Synthesis of value-added N-containing aromatic products from lignins: a review

Abstract

The simultaneous degradation and valorization of the most abundant renewable aromatic lignin provides significant benefits for synthesizing complex N-containing aromatic products, which are used in various applications ranging from pharmaceuticals to materials. Therefore, broadening the range of N-containing aromatic products derived from lignin is one of the key objectives in fulfilling future biorefinery and green chemistry needs. Enormous research efforts have been directed toward lignin depolymerization since the structural characterization of lignin has become increasingly understood. Over the past decade, significant progress has been made in N-mediated degradation strategies utilizing lignin models and extracts as raw materials. This review focuses on various activation strategies for cleaving the lignin C–C/C–O bonds while forming new C–C/C–N bonds in the presence of transition metal and metal-free catalysts. Additionally, insights into the fundamentals of reaction control, understanding reaction pathways, and their applications in the synthesis of active pharmaceutical ingredients and functionalized materials are discussed.

---

Green foundation

1. We discuss strategies for N-mediated lignin degradation to synthesize N-containing aromatics using transition metal and metal-free catalyst systems over the past decade, which focuses on understanding the mechanisms of lignin C–C/C–O bond cleavage and the formation of new C–C/C–N bonds.

2. N-containing aromatics with structural diversity serve as core structures in natural products, medicines, agrochemicals, and organic functional materials. After years of research, developing a library of valuable N-containing aromatics from renewable aromatic lignin offers a potential petroleum-independent option for meeting future biorefinery and green chemistry needs.

3. Most strategies discussed in the review frequently depend on noble transition metal catalysts or stoichiometric oxidants or bases, which could raise environmental and economic concerns. Exploring bio-derived or non-noble transition metal catalysts may lower toxicity and enhance sustainability. Additionally, employing electrochemical and photocatalytic methods for lignin valorization can reveal new possibilities for greener conversion processes.

1. Introduction

The substantial energy crisis and environmental repercussions caused by excessive fossil resource consumption have triggered strong interest in processing lignocellulosic biomass (cellulose, hemicellulose and lignin) into biofuels and biobased chemicals to guarantee energy and environmental security.^1–5 Lignin, the primary aromatic component in lignocellulose, is the most abundant renewable aromatic resource in nature and offers exceptional opportunities as an excellent starting material for manufacturing highly value-added aromatic compounds.^6–8 However, unlike cellulose and hemicellulose (accounting for 60–85 wt% in wood) with defined structures,⁹ the precise structure of lignin (accounting for 15–30 wt% in wood) depends on the plant type.¹⁰ Recent studies have shown that lignin has an inherently complex three-dimensional rigid structure composed of β-O-4, β-5, α-O-4, β–β, 4-O-5, 5–5′, α-O-γ, and other types of linkages (Scheme 1A).^11,12 The irregular and random connection of these units renders lignin depolymerization as being characterized by low reactivity, poor selectivity, and overall inefficiency, which further hinders lignin valorization. Specifically, due to the restrictions of the inherent nature of lignin, most existing degradation strategies, such as hydrogenation,^13–21 oxidation,^22–26 acid or base catalysis,^27–29 redox-neutral depolymerization,^30,31 and others, are limited by their ability to introduce new C–H, C–O, and C–C bonds into the depolymerized aromatic monomers.

Scheme 1 General illustration of the valorization process of N-mediated lignin β-O-4 segments.

N-containing aromatic molecules possess significant physiological properties and offer promising applications in natural products, medicinal chemistry, agrochemicals, and functional materials.³² Current production routes for these valuable N-containing aromatic molecules primarily rely on the amination of pre-functionalized arenes, which are typically sourced from non-renewable petrochemical feedstocks like BTX (benzene, toluene, and xylene) through multi-step processes.^33–35 Moreover, these routes face several additional technological drawbacks, such as the generation of hazardous waste streams and low atom and energy efficiency.³⁶ To transition from petroleum-based to bio-based production using biomass as a renewable resource, it is crucial to develop a viable pathway from lignin to a diverse range of N-containing aromatic molecules. Although existing processes for synthesizing N-containing aromatic molecules from isolated lignin or lignin-based platform molecules are well-established, additional protection-group chemistries or reductive stabilization measures are often required.^37–39 The promising application prospects of lignin-derived N-containing products have sparked growing interest within the biomass valorization community.^32,40–43

With the continued interest of chemists in synthesizing natural products and valuable pharmaceuticals from renewable lignin resources,⁴⁴ several recent studies have reported on the synthesis of paracetamol,⁴⁵ pyridines,⁴⁶ dopamine,⁴⁷ oximes,⁴⁸ tetrahydro-2-benzazepines,⁴⁹ tetrahydroisoquinolines, quinazolinones, indoles, the natural product tetrahydro-papaveroline,³³etc. These works typically involve multiple functionalization steps using O-containing platform molecules derived from lignin as the key building blocks, along with ammonia or organic amines as the amine source, which will undoubtedly increase processing costs and hinder practical applications. In another scenario, extensive efforts have been devoted to converting lignin-derived monophenols with amine sources to deliver value-added aryl amines,^50–52 cyclohexylamines,^53–55 tetrahydro-β-carbolines,⁵⁶ and tetrahydroacridines⁵⁷ by transition metal-catalyzed reductive coupling.⁵⁸ In contrast, the direct construction of specific N-containing aromatics from protolignin/technical lignin in a simple conversion strategy has been rarely reported.⁴⁶

Compared to the intricate research on direct lignin degradation, establishing lignin model studies not only quickly identifies product structures and clarifies the degradation mechanism but also offers potential new methods for native lignin degradation.¹⁰ Lignin β-O-4 models bearing γ-OH, a simplified simulacrum of the β-O-4 linkage (which accounts for approximately 50–65% of all linkages),^59–61 are often utilized to explore various methodologies for constructing N-containing aromatics with structural diversity (Scheme 1B).⁴² Over the past decade, numerous elegant studies have emerged that elaborate on N-mediated lignin degradation processes transforming lignin β-O-4 dimers/polymers or extracted lignin into various value-added N-containing aromatics (Scheme 1C).

This review provides an overview focused on N-mediated degradation strategies using lignin β-O-4 models or lignin extracts as starting materials. These strategies for delivering various N-containing aromatic products were categorized into two groups: metal-catalytic methods and metal-free catalytic methods, which involve the simultaneous cleavage of C–O and C–C bonds in lignin β-O-4 models and the formation of new C–C and C–N bonds. We specifically focus on discussing the fundamentals of reaction control, understanding reaction pathways, and their applications in the synthesis of active pharmaceutical ingredients and functionalized materials. Overall, this review aims to provide a perspective on the current state of the art in strategies for the degradation of lignin β-O-4 models and lignin extracts to harvest N-containing aromatic chemicals while highlighting the exciting potential for future developments in this field.

2. N-mediated degradation modes

The development of N-mediated lignin β-O-4 models/native lignin degradation is generally classified according to the types of different catalysts.

2.1 Metal-catalyzed amination

2.1.1 Copper-catalyzed oxidative systems. As the most abundant and valuable aromatic component of lignocellulosic biomass, lignin is an amorphous aromatic biopolymer mainly connected through β-O-4 linkages. Chemoselective oxidation transforms the secondary benzylic alcohol group of lignin β-O-4 dimeric models into a ketone, which lowers the bond dissociation energy and makes subsequent cleavage reactions easier. Benzamide is a notable compound in the synthesis of various antimicrobial agents. It serves as a key building block for many medications, including those formulated and produced in the pharmaceutical industry.⁶² Additionally, its versatility enables the creation of diverse compounds that can be used in various therapeutic applications.⁶³ Loh and co-workers reported an effective aerobic reaction that converts the β-O-4 lignin model 1 and secondary (cyclic, acyclic, and alkenyl) amine 2 to synthesize α-keto amide 3, amide 4, and phenol 5 at 70 °C by employing CuI (10 mol%) as a transition metal catalyst (Scheme 2A).⁶⁴ An isotope-labelling study under ¹⁸O-labeled oxygen gas (¹⁸O₂) was carried out to gain a deeper understanding of the mechanism. The ratio of ¹⁸O–¹⁸O : ¹⁸O–¹⁶O : ¹⁶O–¹⁶O for the α-keto amide in the isotope-labelling experiment indicates that both oxygen atoms of α-keto amide 3 originate from ¹⁸O₂. The reaction is suitable only for alkyl amines and oxidized β-O-4 ketone dimers, while it is incompatible with aromatic amines and β-O-4 alcohol dimers. Additionally, toluene is toxic and corrosive, potentially leading to neurological damage, skin irritation, and respiratory issues. Its use as a solvent raises concerns about sustainability due to health hazards, environmental impact, and waste generation.

Scheme 2 Chemoselective synthesis of α-keto amides/amides from lignin β-O-4 ketones catalyzed by copper.

