Enantioselective Hydroamination of Alkenes with Sulfonamides Ena- Bled by Proton-Coupled Electron Transfer Casey B

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Enantioselective Hydroamination of Alkenes with Sulfonamides Ena- bled by Proton-Coupled Electron Transfer Casey B. Roos, Joachim Demaerel, David E. Graff, and Robert R. Knowles*

Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States

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ABSTRACT: An enantioselective, radical-based (a) Previous Work: Electrostatic contributions to hydrogen bonding interactions method for the intramolecular hydroamination of alkenes with sulfonamides is reported. These reactions are H-bonded ketyl radical H-bonded indole radical cation proposed to proceed via N-centered radicals formed by ArR R R proton-coupled electron transfer (PCET) activation of N ArR O O H O sulfonamide N–H bonds. Non-covalent interactions be- P O H O P O O N O tween the neutral sulfonamidyl radical and a chiral H O Ph N ArR phosphoric acid generated in the PCET event are hy- R ArR pothesized to serve as the basis for asymmetric induc- H tion in a subsequent C–N bond forming step, achieving neutral ketyl-phosphate anion radical cation-phosphate ion pair selectivities of up to 98:2 er. These results offer further (b) Hypothesis: Hydrogen bonding in PCET successor complex support for the ability of non-covalent interactions to en- n n-1 force stereoselectivity in reactions of transient and *M M O O photocatalyst O O R P highly reactive open-shell intermediates. ET R P chiral base N H O O N H O O O O PCET S S O R1 O R1 PT Can we extend this principle to neutral radical interfaces? Non-covalent interactions provide a powerful means to control selectivity in asymmetric transformations, both in (c) This Work: Enantioselective C–N bond formation enabled by PCET 1 H C nature and in the laboratory. However, a lack of clear un- CH Ir photocatalyst 3 O O 3 CH chiral phosphate base O O 3 S S derstanding about how these weak interactions can serve R N CH 1 3 thiol catalyst R1 N H to bind and activate open-shell intermediates has largely blue LEDs precluded their use a control element in the enantioselec- up to 98:2 er tive reactions of free radical species.2-4 Seeking address this deficit, our group has become interested in the use of Figure 1. (a) Examples of PCET-enabled enantioselective proton-coupled electron transfer (PCET) as a platform for reactions; (b) Hypothesis for PCET-enabled asymmetric developing catalytic asymmetric free radical chemistry. olefin hydroamination. (c) Enantioselective hydroamina- Oxidative PCET—which effects formal bond homolysis tion with sulfonamides through the joint movement of a proton and electron to a This manner of asymmetric PCET activation has Brønsted base and one-electron oxidant, respectively5— been demonstrated previously in a reductive aza-pinacol generally requires pre-equilibrium hydrogen bonding be- cyclization and in the oxidative activation of indoles en tween the reactive E–H bond of the substrate and the route to the formation of pyrolloindolines (Figure 1a).8 Brønsted base prior to the electron transfer step. In addition In these examples, the neutral ketyl radical and indole to controlling site-selectivity,6 this H–bond interface can radical cation remain associated with a chiral anionic remain intact following the PCET event, furnishing a tran- phosphate, wherein the negatively charged acceptor was sient hydrogen-bonded complex between the nascent free proposed to increase the strength of the post-PCET hy- radical and the conjugate acid of the Brønsted base.7 In drogen bonding interaction. We questioned whether this principle, this association can then serve as a basis for blueprint could be extended further to enable high selec- achieving asymmetric induction in subsequent bond form- tivity in the reactions of neutral free radical intermedi- ing steps when chiral bases are employed. ates associated with neutral hydrogen bond donors. To evaluate this hypothesis, we chose to investigate enanti- Table 1. Optimization Studiesa oselective variants of a recently reported hydroamina- 9,10 Me 2 mol% [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 Me tion of alkenes with sulfonamides. This transfor- O Me O O O 2.5 mol% chiral phosphate S S mation proceeds through a key sulfonamidyl radical in- PMP N Me PMP N H 30 mol% TRIP thiol termediate generated via PCET activation of the sub- 0.1 M PhCF3 1 