The Prowess of Photogenerated Amine Radical Cations in Cascade

Article pubs.acs.org/accounts

The Prowess of Photogenerated Amine Radical Cations in Cascade Reactions: From Carbocycles to Heterocycles Published as part of the Accounts of Chemical Research special issue “Photoredox Catalysis in Organic Chemistry”. Scott A. Morris, Jiang Wang, and Nan Zheng* Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, United States CONSPECTUS: Cascade reactions represent a class of ideal organic reactions because they empower efficiency, elegance, and novelty. However, development of cascade reactions remains a daunting task for synthetic chemists. Radicals are known to be well suited for cascade reactions. Compared with widely used carbon-based radicals, nitrogen-based radicals, such as neutral aminyl radicals and protonated aminyl radicals (amine radical cations), are underutilized, although they are behind some notable synthetic methods such as the Hofmann−Löffler−Freytag reaction. The constraint on their usage is generally attributed to the limited number of available stable precursors. Since amine radical cations offer increased reactivity and selectivity in chemical transformations compared with neutral aminyl radicals, their generation is of utmost importance. Recently, a surge of reports has been revealed using visible light photoredox catalysis. It has been demonstrated that amines can act as an electron donor in a reductive quenching cycle while the amine itself is oxidized to the amine radical cation. Although a number of methods exist to generate amine radical cations, the photochemical formation of these species offers many practical advantages. In this Account, we discuss our journey to the development of annulation reactions with various π-bonds and electrophilic addition reactions to alkenes using photogenerated amine radical cations. Various carbocycles and heterocycles are produced by these reactions. In our annulation work, we first show that single electron photooxidation of cyclopropylanilines to the amine radical cations triggers ring opening of the strained carbocycle, producing distonic radical cations. These odd-electron species are shown to react with alkenes and alkynes to yield the corresponding cyclopentanes and cyclopentenes in an overall redox neutral process. Further development of this annulation reaction allows us to achieve the [4 + 2] annulation of cyclobutylanilines with alkynes. In our work on electrophilic addition reactions to alkenes, we reveal that photogenerated amine radical cations are capable of undergoing the electrophilic addition reactions to alkenes to form a variety of indoles and indolines. This chemistry represents a rare oxidative C−N bond-forming reaction using visible light. Conclusions drawn from observational results and proposed mechanisms are outlined in this Account. Additionally, open discussion of our successes and deficiencies in our experiences will give readers helpful insights as to how these species tend to react. The overall utility of photogenerated amine radical cations has yet to reach its full potential. With our current results, we anticipate more new transformations can still be derived from the ring opening processes of cyclopropylanilines and cyclobutylanilines under visible light photocatalysis. Additionally, since utilizing photogenerated amine radical cations in C−N bond-forming reactions has practically been absent in literature, we are confident more new reactions have yet been exploited.

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INTRODUCTION

The chemistry of amine radical cations is usually determined by the functionality around its periphery. For instance, although deprotonation is a major pathway, amine radical cations have been shown to undergo irreversible C−C bond cleavage, electrophilic addition, and hydrogen atom abstraction, which are all determined by the nitrogen atom’s substituents.4 Our group has recently been intrigued by the synthetic potential of photogenerated amine radical cations, particularly their use in cascade reactions. Chemists have generated amine radical cations using various approaches, including the use of UV light with a photosensitizer,5 strong stoichiometric

Compared with carbon radicals, which are considered to be mainstream in synthetic chemists’ toolbox, nitrogen-centered radicals are rather underutilized. The limited number of available precursors often constrains their wide use in organic synthesis.1 Synthetically, amine radical cations (protonated aminyl radicals) are typically preferred over neutral aminyl radicals in large part due to their increased electrophilicity, their ability to add to alkenes, and their propensity to undergo synthetically useful transformations, such as the formation of cyclic amines as seen in the Hofmann−Lö ffler−Freytag reaction.2 In addition, amine radical cations show heightened reactivity and selectivity over neutral aminyl radicals, adding further credence to their importance in chemical synthesis.3 © XXXX American Chemical Society

