2026 Volume 74 Issue 3 Pages 202-211
This review highlights recent progress in transition metal-free reductive transformations using organic electron donors. According to previous reports, pyridine-derived super electron donors enable the selective reduction of nitrobenzenes to azobenzenes and phenazines, while also promoting the efficient desulfurization of thioacetals and thioethers under mild conditions. These transformations proceeded with a broad substrate scope and good functional group compatibility. Additionally, a sodium hydride (NaH)/1,10-phenanthroline system developed for radical-mediated C–C bond formation promoted the hydroarylation and hydroalkylation of styrenes with high anti-Markovnikov selectivities. Mechanistic studies suggested that the in situ-generated anilide anion acts as both an electron donor and a hydrogen source, supporting a radical-based reaction pathway. These works demonstrate the potential of organic electron donors for use as sustainable and practical alternatives to conventional transition metal-based reductive methods in organic synthesis.
Electron-transfer-mediated reductive molecular transformations represent a fundamental and versatile class of reactions in the field of organic chemistry.1,2) These transformations are pivotal for constructing complex molecular architectures, enabling the selective removal or conversion of functional groups such as nitro, halide, carbonyl, azide, and sulfur-containing moieties, in addition to certain heterocycles. Traditionally, electron-transfer processes rely heavily on elemental alkali metals (e.g., Na and K) and a wide range of transition metals, which offer strong reducing abilities and versatile reactivities. However, these methods often have significant drawbacks; they require rigorous handling procedures, generate hazardous waste, and are incompatible with numerous sensitive functional groups. In the pursuit of practical, economical, and environmentally benign alternatives, considerable attention has been directed toward reductive strategies that operate without elemental alkali or transition metals. In this context, the use of organic electron donors has emerged as a powerful strategy for promoting efficient and selective electron-transfer reactions under mild conditions.3–5) Our recent investigations into pyridine-derived super electron donors (SEDs), along with a combination of sodium hydride (NaH) and 1,10-phenanthroline, have demonstrated the effectiveness of such systems in a variety of reductive transformations. In this review, the development and mechanistic features of these emerging approaches are highlighted, emphasizing their synthetic utility and potential contributions to the advancement of electron transfer chemistry.
SEDs are organic reductants that exhibit strong electron-donating abilities, surpassing those of traditional organic donors such as tetrathiafulvalene (TTF) and tetrakis(dimethylamino)ethylene (TDAE).6–8) Originally developed by Murphy et al., SEDs exhibit tunable redox properties that allow the controlled delivery of one or two electrons, depending on the molecular structure. This structural flexibility enables the fine adjustment of the reduction potential, thereby expanding the applicability of SEDs to a wide range of organic transformations.9–13) Motivated by the unique reactivities of these donors, the development of novel reductive transformations using SEDs was considered. In particular, by employing a pyridine-derived SED, two such reactions were established in our group, namely the reductive transformation of nitrobenzenes to azobenzenes and phenazines, and the desulfurization of thioacetals and thioethers.
2.2. Reductive Transformation of Nitrobenzenes to Azobenzenes and PhenazinesAzobenzenes are important structural motifs that are widely used in dyes, pigments, pharmaceuticals, and functional materials.14,15) Although various synthetic methods have been developed for their preparation, the direct reduction of nitrobenzenes is among the most straightforward and atom-economical approaches to synthesize azobenzenes,16–22) although it typically requires the use of toxic or expensive reagents, transition metals, or flammable gases. To overcome these limitations, an alternative strategy was investigated based on the use of an organic SED.23)
Initially, the reduction reaction of nitrobenzene (1a) was performed using pyridine-derived SED 5 generated in situ from its air-stable precursor and NaH as a base in a glove box. This reaction proceeded efficiently to afford azobenzene (3a) in a high yield (Table 1, entry 1). When weaker electron donors such as TDAE or 6 were employed, the desired compound was not obtained, and azoxybenzene (2a) was produced in low yields (entries 2, 3). Following procedural optimization, the reaction was found to reach completion within 15 min without any loss in yield when performed using a glass manifold system instead of a glove box (entry 4). Using this approach, a wide range of nitrobenzenes, including compounds bearing electron-donating or halogen substituents, were selectively reduced to azobenzenes in good yields (Fig. 1, 3b–3h). Additionally, electron-deficient substrates underwent rapid reduction within minutes (3i, 3j). Moreover, when using 2-fluoronitrobenzene (7a) as a substrate, phenazine (8a) was unexpectedly obtained (Table 2). This transformation was also applicable to a number of other 2-fluoronitrobenzenes (7b–7d), albeit in low-to-moderate yields. These findings demonstrate the value of pyridine-derived SEDs for achieving reductive transformations with a broad substrate scope, while avoiding the use of metallic reagents.
