A General Approach to Catalytic Alkene Anti-Markovnikov

Article pubs.acs.org/accounts

A General Approach to Catalytic Alkene Anti-Markovnikov Hydrofunctionalization Reactions via Acridinium Photoredox Catalysis Published as part of the Accounts of Chemical Research special issue “Photoredox Catalysis in Organic Chemistry”. Kaila A. Margrey and David A. Nicewicz* Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States CONSPECTUS: The development of methods for anti-Markovnikov alkene hydrofunctionalization has been a focal point of catalysis research for several decades. The vast majority of work on the control of regioselectivity for this reaction class has hinged on transition metal catalyst activation of olefin substrates. While progress has been realized, there are significant limitations to this approach, and a general solution for catalysis of antiMarkovnikov hydrofunctionalization reactions of olefins does not presently exist. In the past several years, this research lab has focused on alkene activation by single electron oxidation using organic photoredox catalysts to facilitate anti-Markovnikov hydrofunctionalization. By accessing reactive cation radical intermediates, we have realized a truly general approach to anti-Markovnikov olefin hydrofunctionalization reactions. We have identified a dual organic catalyst system consisting of an acridinium photooxidant, first reported by Fukuzumi, and a redox-active hydrogen atom donor that accomplishes a wide range of hydrofunctionalization reactions with complete anti-Markovnikov regiocontrol. This method relies on single electron oxidation of the alkene to reverse its polarity and results in the opposite regioselectivity for hydrofunctionalization. In 2012, we disclosed the anti-Markovnikov hydroetherification of alkenols employing an acridinium photocatalyst and a hydrogen atom donor that proceeds via interwoven polar and radical steps. This general catalyst system has enabled several important reactions in this area, including anti-Markovnikov alkene hydroacetoxylation, hydrolactonization, hydroamination, and hydrotrifluoromethylation reactions. More recently, we have also delineated conditions for intermolecular anti-Markovnikov hydroamination reactions of alkenes using either triflamide or nitrogen-containing heteroaromatic compounds such as pyrazole, indazole, imidazole, and 1,2,3-triazole. Further development led to a method for the anti-Markovnikov addition of mineral acids to olefins using lutidinium halide salts as convenient reagents to deliver the mineral acids. Acids including HCl, HF, H3PO4, and MeSO3H all participate in the hydrofunctionalization reactions, even with alkenes that are highly prone to polymerization. A combination of transient and steady-state absorption spectroscopy tools were employed to observe alkene cation radicals and the resultant acridine radical, lending support for an electron transfer mechanism. The origin of the anti-Markovnikov selectivity in these reactions is likely the result of a reversible addition of the nucleophile to the alkene cation radical resulting in a greater population of the more stable radical. Loss of a proton followed by reaction of the radical intermediate with the hydrogen atom donor completes the transformations. Again, by means of transient absorption spectroscopy, oxidative turnover of the acridine radical was observed to complete the dual catalytic cycle mechanistic picture. Despite the prevalence of Markovnikov, or “normal”, addition of H−X to alkenes, direct access to the opposite, or anti-Markovnikov, regioselectivity from the same starting materials remains a challenge to which a number of research groups have devoted significant time in the development of catalytic strategies.3,4 The vast majority of anti-Markovnikovselective hydrofunctionalization reactions have been achieved using transition metal catalysts. Beller4 and Hartwig5 have disclosed anti-Markovnikov hydroamination reactions of terminal alkynes and styrenes using rhodium catalysts, while

1. INTRODUCTION Perhaps one of the most fundamental transformations in organic synthesis is the reaction of an acid (H−X, where X = OR, O2CR, NR2, halogen, etc.) with an alkene to afford a net addition product, the so-called Markovnikov adduct. From an atom-economy standpoint, the accounting is ideal and the starting materials are readily available. Use of the Markovnikov addition reaction provides the modern global economy with some of the most vital commodity chemicals such as alcohols and amines,1,2 presents synthetic chemists with a reliable disconnection in complex molecule synthesis, and is the basis for important reactivity, including cationic olefin polymerization. © XXXX American Chemical Society

Received: June 18, 2016

A

DOI: 10.1021/acs.accounts.6b00304 Acc. Chem. Res. XXXX, XXX, XXX−XXX

Article

Accounts of Chemical Research Grubbs has developed a hydration methodology using a ruthenium catalyst system.6 To date, the scope of these reactions is mainly monosubstituted styrenesaliphatic alkenes are rarely represented, save for examples where the acid reactant is preoxidized.7−9 Certainly heteroatom-centered radical additions to alkenes exist, but prefunctionalization of the heteroatom is required, hydrogen atom abstraction by the heteroatom radical often competes, and in intramolecular reactions the standard radical cyclization kinetics apply, often giving rise to Markovnikov adducts.10,11 Over the past several years we have been focused on an alternative strategy to reverse the regioselectivity of hydrofunctionalization by exploiting the known reactivity of olefin cation radicals. Polar nucleophiles such as amines and alcohols are known to add to the less substituted position of alkene cation radicals, constituting the first step of an antiMarkovnikov sequence (Scheme 1). Often, the charge density

Scheme 2. Some Common Oxidant and Alkene Redox Potentialsa

Scheme 1. Regioselectivity in Addition of Polar Nucleophiles to Olefin Cation Radicals a

All values in MeCN vs SCE.