Received: May 29, 2016

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DOI: 10.1021/acs.accounts.6b00263 Acc. Chem. Res. XXXX, XXX, XXX−XXX

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Accounts of Chemical Research oxidants,6 enzyme oxidation,7 anodic oxidation,8,9 and visible light photochemistry.10 We specifically target the formation of amine radical cations by direct one-electron oxidation of the corresponding amines using visible light photoredox catalysis. This approach overcomes some commonly observed shortcomings in other methods, such as instability of precursors, use of toxic reagents (e.g., Bu3SnH), and harsh conditions (e.g., strongly acidic conditions) and the need for special apparatus (e.g., quartz). Visible light photoredox catalysis has been a subject of great importance recently, largely due to its ability to generate oddelectron species such as carbon- and nitrogen-centered radicals from stable organic substrates with full valence electrons.11 Amines are typically used as stoichiometric sacrificial electron donors to generate the highly reducing species that initializes radical reactions with organic substrates, and amine radical cations are concomitantly formed. This process is referred to as a reductive quenching cycle, one of the three main cycles for quenching the photoexcited state (Scheme 1).4,12 However,

yielded an unexpected adduct which, upon further analysis, was determined to be the endoperoxide adduct derived from a [3 + 2] annulation with oxygen (Scheme 2A). We speculated Scheme 2. Initial Discovery of the [3 + 2] Annulation Using Cyclopropylanilines

that, as anticipated, the N−N bond cleavage would occur first to produce cyclopropylaniline, which could then undergo the [3 + 2] annulation with oxygen. To verify this hypothesis, we prepared cyclopropylaniline and subjected it to the identical reactions conditions, which yielded the same endoperoxide (Scheme 2B), giving further credence to the proposed [3 + 2] annulation pathway. In order for the annulation to occur, the highly strained cyclopropane ring would need to open first, react with the π bond of the reaction partner, and then close to complete the transformation. The key to this annulation reaction centers on the well-established ring opening reaction of the radical cation of cyclopropylanilines, which would give rise to the corresponding distonic radical cation capable of participating in the annulation in a stepwise fashion (Scheme 3).

Scheme 1. Photogenerated Amine Radical Cations Using a Reductive Quenching Cycle

Scheme 3. Cyclopropylaniline Ring Opening to Generate a Reactive Distonic Radical Cation chemists have only recently exploited amines’ dual role as the sacrificial electron donor and a substrate, which allows the amine to not only reduce the photocatalyst but also serve as a reactive substrate for useful transformations. In our attempts to exploit amines’ dual role, we were able to form a variety of carbocycles and heterocycles using cascade processes initialized by amine radical cations. Our first report, focusing on annulation reactions of cyclopropyl- and cyclobutyl-anilines with alkenes and alkynes, reveals a redox-neutral pathway centered on a ring-opening process to form a reactive distonic ion. Our second usage afforded indoles and indolines by utilizing photogenerated amine radical cations as electrophilic addition partners to alkenes. This work was carried out using benign aerobic reaction conditions and stands in contrast to similar indole syntheses.

Since our group’s goal was to exploit the reactivity of photogenerated amine radical cations, this system seemed appropriate for further study and examination. Furthermore, although distonic radical cations are well-established species in the gas phase, their reactivity in solution phase is not well understood. From the limited published data, they exhibit unique reactivity distinct from conventional radical cations and related even-electron ions.14 We rationalized that this distonic radical cation possesses a dual functionality in which the nucleophilic radical has the capacity to act as a nucleophile with acceptors, such as alkenes in a Giese reaction,15 while the electrophilic iminium ion could engage in a subsequent ring closure as an electrophile with the resulting radical from the Giese reaction to complete the transformation.16

