Iron-catalyzed carbene and carbene radical cascade reactions: Mechanistic study and synthetic applications

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However, these advantages generally promoted by precious metal catalysts, using inexpensive and less toxic iron complexes as catalysts is under development. Moreover, surprisingly little is known about the mechanistic aspects, in particular the structures of these intermediates. Herein, we report an iron-catalyzed cascade reaction of alkyne-tethered diazo compounds, offering an efficient approach for the synthesis of carbocyclic molecules with structural diversity and flexibility under mild conditions. Control experiments and density functional theory calculations unambiguously reveal two distinct reaction pathways catalyzed by either Fe(II) or Fe(III) porphyrin complexes, which involves carbene and carbene radical intermediates, respectively. The structure of the key vinyl iron carbene intermediate has been determined by X-ray diffraction. The synthetic utility has been demonstrated by gram-scale preparation and synthesis of poly-substituted arenes via a streamlined one-pot process. Physical sciences/Chemistry/Catalysis/Catalytic mechanisms Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Physical sciences/Chemistry/Green chemistry/Sustainability Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction The development of sustainable and eco-friendly methodologies constitutes a pivotal long-term research endeavor in synthetic chemistry 1-3 . In this context, transition metal-catalyzed carbene transfer reactions have exhibited remarkable efficacy across a broad spectrum of catalytic applications that otherwise inaccessible chemistry 4-12 . The carbene chemistry has matured into a fruitful area over the past decades 13 -18 . However, since these advantages generally rely on the use of precious metal catalysts, there persists an urgent need to explore readily available, cost-effective, and environmentally benign catalysts in light of economy and environmental concerns 19-21 . In this respect, complexes based on abundantly available iron have attracted sustained attention because of their low cost and potential for distinct and complementary models of reactivity, offering opportunities to explore diverse catalytic synthetic transformations 22-32 . Iron porphyrin complexes have a low toxicity, are easy-to-handle and inexpensive catalysts for carbene transfer reactions 33-35 . Despite the captivating benefits of introducing these iron catalysts, the scope of reaction types remains constrained, such as Csp 3 -H bond alkylation 36,37 , cyclopropanation 38-42 , and few others 43-46 . One shortcoming, which obstructs the development of iron complexes compared to other types of carbene transfer reactions, is that surprisingly little is known about the mechanistic aspects, in particular the structures of the reactive intermediates. 47 Iron porphyrin carbenes (IPCs) are generally suggested as the key intermediates in these Fe(II)/Fe(III) promoted transformations. Over the past decades, only a handful IPC intermediates have been isolated and confirmed by X-ray crystallography (Fig. 1a) 48-53 . For example, Mansuy and co-workers reported the first IPC crystal structure in 1978 48 . This pioneering discovery shed light on the following study on carbene transfer reactions. Later, Chi’s group isolated a donor-donor IPC complex [Fe(TFPP)CPh 2 ] (TFPP = tetrakis( meso -pentafluorophenyl)porphyrin), which provided solid mechanistic information for understanding cyclopropanation and C-H insertion reactions 50 . Thoroughly identifying and characterizing the authentic structure of proposed reactive intermediates is a pivotal task in carbene chemistry, which is not only indispensable for understanding the detailed reaction mechanism, but also crucial for the development of new selective synthetic methodologies 54,55 . Catalytic carbene/alkyne metathesis (CAM) has emerged as a practical method for the straightforward construction of polycyclic frameworks (Fig. 1b) 56,57 . This cascade process is initiated by formation of a metal carbene intermediate, followed by a metathesis process with the alkyne moiety to generate a hypothetic vinyl metallocarbene intermediate and finalized by a distinct carbene transfer reaction 58,59 . In these advancements, vinyl metallocarbene species, which are the proposed key intermediates derived from the CAM process, have hitherto remained a hypothetical entity and has never been isolated yet 60 . Considering the fact that the in situ formed vinyl carbene species is a prototypical donor-donor metal carbene, if it does indeed exist, we envisioned that there might be a chance to isolate and characterize this key intermediate by employing an iron porphyrin as the metal catalyst. To the best of our knowledge, no reports have been published thus far on the porphyrin iron-catalyzed CAM process, let alone the isolation or characterization of carbene intermediate derived from alkyne (Fig. 1b). It should be mentioned that isolation of reactive intermediates has historically provided a great deal of insight into the mechanisms of chemical reactions, but several challenges remains in this area 61 . For example, iron porphyrin carbenes (IPC) have been generally proposed in early studies 36-46 , but [Fe(Por)X] and [Fe(Por)] catalysts could potentially steer the reaction along distinct pathways 62-64 (Fig. 1c). According to the work of White, a stepwise radical mechanism might be involved in Csp 3 -H bond alkylation by using [FePc]Cl as the metal catalyst 62 , which is similar to the Co(II)-MRC (Co(II)-based metalloradical catalysis) system established by the groups of Zhang 63 and de Bruin 47,64,65 . Recently Zhang and co-workers suggested that also [Fe(Por)Cl] might act as a metalloradical catalyst for stereoselective olefin cyclopropanation reactions 66 . While mechanistic questions about oxidation states and spin states remain partially unanswered, control experiments pointed to the involvement of radical-type intermediates in