl in a nitrogen flushed vial using Ir(ppy) 3 (1 mol%) as photocatalyst with visible light, acetonitrile (MeCN) as solvent, and dibasic potassium phosphate (K 2 HPO 4 ) as base, to give the desired coumarin ( 2 2a ) in 1 2% yield, according to the crude 19 F NMR (Table 2 1, entry 1). These results indicated that the approach had potential, and attempts at optimizing the reaction conditions were performed. First we checked different photoredox catalysts, and a variety of solvents. Our preliminary results indicated that Cu(dap) 2 Cl was the best photocatalyst for the conditions attempted, with an 19 F NMR yield calculated at 22 % (Table 2 1, entry 3). Ru( 1,10 phen) 3 Cl 2 was the only other tested catalyst, and the first result of 12% conversion could not be improved upon (Table 2 1, entry 2). Next, we tested solvents like DCM, DCE, DMF, DMSO, THF and dioxane, but no improvements could be made. The temperature was increased in 10 C increments until the boiling point of MeCN was ec lipsed at 85 C, this resulted in a 30% yield calculated by 19 F NMR using trifluorotoluene as internal standard (Table 2 1, entry 4). As a final check, adding additional catalyst, 2.0 mol%, and using three total equivalents CF 3 SO 2 Cl gave the
26 best result at 55% (Table 2 1, entry 8). Increasing the quantity of catalyst, the amount of CF 3 SO 2 Cl, reaction duration, the type of light (blue LED), or temperature did not significantly improve the results. Notably, other CF 3 gave no appreciable amount of product when using these conditions. The reaction also showed no productivity when conducted without visible light irradiation. Table 2 1. Optimization of reaction conditions with CF 3 SO 2 Cl and phenyl 3 phenyl prop iolate. Having optimized the reaction conditions to the best of our abilities, using Cu(dap) 2 Cl, the substrate scope was evaluated using a variety of aryl 3 phenylpropiolates. We focused our attention on para substituted aryl 3 phenylpropiolates, being concerned about getting a mixture of regioisomers with different substitution patterns. Our standard substrate, 2 1a gave the desired product in 55% yield, matching the purified spectra with the literature (Figure 2 2). Substrate para bromophenyl 3 phenylpropiolate, 2 1b yielded 55% of 2 2b indicating halogens
27 could be well tolerated. Only 23% of 2 2c could be detect ed by 19 F NMR, indicating that electron rich substrates may not be beneficial to the reaction. Purified spectra could also be obtained for 2 2d for a calculated yield of 42%, showing that EWG substituents could be endured. Additional substrates were teste d, and while these examples were not isolated, they serve as anchors in furthering our understanding the reaction. The yields represent the observed singlet in the 19 F NMR. Both 2 1e and 2 1f indicated the product was formed in moderate yields of 40% and 42%, respectively, further implying that halogens are neutral substituents in this reaction. A strong electron donating group like methoxy, in 2 1g gave a relatively low yield of 33%, while 2 1h bearing a methyl group, performed much better at 52% conver sion. To end this Figure 2 2. Substrate scope of para substituted phenylpropiolates. Yields calculated using trifluorotoluene as internal standard in the 19 F NMR.
28 Figure 2 3. Expanded s ubstrate scope of para substituted phenylpr opiolates, products not isolated. Yields calculated using trifluorotoluene as internal standard in the 19 F NMR. series of substrates, 2 1i afforded the characteristic singlet at approximately 57ppm in the 19 F NM R, corresponding to a 47% yield. Based on the previously described mechanism, the ester migration may be hindered for electron rich substrates, while halogens and withdrawing substituents do not hinder this mechanistic step. In summary, the para substitute d aryl 3 phenyl propiolates gave low to moderate yields, with strong electron donating groups like methoxy hindering the reaction, and other substituents being tolerated satisfactorily otherwise. A meta substituted aryl 3 phenyl propiolate was also tested, OMe ( 2 1j ) (Figure 2 4). We anticipated the formation of multiple regioisomers, because of the asymmetry of the meta substitution pattern. Interestingly this was not observed for 2 1j Instead, a single signal in the 19 F NMR was detected, identified as 2 2j rather than the sterically hindered 2 3j product, for a calculated yield of 29%. Chen and coworkers did not report the meta methoxyphenyl 3 phenyl propiolate as one of their substrates, but they did obtain mixtures for
29 meta methyl and meta trifluoromethyl, with the less sterically hindered product predominating (2:1 and 1.5:1 ratios, respectively). 39 Figure 2 4. Meta substituted 3 phenylpropiolate affords a single regioisomer. Yields calculated using tr ifluorotoluene as internal standard in the 19 F NMR 2.3 Proposed Mechanism and Conclusion The proposed mechanism, as mentioned previously, is thought to proceed via a radical initiated cascade type reaction. In the context of CF 3 SO 2 Cl and photoredox catalys is in general, the reaction proceed s in a well established manner (Figure 2 5) First the photocatalyst is excited by a photon (1) whereby it reduces the CF 3 SO 2 Cl via a single electron transfer (SET) event (2) to l iberate SO 2 gas, chloride and the CF 3 radical. Next, the CF 3 radical attacks alpha to the carbonyl (3) to form the vinyl radical ( 2 3a ) as the pi bond of the alkyne breaks to form a new bond with the carbon of the trifluoromethyl group. The vinyl radical then can cyclize to the ipso position of the aryl ester in a 5 exo type event (4) to give the radical spiro intermediate ( 2 3b )
30 followed by SET (5) to regenerate the photocatalyst and produce the cation ( 2 3c ) This intermediate then rearranges via an ester migration (6) followed by deprotona tion (7) to give the Figure 2 5. Plausible photocatalytic mechanism for the formation of 3 CF3 coumarins. unexpected substitution pattern regioselectively for most substrates to afford the 3 CF 3 4 phenyl coumarins ( 2 2 ) 3 8 While we did not try to probe the generation of the CF 3 radical using a radical trap like TEMPO, the generation of the CF 3 radical was highly suggested as both groups utilizing photoreodox catalysts observed trace conversion, or no reaction when adding T EMPO to the reaction mixture. In conclusion, while this research endeavor did not have the desired end result in the form of a publication there was still a successful discovery of adding the trifluoromethyl radical to internal alkynes via photoredox catalysis. Additionally, the target skeleton of an important
