Article pubs.acs.org/accounts
Anodic Cyclization Reactions and the Mechanistic Strategies That Enable Optimization Ruozhu Feng, Jake A. Smith, and Kevin D. Moeller* Department of Chemistry, Washington University, St. Louis, Missouri 63130, United States S Supporting Information *
CONSPECTUS: Oxidation reactions are powerful tools for synthesis because they allow us to reverse the polarity of electron-rich functional groups, generate highly reactive intermediates, and increase the functionality of molecules. For this reason, oxidation reactions have been and continue to be the subject of intense study. Central to these efforts is the development of mechanism-based strategies that allow us to think about the reactive intermediates that are frequently central to the success of the reactions and the mechanistic pathways that those intermediates trigger. For example, consider oxidative cyclization reactions that are triggered by the removal of an electron from an electron-rich olefin and lead to cyclic products that are functionalized for further elaboration. For these reactions to be successful, the radical cation intermediate must first be generated using conditions that limit its polymerization and then channeled down a productive desired pathway. Following the cyclization, a second oxidation step is necessary for product formation, after which the resulting cation must be quenched in a controlled fashion to avoid undesired elimination reactions. Problems can arise at any one or all of these steps, a fact that frequently complicates reaction optimization and can discourage the development of new transformations. Fortunately, anodic electrochemistry offers an outstanding opportunity to systematically probe the mechanism of oxidative cyclization reactions. The use of electrochemical methods allows for the generation of radical cations under neutral conditions in an environment that helps prevent polymerization of the intermediate. Once the intermediates have been generated, a series of “telltale indicators” can be used to diagnose which step in an oxidative cyclization is problematic for less successful transformation. A set of potential solutions to address each type of problem encountered has been developed. For example, problems with the initial cyclization reaction leading to either polymerization of the radical cation, elimination of a proton from or solvent trapping of that intermediate, or solvent trapping of the radical cation can be identified in the proton NMR spectrum of the crude reaction material. Such an NMR spectrum shows retention of the trapping group. The problems can be addressed by tuning the radical cation, altering the trapping group, or channeling the reactive intermediate down a radical pathway. Specific examples each are shown in this Account. Problems with the second oxidation step can be identified by poor current efficiency or general decomposition in spite of cyclic voltammetry evidence for a rapid cyclization. Solutions involve improving the oxidation conditions for the radical after cyclization by either the addition of a properly placed electron-donating group in the substrate or an increase in the concentration of electrolyte in the reaction (a change that stabilizes the cation generated from the second oxidation step). Problems with the final cation typically lead to overoxidation. Solutions to this problem require an approach that either slows down elimination side reactions or changes the reaction conditions so that the cation can be quickly trapped in an irreversible fashion. Again, this Account highlights these strategies along with the specific experimental protocols utilized.
