A radical–polar crossover approach to complex nitrogen heterocycles via the triplet state

SUMMARY

The transition from radical to ionic reactivity is a key design feature of many photochemical reactions, enabling complex transformations not possible under either mechanistic regime alone. Ground-state alkenes are common substrates in existing methods of this type, serving as radical acceptors to generate open-shell intermediates from which the radical–polar crossover (RPC) event is oxidatively or reductively triggered by a photocatalyst. Here, we describe an alternative RPC mechanism proceeding via an alkene triplet diradical. In this transformation, an iodine radical liberated during a homolytic aromatic substitution step functions as a single-electron oxidant to generate an iminium electrophile that can be intercepted en route to complex natural-product-like amines. An enantioselective variant of the reaction, enabled by an oxidatively installed sulfinyl leaving group, points to the generality of this underdeveloped pattern of diradical reactivity, paving the way for other triplet-state reactions that incorporate both one- and two-electron bond-forming processes.

Graphical abstract

In brief

Precisely positioning a leaving group has been shown to divert certain alkene photocyclizations from isomerization—the usual result of this type of reaction—to iminium salt formation. Trapping this ionic intermediate with nucleophiles enables the rapid assembly of structurally complex and chemically diverse nitrogen-containing ring systems.

INTRODUCTION

The addition of carbon-centered radicals to ground-state alkenes offers a versatile route for the formation of challenging carbon–carbon bonds, and also enables an increase in molecular complexity through the onward reaction of the subsequently formed radical. This intermediate is often trapped in a radical termination step but may also react via a polar (non-radical) step.¹ When the initial formation of radicals is mediated by an excited-state photocatalyst, these intermediates can undergo a single-electron oxidation (to generate a cationic intermediate) or a single-electron reduction (to generate an anionic intermediate).^2–5 These ionic species may then engage in two-electron reactions to yield diverse products (Figure 1A).

Figure 1. Photochemical approaches to RPC reactions.

(A) Previous work: RPC can occur when alkenes function as radical acceptors; subsequent one-electron oxidation or reduction leads to intermediates that can be trapped in two-electron bond-forming processes. This reactivity can be exemplified in the reductive formation of cyclopropanes^6,7 and the oxidative generation of lactones⁸ from alkenes under photoredox catalysis.

(B) Previous work: alkene radical cations react with nucleophiles to generate radical intermediates; they do not themselves display radical reactivity. Thiols are frequently used to reduce these intermediates via a radical hydrogen atom transfer (HAT) mechanism and facilitate turnover of the highly oxidizing photocatalyst required to activate the alkene substrate⁹; alternatively, when used in stoichiometric quantities, copper(II) salts can promote RPC, permitting two successive two-electron bond-forming processes.¹⁰

(C) This work: a transition from diradical to ionic reactivity occurring from the triplet excited state. Following a regioselective radical cyclization step, ISC and SET lead to an iminium salt that can be intercepted through a polar nucleophilic mechanism.

PC, photocatalyst; EWG, electron-withdrawing group; Mes-Acr, mesityl acridinium; EnT, energy transfer; NuY, nucleophile (e.g., 1-methylindole).

This radical–polar crossover (RPC) is the basis of many photoredox processes and has enabled a wide range of impactful transformations.^{6–8,11–13} A conceptually related yet mechanistically distinct process is the reaction of alkene radical cations with nucleophiles to yield radical intermediates (Figure 1B). Notably, the Nicewicz laboratory has harnessed this reactivity to enable a wide array of photocatalytic anti-Markovnikov functionalizations of alkenes.⁹ Although a radical termination step (such as hydrogen atom transfer) usually follows nucleophilic addition to alkene radical cations, RPC can also be integrated into reaction sequences comprising these intermediates. An impressive example of this reactivity was reported by Yoon and colleagues involving the cyclization of pendent heteroatom nucleophiles onto alkenes following single-electron oxidation of the latter.¹⁰ However, while this reaction incorporates an RPC step, the transition does not enable a merger of radical and polar reactivities; instead, the copper-mediated sequence consists of two successive two-electron bond-forming steps, the latter of which (elimination to form a C=C bond) does not contribute to an increase in molecular complexity.

