Nickel-Catalyzed Electroreductive Cross-Coupling Reactions of Anhydrides and Alkyl Halides Citation Chang, Daniel Kwon (2022) Nickel-Catalyzed Electroreductive Cross-Coupling Reactions of Anhydrides and Alkyl Halides. Master's thesis, California Institute of Technology. doi:10.7907/w0pr-fs28. https://resolver.caltech.edu/CaltechTHESIS:05122022-031448609 Abstract The formation of new carbon–carbon bonds is one of the most important transformations in organic chemistry due to its ability to build the backbone of organic molecules. Nickel-catalyzed reductive cross-coupling reactions have recently emerged as an efficient and powerful strategy for the creation of new carbon–carbon bonds. Furthermore, electrochemistry can be harnessed to overcome some of the challenges encountered in many of the reductive cross-coupling reactions in the literature. Herein, we discuss the development of a new electroreductive nickel-catalyzed cross-coupling of anhydrides with unactivated alkyl bromides in collaboration with Amgen to produce large amounts of substituted cyclobutane products. Item Type: Thesis (Master's thesis) Subject Keywords: Nickel, cross-coupling, electrochemistry Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Reisman, Sarah E. Thesis Committee: None, None Defense Date: 2022 Funders: Funding Agency Grant Number NSF Graduate Research Fellowship DGE‐1745301 Amgen AMGEN.SER2022 Amgen Chem-Bio-Engineering Award S.E.R Record Number: CaltechTHESIS:05122022-031448609 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:05122022-031448609 DOI: 10.7907/w0pr-fs28 ORCID: Author ORCID Chang, Daniel Kwon 0000-0003-4314-5886 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 14577 Collection: CaltechTHESIS Deposited By: Daniel Chang Deposited On: 16 May 2022 18:04 Last Modified: 14 Nov 2025 20:20 Thesis Files PDF - Final Version See Usage Policy. 1MB Repository Staff Only: item control page

Nickel-Catalyzed Electroreductive Cross-Coupling Reactions of Anhydrides and Alkyl Halides Thesis by Daniel Chang In Partial Fulfillment of the Requirements for the degree of Master of Science CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2022 ii ã 2022 Daniel Chang ORCID: 0000-0003-4314-5886 iii ACKNOWLEDGEMENTS First, I would like to thank my advisor Professor Sarah Reisman for the opportunity to work in her lab. Sarah is such a smart and talented chemist that works extremely hard for the success of the group. It was amazing to learn chemistry by working with her. I think out of the many qualities that Sarah possesses, the one that stands out most to me is how much she cares about her students. Graduate school is tough in many ways and Sarah has always gone above and beyond to accommodate me whenever I needed it. She always made my physical and mental health the top priority and she has been an amazing person to have in my support network. I will always be grateful to Sarah for her support and the opportunities she has given me. I would also like to thank Professor Brian Stoltz, who has been incredibly friendly and supportive starting from my first day at Caltech. Learning chemistry from Brian in his mechanism workshop and synthesis classes was an awesome time. Brian gave great advice and I enjoyed talking with him whenever I got the chance. I would like to thank the entire Reisman group for being an incredibly welcoming place to conduct research. Everyone is always willing to lend a helping hand when it is needed. Working with my mentor Alex Shimozono over the past year has been awesome. He encouraged me to try any ideas I had for our project and was patient iv and kind when mentoring me. Whenever I needed help, he was there for me, and he always made sure to check in with me to make sure I was doing okay. I am grateful that I joined the lab with three awesome classmates Jordan, Emily, and Cedric. I will always treasure the conversations and fun times that we had. Jordan, Emily, and Cedric have been amazing friends and colleagues during my time here and I hope that we will stay in touch after I graduate. I would like to thank Dr. Scott Virgil for maintaining the catalysis center and for always being willing to help with method development on instruments in the center with enthusiasm. I am grateful to Dr. David VanderVelde for maintaining the NMR facilities and Dr. Mona Shahgholi for help with obtaining mass spectrometry data. I am also very grateful to Alison Ross for all she does for the CCE graduate program. I would also like to thank Beth Marshall for everything she does for the Reisman group. Without the help of many people at Caltech that work hard to keep things running, none of the research we do would be possible. I would like to thank our industry collaborators at Amgen, Dr. Neil Langille and Dr. Austin Smith. Neil and Austin were great collaborators that allowed us lots of freedom to drive our project and always gave insightful suggestions. Working with them was a highlight of my time here at Caltech. v I would also like to thank the National Science Foundation Center for Synthetic Organic Electrochemistry. It was great being able to discuss ideas and techniques in synthetic organic electrochemistry with peers and experts from many different groups. I learned a lot by participating in the center and am grateful to have had the opportunity to work with everyone in the center. I would also like to thank the National Science Foundation Graduate Research Fellowship Program for financial support during my time at Caltech. I am grateful to my undergraduate professors at Chapman University who taught me so much and continue to support me. I’d like to give special thanks to Professor Warren de Bruyn for allowing me to join his lab as a young first year undergraduate and being an amazing mentor who always had my best interests at heart. I would like to thank Dr. Justin O’Neill for giving me my first research experience in organic chemistry. I would also like to thank Professor Allegra Liberman-Martin. Working in her lab in the couple years leading up to graduate school was some of the most fun I’ve had doing chemistry. I’d also like to thank Professor Elizabeth Jarvo at UC Irvine for allowing me to work in her lab for a summer. The Jarvo group was my first introduction to nickel chemistry and working in a graduate-level research lab. I learned a lot and had a really fun time working in her lab. I would like to give a huge thanks to Professor Elaine Schwartz for giving the best advice. Any time I was vi stressed and needed someone to talk to, it seemed like she always had the perfect solution. I would