these reactions. However, in view of recently reported high-level multiconfigurational computational studies the proposed involvement of discrete “carbene radical” intermediates in these reactions seems rather controversial, because for related Fe(II)-porphyrin complexes CASSCF calculations have shown that such carbene complexes are best regarded as classical Fischer-type carbenes (in contrast to earlier results obtained by DFT calculations pointing to carbene radical intermediates for such species) 67,68 . Remaining both puzzled and motivated by these results, we wondered if iron porphyrin complexes could facilitate the CAM process, and we were thus keen to elucidate the intricate reaction mechanism involving either [Fe III (Por)X] or [Fe II (Por)] catalysts. Herein, we report our endeavors in this direction. We developed an iron porphyrin-catalyzed cascade reaction of alkyne-tethered diazo compounds, which offers an expeditious and efficient approach for the synthesis of carbocyclic molecules with structural diversity and flexibility under mild conditions. Control experiments and density functional theory calculations reveal two distinct reaction pathways catalyzed by Fe(II) and Fe(III) complexes, which involves carbene and carbene radical intermediates, respectively (Fig. 1d). Solid evidence was obtained from the X-ray crystal structure of the key vinyl iron carbene intermediate derived via a CAM process. This study not only extends the horizon of iron-catalyzed carbene transfer reactions by formal carbene radical/alkyne metathesis processes, but also provides solid mechanistic information. The synthetic utility of these reactions is demonstrated by gram-scale preparation and synthesis of poly-substituted arenes in a streamlined one-pot process. Results Reaction development To achieve the designed cascade reaction, we began our investigation by using alkyne tethered diazo compound 1a as the model substrate. After the extensive screening of the reaction parameters (see Supplementary Table 1-6 for details), we identified the following optimal reaction conditions: 5.0 mol% Fe3 [Fe( p -OMeTPP)Cl] and 5.0 mol% NaBArF 4 in1,2-dichloroethane (DCE) at 25 ℃ under argon atmosphere for 24 h, wherein the desired carbocyclic product 2a was obtained in 80% yield (Fig. 2a, entry 1). To illustrate the impact of different parameters on the reaction outcomes, a set of reactions under conditions deviating from the optimized one have been conducted (Fig. 2a). No reaction occurred either in the absence of Fe3 or NaBArF 4 (entries 2-3), and neither FeCl 3 nor FeCl 2 was effective to initiate this reaction under otherwise identical conditions (entries 4-5). Even the Fe(II) porphyrin complex, in situ derived from a combination of Fe3 with iron powder, failed to promoted the transformation (entry 6), however, after a brief optimization of the reaction temperature and solvent using in situ formed Fe(II) catalyst (see Supplementary Table 7 for details), the product 2a was furnished in 51% yield (entry 7). Subsequently, a variety of Fe(III) porphyrin complexes (entries 8-11) and other metal porphyrin catalysts were evaluated (entries 12-14). In general, iron complex contains electronic-rich porphyrin system showed higher efficiency, leading to product 2a with compatible high yields (entry 1 vs 9), and only attenuated results were obtained in other cases in term of yield (Fig. 2b). Substrate scope With the optimal reaction conditions established, we started to evaluate the substrate scope of this iron porphyrin-catalyzed cascade transformation (Fig. 3a). Substrates with aromatic rings containing electron-neutral, electron-donating, and electron-withdrawing groups on different positions all reacted smoothly to give the corresponding products 2a - 2k in generally good to high yields. Moderate yield was observed for the ortho-substituted one, which might be due to the steric effect. Moreover, 1-naphthyl, 3-thienyl, and alkyl groups were also found to be compatible, the reaction with these materials performed well, achieving the products 2l - 2n in 55-70% yields. The substitutions on the aromatic ring tethered to the olefinic part have little influence on the reaction efficiency, all the tested materials were successfully transformed into the desired products in >72% yields. The structure of the product 2g was determined by X-ray crystallography, and the other products were tentatively assigned by analogy. Furthermore, this Fe(III)-catalyzed cascade reaction could be extend to the benzyl Csp 3 -H bond alkylation by replacing the terminating allylic Csp 3 -H unit with a benzyl Csp 3 -H motif. After a brief optimization (see Supplementary Table 8-12 for details), substrate 3a could be successfully converted to product 4a in 82% yield using the same Fe3 catalyst at elevated temperature (90 o C) in DCE. Notably, only slowly decomposition of diazo compounds was observed when this reaction was conducted in the absence of iron catalyst Fe3 , which ruled out the possibility of thermal condition initiated free carbene transformation. Under the optimized conditions, we next evaluated the generality of this benzyl Csp 3 -H bond alkylation reaction (Fig. 3b). In general, diazo compounds containing a variety of substitutions on the two tethering aromatic rings, including methyl, methoxy, fluoro, chloro, bromo, and naphthyl, exert a negligible effect on the reaction’s progress, all affording the desired products 4a - 4q in good to high yield (64-89% yield). The structure of the product 4h was determined by X-ray crystallography, and the other products were tentatively assigned by analogy. Synthetic applications To demonstrate the synthetic utility of the current method, the scale-up experiments were first conducted. Products 2a and 4a were obtained in 72% and 77% yields, respectively (Fig. 4a, 2.0 mmol scale). Given that the polysubstituted aromatic structure represents a key motif in natural products and bioactive molecules 69,70 , an oxidative aromatization process of these resulting carbocyclic products has been established under