2 strate N–H bond by an excited-state Ir(III) oxidant and blue LEDs, −20 ˚C, 24 hr a dialkyl phosphate base. This electrophilic nitrogen- Entry Phosphate Yield (%) er centered radical then undergoes addition to a pendant 1 P1 54 55:45 11 2 P2 30 52:48 olefin to furnish a new C–N bond. We hypothesized 3 P3 96 35:65 that if chiral phosphate bases were employed, then a 4 P4 62 86:14 5 P5 97 93:7 successor H-bonding complex between the chiral phos- 6 P6 98 87:13 phoric acid and the neutral sulfonamidyl radical could 7 P7 85 95:5 nucleate a network of non-covalent interactions that Chiral phosphate bases: N N N ArR C8H17 would in turn differentiate competing diastereomeric ArR 7 transition states for C–N bond formation (Figure 1b). O O O O P O Here, we report the successful realization of this goal, P O NBu4 O O NBu4 and preliminary mechanistic observations consistent C H R 8 17 N Ar Ar with the design hypothesis presented above (Figure 1c). R N N P4 Ar = 9-phenanthryl To put this effort in context, we note that relatively few P1 Ar = C H 6 5 P5 Ar = C6H5 P2 Ar = (2,4,6-iPr)C H methods for catalytic asymmetric C–N bond formation 6 2 P6 Ar = (2,6-iPr)C6H3 P3 Ar = 9-phenanthryl P7 Ar = (3,5-Ph)C H with N-radical intermediates have been reported to date, 6 3 and all involve strong bonding interactions between the Entry Change from Entry 7 Yield (%) er substrates and the chiral catalysts. Meggers and Mac- 8 room temperature 93 89:11 13 Millan have reported methods where a free N-radical 9 thiophenol H-atom donor 81 94:6 10 10 mol% P7 89 95:5 undergoes addition to an alkene acceptor bound to either 11 no base <1 - a chiral Ir-complex or a chiral enamine, respectively, 12 no thiol <5 - while Zhang and Chemler have developed approaches 13 no photocatalyst <1 - 14 no light <1 - using metalloradical complexes.14 a We began by evaluating the cyclization of acy- Reactions were conducted on a 0.05 mmol scale, clic 4-methoxyphenyl (PMP) sulfonamide 1 to form and yields determined by NMR analysis relative to an pyrrolidine 2 under the previously reported PCET con- internal standard. Enantioselectivity was determined ditions for hydroamination in the presence of a variety by HPLC analysis on a chiral stationary phase. of chiral phosphate bases. Phenyl-substituted BINOL With phosphate P7, we next evaluated the sensi- phosphate P1 and commercially available TRIP- tivity of the transformation to variations in other reac- phosphate P2 provided pyrrolidine product 2 in reason- tion parameters. At room temperature, 2 was formed in able yield and low, but measurable levels of selectivity 93% yield, but with a lower selectively of 89:11 er (Ta- (Table 1, Entries 1 and 2). A modest increase in selec- ble 1, entry 8). Further changes to the conditions, such tivity and reactivity was observed with 9-phenanthrene as substituting commercially available thiophenol for substituted P3, affording 2 in 96% yield and 35:65 er TRIP-thiophenol resulted in a similar selectivity of 94:6 (Table 1, Entry 3). Further evaluation of chiral phos- er (Table 1, Entry 9). Increasing the catalyst loading of phate scaffolds led to an improvement in selectivity with P7 to 10 mol% improved the yield marginally, but af- the analogous 1,2,3- triazole containing P4, which pro- 15 forded no enhancement in selectivity (Table 1, Entry vided 2 in 62% yield and 86:14 er (Table 1, Entry 4). 10). Control reactions excluding base, light, and photo- As this 1,2,3-triazole containing chiral phosphate scaf- catalyst resulted in no detectable product formation, and fold provided higher enantioselectivity, we evaluated only trace product was observed in the absence of the the effect of substitution pattern on the aryl triazole moi- thiol HAT catalyst (Table 1, Entries 11–14). ety. The parent phenyl substituted catalyst P5 afforded We then sought to evaluate the reaction scope 2 in 93:7 er. Substituents at the ortho positions (P6) with respect to both the sulfonamide (products 2–22) were detrimental to selectivity compared to P5 yielding and alkene (products 23–27) moieties of the substrate. the product in 87:13 er (Table 1, Entry 5). Of the cata- Uniformly high selectivities were observed upon varia- lysts examined, the highest selectivities were observed tion of the para substituent of the sulfonamide arene with meta substituents on the arene (See SI, Tables S1 and S2). Of these, phosphate P7 proved optimal, affording the product 2 in 85% yield and 95:5 er (Table 1, En- try 7).