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INTRODUCTION Electrochemical oxidation reactions can reverse the polarity of known functional groups, generate highly reactive intermediates, and trigger a variety of synthetically intriguing cyclization reactions.1 Many of these processes proceed through radical cation intermediates. For example, the oxidation of an electronrich olefin (Scheme 1) at an anode leads to the formation of a radical cation that is then trapped by another electron-rich group to generate fused, bridged, or spirocyclic compounds, quaternary carbons, and biologically relevant heterocycles.2−4 Electrochemical oxidations of this type are related to other radical-cation-based transformations that are generated by the use of either a chemical oxidant or a photoelectron transfer catalyst.5 However, while the reactions of this general family © 2017 American Chemical Society
have proven to be synthetically useful, in many ways we are only now learning how to fully control and manipulate the highly reactive intermediates involved. In general, the reactions can be viewed as proceeding through the mechanistic paradigm shown in Scheme 1. In this scheme, a substrate is oxidized to form an initial radical cation that then undergoes a potentially reversible cyclization to form a second radical cation. The removal of a second electron generates a transient dication that then leads to the final product via a series of solvent trapping and/or elimination reactions. In the mechanistic scheme, the initial Received: June 8, 2017 Published: August 31, 2017 2346
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olefin (the enol ether) but not on the double bond leading to the radical cation (Scheme 2).11
Scheme 1. Mechanistic Model for a Radical-Cation-Derived Cyclization
Scheme 2. Steric Influences on the Formation of C−C Bonds (Low k1)
oxidation step is not considered because the oxidations are typically run under constant-current electrolysis conditions.6 In a constant-current electrolysis, an anode and a cathode are inserted into the reaction mixture, and then a constant current is passed through the medium. The potentials at the electrodes are allowed to float. At the beginning of the reaction, the working potential at the anode climbs until it matches the potential of the group in solution that is most easily oxidized. The anode potential then remains constant until not enough of the substrate remains in the reaction to satisfy the current being passed through the cell. At that point, the potential starts to climb again until it matches that of a new substrate, solvent, etc., and the demand for current is satisfied. If the current passed through the cell is kept low (and hence the current density at the anode and the demand for the initial substrate are kept low), then the reaction can be pushed until most of the initial substrate is consumed without having to worry about any subsequent climb in potential. An equal but opposite process occurs at the cathode. There are two consequences of running an electrolysis reaction in this fashion. First, the equipment used and the reaction setup needed can be very simple. Literally anything that can pass a current through a cell can be used to attempt one of the reactions.7 Second, since the potential at the anode will be automatically adjusted to match that of the most easily oxidized substrate in solution, designing substrates to contain suitable electron-rich functionality ensures that the loss of the initial electron to the anode always happens. In Scheme 1, the presence of the enol ether ensures the formation of the initial radical cation. However, formation of the radical cation does not guarantee a successful cyclization reaction. In order for the reaction to generate the desired product, the fate of the subsequent reactive intermediates must be controlled.
However, while a number of the reactions appear to be “radical-like”, the radical cations have pronounced cation character, as illustrated by the fact that they can be trapped by alcohol4a and amine12 nucleophiles. Mechanistic studies showed that the chemoselectivity of the reactions is determined by the polarizability of the reactive intermediates.13 Radical cations that are polar in nature prefer carbon−carbon bond formation, while nonpolar radical cations prefer to form carbon−heteroatom bonds. Examples of this behavior can be seen in Schemes 3 and 4. For the examples shown in Scheme 3,14 two substrates, both containing an allylsilane trapping Scheme 3. Controlling Relative k1 Values: Using a More Polar Radical Cation for Carbon−Carbon Bond Formation
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CYCLIZATIONS AND THE IMPORTANCE OF K1 For many years, those efforts primarily focused on the nature of the cyclization, or k1 in the mechanistic scheme.8 The success or failure of the cyclization was interpreted to be directly correlated with whether the cyclization reaction was fast enough to win out over competitive elimination or solvent trapping side reactions. A high-yielding reaction meant a reactive radical cation and an efficient trapping group, and the better the yield, the better the radical cation trapping group.9 Much of this work was accurate,10 and the application of this thinking taught us much about the nature of radical cation intermediates. For example, the cyclizations of 1 and 3 showed that radical cation cyclizations leading to C−C bonds are similar to radical cyclizations in that they are sensitive to sterics on the trapping
group, were oxidized under very similar conditions. The oxidation of substrate 4 leading to a less polar radical cation afforded only a low yield of the desired product. The reaction was messy, and compound 6 could not be isolated in pure form. On the other hand, the oxidation of substrate 5 generating a more polar radical cation led to the desired product 7 in good yield. This study went on to show that the observed chemoselectivity was due to differences in rate for methanol trapping of the radical cation generated.14 For the chemistry shown in Scheme 4, the opposite approach was taken. In this case, the acceleration of carbon−heteroatom 2347
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Accounts of Chemical Research Scheme 4. Controlling Relative k1 Values: Using a Less Polar Radical Cation for Heteroatom Trapping
cyclic product 14 closed, thus minimizing the cationic character of the radical cation.