mild conditions using DDQ as oxidant, leading to isobenzofuranones 5 and 6 in 86-95% yields (Fig. 4b). The structures of the products 5f and 6f was determined by X-ray crystallography, and the other products were tentatively assigned by analogy. Moreover, these aromatization products could be obtained directly from the corresponding diazo compounds through a one-pot operation in good yields (Fig. 4c). Mechanistic studies To shed light on the mechanism of iron-catalyzed cascade reactions, we undertook a set of control experiments (Fig. 5). Initially, the model reaction of 1a was conducted in the presence of the radical trap TEMPO (5 equiv.), trying to probe the carbene or carbene radical intermediates in this reaction (Fig. 5a) 62,63 . Notably, no desired product 2a was observed when the reaction was catalyzed by Fe(III) porphyrin complex Fe3 ; whereas, under the combination of Fe5 and Fe powder catalysis conditions, 2a was formed in 53% yield. These results suggest that both Fe(III) and Fe(II) porphyrin complexes can catalyze the reaction, and that they follow different reaction pathways. Competitive intermolecular cyclopropanation reactions were investigated. However, above used substrates ( 1a - 1q and 3a-3q ) only led to the corresponding intramolecular cyclization products 2 and 4 , rather than generating the cyclopropanation product with external alkenes. Thus, the equivalent cyclopropanation reactions of diazo compounds 3r without alkyne motif and 3s containing an ortho -substitution steric hindrance were performed (Fig. 5b and 5c). In the reaction of 3r with ( Z )-akene 7 , cyclopropane product 8 with both cis - and trans - diastereoisomers was furnished (see Supplementary Figure 1 and 2 for details) when the reaction was catalyzed by Fe3 (Fig. 5b) 66 . Moreover, the Fe3 -catalyzed reaction of 3s with p -trifluoromethyl styrene or p -methoxy styrene, two alkenes with different electronic properties, gave the corresponding cyclopropanation products 9a and 9b in comparable yields. However, a much lower yield was obtained with p -trifluoromethyl styrene when the reaction was promoted by the Fe(II) system (Fig. 5c, 9a = 8% vs 9b = 37%). These divergent reaction outcomes suggest different reaction pathways, perhaps indicating a radical pathway for the iron(III) system. In the absence of iron catalyst, majority of the diazo compounds remain intact in all these tested reactions, which ruled out the influence of thermal-induced free carbene transformations. Given the fact that Fe(II) porphyrin carbene species might be stable enough for isolation, efforts have been directed towards observing and characterizing the key intermediates involved in this iron carbene cascade transformation. To our delight, when substrate 1a was treated with 1 equivalent of Fe5 and 2 equivalent Fe powder in DCM and MeOH (9:1) mixed solvent at 25 o C under argon atmosphere, the iron carbene intermediate Int II a was formed in 58% yield, which could convert to the final product 2a in 87% yield upon heated at 70 o C for 6 h (Fig. 5d). This combination system of Fe(II) catalysis also work well for the carbene/alkyne metathesis reaction, delivering the carbocyclic products 2 in synthetic useful yields (Fig. 5e). The isolated key iron carbene intermediate Int II a was confirmed by 1 H NMR, 13 C NMR 53 , and X-ray crystallography analysis (Fig. 5f and 5g), which is the first identified vinyl metallocarbene intermediate derived from a CAM process. To shine more light on the divergent mechanisms, density functional theory (DFT) calculations were conducted to further elucidated the details of both the Fe(III) and Fe(II) porphyrin catalyzed pathways (Fig. 6). The DFT investigations were performed at the /B3-LYP/SDD// OPBE/def2TZVP/ level of theory on unsubstituted model systems (R = H) starting at with the carbene species assuming that their formation was readily established. For the Fe(II) reaction pathway the electronic structure of the donor-acceptor carbene species I’ shows the typical pseudo-octahedral d 6 configuration of an ML 5 -Fe(II) low-spin complex without unpaired electrons (Fig. 6a). Decreasing the distance between C 2 and (carbene)-C 5 leads to formation of the 5 membered furanone ring with an activation barrier ΔG ‡ of modest 22.3 kcal/mol ( TS1’ , C 2 -C 5 =1.740 Å). Upon ring formation, the iron-C 5 bond is broken and the newly formed carbene function at C 1 coordinates to the iron-moiety without any intermediate to form the donor-donor vinyl carbene intermediate II ’, which is exergonic by -59.2 kcal /mol with respect to I’ . Formation of the six membered-ring may occur by a concerted C-H insertion of the C 1 carbene into the C 8 -H bond via a triangular transition structure TS2’ revealing a C 1 -C 8 bond distance of 2.141 Å (C 1 -H= 1.177 Å, C 8 -H= 1.460 Å). This pathway shows a high energy barrier of ΔG ‡ = +36.9 kcal/mol, which seems not viable under the current reaction conditions. Alternatively, the formal C-H insertion may proceed in a stepwise manner. First, a 1-6 Hydrogen atom transfer (HAT) takes place with a moderate barrier of ΔG ‡ = +27.3 kcal/mol for TS3’ , which shows an almost linear geometry depicting a C 1 -C 8 bond distance of 2.614 Å with the H -atom in between (C 1 -H= 1.344 Å, C 8 -H= 1.349 Å). Interestingly, the geometry of TS3’ resembles a structure with some biradical character at the B3-LYP/SDD level. However, the OPBE/def2TZVP single point calculations resulted exclusively in the closed shell solution and hence we resorted to CASSCF (8,10) calculations, which confirmed an increased multireference character (b=40%) compared to the carbene precursor (b=12%). The significant biradical contribution to TS3’ is points to a hydrogen atom transfer (HAT) process, but a hydride transfer process with some HAT character is also legible. Upon C 1 -H bond formation, the carbon-iron bond is released while the trans -hexatriene III’ is formed. This process is slightly endergonic by ΔG° = 11.0 kcal/mol with respect to the open shell singlet Fe(II) porphyrin, which may relax to its triplet