Titanocene Complexes Applied in Organic Transformations

Abstract

Titanium, the second most abundant and one of the cheapest, non-toxic transition metals in the Earth’s crust, is highly favorable for catalytic applications due to its widespread availability, low cost, low toxicity, and well-documented biocompatibility. However, because of its high affinity for oxygen and inherent Lewis acidity, titanium complexes generally exhibit lower tolerance toward various functional groups compared with complexes of later transition metals. The incorporation of cyclopentadienyl ligands significantly enhances the structural tunability of these complexes in their 3D configuration. By modifying the ligand framework, it is possible to fine-tune the Lewis acidity of the central titanium atom as well as the lability and binding characteristics of the ligands. This strategy enables precise control over the catalytic performance of titanocene complexes. The main body of this review provides an overview of recent advances in titanocene catalysis within the field of chemical synthesis since 2019. It includes illustrative examples that demonstrate the substrate scope and practical applications of titanocene catalysts in the synthesis of complex organic molecules and natural products. Finally, the review outlines current research opportunities and strategic directions for future developments in titanocene-based catalysis.

1. Introduction

Titanium is one of the most abundant metals in the Earth’s crust and ranks second among transition metals. Its advantages such as environmental non-toxicity and cost-effectiveness make it highly suitable for the development of economically viable and environmentally sustainable catalytic systems [1]. Titanium-based catalysts, such as TiCl₄, are known for their exceptional reactivity and unique selectivity in polymerization of olefins and other organic transformations [2,3,4]. These catalysts were initially studied as traditional Lewis acids [5,6]. Their practical applications have been limited by their extreme sensitivity to moisture and oxygen, often requiring strict anhydrous and anaerobic conditions for effective use. The presence of the cyclopentadienyl ring mitigates this phenomenon, as the metal–carbon (M-C) bond formed through Cp ligand coordination possesses unique properties distinct from conventional M-C bonds. The aromatic system created by the 6 π electrons in the cyclopentadienyl ligand modifies the molecular electronic structure. Compared with the 8-electron configuration of TiCl₄, the 16-electron of central titanium atom in the Cp₂TiCl₂ approaches the stable 18-electron configuration more closely. Consequently, titanocene-based catalysts can operate under less stringent conditions, with catalytic reactions even proceeding effectively in protic solvents such as alcohols or water, albeit with slightly reduced catalytic activity. According to molecular orbital theory, the central metal titanium of Cp₂TiCl₂ undergoes sp³ hybridization. Besides the four orbitals occupied by the two Cp ligands and the two bonded ligands, the titanium atom in the 16-electron metallocene system also possesses an empty non-bonding orbital. This bonding arrangement results in the mixing of d, s, and p orbitals, which extend away from the ring and point outward on the open surface of the titanium metal, thereby causing the ring to bend away from the ligand. As a result, unlike ferrocene, a titanocene complex is not a vertical sandwich structure and has more tunable denaturation in its 3D structure. The design and construction of titanocene complexes through ligand modification can facilitate the adjustment of the Lewis acidity of the central atom [7], as well as the ligand’s leaving and binding capability [8]. This approach enables the modulation of catalytic performance of titanocene complexes [9,10]. Titanocene-based catalysts exhibit superior performance in catalytic reactions, particularly in olefin polymerization reactions that are predominantly governed by Ziegler–Natta mechanisms. These catalysts are extensively utilized in industrial catalytic processes. For instance, Et(Ind)₂TiCl₂ has been employed in the polymerization of propylene to produce isotactic polypropylene, while Me₂Si(Cp)(N-tert-butyl)TiCl₂, as a constrained geometry catalyst, demonstrates high efficiency in catalyzing the copolymerization of ethylene and α-olefins.

In addition to their typical Lewis acid characteristics, titanium catalysts demonstrate versatile redox chemistry, facilitated by their accessible oxidation states (Ti^IV, Ti^III and Ti^II) and ability to undergo facile single-electron transfer [11,12,13,14]. This redox flexibility makes them effective catalysts for radical reactions and enables a wide range of transformations, including the pinacol couplings [15], McMurry reactions [16,17], Barbier-type allylations [18,19,20], umpolung reactions [21,22,23,24] and so on. Originally stemming from stoichiometric processes, titanocene-catalyzed redox reactions have now been adapted to facilitate diverse C–O, C–N, and C–C bond-forming transformations [25]. With its exceptional functional group compatibility, titanocene has emerged as a sustainable and versatile catalyst, capable of activating substrates such as alkenes [26,27], epoxides [28,29], carbonyl compounds [30,31,32,33], hydroxyl compounds [34], nitriles [35,36,37], alkyl halides [38,39], and more.

Numerous reviews have been published on titanium-based catalysts [40,41,42,43,44,45,46,47] or those belonging to the group 4 metallocene complexes [4,48,49,50]; however, limited attention has been given specifically to titanocene-based catalysts. In 2017, Martínez provided a review focusing on titanocene dichloride as a green reagent [51]. In 2020, Nugent and RajanBabu discuss four mechanistic puzzles associated with the reactions of epoxides with titanium(III) reagents [52]. In 2022, Gansäuer and Streuff reviewed the application of low-valent titanocene species as single-electron transfer catalysts in organic reactions [53]. Most recently, in 2023, Gansäuer and Höthker presented a review on the anti-Markovnikov addition of water to alkenes catalyzed by titanocene [54]. The aforementioned reviews mainly focus on the catalytic performance of titanocene catalysts within specific reaction systems. In the body of this review, we emphasize the recent developments in titanocene catalysis since 2019. The discussion is structured according to the key reaction substrates activated by titanocene catalysts, including (1) alkenes, (2) epoxides, (3) aldehydes and ketones, (4) alcohols, (5) nitriles and amines, (6) other types of substrates. In a concluding comment, we will broaden the scope of application for this widely utilized catalyst and forecast the future direction of titanocene catalysis development.

2. Alkenes

One of the key challenges in polymerization reactions is the development of innovative synthetic methodologies that enable the synthesis of polymers with well-defined molecular weight distributions, high chemical selectivity, and controlled stereospecific structures. The design and application of transition metal complexes have been widely recognized as one of the most effective strategies for achieving these goals. Titanocene catalysts are extensively employed in olefin polymerization due to their unique properties, which allow the polymerization of a wide range of monomers such as styrenes, α-olefins, acrylates, and lactones. However, these catalysts often yield oligomers rather than high-molecular-weight polymers, likely because β-hydrogen elimination occurs more readily than repeated monomer insertion during the polymerization process.

Nomura demonstrated the synthesis of high molecular weight polymers with narrow molecular weight distributions via the polymerization of higher α-olefins (1-decene, 1-dodecene, and 1-tetradecene), employing a Cp*TiMe₂(O-2,6-ⁱPr₂C₆H₃) catalyst in conjunction with [Ph₃C][B(C₆F₅)₄] and Al cocatalysts [55]. These findings constitute one of the few successful instances of synthesizing (ultra)high-molecular-weight bottlebrush poly(α-olefin)s with well-controlled molecular weight distributions directly from higher α-olefin monomers (Figure 1A). They subsequently immobilized the titanocene catalyst onto solid methylaluminoxane supports for ethylene polymerization [56], achieving catalytic activity comparable to that of the homogeneous system and producing polymers with shape-controlled features derived from the original support (Figure 1B). In the same year, Nomura and coworkers made half-titanocene complexes stabilized by WCA-NHC ligands, suggesting that such ligands in high-valent early transition metal complexes can effectively stabilize electron-deficient neutral or cationic alkyl species upon activation with Al-based cocatalysts [57]. The copolymerization performance of these complexes was comparable to that of the most active ethylene copolymerization catalysts reported to date, yielding polymers with high molecular weights and unimodal molecular weight distributions (Figure 1C).

Huang reported that binuclear compounds effectively enhance both the molecular weight and the breadth of molecular weight distribution of polymers during olefin polymerization, thereby addressing critical limitations associated with mononuclear catalyst systems. Recently, he reported a binuclear metallocene complex featuring a phenoxy–oxygen bridging motif, which exhibits remarkable catalytic performance in ethylene-1-octene copolymerization [58]. In similar reactions, the dinuclear [Ti]-8 complex exhibits higher catalytic activity than both [Ti]-7 and mononuclear carbene-titanocene complexes such as [Ti]-3, [Ti]-4, [Ti]-5, and [Ti]-6. The incorporation of phenoxy groups provides optimal steric protection at the axial positions, effectively retarding chain transfer and β-hydride elimination processes, leading to the formation of copolymers with higher molecular weights (Figure 1D).