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a) Determined by 1H-NMR spectroscopy using 1,1,2-trichloroethane as the internal standard. b) Isolated yields. c) Reaction was conducted for 15 min using a glass manifold instead of a glovebox.
Isolated yields. a4.0 equivalents (equiv.) of 5 was used. b2.5 equiv. of 5 was used. cReaction was conducted for 5 min.
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Isolated yields.
To further demonstrate the versatility of the pyridine-derived SED, its application in the reductive desulfurization of thioacetals and thioethers was investigated. Notably, compounds containing C–S bonds play diverse roles in organic chemistry, such as stabilizing carbanions,24,25) acting as electrophiles,26–28) and serving as directing groups in transition metal coupling reactions,29–31) thereby rendering them valuable synthetic building blocks. Desulfurization, particularly the conversion of C–S bonds to C–H bonds, is a key transformation that is traditionally achieved using Raney nickel, other nickel species, alkali metals, or stoichiometric transition metals.32,33) However, these methods often involve precious or highly flammable reagents, which present practical challenges such as difficult handling, instability during storage, and increased operational costs. To address these limitations, metal-free alternatives34–36) using pyridine-derived SEDs have been investigated. Specifically, it was hypothesized that the strong reducing capability of the SED could be harnessed to promote efficient C–S bond cleavage, offering a more sustainable, practical, and cost-effective desulfurization strategy.37)
To evaluate this hypothesis, the desulfurization of dithianes was investigated using pyridine-derived SED 5, wherein 2,2-diphenyl-1,3-dithiane (9a) was selected as the model substrate for investigation of the optimal reaction conditions. Through screening of the reaction parameters, including the reagent equivalents, solvent, and temperature, it was found that using SED 5 (1.5 equiv.) in N,N-dimethylformamide (DMF) at 100 °C for 24 h efficiently cleaved the C–S bonds to afford 10a in a high yield (Fig. 2, Condition A). Encouraged by these results, the substrate scope and functional group compatibility of this transformation were examined. Under the optimized conditions, a variety of 2,2-diaryl-1,3-dithianes were efficiently desulfurized, demonstrating the broad substrate scope and functional group tolerance of this approach (10b–10g). This method was also applicable to acyl-substituted dithianes, highlighting its synthetic utility (10h, 10i). Although the standard conditions were ineffective for 2-alkyl-2-aryl-1,3-dithiane (10j), the use of a photoactivated pyridine-derived SED enabled the efficient cleavage of a single C–S bond in the substrate (Condition B).38) This modified protocol furnished the corresponding thiols in moderate yields across a range of alkyl substituents, including benzyl, methyl, and tert-butyl groups (11j–11l). The developed desulfurization protocol was also applicable to thioethers (12a–12e), providing the corresponding hydrocarbons (13a–13c, 10a) in moderate-to-high yields (Table 3). Both aryl and alkyl sulfides were successfully converted under either thermal or photoactivation conditions, depending on the substrate.
Isolated yields. aReaction was conducted at 120 °C. bReaction was conducted at 60 °C. cReaction was conducted at 140 °C.
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Isolated yields. a) 4.5 equiv. of 5 was used.
To gain insight into the reaction mechanism, control experiments were conducted using thiol 14, a putative intermediate formed after a single C–S bond cleavage (Figs. 3a, 3b). Notably, the reaction proceeded in the presence of a base alone, supporting a stepwise mechanism in which the second C–S bond cleavage occurred independently of electron transfer from the SED. Based on control experiments and previous studies, a stepwise mechanism was proposed in which an initial two-electron reduction of dithiane (9a) generates dianionic intermediate 15 (Fig. 3c). Protonation, followed by intramolecular attack and a second C–S bond cleavage step, leads to the formation of the stabilized carbanion 17, which is subsequently protonated to yield the final product (10a).
NaH is a simple and cost-effective reagent that is widely employed as a Brønsted base.39,40) Recently, NaH has also been employed as a hydride donor and reagent in radical-mediated transformations.41–46) Although these reactions have expanded the utility of NaH in synthetic organic chemistry, further investigations are essential for continued development in this area. With this in mind, the synthetic potential of NaH was explored in the context of radical-mediated transformations. Specifically, a transition metal-free coupling protocol was developed using NaH and 1,10-phenanthroline, which enabled efficient C–C bond formation between halo compounds and unsaturated substrates.