tion potentials of many metal catalysts can be tuned through ligand modification, there are still limitations on how electronrich the alkenes must be for oxidation to the cation radical. To aid potential users of this chemistry, a more exhaustive library of oxidation and reduction potentials of commonly used compounds has been produced by our lab along with a computational tool to predict these values.20 At the onset of this work, we aimed to develop a cationradical-based anti-Markovnikov hydrofunctionalization reaction that would be (1) catalytic and (2) able to functionalize more electron-deficient alkenes.21 In 2004, Fukuzumi disclosed an organic photocatalyst, 9-mesityl-10-methylacridinium perchlorate, Mes-Acr-MeClO4, which has a reported excited-state reduction potential (E*red = *Mes-Acr-Me+/Mes-Acr-Me·) of +2.06 V vs SCE.22,23 Because of the highly positive reduction potential of this photocatalyst and the reported long-lived excited state, we believed that it could facilitate single electron oxidation of a variety of alkenes, including unactivated alkenes. This would be followed by nucleophilic addition to furnish antiMarkovnikov hydrofunctionalization adducts. Since catalytic variants of cation radical-mediated hydrofunctionalizations have been difficult to achieve, we thought it would be necessary that the photocatalyst possess reversible redox reactivity. Additionally, it would be crucial to determine how to regenerate the acridinium catalyst after single electron transfer (SET) from the alkene. Mechanistically, we hypothesized that oxidation of the olefin by *Mes-Acr-Me+ would form 3.2 and Mes-Acr-Me· (Scheme 3). Reversible nucleophilic addition to the cation radical and subsequent hydrogen atom transfer would afford the desired adduct 3.5. Careful selection of a hydrogen atom donor could facilitate rapid trapping of 3.4 (step 4), preventing undesired free radical pathways. In selecting H atom donors, we envisioned that Donor· would oxidize Mes-Acr-Me· to complete the catalytic cycle. To accomplish this, an exothermic hydrogen atom transfer step was a prerequisite. We initiated studies in this area investigating intramolecular hydroalkoxylation reactions of alkenol 4.1 (Scheme 4), as it presented a significant challenge due to its high oxidation potential (Ep/2(4.1·+/4.1) = +1.95 V vs SCE).20 We evaluated

on 1.1 is found at the less substituted position, but this is not always the case and is highly structure dependent.12 As a single piece of data, the charge density distribution is not the best predictor of regioselectivity for nucleophilic additions to 1.1, but rather, the site selectivity is best rationalized by the resultant distonic cation radical stability. On the basis of computational studies,12 Arnold proposed that of the two competing distonic cation radicals, 1.2 and 1.3, the more substituted radical 1.3 is likely more highly populated.13−15 Gassman demonstrated the utility of this reactivity profile by developing anti-Markovnikov hydrolactonization and hydroetherification methods.16,17 The body of this work, while regioselective, was low-yielding and required nearly stoichiometric amounts of a photooxidant, 1-cyanonaphthalene. While the reactivity of radical cations in the context of antiMarkovnikov hydrofunctionalization reactions is promising, generation of these highly reactive species via single electron oxidation of an alkene requires a potent oxidant. Redox agents that are capable of this oxidation oftentimes deliver oxygen atoms rather than participate in single electron oxidation, and thus, careful selection of the oxidant is required. 18,19 Cyanoarenes are quite powerful photooxidants (e.g., 1-CNNp, Scheme 2) but are susceptible to side reactivity wherein the cyano group can often act as a nucleofuge following single electron reduction. Commonly used photoredox catalysts such as [Ru(bpy)3]2+ and [Ru(bpz)3]2+ can oxidize electron-rich alkenes (Ep/2 < +1.3 V), but less oxidizable alkenes such as terminal styrenes, as well as mono-, di-, and trisubstituted alkenes, have oxidation potentials outside the range of these transition-metal-based polypyridyl catalysts. While the oxidaB


Article

Accounts of Chemical Research

Scheme 3. Proposed General Mechanism of Photoredox-Catalyzed Anti-Markovnikov Alkene Hydrofunctionalization Reactions

neutralize the acid formed. Importantly, PMN was nearly always observed unchanged in the crude reactions, pointing to its potential to be employed in catalytic quantities. A variety of alkenols furnished the desired anti-Markovnikov adducts when subjected to these reaction conditions (Scheme 5). Trisubstituted aliphatic alkenes were used to demonstrate

Scheme 4. Optimization of the Hydroetherification Hydrogen Atom Donora

Scheme 5. Scope of Intramolecular Anti-Markovnikov Alkenol Hydroetherification

a

Reactions were irradiated with a 15 W 450 nm light-emitting diode (LED) flood lamp. bDetermined by 1H NMR analysis. c50 mol % H atom donor was used.

hydrogen atom donors with relatively low bond dissociation energies (BDEs) (20:1) in 73% yield. We proposed that the low BDE of PMN (77 kcal/mol) allowed for facile hydrogen atom abstraction, but other hydrogen atom donors with similarly low BDEs failed to afford comparable yields (Scheme 4). In part, this could be explained by the electrophilic nature of the C−H bond in PMN being appropriately matched with the resultant nucleophilic tertiary alkyl radical, which likely results in a lower transition state energy for the proposed hydrogen atom transfer event.24 In addition, the PMN radical is sufficiently oxidizing to regenerate the photocatalyst, and the PMN anion can act as a mild base to

the formation of five- to seven-membered-ring systems (5.3− 5.5). Furthermore, a challenging 6-endo cyclization was shown to form tetrahydropyran 5.6 in good yield compared with the more kinetically favorable 5-exo cyclization. Styrene derivatives with both electron-donating and -withdrawing substituents on the aryl ring delivered the products in good yields, and the absence of geminal disubstitution did not negatively impact the reaction efficiency (5.7). C


