Bifunctional iron-catalyzed alkyne Z-selective hydroalkylation and tandem Z-E inversion via radical molding and flipping

The alkene motif is one of the most fundamental and essential organic functional groups for further multiple functionalization and carbon-chain extension, playing an important role in synthetic chemistry, pharmacology, biochemistry, polymer chemistry, and material science. Developing a feasible, universal, and atom-economic strategy to construct stereo-defined alkenes has demonstrated great necessity, given the crucial role they play in these fields. Historically, methods including Wittig and Heck-type reactions, olefin metathesis, and hydrogenation and hydro-functionalization of alkynes have been well established for alkene construction. Nonetheless, preactivated substrates and noble-metal catalysts are usually essential in these cases, and the generated olefins are mostly in the thermodynamic preferred E-type or an uncertain Z-E mixture. It is of great significance to realize the user-defined regulation of olefin geometry on account of an obvious property difference affected by steric configuration. Among the two configurations, preparation of the thermodynamic-unfavored Z-olefin is still challenging due to the uncontrollability and undetectable intermediates. Direct E→Z isomerization by triplet energy transfer requires pre-formed internal olefins and has practical limitations. Transition metal-catalyzed cross-coupling hydroalkylation of alkynes has emerged as a route to in situ cis-olefins (e.g., Hu and Lalic), and photoredox Wittig-type strategies (Silvi) can also deliver cis-olefins. However, these approaches often need excess additives (metal reductants or strong bases), high temperatures, and suffer low atom-economy due to large leaving groups, motivating development of mild, low-cost, atom-economic olefination protocols. Selective C–H activation streamlines synthesis and improves atom economy. Photoinduced hydrogen atom transfer (HAT) enables challenging C(sp3)–H activation of light alkanes, where chlorine radicals generated via Fe–Cl ligand-to-metal charge transfer (LMCT) are efficient HAT catalysts. Iron, an earth-abundant metal, is highly active in alkyne transformations (hydroboration, hydrosilylation, hydromagnesiation, hydrocarbonyla-tion, hydrogenation), yet iron is rarely applied as a partner in photo–metal dual catalysis. To meet the goal of a low-cost, atom-economic cis-olefination, the authors designed a bifunctional iron catalytic system integrating photoinduced C(sp3)–H activation with iron–ligand-mediated configuration control. The Fe–Cl LMCT cycle generates alkyl radicals from alkanes, and an iron–ligand catalytic section controls olefin geometry via steric effects in a radical trapping–molding pathway or an alkyne preactivation–controllable addition pathway. Further, achieving user-defined geometry requires a robust Z→E inversion; the authors target a reversible radical addition–elimination strategy (via arylthiyl radicals) rather than triplet energy transfer to accomplish radical flipping while suppressing double-bond migration.

Prior art for stereodefined alkene synthesis includes Wittig/Heck reactions, olefin metathesis, hydrogenation, and alkyne hydrofunctionalizations, which often generate thermodynamically favored E-alkenes or Z/E mixtures and require preactivation or noble metals. Photochemical E→Z isomerization via triplet energy transfer can isomerize alkenes but needs preformed internal olefins and has scope limitations. Transition-metal-catalyzed Z-selective hydroalkylation of alkynes has been reported (Hu: iron-catalyzed reductive coupling of alkyl halides with arylalkynes; Lalic: Ag-catalyzed hydroalkylation), and Silvi’s photoredox variant integrates ylide generation with Wittig olefination to control geometry. Iron catalysis is broadly established for alkyne transformations (hydroboration, hydrosilylation, hydromagnesiation, hydrocarbonyla-tion, hydrogenation), with numerous contributions by Thomas, Chikkali, Beller, Zhu, and Kirchner. Recent advances in photo-HAT for alkanes include Fe–Cl LMCT systems and other photocatalysts enabling C(sp3)–H functionalization (Zuo, Noël, and others). However, combining photoinduced C–H activation with iron-mediated stereocontrol in a single system, while achieving high atom-economy and broad functional group tolerance, remained underdeveloped, and general, catalytic Z→E inversion protocols avoiding double-bond migration were limited.