Liu and co-workers, inspired by the above work, presented a similar study using a lignin β-O-4 ketone and the less nucleophilic aniline as substrates, catalyzed by CuCl₂ (10 mol%) under an O₂ or air atmosphere at 120 °C to chemoselectively synthesize benzanilide 7 and phenol 5 (Scheme 2B).⁶⁵ Under these experimental conditions, the Cu(II) species showed higher catalytic efficiency than the Cu(I) species, which might be attributed to the greater oxidative properties of the Cu(II) species. They inferred that the oxidative cleavage of the C–C bond and the formation of the C–N bond occurred simultaneously. The proposed enamine intermediate, which was detected in the ¹H NMR spectrum, can be regarded as corroboration of this inference.⁶⁶ They focused solely on lignin β-O-4 ketone dimers and did not investigate the β-O-4 alcohol dimers, which are more representative of real lignin. Notably, DMSO has low toxicity but can cause skin irritation and enhance the absorption of harmful substances through the skin.

In 2020, Wang and co-workers detailed the relationship between different amine feedstocks and the product structures.⁶⁷ When using primary or secondary aliphatic amines as raw materials, the transition metal catalyst Cu(OAc)₂ (10 mol%) worked with green oxygen (O₂) at room temperature to facilitate the oxidative cleavage of the C–C bond in lignin β-O-4 ketone, leading to the formation of a new C–N bond that selectively generates aromatic amides. Even though lignin β-O-4 ketone dimers with a γ-OH group can generate a yield of over 37%, they did not subsequently investigate lignin β-O-4 alcohol dimers. When ammonia was utilized as a starting material, it competed with oxygen during the C–N bond formation, resulting in a mixture of amide and α-keto amide. The ¹⁸O isotope-labelling experiments using dimethylamine as an amine agent demonstrated that the aromatic amide product retained the oxygen atom from lignin β-O-4 ketone. When using ammonia as the nitrogen source, only one of the two carbonyl oxygen atoms was labeled in the α-keto amide, indicating another mechanistic pathway (Scheme 2C).

The currently proposed mechanism, based on previous reports of copper-catalyzed aerobic amide/α-keto amide formation, involves the transient higher valent Cu(II)-oxygen species reacting with the lignin β-O-4 ketone in a single electron oxidation process, yielding an α-keto copper peroxide that is subsequently attacked by an ammonia/1° or 2° amine to form a hemiaminal copper peroxide.⁶⁷ Then, the fragmentation of the C–C bond of the α-hemiaminal copper peroxide intermediate furnishes amide 4 and a formyl ester, which undergoes aminolysis to yield a formyl amine and phenol 5. The hemiaminal intermediate loses a water molecule through another pathway to form the iminium salt intermediate.^68–70 The α-imino copper peroxide intermediate undergoes 4-exo-trig cyclization to give a four-membered ring aminodioxetane intermediate.⁶⁴ Further cleavage of the O–O bond in the four-membered ring, accompanied by the departure of an amine, leads to an arylglyoxylic acid aryl ester, which reacts with the amine to yield the desired α-keto amide 3 and phenol 5. However, the lignin β-O-4 models containing the benzyl alcohol group were found to be incompatible with the copper-catalyzed oxidative cleavage system due to the unactivated C–C and C–O bonds, which have high dissociation energies.^71,72

Benzonitrile serves as an intermediate in the synthesis of high-quality coatings, such as melamine benzoguanamine, and its derivatives can be utilized to produce a range of drugs, including the antimalarial medication pamaquine.⁷³ Benzaldehyde derivatives serve as strong platforms for building complex N-containing compounds. Based on the potential benzaldehyde unit in the lignin β-O-4 model,^74–79 Li et al. developed a protocol for synthesizing benzonitrile 9 using Cu(OAc)₂ (100 mol%) as a catalyst and tetrabutylammonium iodide (TBAI, 10 mol%) as a promoter in the presence of (NH₄)₂CO₃8 at 120 °C (Scheme 3).⁸⁰ The selectivity and yield of the targeted aromatic nitrile 9 and phenol 5 were closely related to the substituents on the aryl ring O-terminus. The negative effects arise as the number of methoxy groups on the aryl ring O-terminus increases. This can be attributed to the electronic effects of the multiple methoxy groups, which enhance the bond dissociation energy and make the substrate more susceptible to oxidation.⁷² When lignin β-O-4 ketone dimers with a γ-OH group are used as substrates, the yield is 17%. In terms of sustainability, Cu(OAc)₂ is toxic as a catalyst and concerns have been raised about its potential for environmental contamination.

Scheme 3 Synthesis of benzonitriles from lignin β-O-4 ketone catalyzed by copper.

The plausible mechanism supported by isotope-labelling and control experimental data is as follows: first, the TBAI is oxidized to Lewis acid I₂, which complexes with the carbonyl group, activating the C–C bond and reducing the bond energy. Next, a single-electron oxidation process, catalyzed by Cu(OAc)₂/O₂, produces the α-keto copper peroxide, which is followed by a tandem [1,2-H] shift and C–C bond cleavage sequence that yields the key benzaldehyde intermediate. Subsequently, the condensation of the benzaldehyde with ammonia, derived from the decomposition of (NH4)₂CO₃8, yields the benzaldimine intermediate, which, upon dehydration, affords benzonitrile 9. Subsequently, Li et al. successfully applied this Cu(OAc)₂/TBAI/O₂ oxidative system to cleave oxidized birch lignin, yielding 4-hydroxy-3,5-dimethoxybenzonitrile in 0.43 wt% yield. This establishes a promising pathway for converting real lignin biomass into value-added aromatic nitriles.

2.1.2 Palladium-catalyzed reductive systems. Palladium-mediated lignin bond-breaking and new bond-forming protocols have expanded the pool of available platform molecules and significantly shortened the synthetic sequence of value-added N-containing molecules.^{52–54,81–83} Benzylamine is a key intermediate in the synthesis of various drugs, including Sulfamylon, an antibacterial used to treat burn infections.⁸⁴ In 2021, Li and coworkers reported a reductive cleavage strategy using Pd/C (5 mol% Pd) that directly converted the lignin β-O-4 model into benzylamine by employing a secondary amine or an additional reductive reagent as a hydrogen source at 120 °C (Scheme 4).⁸⁵ Since primary amines and aryl amines possess relatively weaker dehydrogenation abilities than secondary amines, it is vital to incorporate HCOONa to activate the Pd/C, enabling the reaction to proceed through a low-energy barrier pathway when utilizing primary amines or aryl amines as H₂ donors.⁸⁶ The boiling points of the amine reactants used are significantly lower than those of the β-O-4 model compounds and the corresponding benzylamine products, making it easy to distill the unreacted amines from the reaction mixture for recycling. This efficient recycling process not only recovers valuable amine reactants but also enhances the overall sustainability of the reaction by reducing waste and resource consumption.

Scheme 4 Synthesis of benzylamines from the lignin β-O-4 model catalyzed by palladium.

Experimental data have suggested two possible mechanistic pathways (I and II). Initially, the lignin β-O-4 ketone was obtained via dehydrogenation of the benzylic alcohol unit in 10. In pathway I, the formation of an acetophenone intermediate is proposed based on the cleavage of the C–O bond of the lignin β-O-4 ketone, followed by condensation with an amine to form the imine I intermediate that tautomerizes to enamine I. In pathway II, the generation of the imine II intermediate is assumed, which can tautomerize to enamine II, delivering phenol 5 and enamine I upon fragmentation. Finally, reduction of enamine I gives benzylamine 11. Direct control experimental evidence exists indicating that these intermediates are present and have been identified.

To their disappointment, the amination of native lignin did not occur with the Pd/C reductive cleavage protocol because the dehydrogenation of benzylic alcohol did not take place; only small amounts of phenol derivatives were detected. Instead, a two-step sequence was developed that involved the depolymerization of lignin-oil, catalyzed by a binuclear rhodium complex, followed by the Pd/C reductive cleavage of the resulting keto-monomers. This process effectively converted real lignin into polysubstituted benzylamines 11 with a 0.4 wt% yield.

Spurred on by the identified acetophenone intermediate observed in their previous studies,^85,87 Li and colleagues presented a one-pot multicomponent method to produce imidazopyridine (Scheme 5).⁸⁸ The two-step process involves the key acetophenone intermediate generated from selective C–O bond breaking using a typical Pd/C catalyst (5 mol% Pd) and a commercially available hydrogen source, NaBH₄ (10 mol%). Then, the α-iodination of acetophenone, induced by electrophilic iodine species I⁺ generated from I₂, produces an α-iodine aryl ketone intermediate. Following this, the cyclization of the α-iodine aryl ketone with 2-aminopyridine 12 yields an architecturally bicyclic aminopyridine 13 and the byproduct HI. NH₄HCO₃ has proven to be the most effective base for promoting the iodination and cyclization processes by releasing NH₃ to neutralize HI.

Scheme 5 Synthesis of imidazopyridines from the lignin β-O-4 model catalyzed by Pd/C and I₂ in two steps.

With these results in hand, a plausible mechanism was proposed. The first step involves the abstraction of a hydrogen atom from Cα in the lignin β-O-4 model 10 to produce the lignin β-O-4 ketone. Then, NaBH₄ accelerates the Pd/C catalyst in cleaving the C–O bond to form acetophenone. Subsequently, I₂-promoted α-iodination of acetophenone with NH₄HCO₃ occurs. Following this, the iodine atom in the resulting 2-iodo-1-phenylethanone is attacked by 2-aminopyridine 12, resulting in the formation of the intermediate I with a new C–N bond. The imine nitrogen attacks the proximal carbonyl group to generate bicyclic hemiaminal II, which undergoes aromatization to give imidazo[1,2-a]-pyridine 13.