In contrast, RPC reactions have not been exploited where alkenes act as a chromophore rather than a radical acceptor or electron donor. This approach could allow for the combination of polar reactivities, such as nucleophilic addition, with diradical reactivities characteristic of triplet states but not accessible to either free radicals or alkene radical cations, such as six-electron photocyclization. Here we introduce one such RPC strategy. Following photochemical activation of an alkene by direct excitation or triplet energy transfer, a homolytic aromatic substitution (HAS) mechanism takes place in the triplet state, effectively “interrupting”¹⁴ a 6π-type photocyclization and giving rise to an iminium salt that can be trapped intra- or intermolecularly by diverse two-electron nucleophiles (Figure 1C). This photocyclization–cation trapping cascade^15,16 leads to the generation of complex three-dimensional templates containing an array of functional groups not present in the substrate, with high levels of both regio-(with respect to any arene meta-substituents) and diastereo-selectivity (with respect to the fully substituted ring junction). Thus, the transformation also contrasts with traditional (typically UV-mediated) 6π photocyclizations,^17–21 which give rise to isomerization products via singlet diradical/zwitterionic intermediates, with minimal control over the direction of cyclization in unsymmetrical substrates and no obvious opportunities for vicinal difunctionalization of the mutating chromophore.

RESULTS AND DISCUSSION

We have previously examined the energy transfer-mediated²² isomerization of N-aryl enaminones,²³ and observed that an outlier in their reactivity was that the ortho-iodinated substrate 1 led to the exclusive formation of indole 2 as a single regioisomer, without ipso-H diradical cyclization products 3 in detectable quantities (Figure 2A). It was hypothesized that this product arises from either the cyclization of a photolytically generated aryl radical onto the enone in a 5-endo-trig²⁴ fashion or a selective ipso-I substitution and net-eliminative cyclization process upon excitation of the enone to its triplet state.^25–27 Eliminative photocyclizations such as this have previously been applied in the generation of aromatic systems in natural products and the development of new materials.^28,29 We designed N-allyl substrate 4 to probe the formation of an aryl radical, reasoning that a 5-exo-trig mode would be competitive with any other cyclization (Figure 2B). In the presence of an iridium sensitizer and 467 nm light, 4 yielded indole 5 (86% yield), and bridged cyclobutane 6 (10% yield); 5-exo-trig cyclization products 7 were not observed. This result is consistent with energy transfer activation of the enone in 4 and subsequent ipso-I cyclization to yield 5, with competitive [2+2] cycloaddition onto the N-allyl group to yield 6.³⁰

Figure 2. Overview of reaction development.

(A) Observation of an unexpected product leads to the development of an eliminative alkene difunctionalization reaction.

(B) Tethering an alkene radical acceptor through nitrogen indicates that the intermediacy of an aryl radical is unlikely and that the observed reactivity is more consistent with a triplet-state mechanism. X = H or I.

(C) Reaction design and validation: the formation of an iminium salt as the primary photoproduct of the reaction is supported by the isolation of hemiaminal 11 upon the direct irradiation of a β-methylated substrate, 10, in which re-aromatization is prevented; treating the former compound with trifluoroacetic acid enables the identification of the putative iminium ion intermediate as enol 12.