Catalyst system and general reaction conditions: - Bifunctional iron-catalyzed hydroalkylation (Z-selective): Typical conditions use alkyne (0.3 mmol), alkane (10 equivalents; 1 atm for gaseous substrates), FeCl3 (0.001 equiv; 0.1 equiv for gaseous alkanes), FeCl2·4H2O (0.5 equiv), ligand L6 (0.5 equiv; 1,1'-bi-2-naphthol-based), in CH3CN (3 mL) under N2, irradiated with a 30 W 365 nm LED at room temperature for 24–48 h (up to 7 days for some cases). For scale-up, a 20 mmol scale was demonstrated. Work-up involves dilution with DCM, aqueous washes, concentration, and silica gel chromatography. - Gaseous alkanes: Reaction mixture is degassed/backfilled with the gaseous alkane (ambient pressure) and uses higher FeCl3 loading (0.1 equiv). Irradiation at 365 nm for 48 h. - Tandem Z→E isomerization (radical flipping): After the first step, the crude Z-alkene mixture is treated with 1 mol% 1,2-bis(2,4,6-triisopropylphenyl) disulfide (C1) in n-hexane (3 mL) under N2 and 30 W 455 nm LED irradiation for 12 h at room temperature (electric fan cooling). If incomplete, an additional 1 mol% C1 is added. Prior screening showed I2 (1–5 mol%) or diphenyl disulfide could also mediate isomerization, but bulky diaryl disulfide (C1) and longer wavelength suppressed alkene migration. Mechanistic experiments: - Radical trapping: TEMPO (under standard conditions) affords the TEMPO–cyclohexyl adduct, confirming alkyl radical intermediacy (1H NMR, GC-MS). - Radical clock: Using (2-ethynylcyclopropyl)benzene gives ring-opened allene (5b, 25% yield), not direct olefination, supporting a radical pathway. - Kinetic isotope effects: Using cyclohexane/d12-cyclohexane gave kH/kD = 1.19 (separate runs) and PH/PD = 3.00 (competitive). Indicates HAT is product-determining but not rate-determining. - Quantum yield and light on/off: QY = 0.018; light on/off suggests minimal radical chain contribution. - Fe–substrate interactions: 1H NMR titration of FeCl2 with phenylacetylene shows no obvious complexation; UV–Vis and 1H NMR confirm formation of L4–Fe complexes. Catalysis with FeCl3/L4–FeCl2 and L4–FeCl3/L4–FeCl2 gives outcomes similar to standard, indicating ligand–FeCl2 coordination is key for stereoregulation; FeCl3 and L4–FeCl3 both generate Cl radicals via LMCT. - Isomerization controls: 3a under 365 nm light alone undergoes Z→E isomerization; under full model conditions 3a approaches a Z/E of ~70:30, indicating Z-olefins form during C–C formation and are partially eroded photochemically. Kinetic profiling shows initial Z/E ~93:7, with slight decline over 48 h. - Isotope labeling for hydrogen source: Using d12-cyclohexane shows minimal deuterium incorporation at the benzyl position; adding D2O leads to increased deuteration at that site, indicating protonation of an alkenyl anion from water rather than HAT from alkane as the final hydrogen source. Computational studies: - DFT at M06/6-31G(d,p)-SDD(Fe)/SMD(acetonitrile); single-point M06/6-311+G(d,p)-SDD(Fe)/SMD(acetonitrile). The FeCl3 LMCT generates Cl• for fast HAT to cyclohexane. Two geometry-control routes were examined: (i) radical trapping–molding (favored) and (ii) alkyne preactivation–controlled addition (disfavored due to high barrier ts2). In the favored path, cyclohexyl radical adds to phenylacetylene (ts1, 13.8 kcal/mol) to a benzyl radical, followed by single-electron oxidation by Fe(II) to Fe(III) via ts3-Z or ts3-E to form 6-Z or 6-E; ts3-Z barrier is 11.0 kcal/mol, 1.7 kcal/mol lower than ts3-E, predicting Z selectivity. Protolysis of 6-Z yields Z-alkene and regenerates FeCl3. Energy decomposition analysis indicates steric hindrance dominates cis selectivity (ΔΔEsteric = 9.8 kcal/mol). Excited-state analysis shows LMCT (Cl→Fe) consistent with Cl• generation. - For Z→E inversion with arylthiyl radicals, DFT shows addition of PhS• to the C=C of Z-alkene (ts5, 14.1 kcal/mol, endo 4.1 kcal/mol) gives benzyl radical 10. Alternative attack at benzyl carbon (ts6, 16.1 kcal/mol) and product 11 are disfavored. Radical flipping via C–C bond rotation (ts7, 10.6 kcal/mol) precedes elimination (ts8) to regenerate PhS• and form E-alkene (exergonic by 4.4 kcal/mol).