This one-pot multicomponent strategy was effectively used for the β-O-4 polymer, which mimicked natural lignin, yielding a moderate amount of the desired imidazopyridine product in two steps. This methodology presents a promising option to connect renewable lignin with biologically active N-heterocyclic pharmaceuticals, thereby reducing a significant dependency on petroleum resources. Regrettably, they did not further investigate the reaction using real lignin. Considering sustainability, Pd/C is toxic and can cause respiratory irritation. It is a sustainable catalyst due to its efficiency and reusability. NaBH₄ is toxic, causing skin and eye irritation. As a hydrogen source, it offers sustainability due to efficient energy release.

2.1.3 Vanadium-catalyzed systems. Vanadium catalysts, known for their low toxicity, ease of manipulation, and remarkable activity, have been widely used in numerous oxidation-type reactions, including oxidative C–O/C–C bond cleavage, C–C bond construction, hydrogenation, cyanation, haloperoxidase, ring-opening metathesis polymerization, etc.⁸⁹ Recently, vanadium catalysts have emerged as promising components of the technology for the oxidative degradation of lignin. Several attempts have been made to survey N-mediated lignin deconstruction using vanadium catalysts, achieving notable progress. Carbazoles are types of promising N-containing heterocyclic aromatics that serve as the fundamental structure for various bioactive pharmaceuticals and functional materials.^90,91 In 2023, Zhang and co-workers reported elegant work on the vanadium-catalyzed direct conversion of lignin β-O-4 model 10 with 3-alkenylated indole 14 to afford the carbazole-based BioAIEgen (bioresource-based aggregation-induced emission luminogen) product 15 in a one-pot reaction without external oxidant/reductant resource at a relatively high temperature of 140 °C (Scheme 6).⁹² The vanadium complex featuring the tridentate Schiff-base ligand (V-complex I, 10 mol%) has been demonstrated as the most effective catalyst among the various vanadium-based catalysts tested. They also achieved a 71% yield of the target product when using real lignin β-O-4 alcohol dimers in their research. Notably, when working with the highly toxic VO(OEt)₃ in the reaction, careful handling and sustainable practices are required to help reduce environmental risks.

Scheme 6 Synthesis of carbazoles from the lignin β-O-4 model catalyzed by vanadium.

The triangular A₁–D–A₂ (electronic acceptor–donor–acceptor) configuration of compound 15 enables it to simultaneously possess a core carbazole skeleton with electron-donating capacity and two benzoyl moieties with electron-accepting capability. The structure facilitates excellent twisted intramolecular charge transfer and AIE performance to be exhibited and it holds a unique photophysical property.

The mechanism illustrated in Scheme 6 is supported by DFT calculations and experimental data. The reaction begins with the exchange of the ligand on the vanadium complex by the benzylic alcohol of 10, followed by the abstraction of a hydrogen atom from the benzylic position to the vanadium-oxo to form a ketyl radical. Cleavage of the phenolic C–O bond leads to the formation of an enolate intermediate and an aryloxy radical. The elimination of the hydroxy group of the enolate releases water and results in the formation of the α,β-unsaturated ketone product. The resulting vanadium(IV) complex is re-oxidized by the newly formed oxyradical to regenerate vanadium(V) and close the catalytic cycle.⁹³ Subsequently, the electron-poor α,β-unsaturated ketone intermediate (dieneophile) and electron-rich 3-alkenylated indole 14 (diene) undergo a normal intermolecular electron-demand Diels–Alder cycloaddition, forming the tetrahydrocarbazole skeleton. The driving force is the formation of two new σ-bonds. Finally, the dehydrogenative aromatization of the tetrahydrocarbazole generates the carbazole compound 15. In this process, the vanadium catalyst plays an essential role in intramolecular dehydrogenation.

Lignin-derived carbazoles with A–D–A configurations, originating from renewable substrates, display TICT–AIE performances, endowing lignin-depolymerized derivatives with unique photophysical properties. The current V-complex-catalyzed protocol provides a concise and sustainable method for synthesizing functionalized carbazoles with AIE properties, establishing a clear link between lignin and BioAIEgens.

The outstanding catalytic performance demonstrated by the vanadium complex inspired Zhang and colleagues to synthesize additional valuable heterocyclic molecules. Triazoles, which comprise a five-membered ring containing two carbon atoms and three nitrogen atoms, are types of heterocyclic compounds with a wide range of applications in drug discovery, organocatalysis, bioconjugation, fluorescence imaging, agrochemicals, and materials science.⁹⁴ In 2024, Zhang et al. developed a vanadium-catalyzed cyclization protocol that involved an enone, derived from lignin β-O-4 model 10, with catalysis provided by V-complex I (5 mol%) at 110 °C, coupled with azide 16 to access the 1,2,3-triazole compound 17 in moderate to excellent yield (Scheme 7).⁹⁵

Scheme 7 Synthesis of triazoles from the lignin β-O-4 model catalyzed by vanadium.

V-complex I was identified as the optimal catalyst in this reaction, providing a satisfactory yield of 1,2,3-triazole 17 and guaiacol 5. Moreover, the unprotected phenol motif on the C-terminal was examined as compatible with the catalytic system. The vanadium catalyst system is well-tolerant of the electron-donating group on the aryl ring C-terminus/O-terminus of the lignin β-O-4 model and is suitable for various substituted-azide substrates.

The proposed mechanism involves V-complex I catalyzing the selective cleavage of C–O bonds to form the α,β-unsaturated ketone intermediate, followed by an intermolecular 1,3-dipolar cycloaddition with the azide, resulting in the formation of the triazoline. The triazoline rapidly undergoes dehydrogenation to yield the desired 1,2,3-triazole compound 17. Additionally, this method was employed to establish a link between lignin and carbohydrate derivatives, successfully producing triazole carbohydrate derivatives with broad pharmaceutical bioactivities. However, the compounds used were all model compounds, not real lignin or carbohydrates.

In the same year, continued attention was focused on the synthesis of the quinoline alkaloid skeleton, an important building block in organic chemistry.^96–98 Zhang and coworkers discovered a novel vanadium/copper co-catalyzed method (V-complex I, 5 mol% and Cu(OAc)₂, 20 mol%) for efficiently constructing functional quinolines 19 in moderate to good yield, starting from the lignin β-O-4 model 10 with a γ-OH group and 2-aminobenzylalcohol 18 at 140 °C (Scheme 8).⁹⁹ This is a modified supplementary method of their previous work on the degradation of the lignin β-O-4 model mediated by an inorganic base to synthesize quinoline compounds because the base-catalyzed protocol was incompatible with the γ-OH group in the β-O-4 motif.¹⁰⁰ In the initial stage of the experiment, vanadium complex I was tested as an exclusive catalyst, producing only a minute amount of quinoline. When Cu(OAc)₂·H₂O and TEMPO were added to the reaction mixture, the yield increased to 78%. The control experiment determined that Cu(OAc)₂·H₂O and TEMPO were in charge of oxidizing 2-aminobenzyl alcohol 18 to 2-aminobenzyl aldehyde. Unlike other systems that cleave the γ-OH group, this system effectively utilizes it, incorporating it into the final product. Moreover, TEMPO is relatively low in toxicity and, being an oxidant, it is sustainable because of its efficiency and recyclability, though careful handling is necessarily needed.

Scheme 8 Synthesis of quinolines from the lignin β-O-4 model catalyzed by V and Cu.

The first step in the mechanism involves V-complex I catalyzing the formation of an α,β-unsaturated ketone through the cleavage of aryl ether 10 and the elimination of the hydroxy group from the enolate to release water. Then, an aza-Michael addition occurs between the enone and 2-aminobenzyl aldehyde to form the ketoaldehyde intermediate. An intramolecular 1,2-addition rapidly takes place to construct the tetrahydroquinoline. Aromatization of the tetrahydroquinoline affords the final quinone compound 19. This method shows a broad substrate scope, excellent functional group tolerance, and high yields without external oxidizing and reducing reagents.

In addition to β-O-4 models, there are many works on converting α-O-4 and 4-O-5 models into N-containing aromatic compounds. In 2018, Vos et al. reported the transformation of the α-O-4 dimer compound into primary cyclohexylamines with ammonia, using Rh/C as an excellent catalyst.¹⁰¹ In 2018, Li and co-workers developed cross-coupling methods that used the 4-O-5 dimer as the substrate, employing NaBH₄ as the hydrogen donor, primary and secondary aliphatic amines, as well as ammonia, which served as nitrogen sources, and Pd(OH)₂/C acting as the hydrogen transfer catalyst to produce a variety of aryl and cyclohexyl amines in a one-pot reaction.^102,103 The mechanism involved two aryl C–O cleavages to form phenol intermediates. The phenols were then converted into cyclohexyl amines with amines, followed by Pd-catalyzed dehydrogenation to yield aryl amines.