The formation of π-allylmetal complexes involving allyl radical intermediates has attracted considerable attention. When additives such as Zn are present in the reaction system, the generated Ti^III center coordinates with olefins to form a Ti–olefin π-complex, following which the inner-sphere electron transfer generates a stabilized radical species. Khusainova reported a titanocene-catalyzed borylation system for both aryl- and alkyl-substituted α-olefins utilizing i-Pr₂NBCl₂, revealing distinct reaction pathways contingent upon the substrate type [59]. Aryl-substituted α-olefins undergo selective borylation at ambient temperature, affording trans-1-alkenyl boranes in excellent yields.

Xi reported titanocene-catalyzed, regioselective carbocarboxylation of dienes and alkenes that efficiently constructs versatile carboxylic acids via a three-component coupling involving organic halides, unsaturated hydrocarbons, and CO₂ [60]. Utilizing Cp₂TiCl₂ as the catalyst in the presence of nBuMgCl, this transformation proceeds with excellent regioselectivity, affording either acrylic or benzylic acids in high yields (Figure 2A). The titanocene catalyst serves two critical functions, generating carbon radicals from organic halides and promoting the transmetallation of titanocene intermediates with Grignard reagents.

Gansäuer developed Cp₂Ti(TFA)₂ as a highly versatile catalyst for [2+2] cycloadditions of bisenones via an inner-sphere electron transfer mechanism, with significant advantages over conventional outer-sphere approaches [61]. The catalytic system enables an expanded substrate scope due to the essential coordination of substrates to the Ti^III center prior to electron transfer, thereby eliminating the need for external Lewis acid activation while maintaining excellent sustainability through the use of Zn dust alone as a stoichiometric reductant, without additional additives (Figure 2B). This inner-sphere electron transfer strategy not only simplifies reaction conditions but also demonstrates superior performance compared to previously reported photocatalytic radical cyclization methods, underscoring the transformative role of substrate–metal interactions in cycloaddition chemistry.

Wang developed a titanocene-catalyzed, diastereoselective cyclopropanation method that directly converts readily available carboxylic acid derivatives and terminal olefins into valuable cyclopropanols and cyclopropylamines [62]. This breakthrough represents the first general protocol for converting alkyl carboxylic acids into cyclopropanols, overcoming previous limitations through a sustainable catalytic system that eliminates the need for reactive alkyl Grignard reagents. The transformation exhibits a broad substrate scope with excellent functional group tolerance, mild reaction conditions suitable for late-stage modifications of complex natural products and bioactive molecules, and operational simplicity using stable, commercially available starting materials.

Mashima and colleagues developed highly branched selective hydroaminoalkylation of 1-alkenes with N-methylaniline derivatives using a CpTiMe₃/AlMe₃ catalytic system [63]. That research demonstrated that catalytically active species containing both amido and alkyl ligands enabled Al-assisted C(sp³)-H activation, followed by regioselective alkene insertion into a three-membered azatitanacycle intermediate (Figure 2C). The exceptional branched selectivity was attributed to favorable electronic stabilization through optimal delocalization of the unpaired electron from the Ti^III center into the π orbital of the styrene moiety during the transition state. This mechanistic insight has enabled the identification of bimetallic Ti^III-Al species as key intermediates, a finding analogous to those observed in Ziegler–Natta olefin polymerization catalysts.

Figure 2. Reactions involving alkenes catalyzed by titanocene. (A) Titanocene-catalyzed regioselective carbocarboxylation of dienes and alkenes [60]; (B) Titanocene-catalyzed [2+2] cycloadditions of bisenones via an inner-sphere electron transfer mechanism [61]; (C) Titanocene-catalyzed highly branched selective hydroaminoalkylation of 1-alkenes with N-methylaniline derivatives [63].

Figure 2. Reactions involving alkenes catalyzed by titanocene. (A) Titanocene-catalyzed regioselective carbocarboxylation of dienes and alkenes [60]; (B) Titanocene-catalyzed [2+2] cycloadditions of bisenones via an inner-sphere electron transfer mechanism [61]; (C) Titanocene-catalyzed highly branched selective hydroaminoalkylation of 1-alkenes with N-methylaniline derivatives [63].

3. Epoxides

3.1. Ring Opening of Epoxides

Asymmetric epoxidation represents a crucial transformation in organic synthesis, offering efficient access to valuable chiral building blocks essential for the preparation of bioactive natural products. The field experienced a significant breakthrough with McMurry’s discovery of low-valent titanium-mediated deoxygenation, which established the foundation for contemporary Ti-catalyzed C−O bond cleavage strategies. These reactions utilize Ti^III/^IV redox cycles that act as effective single-electron reductants. The mechanism typically involves Lewis acid coordination to the epoxide, followed by inner-sphere single-electron transfer. This sequence promotes regioselective homolytic cleavage of the more substituted C−O bond, yielding stabilized carbon-centered radicals capable of engaging in various transformations such as hydrogen atom transfer, in addition to π-systems, or elimination reactions. Importantly, chiral Ti complexes can exert stereochemical control over these processes, facilitating the synthesis of enantiomerically enriched alcohols. Although early methods relied on stoichiometric amounts of metallic reductants (Zn, Mn) for catalyst regeneration, recent advancements have significantly enhanced the efficiency of these versatile epoxide functionalization approaches, which are now widely employed in the modification of oxygen-containing organic molecules.

Gansäuer and coworkers presented a catalytic strategy that inverts the conventional regioselectivity of epoxide opening through synergistic titanocene and chromium catalysis [64]. Whereas traditional electrophilic activation typically yields Markovnikov alcohols via an S_N2 attack at the less substituted carbon, this approach achieves anti-Markovnikov selectivity through a radical mechanism (Figure 3A). The titanocene catalyst directs ring opening toward the formation of the more stable, substituted carbon-centered radical, while the chromium cocatalyst facilitates efficient hydrogen atom, proton, and electron transfer from H₂ with perfect atom economy. This cooperative catalytic system operates through well-defined and interconnected catalytic cycles, each of which has been experimentally validated. The method marks a significant departure from classical epoxide-ring-opening pathways by integrating radical generation with molecular hydrogen activation to precisely control regioselectivity.

Light irradiation can induce the formation of free radicals, and titanium-based catalysts, through Ti^III/IV redox transitions, can function as single-electron reductants, thereby initiating radical generation. However, within the field of molecular catalysis, titanium-based systems have not previously been applied in photocatalytic reactions. For the first time, under green light irradiation, Gansäuer’s titanocene system generates an active photoredox catalyst capable of mediating both epoxide reduction and 5-exo cyclizations of unsaturated epoxides [65]. To further investigate the mechanism of ring opening of epoxides, Gansäuer employed PhSiD₃ or Ph(Me)SiD₂ as deuterium sources to systematically investigate the reaction pathways and stereoselectivity of epoxide ring opening through precise deuterium labeling [66]. This titanocene(III)-catalyzed epoxide deuterio-silylation enables the efficient synthesis of β-deuterated anti-Markovnikov alcohols in high yields, with excellent deuterium incorporation (Figure 3B). Moreover, the reaction exhibits remarkable diastereoselectivity after desilylation. The mechanism involves a regioselective electron-transfer-mediated epoxide opening, followed by an intramolecular deuterium-atom transfer from Ti–D to the radical intermediate, thereby forming the critical C–D bond.

While terminal and aromatic epoxides typically exhibit high regioselectivity in ring-opening reactions due to their distinct structural properties, aliphatic endo-epoxides often display reduced selectivity. This issue is further compounded in tetrasubstituted epoxides, where significant steric hindrance markedly decreases reactivity. To address these challenges, Chen developed a Ti^III-mediated reaction system that enables selective epoxide isomerization, which has been successfully applied in the synthesis of natural products [67].

Figure 3. Titanocene-catalyzed ring-opening reactions of epoxides. (A) Epoxide opening with anti-Markovnikov selectivity through synergistic titanocene and chromium catalysis [64]; (B) Titanocene-catalyzed epoxide deuterio-silylation [66]; (C) Titanocene-catalyzed hydrosilylation of epoxide diastereomers to yield anti-Markovnikov alcohols [68]; (D) The design and synthesis of a novel class of titanocene-based catalysts for epoxide hydrosilylation [69].

