Photo-induced catalytic halopyridylation of alkenes

The study addresses whether halopyridines and unactivated alkenes can be coupled under visible-light photoredox catalysis to install both a pyridyl group and a halide across an alkene in a single, atom-economical step. Traditional Heck and reductive Heck reactions form C–C bonds but typically lose halide and often leave products without a versatile C–X handle, and β-H elimination limits product types. Prior intramolecular haloarylations avoid β-H elimination only with specific alkene substitution and sometimes require UV light. Given the synthetic value of C–X bonds and pyridyl motifs, the authors propose an oxidative quenching photoredox strategy that generates pyridyl radicals and forges C–C and C–X bonds simultaneously on a broad set of alkenes under mild, redox-neutral conditions.

Classical Heck arylations and reductive Heck hydroarylations are powerful for alkene functionalization but eliminate halide and often lack handles for further diversification. Intramolecular carbohalogenations by Lautens, Glorius, Tong and others elegantly install C–C and C–X but generally require substrates lacking syn β-H and can be limited in scope; intermolecular variants with aryl halides are scarce and sometimes require UV. Visible-light photoredox catalysis has enabled numerous alkene functionalizations, and pyridylation via pyridyl radicals (e.g., Jui and co-workers) typically uses reductive quenching with Hantzsch ester to effect hydroarylation or related processes. However, these reductive systems are not suited to net halopyridylation because they bias toward hydropyridylation and lack a pathway to C–X installation. The present work seeks a complementary, oxidative quenching approach to enable intermolecular halopyridylation with broad alkene and halopyridine scope.

Reaction development: Model coupling of 2-bromo-6-methylpyridine (1a) with 1-hexene (2a) under blue LEDs (456 nm) was optimized. Reductive-quenching conditions reported by Jui (Ir photocatalyst with Hantzsch ester, HEH) did not produce halopyridylation product. Switching to oxidative quenching with Brønsted acid additives enabled the desired reactivity. Optimal conditions: Ir(ppy)2(dtbbpy)PF6 (Ir-PC A, 1.0 mol%), TFA (1.0 equiv) in trifluoroethanol (TFE, 0.1–0.2 M), blue LEDs (456 nm, 40 W), N2, room temperature, 16 h, delivering 3aa in 89% GC yield. Controls: No photocatalyst or dark gave no product. Alternative photocatalysts (Ir-PC B or D), Eosin Y, and (Acr-Mes)ClO4 were ineffective; Ir-PC C was slightly less effective. Acid was essential; AcOH failed, while (PhO)2POOH and PhSO3H were competent but gave lower yields. Strongly H-bonding, polar protic solvents (TFE, HFIP) were effective; EtOH was not. Air atmosphere or thermal (80 °C, dark) conditions were unsuitable. Substrate scope: Alkenes—terminal α-alkenes and 1,1-disubstituted alkenes afforded products (e.g., 3aa–3ag, up to 89% yield). Free alcohol-containing alkenes were tolerated. Internal alkenes, including acyclic (trans-4-octene, 3ah, 84% yield, 2:1 dr) and cyclic (cyclopentene, cyclohexene, norbornene; 3ai–3ak, 81–90% yields) worked. A trisubstituted alkene gave 3al in 69% yield with exclusive regioselectivity attributed to less hindered radical addition/stabilized tertiary intermediate. Tetrasubstituted alkene gave only trace product (3am). Non-conjugated dienes underwent selective mono-functionalization (3an, 3ao). Halopyridines—bromo-, chloro-, and iodo-pyridines were compatible (3ba–3pa). Positional isomers of alkyl/alkoxy substituents performed similarly. 2-bromopyridine was more reactive than 4-bromopyridine. 2,3- and 2,5-dibromopyridines reacted selectively at C2, preserving the other bromide (3ia, 3ja). 2,6-dibromopyridine gave bis-addition product 3ka (70% yield). Strongly electron-deficient bromopyridines were unsuitable, likely due to unfavorable protonation by TFA. Halogenated alkenes (Cl, Br, I, TsO) coupled with various halopyridines to give dihalo-alkylpyridines (5a–5l) in moderate to good yields. Late-stage applications included transformations of complex natural product and drug-like scaffolds (perilla aldehyde, carbohydrate, sulfonamide, steroid) to halopyridylated products (4a–4d). Mechanistic studies: Radical traps (TEMPO, BHT) suppressed reactivity; a BHT–pyridyl adduct was detected, supporting pyridyl radical intermediates. Stern–Volmer quenching showed only the 1a+TFA mixture quenched the excited Ir photocatalyst, indicating oxidative quenching via protonated halopyridine. Cyclic voltammetry: 1a in TFE E1/2red ≈ −0.76 V vs SCE; 1a+TFA in TFE shifted to −0.69 V; in EtOH, 1a+TFA E1/2red ≈ −0.95 V, consistent with protonation enhancing oxidant ability and with solvent effects. Light on/off experiments showed immediate cessation upon dark and resumption upon irradiation; quantum yield Φ = 0.685 suggests a short or no radical chain. Halide competition/crossover: Adding KBr to reactions of 2-chloropyridine with 1-hexene yielded predominantly bromide product (e.g., 3ga 24% vs 3ma 6% under specific conditions), and KCl with 2-bromopyridine gave mixtures (3ga 60%, 3ma 17%). In crossover reactions without added salts, bromide products dominated over chloride, attributed to solvent-enhanced nucleophilicity of bromide in TFE. No halide exchange occurred when isolated products were resubjected under standard conditions, while slight halogen exchange was observed at the halopyridine starting materials in the presence of extra halide salts. A minor Heck-type elimination byproduct (3aa′, 6%) was detected, consistent with carbocation intermediacy. General procedure: In a N2 glovebox, combine Ir(ppy)2(dtbbpy)PF6 (1.0 mol%), halopyridine (1.0 equiv), alkene (3.0 equiv), TFA (1.0 equiv) in TFE (0.2 M). Irradiate with 456 nm LEDs (40 W) at 25–30 °C for 16 h. Workup: neutralize with NaHCO3 or Et3N, extract with EtOAc, wash with brine, dry (Na2SO4), concentrate, and purify by silica gel chromatography. Scale-up and derivatization: Gram-scale reactions provided 3ma (84%, 1.66 g), 3ga (89%, 2.16 g), 3pa (75%, 2.20 g). Downstream C–X manipulations included base-induced eliminations and nucleophilic substitutions: sulfinate (65%), SCN (64%), thiophenol (72%), and azidations (85%, 61%).