Table 2. Scope of Enantioselective Amination Reactiona

2 mol% [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 R2 R R O O 2 2.5 mol% chiral phosphate P7 O O 3 S S R1 N R3 R1 N H 30 mol% TRIP thiol 0.1 M PhCF3 blue LEDs, -20 ˚C, 72 hr

Sulfonamide Variation (R2 = R3 = Me):

Me OMe R1 = 2 X = OMe 86%, 96:4 er 3 X = Me 83%, 95:5 er OMe 4 X = H 91%, 95:5 er 5 X = Br 76%, 95:5 er Me Me O 6 X = Cl 61%, 96:4 er X 7 X = CN 63%, 96:4 er 9 91%, 92:8 er 10 78%, 90:10 er 11 79 %, 95:5 er 12 92%, 96:4 er

8 X = CF3 74%, 98:2 er

S S Me N

N O Me n

13 53%, 93:7 er 14 79%, 97:3 er 15 n = 1 98%, 91:9 er 17 87%, 92:8 er 18 80%, 94:6 er (R)-12 16 n = 2 98%, 96:4 er

Me CF3 Me Me Me O O O Me O O Me N Me O S S NH Me O O Me N N N O N S O O O Me O O S S S S N N N N N N N Me O N N Me F3C

19 84%, 87:13 erb 20 89%, 96:4 er 21 83%, 95:5 er 22 50%, 96:4 erc

Alkene Variation:

Boc N Me Me O O O O Me O O O O O O S S Me N N S S S N N N Me Me Me Me Me d d from cis: 26 72%, 93:7 er from cis: 27 93%, 98:2 er d d 23 98%, 94:6 er 24 91%, 90: 10 er 25 96%, 95:5 er from trans: 26 83%, 95:5 er from trans: 27 48%, 96:4 er

a Yields and enantioselectivities are for isolated material following chromatography on silica gel and are the average of two experiments. Reactions were conducted on 0.5 mmol scale. b Reaction was run at room temperature. c Reaction was run in dichloromethane. d Reactions were run at 0 ˚C with substitution of TRIP-disulfide for thiol.

(2– 8). Substituents at the ortho positions (9, 91% yield, afforded in 84% yield and 87:13 er at room temperature 92:8 er & 10, 78% yield, 90:10 er) modestly reduced the under otherwise standard conditions. Sultiame-derived observed enantioselectivity, whereas selectivity was re- product 20 was isolated in 89% yield and 96:4 er, and tained upon meta substitution (11, 79% yield, 95:5 er). the reaction of a celecoxib-derived sulfonamide pro- The reaction accommodated benzofuran (12, 92% yield, vided cyclized product 21 in 83% and 95:5 er. The reac- 96:4 er), thiophene (13, 53% yield, 93:7 er), and thiazole tion also tolerated the presence of other hydrogen bond- (14, 79% yield, 97:3 er) heterocycles. Benzyl substitu- ing donor and acceptor functionalities to afford sildena- tion on the sulfonamide led to a modest decrease in se- fil derivative 22 in 50% yield and 96:4 er. lectivity (15, 98% yield, 91:9 er), whereas a longer The selectivity of the reaction was then probed phenethyl chain was well tolerated (16, 98% yield, 96:4 for a variety of alkene substitution patterns (products er). The reaction was also successful for sulfamate ester 23–27). Cyclohexyl-substituted product 23 was deliv- (17, 87% yield, 92:8 er) and sulfamide (18, 80% yield, ered in 98% yield and 94:6 er and protected piperidine- 94:6 er) substrates. We further applied this methodology substituted alkene provided the cyclized chiral product to more complex sulfonamide substrates. Product 19, 24 in 91% yield and 90:10 er. Cyclobutyl-substituted 25 containing a thioether linked 1,2,4-triazole moiety, was was afforded in 96% yield and 95:5 er. The conditions also afforded high levels of selectivity for cis and trans absence of a racemic background reaction proceeding disubstituted alkenes. While initial reactivity of these through alkene oxidation.20 Furthermore, high reactivity substrates was low at –20 ˚C, the yields were signifi- and enantioselectivity were observed in reactions of di- cantly improved with an increase in reaction tempera- substituted alkenes (products 26–27), for which single ture to 0 ˚C and substitution of 15 mol% of TRIP- electron oxidation is prohibitively endergonic (Ep/2(cy- disulfide for the thiol (See SI, Table S2). Product 26 was clopentene) = +1.99 V vs. Fc+/Fc) for the Ir complex afforded in 72% yield and 93:7 er from the cis-disubsti- employed.17 tuted alkene, while the trans isomer afforded 26 in 93% Lastly, an inverse relationship between solvent yield and 95:5 er. A bulkier tert-butyl substituted alkene polarity and enantioselectivity is often been taken as provided product 27 in 93% yield and 98:2 er from the support for an ion pairing mechanism. 21 In contrast, we cis isomer. 27 was also generated in 48% yield and 96:4 observed that the enantioselectivity of this hydroamina- er from the corresponding trans isomer of the starting tion reaction was notably insensitive to solvent dielec- acyclic alkene. tric. Nearly identical selectivities are observed for reac- Seeking to shed light on the enantiodetermining tions run in either toluene (� = 2.4, er = 93:7) or acetoni- step of this transformation, we conducted an amination trile (� = 36.6, er = 94:6), and only a moderate decrease experiment where the thiol co-catalyst was removed was found for reactions run in highly polar propylene from solution and several equivalents of methyl vinyl carbonate (� = 66.2, er = 85:15) (Table 4, Entries 1,5, ketone were added (Figure 2). From this reaction carbo- and 6), though the reactivity was significantly diminsi- amination product 28 was isolated in 65% yield and hed.22 This insensitivity to solvent polarity argues 95:5 er - a nearly identical selectivity to the hydroami- strongly against a key role for ionic intermediates in C– nation reaction of the same sulfonamide substrate. N bond forming step. These results suggest that the common C–N bond forming step is stereoselectivity-determining in both trans- Table 3. Enantioselectivity as a Function of Solvent Die- formations. lectric