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C−C BOND CLEAVAGE AS A POWERFUL TOOL FOR THE CONSTRUCTION OF CARBOCYCLES Our group’s initial work in photoredox-catalyzed C−C and C− N bond formation tandems began with [3 + 2] annulation reactions of cyclopropylanilines with olefins. The discovery of this chemistry began with a serendipitous result stemming from our previous work in photoinduced N−N bond cleavage of aromatic hydrazines.13 In what appeared to be a trivial transformation, photocleavage of the aromatic hydrazine bearing a cyclopropyl group

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[3 + 2] ANNULATION USING ALKENES AND CYCLOPROPYLANILINES We immediately decided to test this reaction system using styrene in the presence of oxygen to generate the corresponding carbocycle.17 Our initial results, obtained by performing the reaction with 2 mol% Ru(bpz)3(PF6)2 in B


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Accounts of Chemical Research

observed in the monocyclic case. When we tested our hypothesis using styrene and an angular-methyl-bearing bicycle, we were pleased to isolate the annulation product 3 as a 4:1 mixture of diastereomers in 77% combined yield, which presumably proceeds through the distonic radical cation int 1 (Scheme 5). This result stands in direct contrast to the monocyclic case in which tertiary amines failed to react. We reasoned that this phenomenon was likely due to the higher ring strain built in fused bicyclic cyclopropanes. Carbocycles 4 and 5 were acquired using the optimized conditions, both of which display variability on the bicycle, albeit low diastereoselectivity. However, in order to further enhance the diastereoselectivity, an angular tert-butyl-bearing bicyclic cyclopropylaniline was subjected to the annulation conditions with the para-methoxy analogue of styrene, which yielded fused 5,5-carbocycle 6 as a single isomer in 30% yield. We attributed the low yield to a sluggish ring opening process or slow addition to the iminium ion to close the ring, since we recovered roughly 50% of the starting material. To justify the observed diastereoselectivity in the [3 + 2] annulation using bicyclic cyclopropylanilines and alkenes, we applied the Beckwith−Houk model, which is generally used to predict the diastereoselectivity of the cyclization of hexenyl radicals (Figure 1).19 We determined that if the hydrogen on the radical carbon is axial to the R1 on the iminium, then the 1,3-diaxial interaction between R1 and R2 is obviated.

nitromethane, gave modest amounts of annulation product 2 (21%) although 100% conversion of 1 was observed (Table 1, entry 1). Presumably, the annulation of the distonic Table 1. Reaction Optimization for the [3 + 2] Annulation

entry

conditions

catalyst

time (h)

yield of 2 (%)

1 2 3 4

open to air degassed degassed degassed

Ru(bpz)3(PF6)2 Ru(bpz)3(PF6)2 Ru(bpy)3(PF6)2 Ir(ppy)2(dtbbpy)PF6

12 3 12 12

21 96 79 73

radical cation with oxygen was competitive against with styrene, resulting in low yield of 2. Further optimization revealed that the desired [3 + 2] annulation required degassed conditions, which yielded 2 as a single regioisomer in 96% yield, albeit as a 1:1 mixture of diastereomers (entry 2). We also noted that under the optimized conditions, other photoredox catalysts failed to match the productivity compared with Ru(bpz)32+ (entries 3 and 4), which bolsters an impressive 1.31 V reduction potential for its excited state (Ru(bpz)32+*/Ru(bpz)3+ versus Ag/AgCl). We subsequently developed a substrate scope that took into consideration both olefin and N-cyclopropylaniline alterations, which is summarized in Scheme 4. As anticipated, we were able to generate a variety of annulation products in moderate to high yields (40−87%). Although the highest reaction efficiency was observed using styrene as the olefin component, we were delighted to find that acrylonitrile and 1-phenyl-1,3-butadiene participated in the annulation as well. We discovered that internal alkenes failed to react under the prescribed conditions, presumably due to steric hindrance, so it was not surprising that the conjugated diene’s terminal double bond was more reactive in the [3 + 2] annulation. Our next goal was to test the viability of using bicyclic cyclopropanes, readily synthesized via Kulinkovich−de Meijere reaction of amide precursors,9,18 to give the corresponding 5,5and 6,5-fused carbocycles. Furthermore, we rationalized that conformational bias imposed by the constraint of bicyclic cyclopropanes could improve the poor diastereoselectivity