Figure 3. Titanocene-catalyzed ring-opening reactions of epoxides. (A) Epoxide opening with anti-Markovnikov selectivity through synergistic titanocene and chromium catalysis [64]; (B) Titanocene-catalyzed epoxide deuterio-silylation [66]; (C) Titanocene-catalyzed hydrosilylation of epoxide diastereomers to yield anti-Markovnikov alcohols [68]; (D) The design and synthesis of a novel class of titanocene-based catalysts for epoxide hydrosilylation [69].

Gansäuer demonstrated that polymethylhydrosiloxane functions as a sustainable and cost-effective terminal reductant in titanocene-catalyzed epoxide hydrosilylation, yielding products analogous to the anti-Markovnikov addition of water to alkenes [70]. Compared with conventional silanes, polymethylhydrosiloxane not only provides greater sustainability and reduced costs but also enhances the diastereoselectivity of the reaction.

In 2023, Gansäuer described a unique Ti/Cr dual-metal catalytic system [71]. In contrast to traditional methods that generate radicals through the reduction of Ti^IV by metallic reductants such as Mn or Zn, this system utilizes [BH₄]⁻ as a stoichiometric hydrogen atom and electron donor under mild reaction conditions. The hydrogen atoms are transferred to the chromium center via hydrogen atom transfer, which plays a pivotal role in the catalytic radical chemistry. In the same year, Gansäuer established a novel method for synthesizing highly enantio- and diastereomerically enriched anti-Markovnikov alcohols from diastereomeric olefin mixtures [68]. This two-step catalytic strategy begins with an enantioselective epoxidation of olefin enantiomers using the Shi protocol, which ensures a consistent absolute configuration at the less substituted stereocenter in both resulting epoxide diastereomers. In the subsequent step, a titanocene complex catalyzes the hydrosilylation of these epoxide diastereomers to yield anti-Markovnikov alcohols (Figure 3C). Later, Gansäuer and coworkers designed and synthesized a chiral titanocene complex, which was subsequently integrated into a photoredox catalytic system [72]. Notably, this reaction circumvented the need for conventional metallic reductants such as Mn or Zn by employing an equimolar quantity of DIPEA, which fulfilled multiple roles, acting as an electron donor, a hydrogen atom donor, and an electrophile to regenerate the active titanocene catalyst following its transformation into an iminium ion.

To further investigate the mechanism of H interaction in the reaction process of Ti center, Gansäuer designed a novel class of titanocene-based catalysts for epoxide hydrosilylation [69]. By incorporating a Lewis acidic silicon center into the cyclopentadienyl ligand, the catalyst facilitated intramolecular coordination of the titanium-bound hydride. This structural modification effectively reduced the hydride transfer capability of the titanocene complex while markedly enhancing its electron transfer activity. The unique architecture of the catalyst enabled efficient intramolecular interaction between hydrogen molecules and the titanium center. As a result, the system demonstrated exceptional regioselectivity in the hydrosilylation of monosubstituted epoxides, allowing for the highly selective synthesis of primary alcohols. Its catalytic performance surpassed that of conventional alkyl-substituted titanocene catalysts by a significant margin (Figure 3D).

Norton developed an environmentally benign titanocene-catalyzed system for the anti-Markovnikov reduction of epoxides to alcohols [73]. This versatile method utilizes readily available LiBH₄ as a dual-function reagent, serving as both a source of electrons and hydrogen atoms. The catalytic system operates under mild reaction conditions and demonstrates excellent substrate tolerance across a broad range of epoxide substrates.

3.2. Radical Arylation of Epoxides

In 2019, Gansäuer presented a novel strategy that integrates titanocene catalysis with photoredox catalysis, significantly expanding the scope of single-electron radical transformations [74]. This dual catalytic system overcomes the limited oxidizing capacity of titanocene(IV) intermediates by employing the photoredox catalyst to oxidize radical species into cationic intermediates, thereby broadening the applicability of radical chemistry. The method enhances sustainability by generating the active catalyst in situ via photoreduction of bench-stable Cp₂TiX₂ precursors, eliminating the need for stoichiometric acidic additives or metallic reductants. The system exhibits particular effectiveness in reductive epoxide ring opening and redox-neutral epoxide radical arylation reactions (Figure 4A). Later, Gansäuer reported a titanocene-catalyzed, regiodivergent radical arylation that selectively yields either enantiopure tetrahydroquinolines or indolines from the same starting materials [75]. The reaction exhibits remarkable regioselectivity in epoxide opening, which determines heterocycle formation, and is governed by two key factors: the absolute configuration of the chiral (C₅H₄R)₂TiX₂ catalyst and the nature of the inorganic ligand. Studies show that while substituted cyclopentadienyl ligands provide primary control over selectivity, the -OTs ligand significantly enhanced both regioselectivity and diastereoselectivity. This simple modification of the X ligand greatly expands the utility of a given titanocene framework, suggesting potential for broader application in optimizing other electron-transfer catalysts (Figure 4B).

In same year, Gansäuer successfully expanded the cyclic voltammetry-based screening platform for Cp₂TiX-catalyzed reactions to systematically evaluate alternative solvents and halide binders [76]. That study demonstrates that CH₃CN is an effective solvent for both the bulk electrolysis of Cp₂TiX₂ precursors and the subsequent radical arylation reactions, without the need for additives.

To apply the Ti-facilitated radical reaction, Chakraborty presented an efficient and novel radical-based strategy for constructing pyrrolo/piperido [1,2-a]indoles via Cp₂TiCl-promoted reductive epoxide opening of N-tethered epoxyindoles [77]. This method involves a facile intramolecular C–C bond-forming cyclization followed by oxidative quenching, thereby enabling the direct assembly of [a]-annelated indole scaffolds in only two steps. The resulting N-fused indole derivatives feature versatile functional groups on the saturated ring, rendering them well suited for further structural modification.

Integration of Ti-catalysis with other means, Doyle developed a photocatalytic cross-electrophile coupling reaction between epoxides and (hetero)aryl iodides, facilitated by the synergistic cooperation of Ni, Ti, and organic photoredox catalysts [78]. This method is applicable to three distinct types of epoxides (styrene oxides, cyclic epoxides, and terminal aliphatic epoxides) and provides moderate to high yields with excellent regioselectivity under mild reaction conditions.

Through an integrated approach combining synthetic methods, electrochemical techniques, and DFT computational studies, Gansäuer elucidated the mechanism by which thiourea, squaramide, and bissulfonamide additives modulate the E_qC_r equilibrium of Cp₂TiCl₂ [79]. This work presents the first quantitative evaluation of the E_qC_r equilibrium, determining the stoichiometry of adduct formation between these additives and titanocene species ([Cp₂Ti(III)Cl₂]⁻, [Cp₂Ti(III)Cl], and [Cp₂Ti(IV)Cl₂]). Importantly, that study introduced bissulfonamides as effective additives in both the bulk electrolysis of Cp₂TiCl₂ in THF and titanocene-catalyzed radical arylation of epoxides. The findings underscore the essential balance between catalyst activity and stability for achieving optimal reaction efficiency, which is governed by complex hydrogen-bonding and polar-group coordination interactions between additives and titanocenes, with results that are fully consistent with electrochemical data (Figure 4C).

Figure 4. Titanocene-catalyzed radical arylation of epoxides. (A) A novel catalytic system combining titanocene catalysis with photoredox catalysis (* Representing the excited state generated following irradiation) [74]; (B) Titanocene-catalyzed regiodivergent radical arylation [75]; (C) Titanocene-catalyzed radical arylation of epoxides with ligand modulation [79]; (D) Titanocene-catalyzed photoredox radical arylation of epoxides [80].

Figure 4. Titanocene-catalyzed radical arylation of epoxides. (A) A novel catalytic system combining titanocene catalysis with photoredox catalysis (* Representing the excited state generated following irradiation) [74]; (B) Titanocene-catalyzed regiodivergent radical arylation [75]; (C) Titanocene-catalyzed radical arylation of epoxides with ligand modulation [79]; (D) Titanocene-catalyzed photoredox radical arylation of epoxides [80].

In 2023, Gansäuer and coworkers investigated the fundamental photochemical mechanisms of an all-Ti-based SET-PR-catalytic system that functions without reliance on a precious-metal PR co-catalyst [80]. By utilizing a combination of time-resolved emission spectroscopy and ultraviolet-pump/mid-infrared-probe (UV/MIR) spectroscopy across femtosecond-to-microsecond timescales, they quantitatively elucidated two essential initiation steps in the catalytic cycle: the singlet-triplet interconversion of the multifunctional titanocene(IV) photoredox catalyst and its subsequent one-electron reduction mediated by an amine sacrificial donor. These mechanistic insights highlight the pivotal role of the catalyst’s singlet-triplet energy gap, identifying it as a crucial design parameter for the development of enhanced titanium-based photoredox systems with the potential to replace conventional precious-metal catalysts (Figure 4D).