O Me 2 mol% [Ir(dF(CF3)ppy)2(5,5’-dCF3bpy)]PF6 Me O Me O O 2 mol% [Ir(dF(CF )ppy) (5,5’-dCF bpy)]PF O 2.5 mol% chiral phosphate P7 3 2 3 6 Me S S 2.5 mol% chiral phosphate P7 PMP N Me PMP N Me H 30 mol% TRIP thiol Me methyl vinyl ketone (4.0 equiv) O O O O Me 0.1 M solvent S S 1 2 N Me 0.1 M PhCF N blue LEDs, −20 ˚C, 24 hr H 3 blue LEDs, −20 ˚C, 72 hr O O Entry Solvent Yield (%) er ! 28 65% yield, 95:5 er 1 toluene 85 93:7 2.4 2 fluorobenzene 77 94:6 5.5 Figure 2. Carboamination Reaction 3 tetrahydrofuran 45 94:6 7.5 4 dichloromethane 54 94:6 8.9 With this information in hand, we sought to better 5 acetonitrile 15 94:6 36.6 6 N,N-dimethylformamide trace 83:17 38.3 understand the nature of the interaction between the sub- 7 propylene carbonate trace 85:15 66.2 strate and the chiral catalyst. While our initial design a conjectured a neutral hydrogen bonding interaction re- Reactions were conducted on a 0.05 mmol sulting from a PCET-generated sulfonamidyl radical, scale, and yields determined by NMR analysis rela- we also considered that an alternative ion-pairing path- tive to an internal standard. Enantioselectivity deter- way may be responsible for asymmetric induction as mined by HPLC analysis on a chiral stationary previously proposed by Luo and Nicewicz.16 This inter- phase. action could arise by an alternative mechanism where In conclusion, we have developed a PCET-based the pendant olefin (Ep/2(2-methyl-2-butene) = +1.60 V protocol for the asymmetric hydroamination of alkenes + vs. Fc /Fc) undergoes an endergonic single electron ox- with sulfonamides to prepare enantioenriched pyrroli- idation by the excited state of the Ir photocatalyst (E1/2 dine products. This method shows high selectivity for a + 17,18 [*Ir(III)/(II)] = +1.30 V vs. Fc /Fc). The resulting variety of alkene substitution patterns and sulfonamide ion pairing interaction between the alkene radical cation substrates, including complex drug-derived examples. A and chiral phosphate anion would then provide a basis variety of observations are consistent with a neutral cat- for enantioinduction. alyst-substrate interaction governing selectivity in an In seeking to distinguish between these pathways, enantiodetermining C–N bond forming step. Further we note that previously reported cyclic voltammetry and work will aim to elucidate the precise interactions un- Stern-Volmer quenching studies were consistent with derlying the observed selectivity, including the potential PCET-activation of sulfonamides under nearly identical role of a post-PCET hydrogen bonding interaction to the 19 conditions using achiral phosphate bases. Moreover, nitrogen radical that served as the key design hypothesis in the absence of the phosphate base (Table 1, Entry 11) in the development of this work. We are optimistic that no cyclized product is detected, and increased loadings the results presented here can be extended more broadly of phosphate (Table 1, Entry 10) do not result in higher observed enantioselectivities. These results suggest the to enable the development of other enantioselective re- Winkler, T. �-Sulfinyl Substituted Radicals; 1. Stereoselective Radi- actions of free radical intermediates mediated solely by cal Addition Reactions of Cyclic �-Sulfinyl Radicals. Synlett, 1991, 2, 101−104. (b) De Mesmaeker, A.; Waldner, A.; Hoffmann, P.; non-covalent associations. Mindt, T. �-Sulfinyl Substituted Radicals; II. Stereoselective Inter- and Intramolecular Addition Reactions of