like to give a huge thanks to my partner Clea Myo. Over the past four and a half years she has been my biggest supporter and best friend. It’s been an amazing journey so far and I’m looking forward to tackling the next chapter of my life with her. Most of all, I’d like to thank my parents Naun and Shawn. My parents have always been my best friends. They have always supported my interests and passions and have worked so hard for my happiness and success. I am so blessed and grateful to have the best parents in the world! vii ABSTRACT The formation of new carbon–carbon bonds is one of the most important transformations in organic chemistry due to its ability to build the backbone of organic molecules. Nickel-catalyzed reductive cross-coupling reactions have recently emerged as an efficient and powerful strategy for the creation of new carbon–carbon bonds. Furthermore, electrochemistry can be harnessed to overcome some of the challenges encountered in many of the reductive cross-coupling reactions in the literature. Herein, we discuss the development of a new electroreductive nickel-catalyzed cross-coupling of anhydrides with unactivated alkyl bromides in collaboration with Amgen to produce large amounts of substituted cyclobutene products. viii TABLE OF CONTENTS Acknowledgements…………………………………………………………...iii Abstract ………………………………………………………………………vi Table of Contents…………………………………………………………….vii List of Abbreviations………………………………………………………….ix 1. Introduction………………………………………………………………….1 2. Reductive Cross-Coupling Development……………………………………6 3. Product Functionalization and Preliminary Scope………………………….12 4. Progress Towards Asymmetry……………………………………………...16 5. Conclusion and Future Directions…………………………………………..18 6. Experimental Section……………………………………………………….19 7. References…………………………………………………………………..26 Appendix: Relevant Spectra…………………………………………………...28 ix LIST OF ABBREVIATIONS BiOX bi(oxazoline) BOX bis(oxazoline) Bu butyl t Bu tert-butyl 13 C carbon-13 isotope °C degrees celcius calc’d calculated CAM cerium ammonium molybdate cat. catalyst cm-1 wavenumber(s) Cs2CO3 cesium carbonate cod 1,5,-cyclooctadine CPME cyclopentyl methyl ether δ chemical shift in ppm d doublet d deutero x DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DMA N,N-dimethylacetamide DMF dimethylformamide DMSO dimethylsulfoxide dtbpy 4,4’-di-tert-butyl-2,2’-bipyridine ee enantiomeric excess equiv. equivalent(s) Et ethyl et al. and other (Latin: et alii) FI field ionization g gram(s) h hour(s) 1 H proton HRMS high resolution mass spectrometry in situ in the reaction mixture IR infrared spectroscopy J coupling constant xi K2CO3 potassium carbonate LiOAc lithium acetate m multiplet M molar or molecular ion Me methyl MeCN acetonitrile mg milligram(s) min minute(s) mL milliliter(s) mol (mole(s) m/z mass-to-charge ratio Na2CO3 sodium carbonate NaOAc sodium acetate NaO2CH sodium formate n.d not detected Ni nickel NMP N-methyl-2-pyrrolidone xii OH hydroxyl Ph phenyl phen 1,10-phenanthroline PHOX phosphinooxazoline PyOx pyridine-oxazoline q quartet R alkyl group RCC reductive cross-coupling s singlet SFC supercritical fluid chromatography t triplet TBABr tetra-n-butylammonium bromide TBACl tetra-n-butylammonium chloride TBAOAc tetra-n-butylammonium acetate TBAPF6 tetra-n-butylammonium hexafluorophosphate THF tetrahydrofuran 1 NICKEL-CATALYZED ELECTROREDUCTIVE CROSS-COUPLING REACTIONS OF ANHYDRIDES AND ALKYL HALIDES 1. INTRODUCTION The formation of carbon–carbon bonds is one of the most important transformations in organic chemistry. Carbon–carbon bonds make up the backbones of organic molecules and the forging of these bonds is often the key to unlocking powerful syntheses of organic molecules. The development and use of transition-metal catalyzed cross-coupling reactions as a tool for carbon– carbon bond construction has been one of the most important recent advances in organic chemistry.1-3 The importance of this work was highlighted by the Nobel Prize in Chemistry which was awarded to Richard F. Heck, Ei-ichi Negishi, and Akira Suzuki in 2010 for their contributions to palladium-catalyzed cross-coupling in organic synthesis. Transition-metal catalyzed cross-coupling reactions have traditionally (Scheme 1.1a) involved the use of a metal nucleophile and an electrophile as coupling partners. Reductive cross-coupling reactions (RCC) (Scheme 1.1b), which use two electrophiles as coupling partners in the presence of a reductant are not as well developed but can provide advantages over traditional cross-coupling reactions. The metal nucleophile in traditional cross coupling reactions, which must often be synthesized from a precursor, introduces several limitations such as the addition of steps in a synthesis, additional handling precautions, and limited functional group compatibility. In contrast, RCC often use organic halide fragments with wide commercial availability and greater functional group compatibility, making it a more direct approach for the coupling of organic fragments. 2 Scheme 1.1 a.) Traditional cross-coupling reactions and b.) reductive cross-coupling reactions (X = Halide, Pseudohalide; R1, R2 = Alkyl, aryl, alkenyl; [M] = metal, metalloid) a.) R1 X R2 [M] b.) R1 X R2 X Transition-Metal Catalyst Transition-Metal Catalyst Reductant R1 R2 R1 R2 Amgen approached our group with an interest in developing a concise method for the synthesis of stereodefined substituted cyclobutanes such as 2 from cyclobutyl anhydride 1 (Scheme 1.2a). While the Amgen process team has developed a highly efficient one-step process to afford cyclobutyl anhydride 1 on multi kilogram scale, attempts to convert cyclobutyl anhydride 1 to target molecule 2 were unsuccessful.4. Our group proposed the use of a RCC approach to this transformation (Scheme 1.2b). Scheme 1.2 a.) Transformation of interest and b.) proposed RCC approach a.) H O H O O H H O 1 b.) H 2 O O H 1 CO2H O H + Br [Ni], Ligand L.G O β α Electrochemistry H L.G CO2H 3 We hypothesized that this reaction would proceed by a chain radical mechanism as shown in Figure 1.1. In this cycle, oxidative addition proceeds with the anhydride first. The resulting nickel(II) intermediate is oxidatively ligated by an alkyl radical generated by halogen abstraction with the alkyl bromide to produce a nickel(III) intermediate. Upon reductive elimination at the cathode and workup with a proton source, the product is liberated and nickel(0) is regenerated. 