3.2. Coupling Reaction of Haloarenes with Unactivated Arenes in the Presence of NaH/1,10-PhenanthrolineBiaryl compounds are among the most important structural motifs in organic synthesis and have a wide range of applications in pharmaceutical, agrochemical, and materials science.47) The direct C–H arylation of unactivated arenes with haloarenes has emerged as an attractive strategy for constructing such frameworks because of its economical and simple steps. This transformation has been predominantly achieved using various transition metal catalysts, including Pd, Rh, Ru, Ir, Ni, and Cu.48,49) However, owing to the cost and environmental concerns associated with transition metal catalysts, radical-based transition metal-free methods, such as base-promoted homolytic aromatic substitution (BHAS), have emerged as promising alternatives.50–54) In this context, a NaH-mediated radical cross-coupling reaction was developed between haloarenes and unactivated arenes under transition metal-free conditions, offering a practical and environmentally benign alternative for biaryl synthesis.55)
Specifically, the optimal conditions for the coupling reaction between 4-iodoanisole (18a) and benzene (19a) were investigated (Table 4). When the reaction was conducted using NaH (2.0 equiv.) in the presence of 1,10-phenanthroline (30 mol%) using benzene (1.5 mL) as both the solvent and the coupling partner at 100 °C for 18 h, the cross-coupled biaryl product (20aa) was obtained in a good yield (entry 1). Notably, the reaction did not proceed in the absence of 1,10-phenanthroline, and LiH proved to be ineffective as a substitute for NaH, thereby highlighting the essential roles of both components.
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|---|---|---|
| Entry | Variation from standard conditions | Yield (%)a) |
| 1 | None | 72 (72)b) |
| 2 | W/O 1,10-phen | 0 |
| 3 | LiH instead of NaH | 0 |
a) Determined by 1H-NMR spectroscopy using 1,1,2-trichloroethane as the internal standard. b) Isolated yields.
Under the optimized reaction conditions, the substrate scope was explored using various haloarenes and unactivated arenes (Table 5). A range of iodoarenes (18b–18f), including halogenated and electron-deficient substrates, were coupled with benzene (19a) to afford the corresponding biaryl products (20ba–20fa) in moderate-to-high yields, although the reagent equivalents required adjustment for each case (entries 1–5). Additionally, the reaction performed using monosubstituted benzene (19c) yielded regioisomeric mixtures, suggesting the presence of aryl radicals (entry 7). This protocol was also applicable to bromoarenes (18g, 18h), demonstrating its broad substrate scope (entries 8, 9). By refining the reaction conditions, the methodology was extended to heteroarenes such as pyrazine (19d), quinoxaline (19e), and quinoline (19f, Fig. 4).
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|---|---|---|---|---|---|---|
| Entry | 18 | 19 | x (equiv.) | y (mL) | Product | Yield (%) |
| 1 | C6H5-I (18b) | Benzene (19a) | 1.5 | 5.0 | 20ba | 74 |
| 2 | 4-MeC6H4-I (18c) | 19a | 1.5 | 1.0 | 20ca | 48 |
| 3a) | 4-ClC6H4-I (18d) | 19a | 1.5 | 3.0 | 20da | 76 |
| 4 | 4-BrC6H4-I (18e) | 19a | 1.5 | 4.0 | 20ea | 80 |
| 5a) | 4-CF3C6H4-I (18f) | 19a | 2.0 | 5.0 | 20fa | 40 |
| 6 | 4-MeOC6H4-I (18a) | 1,4-Difluorobenzene (19b) | 2.0 | 1.5 | 20ab | 64 |
| 7 | 4-MeOC6H4-I (18a) | Benzonitrile (19c) | 2.0 | 2.0 | 20ac | 76b) |
| 8 | 4-MeOC6H4-Br (18g) | 19a | 1.5 | 5.0 | 20ga | 70 |
| 9 | 4-CNC6H4-Br (18h) | 19a | 1.5 | 5.0 | 20 ha | 81 |
Isolated yields. a) Reaction was conducted at 120 °C. b) Ratio of the 2-/3-/4-regioisomers = 56 : 19 : 25.
Isolated yields. aReaction was conducted at 90 °C. Only the C-2 substituted product was obtained. bReaction was conducted at 120 °C. Ratio of the 2-/3-/4-regioisomers = 21 : 25 : 54.