ground state and re-enter the catalytic cycle while the six membered ring of the substrate is easily formed by disrotatory ring closure of the 6-electron system via TS4’ with a low barrier of ΔG ‡ = 16.8 kcal/mol (Fig. 6a). As for the reaction sequence of the Fe(III) porphyrin (without reduction by Fe powder, Fig. 6b), based on the neglectable multi-refence character of the CASSCF (5,10 def2-TZVP, b=1%) results, carbene I can be described as a traditional Fischer-type carbene complex with a formal Fe(III) centre containing a single unpaired metal-d electron. Formation of the 5-membered furanone ring proceeds very similar to the Fe(II) system by decreasing the C5-C2 distance ( TS1 , C 2 -C 5 =2.019 Å), giving rise to a modest activation barrier ΔG ‡ = 21.8 kcal/mol to form donor-donor vinyl Fe(III) carbene II (ΔG° = -60.5). Interestingly, based on the (7.8)-CASSCF calculations the electronic structure of carbene II is very different from carbene I and clearly bears a ligand radical. It is best viewed as a delocalized “carbene radical complex” with the single electron delocalized over the carbene ligand p-system, with non-negligible p-overlap between the carbene p-orbital at C5 with a d p -type orbital (d xz or d yz ) at the formal Fe(IV)-center in an antiferromagnetic coupling arrangement, giving rise to the overall doublet state (Fig. 6c). Obviously, the p-donor Cl - -substituent pushes the d xz orbital up in energy resulting in a better interaction with the carbene p-system. Concerted C-H insertion of the C 1 carbene into the C 8 -H bond to form the six membered ring through triangular transition structure TS2 has an activation barrier of ΔG ‡ = +27.4 kcal/mol, which is quite a bit lower than the barrier for the Fe(II) case. However, the stepwise mechanism has an even lower barrier ( TS3 , ΔG ‡ = 22.3 kcal/mol) for the 1-6 hydrogen transfer, which shows a similar multireference contribution (derived from (7.8)-CASSCF calculations; b=42%) as was observed for the reduced TS3’ . Ring closure of the six membered ring is of course identical to the reduced system (Fig. 6a). From the theoretical point of view, both systems, the Fe(III)-porphyrin as well as the reduced Fe(II) form, show very similar reactivity. This holds for the formation of the 5-membered furanone ring in addition to the C-H insertion by a preferred stepwise mechanism. Surprisingly, the ground state of the Fe(III) ring carbene compound II is almost 100% a Fe(IV)-carbene radical (delocalized). In the TS3 that follows, the HAT has apparently already progressed quite strongly (late TS) so that the radical character on the organic fragment is considerably disappearing and iron has largely been reduced back to Fe(III) in that transition state. The Fe(II) variant TS3’ appears to have a similar multireference character as the Fe(III) variant TS3 (Fig. 6d), but the initial situation is different for Fe(II). Whereas carbene complex II is best described as a nearly 100% Fe(IV)-carbene radical complex, the Fe(II) carbene analog II’ surprisingly has hardly any multireference character and is best describe as a classical Fischer-type carbene complex of Fe(II). This may well be the cause of the higher TS3’ DFT barrier for Fe(II) compared to Fe(III). Anyhow, the CASSCF results of both transition states TS3’ and TS3 , so Fe(II) as well as Fe(III), show quite some multireference character which might explain that not only in the Fe(III) case some radical character is imposed on the carbene-carbon, but also for the Fe(II) in the form of the open shell singlet electronic structure of TS3’ , resulting in similar reactivity for both oxidation states of iron. Conclusions In conclusion, we have developed an iron porphyrin-catalyzed cascade reaction that terminated by benzylic and allylic Csp 3 -H bond functionalization, providing an expeditious and efficient protocol for the synthesis of carbocyclic molecules with structural diversity and flexibility under mild conditions. Control experiments and density functional theory calculations unambiguously reveal two distinct reaction pathways catalyzed by Fe(II) and Fe(III) complexes. Interestingly, and counterintuitively, CASSCF data revealed that the conjugated carbene complex II is best described as a delocalized Fe(IV)-carbene radical complex with an antiferromagnetic coupling between the ligand and Fe-centered unpaired electrons, while the Fe(II) analog II’ is best described as a classical Fischer-type carbene complex of Fe(II). The gram-scale preparation and synthesis of poly-substituted arenes, achieved either via oxidation of the resulting products or through a streamlined one-pot process, have further augmented the synthetic utility and value. This study not only extended the horizon of iron-catalyzed carbene transfer reactions by encompassing formal carbene/alkyne metathesis process, but also provides solid evidence on the mechanistic aspects. Notably, the key donor-donor type vinyl iron carbene intermediate has been isolated and characterized by X-ray crystallography analysis for the first time. With these detailed mechanistic insights, novel iron-promoted carbene transfer reactions can be envisioned in the foreseeable future. Methods General procedure for the formal allylic Csp 3 -H bond insertion reaction To a 10-mL oven-dried vial equipped with a magnetic stir bar, was charged with [Fe( p -OMeTPP)Cl] ( Fe3 , 5 mol%, 4.1 mg) and NaBArF 4 (5 mol%, 4.4 mg) in glovebox. Then, the vial was capped and took out from the glovebox, and DCE (0.5 mL) was injected into vial under argon atmosphere. The resulting reaction mixture was stirred at 25 ℃ for 0.5 h. A solution of diazo compound 1 (0.1 mmol) in DCE (1.0 mL) was added into the reaction vessel through syringe in 3.5 h, then the new mixture was stirred under these conditions for 20 h. After the reaction was completed, the reaction mixture was purified directly by column chromatography on silica gel without any additional treatment (eluent: PE: EA = 10:1 to 6:1) to afford the corresponding products 2 . General procedure for the formal benzyl Csp 3 -H bond insertion reaction To a 10-mL vial equipped with a magnetic stir bar, was charged with [Fe( p -OMeTPP)Cl] ( Fe3 , 10 mol%, 8.2 mg) and 4Å MS (100 mg). Then, the capped vial was evacuated and back-filled with argon (3 times). A solution of diazo compound 3 (0.1 mmol) in DCE (2.0 mL) was added into the reaction vessel in one-time and the reaction mixture was stirred at 90 ℃ for 12 h. After the reaction was completed, the reaction mixture was purified directly by column chromatography on silica gel without any additional treatment (eluent: PE: EA = 10:1 to 5:1) to afford the corresponding products 4 . Declarations Data availability The data supporting the findings of this study are available within the paper and its Supplementary Information or from the corresponding author upon request. The X-ray crystallographic coordinates for structures 2g , 4h , 5f , 6f , and Int IIa reported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC). These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif. Acknowledgments The work was supported by the National Natural Science Foundation of China (22371309) and the Guangdong Basic and Applied Basic Research Foundation (2024B1515040025). Author contributions X.Z. and X.X. devised the project. X.Z., M.Y., K.C., and Y.W. synthesized and characterized all products. X.Z. and Y.W. both got the crystal and collected the X-ray crystallographic data for Int IIa . A.E. and B.B. performed the computational work. X.X supervised the project and drafted the manuscript. X.Z., A.E., B.B., and X.X. revised the manuscript. Competing interests The authors declare no competing interests. Additional information Correspondence and requests for materials should be addressed to Bas de Bruin or Xinfang Xu. References Kar, S., Sanderson, H., Roy, K., Benfenati, E. & Leszczynski, J. Green chemistry in the synthesis of pharmaceuticals. Chem. Rev. 122 , 3637–3710 (2022). Guillemard, L., Kaplaneris, N., Ackermann, L. & Johansson, M. J. Late-stage C-H functionalization offers new opportunities in drug discovery. Nat. Rev. Chem. 5 , 522–545 (2021). Grover, J., Prakash, G., Goswami N. & Maiti, D. Traditional and sustainable approaches for the construction of C-C bonds by harnessing C-H arylation. Nat. Commun. 13 , 1085 (2022). Bergstrom, B. D., Nickerson, L. A., Shaw, J. T. & Souza, L. W. Transition metal catalyzed insertion reactions with donor/donor carbenes. Angew. Chem. Int. Ed. 60 , 6864–6878 (2021). Liu, Z. H., Sivaguru, P., Zanoni, G. & Bi, X. H. N -Triftosylhydrazones: a new chapter for diazo-based carbene chemistry. Acc. Chem. Res. 55 , 1763–1781 (2022). Xia, Y., Qiu, D. & Wang, J. B. Transition-metal-catalyzed cross-couplings through carbene migratory insertion. Chem. Rev. 117 , 13810–13889 (2017). Ye, L. W. et al. Nitrene transfer and carbene transfer in gold catalysis. Chem. Rev. 121 , 9039–9112 (2021). Cheng, Q. Q., Deng, Y. M., Lankelma, M. & Doyle, M. P. Cycloaddition reactions of enoldiazo compounds. Chem. Soc. Rev. 46 , 5425–5443 (2017). Davies, H. M. L. & Manning, J. R. Catalytic C-H functionalization by metal carbenoid and nitrenoid insertion. Nature 451 , 417–424 (2008). Yao, M. H., Dong, S. L. & Xu, X. F. Asymmetric carbene transformations for the construction of all-carbon quaternary centers. Chem. Eur. J. 30 , e202304299 (2024). Wang, T. & Hashmi, A. S. K. 1,2-Migrations onto gold carbene centers. Chem. Rev. 121 , 8948–8978 (2021). Ford, A. et al. Modern organic synthesis with α-diazocarbonyl compounds. Chem. Rev. 115 , 9981–10080 (2015). Candeias, N. R., Paterna, R. & Gois, P. M. P. Homologation reaction of ketones with diazo compounds. Chem. Rev. 116 , 2937–2981 (2016). Cho, H. J. & Kim, J. H. Accessing functionalized furans from reacting enynones and enynals through furyl metal carbenes. Asian J. Org. Chem. 13 , e202300616 (2024). Empel, C., Pham, Q. H. & Koenigs, R. M. Spin states matter-from fundamentals toward synthetic methodology development and drug discovery. Acc. Chem. Res. 57 , 2717–2727 (2024). Zhao, X. M., Rudolph, M., Asiri, A. M. & Hashmi, A. S. K. Easy access to pharmaceutically relevant heterocycles by catalytic reactions involving α-imino gold carbene intermediates. Front. Chem. Sci. Eng. 14 , 317–349 (2020) Mato, M., García-Morales, C. & Echavarren, A. M. Generation of gold(I) carbenes by retro-buchner reaction: from cyclopropanes to natural products synthesis. ChemCatChem 11 , 53–72 (2019). Liu, S. P. et al. Tunable molecular editing of indoles with fluoroalkyl carbenes. Nat. Chem. 16 , 988–997 (2024). Jazzar, R., Soleilhavoup, M. & Bertrand, G. Cyclic (alkyl)- and (aryl)-(amino)carbene coinage metal complexes and their applications. Chem. Rev. 120 , 4141–4168 (2020). Liu, Z. & Arnold, F. H. New-to-nature chemistry from old protein machinery: carbene and nitrene transferases. Curr. Opin. Biotechnol. 69 , 43–51, (2021). Muñoz-Molina, J. M., Belderrain, T. R. & Pérez, P. J. Group 11 tris(pyrazolyl)methane complexes: structural features and catalytic applications. Dalton. Trans. 48 , 10772–10781 (2019). Enthaler, S., Junge, K. & Beller, M. Sustainable metal catalysis with iron: From rust to a rising star? Angew. Chem. Int. Ed. 47 , 3317–3321 (2008). Bolm, C., Legros, J., Le Paih, J. & Zani, L. Iron-catalyzed reactions in organic synthesis. Chem. Rev. 104 , 6217–6254 (2004). Bauer, I. & Knölker, H.J. Iron catalysis in organic synthesis. Chem. Rev. 115 , 3170–3387 (2015). Wei, D. & Darcel, C. Iron catalysis in reduction and hydrometalation reactions. Chem. Rev. 119 , 2550–2610 (2019). Chen, M.S. & White, M.C. A predictably selective aliphatic C-H oxidation reaction for complex molecule synthesis. Science 318 , 783–787 (2007). Hennessy, E.T. & Betley, T.A. Complex N-heterocycle synthesis via iron-catalyzed, direct C-H bond amination. Science 340 , 591–595 (2013). Cheng, L. et al. Iron-catalyzed arene C-H hydroxylation. Science 374 , 77–81 (2021). Liu, L. et al. General method for iron-catalyzed multicomponent radical cascades-cross-couplings. Science 374 , 432–439 (2021). Gan, X.C. et al. Carbon quaternization of redox active esters and olefins by decarboxylative coupling. Science 384 , 113–118 (2024). Kaur, P. & Tyagi, V. Recent advances in iron-catalyzed chemical and enzymatic carbene-transfer reactions. Adv. Synth. Catal. 