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THE SECOND OXIDATION STEP (K2) While the outcomes of many reactions can be explained by the rates of processes involving the radical cation intermediate, it is equally true that there are reactions that do not fit in this picture. Consider the oxidation of substrates 16a and 16b (Scheme 6).17 The yields of the reactions were much different Scheme 6. A Reaction Controlled by the Second Oxidation Step (k2)
bond formation by the use of a less polar radical cation was utilized for the synthesis of a C-pyranoside.15 It should be noted how the use of a less polar vinylsulfide-based radical cation derived from substrate 8a accelerated the cyclization leading to product 9 and avoided the formation of the elimination product 10 resulting from oxidation of 8b and the formation of a more polar enol ether-derived radical cation.15 Other reactions could not be fixed with a simple change of radical cation polarity, but the relative rate of the cyclization could be improved by slowing other reaction pathways available to the radical cation. For example, oxidation of substrate 11a led to product (like 13) derived from the elimination of a proton from radical cation 12 (Scheme 5). The reaction led to
even though shifts in cyclic voltammetry data indicated that the generation and subsequent trapping of the styrene-derived radical cation were very similar for the two reactions. The key turned out to be the rate of the second oxidation step (k2 in Scheme 1). For the cyclization resulting from oxidation of 16a, the intermediate generated contained a methoxy group para to the radical generated (18a), a scenario that aided in the loss of a second electron from the substrate. A high yield of product resulted. In the case of 16b, the methoxy group was not positioned well to aid in the second oxidation (of 18b), and the yield of product was not nearly as high. In such cases, the oxidized products 17b and 18b were stable and could be rereduced at the cathode to afford recovered starting material. The observation that the product yield depends on the rate of the second oxidation is common. Both the chemoselectivity of reactions in which substrates contain both alcohol and sulfonamide trapping groups18 and the yield of reactions that utilize carboxylic acid trapping groups19 have been shown to depend upon the rate at which the second electron is lost from the intermediate. All three cases showed poor current efficiency and recovered starting material when the second oxidation step was not addressed. Additionally, competition studies probing earlier observations about the relative rates of cyclization for reactions involving enol ether and allylsilane coupling partners indicated that the second oxidation played a role in the product yield for those reactions as well.20
Scheme 5. Controlling the Reactivity of the Radical Cation Using a Second Tethered Nucleophile
only small amounts of cyclized product. Trapping of the radical cation by the tethered allylsilane to form both a six-membered ring and a quaternary carbon was simply too slow to avoid the elimination of a proton from the reactive radical cation 12.8a This problem could be avoided by slowing the elimination reaction and, in doing so, providing more time for the cyclization. This was accomplished by adding a second intramolecular nucleophile (a tethered alcohol) to the reaction mixture (substrate 11b) that was known to trap radical cation intermediates very quickly.16 The result was a reduction in the cation character of the radical cation driven by the formation of cyclic acetal 14, a decrease in the rate of the elimination reaction, and a 65% yield of the desired bicyclic product. The lower temperature for the reaction was used to keep the initial
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A NEW OBSERVATION AND THE NEED TO CONSIDER K3 While the reactions above showed how considering cyclization rates and the loss of the second electron can influence the outcome of an oxidative cyclization, the reaction does not end when the second electron is removed from the cyclic product. 2348
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Accounts of Chemical Research The reactive intermediate generated after that point can also play an important role in the reaction yield. For example, we have been examining reactions that lead to cyclization products with a higher net oxidation level than those shown in the cyclizations discussed above. The chemistry is being examined because of products like those shown in Figure 1. For both
Figure 2. Model substrates.
