This article, identified by the code 01237, delves into the innovative realm of photoredox catalysis, highlighting its transformative application in the functionalization of alkenes. Alkene functionalization is a cornerstone of modern organic chemistry, and this work introduces a powerful and versatile methodology employing cyanoarene photocatalysts to achieve reductive alkene–aldehyde coupling, hydroamidation, and hydroaminoalkylation reactions. This approach provides a mild and chemoselective route to synthesize valuable building blocks for pharmaceuticals, agrochemicals, and materials science, overcoming limitations of traditional methods and expanding the synthetic toolkit available to chemists.
Revolutionizing Alkene-Aldehyde Coupling with Photoredox Catalysis
The investigation commenced with a focus on developing an efficient reductive alkene–aldehyde coupling strategy. Traditional methods often suffer from issues with selectivity and harsh reaction conditions. To address these challenges, this research explored the use of photoredox catalysis to mediate the coupling of 1,1-diphenylethylene 1a with propionaldehyde 2a. The rationale was that controlled generation of the alkene radical anion would facilitate selective addition to the aldehyde, minimizing unwanted side reactions like protonation (Fig. 2a).
Initial experiments with heteroleptic Ir complexes, known for their potent photoreductant generation, yielded unexpectedly poor results. However, the investigation shifted to dicyanobenzene donor–acceptor complexes, which exhibit deep reduction potentials. While 4CzIPN showed some improvement, it also led to significant decomposition. A key breakthrough was the discovery that 3tBuCzFIPN, a less reducing catalyst with increased steric bulk, dramatically improved both yields and selectivity. This observation underscored the critical role of controlled radical anion generation; highly reducing catalysts like 3DPA2FPN resulted in complete decomposition, confirming the necessity of a slow and controlled alkene reduction process.
Further optimization of reaction parameters, including catalyst loading, aldehyde stoichiometry, solvent, and concentration, led to the identification of optimal conditions: 2 mol% 3tBuCzFIPN, 3 equivalents of aldehyde, and 1.1 equivalents of iPr2NEt in DMA at 0.05 M concentration, under 448 nm LED irradiation for 15 hours. These optimized conditions afforded the desired alcohol 3a in an impressive 76% isolated yield. Notably, the reaction exhibited complete anti-Markovnikov selectivity, without any observed benzylic radical oxidation or carbanion functionalization.
Fig. 2: Illustration of the alkene–aldehyde coupling reaction mechanism and scope. This figure details the optimized reaction conditions and the range of alkenes and aldehydes successfully coupled using the photoredox catalytic system.
Expanding the Scope: Alkene-Aldehyde Coupling Versatility
With optimized conditions in hand, the synthetic scope of this alkene-aldehyde coupling method was explored extensively using various aryl alkenes (Fig. 2b). Reacting a series of 1,1-diarylethylenes with propionaldehyde 2a effectively produced sterically hindered secondary alcohols (3a–l) with a 1,1-diaryl-pentanol structure. The protocol demonstrated high efficiency, particularly with electron-rich alkenes bearing methyl (3e–g) and methoxy (3b, c) substituents, yielding products with remarkable efficiency. Electron-deficient alkenes also participated in the reaction, albeit with moderate yields (up to 55%), attributed to the reduced nucleophilicity of their radical anions. This electron sensitivity contrasts with traditional Giese reactions, where electron-deficient alkenes react more readily, highlighting the unique reactivity profile of this photoredox approach and its ability to engage electron-rich alkenes in radical cross-coupling.
The method’s mildness was further emphasized by its chemoselectivity. Alkene reduction occurred selectively even in the presence of other reducible functional groups, including aryl chlorides (3k) and amides (3j), showcasing its potential for complex molecule synthesis. Furthermore, the reaction demonstrated excellent compatibility with aliphatic aldehydes (Fig. 2b), generating the expected 1,1-diaryl-pentanols in good overall yields. Notably, sterically demanding aldehydes, including those with secondary, tertiary, and even ɑ-tertiary carbons, were viable substrates. The protocol also tolerated saturated and unsaturated heterocyclic aldehydes, as well as those containing unactivated alkene and alkyne bonds, without competitive reduction or unwanted radical cyclization side products.