3.3. Radical Alkylation of Epoxides

For the part of radical alkylation of epoxides, Chakraborty developed a Cp₂Ti^IIICl-mediated strategy that efficiently converts 3,3′-disubstituted oxindole-derived epoxy-acrylates into tetrahydrofuran-based oxaspirooxindoles via a tandem reductive oxirane ring-opening reaction followed by an intramolecular 5-exo-trig radical cyclization [81]. This single-electron-transfer process enables the formation of structurally complex molecules containing multiple quaternary centers and diverse functional groups, thereby significantly enhancing their synthetic applicability.

Shi described a visible-light-driven titanocene/photoredox dual catalytic system that enables radical-mediated ring opening and spirocyclization of readily accessible epoxyalkynes, thereby facilitating the efficient synthesis of structurally challenging spirocyclic compounds containing all-carbon quaternary stereocenters [82]. This environmentally benign protocol utilizes the organic donor–acceptor fluorophore 4CzIPN as a photocatalyst and a Hantzsch ester as a stoichiometric electron donor, eliminating the need for metallic reductants. Cyclic voltammetry studies confirm Cp₂Ti^IIICl as the catalytically active species, which demonstrates exceptional reactivity under these mild photocatalytic conditions. Mechanistically distinct from conventional metal-reduction protocols, this method relies on the synergistic interaction between titanocene and photoredox catalysis, wherein Cp₂TiCl serves as a highly reactive intermediate toward epoxides. The operational simplicity, scalability, and broad substrate scope of this strategy establish it as a versatile platform for constructing privileged heterospirocyclic frameworks (Figure 5A).

Wang developed a titanocene-catalyzed reductive domino reaction that efficiently transforms trifluoromethyl-substituted alkenes and epoxides into gem-difluorobishomoallylic alcohols through a sequential Ti^III-controlled mechanism [83]. The transformation involves three key steps: initial Ti^III-mediated radical-type epoxide ring opening, followed by allylic defluorinative cross-coupling via radical addition, and concluding with β-fluorine elimination, all occurring with complete regioselectivity and excellent functional group compatibility. The resulting products serve as versatile intermediates that can be readily converted into diverse 6-fluoro-3,4-dihydro-2H-pyrans through simple base-mediated nucleophilic substitution (Figure 5B).

To utilize Ti^III in total synthesis, Chakraborty reported the first stereoselective total syntheses of the fungal secondary metabolites monoterpenoid(+)-pestalotiolactone A, meroterpenoid(−)-myrotheciumone A, and iridoid lactone(+)-scabrol A using a unified strategy based on D-(+)-malic acid [84]. A key Cp₂Ti^IIICl-mediated epoxide-opening/radical cyclization protocol was utilized to construct their core bicyclic lactone structures with complete diastereoselectivity, demonstrating the broad applicability of this transformation across structurally diverse terpenoid frameworks. The synthetic route concluded with deoxygenation and methylation steps to yield the target natural products.

Figure 5. Titanocene-catalyzed radical alkylation of epoxides. (A) Titanocene-catalyzed radical-mediated ring opening and spirocyclization of epoxyalkynes [82]; (B) Titanocene-catalyzed reductive domino reaction [83]; (C) Titanocene-catalyzed transformation of benzylic ethers and amines into acetals and hemiaminals [85]; (D) Titanocene-catalyzed radical allyl transfer reaction [86].

Figure 5. Titanocene-catalyzed radical alkylation of epoxides. (A) Titanocene-catalyzed radical-mediated ring opening and spirocyclization of epoxyalkynes [82]; (B) Titanocene-catalyzed reductive domino reaction [83]; (C) Titanocene-catalyzed transformation of benzylic ethers and amines into acetals and hemiaminals [85]; (D) Titanocene-catalyzed radical allyl transfer reaction [86].

Gansäuer described a titanocene-catalyzed transformation that efficiently converts benzylic ethers and amines into acetals and hemiaminals via a cascade of single-electron-transfer processes [85]. The reaction mechanism comprises three key stages: oxidative epoxide opening initiates the process, followed by hydrogen-atom transfer to yield a benzylic radical intermediate that facilitates radical translocation, end in an organometallic oxygen rebound through reductive elimination. The observed stereoselectivity arises from the most stable conformers of the benzylic radicals, whose spatial arrangements are governed by a combination of hyperconjugative effects and steric interactions between the titanocene catalyst and the aryl groups of the substrate (Figure 5C).

Du developed a mild and highly efficient titanocene-catalyzed protocol for the regioselective ring-opening alkynylation of epoxides with haloalkynes, enabling direct and facile access to a diverse array of propargylic alcohols in moderate to excellent yields [87]. This versatile method is applicable to a wide range of substrates, including aromatic, aliphatic, terminal, and internal epoxides, while exhibiting excellent compatibility with various functional groups. Notably, the reaction proceeds under exceptionally mild conditions and demonstrates remarkable chemoselectivity by effectively suppressing competing epoxide rearrangement pathways that lead to aldehydes.

Dong developed a Ni/Ti dual-catalytic system for the cross-coupling of epoxides with acyl chlorides or anhydrides, enabling efficient and practical access to synthetically valuable β-hydroxy ketones in good to high yields [88]. The reaction integrates titanocene-catalyzed epoxide ring opening with Ni-catalyzed acylation of the resulting benzylic radical intermediate, wherein the use of a modified pyridine–oxazoline ligand was found to be essential for achieving optimal catalytic performance. This method is compatible with both alkyl and aryl acylation reagents, thereby offering a versatile and straightforward synthetic route to β-hydroxy ketones from readily accessible starting materials. Although the protocol demonstrates broad applicability, certain limitations persist, particularly regarding the incompatibility of substrates containing heteroatoms or those sensitive to redox conditions.

Gansäuer and coworkers reported a versatile titanocene-catalyzed radical allyl transfer reaction that enables the regioselective opening of epoxides at the more hindered position, followed by efficient coupling with diverse allyl sulfones to construct quaternary carbon centers bearing synthetically valuable functionalities [86]. This method represents one of the pioneering radical-based approaches for generating functionalized quaternary carbon synthons and significantly expands the synthetic utility of allylation chemistry. Mechanistic studies have elucidated the complete catalytic cycle, which includes epoxide opening, intramolecular addition, fragmentation, and σ-bond metathesis, thereby facilitating the optimization of reaction conditions. The protocol exhibits a broad substrate scope and can be extended to stereoselective variants, such as diastereoselective and enantioselective transformations (Figure 5D).

Gansäuer and coworkers described a stereoconvergent radical epoxide allylation strategy that efficiently constructs diastereo- and enantiomerically enriched α-quaternary alcohols in two steps from olefin precursors [89]. This method synergistically combines the stereospecificity of Shi asymmetric epoxidation with a novel Ti^III-promoted intramolecular radical allylation, enabled by directional isomerization of configurationally labile radical intermediates. The protocol exhibits unique stereoconvergent behavior; starting from an (E)/(Z)-olefin mixture, Shi epoxidation first generates highly enantioenriched diastereomeric epoxides, which are then uniformly converted into a single product featuring an acyclic all-carbon quaternary stereocenter through the radical allylation step. In addition to demonstrating a broad substrate scope, the authors validated the synthetic utility of this method by employing it as the key transformation in the total synthesis of alkaloid (−)-crinane.

4. Aldehydes and Ketones

Titanium complexes have emerged as powerful mediators for the radical allylation of carbonyl compounds, providing a versatile strategy for constructing functionalized building blocks in natural product synthesis. As a Lewis acid, titanium enhances the electrophilicity of carbonyl groups through coordination, while its redox-active nature (Ti^III/IV) enables efficient capture of nucleophilic radicals, thereby avoiding the thermodynamically unfavorable direct radical addition to unactivated carbonyls. The catalytic cycle begins with the reduction of Cp₂TiCl₂ to Cp₂Ti^IIICl, which functions both as a mild single-electron reductant and as a radical trap. This active Ti^III species generates π-allyl–titanium complexes by reducing allylic radicals derived from alkenes via a single-electron transfer process. The resulting nucleophilic allyltitanium species then undergoes addition to the Ti^III-activated carbonyl group, forming a Ti^IV-alkoxide intermediate through a radical coupling pathway. Subsequent protonolysis of the Ti–O bond releases the desired homoallylic alcohol product and regenerates the Ti^IV complex, which is then reduced back to the active Ti^III species, completing the catalytic cycle. This elegant mechanism integrates the benefits of Lewis acid activation with radical reactivity, offering a practical method for C–C bond formation that avoids the use of highly reactive organometallic reagents while maintaining excellent functional group compatibility. The unique capacity of titanium to shuttle between oxidation states (III/IV) and simultaneously activate both reaction partners (carbonyl and allyl components) makes this transformation particularly valuable in the synthesis of complex molecules.