Scheme 8. Proposed Decomposition Pathway for Model Substrates
Figure 1. Retrosynthesis of the 1,4-dicarbonyl motif.
target molecules, it is intriguing to propose a common oxidative cyclization route to the 1,4-dicarbonyl present. Electrochemical reactions are ideally suited for generating such skeletons. However, unlike previous retrosynthetic analyses suggesting an electrochemical oxidation, in these cases the disconnection does not involve the cleavage of a simple carbon−carbon single bond but rather either a double bond (19) or an oxygenfunctionalized carbon−carbon bond (20). In principle, both product types can be made from a common intermediate (21) that would be generated from the anodic oxidation of a functionalized substrate like 22 or 23. The initial plan was to use substrates like 22 for the oxidation, but problems with the synthesis quickly led to the choice of substrates with the general structure of 23. In these cases, the idea was to conduct the oxidation and then hydrolyze the resulting heterocyclic product to the desired functionalized 1,4-dicarbonyl (Scheme 7).
elimination reaction to form an electron-enriched heterocycle (32) instead of trapping a second equivalent of methanol to form the desired product 31. This was problematic because the heterocycle 32 had an oxidation potential lower than that of the initial substrate. This led to overoxidation of the product. Problems of this nature can be challenging to solve because the reactions do require mildly basic conditions that can favor elimination reactions. While electrochemical reactions do remain neutral overall, acid is generated at the anode and base at the cathode. Hence, in the absence of a base to shuttle protons away from the surface of the anode, substrates like 24− 26 can undergo acid-catalyzed cyclizations that in this case afforded the wrong regiochemical addition to the enol ether. The plan to address this issue for the reaction in Scheme 8 was to introduce steric bulk onto the heterocycle. The goal was to decrease the rate of overoxidation by either hindering the ability of the heterocycle to approach the anode, slowing elimination to form 32, or perhaps both. The addition of a t-Bu group to the ring in substrate 26 was ineffective, and overoxidation occurred in a manner similar to the other substrates studied. However, the addition of a trityl protecting group to substrate 26 dramatically improved the reaction (Scheme 9). The idea that the newly added steric bulk slowed the elimination was supported by the observation that 33 could be isolated without formation of the aromatic ring. With the protecting group in place, the reaction led to a 74% yield of the product as measured by integration of the crude proton NMR spectrum relative to an internal standard.21 The product could be isolated in 55% yield, with the loss of material attributable to instability of the product toward chromatography on silica gel. The optimized reaction conditions shown in Scheme 9 did require excess current for the reaction to go to completion. At
Scheme 7. Proposed Oxidation/Hydrolysis Route to HigherOxidized 1,4-Dicarbonyls
With this in mind, model substrates 24, 25, and 26 (Figure 2) were synthesized for study. In general, the desired oxidative cyclization of these substrates failed. Instead, the reactions afforded polymeric materials. It appeared that the cation resulting from the second oxidation and subsequent methanol trapping (30) (Scheme 8) was unstable and underwent an 2349
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reaction by improving the rate of cyclization (k1 in the mechanistic model shown in Scheme 1). The problem was eventually resolved by the addition of water to the reactions. When cation 37 was trapped with water in situ, hemiaminal 40 was generated. The hemiaminal then eliminated the amine to form a stable lactone product (41), which could not undergo a subsequent oxidation reaction. As with the above reaction (Scheme 9), optimization of this reaction involved controlling an intermediate generated downstream rather than the initial oxidation, trapping of the radical cation, or the second oxidation.