363 , 877–905 (2021). Damiano, C., Sonzini, P. & Gallo, E. Iron catalysts with N-ligands for carbene transfer of diazo reagents. Chem. Soc. Rev. 49 , 4867–4905 (2020). Zhu, S.F. & Zhou, Q.L. Iron-catalyzed transformations of diazo compounds. Natl. Sci. Rev. 1 , 580–603 (2014). Batista, V.F., Pinto, D. & Silva, A.M.S. Iron: a worthy contender in metal carbene chemistry. ACS Catal. 10 , 10096–10116 (2020). Lewis, R.D. et al. Catalytic iron-carbene intermediate revealed in a cytochrome c carbene transferase. PNAS 115 , 7308–7313 (2018). Mbuvi, H. M., Klobukowski, E. R., Roberts, G. M. & Woo, L. K. O-H insertion and tandem N-H insertion/cyclization reactions using an iron porphyrin as catalyst with diazo compounds as carbene sources. J. Porphyr. Phthalocya. 14 , 284–292 (2010). Aviv, I. & Gross, Z. Iron(III) corroles and porphyrins as superior catalysts for the reactions of diazoacetates with nitrogen- or sulfur-containing nucleophilic substrates: Synthetic uses and mechanistic insights. Chem. Eur. J. 14 , 3995–4005 (2008). Wolf, J. R., Hamaker, C. G., Djukic, J. P., Kodadek, T. & Woo, L. K. Shape and stereoselective cyclopropanation of alkenes catalyzed by iron porphyrins. J. Am. Chem. Soc. 117 , 9194–9199 (1995). Aggarwal, V.K., de Vicente, J. & Bonnert, R.V. Catalytic cyclopropanation of alkenes using diazo compounds generated in situ. A novel route to 2-arylcyclopropylamines. Org. Lett. 3 , 2785–2788 (2001). Nicolas, I., Le Maux, P. & Simonneaux, G. Synthesis of chiral water-soluble metalloporphyrins (Fe, Ru,): new catalysts for asymmetric carbene transfer in water. Tetrahedron Lett. 49 , 5793–5795 (2008). Carminati, D.M. et al. Designing 'totem' C 2 -symmetrical iron porphyrin catalysts for stereoselective cyclopropanations. Chem. Eur. J. 22 , 13599–13612 (2016). Bartels, K., Schinor, B. & Haufe, G. Diastereoselectivity of cyclopropanation of substituted α-fluorostyrenes versus styrenes by different methods. J. Fluorine Chem. 203 , 200–205 (2017). Chen, Y., Huang, L. Y. & Zhang, X. P. Acid-promoted olefination of ketones by an iron(III) porphyrin complex. Org. Lett. 5 , 2493–2496 (2003). Baumann, L.K., Mbuvi, H.M., Du, G. & Woo, L.K. Iron porphyrin catalyzed N-H insertion reactions with ethyl diazoacetate. Organometallics 26 , 3995–4002 (2007). Liu, C. R. et al. Highly diastereroselective synthesis of dihydrofurans and dihydropyrroles via pyridine catalyzed formal 4 + 1 annulation. Chem. Commun. 47 , 1342–1344 (2011). Day, J., McKeever-Abbas, B. & Dowden, J. Stereoselective synthesis of tetrahydroindolizines through the catalytic formation of pyridinium ylides from diazo compounds. Angew. Chem. Int. Ed. 55 , 5809–5813 (2016). Epping, R. F. J., Vesseur, D., Zhou, M. H. & de Bruin, B. Carbene radicals in transition-metal-catalyzed reactions. ACS Catal. 13 , 5428–5448 (2023). Mansuy, D. et al. Dichlorocarbene complexes of iron(II)-porphyrins-crystal and molecular structure of Fe(TPP)(CCl 2 )(H 2 O). Angew. Chem. Int. Ed. 17 , 781–782 (1978). Collman, J. P., Rose, E. & Venburg, G. D. Reactivity of ruthenium 5,10,15,20-tetramesitylporphyrin towards diazoesters: formation of olefins. J. Chem. Soc., Chem. Commun. 934–935 (1993). Li, Y., Huang, J. S., Zhou, Z. Y., Che, C. M. & You, X. Z. Remarkably stable iron porphyrins bearing nonheteroatom-stabilized carbene or (alkoxycarbonyl) carbenes: Isolation, X-ray crystal structures, and carbon atom transfer reactions with hydrocarbons. J. Am. Chem. Soc. 124 , 13185–13193 (2002). Lu, H. J. et al. Experimental evidence for cobalt(III)-carbene radicals: key intermediates in cobalt(II)-based metalloradical cyclopropanation. J. Am. Chem. Soc. 133 , 8518–8521 (2011). Ma, C. Q. et al. Synthesis and characterization of donor-acceptor iron porphyrin carbenes and their reactivities in N-H insertion and related three-component reaction. J. Am. Chem. Soc. 145 , 4934–4939 (2023). Kornecki, K. P. et al. Direct spectroscopic characterization of a transitory dirhodium donor-acceptor carbene complex. Science 342 , 351–354 (2013). Hu, C. P., Wang, X. F., Li, J. C., Chang, X. Y. & Liu, L. L. A stable rhodium-coordinated carbene with a σ 0 π 2 electronic configuration. Science 383 , 81–85 (2024). Benitez, D. et al. A bonding model for gold(I) carbene complexes. Nat. Chem. 1 , 482–486 (2009). Torres, O. & Pla-Quintana, A. The rich reactivity of transition metal carbenes with alkynes. Tetrahedron Lett. 57 , 3881–3891 (2016). Pei, C., Zhang, C., Qian, Y. & Xu, X. F. Catalytic carbene/alkyne metathesis (CAM): a versatile strategy for alkyne bifunctionalization. Org. Biomol. Chem. 16 , 8677–8685 (2018). Hong, K. M. et al. Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications. Nat. Commun. 14 , 6378 (2023). Zhang, C. et al. Generation and utility of cyclic dienyl gold carbene intermediates. ACS Catal. 13 , 4646–4655 (2023). Zhang, C. et al. Gold(I)-catalyzed intramolecular cyclization/intermolecular cycloaddition cascade as a fast track to polycarbocycles and mechanistic insights. Nat. Commun. 