Rodríguez-García developed an efficient titanocene(III)-mediated methodology employing the in situ generated half-sandwich complex CpTi^IIICl₂ for Barbier-type reactions between aldehydes and propargylic halides, yielding either homopropargylic alcohols or α-allenols depending on the reaction conditions and the nature of the alkyne substituents [90]. This versatile system exhibits broad functional group tolerance and enables a practical two-step synthesis of 2,5-dihydrofurans through sequential Ti^III addition and Ag^I-mediated cyclization. The synthetic utility is demonstrated by the concise preparation of a natural dihydrofuranic labdane isolated from Mikania sp. nov., thereby establishing this method as a valuable tool for natural product synthesis (Figure 6A).

Figure 6. Titanocene-catalyzed allylation of aldehydes and ketones. (A) Titanocene-catalyzed Barbier-type reactions between aldehydes and propargylic halides [90]; (B) Titanocene-catalyzed photocatalytic radical strategy for the generation of homoallylic alcohols [91]; (C) Titanocene-catalyzed photoredox propargylation of aldehydes [92]; (D) Titanocene-catalyzed ketone-nitrile coupling [93]; (E) Titanocene-catalyzed photoredox regioselective synthesis of α-vinyl-β-hydroxy esters [94].

Figure 6. Titanocene-catalyzed allylation of aldehydes and ketones. (A) Titanocene-catalyzed Barbier-type reactions between aldehydes and propargylic halides [90]; (B) Titanocene-catalyzed photocatalytic radical strategy for the generation of homoallylic alcohols [91]; (C) Titanocene-catalyzed photoredox propargylation of aldehydes [92]; (D) Titanocene-catalyzed ketone-nitrile coupling [93]; (E) Titanocene-catalyzed photoredox regioselective synthesis of α-vinyl-β-hydroxy esters [94].

Huang developed a flexible and versatile synthetic strategy that integrates Grignard/Reformatsky additions with titanocene-catalyzed umpolung C–C bond formation, enabling the efficient construction of multifunctional pyrrolidinones, piperidinones, and N-Boc-piperidines containing aza-quaternary carbons (AQCs) from cyclic imides and their analogs [95]. This methodology allows for the preparation of pyrrolidin-2-one hemiaminals and ketoamides as pivotal intermediates, which subsequently participate in titanocene-catalyzed radical cross-coupling reactions with activated alkenes to yield AQC-containing heterocyclic structures.

Cozzi described an environmentally benign photoredox allylation methodology employing catalytic Cp₂TiCl₂ under visible light irradiation, wherein the organic dye 3DPAFIPN enables efficient generation of the active Cp₂Ti^IIICl species without requiring stoichiometric metal reductants [96]. This innovative system combines the advantages of titanium’s natural abundance and low toxicity with the sustainability of photoredox catalysis, utilizing Hantzsch ester as a unique reductant whose oxidized and protonated form facilitates titanocene catalyst turnover. Mechanistic studies have elucidated the dual role of the organic dye in generating the titanocene(III) intermediate while avoiding reliance on traditional Mn/Zn reductants.

Shi developed the first photocatalytic radical strategy for the generation of π-allyltitanium complexes, enabling a highly efficient three-component allylation of carbonyl compounds with 1,3-butadiene to construct over 60 valuable homoallylic alcohols [91]. The operationally simple method represents a significant advancement in allylmetal chemistry by establishing a radical pathway to π-allyltitanium species, demonstrating broad substrate scope across various carbonyl compounds, and offering sustainable access to structurally complex homoallylic alcohols with precise stereocontrol. This work opens new avenues for selective C–C bond formation through photoredox-assisted early transition metal catalysis (Figure 6B). In same year, Shi reported an environmentally benign photocatalytic Barbier-type allylation of aldehydes and ketones using a dual titanocene/photoredox catalytic system [97]. This system integrates the organic photocatalyst 4CzIPN with Hantzsch ester, which serves as both an electron and proton donor, thereby eliminating the need for stoichiometric metal reductants or external additives. The method is operationally simple, scalable, and provides efficient access to valuable homoallylic alcohols in good yields. Its broad applicability is demonstrated through successful extension to propargylation, benzylation, and prenylation reactions.

Cozzi and coworkers developed an efficient photoredox propargylation of aldehydes catalyzed by Cp₂TiCl₂, a process that operates without stoichiometric metals or scavengers, utilizing the inexpensive organic dye 3DPAFIPN as both a photocatalyst and a titanocene reductant [92]. This practical system exhibits a broad substrate scope encompassing both aromatic and aliphatic aldehydes, affording homopropargylic alcohols in good yields. When simple propargyl bromide is employed, the reaction shows complete selectivity for the propargyl isomer; however, substituted propargyl bromides lead to mixtures of propargyl and allenyl products (Figure 6C).

Streuff presented a kinetic analysis of the Cp₂TiCl₂-catalyzed ketone–nitrile coupling, revealing a complex interplay between catalyst speciation and substrate availability, which is modulated by reaction additives and byproducts [93]. That study elucidates how ZnCl₂ plays a dual role in the titanocene(III)-catalyzed system, promoting product release through the formation of HNEt₃ZnCl₃, while simultaneously inhibiting catalysis by generating off-cycle cationic Ti^III species and substrate-bound complexes. This behavior, together with the concentration-dependent formation of Ti^III–HNEt₃Cl coordination complexes mediated by hydrochloride additives, and the system’s intrinsic hidden autocatalysis that dynamically shifts the rate-determining step, highlights a delicate equilibrium between productive catalytic cycles and inhibitory off-cycle reservoirs (Figure 6D).

Calogero reported the first dual photoredox/titanocene-catalyzed system for the regioselective synthesis of α-vinyl-β-hydroxy esters through aldehyde allylation using ethyl-4-bromobut-2-enoate [94]. The reaction employs catalytic quantities of the inexpensive Cp₂TiCl₂ and the organic photocatalyst 3DPAFIPN under visible light irradiation. This sustainable Barbier-type transformation utilizes a Hantzsch ester as a sacrificial organic reductant, eliminating the need for preformed organometallic reagents or stoichiometric metal-based reducing agents, while achieving higher regioselectivity than conventional approaches. The mild reaction conditions allow efficient access to a broad range of functionalized α-vinyl-β-hydroxy esters derived from both aromatic and aliphatic aldehydes, consistently producing single regioisomers with moderate syn diastereoselectivity (Figure 6E).

Shi developed an innovative bimetallic strategy that synergistically integrates photo-induced Co-mediated hydrogen atom transfer (MHAT) with Ti catalysis, enabling versatile carbonyl allylation reactions involving a wide range of amino-, oxy-, thio-, aryl-, and alkyl-substituted allenes [98]. This dual catalytic system offers efficient access to valuable β-functionalized homoallylic alcohols, as evidenced by over 100 examples exhibiting excellent regio- and diastereoselectivity, including the synthesis of vinyl-containing 1,2-aminoalcohols, 1,2-diols, and 1,2-thioalcohols. Mechanistic studies supported by DFT calculations indicate that the selective hydrogen atom transfer from Co hydride to allenes is the critical step in the catalytic cycle leading to the formation of key allyl radical intermediates. The same group developed an innovative three-component aldehyde allylation strategy that integrates radical thiol-ene chemistry with Ti^III catalysis, enabling the direct conversion of feedstock 1,3-butadiene into valuable allylic 1,3-thioalcohols under visible light irradiation [99]. This sustainable methodology combines several advantageous features, including operational simplicity, excellent regio- and diastereoselectivity, and a broad substrate scope, utilizing 1,3-butadiene as an efficient allyl group donor. Later, the Shi group extended this methodology by employing functionalized conjugated dienes instead of allenes in their dual catalytic system combining photo-Co-mediated MHAT with Ti catalysis [100]. This radical process enables the highly selective reductive coupling of readily available 1,3-butadiene with a variety of aldehydes to form homoallylic alcohols with excellent regio- and diastereoselectivity.