- Developed a one-system, bifunctional iron-catalyzed, photochemical protocol to construct Z-alkenes by coupling terminal alkynes with C(sp3)–H bonds of alkanes, featuring 100% atom utilization, mild conditions, and broad functional group tolerance. - Stereoselectivity: Z-selectivity up to >99:1 for numerous aryl alkynes; steric control via iron–ligand complex is key. Thioethers, silyl groups (e.g., 2-cyclohexylvinyl triisopropylsilane, 3ae), and heterocycles are tolerated. An alkyl alkyne (3af) showed only moderate yield and poor Z-selectivity, suggesting aryl–ligand π–π interactions aid stereocontrol. - Representative data (alkanes with phenylacetylene): cyclic alkanes 3ag 83% (Z/E 86:14), 3ah 82% (88:12), 3ai 80% (90:10), 3aj 76% (91:9); linear alkanes 3al 82% (site r.r. 30:47:23; Z/E per site ~81–87:13–19), 3am 76% (30:38:32; Z/E ~87:13), 3an 73% (36:25:39; Z/E 70–75:25–30), 3ao 70% (51:23:26; Z/E 80–88:12–20); 3ap 71% (r.r. 82:18; Z/E 84:16 and 73:27). Iso-butane gas 3aq 35% (r.r. 99:1; Z/E 46:54). THF 3ar 56% (r.r. 62:38; Z/E 77:23, 88:12). - Late-stage functionalization: Amino acid/peptide derivatives 3as 62% (88:12), 3at 55% (88:12), 3au 48% (>99:1). Biorelevant/drugs: thymol 3av 71% (80:20), borneol 3aw 77% (82:18), ibuprofen 3ax 64% (84:16), naproxen 3ay 61% (88:12), acetylsalicylic acid 3az 70% (92:8), amantadine 3ba 86% (84:16), probenecid 3bb 58% (80:20), desloratadine 3bc 49% (95:5), fluoxetine 3bd 65% (84:16), dehydroabietylamine 3be 56% (67:33), lithocholic acid 3bf 22% (90:10). Gram-scale example afforded 3.01 g of 3a without performance loss. - Mechanistic evidence: Radical intermediates confirmed by TEMPO adduct and radical clock ring opening; KIE kH/kD = 1.19 and PH/PD = 3.00 imply HAT is product-determining not rate-determining; QY = 0.018 and light on/off indicate non-chain process predominates; Fe(II)–ligand complex critical for stereocontrol; Z-alkenes form during C–C bond formation and undergo slight photochemical erosion. - DFT rationalizes Z selectivity via lower barrier to form Fe(III) intermediate 6-Z (by 1.7 kcal/mol) with steric interactions (ΔΔEsteric = 9.8 kcal/mol) dominating. Final hydrogen mainly from water (protonation) rather than HAT from alkane. - Tandem Z→E inversion: Using 1 mol% 1,2-bis(2,4,6-triisopropylphenyl) disulfide (C1) in n-hexane at 455 nm gives high E-selectivity up to >99% with migration suppressed. Selected two-step examples: 4a 78% (Z/E 1:99), 4f 75% (<1:99), 4i 76% (1:99), 4l 70% (<1:99), 4p 78% (<1:99); alkanes: 4u 78% (<1:99), 4v 71% (<1:99), 4w 70% (<1:99), 4x 56% (<1:99); biorelevants: from naproxen 4z 58% (4:96), dehydroabietylamine 4aa 50% (<1:99), fluoxetine 4ab 60% (<1:99). Bulky disulfide and longer wavelength eliminate double-bond migration byproducts, achieving up to 99% trans content and excellent two-step yields.