12 , 1182 (2021). Caballero, A. & Pérez, P. J. Dimensioning the term carbenoid. Chem. Eur. J. 23 , 14389–14393 (2017). Griffin, J. R., Wendell, C. I., Garwin, J. A. & White, M. C. Catalytic C(sp 3 )-H alkylation via an iron carbene intermediate. J. Am. Chem. Soc. 139 , 13624–13627 (2017). Cui, X., Xu, X., Jin, L. M., Wojtas, L. & Zhang, X. P. Stereoselective radical C-H alkylation with acceptor/acceptor-substituted diazo reagents via Co(II)-based metalloradical catalysis. Chem. Sci. 6 , 1219–1224 (2015). Epping, R. F. J., Hoeksma, M. M., Bobylev, E. O., Mathew, S. & de Bruin, B. Cobalt(II)–tetraphenylporphyrin-catalyzed carbene transfer from acceptor-acceptor iodonium ylides via N-enolate carbene radicals. Nat. Chem. 14 , 550–557 (2022). Zhou, M., Wolzak, L. A., Li, Z., de Zwart, F. J., Mathew, S. & de Bruin, B. Catalytic synthesis of 1 H -2-benzoxocins; Cobalt(III)-carbene radical approach to 8-membered heterocyclic enol ethers. J. Am. Chem. Soc. 143 , 20501–20512 (2021). Lee, W. C. C., Wang, D. S., Zhu, Y. L. & Zhang, X. P. Iron(III)-based metalloradical catalysis for asymmetric cyclopropanation via a stepwise radical mechanism. Nat. Chem. 15, 1569–1580 (2023). Sharon, D. A., Mallick, D., Wang, B. & Shaik, S. Computation Sheds Insight into Iron Porphyrin Carbenes’ Electronic Structure, Formation, and N-H Insertion Reactivity. J. Am. Chem. Soc. 138 , 9597–9610 (2016). Gräfenstein, J. & Cremer, D. Can Density Functional Theory Describe Multi-Reference Systems? Investigation of Carbenes and Organic Biradicals. Phys. Chem. Chem. Phys. 2 , 2091–2103 (2000). Nilova, A., Campeau, L. C., Sherer, E. C. & Stuart, D. R. Analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients. J. Med. Chem. 63 , 13389–13396 (2020). Subbaiah, M. A. M. & Meanwell, N. A. Bioisosteres of the phenyl ring: recent strategic applications in lead optimization and drug design. J. Med. Chem. 64 , 14046–14128 (2021). Additional Declarations There is NO Competing Interest. Supplementary Files checkcif2g.pdf checkcif_2g checkcif4h.pdf checkcif_4h checkcif5f.pdf checkcif_5f checkcif6f.pdf checkcif_6f 2g.txt 2g.cif 4h.txt 4h.cif 5f.txt 5f.cif 6f.txt 6f.cif IntIIa.txt Int IIa.cif SupplementaryInformation.pdf Supplementary Information checkcifIntIIa.pdf checkcif_Int IIa Cite Share Download PDF Status: Published Journal Publication published 20 Feb, 2026 Read the published version in Nature Catalysis → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5669760","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":408602001,"identity":"5062ca35-5c19-46e6-88f7-3b4e31ef61b0","order_by":0,"name":"Xinfang Xu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7ElEQVRIie3OMQrCMBSA4SeFukRdUwR7hRZX8R5uLxQ6iQiCCA4WCrp4gIqDV9AbtATsIs4FJxF0Vbo4GovoFjMK5ockBN5HAqDT/WgxtMReDt5XFeKLncSvaRUCBaGoSJys6/I+tnt253LKb1NoVDMs5X0JsSIfeYTewD2gT5MpNK0MjXokITXqxbxyN9hmiVsQhK0zNA0iISZlASc4YZtFEl4FmXwlxSsEOVtRA54fQ+cbseZnFCRla+KbdLen7mJ3DOsy4qTdZk5wzFaz9HQdDVt2NfWSXEY+Ni4OKlYpUAEAtuKcTqfT/WEPvZRQnSBCv1YAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0002-8706-5151","institution":"Zhejiang Sci-Tech University","correspondingAuthor":true,"prefix":"","firstName":"Xinfang","middleName":"","lastName":"Xu","suffix":""},{"id":408602002,"identity":"407eb4d5-a60f-402b-b9bf-9438a0bbeaac","order_by":1,"name":"Xinke Zhang","email":"","orcid":"","institution":"Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Xinke","middleName":"","lastName":"Zhang","suffix":""},{"id":408602003,"identity":"2521558d-5dcc-4ee5-a475-ea5f63abf220","order_by":2,"name":"Minghan Yao","email":"","orcid":"","institution":"Sun Yat-Sen University","correspondingAuthor":false,"prefix":"","firstName":"Minghan","middleName":"","lastName":"Yao","suffix":""},{"id":408602004,"identity":"9c96f2df-8146-4e0b-b149-46beaaddab3b","order_by":3,"name":"Kewei Chen","email":"","orcid":"","institution":"Zhejiang Sci-Tech University","correspondingAuthor":false,"prefix":"","firstName":"Kewei","middleName":"","lastName":"Chen","suffix":""},{"id":408602005,"identity":"675894f7-ffca-4883-a4a8-3f8d75a5a995","order_by":4,"name":"Yuecheng Weng","email":"","orcid":"","institution":"Zhejiang Sci-Tech University","correspondingAuthor":false,"prefix":"","firstName":"Yuecheng","middleName":"","lastName":"Weng","suffix":""},{"id":408602006,"identity":"91effd33-8afc-4308-b5e9-2b381a7f339d","order_by":5,"name":"Andreas Ehlers","email":"","orcid":"","institution":"University of Amsterdam","correspondingAuthor":false,"prefix":"","firstName":"Andreas","middleName":"","lastName":"Ehlers","suffix":""},{"id":408602007,"identity":"7bc0e950-6524-43c7-b491-c896bcade4bb","order_by":6,"name":"Bas de Bruin","email":"","orcid":"https://orcid.org/0000-0002-3482-7669","institution":"Universiteit van Amsterdam","correspondingAuthor":false,"prefix":"","firstName":"Bas","middleName":"","lastName":"de Bruin","suffix":""}],"badges":[],"createdAt":"2024-12-18 13:10:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5669760/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5669760/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41929-026-01496-w","type":"published","date":"2026-02-20T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":75066154,"identity":"675dde9d-8ddc-40f8-a8a9-5a8d10305ea9","added_by":"auto","created_at":"2025-01-30 05:40:49","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":156595,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMetal carbene complexes and iron-catalyzed carbene/carbene radical reactions. a\u003c/strong\u003e, X-ray crystal structures of reported metal carbene intermediates.\u003cstrong\u003e b\u003c/strong\u003e, Metal carbene/alkyne metathesis (CAM) reactions. \u003cstrong\u003ec\u003c/strong\u003e, Iron carbene \u003cem\u003evs\u003c/em\u003e iron carbene radical reactions. \u003cstrong\u003ed\u003c/strong\u003e, This work: [Fe(Por)]-catalyzed CAM cascade reaction and [Fe(Por)Cl]-promoted carbene and carbene radical relay.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/49fec850efbcbd85f0f64754.png"},{"id":75066147,"identity":"beca1724-6579-4531-9e9d-1973ef1a8e82","added_by":"auto","created_at":"2025-01-30 05:40:49","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":77425,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReaction condition assessment. a\u003c/strong\u003e, The results of deviation from standard conditions are presented. Optimal reaction conditions: diazo compound \u003cstrong\u003e1a\u003c/strong\u003e (0.1 mmol), catalysts (5.0 mol%) and NaBArF\u003csup\u003e4\u003c/sup\u003e (5.0 mol%) in 1.0 mL DCE at 25 °C for 24 h. \u003csup\u003ea\u003c/sup\u003eYields are given in isolated yields; \u003csup\u003eb\u003c/sup\u003e\u003cstrong\u003eFe3\u003c/strong\u003e (5.0 mol%) + Fe powder (10 mol%) \u003csup\u003ec\u003c/sup\u003eThe reaction conducted at 70 °C in DCM and MeOH (9:1) mixed solvent for 6 h. \u003cstrong\u003eb\u003c/strong\u003e, The structure of used catalysts and additive.