31 bioactive compound was accessed with the CF 3 group adding to the desired position At the time that this experimentation was being conducted, no other reports ut ilizing photoredox catalysis had been revealed to generate the 3 CF 3 coumarins from 3 arylpropiolates Unfortunately, the existing methods to synthesi ze trifluoromethyl coumari ns have several advantages. Specifically, the alternative methods featured much higher yields, and more mild temperatures which are typically found to be strengths for photoredox procedures in general. This project also provided insight into the various li mitations one can encounter when optimizing a reaction, as well as what other goals one can make with respect to the information gathered during unsuccessful trials. 2.4 Experimental All reactions were carried out under N 2 atmosphere. All anhydrous solvent s were purchased from Aldrich and stored over 4 molecular sieves. Reagents were purchased at commercial quality and were used without further purification. All NMR spectra were run using CDCl 3 as solvent, unless otherwise specified. 1 H NMR spectra were re corded at 500 MHz or 300 MHz, and chemical shifts are reported in ppm rela tive to tetramethyl silane (TMS) 19 F NMR spectra were recorded at 282 MHz, and chemical shifts are reported in ppm relative to CFCl 3 as the external standard. 13 C NMR spectra were r ecorded at 125 MHz or 75 MHz with proton decoupling, and chemical shifts are reported in ppm relative to CDCl 3 (77.0 ppm) as the reference. The visible light was generated from a fluorescent light bulb (daylight GE Energy The 3 pheny l aryl propiolate substrates ( 2 1a thru 2 1 j ) were prepared with minor modifications to current li terature procedures (Figure 2 5) To a 25mL round bottom flask cooled to 0 C containing DCC (7.5mmol), and 10mL anhydrous DCM was added catalytic N,N d imethyl amino pyridine (DMAP) 1 10mol% depending on the ArOH used, followed by 3 phenyl propiolic acid (5 mmol). After mixing for 5 minutes, the desired substituted phenol was
32 added portion wise over 15 minutes (6mmol) and the reaction was allowed to warm to room temperature, stirring overnight. Once the reaction was completed, monitored by TLC, dilute HCl was added to wash the organic layer and remove the DCC based urea byproduct (10mL x3). After washing the organic layer with brine, the organic layer was drained and dried over MgSO4, before being subjected to silica gel column chromatography. The products were isolated using first a mixture of DCM, hexanes, and ethyl acetate (EA) (1:50:1) to remove the urea, then a more conventional ethyl acetate, hexanes mixture (1:10). After removing solvent, the compounds were found to be white solids. Figure 2 5. Synthesis of 3 phenyl aryl propiolates. General procedure for the formation of 3 trifluoromethyl courmarins from corresponding 3 phenyl arylpropiolates: To a nitrogen flushed vial containing a solution of a 3 phenyl arylpropiolates (0.1 mmol, 1 eq.) in MeCN (2 mL), was added Cu(dap)2Cl (0.003g, 2 mol%), potassium carbonate (0.2 mmol, 2 eq.) and trifluoromethane sulfonyl chloride (0.3mm ol, 3 eq.) at room temperature. The solution was then heated to 85 C and irradiated with visible light irradiation for 16 24 hours. The crude r eaction was then checked by 19 F NMR to determine crude yields (22 55%). To isolate the trifluoromethyl coumarin product, the solvent was removed, and the crude residue was diluted with DCM, then added directly to a silica gel column where a solvent system of EA and hexanes (1:20) was used to isolate the target compound as a yellow oil, or off white solid.
33 4 phenyl 3 (trifluoromethyl) 2H chromen 2 one (2 2a) 1 H NMR (300 MHz, CDCl 3 7.52 (m, 3H), 7.40 (d, J = 8.4 Hz, 1H), 7.27 7.24 (m, 2H), 7.21 (t, J = 8.1 Hz, 1H), 7.01 (d, J = 8.1 Hz). 19 F NMR (282 MHz, CDCl 3 57.5 (s, 3F). 7 bromo 4 phenyl 3 (trifluoromethyl) 2H chromen 2 one (2 2b) 1 H NMR (300 MHz, CDCl 3 7.49 (m, 3H), 7.32 (dd, J = 8.4, 1.8 Hz, 1H), 7.25 7.20 (m, 2H), 6.86 (d, J = 8.7 Hz, 1H). 19 F NMR (282 MHz, CDCl 3 57.5 (s, 3F). 4,7 diphenyl 3 (trifluoromethyl) 2H chromen 2 one (2 2c) 1 H NMR (300 MHz, CDCl 3 7.58 (m, 3H), 7.57 7.51 (m, 3H), 7.51 7.39 (m, 3H), 7.34 7.26 (m, 2H), 7.05 (d, J = 8.1 Hz, 1H). 19 F NMR (282 MHz, CDCl 3 57.3 (s, 3F). 2 oxo 4 phenyl 3 (trifluoromethyl) 2H chromene 7 carbonitrile (2 2d) 1 H NMR (300 MHz, CDCl 3 7.54 (m, 3H), 7.45 (dd, J = 8.4, 1.2 Hz, 1H), 7.26 7.23 (m 2H), 7.15 (d, J = 8.4 Hz, 1H). 19 F NMR (282 MHz, CDCl 3 57.9 (s, 3F ). 6 methoxy 4 phenyl 3 (trifluoromethyl) 2H chromen 2 one (2 2j) 1 H NMR (300 MHz, CDCl 3 7.52 (m, 3H), 7.35 (d, J = 9.3 Hz, 1H), 7.27 7.24 (m, 2H), 7.19 (dd, J = 9.3, 3 Hz, 1H), 6.41 (d, J = 3 Hz, 1H), 3.64 (s, 3H). 19 F NMR (282 MHz, CDCl 3 57.5 (s, 3F).
34 CHAPTER 3 THROUGH SPACE 19 F 15 N COUPLINGS FOR THE ASSIGNMENT OF STEREOCHEMISTRY IN FLUBENZIMINE 1 3.1 Introduction to Through Space Coupling and Flubenzimine The indirect, scalar couplings between NMR activ e nuclei are generally transmitted through the electrons of the covalent bonds, and therefore vanish rapidly with the increasing number of bonds on the pathway between the two coupling nuclei. The fact that the values of the spin spin coupling constants (S SCC) become in most cases very small after three bonds has been for a long time the basis of structure elucidation by NMR. In particular instances however, a large coupling can be seen between nuclei separated by more than three bonds. Such couplings have 40 Through space couplings occur when two atoms with lone pair orbitals are constrained at a distance smaller than the sum of their van der Waals radii. Mallory was the first to rationalize the origin of TS coupling by the mixing of the two lone pair orbitals from the two nuclei i nvolved in the coupling. 41 The resulting bonding and anti bonding orbitals are both occupied, therefore no chemical bond is formed, nevertheless their electrons convey the spin state information from one nucleus to the other. The magnitude of the TS SSCC d epends not only on the distance between nuclei, but also on the orientation of the orbitals involved in the the coupling mechanism and for the quantitative estima tion of TS SSCCs have been proposed, and this is still an active field of investigation. 42 The first observations of TS couplings were between 19 F nuclei; nowadays the examples encompass various pairs of the 19 F, 15 N, 31 P, 77 Se 1 Reprinted (adapted) with permission from (Ghiviriga, I.; Rubinski, M.A.; Dolbier, W.R., Jr. Magn. Reson. Chem. 2016, 54 592.) Copyright 2016 John Wiley & Sons, Ltd.