A control experiment in which 4 was reduced using a neutral organic super-electron donor³¹ gave a mixture of 5-exo- and 5-endo-trig aryl radical cyclization products, demonstrating the viability of both cyclization modes whenever the aryl radical in question is generated thermally (see Section S3.3.1). Thus, the failure to observe 5-exo-trig products upon sensitized irradiation of 4 suggests that an aryl radical does not form under photochemical activation of this and related compounds. Instead, a mechanism involving the regioselective cyclization of an alkene triplet diradical is more likely (Figure 2C). We reasoned that such a process would lead initially to a radical pair, 8, which could be expected, upon intersystem crossing (ISC) and single-electron transfer (SET), to form an iminium iodide salt, 9. Thus, provided re-aromatization is prevented, it should be possible to effect a net-eliminative 1,2-difunctionalization of the alkene functional group in compounds such as 10 through the thermal trapping of this cationic photoproduct with different two-electron nucleophiles. This would represent a key strategic advance: typically, 6π-type photocyclizations do not allow for diversification through the nucleophilic (or electrophilic) trapping of an ionic intermediate (instead, the formation of singlet zwitterionic/diradical intermediates typically precedes hydrogen shift and/or proton transfer processes, as in our previous work^23,32). Our triplet-state approach to iminium ion formation would also constitute a distinct but complementary strategy to existing RPC processes. To explore this possibility, substrate 10, which absorbs weakly in the visible region and bears a methyl substituent at the enone β-position, was synthesized and irradiated with 427 nm light in an acetonitrile–water mixture. In the absence of a photocatalyst and the presence of potassium acetate, this yielded hemiaminal 11 in 89% yield as a single diastereoisomer. The observed product is consistent with in situ base-promoted hydrolysis of an iminium salt; this putative intermediate was formally generated and characterized by nuclear magnetic resonance (NMR) spectroscopy as enol species 12 by treating the hemiaminal product with trifluoroacetic acid in acetonitrile-d₃ solution.

With evidence in hand for the photochemical generation of an iminium cation, we sought to explore the scope of the reaction with respect to the nucleophilic coupling partner (Figure 3A). (Details of reaction optimization and considerations regarding the use of a photocatalyst can be found in Section S5.) Thus, irradiation of β-methyl substrate 10 with 427 nm light in the presence of N-methylindole in a polar solvent mixture gave the complex heterocycle 13 as a single diastereoisomer in 81% yield and >40:1 ratio of eliminative to non-eliminative cyclization. The N-substituent on the indole is not necessary for reactivity, and 14 can be isolated in 83% yield by the addition of 1H-indole as the nucleophile. Other π-rich heterocycles are also reactive: addition of 2,4-dimethylpyrrole yields 15 (68% yield), while 3-methoxythiophene affords 16 (44% yield) and 2-methylfuran leads to 17 (59% yield). Potassium trifluoroborate salts may also be used as nucleophiles in a process reminiscent of the borono-Petasis reaction,^33,34 enabling the formal addition of furan (18, 55% yield), styrenes (19, 66% yield), and alkynes (20, 53% yield). Reduction of the iminium cation through addition of triethylsilane led to 21 (80% yield); this process also enables the synthesis of the deuterated analog 22 (79% yield, >99% D). Addition of allyltrimethylsilane to form 23 was also successful (80% yield). The trimethylsilyl enol ether derived from acetophenone could be employed in anhydrous nitromethane solvent, in the presence of sodium trifluoroacetate, to generate 1,4-diketone 24 (57% yield), which was subsequently examined by single-crystal X-ray diffraction. Toluenesulfonylmethyl isocyanide (TosMIC) was added smoothly in aqueous acetonitrile to produce amide 25 in 74% yield and with complete diastereo-selectivity. We were also able to move beyond the formation of carbon–carbon bonds. Performing the reaction in the presence of diethylphosphite led to the formation of aminophosphonate 26 in 57% yield as the cis-diastereomer (19:1 diastereomeric ratio). Water (to afford 11 in 89% yield) and methanol (to give 27 in 77% yield) are also proficient trapping agents in the presence of bases. The potential of this process to generate complex natural-product-like³⁵ heterocycles was demonstrated by tethering a nucleophile to enable intramolecular trapping. Irradiation of 28, which bears a pendent carbamate functional group, led to the formation of bridged tetracycle 29 in 88% yield, the structure of which was confirmed through X-ray crystallography.

Figure 3. Scope of the reaction.