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REACTION EXPANSION: UTILIZING TERMINAL ALKYNES, ENYNES, AND DIYNES Following this report, our group revealed further improvements to the substrate scope, documented in subsequent accounts.20 In these instances, we aimed to eliminate diastereoselectivity by using alkynes as the annulation partner to yield the corresponding cyclopentenes. We were also intrigued by the possibility to introduce an alkene functionality into the carbocycle, thus allowing for further elaboration into other useful products. Since alkynes innately have lower reactivity toward the radical addition than the alkene counterparts, a stronger light was shown to be necessary for an efficient annulation.21 As expected, however, the optimized conditions were identical to those described in our first annulation report. Initially, we found that terminal alkynes bearing radicalstabilizing groups, such as the phenyl group, and electronwithdrawing groups were effective partners in these transformations. However, we were particularly impressed when a variety of diynes and enynes reacted well with cyclopropylani-

Scheme 4. Summarized Substrate Scope Using Monocyclic Cyclopropylanilines

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Accounts of Chemical Research Scheme 5. Summarized Substrate Scope Using Bicyclic Cyclopropylanilines

reactivity was more complicated, because the olefin’s steric bulk influenced which π system (alkene or alkyne) participated in the annulation. We found that when dealing with sterically unhindered alkenes, the alkene moiety was the major reacting site whereas the alkyne moiety was favored in the cases involving sterically hindered alkenes. In certain instances when distinguishing between the alkene and alkyne by steric bulk or electronic factors became less clear, poor selectivity was often observed, resulting in a complicated mixture of both predictable and unidentified annulation products. We also noted that, as expected from literature precedence22 and our previous annulation report using alkenes,17 tertiary amines failed to react in this transformation, likely due to a slower ring opening process.

Figure 1. Diastereoselectivity model for bicyclic cyclopropylamines.

lines to give added functionality to the annulation product (Scheme 6). The diynes, whether symmetrical or asymmetrical, exhibited excellent regioselectivity and provided the highest yields when bearing electron-withdrawing groups. Enyne

Scheme 6. Expansion of the [3 + 2] Annulation Using Various Alkynes

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Accounts of Chemical Research Scheme 7. Rationale for Observed Regioselectivity Using Diynes

Scheme 8. Utilizing Substituted Cyclopropanes in the [3 + 2] Annulation

Scheme 9. Oxidative Cleavage of Requisite Aryl Group

We started our study by subjecting α-methylcyclopropylaniline to the optimized conditions with phenylacetylene. After 15 h, we were delighted to observe the α-substituted annulation product 11, albeit in only 33% yield (Scheme 8). We next turned our attention to β-substituted cyclopropylanilines. Both methyl- and phenyl-substitutions were amenable to the annulation, yielding carbocycles 12 and 13 in 46% and 30% yields, respectively. Additionally, we note that the observed regioselectivity of the final product is derived from intermediates similar to int 2, which possess a stabilized carbon radical. The N-aryl substituent quickly emerged to be a critical constituent for these transformations as they were shown to lower the redox potential of amines.23 Cyclic voltammetry experiments on both N-cyclopropylaniline and an N-

Since regioselectivity became a focused point of discussion with diynes and enynes, we decided to probe further into this phenomenon. Using diynes as a representative, we performed DFT calculations on model systems such as vinyl radicals 9 and 10 that reflected the proposed intermediates 7 and 8, respectively (Scheme 7). As expected, resonance-stabilized vinyl radical 9, which led to the major regioisomer, was found to be 10.5 kcal/mol more stable than vinyl radical 10, which led to the minor regioisomer.20b We then shifted our focus to studying substituted cyclopropylanilines, focusing specifically on the cyclopropane ring. We realized that decorating the cyclopropane could result in a larger substrate scope and further improve the utility of this chemistry, since, in our previous reports, we had only examined modified cyclopropanes in the bicyclic examples with alkenes.17 E