35 125 Te nuclei. Transmission pathways other than two overlapping lone pair orbitals have been identified, notably the overlap of a lone pair orbital with an occupied bonding orbital, which explains the TS coupling between 19 F and 13 C or 1 H. 43 Figure 3 1. Ambiguous Flubenzimine structure with position numbering T hrough space couplings have been mostly a field of purely theoretical interest, however there is an earlier study where the 19 F 19 F TS couplings in 19 F labeled amino acids were used for the el ucidation of the folding of a protein. 44 In this work we demonstrate the usefulness of the 19 F 15 N TS coupling in the assignment of the stereochemistry of a small molecule, Flubenzimine. Flubenzimine is a mite growth regulating acaricide patented by Bayer in 1972 [DE2210882] and produced under the trademark of Cropotex. The stereochemistry of flubenzimine has never been determined; therefore the structure is commonly represented with ambiguous stereochemistry (Figure 3 1). 3.2 Results and Discussion A Mole cular mechanics (MM2) calculation provides the energies of six of the more stable configurations of Flubenzimine (Figure 3 2). The other two possbilities having the two trifluoromethyl groups facing each other, are too high in energy. An attempt to measure the chemical shifts of N4 and N5 in a 19 F 15 N Heteronuclear Multiple Bond Correlation ( gHMBC ) experiment revealed that one of the nitrogens couples with the fluorines in both of the trifluoromethyl groups, implying a coupling over two bonds and a
36 coupling over five bonds. The latter is a through space 19 F 15 N coupling, possible only in the structures where a trifluoromethyl group on a nitrogen is facing the lone pair of the other, like Figure 3 2. Possible configurations for flubenzimine. 3 1a 3 1b 3 1d and 3 1f where the distance between the nitrogen and the fluorine five bonds away is somewhere between 2.84 Angstroms () for the lone pair intercalated between two fluorines and 1.95 for the l one pair eclipsing one fluorine, in both cases smaller than 3.02 , the sum of the van der waals radii of the nitrogen (1.55 ) and fluorine (1.47 ). 45 Further NMR investigations, described next, limited the possible structures to 3 1a and 3 1b A 1 H 15 N gHMBC experiment revealed that the phenyl with the ortho protons at 7.02 ppm is on the nitrogen at 278.3 ppm, and that the phenyl with the ortho protons at 7.69 ppm is on the nitrogen at 159.5 ppm. These chemical shifts allowed the assignment of the nitr ogens as N2 and N3, correspondingly. The protons at 7.69 ppm display in a gHMBC experiment optimized
37 for a coupling constant of 3 Hz a coupling with the carbon at 154.7 ppm. This carbon displays a cross peak with the fluorines at 49.2 ppm in a 19 F 13 C gHMBC spectrum, therefore it is C4 and not C2. It is this trifluoromethyl on N4 that also couples with N5, therefore the structure is one of 3 1a and 3 1b At this point N4 and N5 can be assigned, as N5 is the nitrogen that couples with both triflorometh yl groups. The 2 J NF coupling constants, measured as descibed further, confirm the assignment, being around 20 Hz, a value expected for a 2 J F C N coupling. 46 The complete chemical shifts assignments were found and compiled (Figure 3 3). Figure 3 3. 1 H, 19 F 13 C and 15 N chemical shifts assignment in Flubenzimine. The 19 F 13 C couplings have been measured in the 13 C spectrum: 1 J = 255.8 Hz, 1 J = 262.9 Hz, 3 J F4C4 = 8.2 Hz and 3 J F5C5 = 8.6 Hz. A nuclear Overhauser effect ( nOe ) between the protons of the phenyl on N2 and those of the phenyl on N3 would be expected for both 3 1a and 3 1b The initial buildup rate of the nOe however can be used to estimate the distance between these proton. A molecular dynamics simulation at 298 K for 50 ps with a stepsize of 0.001 ps for both 3 1a and 3 1b yielded average thru space distances (r3) value s, r 3 a = 4.14 and r 3 b = 3.07 . In conformationally labile molecules the average distance will be always underestimated using calculations related to the r3 values, therefore the conformation of Flubenzimine is 3 1a
38 Measurement of the 19 F 15 N couplings is challenging because of the low natural abundance of 15 N. Indirect detection methods offer an increase in signal to noise over direct observation of 15 N of 306 times for polarization transfer from 1 H and 263 times for polarization transfer from 19 F. Onl y one however, of ca. 100 19 F 15 N coupling constants given in the literature, was measured by an indirect detection method. 46 For polarization transfer from protons to work, the molecule should have some protons coupling with a fairly large coupling consta nt with the nitrogen of interest. This is not always the case, and Flubenzimine is an example. On the other hand, indirect detection probes on which the high band channel can be tuned on 19 F and the low band on 15 N are not common. The conformation of Flub enzimine was found to be 3 1a using TS 19 F 15 N SSCCs and nOe initial buildup rates. TS 19 F 15 N SSCCs are a valuable tool in stereochemical assignment. They can be measured at natural abund ance with spin state selective indirect detection methods. As 15 N l abelled proteins are routinely synthesized for NMR studies, TS 19 F 15 N SSCCs have the potential to probe the stereochemistry of these proteins by 19 F labelling of some amino acids, or can reveal the site of docking of fluorine contaning drugs. 3.3 Expe rimental Section Flubenzimine was purchased from Aldrich as a viscous liquid and was dissolved in acetone d6 ca 100 mg in 0.8 ml. All of the spectra were run at at 25 C. MM2 calculation were conducted using HyperChem 8.0. The NMR experiments were run on a Varian Inova 3 RF channel spectrometer, operating at 500 MHz for proton. The probe was an indirect 5 mm triple resonance probe, with z axis gradients, and with the high band chanel tunable in the range 1 H 19 F, a 13 C channe l, and a low
39 band chanel tunable in the range 31 P 15 N. The 90 pulses were 5.9 s for 19 F and 24.1 s for 15 N. The chemical shifts are reported in ppm and referenced to tetramethylsilane for 1 H and 13 C, to fluorotrichloromethane for 19 F and to liquid amm onia for 15 N, using the values from the IUPAC recommendations. 54
40 CHAPTER 4 DIRECT ACCESS TO 2 CF 2 H INDOLES VIA PHOTOREDOX CATALYSIS 4 .1 Introduction to Targeted Fluoroalkylation of Indoles Inspired by the enhancement of properties such as lipophilicity, bioavailability, and metabolic stability, chemists have developed numerous methodologies to install fluoroalkyl moieties, especially the trifluoromethyl and difluoromethyl groups. 3 These enhancements are being explored in fields like pharmac euticals, agrochemic als, and even novel materials The expansion of possibilities for realizing direct trifluoromethylation has increased significantly within the last two decade s especially with respect to aromatic and hetero aromatic substrates 47 The C F 2 H group has also seen impressive development, but the need for more general methods to access a similar breadth of compounds as seen for trifluoromethylation is apparent. The CF 2 H group is especially popular as it has hydrogen bond donating capabilities similar to an alcohol or amine, while still bestowing beneficial pharmacological properties like other perfluoroalkyl groups. 48 The desire to install different fluoroalkyl groups into heterocyclic structures has been the goal of many recent publications. 49 Indoles are a class of heterocycle that are widely present in bioactive natural products, as well as pharmaceuticals as a result of established activities like aiding with central nervous and cardiovascular system diseases, antimitotic therapies, anti in flammatory, antidepressant, as well as being an effective option for the treatment of various bacteria and viruses (Figure 4 1) 50 Additionally, indole derivatives containing fluorine atoms, trifluoromethyl groups, or other fluoroalkyl groups have shown pr omise in their own right as potent pharmaceuticals. 50 Direct and indirect access to 2 and 3 CF 3 indole derivatives has been accomplished using a variety of copper mediated, transition metal catalyzed, and photoredox catalyzed approaches. 51, 52 Installing