Variation of (A) the nucleophilic coupling partner (NuY) and (B) the substrate. Reaction conditions (unless otherwise stated): 10 or corresponding substrate (0.3 mmol, 1.0 equiv), NuY (0.9 mmol, 3.0 equiv), solvent(s) (v/v) (0.05 M) (TosMIC [3.0 equiv] and MeCN–H₂O [9:1] for all reactions in B), room temperature (r.t.), 2 × Kessil PR160L 427 nm lamps, 18 h. ^a5.0 equiv NuY. ^b1.5 equiv NuY. ^c6 h reaction time. ^d90 min reaction time. ^eThis compound was isolated and characterized without chromatographic purification owing to its instability on silica and alumina gels; the reported yield was measured for a 0.1 mmol-scale reaction by quantitative ¹H NMR spectroscopy against dimethyl terephthalate. ^f2 h reaction time. ^g3 h reaction time. ^h21 h reaction time. ⁱYield based on recovered starting material.

We were also able to install different substituents in the enone β-position with minimal impact on the efficiency of the cyclization process. A β-ethyl substrate was irradiated in the presence of TosMIC to afford 30 in 64% yield (Figure 3B). An N-acyl piperidinyl substituent was also tolerated, producing 31 in 42% yield. Different N-substitution patterns are also possible: products bearing N-allyl 32 (alongside 6% of a competitive [2+2] product) and N-benzyl 33 groups were effectively generated in yields of 42% and 53%, respectively. Enaminones of varying ring sizes are likewise tolerated, as evidenced by the successful reaction to form fused cyclopentanone 34 in 57% yield. We were able to exemplify the regioselective nature of this transformation through the incorporation of substituents at either meta-position. The cyclization of a 5-chloro-2-iodo substrate and subsequent trapping with TosMIC afforded 35 (62% yield) without formation of the alternative regioisomer in detectable quantities. Similarly, a 3-methyl-2-iodo substrate cyclizes regioselectively to yield 36 (58% yield). The introduction of para-substituents on the aromatic ring is also possible. While para-nitro product 37 was generated in moderate yield (29%) with substantial starting substrate recovery, other groups in this position cyclize effectively: para-N-acetyl 38 (69% yield), para-bromo 39 (79% yield), and para-iodo 40 (72% yield) products were all formed efficiently.

Although we had satisfactorily demonstrated that the reaction does not proceed via an aryl radical, the origin of the underlying regioselectivity was challenging to interpret, and hence we applied a combination of experimental and computational techniques to address this problem. UV-visible absorption spectroscopy revealed a band centered at ca. 345 nm that extends above 400 nm for β-methyl substrate 10; due to its weakly absorbing nature, this was assigned to an nπ* transition between the ground and first excited singlet (S₁) state, in accordance with previous photophysical studies of cyclohexenones and their derivatives.^36–38 Since ISC from this state is known to be fast for cyclic enones,^39,40 we expect that bond formation proceeds via the T₁ state. This tenet is consistent with the substantial rate acceleration observed (without change in product distribution) for the photocyclization of 41 (triplet-state energy, E_T ≈ 48 kcal mol⁻¹) in the presence of catalytic Ir(dFppy)₃ (E_T = 60.1 kcal mol⁻¹).⁴¹ Upon irradiation with a 467 nm Kessil lamp in acetonitrile solution, indole 42 was formed in 99% yield under these conditions; in contrast, a significantly lower yield of 13% (14% conversion) was obtained in the photocatalyst’s absence (Figure 4A). The iridium complex is not sufficiently oxidizing (E_1/2[Ir^III*/Ir^II] = +0.39 V vs. Fc⁺/Fc [ferrocenium/ferrocene]) or reducing (E_1/2[Ir^IV/Ir^III*] = −1.23 V vs. Fc⁺/Fc) in the excited state to activate 41 (whose half-wave oxidation and reduction potentials were measured as +0.73 V and −2.42 V, respectively, vs. Fc⁺/Fc) by SET, implicating triplet energy transfer as the mode of catalysis. Moreover, Mulliken spin density calculations (see Section S4.5) suggest that single-electron oxidation of the enaminone substrates used here would yield what is essentially an amine radical cation with negligible radical character at the enone β-position, further undermining the possibility of cyclization via an alkene radical cation.

Figure 4. Experimental and computational mechanistic investigations.

(A) A sensitization experiment is consistent with the reaction proceeding via the triplet state. Conversions and yields were measured by quantitative ¹H NMR spectroscopy against dimethyl terephthalate; redox potentials are relative to Fc⁺/Fc.