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Accounts of Chemical Research alkylcyclopropylamine revealed roughly a 0.6 V lower oxidation peak potential when the nitrogen atom bears a phenyl rather than an alkyl group.17 We realized that this posed a limitation to our chemistry; therefore, we set our final focus on the removal of the requisite aryl group. Oxidative cleavage has shown to be effective in the removal of electron-rich N-aryl groups, typically being mediated by strong oxidants like ceric ammonium nitrate (CAN), periodic acid, or trichloroisocyanuric acid (TCCA).24 We synthesized a variety of cyclopropylamines bearing a removable aryl group in hopes they would participate in the annulation reaction. Among the groups screened, the para-methoxy phenyl (PMP) group was found to be the best, being capable of undergoing the annulation reaction while also being removable. Indeed, we were excited to see that the annulation reaction proceeded in 47% yield to give the corresponding PMP-bearing cyclopentene 14, which after much screening was cleaved using CAN/H2SO4 and then acylated to give amide 15 in 68% yield over 2 steps (Scheme 9). In accordance with the data presented in these reports, an overall redox-neutral pathway was proposed (Scheme 10).

Scheme 11. Key Physical Data of Cyclobutylaniline and Cyclopropylaniline

11B).27 On the other hand, it was reported that fragmentation of amine radical cations was significantly faster than their neutral aminyl radical counterpart.28 Since amine radical cations were the proposed intermediate to undergo the ring opening, we felt that the ring opening’s rate might be sufficient for the annulation to occur. With these in mind, we used 4-tert-butyl-N-cyclobutylaniline 16 and phenylacetylene as the model substrates to examine the proposed [4 + 2] annulation (Table 2).29 The catalyst system

Scheme 10. Proposed Mechanism for the [3 + 2] Annulation

Table 2. Reaction Optimization for the [4 + 2] Annulation

entry

Upon irradiation with visible light, the photocatalyst gets excited to its triplet state, which is capable of oxidizing the cyclopropylaniline to the corresponding amine radical cation. Subsequent C−C bond cleavage results in the distonic radical cation, which adds via a radical pathway to the π bond, whether alkene or alkyne. The resulting alkyl or vinyl radical then cyclizes onto the iminium ion to yield another amine radical cation that can readily be reduced by the Ru+ complex, yielding both the annulation product and starting photocatalyst.

catalyst

1

Ru(bpz)3(PF6)2

2 3 4

Ru(bpz)3(PF6)2 Ir(ppy)2(dtbbpy)PF6 Ir(ppy)2(dtbbpy)PF6

conditions CH3NO2, 2 LED MeOH, 2 LED MeOH, 2 LED MeOH, 1 LED

time (h)

GC yield of 17 (%)

16

30

16 12 16

37 97 27

optimized for the [3 + 2] annulation, 2 mol% Ru(bpz)3(PF6)2 in nitromethane under nitrogen, was initially examined. The desired [4 + 2] annulation product 17 was obtained in 30% yield after irradiatioin for 16 h by two 18 W LED light bulbs (entry 1). Encouraged by this success, we underwent systematic screening of the catalyst system. Methanol was found to be a better solvent than nitromethane (entry 2). Switching the catalyst to Ir(ppy)2(dtbbpy)PF6 made the largest impact on the annulation, affording product 17 in 97% yield (entry 3). The use of two lights was critical because they provided more photon flux and higher temperature. By comparison, irradiation with one LED light furnished product 17 in 27% yield (entry 4). The need for stronger light in the [4 + 2] annulation was consistent with the premise that the amine radical cation of cyclobutylanilines undergoes the ring opening more slowly than that of cyclopropylanilines (vide supra). We next established the substrate scope by varying substituents on the N-aryl group and alkyne. Substituents with various electronic and steric characters were generally tolerated, and heterocycles showed no ill effects toward the annulation (Scheme 12). With respect to alkynes, we also observed a notable difference in the substrate scope between the [3 + 2] and [4 + 2] annulation. Unlike the [3 + 2] annulation, the [4 + 2] annulation was not limited to the annulation with terminal alkynes, and internal alkynes also