2.1.4 Conclusions on metal-catalyzed amination. In conclusion, Cu-catalytic systems are only suitable for the β-O-4 ketone model compound, which has a low C–C bond cleavage energy barrier. The oxidation ability of Cu-catalytic systems is not enough to abstract the hydrogen atom at the benzyl position of the β-O-4 alcohol dimer. With regard to Pd-catalytic systems, the Pd/C catalyst, due to the characteristics of heterogeneous catalysis, shows insufficient oxidation capacity. This makes it challenging to activate the benzyl hydrogen atom in real lignin, necessitating its combination with the noble-transition metal Ru-complex catalyst for lignin depolymerization and amination. The V-based catalytic systems have difficulty breaking the γ-OH in natural lignin via a six-membered ring transition state, making it unsuitable for direct application in lignin depolymerization. To address these challenges, new organic ligands can be complexed with metal centers to enhance the oxidation performance of transition metals. Additionally, alloying two or more transition metal elements can further improve catalytic performance. The preparation of transition metal catalysts as nanoparticles significantly increases their surface area, providing more active sites for reactions.

Furthermore, the development of new catalysts, such as single-atom and zeolite-based catalysts, has shown enhanced activity and selectivity, effectively improving the efficiency of lignin depolymerization and amination processes.

2.2 Metal-free-mediated amination

2.2.1 Hydroxylamine-mediated systems. The Beckmann rearrangement is a traditional organic reaction that converts aldoximes or ketoximes into the corresponding amides under acidic conditions. It underpins the established industrial need for synthesizing the polyamide monomer ε-caprolactam used to produce synthetic fibers. Modifying the lignin structure with hydroxylamine hydrochloride to access ketoxime for simultaneously constructing different N-containing molecules in a divergent manner is highly attractive.

In 2018, Zhang and He et al. reported a Beckmann rearrangement using lignin β-O-4 ketoxime 20 as a substrate, which was acid-mediated (SOCl₂, 50 mol%) at 80 °C, to directly produce benzonitrile 9, benzamide 7, oxazole 21, and aniline 22 in a one-pot process, achieving an overall yield of up to 96% (Scheme 9A).¹⁰⁴ It should be noted that the ketoxime 20 consists of a mixture of Z (Ar¹ is anti to OH) and E (Ar² is anti to OH) isomers and the absolute configuration of the Z-ketoxime was confirmed by X-ray single-crystal structure analysis. For the Z-ketoxime, thionyl chloride (SOCl₂) activates a normal Beckmann rearrangement to obtain the anilide, which could be further hydrolyzed to form aniline and carboxylic acid. In contrast, the SOCl₂-induced E-ketoxime undergoes an abnormal Beckmann rearrangement called Beckmann fragmentation, which often competes with the conventional Beckmann rearrangement to produce benzonitrile. This occurs due to the functional group adjacent to the oxime, which stabilizes carbocation formation, making fragmentation a viable reaction pathway. When the E-ketoxime bears a γ-OH group, the Beckmann rearrangement affords a C-2 monosubstituted oxazole along with the aforementioned N-containing products due to the nucleophilicity of the γ-OH group. Additionally, SOCl₂ is extremely toxic and corrosive, leading to significant irritation of the skin, eyes, and respiratory system. While it is effective in reactions, its use necessitates proper safety measures and disposal to ensure environmental sustainability.

Scheme 9 Synthesis of benzonitrile, benzamide, oxazole and aniline from lignin β-O-4 ketone mediated by hydroxylamine.

In the first step of the mechanism, the hydroxyl group of the ketoxime is converted into a sulfate ester by reacting with the electrophilic SOCl₂. For the Z-ketoxime, the departure of the ClSOOH leaving group from the sulfate ester I is accompanied by the [1,2]-shift of the Ar¹ group, which is anti to the sulfate ester group. The resulting carbocation I reacts with a water molecule, affording the anilide after tautomerization. The aniline 22 and carboxylate are obtained by hydrolyzing the anilide intermediate. For the E-ketoxime, the departure of the ClSOOH leaving group from the sulfate ester II generates nitrile 9 and carbocation II, which is quickly intercepted to form phenol 5. The hydrolysis of nitrile 9 yields the final benzamide 7. For the E-ketoxime with a γ-OH group, a Beckmann rearrangement to give carbocation III is favored, which is attacked by the intramolecular hydroxyl group to yield oxazole 21 after aromatization. Additionally, a related protocol that utilized NaN₃ to produce aniline 22 was detailed in a recent review by Wang et al.^32,105

In the same year, the Wang group developed a hydroxylamine-mediated protocol to form isoxazole and aromatic nitrile products through lignin degradation (Scheme 9B).¹⁰⁶ MgO (2 equiv.) possesses the best properties to promote acceleration of C–O bond cleavage in lignin β-O-4 ketoxime and isoxazole construction. In the course of the experiment, the confirmation of the oxiran oxime intermediate indicates the formation of isoxazole 23 and aromatic nitrile 9 through two types of oxiran oximes. The condensation between the hydroxyl group and oxiran of the (Z)-oxiran oxime under MgCl₂ produces the isoxazole, while the (E)-oxiran oxime may undergo Beckmann rearrangement to give the aromatic nitrile due to the spatial position of the hydroxyl group being anti to the oxirane. Unfortunately, this elegant one-step hydroxylamine-mediated lignin degradation strategy cannot be directly applied to real lignin with complex three-dimensional structures. After optimization, SA (hydroxylamine-O-sulfonic acid) was identified as an ideal additive for addressing the problem, resulting in the formation of isoxazole and aromatic nitrile products from pre-oxidized birch lignin at 1.16 wt% and 1.76 wt%, respectively.³² The reaction system shows strong compatibility with β-O-4 ketone dimers containing γ-OH; however, when β-O-4 alcohol dimers with γ-OH are used as substrates, the target product does not form.

In 2019, Fokin and co-workers employed SO₂F₂ gas to induce the Beckmann rearrangement of a mixture of lignin β-O-4 ketoxime isomers to yield anilide 24, which facilitates smooth hydrolysis to yield aniline 22 with a base, achieving excellent chemoselectivity and yield values (Scheme 9C).¹⁰⁷ The lignin β-O-4 ketone compound was initially found to exhibit sluggish reactivity with Et₃N (1.5 equiv.) and SO₂F₂ (2 equiv.) at room temperature, leading to the use of lignin β-O-4 ketoxime as an alternative substrate. Among the above hydroxylamine-mediated lignin degradation strategies, the lignin β-O-4 model with the α-hydroxyl group is incompatible with these reaction conditions and no product is obtained. This may be due to the difficulty of the spontaneous oxidation of the α-hydroxyl group in an axiomatic basic medium, along with the higher dissociation energy of the C_β–O bond compared to that in the oxime.

2.2.2 Inorganic base-mediated systems. Quinoline and its derivatives are vital intermediates in synthesizing various drugs. For instance, quinine and quinidine, both derivatives of quinoline, are utilized to treat malaria, while procainamide, which contains a quinoline ring in its structure, is used for the treatment of arrhythmia.¹⁰⁸ Acetophenone derivatives contain an electrophilic ketone group and a nucleophilic α-carbon adjacent to the carbonyl group, rendering them multifunctional synthons for constructing structurally complex heterocyclic aromatic products. Gaining insight into the potential acetophenone unit in the lignin β-O-4 model, Li and colleagues first utilized the lignin β-O-4 model 10 as a feedstock to react with air- and moisture-insensitive (2-aminophenyl) methanol 18 in a basic medium (NaOH, 4 equiv.) at 140 °C to synthesize biologically active quinoline 26 in moderate to excellent yield (Scheme 10).¹⁰⁰ The control experiments indicate that the one-pot cascade reaction started with NaOH-mediated C–O bond breakdown of the lignin β-O-4 model 10, generating the key acetophenone intermediate. Additionally, the NaOH base played an essential initiating role. As the number of methoxyl substitutions on the aryl ring C-terminus increases, the yield of quinoline decreases; however, the number of methoxyl substitutions on the aryl ring O-terminus does not significantly affect the yield and conversion. This phenomenon suggests that the electron-donating effect of the aryl ring C-terminus may hinder the acetophenone synthesis, consequently reducing quinoline formation. Notably, NaOH is highly caustic and toxic, leading to severe skin and eye irritation. As a catalyst, it is sustainable because of its effectiveness, but proper handling and disposal are essential to reduce environmental impact.

Scheme 10 Synthesis of quinolines from the lignin β-O-4 model mediated by NaOH.

The control experiments and detailed DFT calculations clarified the possible reaction mechanisms and a favored pathway. The lignin β-O-4 model 10 is initially deprotonated at the Cα-H bond and cleaved at the C–O bond by NaOH, resulting in the formation of the key acetophenone intermediate and phenol 5. The ketoamine condensation of acetophenone with (2-aminophenyl) methanol 18 occurs to produce imine I, followed by dehydrogenation to imine II (Path I). In another scenario, the amine or aldehyde group of 2-aminobenzyl aldehyde, oxidized from (2-aminophenyl) methanol, condensed with acetophenone to afford imine II (Path II) or chalcone (Path III), respectively. Although both intermediates, imine II and chalcone, can undergo dehydration and aromatization to form quinoline 26, the yield of 26 from imine II is three times greater than that from chalcone, indicating that Path II is the preferred pathway. The sequences of the whole cascade reaction involve base-mediated C–O bond cleavage, dehydrogenation, aldol condensation, C–N bond formation and aromatization.