Article


2. INTRAMOLECULAR HYDROAMINATION Rhodium-catalyzed intramolecular anti-Markovnikov hydroamination of unsaturated amines was reported by Hartwig and remains one of the only examples.25 In a manner analogous to the hydroetherification reaction, we believed that this photoredox system could facilitate anti-Markovnikov hydroamination reactions.26 Because of the susceptibility of amines to oxidation, careful nucleophile selection was vital to the intended reactivity. Initial attempts with primary amines were unsuccessful, so we turned our attention to protected primary amines and observed hydroamination products in modest yields. Screening of a variety of nitrogen protecting groups showed that tosylate (Ts)- and tert-butoxycarbonate (Boc)protected amines gave similar yields of the intended adducts; however, we opted to employ the Ts-derived amines for ease of characterization. With appropriate substrates in hand and knowledge that the nitrogen was sufficiently nucleophilic for cyclization, we turned our attention to the choice of hydrogen atom donor. Unfortunately, PMN afforded the product in only 16% yield, but after a more exhaustive H atom donor screen, 0.2 equiv of thiophenol furnished the desired product 6.3 in 70% yield (Scheme 6).

3. INTRAMOLECULAR AMIDE AND THIOAMIDE CYCLIZATIONS On the basis of the precedent of intramolecular hydrofunctionalizations from our lab, we developed the cyclization of amides and thioamides onto alkenes to produce oxazolines and thiazolines27 with phenyl disulfide as the cocatalyst. Various substitution patterns on the alkene and the amide were tolerated to construct five- or six-membered rings (7.3−7.5), and resident stereocenters imparted modest diastereoselectivities (7.6) (Scheme 7). Thioamides also participated in the desired cyclization, affording thiazolines with both styrenyl and disubstituted alkenes (7.7−7.9). Scheme 7. Scope of the Intramolecular Addition of Amides and Thioamides to Alkenes

Scheme 6. Scope of the Intramolecular Hydroamination

The oxidation potentials of the unsaturated amides and thioamides provided valuable mechanistic insight. The starting unsaturated thioamide that gave rise to 7.8 had a far lower redox potential (Ep/2 = +1.53 V vs SCE) than the analogous unsaturated amide derivative (Ep/2 > +2.5 V vs SCE). In addition, substrate 7.9 was formed as a nearly 1:1 mixture of Markovnikov and anti-Markovnikov regioisomers, indicating a potential change in mechanism. On the basis of these data and the excited-state redox data for the acridinium salt, it is likely that formation of 7.8 and 7.9 occurs via oxidation of the thioamide functionality, resulting in intermediate 7.11 after deprotonation, allowing for a thiyl radical cyclization onto the alkene.

4. INTERMOLECULAR HYDROACETOXYLATION To advance the methodology that we developed in intramolecular systems, we next investigated the use of the catalyst system for intermolecular anti-Markovnikov alkene hydrofunctionalization reactions. We preliminarily focused on the development of carboxylic acid additions to alkenes. The use of phenyl malononitrile and 9-cyanofluorene as H atom donors resulted in low yields of the anticipated adduct, but the use of benzenesulfinic acid as the cocatalyst afforded a significant increase in yield in the presence of exogenous base. To simplify the reaction setup, we ultimately employed sodium benzene-

Employing 1,1-disubstituted alkenes to form piperidines such as 6.4 was possible via a 6-endo cyclization, again favored despite a more kinetically accessible 5-exo cyclization. The formation of 6.5 demonstrated that even challenging 5-endo cyclizations are achievable, furnishing the octahydroindole product with good diastereocontrol (12:1). The nucleophile scope was not limited to sulfonamides and included sulfamates to forge adducts such as 6.6. A variety of styrenyl derivatives were used, demonstrating a wide substrate scope with electronrich arenes (6.7). D


Article


addition to this being indicative of hydrogen atom transfer as the rate-determining step (Step 4, Scheme 3), it also points to acetic acid (pKa = 4.8), which is present in 40-fold excess relative to PhSO2Na, as the ultimate source of hydrogen atoms via proton exchange with benzenesulfinic acid (pKa = 2.1).

sulfinate as the cocatalyst in the absence of base (Condition A, Scheme 8). A second set of conditions using thiophenol was also developed (Condition B) that proved to be useful for acids other than acetic acid. Scheme 8. Catalytic Anti-Markovnikov Addition of Carboxylic Acids to Olefins

5. INTERMOLECULAR HYDROAMINATION A potentially powerful strategy for the synthesis of amines is the direct intermolecular hydroamination of alkenes, and many examples affording Markovnikov reactivity are known.28,29 Formal anti-Markovnikov addition reactions have been accomplished by Buchwald using hydroxylamine derivatives,30 and Lalic has intercepted hydroborated alkene intermediates via Cu-catalyzed amination reactions.8 Additionally, Studer has disclosed an innovative strategy for nitrogen-centered radical addition to alkenes from aminated cyclohexadiene precursors.11 While these methods are all excellent for regiocontrolled formation of alkylamines, all of the aforementioned methods require either a preoxidized amine or interception of an alkylborane species. We hoped to be able to accomplish an antiMarkovnikov-selective intermolecular alkene hydroamination with simple amines and alkenes without the need for prefunctionalized starting materials. After examining a variety of ammonia surrogates such as TsNH2, NsNH2, and BocNH2, we found that TfNH2 afforded the highest yield of anti-Markovnikov hydroamination with βmethylstyrene using 20 mol % thiophenol as the cocatalyst, furnishing the expected addition product in 87% isolated yield. Perhaps unsurprisingly, after analysis of the crude reaction mixtures, we found that the thiophenol was converted to phenyl disulfide. This prompted us to investigate the use of 10 mol % phenyl disulfide in place of thiophenol to avoid the odors and toxicity associated with thiophenol, and we were pleased to find that the anti-Markovnikov adduct could be isolated in 89% yield. While we did not yet fully understand the mechanism behind the interchangeable use of phenyl disulfide for thiophenol (vide inf ra), we further examined the scope of the transformation with respect to both reaction partners (Scheme 9). The reaction tolerated a variety of substituents at all positions on the arene ring (9.3). Allylic amines and alcohols were shown to produce diamines and amino alcohols (9.4).