(B) Proposed reaction mechanism, in which an irreversible ipso-I cyclization step is selectivity-determining.

(C) Potential energy surfaces for the ipso-H and ipso-I cyclization pathways available to intermediate ³A, computed at the M06-2X-D3/def2-QZVPP(SMD=MeCN)//M06-2X-D3/def2-TZVP(SMD=MeCN) level.

(D) IRC computed for TS-I.

(E) Computed structures of transition states TS-I–III and triplet intermediate ³B; distances, d, in Å are indicated by dotted lines. MECP, minimum energy crossing point; amu, atomic mass units; WBO, Wiberg bond order; ρ_S, natural spin density.

Additional evidence for triplet-state generation in the absence of sensitizer includes the observation of a competing [2+2]-photocycloaddition (known to be a fast triplet process)^42,43 in the reaction to form 32, as well as a substantial reduction in conversion (and attendant formation of oxidative degradation products) observed when 10 was irradiated in the presence of oxygen^44,45; see Sections S3.2.5, S3.2.6, and S3.2.7 for more detail.

We proceeded to study the reaction mechanism with density functional theory (DFT) at the M06-2X-D3/def2-QZVPP//M06-2X-D3/def2-TZVP level (Figures 4B and 4C). Once the triplet-state ³A (which has an adiabatic triplet energy of 48.3 kcal mol⁻¹) is reached, a conrotatory ring-closure to form a new C–C bond can proceed either ipso- to the iodine substituent (via TS-I [TS, transition state] to furnish intermediate ³B) or at the unsubstituted position (via TS-II leading to intermediate ³C). Computation predicts selective attack at the carbon bearing the iodine substituent (ΔΔG^‡ = −0.4 kcal mol⁻¹); this selectivity is maintained across several commonly employed DFT levels of theory, albeit to varying degrees (see Section S4.2). We further performed single-point corrections using multiconfiguration methods (NEVPT2:CASSCF(10,10)/Def2-TZVP) that indicated greater selectivity (ΔΔG^‡ = −2.6 kcal mol⁻¹), suggesting that the competition between TS-I and TS-II is selective toward the formation of intermediate ³B in an irreversible and highly exergonic fashion (−40.7 kcal mol⁻¹). Intrinsic reaction coordinate (IRC) calculations performed from TS-I revealed that the minimum energy path directly connects intermediate ³A to ³B without forming a stable σ-intermediate (Figure 4D). Natural bond orbital (NBO) analysis of TS-I revealed a Wiberg bond order (WBO) of 0.28 for the forming C–C bond, indicative of an early TS (Figure 4E). The WBO of the C–I bond is 0.90, and the natural spin density on iodine is 0.13, suggesting partial bond-breaking in the TS. That the ipso-I cyclization (via TS-I) is concerted is consistent with its lower activation energy (vs. TS-II): the partial breaking of the C–I bond in the transition structure enables the stabilization of one of the unpaired electrons on the iodine atom. Second-order perturbation theory analysis of natural bonding orbitals indicated that donation into the σ*_C–I orbital from adjacent C–C σ and π bonds of the aromatic system is worth 14.6 kcal mol⁻¹, consistent with a direct and concerted radical ipso-I substitution mechanism.^46–48 Similarities can be drawn between this homolytic mechanism and that of recently identified concerted nucleophilic aromatic substitutions, where a lone pair assists the elimination of bromide in a concerted fashion.^49,50 The resulting triplet radical pair ³B is expected to undergo spontaneous ISC, as one of the unpaired electrons is fully localized on a heavy iodine atom. The putative singlet radical pair could then readily participate in an outer-sphere SET event (ΔG^‡ = 6.0 kcal mol⁻¹) to form the experimentally observed iminium iodide product, ¹B; alternatively, SET could be viewed as an inner-sphere process occurring when there is still a significant degree of bonding between the iodine atom and the rest of the molecule (see Section S4.4.1). In contrast, regioisomeric cyclization via TS-II to form triplet diradical ³C—a pathway that could account for the formation of trace side-products in some reactions but that otherwise is not observed experimentally—was found to be only mildly exergonic (−3.9 kcal mol⁻¹). This intermediate could undergo ISC to ground-state zwitterion ¹C, passing through a relatively high minimum energy crossing point of 9.6 kcal mol⁻¹, affording product ¹D via an intramolecular hydrogen transfer (TS-III, ΔG^‡ = 20.9 kcal mol⁻¹).