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[4 + 2] ANNULATION: OPENING CYCLOBUTANE USING VISIBLE LIGHT Encouraged by the successful results of the [3 + 2] annulation of cyclopropylanilines with various π bonds, we questioned whether cyclobutylanilines could participate in the annulation reaction in an analogous manner to produce the [4 + 2] annulation products. Similar ring strain between cyclobutane and cyclopropane (27.5 vs 26.7 kcal/mol)25 as well as oxidation peak potential between cyclopropyl- and cyclobutyl-aniline lent credence to this idea, as shown in Scheme 11A. However, ring opening of cyclobutylcarbinyl radicals was reported to be significantly slower than that of cyclopropylcarbinyl radicals.26 The same phenomenon was observed with respect to cyclobutyl-n-propylaminyl and cyclopropyl-n-propylaminyl radicals, whereas the rate constant of the latter was determined to be more than 100 times larger than the former (Scheme F



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AMINE RADIAL CATIONS AS A WAY TO FORM SUBSTITUTED HETEROCYCLES One of the hallmark features of carbon radicals is their ability to engage in inter- and intramolecular addition to various types of π bonds in cascade reactions. We wondered whether photogenerated amine radical cations could mimic carbon radicals in these types of cascade reactions leading to indoles and indolines, two important motifs in medicinal chemistry. Similar transformations have been successfully realized using metals, such as Pd. Our approach was centered on a C−N bond forming photoredox cascade in which an Umpolung reaction of anilines was employed. The amine radical cations of anilines acted as an electrophile, while alkenes functioned as a nucleophile. Thus, it was mechanistically distinct from the Pd-catalyzed process and offered advantages, including lower reaction temperatures. More importantly, our approach utilized the cascade reaction initialized by the photogenerated amine radical cations, which could furnish fused indoles and indolines. Initially, we designed styrene 18 bearing an ortho sulfonamide as the substrate to test the cascade reaction, as shown in Scheme 15A. The sulfonamide group was chosen as the nucleophile because it was not photo-oxidizable.32 The alkene moiety would be oxidized to the electrophilic alkene radical cation by single electron photooxidants, such as the photoexcited Ru(bpz)32+*. The targeted C−N bond formation would be realized via nucleophilic capture of the radical cation by the sulfonamide group. Instead of yielding the anticipated αphenyl indole, dimerization adduct 19 was observed. We immediately revised our strategy and decided to attempt an Umpolung approach in which an electron-rich amine, such as aniline, would be oxidized to the amine radical cation by the photoexcited Ru(bpz)32+*. The amine radical cation would then act as an electrophile in the addition reaction to the alkene. The use of amine radical cations in electrophilic addition reactions to alkenes is an established pathway and has been applied to the synthesis of many interesting molecules.33 The sulfonamide group was replaced by an aniline, as shown in Scheme 15B with compound 20, which resulted in no reaction. This was a puzzling observation, since cyclic voltammetry experiments revealed an oxidation peak potential of 0.9 V for 20, which suggested that 20 should be readily oxidized by the photoexcited Ru(bpz)3(PF6)2 (1.31 V reduction potential for Ru(bpz)32+*/Ru(bpz)3+ vs Ag/AgCl).34,35 Nonetheless, since electron-rich para-alkoxyphenyl groups lower the oxidation

Scheme 12. [4 + 2] Annulation Scope of Monocyclic Cyclobutylanilines

reacted with predictable regioselectivity based on the substituent’s ability to stabilize the vinyl radical. We attributed this difference to cyclobutylanilines’ increased stability toward light and the primary carbon radical of the distonic radical cation derived from cyclobutylanilines being more nucleophilic.30 We sought to further expand the substrate scope by studying cis fused 5,4-membered and 6,4-membered bicyclic cyclobutylanilines, which were readily prepared in four steps. These cyclobutylanilines generally gave higher yields of the annulation products than the monocyclic ones, and modest to good diastereoselectivities were achieved (Scheme 13). The opening of bicyclic cyclobutylanilines was completely regioselective, producing the more stable carbon radical.