Investigation of the reaction scope again revealed that βmethylstyrenes bearing a range of electronics were excellent substrates (8.4). A range of carboxylic acids was reacted with anethole to form the anticipated adducts (8.5) in high yields, with the more sterically demanding acids requiring increased reaction times. Trisubstituted olefins such as 2-methyl-2-butene and 1-phenylcyclohexene furnished 8.6 and 8.7, respectively, albeit with poor diastereocontrol. Surprisingly, acid-labile alkenes such as Cbz-protected tetrahydropyridine reacted under these conditions with complete regiocontrol to afford 8.8. Even dihydropyran produced the desired regioisomer with benzoic acid, albeit in a 1:2 ratio with the Markovnikov adduct, underscoring that the photoredox conditions are competitive with acid-promoted acetal formation. To track the source of the hydrogen atom in the reaction, we employed acetic acid-d4 in the reaction with anethole using sodium benzenesulfinic acid as the cocatalyst. While we observed 87% deuterium incorporation in the final adduct (8.10), the reaction time was noticeably longer (120 vs 24 h) and the yield much lower (38% vs 71%) using acetic acid-d4. In

Scheme 9. Intermolecular Anti-Markovnikov Addition of Amines to Alkenes

E


Article

Accounts of Chemical Research Trisubstituted alkenes were able to afford products 9.5 and 9.6 with modest diastereoselectivity. Extending the nucleophile scope to include nitrogencontaining heterocycles allowed a wider range of hydroamination adducts such as 10.2 to be accessed through this methodology and provided a simple method to introduce this valuable class of aromatic compounds onto sp3-hybridized carbon atoms (Scheme 10).31 Heterocycles such as pyrazole

Scheme 11. Hydrogen Chloride Addition to Alkenes

Scheme 10. Scope of Nitrogen Heterocycle Addition to Olefins

instead. In conjunction with 4-methoxythiophenol as the hydrogen atom donor, the desired hydrochlorination adduct was formed with good levels of reaction efficiency. Electron-withdrawing arene substituents furnished the antiMarkovnikov adducts in high yields with good selectivity (11.4 and 11.5), but electron-donating substituents afforded products in lower yields with modest selectivity for the anti-Markovnikov product (3:1) (11.6). Terminal styrenes as well as α-substituted styrenes gave the anticipated hydrochlorination adducts 11.7 and 11.8, also with complete regiocontrol using the lutidinium HCl salt (Condition B). We postulated that the increased yields of the hydrohalogenation adducts when 4-methoxythiophenol was used in place of thiophenol were due to the increased basicity of the conjugate thiolate of 4-methoxythiophenol, allowing for more efficient turnover of the hydrogen atom donor and catalyst. In addition to hydrochlorination, anti-Markovnikov hydrofluorination of alkenes was also accomplished by a slight modification of the catalyst system. Initial screens of fluoride sources failed to furnish the hydrofluorinated adducts. Further investigation of the crude reaction mixtures revealed that catalyst decomposition was occurring via nucleophilic demethylation of the N-methylacridinium moiety, resulting in deactivation of the catalyst due to loss of the main chromophore. In an effort to insulate the catalyst from this degradation pathway, we synthesized N-phenyl derivative 12.3, which ultimately proved vital to the success of this reaction (Scheme 12). Though the N-phenyl variant was more stable toward the reaction conditions than the parent catalyst, nucleophilic dearomatization of the acridinium moiety was also observed when CsF was used, leading us to further derivatize the photocatalyst. Fukuzumi had previously reported the 9-mesityl-2,7-dimethylacridinium catalyst,23 and we envisioned that introduction of the N-phenyl substitution in place

(10.3), indazole (10.4), and 1,2,3-triazole (10.5 and 10.6; preference for N1 over N2 alkylation) also participated in the hydroamination reaction.

6. ANTI-MARKOVNIKOV ADDITION OF MINERAL ACIDS TO ALKENES Olefin hydrohalogenation is one of the most fundamental reactions in organic chemistry and almost exclusively proceeds with “normal” selectivity. The only halogen acid that reacts in an anti-Markovnikov sense is HBr, which requires the use of hydrogen peroxide to ultimately generate bromine radicals that add to the alkene with inverse selectivity. The remaining halogen acids cannot participate in this reaction mode, as the enthalpic driving force from either breaking the H−X bond (in the case of HF and HCl) or the alkene π bond (in the case of HI) renders the net reactions endothermic. We viewed this as an opportunity to employ organic photoredox catalysis once again to provide a mild method for anti-Markovnikov alkene hydrohalogenation. Again, using Mes-Acr-Me+ along with phenyl disulfide, we were able to form the desired anti-Markovnikov hydrochlorination product using pivaloyl chloride and TFE to generate anhydrous hydrogen chloride in situ.32 The photoredox pathway was shown to outcompete the background addition of hydrogen chloride since β-methylstyrene produced adduct 11.3 with greater than 20:1 selectivity for the antiMarkovnikov regioisomer (Scheme 11). However, when the photocatalyst or the hydrogen atom donor was omitted, the Markovnikov product was observed. While generation of the nucleophile in situ was a viable method for hydrochlorination, we ultimately found that the more convenient and functionalgroup-tolerant 2,6-lutidinium hydrochloride salts could be used F