Subsequently, the synthesized lignin β-O-4 polymer, which mimics real lignin, is degraded to form para-hydroxy acetophenone. Initially, the NaOH-catalytic system was unsuitable for the polymer reaction; therefore, a binuclear rhodium complex was used to catalyze the mild depolymerization of the β-O-4 polymer. para-Hydroxy acetophenone is unsuitable for the basic reaction conditions because sodium phenolate salt forms competitively. Alternatively, the protocol of hydroxyl group protection is carried out to facilitate the smooth synthesis of quinoline, achieving an overall yield of 56 wt% based on the β-O-4 polymer. The sustainable three-step process offers a potential opportunity for producing petroleum-independent biological aromatics.

After disclosing the degradation and oxidative mechanisms of the lignin β-O-4 model compound and benzyl alcohol under basic conditions, respectively, Li and colleagues continued processing inedible lignin to create various N-containing products. In the same year, Li and co-workers introduced another protocol involving an exquisite NaOH-induced multi-component cascade reaction for quickly constructing 2,4,6-triphenylpyrimidine 29 in a one-pot process without additional transition metal catalysts or external oxidants or reductants (Scheme 11).¹⁰⁹ The solvent tert-amyl alcohol can be easily distilled from the reaction mixture for recycling, as its boiling point (101.8 °C) is significantly lower than that of both the reactants and products. This efficient recycling process not only minimizes waste but also enhances the sustainability of the reaction by enabling the reuse of the solvent in subsequent cycles.

Scheme 11 Synthesis of pyrimidines from the lignin β-O-4 model mediated by NaOH.

Similar to the mechanism of the NaOH-induced quinoline synthesis from the lignin β-O-4 model described above, the mechanism of pyrimidine synthesis starts with NaOH-catalyzed Cα-H abstraction and C–O bond breakdown of compound 10 to deliver acetophenone, accompanied by benzyl alcohol 28 being oxidized into benzaldehyde. Furthermore, aldol condensation occurs between the resulting two intermediates, giving the key product chalcone. Then, the cyclization between chalcone and benzamidine hydrochloride 27 forms a dihydropyrimidine intermediate, followed by oxidative aromatization to produce pyrimidine 29.

Meridianin derivatives represent an important class of natural marine alkaloids that exhibit unique bioactivities, including significant antitumor activity, and are consequently widely utilized in the pharmaceutical industry.¹¹⁰ To emphasize the feasibility of application in pharmaceutical synthesis, Li and co-workers employed all three reaction components: the lignin β-O-4 model compound, guanidine hydrochloride, and (1-benzyl-1H-indol-3-yl) methanol to synthesize an important meridianin derivative marine alkaloid with a total yield of 49% in two steps. This simple methodology does not require any transition metal catalysts, thereby offering a cost-effective alternative for synthesizing value-added meridianin derivatives.

Based on the aforementioned outcomes, Zhang et al. presented a feasible [3 + 1 + 2] cyclization protocol for the synthesis of carbazole derivatives using the lignin β-O-4 model 10, indole-formaldehyde 30 and 3-chloropropiophenone 31 as starting materials (Scheme 12).¹¹¹ The one-pot process employed commercially available NaOH (4 equiv.) and CuCl₂·2H₂O (50 mol%) as reaction catalysts for the two-step transformations, respectively. Notably, the cyclization between 3-alkenylated indole 14 and 3-chloropropiophenone 31 occurs with low conversion and yield in a strongly basic medium. However, the addition of acetic acid to the reaction mixture can significantly increase the overall yield of carbazole.

Scheme 12 Synthesis of carbazoles from the lignin β-O-4 model mediated by NaOH and CuCl₂.

The control experiments revealed a possible reaction mechanism involving the cleavage of the C–O bond in the lignin β-O-4 model 10, leading to the formation of the acetophenone intermediate, followed by an aldol condensation between acetophenone and indole-formaldehyde 30 to deliver compound 14. The α,β-unsaturated ketone, originating from 3-chloropropiophenone via dehydrochlorination, undergoes Diels–Alder cyclization with compound 14 to form tetrahydrocarbazole, followed by aromatization to produce carbazole 15, which exhibits favorable twisted-intramolecular charge transfer (TICT) and aggregation-induced emission (AIE) effects. This method also uses lignin β-O-4 alcohol dimers containing γ-OH as raw materials to obtain 45% of the corresponding carbazole, making a significant contribution to the utilization of lignin in fluorescent materials.

Quinoxalines are widely recognized as privileged core scaffolds utilized in pharmaceuticals, agrochemicals, and bioactive compounds.^112–114 Zhang et al. developed an efficient method for sustainably synthesizing quinoxaline from the lignin β-O-4 model 10 and 1,2-diaminobenzene 32 in KOH (5 equiv.) at 140 °C (Scheme 13).¹¹⁵ When using unsymmetrical 1,2-diaminobenzenes as substrates, the poor regio-chemoselectivity of the reaction generates a pair of regio-isomer products with similar physicochemical properties, making them difficult to separate. The researchers employed a three-step process in which the synthetic lignin β-O-4 polymer, mimicking real lignin, was degraded to form 4-hydroxyacetophenone. The hydroxyl group was then protected to facilitate the formation of quinoline.

Scheme 13 Synthesis of quinoxalines from the lignin β-O-4 model mediated by KOH.

Based on the findings of control experiments, a plausible reaction mechanism was proposed (Scheme 13). First, the key intermediate of acetophenone is obtained by cleaving the C–O bond of the lignin β-O-4 model 10. Then, acetophenone reacts with 1,2-diaminobenzene 32 to generate a ketimine, followed by the oxidative activation of the sp³ C–H bond, resulting in a superoxide radical species, which can further yield an imine aldehyde in the presence of KOH under air. Finally, intramolecular condensation between the aldehyde and amine, followed by a dehydration reaction, produces quinoxaline 19 as the desired product.

AG1295, used for inhibiting the platelet-derived growth factor receptor tyrosine kinase, is an important drug compound.¹¹⁶ It can be synthesized from lignin β-O-4 model compounds and β-O-4 polymer using the KOH-catalytic protocol, potentially bridging lignin to pharmaceuticals.

2.2.3 Oxidant-mediated systems. Hydrogen peroxide (H₂O₂) is a mild oxidant regarded as a “green” reagent, generating only water and oxygen as by-products.¹¹⁷ In 2022, Liu and colleagues used the lignin β-O-4 model 1 as raw material and H₂O₂ (27 wt%) as a green oxidant to react with aniline 2 in water, successfully generating biologically active benzanilide 7, in yields ranging from 17% to 87% (Scheme 14).¹¹⁸ The substitution of methoxy groups on the O-terminal aromatic ring of lignin β-O-4 model compounds slightly impacts the yield of benzanilide 7. The yield sharply decreased when a single chlorine atom was introduced onto the O-terminal aromatic ring. This phenomenon suggests that the electron-withdrawing effect of the O-terminal aromatic ring may hinder the cleavage of the C–C bond, further decreasing the production of benzanilide. The lignin β-O-4 model compound with γ-OH also decreases the production of benzanilide due to the increasing steric hindrance of the aryl dimer.

Scheme 14 Synthesis of amides from lignin β-O-4 ketone catalyzed by H₂O₂.

Control experiments have shown that the oxidative decomposition of H₂O₂ to produce the hydroperoxyl radical is vital as the reaction did not proceed when H₂O₂ was replaced with O₂, or with the addition of equal amounts of free radical scavengers TEMPO and BHT. The possible mechanism involves the condensation of aniline with the lignin β-O-4 model 1 to form the enamine intermediate. The resulting enamine can be activated by the hydroperoxyl radical (HOO˙) generated in situ by H₂O₂, yielding an α-radical peroxide intermediate, which further couples with the hydroxyl radical (HO˙) to give an α-imine peroxide. Subsequently, the intramolecular C–C bond cleavage of the α-imine peroxide produces an iminol intermediate and phenol 5. The tautomerization of the iminol generates the final benzanilide product 7. This method is specific to reactions using lignin β-O-4 ketone dimers as substrates. The researchers designed a two-step process to convert lignin β-O-4 alcohol into benzamide. In this process, TEMPO (5 mol%) was used as the oxidizing agent, with NaNO₂ (2 mol%) serving as an additive for the oxidation of β-O-4 alcohol dimers. Although H₂O₂ is corrosive and toxic, its use as a green oxidant to degrade lignin presents an important concept for developing sustainable green processes.

Simultaneous depolymerization and valorization of lignin into aza-aromatics is challenging due to the incompatibility and low efficiency of the existing catalytic methods in breaking C–C/C–O bonds in lignin while forming C–N bonds. In 2022, Zhang and co-workers utilized a Lewis acid to activate the oxidized lignin β-O-4 model 1 in combination with o-phenylenediamine 32, in the presence of the toxic catalyst 2,3-dichloro-5,6-dicyano-1,4-dibenzoquinone (DDQ, 5 mol%) at 150 °C, resulting in the formation of 2-phenylbenzimidazole 34 and benzimidazole 35 in good to excellent yield (Scheme 15).¹¹⁹ This method fully utilizes each carbon atom (Cα atom, Cβ atom, and Cγ atom) of the lignin β-O-4 ketone to synthesize the corresponding benzimidazoles, rendering it a high-atom-economy degradation strategy. However, the regioselectivity of the reaction did not reveal further details, as the substrates used led to the formation of axisymmetric benzimidazoles.