The carboradical-mediated hydrocarbonation of alkenes is a powerful approach for constructing carbon frameworks because it offers a high anti-Markovnikov selectivity owing to the stability of the alkyl radical intermediates.56–58) However, existing methods often rely on transition metals and are limited to specific halide substrates. Since aryl radicals were assumed to be generated in the NaH/1,10-phenanthroline system described in Section 3.2, it was envisioned that this system could be applied to the hydrocarbonation of alkenes. Indeed, styrenes underwent smooth hydrocarbonation under these transition metal-free conditions, and the reaction demonstrated a broad substrate scope, including various aryl and alkyl halides, with mechanistic studies indicating that the in situ generated anilide anion acts as both an electron donor and a hydrogen source.59)
After extensive optimization of the coupling reaction between bromobenzene (21a) and 1,1-diphenylethylene (22a), the optimal result was obtained when the reaction was conducted using NaH (dry powder, 2.5 equiv.) and 1,10-phenanthroline (60 mol%) as an additive in benzene at 120 °C for 18 h, affording the cross-coupled product (23aa) in a high yield with complete anti-Markovnikov selectivity (Fig. 5). Under the optimized conditions, the substrate scope of the coupling reaction was explored using various bromoarenes and styrenes. Bromoarenes bearing electron-donating or electron-withdrawing groups, halogens, and sensitive functional groups (e.g., silyl and boryl groups) were well tolerated, affording the desired products in moderate-to-high yields (23ba–23ha). This method was also extended to hydroalkylation using various alkyl halides (23ia–23ka), although substrates bearing β-hydrogen atoms tended to undergo E2 elimination reactions. Furthermore, a broad range of styrenes, including 1,1-diarylethylenes, heteroarene-containing styrenes, and 1,1-arylalkyl-substituted alkenes, underwent smooth hydroarylation with complete anti-Markovnikov selectivity (23ab–23af), although the internal alkene afforded a lower yield (23ag).
Isolated yields. a6.0 equiv. of 22 was used. b1.5 equiv. of NaH was used. c3.0 equiv. of 22 was used. d1.2 equiv. of NaH was used. eReaction was conducted at 140 °C.
Further experiments were also conducted to elucidate the reaction mechanism (Chart 1). The addition of (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl (TEMPO) inhibited the formation of the hydroarylated product and led to the detection of an aryl–TEMPO adduct by high-resolution mass spectrometry, indicating the presence of aryl radical intermediates (Chart 1a). To identify the electron donor, the reaction between 1,10-phenanthroline and NaH was quenched with methyl chloroformate, affording a carbamate product, and suggesting the formation of an anilide anion60) (Chart 1b). Further evidence was obtained from reactions performed using acridine derivatives; 9,10-dihydroacridine (26) promoted hydroarylation and was oxidized to acridine, whereas N-phenyl-9,10-dihydroacridine (27) did not, thereby supporting the role of an anilide anion as the electron donor (Chart 1c). Additionally, a deuterium-labeling experiment performed using 1,10-phenanthroline-d8 showed deuterium incorporation into the product, suggesting that 1,10-phenanthroline also serves as a hydrogen source in the reaction (Chart 1d). Taken together, these results clarified the key mechanistic features of the NaH/1,10-phenanthroline system.
Based on these results, two possible pathways were proposed for the hydrocarbonation reaction, as illustrated in Fig. 6. In the first pathway (Mechanism A), NaH reduces 1,10-phenanthroline to form the corresponding anilide anion A, which then transfers a single electron to haloarene 21a, generating aryl radical B and nitrogen-centered radical C. Aryl radical B adds to styrene (22a) to form alkyl radical intermediate D, which subsequently abstracts a hydrogen atom from radical C, yielding 23aa and regenerating 1,10-phenanthroline. An alternative pathway (Mechanism B) involves anilide anion A serving directly as the hydrogen donor, with radical anion Aʹ functioning as the electron donor to initiate aryl radical formation.
In this review, the recent advances in transition metal-free reductive transformations mediated by organic electron donors were summarized, with a particular focus on pyridine-derived SEDs and the NaH/1,10-phenanthroline system. Pyridine-derived SEDs have proven to be powerful tools for the selective reduction of nitroarenes and the desulfurization of thioethers and thioacetals under mild conditions, offering both operational simplicity and a broad functional group compatibility. Furthermore, the NaH/1,10-phenanthroline system enabled efficient radical-mediated C–C bond formation through the coupling of halo compounds with unactivated arenes and styrenes, including hydroarylation and hydroalkylation reactions, yielding excellent anti-Markovnikov selectivities. Mechanistic investigations provided key insights into the generation of carbon radicals and the dual role of 1,10-phenanthroline as both an electron and hydrogen source. These findings collectively demonstrate the significant synthetic potential of organic electron donor systems as sustainable alternatives to traditional metal-based reductive methods, while also opening new avenues for their further exploration in the fields of radical chemistry and molecular synthesis.
I would like to express my deepest appreciation to Professor Yoshinori Kondo (Tohoku University) for his generous guidance, support, and encouragement throughout this research. I am also grateful to all collaborators for their dedicated efforts and valuable contributions to the research. This work was financially supported by a Grant-in-Aid for Young Scientists and Scientific Research (C) from the Japan Society for the Promotion of Science, and by the Takeda Science Foundation.
The author declares no conflict of interest.
This review of the author’s work was written by the author upon receiving the 2022 Pharmaceutical Society of Japan Incentive Award for Women Scientists.