Scheme 9. Addition of a Bulky Trityl Protecting Group Dramatically Improves the Conversion to Product
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CONCLUSIONS When an anodic cyclization reaction is used, understanding the nature and reactivity of the initial radical cation intermediate generated is frequently the key to channeling the reaction down a productive pathway. The chemoselectivity and yield of these reactions are dependent on both the polarizability of the reactive intermediate and the nature of the trapping groups used. However, for a number of anodic cyclization reactions, efficient trapping of the radical cation alone is not sufficient to ensure a synthetically useful yield of product. In these cases, the reactions typically fall into two classes: reactions that benefit from better management of a second oxidation reaction downstream of the cyclization and reactions that require consideration of the cationic intermediates generated from the second oxidation. For reactions requiring a more efficient second oxidation step, the current for the reaction can be increased to accelerate the oxidation,17,19 the electrolyte concentration can be increased in order to help stabilize the cation generated from the oxidation,17 or changes to the substrate can be made to make the radical to be oxidized in the second step more electron-rich.17,19 For reactions requiring consideration of the cation generated from the second oxidation, it is important to either stop or circumvent elimination reactions that lead to electron-rich products. Doing so avoids overoxidation reactions that reduce the yield of the desired product. While the overall mechanism of the reactions can be complex, there are telltale signs that can help identif y the problem spot for any given cyclization. For example, if a reaction leads to either an elimination or solvent trapping product derived from the initial radical cation, or uncyclized polymer, then the issue is likely with the initial cyclization (k1 in Scheme 1). Attention needs to be paid to the nature of the radical cation, the effectiveness of the trapping group, and reaction condition changes that can be used to buy time for the cyclization. Such situations are easy to recognize because the product mixture contains significant quantities of molecules with one of the coupling partners intact and the other oxidized. On the other hand, if a reaction goes cleanly but not efficiently or provides a low yield of product even though shifts in the CV data for the substrate indicate a fast cyclization,23 then the reaction most likely is being hindered by an inefficient second oxidation step (k2 in Scheme 1). In these cases, the reaction can frequently be improved by increasing the current in the reaction to directly accelerate the rate of the second oxidation, increasing the concentration of electrolyte to stabilize the cation formed by the second oxidation, and/or modification of the substrate that increases the electron density of the radical generated from the cyclization. If a reaction appears to cyclize nicely but leads to overoxidation products, then elimination reactions involving the cation generated from the second oxidation reaction are a
this point, it is not known whether this excess current is needed because the substrate has difficulty reaching the anode as a result of sterics, leading to background oxidation of the solvent, or if the initial cyclization is reversible and the second oxidation of an intermediate like 24 is slow. Such scenarios lead to poor current efficiency due to migration of the radical cation intermediate to the cathode followed by reduction of the intermediate back to the starting material.17 In either event, protecting intermediates like 34 from elimination did allow for isolation of the desired product. This was not the first time that consideration of a cation generated downstream of the second oxidation proved critical for optimization of an anodic cyclization reaction.22 Earlier studies that examined the trapping of ketene dithioacetalderived radical cations (35) by amide trapping groups to form lactones required the addition of water for the same reason (Scheme 10). In this case, the product from the second Scheme 10. Water Scavenges the Unstable Intermediate Cation, Avoiding Overoxidation
oxidation, 37, was trapped by methanol to reversibly form product 38 (which in the initial plan was to be hydrolyzed to the desired lactone upon workup). Because of the reversibility of the reaction, intermediate 37 persisted in solution, a situation that allowed time for an elimination to generate the very electron-rich ketene aminal 39. The oxidation of 39 led to a significant decrease in the yield of the desired lactone product. One key observation was that the more electron-rich the N of the amide was, the poorer was the yield of product. This was initially confusing, because more strongly donating N groups were viewed as making the amide in 35 a better nucleophile, accelerating the radical cation trapping step. In short, our first attempt had been to fix the yield of the anodic oxidation 2350
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Accounts of Chemical Research concern. In these cases, the reaction can frequently be improved by modifications to the substrate or reaction conditions that either slow or circumvent the elimination. It is important to note that in each case efforts to optimize the yield of product formed typically involve a careful physical organic chemistry study of the reaction. In electrochemical reactions, the initial electron transfer at the anode to generate the radical cation is typically not a problem. Rather, the challenge is controlling the reactive intermediates generated downstream of the electron transfer. For many organic chemists interested in attempting their first electrochemical reaction, it is frequently their unfamiliarity with the initial electron transfer and the chemistry surrounding that event that presents the most significant barrier. This does not need to be the case, as they are already prepared to face the far more familiar physical organic chemistry problems that will most likely require the majority of their attention.