Scheme 15 Synthesis of benzimidazoles from lignin β-O-4 ketone catalyzed by DDQ.

Control experiments have shown that the possible mechanism begins with the activation of the carbonyl group in the lignin β-O-4 model 1 by the Lewis acid DDQ, followed by coupling with o-phenylenediamine to form an imine intermediate. The amino group then attacks the imine group to form an aminal ring, which is further oxidized by oxygen to generate a peroxide intermediate, followed by C–C bond cleavage to produce 2-phenylbenzimidazole 34 and phenyl formate. Subsequently, the hydrolysis of phenyl formate produces phenol 5 and formic acid, which rapidly cyclizes with o-phenylenediamine 32 to form benzimidazole 35 compounds.

Furthermore, both oxidized hardwood (birch) and softwood (pine) lignin could be transformed into the corresponding benzimidazole derivatives at 45 wt% and 30 wt%, respectively. This demonstrates the applicability of the DDQ degradation strategy for degrading real lignin.

2.2.4 Photocatalytic systems. Metal-promoted photocatalytic C–C bond cleavage reactions have been well-developed to complement traditional chemical processes.^120–124 Recently, photocatalytic methods have been applied to lignin to generate N-containing compounds.^125,126 However, elaborate and intricate ligand-based noble metal photocatalysts may increase production costs and hinder their industrial applications. Therefore, inexpensive, commercially available non-noble metal photocatalysts with high efficiency and good stability are becoming increasingly appealing. In 2022, Zhang and co-workers employed commercially available CeCl₃ (5 mol%) to activate the lignin β-O-4 model 10 coupled with di-tert-butyl azodicarboxylate (DBAD, 1.1 equiv.) at room temperature to generate benzaldehyde and hydrazinium 36 under blue-light irradiation with high efficiency (Scheme 16).¹²⁷ The mechanistic studies revealed that CeCl₃, acting as a precatalyst, can be converted into Ce^IV species, the real catalyst for the reaction, which will revert to Ce^III species by photoinduced ligand-to-metal charge transfer (LMCT). The α-OH group of the lignin β-O-4 model compound plays an essential role in the β-scission, and the cleavage and amination processes of the C–C bond can be precisely controlled by light on/off switching experiments. Notably, DBAD is toxic and potentially harmful if inhaled or ingested. It should be used with caution, while sustainable alternatives are encouraged to minimize environmental impact.

Scheme 16 Synthesis of hydraziniums from lignin β-O-4 ketone catalyzed by a photocatalyst.

Based on data from mechanistic studies, a plausible mechanism is described as follows: first, CeCl₃ coordinates with the lignin β-O-4 model 10, forming a Ce^IIICl_n/lignin complex I, followed by the single-electron oxidation with a DBAD* to generate a Ce^IVCl_n/lignin species II with the ejection of molecular DBAD. Subsequently, Ce^IVCl_n/lignin species II undergoes photoinduced homolysis to generate an alkoxy radical, accompanied by the release of a molecule of Ce^IIICl₃ into the next catalytic cycle. Then, the β-scission of the alkoxy radical intermediate occurs to form benzaldehyde and a key alkyl radical, which can be coupled with DBAD, yielding a nitrogen-centered radical intermediate to produce hydrazinium 36 by the single-electron transfer/proton transfer (SET/PT) process.

The CeCl₃-promoted photocatalyst for C–C bond cleavage was employed on real lignin to afford the corresponding hydraziniums, identified through two-dimensional HSQC spectra, with a total yield of 11.94 wt%.¹²⁷ The versatility of this strategy renders it appropriate for converting real lignin into a sustainable source of diverse hydrazinium products.

2.2.5 Conclusions on metal-free-mediated amination. In conclusion, both the hydroxylamine-mediated and the oxidant-mediated systems demonstrate compatibility with β-O-4 ketone dimers that contain γ-OH. However, when β-O-4 alcohol dimers with γ-OH are utilized as substrates, the target product fails to form. Therefore, when using these systems for the coupling of natural lignin cleavage and amination, pre-oxidation operations are essential. The NaOH-catalytic system was unsuitable for polymer cleavage because sodium phenolate salt forms competitively. Instead, a binuclear rhodium complex was used to catalyze the mild depolymerization of the β-O-4 polymer. Additionally, DBAD used in photocatalytic systems is toxic and not conducive to sustainable development. To address the aforementioned issues, it is advisable to develop more compatible oxidation methods that can oxidize benzylic alcohol, cleave the C–C/C–O bonds, and facilitate the amination process in tandem. Furthermore, enzyme catalysis, electrocatalysis, and photocatalysis would serve as robust methods for achieving high selectivity in the catalytic depolymerization of lignin.

3. Conclusions and outlook

This paper provides an overview of strategies for lignin depolymerization and its potential for producing value-added N-containing aromatic compounds. Over the past decade, significant advancements in lignin degradation and valorization have been made, primarily through the use of transition metal and metal-free catalysts. This review highlights the advantages of lignin's natural aromatic structures, particularly the β-O-4 linkage, which is well-suited for synthesizing heteroatomic aromatic compounds such as amides, benzonitriles, benzylamines, and nitrogen-containing heterocyclic compounds like carbazoles, quinoxalines, and benzimidazoles. These studies have accelerated the development of a diverse library of value-added nitrogen-containing aromatic compounds derived from lignin. In particular, this article focuses on mechanistic studies of C–C/C–O bond cleavage and the formation of C–C/C–N bonds during transformation processes. It also examines reaction conditions, substrate scope, and the effects of electron density and steric hindrance. Despite these advancements, most methods are still limited to lignin models and are not fully compatible with the complex structure of real lignin, primarily due to low catalytic efficiency and competing reactions. Overall, this review offers a comprehensive summary of common approaches that can effectively couple lignin C–C/C–O bond cleavage with the amination, according to the type of catalyst used.

This review points out several key challenges faced when using transition metal catalysts, acid/base or neutral catalysts, and photocatalysts in lignin valorization. These include the following: (1) insufficient oxidation capacity; (2) low efficiency at the heterogeneous catalytic interface; (3) inability to abstract benzyl hydrogen atoms from natural lignin; and (4) poor selectivity in C–C bond cleavage and γ-OH bond fracture. Additionally, the reliance on noble transition metal catalysts and stoichiometric reagents raises notable economic and environmental concerns. To address these issues, exploring bio-derived or non-noble transition metal catalysts holds great promise for reducing toxicity and improving the sustainability of lignin valorization processes. Furthermore, the integration of electrochemical and photocatalytic methods could offer exciting new pathways for lignin conversion, potentially revolutionizing future biorefinery and industrial processes. These advancements could pave the way for more efficient, environmentally friendly, and cost-effective solutions in lignin valorization.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Acknowledgements

Generous financial support for this work was provided by the Natural Science Foundation of Fujian Province (2024J08046), the National Natural Science Funds for Distinguished Young Scholars (32425039), the Fellowship of China Agriculture Research System (CARS-44), and the CACMS Innovation Fund (CI2021A04118 and CI2021B014).