41 Figure 4 1. Representative pharmaceutical indole derivatives. Adapted from Ref. 50. a variety of other fluoroalkyl groups into the indole substructure has also been accomplished using a copper mediated apporoach. 53 However reports for the generation of d ifluoromethyl indole s are significantly less prevalent in the literature, especially on 3 substituted indoles bearing unprotected amines. One difficulty in utilizing previously established fluoroalkylation strategies for an alogous difluoromethylation reactions is that the reactivity of the intermediates necessary to accomplish the desired products have different properties. 54 Copper complexes that are suitable for generating relatively stable and isolabl 3 tes are more challenging to gene 2 report s being available. 52d, 55 Additionally, the CF 2 H radical is relatively nucleophilic as compared to other CF 2 R radicals, like the CF 3 CF 2 CO 2 Et, CF2CF 2 R, and CF 2 Cl. 56 As a result, predicting the regiochemistry by using the same method to generate each fluoroalkyl radical is unlikely. Excluding pathways that
42 involve direct fluorination of a carbonyl to gain access to the CF 2 R moiety, the options are relatively limited (Figure 4 2 ). In 2004, Konno and coworkers demonstrated the intermolecular annulation of 2 iodoanilines with internal alkynes bearing CF 3 and CF 2 H groups to furnish 2 and 3 fluoroalkyl indoles using different Pd catalyst to control the regiochemistry (a Figure 4 2 ). 57 Next, in 2007 Wang et al. first synthesized 2 benzyl bromide N aryl difluoromethyl imidoyl chlorides in order to access the 2 CF 2 H indoles via an intramolecular Grignard attack (b Figure 4 2 ). 58 Two separate reports of direct ethoxycarbonyldifluoromethyl ation of alkenes and he terocycles were reported by Lin et al. in 2013, and then by Jung in 2014, both using photore dox catalysis ethyl bromodifluoro acetate (c Figure 4 2 ). 59, 60 While neither group focused on indoles, there were several examples synthesiz ed by both groups especially 3 methyl 1H indole Further utili zation of the ethyl bromodifluoro acetate as a precursor to the difluoromethyl group was achieved by Guan et al. in 2015 via a Pd(PPh 3 ) 4 catalyzed approach using XantPhos as a ligand for regiose lective ethoxycarbonyl difluoromethylation of several electron rich 3 and 5 substituted indoles (d Figure 4 2 ). 61 Copper catalyzed methods were then developed by the Shi group, with the utilization of N substituted indoles for regiocontrol being a novel strategy in substrates containing a substituent in the 3 position, or being unsubstituted apart from the N directing group, for another example of difluoroalkylation (e Figure 4 2 ). 62 Ba sed on our recent publications related to the pairing of photoredox catalysis and fluoroalkylation, and the need for the development of direct difluoromethylation strategies, we sought to take advantage of the mild reaction conditions provided by photoredox with respect to synthesizing 2 CF 2 H indoles. 63 This work is, to th e best of our knowledge, the first report of direct regioselective difluoromethylation of indoles using photoredox catalysis.
43 Figure 4 2. M ethodologies to synthesize CF2R indoles.
44 4 .2 Results and Discussion Initially, we sought to determine which difluoromethyl radical source would be suitable for the regioselective difluoromethylation of indoles using photoredox catalysis. To this end, we tested three common CF 2 H radical precursors, CF 2 HSO 2 Cl, difluoromethane sulfonyl benzothiazole (CF 2 HSO 2 BOT), and difluoromethyl triphenylphosphonium bromide (CF 2 HPPh 3 Br). To our tentative satisfaction we detected the desired 2 CF 2 H indole 4 2a using eit her CF 2 HSO 2 Cl or CF 2 HPPh 3 Br in 34% and 39% yie lds, respectively, using 3 methyl 1H indole 4 1a as the standard substrate with Ir(ppy) 3 Na 2 CO 3 as an additive, and acetonitrile as solvent (Table 4 1, entry 1). Next, we subjected the discovery to an optimization protocol by varying the photocatalyst, solvent, and additive. The alternative photocatalysts that were screened proved ineffective, shown in Figure 4 3, providing little to no reactivity in most cases such that Ir(ppy) 3 was determined to be t he best option moving forward (E ntries 2 7). Then a v ariety of solvents like DMF, DMSO dioxane, DCE and acetone were evaluated, and only acetone s howed an improvement in yield at 44%, Entry 13 ( Entries 8 13 ). Typically with highly polar solvents like DMF and DMSO, there was a significant mixture of product based on the crude 19 F NMR. These byproducts were also observed when adding an excess, 3 6 equivalents of CF 2 H source, as well. Having an optimized photocatalyst and solvent combination, we then examined the effectiveness of different additives on the cour se of the reaction ( Entries 14 21 ). Using a weak base, NaHCO 3 proved to be beneficial to the reaction, giving our best yield at 53% suggesting the phosphonium may be sensitive to stronger bases. Using an organic base like Et 3 N or a cocatalys t like Cu(OA c) 2 did not improve the reaction with trace product being formed in both cases (E ntries 20 21 ). We also attempted to optimize the reaction when using CF 2 HSO 2 Cl as the difluoromethyl radical source, achieving a competitive yield of 41% when using dioxane as solvent (Entry 22). Further attempts at optimizing the use of CF 2 HSO 2 Cl were
45 Table 4 1. Optimization of reaction conditions for the difluoromethylation of indoles ended, as CF 2 HPPh 3 Br has several advantages, such as s implistic production of multigram quantities, and the relative ease of handling it as a bench stable solid. Difluoromethanesulfonyl chloride is not easily synthesized as it requires a difficult reaction set up, a tedious distillation, and is isolated as a liquid that is air and moisture sensitive as well as a potent lachrymator.
46 Satisfied with our optimized conditions we then wanted to expand the substrate scope, starting with varying the substituent in the 3 position (Figure 4 4 ). Figure 4 3. Photocatalysts tested. Our s tandard substrate 3 Me indole, 4 1a gave th e corresponding 2 CF 2 H indole, 4 2a in 53% yield according to the crude 19 F NMR. Subsequent substrates were tested with differing para substituted phenyl groups in the 3 position, with only halogens, alkyl and methoxy
47 derivatives giving moderate to good yields (compounds 4 2b through 4 2f ). Phenyl groups with para EWG were not well tolerated under these conditions and consequently were not extensively screened but 3 (4 nitrophenyl) indole ( 4 1g ) was found to yield 17% of the desired product ( 4 2g ) When the substituent was a withdrawing group like 3 carboxyaldehyde indole the observed yield was 35% (compound 4 2h ). Switching the substituent to a heteroatom like 3 (4 chlor ophenyl)thio indole, 4 1i also did not improve the yield giving only 28% yie ld of the product (compound 4 2i ). Finally, with no modification to th e indole structure we found 4 1j to react well with high conversion at 53%, however this resulted i n a mixture of several products, with the desired compound being isolated in 15% yield (compound 4 2j ). Thin layer chromatography indicated that the unreacted substrates could be recovered, as well as the PPh 3 byproduct. Other indoles bearing no substituen t on the 3 rd position were tested (not described), and the results indicated that the reaction benefits immensely from both the directing effecting of that position being blocked, as well as the stabilizing effect that a substituent would have on the inter mediates produced during the course of the reaction. Overall, the reaction works best with electron rich substituents in the 3 positio n, and tolerates a variety of substituents, albeit in low to moderate yields. Next, we explored the impact of varyin g the substituent on the benzo portion of the indole structure, with an emphasis on the 5 th position (Figure 4 5 ). Interestingly, the yield of 3 phenyl 5 methoxy indole ( 4 1l ) have a lower yield than anticipated at 37% for compound 4 2l This could possibly be d ue to the increased basicity of the indole thus interfering with the generation of the CF 2 H radical by reacting counterproductively with the phosphonium. Substrates 4 1k and 4 1l gave the corresponding 2 CF 2 H indole in moderate yields of 49% and
48 Figure 4 4 Substrate scope 3 substituted indoles. Crude yields were calculated using 19 F NMR with trifluorotoluene as an internal standard. Isolated y ields in parentheses.