Motivated by these emerging computational insights, which suggest that delocalization within the σ*_C–I may be responsible for the energetic lowering of TS-I, we decided to investigate the electronic influence of the linking heteroatom. Experimentally, both the O-linked²³ and S-linked analogs 43 and 45 were found to selectively undergo ipso-H cyclization upon sensitized irradiation, affording compounds 44 and 46 in high yields, with no discernible formation of attendant RPC products, even in the presence of allyltrimethylsilane to report on possible cation generation via an ipso-I pathway (Figure 5A). Computational analysis using both DFT and NEVPT2:CASSCF theoretical frameworks on these heterocyclic systems was found to accurately reproduce experimental observations (Figure 5B). In contrast to N-alkyl-linked systems, O-linked and S-linked systems exhibited high selectivity toward ipso-H cyclization, with computed energy differences of 4.6 and 7.5 kcal mol⁻¹, respectively. Further NBO analysis of the ipso-I cyclization transition structures (TS-I, TS-IV, and TS-VI) revealed that they were of similar lateness, as indicated by their corresponding WBO of 0.28–0.29 for the forming C–C bond and 0.90–0.93 for the breaking C–I bond. However, their corresponding C–I σ* NBO showed distinct electron occupancies of 0.105, 0.088, and 0.073, respectively. This suggests delocalization from the linking heteroatom into the σ*_C–I orbital during C–C bond formation, leading to greater energetic stabilization for nitrogen-linked systems than for those linked by oxygen and sulfur. Further supporting this proposal is the reduced, yet still moderate, ipso-I selectivity observed for an N-carbamoyl-linked substrate when compared with N-alkyl-linked substrates (see Sections S2.25 and S4.7). Taken together, these findings offer a compelling framework for designing new types of homolytic aromatic or vinylic substitution reactions, where site selectivity (leading to RPC) can be influenced by stereoelectronic effects.

Figure 5. Experimental and computational studies to probe the regioselectivity of analogous photochemical cyclizations of oxygen- and sulfur-linked enones.

(A) Both O- and S-linked substrates give ipso-H rather than ipso-I cyclization products when irradiated in the presence of an iridium sensitizer.

(B) Transition structures TS-IV-VII computed at the M06-2X-D3/def2-QZVPP(SMD=MeCN)//M06-2X-D3/def2-TZVP(SMD=MeCN) level. In both cases, the ipso-H transition state is lower in energy.

One implication of a diradical cyclization mechanism is that leaving groups other than iodine should also be viable; moreover, radical addition to the arene would represent the stereodetermining step of any asymmetric variant. Reactions involving the loss of sulfur-centered radicals are well-studied,^51–55 particularly in the context of Smiles-type rearrangements.^56–59 An elegant example of this class of reaction was recently reported by the Nevado group,⁶⁰ who showed that the addition of radicals generated under photoredox catalysis to enantioenriched N-arylsulfinyl acrylamides initiates a stereospecific radical sulfinyl Smiles rearrangement.^61–63 Inspired by these precedents, we theorized that the successful use of an S-chiral leaving group in our system would serve as additional evidence in support of the ipso-substitution mechanism (the suitability of other halogen and sulfur-based leaving groups is discussed in Sections S2.23 and S2.24). Thus, we synthesized an enantioenriched N-aryl enaminone substrate, (+)-48, bearing an ortho-sulfinyl substituent in 75% yield and 98:2 enantiomeric ratio (e.r.) from the corresponding sulfide, 47, under Kagan oxidation conditions (Figure 6).⁶⁵ Pleasingly, when irradiated in the presence of triethylsilane and trifluoroacetic acid in acetonitrile solution, this compound underwent eliminative photocyclization with transfer of chirality from sulfur to carbon, delivering the expected iminium reduction product, (−)-21, in 75% yield and 96:4 e.r.