Mechanistic Insights: Unraveling the Reaction Pathway
To gain a deeper understanding of the reaction mechanism, a series of experimental and computational mechanistic studies were conducted. Control experiments revealed that aliphatic aldehydes are stable under the reaction conditions and that ketyl radicals are unlikely intermediates, despite the similar reduction potentials of propionaldehyde 2a and diphenylethylene 1a. Further investigations using cyclic voltammetry, UV-visible spectroscopy, and luminescence quenching experiments confirmed that direct electron or energy transfer from the excited photocatalyst to the alkene or aldehyde was not occurring. Instead, the photocatalyst 3tBuCzFIPN was shown to be reduced by iPr2EtN, generating the catalyst radical anion [3tBuCzFIPN]⋅−.
DFT calculations further supported a mechanism involving single-electron transfer from the excited catalyst radical anion (PC⋅−)* to the alkene. The calculations indicated a lower energy barrier for electron transfer to the alkene compared to the aldehyde, despite their similar reduction potentials, suggesting a kinetic preference for alkene reduction. The proposed mechanism involves the alkene radical anion Int-1 undergoing nucleophilic addition to the aldehyde, forming a distonic radical anion Int-3, which is subsequently reduced and protonated to yield the alcohol product. Deuterium labeling experiments with D2O supported this protonation step.
Fig. 3: Diagram illustrating key mechanistic investigations. This figure summarizes control experiments, spectroscopic studies, and computational data that elucidate the reaction mechanism, confirming alkene radical anion involvement and excluding alternative pathways.
Alkene Hydroamidation: Accessing Amide Functionality
Building upon the success of alkene-aldehyde coupling, the researchers extended the photoredox catalytic strategy to alkene hydroamidation. Amides are ubiquitous functional groups, and isocyanates, despite their atom economy, are underexploited reagents for amide synthesis. Inspired by the alkyl carbanion equivalent nature of alkene radical anions, the team hypothesized that they could add to isocyanates in a manner similar to Grignard reagents, leading to amide bond formation.
Reacting 1,1-diphenylethylene 1a with phenyl isocyanate 9g under optimized conditions resulted in the formation of the desired amide 10l, albeit in a modest 31% yield after optimization. This transformation represented the first example of a metal-free direct alkene hydroamidation strategy. The scope of the reaction was then explored (Fig. 4), demonstrating that both electron-neutral and electron-rich diarylethylenes, as well as alkyl isocyanates, could be efficiently converted to the corresponding amides. Lower yields were sometimes observed due to isocyanate oligomerization, highlighting the challenges associated with isocyanate reactivity.
Fig. 4: Reaction scope of photoredox-catalyzed hydroamidation of alkenes. This figure showcases the variety of alkenes and isocyanates that can be employed in this novel hydroamidation reaction, yielding diverse amide products.
Alkene Hydroaminoalkylation: A Novel Route to Amines
The investigation further expanded to alkene hydroaminoalkylation, targeting the synthesis of amines, another crucial class of organic compounds. Traditional amine synthesis often relies on enolates or organometallic reagents. Photoredox catalysis offers an alternative approach through the addition of alkyl radicals to imine electrophiles. The researchers proposed a mechanistically distinct strategy involving the simultaneous oxidative C–H activation of amines and reductive π activation of aryl alkenes, generating tertiary and secondary amines with complementary selectivity to Giese-type radical additions.
The key concept was the in situ generation of iminium ions through amine oxidation, followed by interception with alkene radical anions. Initial studies with 1,1-diphenylethylene 1a and diisopropylmethylamine 11 using 3tBuCzFIPN resulted in low yields and over-alkylation. Catalyst screening revealed that [Ir(dFppy)2(dtb-bpy)]PF6, an Ir complex capable of tandem photoredox catalysis, significantly improved the yield of the desired aminoalkylated adduct 12a to 81% (NMR yield).
With optimized conditions, the scope of the alkene hydroaminoalkylation reaction was investigated (Fig. 5b). The reaction proved to be broadly applicable to both electron-deficient and electron-rich diarylethylenes, demonstrating insensitivity to alkene electronic properties. Even challenging substrates like ɑ-alkyl and styrene derivatives were competent coupling partners using different photocatalysts like [Ir(ppy)2(dtb-bpy)]PF6 and 4CzIPN, the latter being particularly effective for sterically hindered alkenes. β-substituted styrenes also participated, forming sterically congested C–C bonds with high regioselectivity. The reaction was also compatible with aryl halides.