3 Figure 1.1 Proposed catalytic cycle for RCC of cyclobutyl anhydride H O R OH H H H+ work-up O R O H O H ZnIIBr O O O LnNi0 Zn0 H O Cathodic Reduction O H R O H Oxidative Addition NiIIBrLn O Halogen Abstraction RBr H NiIILn O R H H O R O H O O NiILn Reductive Elimination O Oxidative Ligation H H O R NiIIILn O O Prior to our development of a RCC approach for the desymmetrization of anhydrides, there have been multiple reports of anhydride desymmetrization in the literature. In 2002 Rovis reported the functionalization of anhydrides using organozinc nucleophiles in up to 95% yield. The use of a chiral phosphinooxazoline ligand allowed for the desymmetrization of a meso-anhydride in 85% yield and 79% ee (Scheme 1.3a).5 Years later, Doyle and Rovis reported an enantioselective desymmetrization of meso-anhydrides in up to 90% yield and 94% ee using a dual nickel- and photoredox-catalyzed cross-coupling reaction (Scheme 1.3b).6 In recent years, Walsh and Mao have reported the desymmetrization of cyclic meso-anhydrides with aryl halides in up to 94% yield using a RCC approach (Scheme 1.3c).7 Most recently, Walsh and Mao reported the decarbonylative coupling of monocyclic anhydrides with unactivated alkyl halides in up to 92% yield (Scheme 4 1.3c). However, there have been few examples of cross-coupling reactions involving cyclobutyl 8 anhydride 1. Furthermore, the reported examples of alkyl coupling partners did not contain the functionality needed to arrive at target compound 2. Scheme 1.3 Nickel-catalyzed cross-coupling reactions of anhydrides a. Rovis 2002 H R O O R H + [Ni] R’2Zn up to 95% yield one asymmetric example: 79% ee R’ R O O H R CO2H H R’ = Alkyl b. Doyle and Rovis 2017 H R O O R H BF3K [Ni] R Ar 4CzPIN Blue LED R + O H H O Ar CO2H c. Walsh and Mao 2018 H R H R’ O X O R enantioselective up to 94% ee up to 90% yield + R’ [Ni] Reductant O R R d. Walsh and Mao 2020 H O H up to 94% yield CO2H O O n + Alkyl Br O [Ni] -CO Alkyl up to 92% yield OH O n = 1, 2 One of the primary challenges in RCC is achieving cross-selectivity.9. The two electrophiles must have sufficiently different electronic properties such that one of the coupling partners selectively undergoes oxidative addition with the metal catalyst before the other to avoid significant homocoupling. The direct coupling of two Csp2 electrophiles such as an anhydride and an alkenyl halide may be difficult due to cross-selectivity. Using an alkyl bromide in place of an alkenyl halide could be more suitable for achieving cross-selectivity (Scheme 1.2b). The desired enone product 2 could then be unmasked by elimination of a beta leaving group installed on the alkyl coupling partner. 5 A second challenge in RCC is the use of superstoichiometric amounts of heterogeneous metalpowder reductants, which can introduce reproducibility issues due to sensitive stir rates, metal purity, and metal mesh size.10-11 One approach to overcome these challenges is to leverage electrochemistry as the source of electrons, instead of terminal reductants like Zn0 and Mn0.12 Furthermore, studying the mechanism of RCC systems can be challenging, since NiI and NiIII species can be unstable and therefore difficult to isolate. This is another case where electrochemistry can be leveraged to study catalytically active species in situ to gain key mechanistic insight.13 By developing an electroreductive nickel-catalyzed cross-coupling reaction, we aim to expand on the scope of current anhydride cross-coupling reactions in the literature and gain mechanistic insight into these reactions. Furthermore, we aim to leverage electrochemistry to avoid reproducibility issues associated with metal-dust reductants especially when the reaction is scaled up by the Amgen process team. 6 2. REDUCTIVE CROSS-COUPLING DEVELOPMENT Scheme 2.1 a. Cyclohexyl Anhydride RCC initial conditions and b. conditions after optimization N N O H F a.) O H + DMA (0.1M), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA Br O 5 4 phen (11 mol%) NiBr2 DME (10 mol%) TBAPF6 (27 mol%) 1.5 Equiv. H H O CO2H F 6 37% Yield by 1HNMR t-Bu N N t-Bu O H F b.) O H 4 + Br O 5 1.5 Equiv. L1 (11 mol%) NiBr2 DME (10 mol%) TBAOAc (27 mol%) DMA (0.1M), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA H H O CO2H F 6 88% Yield by 1HNMR We began our optimization of the RCC of cyclobutyl anhydride 1 with important information gained from a similar RCC using cyclohexyl anhydride 4 that we were developing concurrently (Scheme 2.1). Initially, we were able to obtain cross-coupled product 6 in 37% yield by 1HNMR using a phenanthroline ligand and tetrabutylammonium hexafluorophosphate electrolyte (Scheme 2.1a) and after focusing our efforts on the optimization of the ligand and electrolyte choice we were pleased to arrive at conditions that yielded cross-coupled product 6 in 88% yield by 1HNMR (Scheme 2.1b). The reaction was run under constant current with an RVC cathode and Zn anode in an undivided cell, like other electrochemical RCC reactions in the literature.12,15 An electron-rich bipyridine ligand L1 with a coordinating tetrabutyl ammonium acetate electrolyte in an amide solvent were found to be optimal and afforded cross-coupled product 6 in 88% yield by 1HNMR. Control experiments on the RCC of cyclohexyl anhydride 4 with alkyl bromide 5 were conducted in order to confirm that the nickel catalyst was needed to promote reactivity. In the absence of nickel 7 (Table 2.1, Entry 2) and in the absence of ligand (Table 2.1, Entry 3), no product was detected by 1 HNMR, showing that the nickel catalyst plays an important role in the reaction. Furthermore, changing the catalyst loading from 10 mol% (Table 2.1, Entry 1) to 20 mol% resulted in no change in yield (Table 2.1, entry 4). Decreasing the catalyst loading to 5 mol % resulted in a decrease in yield (Table 2.1, entry 5) Changing the ratio of ligand to nickel from 11:10 to 20:10 resulted in a small decrease in yield (Table 2.1, entry 6). Table 2.1 Effects of Nickel and Ligand Loading on Reactivity t-Bu N N t-Bu O H F O H 4 + Br O 5 L1 (11 mol%) NiBr2 DME (10 mol%) TBAOAc (27 mol%) H DMA (0.1M), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA H O CO2H F 6 1.5 Equiv. Entry Deviation % Yielda 1 None 88 2 No Nickel n.d 3 No Ligand n.d 4 20% Ni, 22% Ligand 88 5 5% Ni, 6% Ligand 75 6 20 mol% Ligand 83 a. Determined by 19FNMR using CF3PH as an external standard. We were particularly interested in the effect of electrolyte loading and identity on our reaction. Doubling the electrolyte loading from 27 mol % (Table 2.2, Entry 1) to 54 mol % (Table 2.2, entry 2) resulted in a decrease in yield from 88% to 76%. Halving the electrolyte loading from 27 mol % to 13.5 mol % (Table 2.2, Entry 3) resulted in a large decrease in yield to 48%. Ammonium