5. Alcohols

The direct transformation of C(sp³)–O bonds in alcohols and their derivatives has become an increasingly important strategy in modern synthetic chemistry, providing a more efficient alternative to conventional multi-step deoxygenation protocols. Whereas traditional approaches typically require the pre-functionalization of hydroxyl groups before reduction, recent developments have enabled direct dehydroxylation through various mechanistic pathways such as carbocation reduction, carbanion protonation, hydrogen atom transfer, and transition-metal-catalyzed cleavage of the C–OH bond. Among these strategies, Cp₂TiCl have demonstrated particular efficacy as mild yet potent single-electron transfer agents, capable of generating carbon radicals from C–O electrophiles for subsequent C–C bond formation. Despite considerable advances in cross-coupling reactions employing alcohol derivatives as radical precursors, the direct activation of free alcohols via homolytic cleavage of the C–O bond remains a significant challenge. Titanium, as an abundant and environmentally benign transition metal, exhibits distinctive reactivity in this field due to its strong oxophilicity and high reduction potential. Although methods for the dehydroxylation of primary and secondary alcohols have advanced significantly, the direct conversion of tertiary aliphatic alcohols into C(sp³)–H bonds remains underexplored, marking a crucial challenge and opportunity for future research in this rapidly progressing area. These titanocene-based systems continue to draw considerable interest due to their potential to simplify synthetic pathways and enable innovative retrosynthetic disconnections in the construction of complex molecules.

The direct formation of C−C bonds through deoxygenative radical pathways from alcohols remains a significant challenge in synthetic chemistry, as current methods typically involve complex multi-step procedures. Shu reported the first direct dehydroxylative radical C−C coupling of unactivated tertiary alcohols, thereby establishing a novel and practical approach for constructing all-carbon quaternary centers from readily accessible alcohol precursors [101]. This transformative method addresses a longstanding challenge in synthesis by enabling single-step deoxygenative alkylation, previously achievable only via multistep sequences. It uses titanocene-catalyzed homolysis of the C−OH bond to generate key tertiary carbon radicals. The reaction exhibits high selectivity for tertiary alcohols while leaving secondary and primary alcohols, as well as phenols, unaffected, and it is compatible with various coupling partners including activated alkenes, allylic carboxylates, (hetero)aryl/vinyl electrophiles, and primary alkyl halides. Mechanistic investigations integrating experimental data and DFT calculations support a radical pathway involving Ti-mediated cleavage of the C−OH bond (Figure 7A).

Chen developed a titanocene-catalyzed dehydroxylation method for tertiary aliphatic alcohols, inspired by titanocene-mediated epoxide opening [102]. This method utilizes silane as the primary hydrogen donor and zinc as the reducing agent, and it demonstrates applicability not only to tertiary aliphatic alcohols but also to secondary and tertiary benzylic alcohols. The protocol is mild in reaction conditions and exhibits broad substrate compatibility, enabling the successful modification of pharmaceutical compounds and natural product derivatives. Moreover, the method is scalable to gram quantities and shows excellent chemoselectivity for tertiary alcohols in diol systems (Figure 7B).

Figure 7. Titanocene-catalyzed dehydroxylation of alcohols. (A) Titanocene-catalyzed direct dehydroxylative radical C−C coupling of unactivated tertiary alcohols [101]; (B) Titanocene-catalyzed dehydroxylation for tertiary aliphatic alcohols [102]; (C) Titanocene-catalyzed synthesis of functionalized organofluorine compounds [103]; (D) Titanocene-catalyzed direct dehydroxylative ring-opening Giese reaction [104].

Figure 7. Titanocene-catalyzed dehydroxylation of alcohols. (A) Titanocene-catalyzed direct dehydroxylative radical C−C coupling of unactivated tertiary alcohols [101]; (B) Titanocene-catalyzed dehydroxylation for tertiary aliphatic alcohols [102]; (C) Titanocene-catalyzed synthesis of functionalized organofluorine compounds [103]; (D) Titanocene-catalyzed direct dehydroxylative ring-opening Giese reaction [104].

Wu reported a breakthrough in homogeneous transition-metal catalysis, describing a general and unprecedented method for the exhaustive reduction of carboxylic acids and their derivatives directly to methyl groups, a transformation that has remained rare and challenging [105]. Utilizing titanocene as the catalyst, this protocol exhibits remarkable functional group tolerance, accommodating a broad array of oxo-functional groups such as alcohols, aldehydes, ketones, lactones, and carboxylates. The system enables the efficient synthesis of methylated products that traditionally require multi-step synthetic sequences. Mechanistic studies indicate that the in situ generation of Ti^III–H species from Ti^IV–Cl is critical to facilitating this transformation.

Shu developed a groundbreaking titanocene-catalyzed system for the direct dehydroxylative vinylation of tertiary alcohols, addressing the long-standing challenge in metal-catalyzed formation of C(sp³)–C(sp²) bonds from unactivated alcohols [106]. This radical-mediated transformation efficiently constructs valuable all-carbon quaternary centers bearing vinyl groups under mild conditions, exhibiting excellent functional group tolerance and a broad substrate scope encompassing all types of vinyl halides. Notably, the reaction displays unique stereoconvergence, selectively converting both cis- and trans-haloalkenes into trans-products, while showing high chemoselectivity for vinyl halides over aryl electrophiles.

Takatori presented an efficient, low-valent titanocene-mediated synthesis of substituted succinonitrile derivatives from readily accessible cyanohydrin precursors, which can be conveniently derived from a variety of ketones [107]. This transformation proceeds via a unique reactive intermediate, best characterized as a resonance-stabilized hybrid between a Ti^IV nitrile enolate and a Ti^III cyanoalkyl radical species, as evidenced by mechanistic studies. The ambiphilic nature of this key intermediate allows it to engage in coupling reactions with a range of electrophiles and radical acceptors, thereby offering significant potential for expanding the reaction’s scope.

Fleischer presented a sustainable catalytic system for the deoxygenation of benzylic alcohols using Cp₂TiCl₂ as a precatalyst and bio-derived 2-MeTHF as the solvent [108]. A key feature of this transformation is the dual role of Me(EtO)₂SiH, which functions simultaneously as a hydrogen donor and a reagent for catalyst regeneration, as revealed by mechanistic studies. The method exhibits excellent functional group tolerance, accommodating various protecting groups while selectively reducing carbonyl functionalities. Importantly, the system enables sequential transformations, thereby streamlining traditionally multi-step processes into efficient one-pot operations. This versatility is further demonstrated through its successful application to lignin model compounds, achieving complete deoxygenation and yielding value-added aromatic building blocks, thus highlighting its potential in biomass valorization.

Wang presented a versatile Ti-catalyzed protocol for the deoxygenative radical coupling of free alcohols with trifluoromethyl alkenes through C-O cleavage and C-C bond formation, enabling efficient and divergent synthesis of functionalized organofluorine compounds [103]. This method exhibits remarkable substrate-controlled selectivity; under acidic conditions, Ti-catalyzed C-O homolysis of tertiary alcohols yields trifluoromethyl alkanes without defluorination, whereas Ti-mediated activation of benzyl alcohols under basic conditions leads to gem-difluoroalkenes via defluorination. The reaction is compatible with a broad range of trifluoromethyl alkenes and various alcohol types, demonstrating excellent functional group tolerance and scalability up to gram quantities (Figure 7C).

Wang presented a titanocene-catalyzed strategy that efficiently converts readily available carboxylic acids and their derivatives into functionalized ketones through reaction with gem-dihaloalkanes [109]. This method constitutes the first Ti-catalyzed olefination of carboxylic acids, thereby addressing a notable gap in the synthetic methodology. The protocol involves a sequential olefination–electrophilic functionalization process, enabling the efficient construction of diverse ketone structures with excellent functional group tolerance. Notably, the system permits late-stage modifications of complex natural products and bioactive molecules, demonstrating broad applicability. Mechanistic studies indicate the formation of key intermediates such as alkylidene titanocene and gem-bimetallic complexes.