Acyclic �-Sulfinyl Radi- ASSOCIATED CONTENT cals. Synlett, 1993, 11, 871−874. (c) Curran, D. P.; Kuo, L. H. Alter- ing the stereochemistry of Allylation Reactions of Cyclic �-Sulfinyl Supporting Information. Radicals with Diarylureas. J. Org. Chem. 1994, 59, 3259−3261. (d) The Supporting Information is available free of charge on Böhm, A.; Bach, T. Synthesis of Supramolecular Iridium Catalysts the ACS Publications website. and Their Use in Enantioselective Visible-Light-Induced Reactions. Synlett, 2016, 27, 1056−1060. (e) Bauer, A.; Westkämper, F.; Experimental procedures, spectral data, and optical purity Grimme, S.; Bach, T. Catalytic enantioselective Reactions Driven by Photoinduced Electron Transfer. Nature 2005, 436, 1139−1140. (f) determinations (PDF). Bach, T.; Bergmann, H.; Grosch, B.; Harms, K. Highly Enantioselec- Crystal structure of 12 (CIF) tive Intra- and Intermolecular [2 + 2] Photocycloaddition Reactions Crystal structure of 14 (CIF) of 2-Quinolones Mediated by a Chiral Lactam Host: Host−Guest In- teractions, Product Configuration, and the Origin of the Stereoselec- tivity in Solution. J. Am. Chem. Soc. 2002, 124, 7982−7990. (g) AUTHOR INFORMATION Aechtner, T.; Dressel, M.; Bach, T. Hydrogen Bond Mediated Enan- tioselectivity of Radical Reactions. Angew. Chem. Int. Ed. 2004, 43, Corresponding Author 5849−5851. (h) Müller, C.; Bauer, A.; Bach, T. Light-Driven Enan- tioselective Organocatalysis. Angew. Chem., Int. Ed. 2009, 48, [email protected] 6640−6642. (i) Sandoval, B. A.; Meichan, A. J.; Hyster, T. K. Enan- tioselective Hydrogen Atom Transfer: Discovery of Catalytic Prom- ACKNOWLEDGMENT iscuity in Flavin-Dependent ‘Ene’-Reductases. J. Am. Chem. Soc. Financial support was provided by the NIH (R35 2017, 139, 11313−11316. (j) Proctor, R. S. J.; Davis, H. J. Phipps, R. J. Catalytic enantioselective Minisci-Type addition to heteroarenes. GM134893). Qilei Zhu is thanked for generously provid- Science, 2018, 360, 419−422. (k) Uraguchi, D.; Kinoshita, N.; Kizu, ing substrates. J.D. kindly acknowledges the MolDesignS T.; Ooi, T. Synergistic Catalysis of Ionic Brønsted Acid and Photo- lab for financial support, and also the Research Foundation sensitizer for a Redox Neutral Asymmetric �-Coupling of N-Aryla- - Flanders (FWO) for generous funding through Funda- minomethanes with Aldimines. J. Am. Chem. Soc. 2015, 137, mental Research fellowship 11ZY118N and travel grant 13768−13771. (l) Shevchenko, G. A.; Oppelaar, B.; List, B. An Un- expected �-Oxidation of Cyclic Ketones with 1,4-Benzoquinone by V416618N. Enol Catalysis. Angew. Chem. Int. Ed. 2018, 57, 10756−10759. (m) Cao, K.; Tan, S. M.; Lee, R.; Yang, S.; Jia, H.; Zhao, X.; Qiao, B.; REFERENCES Jiang, Z. Catalytic Enantioselective Addition of Prochiral Racicals to (1) (a) Knowles, R. R.; Jacobsen, E. N. Attractive Noncovalent In- Vinylpyridines. J. Am. Chem. Soc. 2019, 141, 5437−5443. teractions in Asymmetric Catalysis: Links Between Enzymes and (5) (a) Weinberg, D. R.; Gagliardi, C. J.; Hull, J. F.; Murphy, C. Small Molecule Catalysts. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess, D. H.; McCafferty, D. 20678−20685. (b) Davis, H. J.; Phipps, R. J. Harnessing non-covalent G.; Meyer, T. J. Proton-Coupled Electron Transfer. Chem. Rev. 2012, interactions to exert control over regioselectivity and site-selectivity 112, 4016−4093. (b) Mayer, J. M. Proton-Coupled Electron Transfer: in catalytic reactions. Chem. Sci. 2017, 8, 864−877. (c) Raynal, M.; A Reaction Chemist’s View. Annu. Rev. Phys. Chem. 2004, 55, Ballester, P.; Vidal-Ferran, A.; van Leeuwen, P. W. N. M. Supramo- 363−390. (c) Hoffmann, N. Proton-Coupled Electron Transfer in lecular catalysis. Part 2: artificial enzyme mimics. Chem. Soc. Rev. Photoredox Catalytic Reactions. Eur. J. Org. Chem. 2017, 15, 2014, 43, 1734−1787. (d) Taylor, M. S.; Jacobsen, E. N. Asymmetric 1982−1992. (d) Miller, D. C.; Tarantino, K. T.; Knowles, R. R. Pro- Catalysis by Chiral Hydrogen-Bond Donors. Angew, Chem. Int. Ed. ton-Coupled Electron Transfer in Organic Synthesis: Fundamentals, 2006, 45, 1520−1543. Applications, and Opportunities. Top. Curr. Chem. 2016, 374, 30. (2) For studies of hydrogen bonding to radicals, see: (a) Johnson (6) Qiu, G.; Knowles, R. R. Understanding Chemoselectivity in E. R.; Salamone, M.; Bietti, M.; DiLabio, G. A. Modeling Noncova- Proton-Coupled Electron Transfer: A Kinetic Study of Amide and lent Radical-Molecule Interactions Using Convetional Density-Func- Thiol Activation. J. Am. Chem. Soc. 2019, 141, 16574−16578. tional Theory: Beware Erroneous Charge Transfer. J. Phys Chem. A (7) (a) Mayer, J. M.; Hrovat, D. A.; Thomas, J. L.; Borden, W. T. 2014, 117, 947−952. (b) Hernández-Soto, H.; Weinhold, F.; Fran- Proton-Coupled Electron Transfer versus Hydrogen Atom Transfer cisco, J. S. Radical hydrogen bonding: Origins of stability of radical- in Benzyl/Toluene, Methoxyl/Methanol, and Phenoxyl/ Phenol Self- molecule complexes. J. Chem. Phys. 2007, 127, 164102. (c) Johnson, Exchange Reactions. J. Am. Chem. Soc. 2002, 124, 11142−11147. (b) E. R.; DiLabio, G. A. Radicals as Hydrogen Bond Donors and Ac- Mader, E. A.; Mayer, J. M. The Importance of Precursor and Succes- ceptors. Interdiscip. Sci. Comput. Life Sci. 2009, 1, 133−140. sor Complex Formation in a Bimolecular Proton-Electron Reaction. (3) For general reviews of enantioselective radical reactions. (a) Inorg. Chem. 2010, 49, 3685−3687. Studer, A.; Curran, D. P. Catalysis of Radical Reactions: A Radical (8) (a) Rono, L. J.; Yayla, H. G.; Wang, D. Y.; Armstrong, M. F.; Chemistry Perspective. Angew. Chem. Int. Ed. 2016, 55, 58−102. (b) Knowles, R. R. Enantioselective Photoredox Catalysis Enabled by Sibi, M. P.; Manyem, S.; Zimmerman, J. Enantioselective Radical Proton-Coupled Electron Transfer: Development of an Asymmetric Processes. Chem. Rev. 2003, 103, 3263−3295. (c) Zhang, L.; Meg- Aza-Pinacol Cyclization. J. Am. Chem. Soc. 2013, 135, gers, E. Steering Asymmetric Lewis Acid Catalysis Exclusively with 17735−17738. (b) Gentry, E. C.; Rono, L. J.; Hale, M. E.; Matsuura, Octahedral Metal-Centered Chirality. Acc. Chem. Res. 2017, 50, R.; Knowles, R. R. Enantioselective Synthesis of Pyrroloindolines 320−330. (d) Yoon, T. P. Photochemical Stereocontrol Using Tan- via Non-Covalent Stabilization of Indole Radical Cations and Appli- dem Photoredox-Chiral Lewis Acid Catalysis. Acc. Chem. Res. 2016, cations to the Synthesis of Alkaloid Natural Products. J. Am. Chem. 49, 2307−2315. (e) Silvi, M.; Melchiorre, P. Enhancing the potential Soc. 2018, 140, 3394−3402. of enantioselective organocatalysis with light. Nature, 2018, 554, (9) Zhu, Q.; Graff, D. E.; Knowles, R. R. Intermolecular Anti-Mar- 41−49. kovnikov Hydroamination of Unactivated Alkenes with Sulfona- (4) For examples of a role for hydrogen bonding in radical reac- mides Enabled by Proton-Coupled Electron Transfer. J. Am. Chem. tions: (a) Waldner, A.; De Mesmaeker, A.; Hoffmann, P.; Mindt, T.; Soc. 2018, 140, 741−747.