salt electrolytes containing coordinating anions such as halides (Table 2.2, Entries 4-6) performed comparably to the ammonium acetate electrolyte, with tetrabutylammonium iodide (Table 2.2, Entry 4) performing slightly worse at 75% yield. An ammonium salt electrolyte containing a non- 8 coordinating hexafluorophosphate anion resulted in a large decrease in yield to 49% yield (Table 2.2, Entry 7). This could suggest that the electrolyte could be serving a dual role as an additive. Although the mechanistic role of the electrolyte in our reaction has not yet been investigated, we have used additives such as sodium iodide in cross-coupling reactions developed in our lab.15 Table 2.2 Effects of electrolyte type and loading t-Bu N N t-Bu O H F O H 4 + Br O 5 L1 (11 mol%) NiBr2 DME (10 mol%) Electrolyte (27 mol%) H DMA (0.1M), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA H O CO2H F 6 1.5 Equiv. Entry Electrolyte % Yielda 1 2 3 4 5 6 7 8 9 10 TBAOAc (27 mol%) TBAOAc (54 Mol %) TBAOAc (13.5 Mol %) TBAI TBABr TBACl TBAPF6 NaOAc LiOAc NaO2CH 88 76 48 75 86 85 49 80 85 76 a. Determined by 19FNMR using CF3PH as an external standard. We were also interested in increasing the concentration of the reaction to help us increase the yield while also generating more product with less solvent, which would be especially important when the Amgen team scales the reaction up. Increasing the concentration from 0.1 M (Table 2.3, Entry 1) to 0.3 M (Table 2.3, Entry 2) resulted in an increase in yield from 88% to 94%. Increasing the concentration farther to 0.45 M (Table 2.3, Entry 3) resulted in a comparable increase in yield to 94%. We though that decreasing equivalents of alkyl bromide was another way we could increase the efficiency of the reaction. Unfortunately, when the amount of alkyl bromide was reduced to 1.0 and 1.2 equivalents the yield dropped to 53% and 59%, respectively (Table 2.3, Entries 4-5). At 9 higher concentrations, using 1.2 equivalents of alkyl bromide still resulted in a decrease in yield (Table 2.3, Entries 6-7). Table 2.3 Concentration and Alkyl Halide Loading Optimization t-Bu N N t-Bu O H F O H 4 + Br O 5 L1 (11 mol%) NiBr2 DME (10 mol%) TBAOAc (27 mol%) H DMA (0.1M), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA H O CO2H F 6 1.5 Equiv. Deviation % Yielda 1 None 88 2 0.3 M 94 3 0.45 M 93 4 1.0 Equiv. Alkyl-Br 53 5 1.2 Equiv. Alkyl-Br 59 6 0.3 M, 1.2 Alkyl-Br 81 7 0.45 M, 1.2 Alkyl-Br 82 Entry a. Determined by 19FNMR using CF3PH as an external standard. While ligand is another crucial component of the reaction, we did not extensively screen achiral ligands after quickly finding that bipyridine ligands allowed us to obtain significant amount of racemic cross-coupled product. The final goal of this project is to develop an asymmetric RCC, so most of our efforts to explore ligand space were focused on chiral ligand frameworks in both the cyclohexyl and the cyclobutyl anhydride systems. After achieving high yields of cross-coupled product 6 from cyclohexyl anhydride 4, we began to optimize on the cyclobutyl anhydride 1. Similar optimal conditions with bipyridine ligand L2 afforded cross-coupled product 3a in 90% yield by 1HNMR and 76% yield after isolation by flash column chromatography (Scheme 2.2). 10 Scheme 2.2 Initial Cyclobutyl RCC Conditions N N O H O H + Br OPh O 1 L2 (11 mol%) NiBr2 DME (10 mol%) TBAOAc (27 mol%) H DMA (0.1M), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA H O OPh CO2H 3a 7a 76 % Isolated Yield 90 % Yield by 1HNMR Table 2.4 Concentration Optimization N N H O O H 1 + Br OPh O 7a L2 (11 mol%) NiBr2 DME (10 mol%) TBAOAc (27 mol%) H DMA (Concentration), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA H O OPh Entry Concentration % Yielda 1 0.1 M 88 2 0.3 M 55 3 0.5 M 63 CO2H 3a a. Determined by 1HNMR using 2,3,4,5-Tetrachloronitrobenzene as an external standard. In contrast to the trend observed in the coupling of cyclohexyl anhydride 4, increasing the concentration of the coupling reaction of cyclobutyl anhydride 1 to 0.3 or 0.5 M resulted in a decrease in yield to 55% and 63%, respectively (Table 2.4, Entries 2-3). One of the parameters in the cyclohexyl system that was not extensively investigated was solvent choice. We decided to screen a variety of polar aprotic solvents of interest to Amgen and found that amide solvents such as DMA and NMP were still optimal (Table 2.5, Entry 1 and 3). Using DMF (Table 2.5, Entry 2) and DMSO (Table 2.5, Entry 5) resulted in decreased the yield to 47% and 37%, and acetonitrile yielded only trace amounts of cross-coupled product (Table 2.5, Entry 4). Co- 11 mixtures of ethereal solvents and amide solvents were also evaluated (Table 2.5, Entries 6-8). Mixtures composed of primarily amide solvent performed slightly worse with CPME:NMP (1:2) resulting in a decrease to 84% yield and THF:NMP (1:2) resulting in a decrease to 81% yield (Table 2.5, Entries 9-10). While these mixed solvent systems performed slightly worse, we have found that ethereal cosolvents could be important in achieving selectivity in asymmetric reactions so these mixtures could be leveraged in our development of an asymmetric reaction. Table 2.5 Solvent optimization N N H O O H 1 + Br OPh O 7a L2 (11 mol%) NiBr2 DME (10 mol%) TBAOAc (27 mol%) H Solvent (0.1M), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA H O OPh CO2H 3a Entry Solvent % Yielda 1 DMA 88 2 DMF 47 3 NMP 92 4 MeCN trace 5 DMSO 37 6 DME/DMF (14:1) trace 7 CPME:DMA (2:1) 40 8 THF:DMA (2:1) No Rxnb 9 CPME:NMP(1:2) 84 10 THF:NMP (1:2) 81 a. Determined by 1HNMR using 2,3,4,5-Tetrachloronitrobenzene as an external standard. b. Voltage of reaction spiked and exceeded electrasyn maximum voltage. 12 3. PRODUCT FUNCTIONALIZATION AND PRELIMINARY SCOPE Table 3.1 E1cB solvent optimization OPh H H O K2CO3 (5 Equiv.), O CO2H 0.1M, Solvent, 23oC 2 hr CO2H 3a 2 Entry Solvent % Yielda 1 2 3 4 5 DMSO MeOH t-BuOH MeCN DMF 65 trace 38 19 37 a. Determined by 1HNMR using 2,3,4,5-Tetrachloronitrobenzene as an external standard. With a procedure to generate 3a in good yield, we began development of an E1cB protocol to generate target molecule 2. Our initial conditions used DMSO as a solvent and 5 equivalents of K2CO3 (Table 3.1, Entry 1) and were able to obtain the target 2 in 65% yield. Switching the solvent to methanol resulted in only trace amounts of product with most of the starting material being converted to a side product that resulted from nucleophilic addition of methanol to the terminal enone (Table 3.1, Entry 2). Moving to a more hindered polar protic solvent like tert-Butanol, resulted in a decrease in yield to 38% when compared with DMSO (Table 3.1, Entry 3). Other polar aprotic solvents such as acetonitrile (Table 3.1, Entry 4) and DMF (Table 3.1, Entry 5) also resulted in a decrease in yield. After establishing a procedure that could produce 2 in moderate yield, we were curious how reaction time was affecting yield. By running the E1cB reaction in deuterated DMSO, we found that after 2 hours the yield began to drop. We hypothesized that this was due to decomposition of the reactive enone 2. 