Article


7. MECHANISTIC STUDIES Given the novelty of this acridinium/hydrogen atom donor dual catalyst system, we were keen to gain insight into the general mechanism of the alkene hydrofunctionalization reactions.33 Regarding the catalyst excited-state topology, Verhoeven reported that the first singlet locally excited (LE) state of *Mes-Acr-Me+ (13.1), localized on the acridinium, undergoes intramolecular charge transfer (CT) from the mesityl substituent.34 Both Verhoeven34 and Fukuzumi35 reported a long-lived transient species; however, the nature of this intermediate has been contested. Fukuzumi provided evidence for transient species CTT (13.3) having CT character and reported an associated reduction potential of E*red = +1.88 V vs SCE (Scheme 13). Verhoeven, on the other hand, believed

Scheme 12. Catalytic Anti-Markovnikov Mineral Acid Addition to Olefins

Scheme 13. Jablonski Diagram for Mes-Acr-Me+

a

5 mol % catalyst 12.3, phenyl disulfide (10 mol %), 2,6-lutidine (10 mol %), and dibutyl phosphate (2 equiv) in CH2Cl2 (0.7 M). b5 mol % catalyst 12.4, 4-methoxythiophenol (20 mol %), and the 2,6-lutidine salt of the sulfonate nucleophile (2 equiv) in CH2Cl2 (0.5 M).

that the transient species is the locally excited triplet state LET (13.4), which has a reduction potential of E*red = +1.45 V vs SCE.34 While this previous work could be plausible mechanistic support for olefin oxidation, we observed reactivity of alkenyl substrates with oxidation potentials greater than the reported reduction potentials.21,26 A series of catalyst excited-state quenching studies provided valuable insight into the rate at which single electron oxidations occur. Stern−Volmer plots revealed that highly oxidizable alkenes such as anethole quenched the catalyst excited state at near diffusion-controlled rates (9.9 × 109 M−1 s−1), and alkenes that were not as electron-rich, such as alkenol substrates used in the hydroetherification chemistry, still exhibited high quenching rates (1.2 to 5.9 × 109 M−1 s−1). The cocatalysts thiophenol and phenyl disulfide also quenched the catalyst excited state at rates comparable to those of the alkenes, somewhat deepening the mystery of how these cocatalysts are able to coexist in solution with the alkene substrates. We felt that knowledge of whether an LE or CT state is the active oxidant in our system is important for reaction development and catalyst design. If the reaction occurs through an LE state, modifications to the acridinium could perturb the catalyst reduction potential, limiting the charge transfer pathway. However, if the active oxidant is the CT state, then the reduction potential is limited by the oxidizing power of the mesityl cation radical. To probe this, we synthesized Xyl-AcrMe+, a catalyst containing a xylyl group, which is known not to participate in charge transfer formation, in place of the mesityl substituent.36,37

of the N-methyl one could render the catalyst more stable toward the fluorination conditions. When this new catalyst (12.4) was used along with 4-nitrophenyl disulfide as the cocatalyst and Et3N·3HF as a source of hydrogen fluoride, the yields of the desired anti-Markovnikov hydrofluorination products were dramatically improved. Several β-methylstyrenes were reactive under the fluorination conditions with complete regiocontrol (12.5−12.7), In addition, α-methylstyrene, indene, and 3-vinylthiophene could be utilized as substrates to furnish the corresponding hydrohalogenation adducts (12.8−12.10). Finally, we were able to extend this general transformation to include additional inorganic acid equivalents, such as phosphoric acid and sulfonic acid derivatives. The use of phosphoric acids as nucleophiles required the use of more sterically encumbered catalyst 12.4 and phenyl disulfide. Similarly to the hydrochlorination chemistry, the use of 2,6lutidinium salts proved to be a viable route for the installation of both phosphates (12.11) and sulfonates (12.12), although the addition of the more basic 4-methoxythiophenol was required. G


Article

Accounts of Chemical Research We observed that *Xyl-Acr-Me+ was quenched by βmethylstyrene, indicating that the LE pathway is operative and that the presence of CT states on the catalyst is not necessary for alkene oxidation. SET from alkenes to this class of catalyst could be more efficient if the unproductive CT pathway were not possible; however, the active oxidant may still be the CT state for *Mes-Acr-Me+. To support the involvement of cation radical intermediates, we turned to laser flash photolysis techniques in an effort to observe these fleeting species. Irradiation of a mixture of MesAcr-Me+ and anethole resulted in a new feature in the transient absorption spectrum near 600 nm after subtraction of the contribution of Mes-Acr-Me· to the overall absorption spectrum. The red-shifted absorption closely matches the previously reported absorption spectrum for anethole cation radical generated via photoionization techniques. In addition, cation radicals of anethole, β-methylstyrene, and alkenols used in the hydroetherification reactions were observed, and on the basis of the calculated lifetimes, we were able to estimate the low end for the rate of nucleophilic capture by the tethered alcohol in the 5-exo cyclization mode (2.5 × 107 s−1). We also wanted to gain insight into how phenyl disulfide participates in the catalytic cycle. Our working hypothesis was that phenylthiyl radicals are generated and then are responsible for acridine radical oxidation and regeneration of Mes-Acr-Me+, potentially setting up an equilibrium between the disulfide and thiophenol. Indeed, when Ph2S2 was used as the cocatalyst, thiophenol was detected at the end of the reaction by in situ IR experiments, supporting this postulated equilibrium. It is unlikely that the disulfide bond is reductively cleaved because of the very negative reduction potential of Ph2S2 (Ep = −1.65 V vs Ag/AgCl). For this reason, we believed that homolytic cleavage of the sulfur−sulfur bond occurs. To test this, a simple crossover reaction was performed between Ph2S2 and 14.2, two symmetrical disulfides, in the presence of Mes-Acr-Me+ with irradiation (Scheme 14). A mixture of the two starting