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the University of WisconsinMadison (Professor Barry M. Trost) from 1985 to 1987. His long-standing research interests center on the interplay between electrochemistry and organic synthesis, efforts that have ranged from using electrochemical reactions to construct complex molecules to using electrochemically directed synthetic methods to construct the complex molecular surfaces used on bioanalytical devices. In 2016 he received the Manuel M. Baizer Award in Organic Electrochemistry from the Electrochemical Society. He can be reached at
[email protected].
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ACKNOWLEDGMENTS We thank the National Science Foundation (CHE-1463913) for their generous support of our work.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.accounts.7b00287. Experimental descriptions of the synthesis of all new substrates and spectral data for all new compounds (PDF)
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REFERENCES
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Kevin D. Moeller: 0000-0002-3893-5923 Notes
The authors declare no competing financial interest. Biographies Ruozhu Feng joined the Washington University Department of Chemistry as a graduate student in 2013. She earned her B.A. degree in Chemistry from Nankai University in 2013, where she did research with Professor Chi Zhang on the iodosobenzene-mediated intramolecular aminofluorination of homoallylic amines. She received the Excellent Undergraduate Thesis Award in 2013. Her graduate thesis work centers on the development of new electrochemical methods for synthesis and understanding the mechanistic parameters that govern the success of those methods. Jake A. Smith earned a B.S. degree in Chemistry from Rice University in 2009 and a Ph.D. degree in Chemistry (Professor Kevin D. Moeller) from Washington University in St. Louis in 2015. He was a Postdoctoral Fellow at the University of Utah (Assistant Professor Danny Hung-Chieh Chou) from 2015 to 2016 and is currently a Postdoctoral Scientist at the Infectious Disease Research Institute in Seattle, WA. His research interests include organic synthesis, methodology development, and their applications. Kevin D. Moeller joined the chemistry faculty at Washington University in St. Louis in 1987, and he has been Professor of Chemistry since 1999. He was born in Scranton, Pennsylvania, on November 25, 1958, earned a B.A. degree in Chemistry from the University of CaliforniaSanta Barbara in 1980, and then received his Ph.D. degree in Organic Chemistry (Professor R. Daniel Little) from the same institution in 1985. He was an NIH Postdoctoral Fellow at 2351
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Accounts of Chemical Research (5) For radical-cation-initiated cyclizations derived from chemical and photoelectron-transfer-based oxidations, see: (a) Crich, D.; Ranganathan, K.; Neelamkavil, S.; Huang, X. Tandem Polar/Radical Crossover Sequences for the Formation of Fused and Bridged Bicyclic Nitrogen Heterocycles Involving Radical Ionic Chain Reactions, and Alkene Radical Cation Intermediates, Performed under Reducing Conditions: Scope and Limitations. J. Am. Chem. Soc. 2003, 125, 7942−7947. (b) Crich, D.; Shirai, V.; Brebion, F.; Rumthao, S. Enantioselective Alkene Radical Cations Reactions. Tetrahedron 2006, 62, 6501−6518. (c) Crich, D.; Ranganathan, K. Stereochemical Memory Effects in Alkene Radical Cation/Anion Contact Ion Pairs: Effect of