The amine scope was also explored extensively (Fig. 6), demonstrating compatibility with sterically hindered amines, reducible functional groups (nitrile, ester, ketone), and even protic groups (unprotected primary amine and alcohol). Regioselectivity was excellent, favoring primary methyl C–H activation in tertiary amines. Notably, aqueous trimethylamine was also a viable substrate. For secondary amines, reaction conditions were re-optimized, enabling successful monoalkylation of acyclic and cyclic secondary amines, including pyrrolidine, piperidine, morpholine, and azepane, with good to high yields and excellent selectivity.
Fig. 5: Photoredox-catalyzed aminoalkylation of alkenes: reaction scope and methodology. This figure compares established methods with the newly developed approach and showcases the diverse range of alkenes successfully employed in the aminoalkylation reaction.
Fig. 6: Amine scope in photoredox-catalyzed aminoalkylation. This figure illustrates the broad applicability of the method to various tertiary and secondary amines, highlighting the functional group tolerance and selectivity of the reaction.
Mechanistic Insights into Alkene Hydroaminoalkylation
Mechanistic studies were crucial to understanding the alkene hydroaminoalkylation reaction. Experiments ruled out a simple Giese reaction between ɑ-amino radicals and alkenes. Catalyst screening revealed a correlation between potent photoreductant formation and product yield, supporting the involvement of alkene radical anions. Stern–Volmer quenching experiments confirmed that 1,1-diphenylethylene effectively quenched the phosphorescence of [IrB]°*, consistent with alkene reduction.
Radical trapping experiments with TEMPO and base-effect studies further suggested that ɑ-amino radicals are not key intermediates. Instead, the iminium ion, generated by oxidation of the amine, was implicated as the electrophilic species reacting with the alkene radical anion. Trapping experiments with malonitrile, which intercepts iminium ions, and solvent isotope effect studies using MeOH-d4, supported the involvement of iminium ions and a mechanism involving iminium–enamine tautomerization before C–C bond formation. DFT calculations corroborated the facile oxidation of ɑ-amino radicals to iminium cations, reinforcing the proposed mechanism.
Fig. 7: Detailed mechanistic investigation of the aminoalkylation reaction. This figure summarizes the experimental and computational evidence supporting the proposed reaction mechanism, including radical trapping, catalyst studies, and DFT calculations.
Synthetic Applications: Pharmaceuticals and GABA Derivatives
To demonstrate the practical utility of this methodology, the researchers showcased its application in synthesizing biologically active amines, including H1-antihistamine drugs, in a single step from readily available amines and alkenes (Fig. 8a). The protocol’s simplicity and scalability were highlighted through a scaled-up flow synthesis of diisoproimine 12a, achieving a 79% yield on a gram scale. Late-stage functionalization was demonstrated by selectively alkylating complex pharmaceutical agents like lidocaine, clomipramine, and desipramine (Fig. 8b), underscoring the method’s chemoselectivity and mildness.
Finally, the alkene was envisioned as a dicarbanion synthon, enabling orthogonal functionalization. By combining aminoalkylation with CO2 fixation, a protocol for synthesizing γ-aminobutyric acid (GABA) scaffolds was developed (Fig. 8c). Flow chemistry optimization using a highly reducing 3DPAFIPN catalyst and CO2 gas pressure afforded various GABA derivatives, including those from complex pharmaceutical agents like Boc-protected lidocaine, in moderate to good yields within a short reaction time. This established the alkene as a versatile dicarbanion synthon with potential for diverse dicarbofunctionalization reactions.
Fig. 8: Illustrative synthetic applications of alkene aminoalkylation. This figure demonstrates the utility of the developed methodology for late-stage functionalization of pharmaceuticals, synthesis of drug molecules, and access to γ-aminobutyric acid (GABA) derivatives.
Conclusion
This research presents a groundbreaking photoredox catalytic system utilizing cyanoarene dyes, particularly 3tBuCzFIPN, for the efficient and selective functionalization of alkenes. The developed methodologies for reductive alkene–aldehyde coupling, hydroamidation, and hydroaminoalkylation offer mild, chemoselective, and versatile routes to valuable chemical building blocks. Detailed mechanistic investigations have elucidated the reaction pathways, highlighting the crucial role of alkene radical anions and iminium ions. The synthetic utility of these methods has been demonstrated through the synthesis of pharmaceuticals and GABA derivatives, showcasing their potential for late-stage functionalization and complex molecule synthesis. This work significantly expands the scope of photoredox catalysis and provides powerful new tools for organic synthesis, paving the way for future advancements in chemical discovery and manufacturing.