References

1. J. Zakzeski, P. C. Bruijnincx, A. L. Jongerius and B. M. Weckhuysen, Chem. Rev., 2010, 110, 3552–3599.
2. C.-H. Zhou, X. Xia, C.-X. Lin, D.-S. Tong and J. Beltramini, Chem. Soc. Rev., 2011, 40, 5588–5617.
3. C. Li, X. Zhao, A. Wang, G. W. Huber and T. Zhang, Chem. Rev., 2015, 115, 11559–11624.
4. Z. Sun, B. Fridrich, A. de Santi, S. Elangovan and K. Barta, Chem. Rev., 2018, 118, 614–678.
5. B. Beig, M. Riaz, S. R. Naqvi, M. Hassan, Z. Zheng, K. Karimi, A. Pugazhendhi, A. E. Atabani and N. T. L. Chi, Fuel, 2021, 287, 119670.
6. Z. Zhang, J. Song and B. Han, Chem. Rev., 2017, 117, 6834–6880.
7. Z. Sun, G. Bottari, A. Afanasenko, M. C. Stuart, P. J. Deuss, B. Fridrich and K. Barta, Nat. Catal., 2018, 1, 82–92.
8. A. J. Ragauskas, G. T. Beckham, M. J. Biddy, R. Chandra, F. Chen, M. F. Davis, B. H. Davison, R. A. Dixon, P. Gilna and M. Keller, science, 2014, 344, 1246843.
9. H. Xu, B. Li and X. Mu, Ind. Eng. Chem. Res., 2016, 55, 8691–8705.
10. C. Zhang and F. Wang, Acc. Chem. Res., 2020, 53, 470–484.
11. S. S. Wong, R. Shu, J. Zhang, H. Liu and N. Yan, Chem. Soc. Rev., 2020, 49, 5510–5560.
12. R. Rinaldi, R. Jastrzebski, M. T. Clough, J. Ralph, M. Kennema, P. C. Bruijnincx and B. M. Weckhuysen, Angew. Chem., Int. Ed., 2016, 55, 8164–8215.
13. C. Zhao, Y. Kou, A. A. Lemonidou, X. Li and J. A. Lercher, Angew. Chem., Int. Ed., 2009, 48, 3987–3990.
14. J. M. Nichols, L. M. Bishop, R. G. Bergman and J. A. Ellman, J. Am. Chem. Soc., 2010, 132, 12554–12555.
15. Q. Song, F. Wang, J. Cai, Y. Wang, J. Zhang, W. Yu and J. Xu, Energy Environ. Sci., 2013, 6, 994–1007.
16. S. Van den Bosch, W. Schutyser, R. Vanholme, T. Driessen, S.-F. Koelewijn, T. Renders, B. De Meester, W. Huijgen, W. Dehaen and C. Courtin, Energy Environ. Sci., 2015, 8, 1748–1763.
17. X. Wu, X. Fan, S. Xie, J. Lin, J. Cheng, Q. Zhang, L. Chen and Y. Wang, Nat. Catal., 2018, 1, 772–780.
18. L. Dong, L. Lin, X. Han, X. Si, X. Liu, Y. Guo, F. Lu, S. Rudić, S. F. Parker and S. Yang, Chem, 2019, 5, 1521–1536.
19. X. Li, B. Zhang, X. Pan, J. Ji, Y. Ren, H. Wang, N. Ji, Q. Liu and C. Li, ChemSusChem, 2020, 13, 4409–4419.
20. H. Ning, Y. Chen, Z. Wang, S. Mao, Z. Chen, Y. Gong and Y. Wang, Chem, 2021, 7, 3069–3084.
21. X. Shen, C. Zhang, B. Han and F. Wang, Chem. Soc. Rev., 2022, 51, 1608–1628.
22. C. Crestini, P. Pro, V. Neri and R. Saladino, Bioorg. Med. Chem., 2005, 13, 2569–2578.
23. S. K. Hanson and R. T. Baker, Acc. Chem. Res., 2015, 48, 2037–2048.
24. S. Guadix-Montero and M. Sankar, Top. Catal., 2018, 61, 183–198.
25. Z. Cai, J. Long, Y. Li, L. Ye, B. Yin, L. J. France, J. Dong, L. Zheng, H. He and S. Liu, Chem, 2019, 5, 2365–2377.
26. K. Su, H. Liu, C. Zhang and F. Wang, Chin. J. Catal., 2022, 43, 589–594.
27. A. Rahimi, A. Ulbrich, J. J. Coon and S. S. Stahl, Nature, 2014, 515, 249–252.
28. W. Lan, J. B. de Bueren and J. S. Luterbacher, Angew. Chem., Int. Ed., 2019, 58, 2649–2654.
29. P. J. Deuss, M. Scott, F. Tran, N. J. Westwood, J. G. de Vries and K. Barta, J. Am. Chem. Soc., 2015, 137, 7456–7467.
30. Y. Liu, C. Li, W. Miao, W. Tang, D. Xue, C. Li, B. Zhang, J. Xiao, A. Wang and T. Zhang, ACS Catal., 2019, 9, 4441–4447.
31. Y. Liu, C. Li, W. Miao, W. Tang, D. Xue, J. Xiao, T. Zhang and C. Wang, Green Chem., 2020, 22, 33–38.
32. H. Li, A. Bunrit, N. Li and F. Wang, Chem. Soc. Rev., 2020, 49, 3748–3763.
33. A. M. Afanasenko, X. Wu, A. De Santi, W. A. M. Elgaher, A. M. Kany, R. Shafiei, M.-S. Schulze, T. F. Schulz, J. Haupenthal, A. K. H. Hirsch and K. Barta, Angew. Chem., Int. Ed., 2024, 63, e202308131.
34. J. Zakzeski, P. C. A. Bruijnincx, A. L. Jongerius and B. M. Weckhuysen, Chem. Rev., 2010, 110, 3552–3599.
35. Z. Sun, B. Fridrich, A. de Santi, S. Elangovan and K. Barta, Chem. Rev., 2018, 118, 614–678.
36. K. Weissermel and H.-J. Arpe, Industrial Organic Chemistry, Wiley-VCH Verlag GmbH, 2003.
37. P. Ferrini and R. Rinaldi, Angew. Chem., 2014, 126, 8778–8783.
38. L. Shuai, M. T. Amiri, Y. M. Questell-Santiago, F. Héroguel, Y. Li, H. Kim, R. Meilan, C. Chapple, J. Ralph and J. S. Luterbacher, Science, 2016, 354, 329–333.
39. Y. Liu, N. Deak, Z. Wang, H. Yu, L. Hameleers, E. Jurak, P. J. Deuss and K. Barta, Nat. Commun., 2021, 12, 5424.
40. M. Pelckmans, T. Renders, S. Van de Vyver and B. Sels, Green Chem., 2017, 19, 5303–5331.
41. J. Park, M. A. Kelly, J. X. Kang, S. S. Seemakurti, J. L. Ramirez, M. C. Hatzell, C. Sievers and A. S. Bommarius, Green Chem., 2021, 23, 7488–7498.
42. C. Zhang, X. Shen, Y. Jin, J. Cheng, C. Cai and F. Wang, Chem. Rev., 2023, 123, 4510–4601.
43. E. Blondiaux, J. Bomon, M. Smoleń, N. Kaval, F. Lemière, S. Sergeyev, L. Diels, B. Sels and B. U. Maes, ACS Sustainable Chem. Eng., 2019, 7, 6906–6916.
44. A. Afanasenko and K. Barta, Iscience, 2021, 24, 102211.
45. S. D. Karlen, V. I. Timokhin, C. Sener, J. K. Mobley, T. Runge and J. Ralph, ChemSusChem, 2024, 17, e202400234.
46. L. Xu, M. Cao, J. Zhou, Y. Pang, Z. Li, D. Yang, S.-Y. Leu, H. Lou, X. Pan and X. Qiu, Nat. Commun., 2024, 15, 734.
47. L. Dong, Y. Wang, Y. Dong, Y. Zhang, M. Pan, X. Liu, X. Gu, M. Antonietti and Z. Chen, Nat. Commun., 2023, 14, 4996.
48. W. Zheng, S. Feng and C. Hu, ChemSusChem, 2024, 17, e202301364.
49. S. Elangovan, A. Afanasenko, J. R. Haupenthal, Z. Sun, Y. Liu, A. K. Hirsch and K. Barta, ACS Cent. Sci., 2019, 5, 1707–1716.
50. Z. Chen, H. Zeng, S. A. Girard, F. Wang, N. Chen and C. J. Li, Angew. Chem., 2015, 127, 14695–14699.
51. A. Dominguez-Huerta, I. Perepichka and C. J. Li, ChemSusChem, 2019, 12, 2999–3002.
52. Z. Qiu, L. Lv, J. Li, C.-C. Li and C.-J. Li, Chem. Sci., 2019, 10, 4775–4781.
53. B. Zheng, H. Wu, J. Song, W. Wu, X. Mei, K. Zhang, C. Xu, J. Xu, M. He and B. Han, Green Chem., 2021, 23, 8441–8447.
54. Z. Chen, H. Zeng, H. Gong, H. Wang and C.-J. Li, Chem. Sci., 2015, 6, 4174–4178.
55. T. Cuypers, T. Morias, S. Windels, C. Marquez, C. Van Goethem, I. Vankelecom and D. E. De Vos, Green Chem., 2020, 22, 1884–1893.
56. Z. Wang, J. Niu, H. Zeng and C.-J. Li, Org. Lett., 2019, 21, 7033–7037.
57. J. Yu, R. Zhan, C.-J. Li and H. Zeng, Green Chem., 2024, 26, 3722–3726.
58. Z. Qiu and C.-J. Li, Chem. Rev., 2020, 120, 10454–10515.
59. W. Boerjan, J. Ralph and M. Baucher, Annu. Rev. Plant Biol., 2003, 54, 519–546.
60. F. G. Calvo-Flores and J. A. Dobado, ChemSusChem, 2010, 3, 1227–1235.
61. D. Shen, S. Gu, K. Luo, S. Wang and M. Fang, Bioresour. Technol., 2010, 101, 6136–6146.