Scheme 15. (A) Acridine Radical Oxidation in the Presence of Phenyl Disulfide; (B) Bleach in Absorbance at 520 nm (blue) Corresponding to Consumption of 15.1, Fit to a Monoexponential Curve (dashed red) with an Observed Rate Constant of (2.5 ± 0.4) × 105 s−1, and Appearance of a Signal at 445 nm (gold) Corresponding to the Formation of 15.2

photolytically generated PhS·. This signifies that Mes-Acr-Me· can undergo oxidation by the thiyl radical (16.6) generated after hydrogen atom transfer (HAT), allowing the acridinium photocatalyst to reenter the cycle. On the basis of DFT calculations, the hydrogen atom donors PMN and thiophenol are oriented so that the aryl ring is perpendicular to the bond that is cleaved (C−H and S−H, respectively). The free energy barrier for HAT was calculated to be 9.5 kcal/mol for the thiol compared with 15.1 kcal/mol for PMN, demonstrating that the dihedral angle required for HAT puts significant strain on the sterically encumbered benzylic carbon of PMN. This difference in the activation barriers results in an approximately 104-fold difference in the rates for the two hydrogen atom donors. On the basis of the significantly lower activation barrier, it is easily understood why thiophenol is a more efficient hydrogen atom donor. Given all of these pieces of data, we believe that a general mechanism for the anti-Markovnikov hydrofunctionalization of alkenes developed in our lab is best described by Scheme 16. Single electron transfer from the alkene to the excited acridinium photocatalyst, *Mes-Acr-Me+, forms the reactive cation radical intermediate 16.2. Nucleophilic addition to the cation radical affords 16.3, after which deprotonation gives radical 16.4. Subsequent HAT from thiophenol furnishes the desired anti-Markovnikov hydrofunctionalization adduct 16.5. On the basis of our mechanistic studies, we believe that the thiyl radical 16.6 is able to act as a single electron oxidant to regenerate Mes-Acr-Me+. Thiolate 16.7 participates in a proton transfer step to regenerate the thiophenol catalyst, demonstrating the dual catalytic cycle required for the developed antiMarkovnikov hydrofunctionalizations of alkenes.

Scheme 14. Disulfide Crossover Experiment

disulfides and the crossover product 14.1 in a 1:1:2 ratio was found. Surprisingly, 14.1 was observed without the photocatalyst, which is most likely explained by S−S bond homolysis due to the spectral overlap of the disulfide absorption and LED emission. Stoichiometric generation of the intermediate Mes-Acr-Me· (15.1) by reduction with CoCp2 allowed an investigation of whether phenyl disulfide could oxidize MesAcr-Me· to MesAcr-Me+ (Scheme 15A). Through transient absorption spectroscopy, direct observation of the catalyst turnover from 15.1 to 15.2 was observed in the presence of phenyl disulfide (Scheme 15B). Mes-Acr-Me+ forms at a rate equal to that for the disappearance of Mes-Acr-Me· when in the presense of H


Article

Accounts of Chemical Research Scheme 16. Proposed General Mechanism for Catalytic Anti-Markovnikov Alkene Hydrofunctionalization

■

8. SUMMARY AND OUTLOOK An array of anti-Markovnikov alkene hydrofunctionalization reactions have been accomplished employing a dual catalyst system consisting of an acridinium photoredox catalyst in conjunction with a redox-active hydrogen atom donor or surrogate (aryl disulfide). The use of photophysical and computational techniques has supported the intervention of alkene cation radicals, and the key redox turnover event for the catalyst system was observed spectroscopically. There are still remaining challenges such as the inclusion of terminal aliphatic alkenes in the reaction scope as well as enantioselective variants. However, the prospects for employing this catalytic reactivity in complex molecule synthesis and potentially in the synthesis of compound libraries for medicinal chemistry applications are high.

■

ACKNOWLEDGMENTS This work was supported by a David and Lucile Packard Foundation Fellowship in Science and Engineering (D.A.N.), Award R01 GM098340 from the National Institute of General Medical Sciences, and a Boehringer Ingelheim New Investigator Award.