13 Table 3.2 Time-course study of E1cB reaction OPh H K2CO3 (5 Equiv.), O H O 0.1M, DMSO-d6, 23oC Time CO2H CO2H 3a 2 Entry Time % Yielda 1 2 3 1 hr 2 hr 3 hr 23 58 21 a. Determined by 1HNMR using 2,3,4,5-Tetrachloronitrobenzene as an external standard. After studying the effect of time on the reaction, we explored different carbonate bases. Switching to a smaller counter-ion such as sodium (Table 3.3, Entry 1), resulted in a decrease in yield to 18% when compared to potassium (Table 3.3, Entry 2). Switching to a larger counter-ion such as cesium (Table 3.3, Entry 3), resulted in no yield of target 2. Additionally, using a bulky organic base such as DBU resulted in a decrease in yield to 35% (Table 3.3, Entry 4). From preliminary studies, we found that the use of K2CO3 with DMSO for 2 hours at room temperature was the best procedure for generating target 2 in moderate yield. Table 3.3 E1cB carbonate base screen OPh H Base (5 Equiv.), O H CO2H O 0.1M, DMSO-d6, 23oC 2 hr CO2H 3a 2 Entry Base % Yielda 1 2 3 4 Na2CO3 K2CO3 Cs2CO3 DBU 18 65 0 35 a. Determined by 1HNMR using 2,3,4,5-Tetrachloronitrobenzene as an internal standard. 14 Once we could access 2 in moderate yield, we were curious in exploring the scope of both the reductive cross-coupling and E1cB reaction. We found that the addition of an electron donating ethoxy group to the arene and a weakly withdrawing halide to the arene was tolerated under the reaction conditions. Coupling anhydride 1 with halides 7a-c yielded cross-coupled products 3a-c in comparable yields (Scheme 3.1), with the substitution on the arene resulting in a small increase in yield. Scheme 3.1 Preliminary reductive cross-coupling scope N N H O O H + Br OR O 1 L2 (11 mol%) NiBr2 DME (10 mol%) TBAOAc (27 mol%) H DMA (0.1M), 23°C RVC Cathode/ Zn Anode 0.35 mmol, 2.3 F/mol -7 mA H 7a-c O OR CO2H 3a-c O F 3a 76% 3b 79% 3c 80% Isolated yields are reported Unless otherwise stated, all compounds characterized by 1HNMR, 13CNMR, and HRMS Compound 3b characterized by 1HNMR and 13CNMR Subjecting 3a and 3b to the E1cB conditions (Scheme 3.2) yielded target enone 2 in moderate yields. Interestingly, when ketone 3c was subjected to elimination conditions, no 2 was detected by 1 HNMR. We plan to expand the scope of the cross-coupling reaction to secondary bromides and bromides containing heteroatoms other than oxygen to observe how the resulting ketones would behave under elimination conditions. However, most of our efforts after obtaining a procedure to generate racemic target molecule 2 were focused on developing an asymmetric reaction. While a 15 chiral resolution could be used to obtain 2 as a single enantiomer, developing a procedure that allows for direct access to enantiopure material would be ideal. Scheme 3.2 E1cB leaving group effect OR H O H CO2H K2CO3 (5 Equiv.), O 0.1M, DMSO-d6, 23oC 2 hr 3a-c CO2H 2 O F 3a 65% 3b 58% 3c 0% 1HNMR Yields are reported using 2,3,4,5-Tetrachloronitrobenzene as an internal standard Enone 2 characterized by 1HNMR and 13CNMR 16 4. PROGRESS TOWARDS ASYMMETRY After developing a sequence of reactions that could be used to generate racemic substituted cyclobutene 2 in moderate yields, we attempted to apply our reductive cross-coupling conditions with chiral ligands as proof-of-concept. Our initial attempts using the same conditions with different chiral ligand frameworks were unsuccessful. We were unable to produce more than trace amounts of compound 3 with chiral ligands. In order to decouple yield and selectivity, we conducted a series of stoichiometric experiments with chiral ligands (Scheme 4.1). We were pleased to observe that by using chiral BOX ligands like L3 we were able to achieve moderate selectivity. We plan to improve this selectivity by developing new ligands in the BOX framework like the “scorpionate” ligands shown in Scheme 4.2. We also plan to screen different chiral ligand classes once we can obtain moderate yields of cross-coupled product in an asymmetric catalytic RCC system. A representative set of these ligands is shown in Scheme 4.2. We also plan to try using different substrates such as the a-chlorosilane shown in Scheme 4.3. One hypothesis for the lack of reactivity with chiral ligands is that the Nickel(I) complex is unable to initiate halide abstraction with less reactive electrophiles. Using an activated electrophile could be a way to test this hypothesis and potentially promote reactivity with chiral ligands. 17 Scheme 4.1 Proof of principle for asymmetric reductive cross-coupling H O O H Ni(COD)2 + 1.05 Equiv H O 1 L3 1.1 Equiv O H OPh O OPh 7a, 1.5 equiv NiII 0.1 M, CPME:DMA ZnBr2 (1 equiv.) (1:2), 23oC, 30 min pre-complex 15 minutes Br O TBAOAc (1 equiv.) 2 hr CO2H O 3a 42% yield by 1HNMR 70% ee O O N N L3 Scheme 4.3 Representative ligand classes of interest for an asymmetric catalytic RCC reaction O O N N O N N BiOx Ligands N O O O O N N N PyOx Ligands N O N PPh2 BOX Ligands “Scorpionate” Ligands PhOx Ligands Scheme 4.3 Example of a potential activated secondary chloride substrate Cl Me Si Me 18 5. CONCLUSION AND FUTURE DIRECTIONS In conclusion, we have developed a racemic nickel-catalyzed electroreductive cross-coupling reaction to access substituted cyclobutanes. Unactivated alkyl bromides can be coupled with cyclobutyl anhydrides to afford cross-coupled product in up to 80% isolated yield. These products can then be subjected to elimination conditions to access a terminal enone in up to 65% yield. Precedent for an asymmetric cross-coupling reaction has been established with stoichiometric experiments in the BOX ligand framework with cross-coupled product obtained in up to 68% ee. We plan to expand on the substrate scope of the racemic reaction and continue development of an asymmetric cross-coupling reaction. 