62. Y.-H. Sun, T.-Y. Sun, Y.-D. Wu, X. Zhang and Y. Rao, Chem. Sci., 2016, 7, 2229–2238.
63. R. Houska, M. B. Stutz and O. Seitz, Chem. Sci., 2021, 12, 13450–13457.
64. J. Zhang, Y. Liu, S. Chiba and T.-P. Loh, Chem. Commun., 2013, 49, 11439–11441.
65. X. Liu, H. Zhang, C. Wu, Z. Liu, Y. Chen, B. Yu and Z. Liu, New J. Chem., 2018, 42, 1223–1227.
66. G. Karabatsos and S. Lande, Tetrahedron, 1968, 24, 3907–3922.
67. H. Li, M. Liu, H. Liu, N. Luo, C. Zhang and F. Wang, ChemSusChem, 2020, 13, 4660–4665.
68. P. Gamez, P. G. Aubel, W. L. Driessen and J. Reedijk, Chem. Soc. Rev., 2001, 30, 376–385.
69. E. A. Lewis and W. B. Tolman, Chem. Rev., 2004, 104, 1047–1076.
70. M. Rolff and F. Tuczek, Angew. Chem., Int. Ed., 2008, 47, 2344–2347.
71. S. Kim, S. C. Chmely, M. R. Nimlos, Y. J. Bomble, T. D. Foust, R. S. Paton and G. T. Beckham, J. Phys. Chem. Lett., 2011, 2, 2846–2852.
72. M. Wang, J. Lu, X. Zhang, L. Li, H. Li, N. Luo and F. Wang, ACS Catal., 2016, 6, 6086–6090.
73. Z. Li, T. Wang, X. Qi, Q. Yang, L. Gao, D. Zhang, X. Zhao and Y. Wang, RSC Adv., 2019, 9, 17631–17638.
74. P. L. Arnold, J. M. Purkis, R. Rutkauskaite, D. Kovacs, J. B. Love and J. Austin, ChemCatChem, 2019, 11, 3786–3790.
75. E. Ota, H. Wang, N. L. Frye and R. R. Knowles, Org. Lett., 2019, 141, 1457–1462.
76. W. Liu, Q. Wu, M. Wang, Y. Huang and P. Hu, Org. Lett., 2021, 23, 8413–8418.
77. X. Xu, S. Dai, S. Xu, Q. Zhu and Y. Li, Angew. Chem., 2023, 135, e202309066.
78. Y. Li, J. Wen, S. Wu, S. Luo, C. Ma, S. Li, Z. Chen, S. Liu and B. Tian, Org. Lett., 2024, 26, 1218–1223.
79. E. Xu, F. Xie, T. Liu, J. He and Y. Zhang, Chem. – Eur. J., 2024, 30, e202304209.
80. Q. Luo, S. Tian, Q. Qiang, W. Su, H. He, Q. An and C. Li, J. Environ. Sci., 2025, 151, 505–515.
81. Z. Chen, H. Zeng, S. A. Girard, F. Wang, N. Chen and C. J. Li, Angew. Chem., 2015, 127, 14695–14699.
82. M. V. Galkin, C. Dahlstrand and J. S. Samec, ChemSusChem, 2015, 8, 2187–2192.
83. H. Zeng, D. Cao, Z. Qiu and C. J. Li, Angew. Chem., 2018, 130, 3814–3819.
84. R. J. Holt, R. Murphy and P. J. O'Donnell, Br. J. Plast. Surg., 1968, 21, 106–110.
85. B. Zhang, T. Guo, Y. Liu, F. E. Kühn, C. Wang, Z. K. Zhao, J. Xiao, C. Li and T. Zhang, Angew. Chem., 2021, 133, 20834–20839.
86. L. Jia, C.-J. Li and H. Zeng, Chin. Chem. Lett., 2022, 33, 1519–1523.
87. H. Guo, D. M. Miles-Barrett, B. Zhang, A. Wang, T. Zhang, N. J. Westwood and C. Li, Green Chem., 2019, 21, 803–811.
88. L. Guo, Y. Ding, H. Wang, Y. Liu, Q. Qiang, Q. Luo, F. Song and C. Li, iScience, 2023, 26, 106834.
89. R. R. Langeslay, D. M. Kaphan, C. L. Marshall, P. C. Stair, A. P. Sattelberger and M. Delferro, Chem. Rev., 2018, 119, 2128–2191.
90. A. W. Schmidt, K. R. Reddy and H.-J. Knölker, Chem. Rev., 2012, 112, 3193–3328.
91. H.-J. Knölker and K. R. Reddy, Chem. Rev., 2002, 102, 4303–4428.
92. T. Guo, Y. Lin, D. Pan, X. Zhang, W. Zhu, X.-M. Cai, G. Huang, H. Wang, D. Xu, F. E. Kühn, B. Zhang and T. Zhang, Nat. Commun., 2023, 14, 6076.
93. S. Son and F. D. Toste, Angew. Chem., Int. Ed., 2010, 49, 3791.
94. K. Bozorov, J. Zhao and H. A. Aisa, Bioorg. Med. Chem., 2019, 27, 3511–3531.
95. W. Zhu, Y. Shi, J. Lu, F. Han, W. Luo, D. Xu, T. Guo, G. Huang, F. E. Kühn and B. Zhang, ChemSusChem, 2024, 17, e202301421.
96. S. Kumar, S. Bawa and H. Gupta, Mini-Rev. Med. Chem., 2009, 9, 1648–1654.
97. A. Marella, O. P. Tanwar, R. Saha, M. R. Ali, S. Srivastava, M. Akhter, M. Shaquiquzzaman and M. M. Alam, Saudi Pharm. J., 2013, 21, 1–12.
98. B. S. Matada, R. Pattanashettar and N. G. Yernale, Bioorg. Med. Chem., 2021, 32, 115973.
99. W. Zhu, J. S. Reinhold, J. Lu, D. Xu, T. Guo, W. Luo and B. Zhang, Chem. Eng. Sci., 2024, 290, 119899.
100. Y. Ding, T. Guo, Z. Li, B. Zhang, F. E. Kühn, C. Liu, J. Zhang, D. Xu, M. Lei and T. Zhang, Angew. Chem., 2022, 134, e202206284.
101. P. Tomkins, C. Valgaeren, K. Adriaensen, T. Cuypers and D. E. D. Vos, ChemCatChem, 2018, 10, 3689–3693.
102. D. Cao, H. Zeng and C.-J. Li, ACS Catal., 2018, 8, 8873–8878.
103. H. Zeng, D. Cao, Z. Qiu and C.-J. Li, Angew. Chem., Int. Ed., 2018, 57, 3752–3757.
104. Y. Wang, Y. Du, J. He and Y. Zhang, Green Chem., 2018, 20, 3318–3326.
105. J. Liu, X. Qiu, X. Huang, X. Luo, C. Zhang, J. Wei, J. Pan, Y. Liang, Y. Zhu and Q. Qin, Nat. Chem., 2019, 11, 71–77.
106. H. Li, M. Wang, H. Liu, N. Luo, J. Lu, C. Zhang and F. Wang, ACS Sustainable Chem. Eng., 2018, 6, 3748–3753.
107. J. Gurjar and V. V. Fokin, Chem. – Eur. J., 2020, 26, 10402–10405.
108. A. Weyesa and E. Mulugeta, RSC Adv., 2020, 10, 20784–20793.
109. B. Zhang, T. Guo, Z. Li, F. E. Kühn, M. Lei, Z. K. Zhao, J. Xiao, J. Zhang, D. Xu and T. Zhang, Nat. Commun., 2022, 13, 3365.
110. M. A. A. Radwan and M. El-Sherbiny, Bioorg. Med. Chem., 2007, 15, 1206–1211.
111. J. Ji, C. Ding, S. Li, T. Guo, J. S. Reinhold, S. Meng, W. Zhu, X. Ji, X.-M. Cai and B. Zhang, Green Chem., 2024, 26, 3479–3487.
112. M. Montana, F. Mathias, T. Terme and P. Vanelle, Eur. J. Med. Chem., 2019, 163, 136–147.
113. J. A. Pereira, A. M. Pessoa, M. N. D. Cordeiro, R. Fernandes, C. Prudêncio, J. P. Noronha and M. Vieira, Eur. J. Med. Chem., 2015, 97, 664–672.
114. S. Tariq, K. Somakala and M. Amir, Eur. J. Med. Chem., 2018, 143, 542–557.
115. Y. Liu, Q. Luo, Q. Qiang, H. Wang, Y. Ding, C. Wang, J. Xiao, C. Li and T. Zhang, ChemSusChem, 2022, 15, e202201401.
116. M. Chorny, I. Fishbein, H. D. Danenberg and G. Golomb, J. Controlled Release, 2002, 83, 401–414.
117. B. Burek, S. Bormann, F. Hollmann, J. Bloh and D. Holtmann, Green Chem., 2019, 21, 3232–3249.
118. X. Liu, L. Wang, L. Zhai, C. Wu and H. Xu, Green Chem., 2022, 24, 4395–4398.
119. T. Guo, T. Liu, J. He and Y. Zhang, Eur. J. Org. Chem., 2022, e202101152.
120. S. Gazi, W. K. H. Ng, R. Ganguly, A. M. P. Moeljadi, H. Hirao and H. S. Soo, Chem. Sci., 2015, 6, 7130–7142.
121. H. Liu, H. Li, J. Lu, S. Zeng, M. Wang, N. Luo, S. Xu and F. Wang, ACS Catal., 2018, 8, 4761–4771.
122. E. Ota, H. Wang, N. L. Frye and R. R. Knowles, J. Am. Chem. Soc., 2019, 141, 1457–1462.
123. P. Sivaguru, Z. Wang, G. Zanoni and X. Bi, Chem. Soc. Rev., 2019, 48, 2615–2656.
124. Y. Wang, Y. Liu, J. He and Y. Zhang, Sci. Bull., 2019, 64, 1658–1666.
125. N. E. Tay and D. A. Nicewicz, J. Am. Chem. Soc., 2017, 139, 16100–16104.
126. H. Li, A. Bunrit, J. Lu, Z. Gao, N. Luo, H. Liu and F. Wang, ACS Catal., 2019, 9, 8843–8851.
127. Y. Wang, J. He and Y. Zhang, CCS Chem., 2020, 2, 107–117.

---