■

REFERENCES

(1) Papa, A. J. Propanols. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley-VCH: Weinheim, Germany, 2000. (2) Bergfeld, M.; Nywlt, M. Method for Manufacturing tertButylamine. US5648546 A, July 15, 1997. (3) Han, L.-B.; Tanaka, M. Chem. Commun. 1999, 395−402. (4) Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Catalytic Markovnikov and Anti-Markovnikov Functionalization of Alkenes and Alkynes: Recent Developments and Trends. Angew. Chem., Int. Ed. 2004, 43, 3368−3398. (5) Utsunomiya, M.; Hartwig, J. F. Ruthenium-Catalyzed AntiMarkovnikov Hydroamination of Vinylarenes. J. Am. Chem. Soc. 2004, 126, 2702−2703. (6) Dong, G.; Teo, P.; Wickens, Z. K.; Grubbs, R. H. Primary Alcohols from Terminal Olefins: Formal Anti-Markovnikov Hydration via Triple Relay Catalysis. Science 2011, 333, 1609−1612. (7) Strom, A. E.; Hartwig, J. F. One-Pot Anti-Markovnikov Hydroamination of Unactivated Alkenes by Hydrozirconation and Amination. J. Org. Chem. 2013, 78, 8909−8914. (8) Rucker, R. P.; Whittaker, A. M.; Dang, H.; Lalic, G. Synthesis of Tertiary Alkyl Amines from Terminal Alkenes: Copper-Catalyzed Amination of Alkyl Boranes. J. Am. Chem. Soc. 2012, 134, 6571−6574. (9) Zhu, S.; Niljianskul, N.; Buchwald, S. L. Enantio- and Regioselective CuH-Catalyzed Hydroamination of Alkenes. J. Am. Chem. Soc. 2013, 135, 15746−15749. (10) Beckwith, A. L. J.; Hay, B. P.; Williams, G. M. Generation of Alkoxyl Radicals from O-Alkyl Benzenesulphenates. J. Chem. Soc., Chem. Commun. 1989, 1202−1203. (11) Guin, J.; Mück-Lichtenfeld, C.; Grimme, S.; Studer, A. Radical Transfer Hydroamination with Aminated Cyclohexadienes Using Polarity Reversal Catalysis: Scope and Limitations. J. Am. Chem. Soc. 2007, 129, 4498−4503. (12) Arnold, D. R.; Chan, M. S.; McManus, K. A. Photochemical Nucleophile-Olefin Combination, Aromatic Substitution (photoNOCAS) Reaction, Part 12. Factors Controlling the Regiochemistry of the Reaction with Alcohol as the Nucleophile. Can. J. Chem. 1996, 74, 2143−2166. (13) Neunteufel, R. A.; Arnold, D. R. Radical Ions in Photochemistry. I. 1, 1-Diphenylethylene Cation Radical. J. Am. Chem. Soc. 1973, 95, 4080−4081.

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies Kaila A. Margrey studied chemistry at the College of William & Mary, where she obtained her B.S. and M.S. in 2012 and 2013, respectively, with Professor Jonathan Scheerer. In 2013, she moved to the University of North Carolina at Chapel Hill, beginning her graduate studies with Prof. Nicewicz. Her research has primarily focused on the development of novel transformations using acridinium photoredox catalysts. David A. Nicewicz completed his B.S. and M.S. in chemistry in 2000 and 2002, respectively, at the University of North Carolina at Charlotte under the direction of Professor Craig A. Ogle and his Ph.D. with Professor Jeffrey S. Johnson in 2006 at the University of North Carolina at Chapel Hill. From 2007 to 2009, he was a Ruth L. Kirschstein National Institutes of Health Postdoctoral Researcher in the laboratories of Professor David MacMillan at Princeton University. In July 2009, he returned to the University of North Carolina at Chapel Hill as an Assistant Professor and in 2015 was promoted to Associate Professor. Research in the Nicewicz laboratory focuses on harnessing photoinduced single electron redox manifolds to discover and invent new and complex transformations in organic synthesis. I


Article

Accounts of Chemical Research (14) Arnold, D. R.; Du, X.; Chen, J. The Effect of Meta- or ParaCyano Substitution on the Reactivity of the Radical Cations of Arylalkenes and Alkanes. Radical Ions in Photochemistry, Part 34. Can. J. Chem. 1995, 73, 307−318. (15) Mangion, D.; Arnold, D. R. Photochemical Nucleophile−Olefin Combination, Aromatic Substitution Reaction. Its Synthetic Development and Mechanistic Exploration. Acc. Chem. Res. 2002, 35, 297−304. (16) Gassman, P. G.; Bottorff. Photoinduced Lactonization. A Useful but Mechanistically Complex Single Electron Transfer Process. J. Am. Chem. Soc. 1987, 109, 7547−7548. (17) Gassman, P. G.; Bottorff, K. J. Anti-Markovnikov Addition of Nucleophiles to a Non-Conjugated Olefin via Single Electron Transfer Photochemistry. Tetrahedron Lett. 1987, 28, 5449−5452. (18) Nicewicz, D. A.; Nguyen, T. M. Recent Applications of Organic Dyes as Photoredox Catalysts in Organic Synthesis. ACS Catal. 2014, 4, 355−360. (19) Romero, N. A.; Nicewicz, D. A. Organic Photoredox Catalysis. Chem. Rev. 2016, DOI: 10.1021/acs.chemrev.6b00057. (20) Roth, H.; Romero, N.; Nicewicz, D. Experimental and Calculated Electrochemical Potentials of Common Organic Molecules for Applications to Single-Electron Redox Chemistry. Synlett 2016, 27, 714−723. (21) Hamilton, D. S.; Nicewicz, D. A. Direct Catalytic AntiMarkovnikov Hydroetherification of Alkenols. J. Am. Chem. Soc. 2012, 134, 18577−18580. (22) Fukuzumi, S.; Kotani, H.; Ohkubo, K.; Ogo, S.; Tkachenko, N. V.; Lemmetyinen, H. Electron-Transfer State of 9-Mesityl-10Methylacridinium Ion with a Much Longer Lifetime and Higher Energy Than That of the Natural Photosynthetic Reaction Center. J. Am. Chem. Soc. 2004, 126, 1600−1601. (23) Ohkubo, K.; Mizushima, K.; Iwata, R.; Souma, K.; Suzuki, N.; Fukuzumi, S. Simultaneous Production of p-Tolualdehyde and Hydrogen Peroxide in Photocatalytic Oxygenation of p-Xylene and Reduction of Oxygen with 9-Mesityl-10-Methylacridinium Ion Derivatives. Chem. Commun. 2010, 46, 601. (24) Roberts, B. P. Polarity-Reversal Catalysis of Hydrogen-Atom Abstraction Reactions: Concepts and Applications in Organic Chemistry. Chem. Soc. Rev. 1999, 28, 25−35. (25) Takemiya, A.; Hartwig, J. F. Rhodium-Catalyzed Intramolecular, Anti-Markovnikov Hydroamination. Synthesis of 3-Arylpiperidines. J. Am. Chem. Soc. 2006, 128, 6042−6043. (26) Nguyen, T. M.; Nicewicz, D. A. Anti-Markovnikov Hydroamination of Alkenes Catalyzed by an Organic Photoredox System. J. Am. Chem. Soc. 2013, 135, 9588−9591. (27) Morse, P. D.; Nicewicz, D. A. Divergent Regioselectivity in Photoredox-Catalyzed Hydrofunctionalization Reactions of Unsaturated Amides and Thioamides. Chem. Sci. 2015, 6, 270−274. (28) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Hydroamination: Direct Addition of Amines to Alkenes and Alkynes. Chem. Rev. 2008, 108, 3795−3892. (29) (a) Kumar, K.; Michalik, D.; Garcia Castro, I.; Tillack, A.; Zapf, A.; Arlt, M.; Heinrich, T.; Böttcher, H.; Beller, M. Biologically Active Compounds through Catalysis: Efficient Synthesis of N-(Heteroarylcarbonyl)-N′-(arylalkyl)piperazines. Chem. - Eur. J. 2004, 10, 746− 757. (b) Beller, M.; Trauthwein, H.; Eichberger, M.; Breindl, C.; Herwig, J.; Müller, T. E.; Thiel, O. R. The First Rhodium-Catalyzed Anti-Markovnikov Hydroamination: Studies on Hydroamination and Oxidative Amination of Aromatic Olefins. Chem. - Eur. J. 1999, 5, 1306−1319. (c) Utsunomiya, M.; Kuwano, R.; Kawatsura, M.; Hartwig, J. F. Rhodium-Catalyzed Anti-Markovnikov Hydroamination of Vinylarenes. J. Am. Chem. Soc. 2003, 125, 5608−5609. (d) Takaya, J.; Hartwig, J. F. Mechanistic Studies of Ruthenium-Catalyzed AntiMarkovnikov Hydroamination of Vinylarenes: Intermediates and Evidence for Catalysis through π-Arene Complexes. J. Am. Chem. Soc. 2005, 127, 5756−5757. (e) Brinkmann, C.; Barrett, A. G. M.; Hill, M. S.; Procopiou, P. A. Heavier Alkaline Earth Catalysts for the Intermolecular Hydroamination of Vinylarenes, Dienes, and Alkynes. J. Am. Chem. Soc. 2012, 134, 2193−2207. (f) Guin, J.; Mück-Lichtenfeld, C.; Grimme, S.; Studer, A. Radical Transfer Hydroamination with