19 6. EXPERIMENTAL SECTION Note: At the time this section was compiled, characterization of reaction products was still in progress. Not all products that will appear in the final publication will have all of their characterization data available in this document. GENERAL INFORMATION Unless otherwise stated, reactions were performed under a nitrogen atmosphere in a glovebox using dried solvents. Solvents, electrolytes, and ligands were purchased from Millipore Sigma. Nickel(II) bromide dimethoxyethane adduct (NiBr2•dme) was purchased from Strem. Cyclobutane substrate 1 was sent to us by Amgen. Chemicals and reagents were stored in the glovebox and used as received unless otherwise stated. All electrochemical reactions were conducted using an IKA Electrasyn with electrodes purchased from IKA. Reactions were monitored by thin-layer chromatography (TLC) using EMD/Merck silica gel 60 F254 pre-coated plates (0.25 mm) and were visualized by ultraviolet (UV) light or with cerium ammonium molybdate or potassium permanganate staining. Flash column chromatography was performed as described by Still et al. (W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923.) using silica gel (230- 400 mesh) purchased from Silicycle. 1H and 13C NMR spectra were recorded on a Bruker Avance III HD with Prodigy cryoprobe (at 400 MHz and 101 MHz, respectively). NMR data is reported relative to internal CHCl3 (1H, δ = 7.26) and CDCl3 (13C, δ = 77.0). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm-1). HRMS were acquired from the Caltech Mass Spectral Facility using field ionization (FI). 20 CROSS-COUPLING REACTIONS General Procedure A: Racemic reaction on 0.35 mmol scale In the glovebox, to a 5 mL oven-dried Electrasyn vial equipped with a 2-dram teflon-coated stir bar was added anhydride (1.0 equiv., 0.35 mmol), alkyl bromide (1.5 equiv., 0.53 mmol), TBAOAc (27 mol%, 0.09 mmol), ligand (11 mol%, 0.04 mmol), and NiBr2•dme (10 mol%, 0.04 mmol). DMA (3.5 mL, 0.1 M) was added by syringe and the reaction solution was stirred until homogeneous. An Electrasyn cap equipped with an oven-dried RVC electrode (working) and a Zn anode (counter, cleaned by dipping in HCl and scuffing with 400 or 600 grit sandpaper) was attached to the Electrasyn vial. The Electrasyn vial was capped tightly with a rubber septum and brought out of the glovebox. Electrolysis was commenced using an IKA Electrasyn with constant current under positive N2 (-7 mA, 0.45 mmol, 2.3 F/mol, 1000 rpm stir rate) and left until completion. Upon completion of electrolysis, the electrasyn cap was removed and the electrodes were rinsed with EtOAc into a 125 ml sep funnel. The RVC electrode was transferred to a 20 ml scint vial, which was filled with EtOAc then sonicated for 2 mins. The EtOAc was transferred to the sep funnel and the scint vial was filled with 3N HCl and sonicated for 2 mins. The HCl was transferred to the separatory funnel. The electrodes were washed with water (3x, do not collect) then with acetone (3x, leave full on the 3rd cleaning), and the vial was capped and left on the bench overnight. 20 mL 1M LiCl was added to the sep funnel, the phases were separated, and the aqueous phase was extracted with EtOAc (3x 20 ml, 80 ml total). The combined organic phases were washed with 1M LiCl (ca. 40 mL), dried over Na2SO4, and concentrated in vacuo. The crude material was then purified by silica gel column chromatography to afford the desired product (20 mL SiO2, 20% EA/1% AcOH/ 69% Hexane, UV/CAM/KMnO4). 21 Characterization of Cross-Coupling Reaction Products: H 3a (DKC-01-185): Prepared from cis-cyclobutylanhydride (1, 44.1 mg, 0.35 O OPh H mmol) and benzyl 2-bromoethyl ether 7a according to General Procedure A CO2H with 2-2’-Bipyridal L2 to produce 3a in 76% yield as a white powder. 1 H NMR (400 MHz, CDCl3): δ 7.29 – 7.24 (m, 2H), 6.94 (tt, J = 7.4, 1.1 Hz, 1H), 6.90 – 6.86 (m, 2H), 4.33 – 4.15 (m, 2H), 3.61 (tdd, J = 8.3, 5.2, 1.9 Hz, 1H), 3.51 – 3.38 (m, 1H), 2.97 – 2.80 (m, 2H), 2.47 – 1.98 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ 207.70, 177.47, 129.56, 121.03, 114.62, 77.32, 62.87, 47.77, 40.69, 40.43, 21.89, 21.72. FTIR (NaCl, thin film): 2952, 1708, 1600, 1496, 1243, 1243, 751, 690 cm-1 HRMS (FI, m/z): calc’d for C14H16O4 [M]+: 248.1043; found: 248.1035. H 3b (DKC-01-177): Prepared from cis-cyclobutylanhydride (1, 44.1 mg, O 0.35 mmol) and 2-(2-ethoxyphenoxy)ethylbromide (7b, 129 mg, 0.53 O H CO2H O mmol) according to General Procedure A with 2-2’-Bipyridal L2 to produce 3b in 79% yield as a white powder. 1 H NMR (400 MHz, CDCl3): δ 6.92 – 6.85 (m, 4H), 4.47 – 4.37 (m, 1H), 4.20 – 3.99 (m, 3H), 3.71 – 3.58 (m, 1H), 3.54 (dddt, J = 9.8, 8.8, 6.4, 1.0 Hz, 1H), 3.17 – 3.00 (m, 1H), 2.70 (ddd, J = 17.3, 5.7, 4.0 Hz, 1H), 2.59 – 2.05 (m, 5H), 1.47 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 207.20, 176.26, 148.23, 121.24, 121.06, 113.09, 112.89, 64.64, 63.14, 47.63, 41.05, 40.37, 29.72, 21.18, 20.59, 14.70. FTIR (NaCl, thin film): 2921, 1710, 1592, 1507, 1451, 1331, 1252, 1228, 1125, 1038, 743 cm-1 22 H F O 0.35 mmol) and 1-(2-bromoethoxy-4-fluorobenzene) (7c, 115 mg, 0.53 O H 3c (DKC-01-164): Prepared from cis-cyclobutylanhydride (1, 44.1 mg, CO2H mmol) according to General Procedure A with 2-2’-Bipyridal L2 to produce 3c in 80% yield. 1 H NMR (400 MHz, CDCl3): δ 7.01 – 6.90 (m, 1H), 6.82 (ddd, J = 9.2, 4.5, 2.6 Hz, 1H), 4.28 – 4.08 (m, 1H), 3.65 – 3.53 (m, 1H), 3.49 – 3.38 (m, 1H), 2.96 – 2.78 (m, 1H), 2.44 – 2.17 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 177.77, 115.93, 115.70, 115.62, 115.54, 77.23, 63.49, 47.65, 40.55, 40.36, 30.96, 21.80, 21.60. FTIR (NaCl, thin film): 2944, 1709, 1505, 1205, 826 cm-1 HRMS (FI, m/z): calc’d for C14H15O4F [M]+: 266.0949; found: 266.0946. H 6 (AMS-05-100): Prepared from cis-cyclobutylanhydride (1, 44.1 mg, O 0.35 mmol) and 1-(2-bromoethoxy-4-fluorobenzene) (7c, 115 mg, 0.53 H CO2H F mmol) according to General Procedure A with 2-2’-Bipyridal L2 to produce 6 in up to 88% yield by 1HNMR, 1 H NMR (400 MHz, CDCl3): δ 7.21 – 7.08 (m, 2H), 7.04 – 6.89 (m, 2H), 2.91 – 2.67 (m, 6H), 2.08 (ddd, J = 13.1, 9.5, 6.4 Hz, 1H), 2.02 – 1.90 (m, 1H), 1.80 (tq, J = 7.9, 4.6 Hz, 2H), 1.59 (tt, J = 11.1, 6.1 Hz, 1H), 1.39 (qd, J = 10.0, 5.7 Hz, 3H). 13 C NMR (101 MHz, CDCl3): 13C NMR (101 MHz, CDCl3) δ 210.55, 179.92, 162.56, 160.14, 136.98, 136.94, 129.82, 129.74, 115.24, 115.03, 49.42, 42.36, 41.85, 28.73, 25.98, 25.88, 23.93, 23.44. 23 Elimination Reactions: OR H O H CO2H K2CO3 (5 Equiv.), O 0.1M, DMSO-d6, 23oC CO2H 2 hr 3a-c 2 Outside of the glovebox, to a 2-dram oven-dried vial equipped equipped with a stir bar (ends of the stir-bar were shaved with a razor blade for even stirring) was added cross-coupled product 3a-c (1 equiv., 0.1 mmol) and K2CO3 (5 equiv., 124 mg, 0.5 mmol, 5 equiv.). 