Zhu developed a synergistic photoredox/titanium dual-catalyzed system that enables the direct dehydroxylative ring-opening Giese reaction of cyclobutanone oximes, providing efficient access to valuable distally cyano-substituted amides without requiring oxime prefunctionalization or stoichiometric phosphine reagents [104]. This mild and operationally simple protocol exhibits a broad substrate scope, excellent functional group tolerance, gram-scale applicability, and diverse applications such as late-stage functionalization of pharmaceuticals, natural product derivatives, and oligopeptides. Mechanistic studies indicate a synergistic catalytic pathway in which titanium mediates C–C bond cleavage while photoredox catalysis promotes radical generation, thereby establishing a novel strategy for transforming strained ketones into linear amide architectures with considerable synthetic value (Figure 7D).

Shu reported a direct radical C-glycosylation method that generates anomeric radicals via titanocene-catalyzed homolysis of the C−OH bond in unprotected saccharides, circumventing conventional protection/deprotection steps [110]. This streamlined strategy enables highly stereoselective coupling with activated alkenes to form C-glycosides, exhibiting broad substrate compatibility with various native monosaccharides (including L-arabinose and D-glucose anomers) as well as oligosaccharides (α-lactose, melibiose, and acarbose).

Fleischer developed a Ni-catalyzed, Lewis acid-assisted cross-electrophile coupling reaction between benzylic alcohols and thioesters for ketone synthesis, utilizing an air-stable Ni precatalyst in combination with titanocene dichloride under reductive conditions [111]. The reaction exhibits specific substrate dependencies; electron-withdrawing thiol substituents effectively suppress the formation of thioether byproducts, while electron-rich benzylic alcohols are most reactive, although benzylic chlorides display broader functional group tolerance. Mechanistic studies indicate that TMSCl mediates the in situ conversion of alcohols into reactive benzyl chlorides, which subsequently generate radicals, ruling out the involvement of silyl ether or organomanganese intermediates.

6. Nitriles and Amines

Titanium exhibits strong Lewis acidity, enabling it to coordinate with lone pair electrons on nitrogen atoms via its empty d-orbitals. It possesses a unique activation capability toward nitrogen-containing functional groups, making it indispensable in the transformation of amines and nitriles. When the titanium center, particularly in low oxidation states such as Ti^III or Ti^II, coordinates with the lone pair electrons of a nitrile group, it can polarize the C≡N triple bond, thereby significantly reducing its bond strength and enhancing the electrophilicity of the α-carbon. This activation mechanism allows otherwise inert nitriles to engage in subsequent chemical transformations. Furthermore, low-valent titanium species, such as Cp₂Ti^IIICl can function as single-electron reducing agents. Through a single-electron transfer process, they are capable of reducing nitriles to imine radical anion intermediates or initiating radical formation at adjacent carbon atoms.

Khafizova reported a novel one-pot synthetic method for the preparation of 2,3,5-substituted 1H-pyrroles via a multicomponent reaction of terminal acetylenes with nitriles and EtAlCl₂, catalyzed by Cp₂TiCl₂ in the presence of Mn [112]. This efficient approach enables direct access to valuable and structurally diverse five-membered N-heterocycles in a single preparative step under optimized reaction conditions.

Streuff described a titanocene(III)-catalyzed cyclization method for the synthesis of aminated N-heterocycles under exceptionally mild conditions [113]. This approach, combined with a simple acid/base workup, enables straightforward isolation and direct N-functionalization of these otherwise unstable, electron-rich heterocycles. The synthetic challenge stems from the inherent instability of unprotected 3-aminoindoles and -pyrroles, which are otherwise ideal building blocks for further derivatization (Figure 8A). Later, the same group reported a groundbreaking titanocene(III)-catalyzed mono-decyanation of geminal dinitriles, representing the first example of a single electron-transfer catalytic decyanation process [114]. This reaction operates under mild conditions, exhibits broad functional group tolerance and demonstrates excellent chemoselectivity. In contrast to traditional stoichiometric radical processes, mechanistic studies reveal a unique catalyst-controlled pathway involving two Ti^III species for C–CN bond cleavage without the formation of free radical intermediates, with ZnCl₂ and 2,4,6-collidine hydrochloride serving as crucial additives (Figure 8B). In 2020, Streuff reported the design and synthesis of three novel chiral titanocene complexes incorporating a readily accessible C₂-symmetric tetrahydropentalenyl ligand framework, encompassing both unsymmetrical variants and a symmetrical bis(tetrahydropentalenyl) structure [115]. Cyclic voltammetry studies revealed distinct redox behaviors; while complexes [Ti]-26 and [Ti]-28 exhibited reduction potentials similar to those of Cp₂TiCl₂, the Cp*-containing derivative [Ti]-27 displayed a negatively shifted and irreversible reduction wave, probably due to ligand lability. Preliminary catalytic evaluations demonstrated promising asymmetric induction in both ketone-nitrile cyclizations and cross-coupling reactions, with the latter transformation showing superior performance compared to the benchmark (R,R)-ebthi-TiCl₂ catalyst (Figure 8C).

Liu presented a synergistic Ni/Ti-catalyzed system that enables the direct transformation of disubstituted malononitriles into valuable quaternary organosilanes and organogermanes via catalytic C(sp³)–CN bond cleavage followed by C(sp³)–Si/Ge bond formation using chlorosilanes and chlorogermanes [116]. This earth-abundant dual catalytic strategy overcomes significant steric challenges by employing readily available malononitriles as tertiary C(sp³) coupling partners, thereby enabling unprecedented access to structurally diverse quaternary organometallic compounds that were previously difficult to synthesize. Importantly, this approach represents a rare example of catalytic C–CN activation followed by C–Si/Ge bond formation, opening new avenues for the construction of sterically congested molecular architectures.

Streuff developed robust synthetic routes to one achiral and two chiral dinuclear titanocene catalysts featuring C₃ tethers, and established their proof-of-concept application in titanocene(III)-catalyzed reactions [117]. Although these dinuclear complexes exhibited cyclization performance comparable to that of their mononuclear analogs, they did not improve cross-coupling efficiency or achieve significant asymmetric induction. This outcome suggests that enhancing enantioselectivity in Ti^III-catalyzed couplings will require strategies beyond bimetallic design. Notably, kinetic studies of ketone–nitrile couplings revealed a reduction in the catalyst order from two to one when switching from a mononuclear to a dinuclear titanocene catalyst (Figure 8D).

Li developed a versatile titanocene-catalyzed cross-coupling system that efficiently converts alkyl halides and nitriles into valuable ketones under mild conditions, thereby addressing key limitations of existing transition metal-catalyzed methods [118]. The approach features a broad substrate scope encompassing various alkyl halides and nitriles, excellent functional group compatibility, and scalability up to the gram level. Mechanistic investigations elucidated the dual function of the titanocene(III) catalyst as both a carbon radical initiator and a cyano-group activator.

Figure 8. Reactions involving nitriles catalyzed by titanocenes. (A) Titanocene-catalyzed synthesis of aminated N-heterocycles [113]; (B) Titanocene-catalyzed mono-decyanation of geminal dinitriles [114]; (C) Design and synthesis of three novel chiral titanocene complexes [115]; (D) Design and synthesis of one achiral and two chiral dinuclear titanocene catalysts [117].

Figure 8. Reactions involving nitriles catalyzed by titanocenes. (A) Titanocene-catalyzed synthesis of aminated N-heterocycles [113]; (B) Titanocene-catalyzed mono-decyanation of geminal dinitriles [114]; (C) Design and synthesis of three novel chiral titanocene complexes [115]; (D) Design and synthesis of one achiral and two chiral dinuclear titanocene catalysts [117].

Datta reported developed a highly efficient one-pot method for the chemoselective synthesis of N-arylmethyl benzimidazoles using Cp₂TiCl₂ as catalyst in THF [119]. This versatile protocol enables the condensation of diverse aldehydes with various ortho-phenylenediamines, offering significant advantages including clean reactions, fast completion, easy purification, and high product yields.