Substituents, and Models for Diastereoselectivity. J. Am. Chem. Soc. 2005, 127, 9924−9929. (d) Crich, D.; Shirai, M.; Rumthao, S. Enantioselective Cyclization of Alkene Radical Cations. Org. Lett. 2003, 5, 3767−3769. (e) Conrad, J. C.; Kong, J.; Laforteza, B. N.; MacMillan, D. W. C. Enantioselective α-Arylation of Aldehydes via Organo-SOMO Catalysis. An Ortho-Selective Arylation Reaction Based on an Open-Shell Pathway. J. Am. Chem. Soc. 2009, 131, 11640−11641. (f) Jui, N. T.; Lee, E. C. Y.; MacMillan, D. W. C. Enantioselective Organo-SOMO Cascade Cycloadditions: A Rapid Approach to Molecular Complexity from Simple Aldehydes and Olefins. J. Am. Chem. Soc. 2010, 132, 10015−10017. (g) Rendler, S.; MacMillan, D. W. C. Enantioselective Polyene Cyclization via OrganoSOMO Catalysis. J. Am. Chem. Soc. 2010, 132, 5027−5029. (h) Perkowski, A. J.; Nicewicz, D. A. Direct Catalytic AntiMarkovnikov Addition of Carboxylic Acids to Alkenes. J. Am. Chem. Soc. 2013, 135, 10334−10337. (6) For a description of basic electrochemical concepts for synthetic chemists, see: Moeller, K. D. Synthetic Applications of Anodic Electrochemistry. Tetrahedron 2000, 56, 9527−9554. (7) For three simple reaction setups, see: (a) Frey, D. A.; Wu, N.; Moeller, K. D. Anodic Electrochemistry and the Use of a 6-V Lantern Battery: A Simple Method for Attempting Electrochemically Based Synthetic Transformations. Tetrahedron Lett. 1996, 37, 8317−8320. (b) Nguyen, B. H.; Redden, A.; Moeller, K. D. Sunlight, Electrochemistry, and Sustainable Oxidation Reactions. Green Chem. 2014, 16, 69−72. (c) Frankowski, K. J.; Liu, R.; Milligan, G. L.; Moeller, K. D.; Aubé, J. Practical Electrochemical Anodic Oxidation of Polycyclic Lactams for Late Stage Functionalization. Angew. Chem., Int. Ed. 2015, 54, 10555−10558. (8) (a) Hudson, C. M.; Moeller, K. D. Intramolecular Anodic Olefin Coupling Reactions and the Use of Vinylsilanes. J. Am. Chem. Soc. 1994, 116, 3347−3356. (b) Frey, D. A.; Krishna Reddy, S. H.; Moeller, K. D. Intramolecular Anodic Olefin Coupling Reactions: The Use of Allylsilane Coupling Partners with Allylic Alkoxy Groups. J. Org. Chem. 1999, 64, 2805−2813. (c) Sun, Y.; Moeller, K. D. Anodic Olefin Coupling Reactions Involving Ketene Dithioacetals: Evidence for a ‘Radical-type’ Cyclization. Tetrahedron Lett. 2002, 43, 7159−7161. (d) Tang, F.; Moeller, K. D. Anodic Oxidations and Polarity: Exploring the Chemistry of Olefinic Radical Cations. Tetrahedron 2009, 65, 10863−10875. (e) Redden, A.; Moeller, K. D. Anodic Coupling Reactions: Exploring the Generality of Curtin−Hammett Controlled Reactions. Org. Lett. 2011, 13, 1678−1681. (9) For examples, see: (a) Tinao-Wooldridge, L. V.; Moeller, K. D.; Hudson, C. M. Intramolecular Anodic Olefin Coupling Reactions: A New Approach to the Synthesis of Angularly Fused, Tricyclic Enones. J. Org. Chem. 1994, 59, 2381−2389. (b) Sun, Y.; Liu, B.; Kao, J.; d’Avignon, D. A.; Moeller, K. D. Anodic Cyclization Reactions: Reversing the Polarity of Ketene Dithioacetal Groups. Org. Lett. 2001, 3, 1729−1732. (c) Reddy, S. H. K.; Chiba, K.; Sun, Y.; Moeller, K. D. Anodic Oxidations of Electron-rich Olefins: Radical Cation Based Approaches to the Synthesis of Bridged Bicyclic Ring Skeletons. Tetrahedron 2001, 57, 5183−5197. (10) Campbell, J. M.; Smith, J. A.; Gonzalez, L.; Moeller, K. D. Competition Studies and the Relative Reactivity of Enol Ether and Allylsilane Coupling Partners toward Ketene Dithioacetal Derived Radical Cations. Tetrahedron Lett. 2015, 56, 3595−3599.