5.0 mL DMSO-d6 was then added (0.1 M) and the reaction was stirred at 1000 rpm for 2 hours. Reactions were typically monitored by 1HNMR using 2,3,4,5-tetrachloronitrobenzene as an internal standard. After 2 hours, the reaction was diluted to 20 mL with EtOAc and added to a separatory funnel. 20 mL 3M HCl was added, and the organic layer was extracted. The organic layer was washed with water (4 x 20 mL) and then filtered over Na2SO4. The organic filtrate was then concentrated in vacuo. The crude material was purified by silica gel column chromatography (20 mL SiO2, 10% EA/90% Hexane, UV). Isolated yield TBD, small amounts were purified for NMR characterization and further characterization by Amgen. 1 H NMR (400 MHz, C6D6): δ 6.17 (dd, J = 17.7, 10.6 Hz, 1H), 5.99 (dd, J = 17.7, 1.2 Hz, 1H), 5.31 (dd, J = 10.6, 1.2 Hz, 1H), 3.66 – 3.45 (m, 2H), 2.21 – 1.97 (m, 1H), 1.96 – 1.63 (m, 3H). 13 C NMR (101 MHz, C6D6): δ 198.10, 175.87, 134.58, 44.92, 39.28, 29.87, 21.55, 21.06. 24 Stochiometric Enantioselective Reactions: H O O H Ni(COD)2 + 1.05 Equiv L3 1.1 Equiv H O Br O 1 NiII O 0.1 M, CPME:DMA ZnBr2 (1 equiv.) (1:2), 23oC, 30 min H OPh O TBAOAc (1 equiv.) 2 hr O O OPh 7a, 1.5 equiv CO2H 3a O N N L3 Inside of the glovebox, to an oven-dried 1-dram vial equipped with a stir-bar was added Ni(COD)2 (28.9 mg, 1.05 equiv, 0.105 mmol) and L3 (39.9 mg, 1.1 equiv., 0.11mmol) in 2 mL DMA:THF 3:7. The solution was stirred for 15 minutes inside of the glovebox at which point, 1 (12.6 mg, 1.0 equiv., 0.1 mmol) and ZnBr2 (22.5 mg, 1.0 equiv., 0.1 mmol) was added to the reaction vial and stirred for an additional 30 minutes. After 30 minutes, alkyl bromide 7a (30.2 mg, 1.5 equiv., 0.15 mmol) and TBAOAc (30.2 mg, 1.0 equiv., 0.1 mmol) was added to the vial and stirred for an additional 2 hours. After 2 hours, the reaction was diluted to 20 mL with EtOAc and transferred to a separatory funnel. 10 mL 1 M LiCl and 10 mL 1 M HCl were added to the separatory funnel. The aqueous layer was then extracted with EtOAc (3 x 15mL). The combined organics were then washed with 20 mL of 1 M LiCl and filtered over Na2SO4. The filtrate was concentrated in vacuo. The crude material was analyzed by 1HNMR with 2,3,4,5tetrachloronitrobenzene added as an external standard and the NMR yield was determined to be 42%. The crude material was purified by silica gel column chromatography (20 mL SiO2, 20% EA/1% AcOH/ 69% Hexane, UV/CAM/KMnO4) to yield a white powder. 25 The enantiomeric excess of the purified material was determined to be 70% by chiral SFC (ASH, 2.5 mL/min, 25% IPA in CO2, λ = 210 nm) SFC Data for Racemic 3a SFC Data for Enantioenriched 3a 26 7. REFERENCES 1. Cherney, A. H.; Kadunce, N. T.; Reisman, S. E. Enantioselective and Enantiospecific Transition-Metal-Catalyzed Cross-Coupling Reactions of Organometallic Reagents to Construct C-C Bonds. Chem. Rev. 2015, 115(17), 9587–9652. 2. Poremba, K. E.; Dibrell, S. E.; Reisman, S. E. Nickel-Catalyzed Enantioselective Reductive Cross-Coupling Reactions. ACS Catal. 2020, 11(15), 8237–8246. 3. Lucas, E. L.; Jarvo, E. R. Stereospecific and Stereoconvergent Cross-Couplings Between Alkyl Electrophiles. Nat Rev Chem, 1, 2017, 0065. 4. Beaver, M. G.; Zhang, E.–X.; Liu, Z.–Q.; Zheng, S.–Y.; Wang, B.; Lu, J.–P.; Tao, J.; Gonzalez, M.; Jones, S.; Tedrow, J. S. Development and Execution of a Production-Scale Continuous [2+2] Photocycloaddition. Org. Process. Res. Dev. 2020, 24, 2139–2146. 5. Bercot, E. A.; Rovis, T. A Mild and Efficient Catalytic Alkylative Monofunctionalization of Cyclic Anhydrides. J. Am. Chem. Soc. 2002, 124(2), 174–175. 6. Stache, E. E.; Rovis, T.; Doyle, A. G. Dual Nickel- and Photoredox-Catalyzed Enantioselective Desymmetrization of Cyclic meso-Anhydrides. Angew. Chem. Int. Ed. 2017, 56(13), 3679 – 3683. 7. Lin, T.; Mi, J.; Song, L.; Gan, J.; Luo, P.; Mao, J.; Walsh, P. J. Nickel-Catalyzed Desymmetrizing Cross-Electrophile Coupling of Cyclic Meso-Anhydrides 8. Lin, T.; Gu, Y.; Qian, P.; Guan, H.; Walsh, P. J.; Mao, J. Nickel-catalyzed reductive coupling of homoenolates and their higher homologues with unactivated alkyl bromides. Nat. Commun. 2020, 11, 5638. 9. Everson, D. A.; Weix, D. J. Cross-Electrophile Coupling: Principles of Reactivity and Selectivity. J. Org. Chem. 2014, 79(11), 4793–4798. 10. Yin, J.; Maguire, C. K.; Yasuda, N.; Brunskill, A. P.; Klapars, A. Impact of Lead Impurities in Zinc Dust on the Selective Reduction of a Dibromoimidazole Derivative. Org. Process Res. Dev. 2017, 21(1), 94–97. 11. Lin, Q.; Diao, T. Mechanism of Ni-Catalyzed Reductive 1,2-Dicarbofunctionalization of Alkenes. J. Am. Chem. Soc. 2019, 141(44), 17937–17948. 12. Delano, T. J.; Reisman, S. E. Enantioselective Electroreductive Coupling of Alkenyl and Benzyl Halides via Nickel Catalysis. ACS Catal.2019, 9(8), 6751–6754. 27 13. Lin, Q.; Fu, Y.; Diao, T. Monovalent Nickel-Mediated Radical Formation: A Concerted Halogen-Atom Dissociation Pathway Determined by Electroanalytical Studies. J. Am. Chem. Soc. 2021, 143(35), 14196–14206. 14. Perkins, R. J.; Pedro, D. J.; Hansen, E. C. Electrochemical Nickel Catalysis for Sp2-Sp3 Cross-Electrophile Coupling Reactions of Unactivated Alkyl Halides Org. Lett. 2017, 19, 3755–3758. 15. Cherney, A. H.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Between Vinyl and Benzyl Electrophiles. J. Am. Chem. Soc. 2014, 136, 14365−14368. 28 Appendix: Relevant Spectra 10.0 Parameter nmrsu zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 197.4 1.0000 12.5000 Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-10-18T21:55:34 Modification Date 32768 65536 0.12 Acquired Size Spectral Size Digital Resolution 8.5 1H Nucleus 9.0 -1545.3 Lowest Frequency 9.5 8012.8 Spectral Width Spectrometer Frequency 400.13 8.0 2021-10-18T21:55:34 Acquisition Date Class 4.0894 Acquisition Time 7.5 297.1 Temperature Presaturation Frequency CDCl3 Solvent Author Instrument spect Bruker BioSpin GmbH Owner Site Value DKC-01-185-Iso-HNMR.1.fid Origin Comment Title DKC-01-185-Iso-HNMR.1.fid 7.0 0.98 1.94 1.89 6.5 6.0 H H 5.5 3a CO2H O 5.0 4.5 f1 (ppm) OPh 4.0 1.02 1.00 3.5 1.96 3.0 2.5 2.0 1.5 1.0 0.5 29 3.56 2.08 Parameter 207.70 nmrsu Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 55.5 1.0000 10.0000 Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-10-18T22:16:48 Modification Date 65536 0.37 Spectral Size Digital Resolution 180 32768 Acquired Size 190 13C Nucleus 200 -1949.3 Lowest Frequency 210 24038.5 Spectral Width Spectrometer Frequency 100.62 170 2021-10-18T22:16:48 Acquisition Date Class 1.3631 Acquisition Time 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.1 Temperature Presaturation Frequency CDCl3 Solvent Author Instrument spect Bruker BioSpin