Gao developed a sustainable water-tolerant titanocene catalytic system [120]. After in situ dissociation of the cyclopentadienyl ring, Cp₂TiCl₂ coordinates with carboxylic acid ligands and alcohol solvent, forming an active half-titanocene catalyst. Remarkably, this system maintains high catalytic efficiency even with significant water content and demonstrates excellent stability through at least five operational cycles (Figure 9A). Based on this work, the same group combined the sustainable water-tolerant titanocene catalytic system with a ppm-level T-NHC-Pd catalyst in a bimetallic relay catalysis, enabling the direct synthesis of benzodiazepines from small molecules without intermediate separation [121]. In this reaction, the palladium and titanium metal catalysts exhibit no mutual interference. Gao and colleagues described a ligand modulation strategy, entailing the synthesis of N-heterocyclic compounds using identical raw materials and precatalyst while modulating various reaction conditions and ligands, which can selectively produce benzimidazole and benzodiazepine with high selectivity [122]. Specifically, 3-hydroxy-2-naphthoic acid or L-threonine form Lewis acid-Brønsted acid/base systems in conjunction with the Cp₂TiCl₂ precatalyst, thereby fine-tuning the Lewis acidity of the titanocene catalyst (Figure 9B). Gao reported a strategy for the synthesis of N-heterocycles employing Cp₂TiCl₂ as a pre-catalyst. High yields were achieved within merely 10 min [123]. When alcohol is utilized as a solvent in the reaction, the precatalyst tends to coordinate with alcohol, thereby generating the actual catalytically active species (Figure 9C). This phenomenon has also been observed and reported in prior studies by this research group [124,125].

Figure 9. Reactions involving amines catalyzed by titanocenes. (A) A sustainable water-tolerant titanocene catalytic system [120]; (B) A ligand modulation strategy for selectively produce benzimidazole and benzodiazepine [122]; (C) Titanocene-catalyzed synthesis of N-heterocycles [123].

Figure 9. Reactions involving amines catalyzed by titanocenes. (A) A sustainable water-tolerant titanocene catalytic system [120]; (B) A ligand modulation strategy for selectively produce benzimidazole and benzodiazepine [122]; (C) Titanocene-catalyzed synthesis of N-heterocycles [123].

7. Others

Other significant substrate types, in addition to those mentioned above, are discussed here.

Manners reported the first isolable early transition metal catalysts for amine–borane dehydropolymerization: the well-defined titanocene(III) complexes Cp*₂TiMe and Cp*₂TiH [126]. These catalysts demonstrate exceptional catalytic activity and an unprecedented substrate scope, enabling the successful polymerization of various primary amine-boranes, including challenging substrates bearing olefinic functionalities and aryl halides that are incompatible with late transition metal catalysts. The resulting polyaminoboranes [RNH-BH₂]_n possess tunable material properties through side-chain functionalization. Mechanistic investigations into secondary amine-borane dehydrogenation reveal a redox-neutral reaction pathway involving bond metathesis followed by β-hydride elimination, with a Ti^III-H species as the resting state, which represents a distinct mechanism compared with previously reported systems (Figure 10A).

Lamač developed an efficient hydrodehalogenation system for aliphatic organohalides by employing commercially available group 4 metal catalysts in conjunction with B(C₆F₅)₃ as an activator and Et₃SiH as a reductant [127]. Notably, metallocene-based catalysts exhibit superior selectivity due to their ability to effectively suppress undesirable Friedel–Crafts alkylation side reactions, particularly in the case of aromatic substrates such as PhCF₃. The simplicity of the catalyst system, based on readily accessible group 4 metal compounds and a borane activator, offers a practical and highly selective method for reductive dehalogenation transformations (Figure 10B).

Streuff developed an efficient titanocene(III)-catalyzed desulfonylation protocol that converts α-sulfonyl nitriles into valuable alkyl nitrile building blocks under mild conditions via a radical pathway involving Ti^III-catalyzed single-electron transfer and homolytic C–S bond cleavage [128]. This approach overcomes the limitations of traditional base-mediated methods and demonstrates excellent functional group tolerance, while also being applicable to the α-desulfonylation of ketones. The method is sustainable and features a one-pot desulfonylative alkylation protocol using acrylonitrile as a Michael acceptor (Figure 10C).

Figure 10. Other transformations catalyzed by titanocenes. (A) Titanocene-catalyzed amine-borane dehydropolymerization [126]; (B) Titanocene-catalyzed hydrodehalogenation for aliphatic organohalides [127]; (C) Titanocene-catalyzed desulfonylation for α-sulfonyl nitriles [128].

Figure 10. Other transformations catalyzed by titanocenes. (A) Titanocene-catalyzed amine-borane dehydropolymerization [126]; (B) Titanocene-catalyzed hydrodehalogenation for aliphatic organohalides [127]; (C) Titanocene-catalyzed desulfonylation for α-sulfonyl nitriles [128].

Wu reported the first general titanocene-catalyzed boration of alkyl halides using pinacolborane and catecholborane, providing efficient access to synthetically valuable alkyl boronate esters with yields up to 95% [129]. This system exhibits remarkable functional group tolerance, enabling the efficient borylation of primary, secondary, and tertiary alkyl bromides bearing reducible functionalities such as esters, alkenes, and carbamates. Notably, the titanocene catalyst effectively suppresses competing hydrodehalogenation pathways that are typically prevalent with other transition metal catalysts. The methodology extends beyond alkyl bromides to include challenging unactivated alkyl chlorides, iodides, and mesylates, and is also applicable to aryl bromides. Preliminary mechanistic studies indicate that a radical pathway is involved in this transformation.

Hanna and Asandei described a series of methylene-bridged titanium bisphenolate complexes [130]. These titanium-based complexes were examined in two polymerization processes: the controlled radical polymerization of styrene and the living ring-opening polymerization of ε-caprolactone. The ring-opening polymerization of ε-caprolactone is initiated via radical ring-opening of epoxide precursors and mediates controlled radical polymerizations through reversible endcapping of polymer radicals. These reactions are believed to be facilitated by trace water-promoted anionic-coordination and activated monomer mechanisms.

Hazari and Uehling presented a novel dual catalytic system that combines Ni and Ti catalysts to enable cross-electrophile coupling between traditionally unreactive alkyl chlorides and aryl halides [131]. The strategy exploits the distinct reactivities of the two metals: the Cp*₂TiCl₂ activates inert alkyl chlorides via single-electron reduction, generating alkyl radicals, while the Ni catalyst engages in conventional oxidative addition to activate aryl halides. The efficiency of this system depends on precisely adjusted catalyst loadings, which ensure a balance between radical generation and capture rates. Due to their lower reactivity, primary alkyl chlorides require higher concentrations of Ti, whereas less reactive aryl bromides demand greater Ni proportions compared to aryl iodides.

8. Conclusions

The field of titanocene catalysis has continued to evolve over the past few decades. Owing to the abundance of titanium resources, low toxicity, variable oxidation states (II–IV), and unique Lewis acidity, titanocene catalysts exhibit catalytic activities and have been widely utilized across a range of applications. These properties allow compatibility with sensitive functional groups such as halides and silanes, enabling novel pathways for classical transformations. Initially, titanocenes were predominantly used in olefin polymerization and stoichiometric reactions. However, their applications have since expanded into diverse areas, such as redox-involved processes and hydrofunctionalization. Additionally, their ability to mediate radical reactions and facilitate C–C bond formations has unlocked new synthetic pathways in fine chemical and pharmaceutical synthesis. Recent advances in chemical research have been particularly noteworthy across several key areas. The development of catalytic approaches to processes that were traditionally stoichiometric represents a significant breakthrough, markedly improving atom economy and minimizing waste generation. Furthermore, single-electron transfer processes mediated by titanocene complexes have introduced novel pathways in radical chemistry. Most notably, the integration of titanocene-based chemistry with emerging technologies such as photocatalysis and electrocatalysis has led to the creation of synergistic systems capable of operating under mild conditions with improved selectivity.

Despite challenges such as the empirical nature of ligand selection and the lack of systematic principles guiding catalyst design, recent breakthroughs have provided promising directions for the development of titanocene catalysis. Future research should focus on the following: (1) elucidating the quantitative relationship between catalyst structure and activity through ligand optimization and mechanistic studies; (2) developing highly regio- and stereoselective catalytic systems; (3) expanding the substrate scope to traditionally inert molecules; and (4) integrating multiple catalytic modes, such as photoredox–Ti synergies. With ongoing research and in-depth exploration, titanocene-based complexes are expected to become a significant class of catalysts in the field of green synthesis, promoting the resurgence of early transition metal catalysis, and offering synthetic chemists an efficient, environmentally friendly, and economically viable catalytic platform.

Looking ahead, titanocene catalysis holds significant potential for addressing current challenges in the field of green chemistry. By enabling more sustainable synthetic pathways, and benefiting from titanium’s natural abundance and low toxicity, it emerges as a promising alternative to traditional precious metal catalysts. As the fundamental understanding of these catalytic systems continues to expand and novel applications are developed, titanocene chemistry is expected to play an increasingly vital role in both academic research and industrial applications.