Aminated Cyclohexadienes Using Polarity Reversal Catalysis: Scope and Limitations. J. Am. Chem. Soc. 2007, 129, 4498−4503. (g) Yasuda, M.; Kojima, R.; Tsutsui, H.; Utsuno- Miya, D.; Ishii, K.; Jinnouchi, K.; Shiragami, T.; Yamashita, T. Redox-Photosensitized Aminations of 1,2Benzo-1,3-Cycloalkadienes, Arylcyclopropanes, and Quadricyclane with Ammonia. J. Org. Chem. 2003, 68, 7618−7624. (30) Zhu, S.; Buchwald, S. L. Enantioselective CuH-Catalyzed AntiMarkovnikov Hydroamination of 1,1-Disubstituted Alkenes. J. Am. Chem. Soc. 2014, 136, 15913−15916. (31) (a) Wamhoff, H. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, U.K., 1984; Vol. 5, pp 669−732. (b) Dehne, H. In Methoden der Organischen Chemie, Vol. E8d; Schumann, E., Ed.; Thieme: Stuttgart, Germany, 1994; pp305−320. (c) Kolb, H. C.; Sharpless, K. B. Drug Discovery Today 2003, 8, 1128. (32) Wilger, D. J.; Grandjean, J.-M. M.; Lammert, T. R.; Nicewicz, D. A. The Direct Anti-Markovnikov Addition of Mineral Acids to Styrenes. Nat. Chem. 2014, 6, 720−726. (33) Romero, N. A.; Nicewicz, D. A. Mechanistic Insight into the Photoredox Catalysis of Anti-Markovnikov Alkene Hydrofunctionalization Reactions. J. Am. Chem. Soc. 2014, 136, 17024−17035. (34) Benniston, A. C.; Harriman, A.; Li, P.; Rostron, J. P.; van Ramesdonk, H. J.; Groeneveld, M. M.; Zhang, H.; Verhoeven, J. W. Charge Shift and Triplet State Formation in the 9-Mesityl-10Methylacridinium Cation. J. Am. Chem. Soc. 2005, 127, 16054−16064. (35) Fukuzumi, S.; Ohkubo, K.; Suenobu, T. Long-Lived Charge Separation and Applications in Artificial Photosynthesis. Acc. Chem. Res. 2014, 47, 1455−1464. (36) Kuruvilla, E.; Ramaiah, D. Selective Interactions of a Few Acridinium Derivatives with Single Strand DNA: Study of Photophysical and DNA Binding Interactions. J. Phys. Chem. B 2007, 111, 6549−6556. (37) Kuruvilla and Ramaiah (ref 36) reported that the iodide salt of Xyl-Acr+ possesses a CT singlet state in aqueous buffer exhibiting a fluorescence lifetime of τ = 3.6 ns, compared with the value of 17 ns measured in DCE in our hands.

J


A General Approach to Catalytic Alkene Anti-Markovnikov

Recommend Documents