49 43% respectively. Finally, Substrate 4 1m bearing, 4, 6 dichloro 3 phenyl indole, also worked well with a similar yield observed as other halogen containing substrates (42%, 4 2m ). Interestingly, 5 nitro 3 phenyl indole, 4 1n afforded better reactivity when compared to the 3 Figure 4 5. Substrates tested with differing substituents on the benzo portion of indole C rude yields calculated using 19 F NMR and trifluorotoluene as an internal standard Isolated yields in parentheses. p ara nitro phenyl indole, 4 1g most likely a result of the the 5 th position not heavily destabilizing any radical or cationic intermediates formed with the charge in the 3 rd position, as opposed to the para substituted phenyl being directly conjugated with this position (17% vs.
50 31% yi eld, 4 2n and 4 2g respectively). Overall, the substituents on the benzo portion of the indole are well tolerated, giving moderate yields overall. Protecting groups on the indole nitrogen were not extensively screened, however N Ac 3 Me indole, 4 1p provi ded the desired compound in 56% yield. We tested the viability of other N based substituents with 3 Me and 3 Ph indoles, with other carbonyl based protecting groups like Boc ( 4 1q ) and Bz ( 4 1r ) giving 41% and 43% yield, respectively, referring to the m ain peak detected in the crude 19 F NMR. We also tested N Bn 3 Me indole ( 4 1s ), giving a reasonable yield for a major product in the crude 19 F NMR of 31%. Unfortunately these examples were not isolated to confirm their structures, but the crude 19 F NMR indicated significant conversion of one major regioisomer, similar to 4 2p presumably the desired product. These results indicate that the reaction is able to tolerate N protected indoles with a preference for EWGs being apparent. Interestingly, 2 M e indole ( 4 1t ) proved to be relatively unreactive, giving only trace signals in the crude 19 F NMR This result reaffirms the relatively nucleophilic CF 2 H radical will prefer the electron deficient 2 position, which is a significant contributor to the LUMO based on a recent computational and experimental report. 52c The 4 th and 7 th positions were found to also be significant contributors to the LUMO of indole structures. Several other substrates were tested in order to establish some generality between indo les and other heterocycles. Specifically, 1,3 benzofuran ( 4 1u ) was screened, and found to give a major produc t in 26% yield, based on the 19 F NMR, with a complex mixture of side products being formed as well. Next, we tested benzimidazole ( 4 1v ) and found very poor reactivity, resulting in a low yield of 16% for one major product, possibly due to the basicity inherent to benzimidazoles relative to indoles.
51 Figure 4 6. N protected indole example. C rude yields calculated us ing 19 F NMR and trifluorotoluene as an internal standard Isolated yields in parentheses. Figure 4 7. Other substrates screened Crude yields calculated using 19 F NMR and trifluorot oluene as an internal standard. 4.3 Mechanism and Conclusion A plausible reaction mechanism for photoredox mediated radical addition to indoles is well established in the literature (Figure 4 8). First, the photocatalyst is excited by visible light irradiation (1) whereby it reduces the difl uoromethyl triphenylphosphonium via a single electron transfer process (SET) generating the CF 2 H radical, and triphenyl phosphine as a byproduct (2) The CF 2 H radical can then add regioselectively (3) to the 2 position of the starting indole ( 4 1 ) formi ng a highly stabilized radical ( 4 3 ). The photocatalyst can then be regenerated by SET transfer (4) from the intermediate tertiary radical ( 4 3 ), thus oxidizing t he indole to the corresponding cation ( 4 4 ). Finally, the cationic intermediate can be deproton ated (5) to afford the 2 CF2H indole ( 4 2 ).
52 Figure 4 8. Plausible mechanism for the photoredox difluoromethylation of indoles. Several experiments were conducted to increase our confidence in the proposed reaction mechanism (Table 4 2). First, we conducted the reaction in complete darkness, resulting in no reaction occurring (entry 1). Then, we added TEMPO, a radical scavenger, and the corresponding TEMPO CF 2 H adduct could be detected in 54% yield ( 4 5 ), as well as 22% of the product, 4 2a suggesting the production of the CF 2 H radical (entry 2). We also tested the reaction by irra diating the reagents without any photocatalyst, which afforded no product,
53 however the difluoromethyl source mostly decomposed (entry 3). These results indicate that the proposed mechanism is both reasonable, and highly likely given the need for photocatalyst, visible light irradiation, and the formation of 4 5 which is formed by trapping the CF 2 H radical. Table 4 2. Mechanistic investigati ons. In conclusion, we have developed the first report of photoredox mediated regioselective direct difluoromethylation of 3 and 3, 5 substituted indoles. This methodology is useful as it does not require and protecting or directing groups on the indole nitrogen, but these substituents can be tolerated if desired. Additionally, the reaction utilizes the easily synthesized CF2HPPh3Br, does not require expensive additives, and uses benign solvents as well as ambient tempera tures. The PPh 3 produced in the reaction can be recovered from the column post reaction, and the unreacted substrates can also be recovered, reaffirming the minimal production of alternative regioisomers indicated by the crude 19 F NMR. This reaction also r epresents a late stage functionalization of readily synthesized substrates to afford the corresponding 2 CF 2 H indoles, which is beneficial when compared to other routes the 2 CF 2 H indoles that require