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[4 + 2] ANNULATION IN FLOW In line with other reported photochemistries, we encountered long reaction time and difficulty in scale up during our studies of the [4 + 2] annulation. Flow is often considered to be the de facto solution to these issues. We applied flow to the [4 + 2] annulation of cyclobutylanilines with alkenes, alkynes, and diynes.31 The reaction time was often cut by half in flow (Scheme 14A). A gram scale annulation was also successfully achieved in flow with a slightly lower yield (Scheme 14B).

Scheme 13. [4 + 2] Annulation Scope of Bicyclic Cyclobutylanilines

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Accounts of Chemical Research Scheme 14. [4 + 2] Annulation in Flow

Scheme 15. Preliminary Data for Indole Synthesis Using Visible Light

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peak potential of anilines, the phenyl group was exchanged for a para-methoxyphenyl (PMP) group (compound 21). When this compound was subjected to the photochemistry conditions, the desired indole 22 was formed. This result marked the firstreported example of electrophilic addition to an olefin using photogenerated amine radical cations. With this new reaction in hand, we set out to find the optimal reaction conditions and a substrate scope tolerant of this process.34

VISIBLE LIGHT PHOTOCATALYZED SYNTHESIS OF SUBSTITUTED INDOLES

Initial screening revealed Ru(bpz)3(PF6)2 as the optimal photocatalyst in acetonitrile (Table 3, entries 1 and 2). It was found that silica gel significantly increased reaction efficiency, probably due to its mild acidity and ability to adsorb oxygen (entry 2). This reaction only proceeded under aerobic conditions, suggesting a critical role of atmospheric oxygen for catalyst turnover (entry 3). Ru(bpy)3(PF6)2, possessing a H



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FUSED INDOLINE SYNTHESIS USING TETHERED STYRENYL ANILINES We later expanded the scope of this chemistry by exploiting the presumable benzylic cation to generate fused indolines.38 We wondered whether a tethered styrenyl aniline bearing a nucleophile could efficiently trap the cation in an intramolecular SN1 fashion to yield the C2,C3-fused indoline. To test this hypothesis, we synthesized styrenyl aniline 26 and subjected it to the photochemistry conditions (Scheme 18). Fused indoline 27 was obtained as a single diastereomer. Further reaction screening identified the optimal conditions to include Ru(bpy)3(PF6)2 and acetic acid with exposure to air. A substrate scope was also developed for this chemistry, which included a variety of oxygen- and nitrogen-based nucleophiles with a range of structural modifications (Scheme 19A). As expected, the olefin’s geometry had no effect on the diastereoselectivity of the reaction, since >99:1 dr was observed in all cases. Additionally, the 3,4,5-trimethoxyphenyl group was identified as the removable N-aryl group, which was cleaved using CAN in sulfuric acid, thus improving the substrate scope (Scheme 19B). These findings revealed a photocatalyzed indoline formation by way of diamination39 or aminohydroxylation40 of alkenes to form two consecutive chiral centers, including a tetrasubstituted carbon center.

Table 3. Reaction Screen

entry

additive

catalyst

time (h)

yield of 23 (%)