(10) Representative reviews and reports of enantioselective hy- (14) (a) Lang, K.; Torker, S.; Wojtas, L.; Zhang, X. P. Asymmetric droamination reactions: (a) Hannedouche, J.; Schulz, E. Asymmetric Induction and Enantiodivergence in Catalytic Radical C–H amination Hydroamination: A Survey of the Most Recent Developments. Chem. via Enantiodifferentiative H-Atom Abstraction and Stereoselective Eur. J. 2013, 19, 4972−4985. (b) Michon, C.; Abadie, M.-A.; Me- Radical Substitution. J. Am. Chem. Soc. 2019, 141, 12388–12396. (b) dina, F.; Agbossou-Niedercorn, F. Recent Metal-Catalyzed Asym- Li, J.; Zhang, Z.; Wu, L.; Zhang, W.; Chen, P.; Lin, Z.; Liu, G. Site- metric Hydroaminations of Alkenes. J. Organometallic Chem. 2017, Specific allylic C–H bond functionalization with a copper-bound N- 847, 13–27. (c) Hultzsch, K. C. Transition Metal-Catalyzed Asym- centered radical. Nature 2019, 574, 516–522. (c) Turnpenny, B. W.; metric Hydroamination of Alkenes (AHA). Adv. Synth. Catal. 2005, Hyman, K. L.; Chemler, S. R. Chiral Indoline Synthesis via Enanti- 347, 367–391. (d) Hii, K. K. Development of Palladium Catalysts for oselective Intramolecular Copper-Catalyzed Alkene Hydroamina- Asymmetric Hydroamination Reactions. Pure Appl. Chem. 2006, 78, tion. Organometallics, 2012, 31, 7819–7822. 341–349. (e) Aillaud, I.; Collin, J.; Hannedouche, J.; Schulz, E. (15) Orlandi, M.; Toste, F. D.; Sigman, M. S. Multidimensional Asymmetric Hydroamination of Non-Activated Carbon–Carbon Correlations in Asymmetric Catalysis through Parameterization of Multiple Bonds. Dalton Trans. 2007, 44, 5105–5118. (f) Yu, F.; Uncatalyzed Transition States. Angew. Chem. Int. Ed. 2017, 56, Chen, P.; Liu, G. Pd(II)-catalyzed intermolecular enantioselective 14080–14084. hydroamination of styrenes. Org. Chem. Front. 2015, 2, 819–822. (g) (16) (a) Morse P. D.; Nguyen, T. M.; Cruz, C. L.; Nicewicz, D. Yang, Y.; Shi, S.-L.; Niu, D.; Liu, P.; Buchwald, S. L. Catalytic A. Enantioselective Counter-Anions in Photoredox Catalysis: The Asymmetric Hydroamination of Unactivated Internal Olefins to Ali- Asymmetric Cation Radical Diels-Alder Reaction. Tetrahedron phatic Amines. Science 2015, 349, 62–66. (h) Zhou, Y.; Engl, O. D.; 2018, 74, 3266–3272. (b) Yang, Z.; Li, H.; Li, S.; Zhang, M.-T., Luo, Bandar, J. S.; Chant, E. D.; Buchwald, S. L. CuH-Catalyzed Asym- S.; A chiral ion-pair photoredox organocatalyst: Enantioselective metric Hydroamidation of Vinylarenes. Angew. Chem. Int. Ed. 2018, anti-Markovnikov hydroetherification of alkenols. Org. Chem. 57, 6672–6675. (i) Lutete, L. M.; Kadota, I.; Yamamoto, Y. Palla- Front. 2017, 4, 1037–1041. dium-Catalyzed Intramolecular Asymmetric Hydroamination of Al- (17) Roth, H. G.; Romero, N.A; Nicewicz, D. A. Experimental and kynes. J. Am. Chem. Soc. 2004, 126, 1622–1623. (j) LaLonde, R. L.; Calculated Electrochemical Potentials of Common Organic Mole- Sherry B. D.; Kang, E. J.; Toste, F. D. Gold(I)-Catalyzed Enantiose- cules for Applications to Single Electron Redox Chemistry. Synlett lective Intramolecular Hydroamination of Allenes. J. Am. Chem. 2016, 27, 714–723. Soc. 2007, 129, 2452–2453. (k) Sevov, C. S.; Zhou, J. S.; Hartwig, J. (18) Yayla, H. G.; Wang, H.; Tarantino, K. T.; Orbe, H. S.; F. Iridium-Catalyzed Intermolecular Hydroamination of Unactivated Knowles, R. R. Catalytic Ring-Opening of Cyclic Alcohols Enabled Aliphatic Alkenes with Amides and Sulfonamides. J. Am. Chem. by PCET Activation of Strong O-H Bonds. J. Am. Chem. Soc. 2016, Soc. 2012, 134, 11960–11963. (l) Hannedouche, J.; Schulz, E. Hy- 138, 10794–10797. droamination and Hydroaminoalkylation of Alkenes by Group 3–5 (19) In Stern-Volmer luminescence experiments, quenching is