(11) Sun, Y.; Moeller, K. D. Anodic Olefin Coupling Reactions Involving Ketene Dithioacetals: Evidence for a ‘Radical-type’ Cyclization. Tetrahedron Lett. 2002, 43, 7159−7161. (12) Xu, H.-C.; Moeller, K. D. Intramolecular Anodic Olefin Coupling Reactions: Use of the Reaction Rate To Control Substrate/Product Selectivity. Angew. Chem., Int. Ed. 2010, 49, 8004−8007. (13) Tang, F.; Moeller, K. D. Anodic oxidations and polarity: exploring the chemistry of olefinic radical cations. Tetrahedron 2009, 65, 10863−10875. (14) Huang, Y.; Moeller, K. D. Anodic cyclization reactions: probing the chemistry of N,O-ketene acetal derived radical cations. Tetrahedron 2006, 62, 6536−6550. (15) Xu, G.; Moeller, K. D. Anodic Coupling Reactions and the Synthesis of C-Glycosides. Org. Lett. 2010, 12, 2590−2593. (16) Redden, A.; Perkins, R. J.; Moeller, K. D. Oxidative Cyclization Reactions: Controlling the Course of a Radical Cation-Derived Reaction with the Use of a Second Nucleophile. Angew. Chem., Int. Ed. 2013, 52, 12865−12868. (17) Smith, J. A.; Moeller, K. D. Oxidative Cyclizations, the Synthesis of Aryl-Substituted C-Glycosides, and the Role of the Second Electron Transfer Step. Org. Lett. 2013, 15, 5818−5821. (18) Campbell, J. M.; Xu, H.-C.; Moeller, K. D. Investigating the Reactivity of Radical Cations: Experimental and Computational Insights into the Reactions of Radical Cations with Alcohol and pToluene Sulfonamide Nucleophiles. J. Am. Chem. Soc. 2012, 134, 18338−18344. (19) Perkins, R. J.; Xu, H.-C.; Campbell, J. M.; Moeller, K. D. Anodic Coupling of Carboxylic Acids to Electron-rich Double Bonds: A Surprising Non-Kolbe Pathway to Lactones. Beilstein J. Org. Chem. 2013, 9, 1630−1636. (20) Campbell, J. M.; Smith, J. A.; Gonzalez, L.; Moeller, K. D. Competition Studies and the Relative Reactivity of Enol Ether and Allylsilane Coupling Partners toward Ketene Dithioacetal Derived Radical Cations. Tetrahedron Lett. 2015, 56, 3595−3599. (21) For details, see the Supporting Information. (22) Brandt, J. D.; Moeller, K. D. Oxidative Cyclization Reactions: Amide Trapping Groups and the Synthesis of Furanones. Org. Lett. 2005, 7, 3553−3556. (23) For examples, see ref 10 and: (a) Moeller, K. D.; Tinao, L. V. Intramolecular Anodic Olefin Coupling Reactions: The Use of Bis Enol Ether Substrates. J. Am. Chem. Soc. 1992, 114, 1033−1041. (b) Reddy, S. H. K.; Chiba, K.; Sun, Y.; Moeller, K. D. Anodic Oxidations of Electron-rich Olefins: Radical Cation Based Approaches to the Synthesis of Bridged Bicyclic Ring Skeletons. Tetrahedron 2001, 57, 5183−5197. (c) Huang, Y.; Moeller, K. D. Anodic Cyclization Reactions: Probing the Chemistry of N,O-ketene Acetal Derived Radical Cations. Tetrahedron 2006, 62, 6536−6550.
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DOI: 10.1021/acs.accounts.7b00287 Acc. Chem. Res. 2017, 50, 2346−2352