The study addresses the challenge of constructing thermodynamically disfavored Z-olefins from simple feedstocks by merging two catalytic functions—photoinduced C(sp3)–H activation and iron–ligand-based stereocontrol—within a single, earth-abundant iron platform. The Fe–Cl LMCT cycle efficiently generates alkyl radicals from alkanes under mild conditions, while the iron–ligand environment controls the configuration during radical capture/oxidation, favoring cis-alkenes via steric effects. Comprehensive mechanistic experiments and DFT calculations corroborate a radical trapping–molding pathway in which formation of the Fe(III) intermediate leading to Z-olefins is kinetically favored. The method demonstrates broad scope (aryl alkynes, diverse alkanes, complex molecules) with high Z selectivity and excellent atom economy. Recognizing that photolysis can erode Z-selectivity over time, the work further delivers a user-defined geometry solution via a second, catalytic radical flipping step using a bulky diaryl disulfide. This tandem strategy selectively converts Z- to E-alkenes while suppressing double-bond migration, enabling access to either geometric isomer set under mild, operationally simple conditions. The approach highlights the value of integrating traditional transition-metal catalysis with photochemical HAT and radical isomerization to achieve stereocontrolled olefin synthesis relevant to late-stage functionalization and drug-like substrates.

A bifunctional iron-catalyzed, photochemical protocol was developed for Z-selective hydroalkylation of terminal alkynes with alkanes, featuring 100% atom utilization, mild conditions, and broad functional-group tolerance. High Z-selectivities (up to >99:1) arise from an iron–ligand-controlled radical molding step after Fe–Cl LMCT-mediated HAT. Mechanistic experiments and DFT elucidate the pathway and the steric origin of Z selectivity, and deuterium studies indicate water-derived protonation in the final step. A tandem, catalytic Z→E isomerization using a sterically encumbered diaryl disulfide under 455 nm light achieves high E-selectivity (up to >99%) while suppressing alkene migration, enabling user-defined stereochemical outcomes. Future directions could include extending the platform to other hydrofunctionalization manifolds and gaseous feedstocks, developing enantioselective variants, and implementing flow photochemistry for scale-up.

- Substrate dependence: Alkyl alkynes provided only moderate yields and poor Z-selectivity compared to aryl alkynes, indicating a reliance on favorable aryl–ligand interactions for stereocontrol. - Gaseous alkanes required higher FeCl3 loading and showed reduced efficiency and Z-selectivity (e.g., isobutane 35% yield, Z/E ~46:54), likely due to solubility and mass transfer limitations in acetonitrile. - Photochemical erosion of Z-selectivity occurs over extended irradiation; maintaining high Z requires careful control of reaction time/conditions. - Catalyst loadings: 0.5 equiv each of FeCl2·4H2O and ligand are required to efficiently trap radical intermediates and ensure stereocontrol. - Reaction times can be long (24–48 h; up to 7 days in some cases). - In the isomerization step, less bulky mediators (e.g., I2, diphenyl disulfide) lead to double-bond migration; suppression requires specially designed bulky diaryl disulfides and tuned wavelengths.