54 multistep synthesis of substrates, high reaction temper atures, high catalyst loading, and can require the formation of the difluoromethyl unit post reaction. Moderate yields, and lacking generality in terms of substrate electronics and substitution patterns are both drawbacks, but these results are promising f or direct synthesis of biologically active indole derivatives bearing a difluoromethyl group in the 2 position. 4. 4 Experimental Data All reactions were carried out under N 2 atmosphere. All anhydrous solvents were purchased from Aldrich and stored over 4 molecular sieves. Reagents were purchased at commercial quality and were used without further purification. All NMR spectra were run using CDCl 3 as solvent, unless otherwise specified. 1 H NMR spectra were recorded at 500 MHz or 300 MHz, and chemical shifts are reported in ppm relative to TMS. 19 F NMR spectra were recorded at 282 MHz, and chemical shifts are reported in ppm relative to CFCl 3 as the external standard. 13 C NMR spectra were rec orded at 125 MHz or 75 MHz with proton decoupling, and chemical shifts are reported in ppm relative to CDCl 3 (77.0 ppm) as the reference The photocatalyst f ac tris(2 phen ylpyridinato) iridium(III) (Ir(ppy)3) was synthesized using a modified report from th e literature. 64 Iridium (III) chloride hydrate (0.65 g 2.18 mmol, 1.0 equiv) 2 phenylpyridine (3.74 mL, 26.1 mmol, 12.0 equiv) sodium carbonate (2.7 g, 6 eq.), and 0.65 L of DI water (0.003 M with respect to IrCl 3 ) is added t o a 1 L Parr reactor (Figur e 4 8). The reaction mixture is pressurized with argon (10.0 psi), stirred and then depressurized three times, and finally charged again wi th argon before sealing The reaction mixture is heated to 225 C for 56 h. Then the reactor is cooled to room temper ature, and carefully vented using the valve attachments After cooling and venting the reactor is opened revealing an insoluble yellow solid on the surfaces and dispers ed in the aqueous phase All contents are transferred slowly to a 6 L separatory funnel aided by a large 5 cm glass funnel. Then the interior of the reactor is
55 mechanically scraped (to extract the yellow material), wi th metal tongs, cotton balls (10 in total), and 500 mL of dichloromethane (DCM) from a spray bottle, and again all contents ar e added to the se paratory funnel Figure 4 9. Synthesis of fac Ir(ppy) 3 While still in the funnel, the cotton is rinsed with 25 mL of DCM from a spray bottle and evenly pressed with tongs to release the yellow material fr om the cotton After removing the cotton, the solution is then diluted with 1 .5 L of DCM. The separatory funnel is shaken vigorously, allowed to settle and again shaken, and the organic layer is then slowly separated from the aqueous layer and the aqueous layer is further extracted with more DCM (3 x 10 0 mL), and the organ ic layers are combined The combined organic layer is washed with a 1 M HCl solution, with vigorous mixing prior to separation (3 x 900 mL). Each HCl wash is then back extracted with DCM ( 3 x 10 0 mL) to insure complete recovery of the product. After the final wash, the organic layer is filtered slow ly (20 min) through a Celite (50 g) pad on top of a large Buchner funnel into a 3 L Erlenmeyer flask, and then dried with 30 g of MgSO4. After filtering the drying reagent using a 1 L round bottom flask, the solvent is evaporated and the flask refilled until all of the solvent is removed, ultimately transferring the solvent into a 100mL pear shaped flask to transfer into the column. The column is eluted with DCM and hexanes (1:1) to afford 0.45 g (32 %) of Ir(ppy)3 as a bright yellow solid. The resulting solid was then checked using H1 NMR, and found suitable for use, after being tested in several reaction. The catalyst should be stored in a dark v ial, at room temperature or in a freezer.
56 (Difluoromethyl)triphenylphosphonium bromide was synthesized according to a known literature procedure with minor modifications (Figure 4 9). 65 First, potassium hydroxide (4.03 g, 71.7 mmol, 1.00 equiv) was dissolv ed in MeOH (70 mL) at 0 C. Ethyl bromo 2 ,2 difluoroacetate (9.48 mL, 15.0 g, 71.7 mmo l, 1.00 equiv) was added slowly to the reaction mixture at 0 C in a tared 500mL round bottom flask The reaction mixture was slowly allowed to warm up to rt overnight, the solvent was removed under reduced pr essure, and the resulting solid was rinsed with hexanes (50mL x 3) to help remove all volatiles. The corresponding acetate salt, potassium 2 bromo 2,2 difluoroacetate, was obtained as a white solid, assuming full con version based on the tared mass difference. Next, in the same round bottom flask, was added triphenyl phosphine (1.0 eq.), and the solids were dissolved in DMF after stirring for 1 hour (80mL). After stirring overnight, a solid is formed, and is filtered off onto a Buchner funnel, rinsed with cold DMF (20mL x 1), water (20mL x 20mL), and Et2O (20mL x 3), to afford the corresponding zwitterion, 2,2 difluoro 2 (triphenylphosphonio) acetate, as a white solid (11.7g) Finally, to a new RBF is added the zitte rion from the previous step, and is dissolved in THF (3mL/ g of starting material). To this suspension, 1.2 equivalents of 48% HBr is added (0.4mL/ g of starting material) and the reaction mixture was refluxed for 2h. The reaction was quenched by adding 10 mL of water, and the volatiles are then removed via rotoevaporation to afford a residue. The residue is then dissolved in DCM, which partitions into two layers, and washed with additional water twice. After drying the organic layer with MgSO4, the solvent was removed using rotoevaporation, affording a sticky off white solid. Suspension of this solid in THF, followed by vacuum filtration using a sintered glass funnel and furthering rinsing with THF afford the desired compound as an off white solid in an over all yield of 8.8g (42%).
57 Figure 4 10. Synthesis of difluoromethyl phosphonoum bromide Phenyl acetaldehyde was purchased from Sigma Aldrich and used without further purification. All other aryl acetaldehydes were synthesized according to a reported general procedure from the corresponding 2 aryl ethanols, and modified as needed (Figure 4 10) To a RBF containing the desired 2 aryl ethanol (10mmol) was added dry MeCN (25mL), and cooled to 0 C. Once the reaction mixture was cooled, 1.5 3.0 eq. of Des Martin Periodinane reagent was used. The reaction was monitored using TLC, and once complete w as quenched with a solution of NaHCO3 (10%). The organic layer was then washed with aqueous Na2SO3 (10%), dried over MgSO4, filtered, and solvent rotoevaporated. The crude NMR was checked to determine if a column would be necessary. The corresponding aldeh ydes were isolated as viscous pale yellow oils. Yields range between 10% and 70%. Figure 4 11. Synthesis of aryl acetaldehydes.