1 2 3 4 5

none silica gel silica gel (degassed) silica gel TFA

Ru(bpz)3(PF6)2 Ru(bpz)3(PF6)2 Ru(bpz)3(PF6)2 Ru(bpy)3(PF6)2 Ru(bpz)3(PF6)2

24 5 24 24 24

31 88 0 19 21

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lower reduction potential for its photoexcited state (0.78 V), was less effective in the transformation (entry 4). In order to test the acidity parameters, trifluoroacetic acid was examined, and a lower yield of the indole product 23 was obtained due to immediate decomposition of the product by the strong acid (entry 5). A substrate scope was then developed to demonstrate applicability of this new reaction. Virtually every position of the indole ring could be varied when generating monosubstituted indoles. In fact, the only structural requirement for this chemistry was the para-alkoxyphenyl group on the nitrogen atom. A condensed substrate scope is shown in Scheme 16. An additional observation was made when using internal olefins such as 24 in Scheme 17. In this case, a 1,2-alkyl shift/ aromatization generated the 2,3-disubstituted indole product. This phenomenon has been documented by the Driver group when a benzylic cation intermediate is formed.36 Therefore, we concluded that our chemistry would likely go through a similar intermediate. In all our 1,2-shift cases, aromatic groups were found to migrate much faster than alkyl groups, resulting in a single disubstituted indole product of type 25. This chemistry marked a new way to use photogenerated amine radical cations, effectively achieving amination of vinylic C−H bonds using mild, aerobic conditions. The only other known example to date was reported by Knowles, in which his group generated substituted pyrrolidines and piperidines through olefin hydroamination using photogenerated amine radical cations.37

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MECHANISM A mechanism for these transformations is detailed in Scheme 20. Upon visible light irradiation, the photogenerated amine radical cation, which remains in the protonated form presumably due to the presence of the weak acid, adds electrophilically to the styrene, generating the quaternary ammonium salt. Although we present this as an electrophilic addition, we cannot rule out a 5π pericyclic Nazarov-like cyclization,41 which could give the same intermediate. Subsequent deprotonations and redox manipulations provide the key benzylic cation, which sets up the indole formation by way of deprotonation or 1,2-shift/deprotonation. Alternatively, the key benzylic cation is trapped intramolecularly by a tethered nucleophile to afford a fused indoline.

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CONCLUSION In summary, photogenerated amine radical cations were exploited to generate a variety of carbocycles and heterocycles.

Scheme 16. Summarized Substrate Scope

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Accounts of Chemical Research Scheme 17. 1,2-Shift Substrate Scope

Scheme 18. Examination of Indoline Formation

Scheme 20. Proposed Mechanism

Scheme 19. Substrate Scope and Removal of paraAlkoxyphenyl Component

synthetically useful benzylic cation intermediate, and a series of redox manipulations. All of our chemistries display the power of photogenerated amine radical cations to participate in cascade reactions to provide structurally diverse and interesting products.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Funding

Our initial reports centered on the C−C bond cleavage of photogenerated amine radical cations derived from cyclopropyl- and cyclobutyl-anilines to generate distonic radical cations. These odd-electron species displayed some unique reactivity, permitting the annulation reaction with various alkenes and alkynes in an overall redox neutral process. We also developed a new application of photogenerated amine radical cations in electrophilic addition to tethered alkenes. Substituted indoles and indolines were synthesized from styryl anilines. The amine radical cations set up the cascade reaction including the electrophilic addition to the styrene, the formation of a

This work was funded by the University of Arkansas, the Arkansas Biosciences Institute, NIGMS (Grant P30 GM103450), and NSF (Career CHE-1255539). Notes

The authors declare no competing financial interest. Biographies Scott Morris received a B.S. in Biochemistry from Stephen F. Austin State University in 2010. He is now completing his Ph.D. in organic chemistry at the University of Arkansas under the guidance of J


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Professor Nan Zheng, focusing on the formation of C−N bonds using visible light photoredox catalysis. Jiang Wang received his B.S. in Chemistry from Lanzhou University, China. He joined the University of Arkansas in 2011 and is currently a Ph.D. candidate under the direction of Professor Nan Zheng, studying photoredox catalysis. Nan Zheng did his undergraduate studies at the University of Science and Technology of China and obtained his Ph.D. from the University of Michigan with Professor William R. Roush. He then performed postdoctoral studies at MIT with Stephen L. Buchwald before starting his independent career at the University of Arkansas in 2008. His research interest is centered on photoredox catalysis.

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ACKNOWLEDGMENTS

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REFERENCES

We are grateful to all our co-workers for their outstanding intellectual and experimental contribution.

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The Prowess of Photogenerated Amine Radical Cations in Cascade

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