Figure 6. Enantioselective visible-light-mediated cyclization with loss of a sulfur-based leaving group.

Reaction conditions: (i) substrate 47 (1.0 equiv), Ti(Oi-Pr)₄ (1.0 equiv), (+)-diethyl L-tartrate (2.0 equiv), H₂O (1.0 equiv), t-BuOOH (2.0 equiv), CH₂Cl₂ ([47] = 0.1 M), −20°C, 21 h. (ii) Substrate (+)-48 (0.1 mmol), Et₃SiH (0.5 mmol), CF₃CO₂H (0.3 mmol), Kessil PR160L 427 nm lamp, MeCN ([(+)-48] = 0.05 M), r.t., 12 h. E.r. determined by chiral stationary phase high-performance liquid chromatography. Sulfoxide (+)-48 and cis-fused indoline (−)-21 are enantioenriched compounds whose absolute configurations are unknown.⁶⁴

In conclusion, we have discovered that incorporating an ortho-iodine substituent is an effective strategy for transitioning from diradical to ionic reactivity during photocyclizations of the N-aryl enaminone substrate class. Quantum calculations in conjunction with experimental mechanistic investigations identify an irreversible ipso-I substitution process in the triplet state as the central step of this complexity-generating cascade. The availability of this pathway enables the course of the photocyclization to be strategically redirected from isomerization (via singlet zwitterion/diradical intermediates) to RPC. ISC and SET within the radical pair resulting from ipso-substitution lead to the formation of an iminium iodide salt as the primary photoproduct of the reaction, which can be intercepted thermally by a variety of two-electron nucleophiles. The intermediacy of an alkene triplet diradical (as opposed to an aryl radical) circumvents the need for a photolabile bond to achieve regioselective cyclization, permitting control over the absolute stereochemistry of the C(sp³)-rich indoline products through the use of an ortho-sulfinyl group in place of iodine. We anticipate that the reactivity described herein will inspire the development of other triplet-state reactions incorporating RPC.

METHODS

Synthetic procedures, characterization data, and details of computational studies are contained in the supplemental information.

RESOURCE AVAILABILITY

Lead contact

Requests for further information and resources should be directed to and will be fulfilled by the lead contact, Martin Smith (martin.smith@chem.ox.ac.uk).

Materials availability

Chemicals were obtained from commercial suppliers or prepared as indicated in the supplemental information.

Data and code availability

All relevant datasets generated within this study are available in the supplemental information. Single-crystal X-ray diffraction data have been deposited in the Cambridge Crystallographic Data Centre: CCDC 2243732 (29), 2243733 (24), and CCDC 2330002 (41) contain the crystallographic data for this paper.

Supplementary Material

Supplemental information can be found online at https://doi.org/10.1016/j.chempr.2025.102904.

THE BIGGER PICTURE.

Triplet excited states typically undergo radical-like addition and recombination processes in a stepwise manner. Here, we introduce a new radical–polar crossover (RPC) method that integrates the one-electron (radical) reactivity of triplet excited states with the two-electron (polar) reactivity of nucleophiles, using alkenes as a chromophore instead of a radical acceptor or electron donor and affording complex three-dimensional heterocycles that are not available by other photochemical means. The mechanistic insights presented here into this “interrupted” photocyclization will inspire the development of other triplet-state reactions incorporating RPC. In time, broader application of triplet-mediated RPC methods could reduce the resource intensity of pharmaceutical, agrochemical, and materials development, aligning with sustainable chemistry goals such as responsible consumption and production (UN SDG 12).

Highlights.

• Visible-light excitation of N-(2-iodoaryl) enaminones yields iminium salts

• A homolytic aromatic substitution (HAS) mechanism prevails in the triplet state

• Electron donation into the σ*_C–I orbital during cyclization dictates selectivity

• S-to-C chirality transfer occurs when an ortho-sulfinyl substituent is used