58 Indole substrates 4 1a 4 1h and 4 1j were acquired commercially from Sigma Aldrich and used without further purification. Indole substrates 4 1b thru 4 1g and 4 1k thru 4 1o were synthesized via the Fischer Indole synthesis according to a general procedure (Figure 4 11).To a RBF containing the desired 1 aryl hydrazine hydrochloride salt (5.0 mmo l), was added absolute ethanol (20mL) followed by the desired aryl acetaldehyde (6.0 mmol) and a catalytic amount of pTsOH (10%) and allowed to stir for 1hr at room temperature. A full equivalent of pTsOH (5.0mmol) was then added to the reaction mixture, a nd the heating was increased to reflux EtOH overnight. The ethanol was then rotoevaporated, and the resulting crude residue was quenched with aqueous NaHCO3 (10%), and the aqueous layer was then extracted with ethyl acetate (50mL x 3). Upon removing the or ganic solvent, the crude residue was subjected to column chromatography, and the corresponding indole was isolated after carefully eluting with a gradient solvent system of hexanes and EA (200:1 to 50:1). The isolated indoles were usually isolated as off w hite or brown solids. Figure 4 12. Synthesis of indole substrates. General method: To an oven dried 17 60 mm (8 mL) borosilicate vial equipped with a magnetic stirrer were added 0.004 mmol (2.8 3.6 mg, 2.0 mol%) Ir(ppy)3, 0.2 mmol (26.2 mg) of 3 Me 1 H indole (4 1a), 0.4 mmol (32mg, 2.0 eq.) of NaHCO3, 0.4mmol (160mg, 2.0 eq.) of CF2HPPh3Br, and 2mL of acetone. The vial was then flushed with nitrogen, and sealed. The reaction mixture was stirred under Blue LED ligh t at room temperature for 18 24h. Subsequently
59 the solvent was removed, and the residue was diluted with DCM and added directly to a chromatographic column for purification with silica gel, using hexanes and ethyl acetate as the eluent (100:1). The product 4 2a was obtained as an off white solid (14.1mg, 39% isolated yield). Figure 4 13. Representative 1 H NMR spectrum of 3 (4 chlorophenyl) 2 (difluoromethyl) 1 H indole Figure 4 14. Represen tative 13 C NMR spectrum of 3 (4 chlorophenyl) 2 (difluoromethyl) 1 H indole
60 Figure 4 15. Representative 19 F NMR spectrum of 3 (4 chlorophenyl) 2 (difluoromethyl) 1 H indole 2 (difluoromethyl) 3 methyl 1 H indole (4 2a) 1 H NMR (500 MHz, CDCl 3 1H), 7.29 (t, J = 8 Hz, 1H), 7.16 (t, J = 8 Hz, 1H), 6.94 (t, J = 51.2 Hz, 1H), 2.39 (s, 3H). 13 C NMR (126 MHz, CDCl 3 119.9 (s), 119.7 (s), 109.9 (t, J = 234.6 Hz), 111.5 (s), 8.2 (s). 19 F NMR (282 MHz, CDCl 3 110.7 (d, J = 54.4 Hz, 2F). 2 (difluoromethyl) 3 phenyl 1 H indole (4 2b) 1 H NMR (300 MHz, CDCl 3 7.41 (m, 6H), 7.48 (d, J = 7.5 Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 6.79 (t, J = 54 Hz, 1H). 13 C NMR (126 MHz, CDCl 3 20.9 (s), 120.6 (s), 110.7 (t, J = 233Hz), 111.8 (s). 19 F NMR (282 MHz, CD Cl 3 108.3 (d, J = 53.6 Hz, 2F). 2 (difluoromethyl) 3 (4 methoxyphenyl) 1 H indole (4 2c) 1 H NMR (300 MHz, CDCl 3 (t, J = 8.1 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H) 7.06 (d, J = 8.7 Hz, 2H), 6.78 ( t, J = 54 Hz, 1H), 3.89
61 (s, 3H). 13 C NMR (126 MHz, CDCl 3 (s), 1 24.6 (s), 114.4 (s), 110.2 (t, J = 233 Hz), 111.7 (s), 55.4 (s). 19 F NMR (282 MHz, CDCl 3 ) 108.2 (d, J = 53.6 Hz, 2F) 3 (4 bro mophenyl) 2 (difluoromethyl) 1 H indole (4 2d) 1 H NMR (300 MHz, CDCl 3 Hz, 1H), 6.75 (t, J = 54 Hz, 1H). 13 C NMR (126 MHz, CDCl 3 131.2 (s), 126.2 (s), 124.9 (s), 121.6 (s), 121.2 (s), 120.3 (s), 111.9 (s), 109.9 (t, J = 234 Hz). 19 F NMR (282 MHz, CDCl 3 108.3 (d, J = 53.6 Hz, 2F). 3 (4 chlorophenyl) 2 (difluoromethyl) 1 H indole (4 2e) 1 H NMR (300 MHz, CDCl 3 (m, 5H), 7.37 (t, J = 7.5 Hz, 1H), 7.22 (t, J = 7.8 Hz, 1H), 6.76 (t, J = 54 Hz, 1H). 13 C NMR (126 MHz, CDCl 3 ) 118.7 (s), 111.9 (s), 109.9 (t, J = 234 Hz). 19 F NMR (282 MHz, CDCl 3 108.3 (d, J = 53.6 Hz, 2F) 2 (difluoromethyl) 3 (p tolyl) 1 H indole (4 2f) 1 H NMR (300 MHz, CDCl 3 7.40 (m, 3H), 7.37 7.30 (m, 4H), 7.20 (t, J = 7.8 Hz, 1H), 6.78 (t, J = 53.6 Hz, 1H), 2.44 (s, 3H). 19 F NMR (282 MHz, CDCl 3 108.2 (d, J = 53.6, 2F). 2 (difluoromethyl) 3 (4 nitrophenyl) 1 H indole (4 2g) 1 H NMR (300 MHz, CDCl 3 7.67 (m, 3H), 7.53 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 8.1 Hz, 1H), 7.27 (dt, J = 8.1, 1.2 Hz, 1H), 6.78 (t, J = 53.6 Hz, 1H). 13 C NMR (126 MHz, CDCl 3 30.0 (s), 125.8 (s), 125.2
62 (s), 124.3 (s), 121.8 (s), 120.0 (s), 111.4 (s), 109.5 (t, J = 235 Hz). 19 F NMR (282 MHz, CDCl 3 108.5 (d, J = 53.6 Hz, 2F). 2 (difluoromethyl) 1 H indole 3 carbaldehyde (4 2h) 1 H NMR (300 MHz, DMSO d 6 7.74 (t, J = 53.6 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.39 7.26 (m, 2H). 13 C NMR (126 MHz, DM SO d 6 113.4 (s), 109.9 (t, J = 236 Hz). 19 F NMR (282 MHz, CDCl 3 113.1 (d, J = 53.9 Hz, 2F). 3 ((4 chlorophenyl)thio) 2 (difluoromethyl) 1 H indole (4 2i) 1 H NMR ( 300 MHz, CDCl 3 1H), 7.37 (t, J = 8.1 Hz, 1H), 7.24 7.13 (m, 3H), 7.1 (t, J = 53.7 Hz, 1H), 7.0 6.9 (m, 2H). 13 C NMR (126 MHz, CDCl 3 27.7 (s), 125.3 (s), 121.8 (s), 120.3 (s), 112.2 (s), 111.1 (s), 109.0 (t, J = 283 Hz). 19 F NMR (282 MHz, CDCl 3 111.7 (d, J = 53.6, 2F). 2 (difluoromethyl) 1 H indole (4 2j) 1 H NMR (300 MHz, CDCl 3 8.1 Hz, 1H), 7.29 (t, J = 8.1 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 6.84 (t, J = 55.5 Hz, 1H), 6.76 (s, 1H). 19 F NMR (282 MHz, CDCl 3 110.5 (d, J = 55.3 Hz, 2F). 2 (difluoromethyl) 5 methoxy 3 phenyl 1 H indole (4 2k) 1 H NMR (300 MHz, CDCl 3 ), 7.66 7.36 (m, 7H), 7.12 (d, J = 9 Hz, 1H), 6.86 (t, J = 53.7 Hz, 1H), 3.94 (s, 3H). 13 C NMR (126 MHz, CDCl 3 (s), 129.5 (s), 128.9 (s), 127.3 (s), 126.8 (s), 126.4 (t, J = 22.4 Hz), 119.7 (s), 115.5 (s), 112.7 (s), 110.0 (t J = 234 Hz), 101.5 (s), 55.9 (s). 19 F NMR (282 MHz, CDCl 3 108.2 (d, J = 53.6 Hz, 2F).