GmbH Owner Site Value DKC-01-185-Iso-13C.3.fid Origin Comment Title 177.47 DKC-01-185-Iso-13C.3.fid 129.56 130 121.03 120 110 H H OPh 100 90 f1 (ppm) 3a CO2H O 77.32 77.16 CDCl3 80 70 62.87 60 47.77 50 40.69 40.43 40 30 21.89 21.72 20 10 0 -10 30 114.62 10.0 Parameter nmrsu zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 197.4 1.0000 12.5000 Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-09-21T13:18:44 Modification Date 32768 65536 0.12 Acquired Size Spectral Size Digital Resolution 8.5 1H Nucleus 9.0 -1545.3 Lowest Frequency 9.5 8012.8 Spectral Width Spectrometer Frequency 400.13 8.0 2021-09-21T13:18:44 Acquisition Date Class 4.0894 Acquisition Time 7.5 297.1 Temperature Presaturation Frequency CDCl3 Solvent Author Instrument spect Bruker BioSpin GmbH Owner Site Value DKC-01-177-HNMR-New.1.fid Origin Comment Title DKC-01-177-HNMR-New.1.fid 7.0 4.08 6.5 H H 6.0 3b CO2H O O 5.5 O 1.29 5.0 4.5 f1 (ppm) 3.39 4.0 1.00 0.92 3.5 1.19 3.0 4.71 2.5 2.0 2.79 1.5 1.0 0.5 31 0.97 Parameter 207.20 nmrsu Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 43.7 1.0000 10.0000 Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-09-20T18:26:25 Modification Date 65536 0.37 Spectral Size Digital Resolution 180 32768 Acquired Size 190 13C Nucleus 200 -1958.4 Lowest Frequency 210 24038.5 Spectral Width Spectrometer Frequency 100.62 170 2021-09-20T18:26:25 Acquisition Date Class 1.3631 Acquisition Time 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.1 Temperature Presaturation Frequency CDCl3 148.23 Solvent Author Instrument spect Bruker BioSpin GmbH Owner Site Value DKC-01-177-CNMR.3.fid 176.26 Origin Comment Title DKC-01-177-CNMR.3.fid 130 H 120 3b 110 O 113.09 112.89 CO2H O 121.24 121.06 H 100 90 f1 (ppm) O 80 70 64.64 63.14 60 40 47.63 41.05 40.37 50 29.72 30 21.18 20.59 14.70 20 10 0 -10 32 10.0 zg30 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 197.4 1.0000 12.5000 Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-08-19T18:05:10 Modification Date 32768 65536 0.12 Acquired Size Spectral Size Digital Resolution 8.5 1H Nucleus 9.0 -1545.2 Lowest Frequency 9.5 8012.8 Spectral Width Spectrometer Frequency 400.13 8.0 2021-08-19T18:05:10 Acquisition Date Class 4.0894 Acquisition Time 7.5 297.2 Temperature Presaturation Frequency CDCl3 Solvent Author Instrument spect nmrsu Owner Site Bruker BioSpin GmbH Origin 7.0 1.00 0.97 6.5 H H 6.0 3c CO2H O DKC-01-164-Iso-HNMR.3.fid Comment Title Value / Users/ dkc213/ Desktop/ untitled folder 2/ DKC-01-164-Iso-HNMR/ 3/ fid Data File Name Parameter DKC-01-164-Iso-HNMR.3.fid 5.5 O 5.0 4.5 f1 (ppm) F 4.0 0.55 0.50 3.5 1.03 3.0 2.5 2.0 1.5 1.0 0.5 0.0 33 1.57 1.06 Parameter nmrsu Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 512 43.7 1.0000 10.0000 Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-08-19T18:26:59 Modification Date 65536 0.37 Spectral Size Digital Resolution 180 32768 Acquired Size 190 13C Nucleus 200 -1958.4 Lowest Frequency 210 24038.5 Spectral Width Spectrometer Frequency 100.62 170 2021-08-19T18:26:59 Acquisition Date Class 1.3631 Acquisition Time 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.1 Temperature Presaturation Frequency CDCl3 Solvent Author Instrument spect Bruker BioSpin GmbH Owner Site Value DKC-01-164-Iso-13C.4.fid 177.77 Origin Comment Title DKC-01-164-Iso-13C.4.fid 3c 120 O 110 115.93 115.70 115.62 115.54 CO2H O 130 H H 100 90 f1 (ppm) F 77.23 80 70 63.49 60 47.65 50 40.55 40.36 40 30.96 30 21.80 21.60 20 10 0 -10 34 7.26 CDCl3 nmrsu zg30 1D Z116098_0314 (PA BBO 400S1 BBF-H-D-05 Z SP) 16 101.0 1.0000 10.0000 Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-03-23T11:50:17 Modification Date 65536 0.13 Spectral Size Digital Resolution 8.5 32768 Acquired Size 9.0 1H Nucleus 9.5 -1637.0 Lowest Frequency 10.0 8196.7 Spectral Width Spectrometer Frequency 400.15 8.0 2021-03-23T08:50:39 Acquisition Date Class 3.9977 Acquisition Time 7.5 298.1 Temperature Presaturation Frequency CDCl3 Solvent Author Instrument Avance Bruker BioSpin GmbH Owner Site Value ams-05-100isolation.1.1.1r Origin Comment Title Parameter ams-05-100isolation.1.1.1r 1.91 7.0 1.92 6.5 6 CO2H O 6.0 H H 5.5 5.0 4.5 f1 (ppm) F 4.0 3.5 3.0 2.5 1.5 1.26 1.00 2.17 1.32 3.00 2.0 1.0 0.5 35 5.85 210.55 nmrsu 298.2 zgpg30 1D Z116098_0314 (PA BBO 400S1 BBF-H-D-05 Z SP) 256 101.0 2.0000 9.9000 Pulse Sequence Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-03-23T09:07:52 2021-03-23T12:07:31 Acquisition Date Modification Date -1843.0 13C 32768 32768 0.73 Lowest Frequency Nucleus Acquired Size Spectral Size Digital Resolution H H 6 CO2H O 115.24 115.03 F 210 200 190 180 170 160 150 140 130 120 110 100 90 f1 (ppm) 23809.5 Spectral Width Spectrometer Frequency 100.63 Class 1.3763 Acquisition Time Presaturation Frequency CDCl3 Temperature 136.98 136.94 129.82 129.74 Solvent Author Instrument Avance Bruker BioSpin GmbH Owner Site Value 162.56 160.14 ams-05-100isolation.3.1.1r 179.92 Origin Comment Title Parameter ams-05-100isolation.3.1.1r 80 70 60 49.42 50 42.36 41.85 40 20 28.73 25.98 25.88 23.93 23.44 30 10 0 -10 36 10.0 Parameter nmrsu 1D Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 16 156.2 1.0000 12.5000 Experiment Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-05-27T18:08:05 Modification Date 32768 65536 0.12 Acquired Size Spectral Size Digital Resolution 8.5 1H Nucleus 9.0 -1490.6 Lowest Frequency 9.5 8012.8 Spectral Width Spectrometer Frequency 400.13 8.0 2021-05-27T18:08:05 Acquisition Date Class 4.0894 Acquisition Time 7.0 zg30 Pulse Sequence 7.5 297.2 Temperature Presaturation Frequency C6D6 Solvent Author Instrument spect Bruker BioSpin GmbH Owner Site Value DKC-01-103-Iso-A-HNMR.1.fid Origin Comment Title 6.5 0.99 1.01 6.0 2 5.5 CO2H O 5.0 4.5 f1 (ppm) 1.00 DKC-01-103-Iso-A-HNMR.1.fid 4.0 1.98 3.5 3.0 2.5 1.04 2.0 1.5 1.0 0.5 0.0 37 3.30 198.10 Parameter nmrsu Z122623_0045 (CPP BBO 400S1 BB-H&F-D-05 Z) 1024 43.7 1.0000 10.0000 Probe Number of Scans Receiver Gain Relaxation Delay Pulse Width 2021-04-30T01:55:04 Modification Date 65536 0.37 Spectral Size Digital Resolution 180 32768 Acquired Size 190 13C Nucleus 200 -1958.4 Lowest Frequency 210 24038.5 Spectral Width Spectrometer Frequency 100.62 170 2021-04-30T01:55:04 Acquisition Date Class 1.3631 Acquisition Time 140 1D Experiment 150 zgpg30 Pulse Sequence 160 297.2 Temperature Presaturation Frequency C6D6 Solvent Author Instrument spect Bruker BioSpin GmbH Owner Site Value DKC-01-056-C6D6-CNMR.3.fid 175.87 Origin Comment Title DKC-01-056-C6D6-CNMR.3.fid 130 120 110 2 100 90 f1 (ppm) CO2H O 80 70 60 50 39.28 40 29.87 30 21.55 21.06 20 10 0 -10 38 44.92 134.58