ob- Elements: Recent Developments and Comparison with Late Transi- served only when both base and sulfonamide are present. Results of tion Metals. Organometallics 2018, 37, 4313–4326. (m) Brown, A. cyclic voltammetry experiments show an earlier onset potential and R.; Uyeda, C.; Brotherton, C. A.; Jacobsen, E. N. Enantioselective increased current response upon increasing the concentration of base. Thiourea-Catalyzed Intramolecular Cope-Type Hydroamination. J. For more information, see reference 7. Am. Chem. Soc. 2013, 135, 6747–6749. (n) Hong, S.; Tian, S.; Metz, (20) (a) Nguyen, T. M.; Nicewicz D. A. Anti-Markovnikov hy- M. V.; Marks, T. J. C2-Symmetric Bis(oxazolinato)lanthanide Cata- droamination of Alkenes Catalyzed by an Organic Photoredox Sys- lysts for Enantioselective Intramolecular Hydroamination/Cycliza- tem. J. Am. Chem. Soc. 2013, 135, 9588–9591. (b) Nguyen, T. M.; tion. J. Am. Chem. Soc. 2003, 125, 14768–14783. Manohar, N.; Nicewicz, D. A. Anti-Markovnikov Hydroamination of (11) Horner, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M. Ab- Alkenes Catalyzed by a Two Component Photoredox System: Direct solute Kinetics of Amidyl Radical Reactions. J. Am. Chem. Soc. Access to Phenethylamine Derivatives. Angew. Chem. Int. Ed. 2014, 1998, 120, 7738–7748. 53, 6198–6201. (12) Representative reviews on the generation and synthetic utility (21) (a) Loupy, A.; Tchoubar, B. Salt Effects in Organic and Or- of nitrogen centered radicals: (a) Zard, S. Z. Recent Progress in the ganometallic Chemistry, VCH Publishers, Inc.: New York, NY, Generation and Use of Nitrogen-Centred Radicals. Chem. Soc. Rev. 1991. (b) Wynberg, H.; Greijdanus, B. Solvent effects in homogene- 2008, 37, 1603–1618. (b) Xiong, T.; Zhang, Q. New Amination Strat- ous asymmetric catalysis. J. Chem. Soc., Chem. Commun. 1978, 427– egies Based on Nitrogen-Centered Radical Chemistry. Chem. Soc. 428. (c) Brak. K.; Jacobsen, E. N. Asymmetric Ion-Pairing Catalysis. Rev. 2016, 45, 3069–3087. (c) Chen. J.-R.; Hu, X.-Q.; Lu, L.-Q.; Angew. Chem. Int. Ed. 2013, 52, 534–561. (d) Bendelsmith, A. J.; Xiao, W.-J. Visible Light Photoredox-Controlled Reactions of N- Kim, S. C.; Wasa, M.; Roche, S. P.; Jacobsen, E. N. Enantioselective Radicals and Radical Ions. Chem. Soc. Rev. 2016, 45, 2044–2056. (d) Synthesis of �-Allyl Amino Esters via Hydrogen Bond-Donor Catal- Kärkäs, M. D. Photochemical Generation of Nitrogen-Centered ysis. J. Am. Chem. Soc. 2019, 141, 11414–11419. Amidyl, Hydrazonyl, and Imidyl Radicals: Methodology Develop- (22) Wohlfarth, C. Permittivity (Dielectric Constant) of Liquids. ments and Catalytic Applications. ACS Catal. 2017, 7, 4999–5022. In CRC Handbook of Chemistry and Physics, 97th edition, Haynes, (13) (a) Cecere, G.; König, C. M.; Alleva, J. L.; MacMillan, D. W. W. M.; Lide, D. R.; Bruno, T. J., Eds.; CRC, Press: Boca Raton, Flor- C. Enantioselective Direct α-Amination of Aldehydes via a Photore- ida, 2016; 6–199. dox Mechanism: A Strategy for Asymmetric Amine Fragment Cou- pling. J. Am. Chem. Soc. 2013, 135, 11521–11524. (b) Huang, X.; Webster. R. D.; Harms, K.; Meggers, E. Asymmetric Catalysis with Organic Azides and Diazo Compounds Initiated by Photoinduced Electron Transfer. J. Am. Chem. Soc. 2016, 138, 12636–12642. (c) Zhou, Z.; Li, Y.; Han, B.; Gong, L.; Meggers, E. Enantioselective catalytic β-amination through proton-coupled electron transfer fol- lowed by stereocontrolled radical–radical coupling. Chem. Sci., 2017, 8, 5757–5763.

Me O Me O H N Me N Ir photocatalyst NH NH Me O O Me O O N N chiral phosphate S S N N N Me N H thiol HAT catalyst Me O Me O blue LEDs Me Me 96:4 er Enantioselective Hydroamination Enabled by Sulfonamide N–H PCET