63 2 (difluoromethyl) 5 fluoro 3 phenyl 1 H indole (4 2l) 1 H NMR (300 MHz, CDCl 3 7.47 (m, 4H), 7.45 7.35 (m, 3H), 7.12 (dt, J = 8.7, 1.8 Hz, 1H), 6.78 (t, J = 53.7 Hz, 1H). 19 F NMR (282 MHz, CDCl 3 108.6 (d, J = 53.6 Hz, 2F), 122.6 (td, 9, 4.5 Hz, 1F). 5 bromo 2 (difluoromethyl) 3 phenyl 1 H indole (4 2m) 1 H NMR (300 MHz, CDCl 3 7.34 (m, 7H), 6.76 (t, J = 53.4 Hz, 1H). 19 F NMR (282 MHz, CDCl 3 108.7 (d, J = 53.6, 2F). 4, 6 dichloro 2 (difluoromethyl) 3 phenyl 1 H indole (4 2n) 1 H NMR (300 MHz, CDCl 3 7.29 (m, 6H), 7.14 (d, J = 3 Hz, 1H), 6.49 (t, J = 53.7 Hz, 1H). 13 C NMR (126 MHz, CDCl 3 130.1 (s), 127.9 (s), 127.7 (s), 127.5 (s), 127.0 (s), 125.6 (s), 122.4 (s), 121.9 (s), 110.5 (s), 109.4 (t, J = 234.6 Hz). 19 F NMR (282 MHz, CDCl 3 109.8 (d, J = 53.6 Hz, 2F). 2 (difluoromethyl) 5 nitro 3 phenyl 1 H indole (4 2o) 1 H NMR (300 MHz, CDCl 3 7.45 (m, 6H), 6.79 (t, J = 53.1 Hz, 1H). 19 F NMR (282 MHz, CDCl 3 109.4 (d, J = 53.3 Hz, 2F). 1 (2 (difluoromethyl) 3 methyl 1 H indol 1 yl)ethan 1 one (4 2p) 1 H NMR (300 MHz, CDCl 3 7.31 (m, 5H), 2.82 (s, 3H), 2.47 (s, 3H). 13 C NMR (126 MHz, CDCl 3 120.4 (s), 114.4 (s), 111.4 (t, J = 2 39 Hz), 27.2 (s), 9.28 (s). 19 F NMR (282 MHz, CDCl 3 110.7 (d, J = 53.9 Hz, 2F).
64 CHAPTER 5 CONCLUSION The keys to an ideal method for the generation of a CF 2 R containing compound in the realms of pharmaceuticals or aggrochemicals, are late stage insertion, mild reaction conditions, and scalability. Radical fluoroalkylation using photoredox catalysis is an operationally simple a pproach to generate a wide variety of fluorolakylated bioactive structures, and excels in late stage insertion, and the utilization mild reaction conditions. Other advantages of photoredox catalysis include: broad functional group tolerance, a wide array of photocatalysts that are commercially available, low catalysts loading, flexibile pairing with cocatalysts, and the ability to harness sunlight and O 2 as means to generate a wide array of organic frameworks. However, increasing the scale of photoredox mediated reactions is possible, but can require special reaction set ups like a continuous flow photoreactor, which reduce the inherent simplicity to the approach 66 Adding to the challenge is the availability and atom economy of the current reagents for trifluoromethylation and difluoromethylation, two of the most commonly targeted groups. 3 The research presented in the preceding chapters are representations of the fluoroalkylated compounds than can be accessed using photoredox catalysis, but more work is needed especially with the targeting of specific pharma ceutically relevant compounds as substrates, and the scalability of such an endeavor. In the context of the bioactive skeletons that were described in this dissertation, specifically coumarins and indoles, there are several ideal existing drugs that can be synthesized using techniques and reagents that have been developed, in part, by our research group. Coumarins in particular are known for anticoagulant activity, especially in the case of 4 hydroxy coumarins like warfarin which are dependent on the bulky substitutents found in the 3 position for some of its enzyme blocking capabilites (Figure 5 1). 67 Interestingly, few publications exist
65 regarding the synthesis of coumarins containing 4 CF 2 R groups, and many 4 CF 3 coumarins are commercially available. 68 Co nsidering the analogy that is often made between the CF 2 H group and hydroxy groups in terms of H bond donating potential, it seems only natural to explore the properties of coumarins containing fluoroalkyl groups in the 4 position. 24 This goal could potent ially be accomplished by direct radical fluoroalkyl at tack to a coumarin containing a bulky R group in the 3 position, similar to those found in a drug like warfarin, for a late stage insertion utilizing photoredox catalysis. Figure 5 1. 4 CF 2 R coumarins as a target using fluoroalkyl radicals generated by photoredox. Indoles are another class of heterocycle that have several renown drugs, indomethacin and pravadoline are two examples of such compounds (Figure 5 2). 50 In bo th of these compounds, the 2 position contains a methyl group. Based on our results with the generation of Figure 5 2. Pharmaceutically relevant indoles containing a methyl group in the 2 position.
66 2 CF 2 H indoles directly, using photoredox catalyzed radical difluoromethylation, synthesizing exact analogs of these drugs, only changing the methyl group to the CF 2 H group could produce a compound with desirable qualities. This hypothesis is well sup ported in the literature, as a CF 3 containing indomethacin analog was synthesized and tested in 2013, and found to be a selective cyclooxygenase 2 (COX 2) inhibitor while also bearing activity and potetency similar to the parent drug, with the exception that indomethacin preferrential ly inhibits COX 1 over COX Figure 5 3. 2 CF 2 H Indomethacin derivative. 2 (Figure 5 3). 69 A similar approach can be taken with sythesizing a 2 CF 2 H pravadoline derivative, some of these structurally unique relatives have b een found to have cannabinoid agonist activity. 70 Before attempting to synthesize the difluoromethyl containing drug analogs, the effect of having a protecting group on the indole nitrogen must be evaluated for the general method we previously described. S uch an investigation would be highly valuable, as it would
67 expand the substrate scope of the existing methodology, and it would increase our certainty in the success of direct difluoromethylation to access the 2 CF 2 H drug candidate. Ultimately, these ideas represent future goals for the research described in this dissertation. The methodologies enabled for radical fluoroalkylation by photoredox catalysis have the potential to be highly impactful. While the established substrate scope is illustrative of the limits of the each reaction, the true extent of their scope may be realized by targeting exact derivatives of pharmaceuticals, and altering them by including me aningful groups in the form of CF 3 and CF 2 H groups
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75 BIOGRAPHICAL SKETCH Miles Rubinski was born in Cape Coral, FL. He received his B.S. degree in and focused on developing novel methodologies to synthesize fluorine containing organic compounds. In 2018, he received a Ph. D. in chemistry from the University of Florida.