• Developed a visible-light, photoredox-catalyzed halopyridylation that installs both pyridyl and halide across unactivated alkenes under mild, redox-neutral conditions.
• Optimal conditions: Ir(ppy)2(dtbbpy)PF6 (1 mol%), TFA (1 equiv), TFE solvent, 456 nm blue LEDs, rt, N2, 16 h; model product 3aa in up to 89% yield.
• Broad substrate scope: terminal, internal (acyclic and cyclic), and trisubstituted alkenes; tolerance of free alcohols and complex molecular scaffolds; selective mono-functionalization of dienes; tetrasubstituted alkenes largely unreactive (trace 3am).
• Halopyridines scope includes bromo-, chloro-, and iodo-pyridines, and dihalopyridines with site-selective activation at C2. Strongly electron-withdrawing substituted bromopyridines are unsuitable.
• Dihalo-alkylpyridines accessible from halogenated alkenes (Cl, Br, I, TsO), yielding 5a–5l in moderate to good yields.
• Mechanistic evidence supports oxidative quenching and radical-polar crossover: only 1a+TFA quenches Ir*; radical traps halt reaction; BHT–pyridyl adduct observed; light on/off dependence; low quantum yield Φ = 0.685; CV shows protonation raises reduction potential (1a E1/2red −0.76 V to −0.69 V in TFE; −0.95 V in EtOH); alkyl radical oxidation (E1/2ox ≈ 0.47 V) compatible with IrIV/IrIII (1.21 V) to form carbocation trapped by halide.
• Halide competition shows bromide predominance in TFE due to hydrogen-bonding-modulated nucleophilicity; no post-formed C–X scrambling under reaction conditions.
• Minor Heck-type elimination byproduct (3aa′) indicates carbocation intermediate.
• Gram-scale feasible; retained C–X bonds enable diverse downstream transformations (elimination, sulfinate, SCN, SPh, N3 substitutions).

The work demonstrates that an oxidative quenching photoredox manifold using TFA in TFE can divert pyridyl radical chemistry from hydropyridylation to halopyridylation, thereby overcoming limitations of classical and reductive Heck strategies. By avoiding β-H elimination and leveraging radical-polar crossover, both a C–C bond (pyridyl addition) and a C–X bond are formed in a single step, providing products with embedded pyridyl and halide handles for subsequent functionalization. Mechanistic studies corroborate the proposed sequence: protonation-enhanced reduction of halopyridines by excited Ir catalyst, radical addition to alkenes, oxidation to carbocations, and halide trapping. The approach complements transition-metal-mediated carbohalogenations by operating under visible light, room temperature, and without UV or stoichiometric metals, while expanding substrate compatibility (including chloro- and iodopyridines) and enabling late-stage modification of complex molecules. The observed solvent-controlled halide nucleophilicity inversion underscores the importance of medium effects in designing ATRA-type processes.

A general, atom- and step-economical photo-induced halopyridylation of unactivated alkenes has been established. Under Ir photoredox catalysis with TFA in TFE, diverse alkenes and halopyridines couple to give ATRA-type products bearing both pyridyl and halide groups with good yields and regioselectivity. Mechanistic evidence supports a domino oxidative quenching activation and radical-polar crossover pathway via a carbocation intermediate. The method operates under mild, redox-neutral conditions, is scalable, and the preserved C–X bonds enable versatile downstream derivatizations. Future work could explore expanding to other heteroaryl halides, asymmetric induction, alternative photocatalysts/greener solvents, and addressing challenging substrates such as strongly electron-deficient pyridines and highly substituted alkenes.

• Strongly electron-withdrawing substituted bromopyridines were unsuitable, likely due to disfavored protonation by TFA.
• Tetrasubstituted alkenes gave only trace product (low reactivity).
• Reaction is sensitive to light, photocatalyst, and atmosphere: no product in dark, without photocatalyst, or under air; EtOH solvent failed; less acidic acids (e.g., AcOH) ineffective.
• Some diastereoselectivities were modest (e.g., 2:1 dr for trans-4-octene; 1:1 dr for certain cases). Minor β-H elimination (Heck-type) byproduct detected (6%).
• Organophotocatalysts tested (Eosin Y, (Acr-Mes)ClO4) were ineffective, implying reliance on specific Ir photocatalyst.
• Solvent choice (TFE/HFIP) critical; generality in other media not demonstrated.