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/6e9bcc1c9994ad5654c28deb.png"},{"id":75067288,"identity":"1ed23ae9-28f6-463e-b215-6db26fb32619","added_by":"auto","created_at":"2025-01-30 06:04:49","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":122207,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope\u003c/strong\u003e. For allylic Csp\u003csup\u003e3\u003c/sup\u003e-H bond insertion conditions: a solution of styryl diazoacetate\u003cstrong\u003e 1\u003c/strong\u003e (0.1 mmol) in 1.0 mL DCE was added to a mixture of [Fe(\u003cem\u003ep\u003c/em\u003e-OMeTPP)Cl] (\u003cstrong\u003eFe3\u003c/strong\u003e, 5.0 mol%, 4.1 mg) and NaBArF\u003csup\u003e4\u003c/sup\u003e (5.0 mol%, 4.4 mg) in DCE (0.5 mL) under an argon atmosphere at 25 \u003csup\u003eo\u003c/sup\u003eC in 3.5 h, and the resulting mixture is stirring for additional 20 h; For benzyl Csp\u003csup\u003e3\u003c/sup\u003e-H bond insertion conditions: diazoacetate\u003cstrong\u003e 3\u003c/strong\u003e (0.1 mmol), [Fe(\u003cem\u003ep\u003c/em\u003e-OMeTPP)Cl] (\u003cstrong\u003eFe3\u003c/strong\u003e, 10 mol%, 8.2 mg) and 4Å MS (100 mg) in DCE (2.0 mL) under an argon atmosphere at 90 \u003csup\u003eo\u003c/sup\u003eC for 12 h.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/bd545e667c8f21454082e1f6.png"},{"id":75066171,"identity":"1d8ff566-370f-46d7-8517-f6f01cfd0829","added_by":"auto","created_at":"2025-01-30 05:40:50","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":108913,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSynthetic transformations\u003c/strong\u003e. \u003cstrong\u003ea\u003c/strong\u003e, Scale-up experiments. \u003cstrong\u003eb\u003c/strong\u003e, Oxidative aromatization for the synthesis of polysubstituted arenes; DDQ (2,3-dicyano-5,6-dichlorobenzoquinone); IBX (2-iodoxybenzoic acid); \u003cem\u003em\u003c/em\u003e-CPBA (\u003cem\u003em\u003c/em\u003e-chloroperbenzoic acid); BPO (dibenzoyl peroxide); TBPB (\u003cem\u003et\u003c/em\u003e-butyl peroxybenzoate); TBHP (\u003cem\u003et\u003c/em\u003e-butyl hydroperoxide). \u003cstrong\u003ec\u003c/strong\u003e, One-pot operation for the synthesis of polysubstituted arenes.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/13e35de34a32b7523dbfcd53.png"},{"id":75066148,"identity":"c50aa99d-decf-484b-a4ef-f88746ae8055","added_by":"auto","created_at":"2025-01-30 05:40:49","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":140562,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eControl experiments\u003c/strong\u003e.\u003cstrong\u003e a\u003c/strong\u003e, Radical inhibition experiments in the presences of TEMPO. \u003cstrong\u003eb\u003c/strong\u003e, Cyclopropanation reaction of diazo compound \u003cstrong\u003e3s\u003c/strong\u003e with (\u003cem\u003eZ\u003c/em\u003e)-alkene \u003cstrong\u003e7\u003c/strong\u003e in the presence of \u003cstrong\u003eFe3\u003c/strong\u003e. \u003cstrong\u003ec\u003c/strong\u003e, Cyclopropanation reaction of diazo compound \u003cstrong\u003e3r\u003c/strong\u003e with electron-rich or electron-deficient olefins under Fe(III)/Fe(II) catalytic system.\u003cstrong\u003e d\u003c/strong\u003e, Observation and isolation of key intermediate \u003cstrong\u003eInt IIa\u003c/strong\u003e in the Fe(II)-catalyzed transformation for the synthesis of \u003cstrong\u003e2a\u003c/strong\u003e. \u003cstrong\u003ee\u003c/strong\u003e, Synthesis of \u003cstrong\u003e2\u003c/strong\u003e under Fe(II)-catalyzed conditions. \u003cstrong\u003ef\u003c/strong\u003e, The \u003csup\u003e13\u003c/sup\u003eC NMR signal of iron carbene (Fe = C) intermediate \u003cstrong\u003eInt IIa\u003c/strong\u003e. \u003cstrong\u003eg\u003c/strong\u003e, The X-ray crystal structure of \u003cstrong\u003eInt IIa\u003c/strong\u003e.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/dc6486cb2b47df49880f1ab8.png"},{"id":75066156,"identity":"be73b6ed-e842-4d0a-9007-ce2978f427e7","added_by":"auto","created_at":"2025-01-30 05:40:49","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":210217,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDFT calculations\u003c/strong\u003e. \u003cstrong\u003ea\u003c/strong\u003e, Reaction pathways of the Fe-Por model system (R = H) for the reduced carbene system at /the B3-LYP/SDD//OPBE/def2TZVP/ level of theory. \u003cstrong\u003eb\u003c/strong\u003e, Reaction pathways of the Fe-Por model system (R = H) for the Fe(III) porphyrin system at /the B3-LYP/SDD// OPBE/def2TZVP/ level of theory. \u003cstrong\u003ec\u003c/strong\u003e, Spin density distribution of vinyl Fe(IV) carbene \u003cstrong\u003eII\u003c/strong\u003e(isosurface values at 0.004 a.u.). \u003cstrong\u003ed\u003c/strong\u003e, Spin density distribution of the transition state \u003cstrong\u003eTS3\u003c/strong\u003e (isosurface values at 0.004 a.u.).\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/861e4d048e80d92172b8b40f.png"},{"id":103119151,"identity":"ef439a7b-767b-4b30-9be9-60f631364938","added_by":"auto","created_at":"2026-02-21 08:07:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1587070,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/7588fc63-d58a-4385-b1aa-0241d57fb32b.pdf"},{"id":75066153,"identity":"d6fd1896-fc6d-4c8d-a5cf-9f1acb87c690","added_by":"auto","created_at":"2025-01-30 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05:40:49","extension":"txt","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":4834,"visible":true,"origin":"","legend":"Int IIa.cif","description":"","filename":"IntIIa.txt","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/68984d3db28d850c0e4a9a2d.txt"},{"id":75066179,"identity":"1fa373d6-ce8e-411a-9353-9e6dd3d6b06b","added_by":"auto","created_at":"2025-01-30 05:40:50","extension":"pdf","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":10873721,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"SupplementaryInformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/08745e86d4d73f3f692e5956.pdf"},{"id":75067293,"identity":"dff9e1b3-31c7-4c53-9c79-6c796a3c89d9","added_by":"auto","created_at":"2025-01-30 06:04:50","extension":"pdf","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":92603,"visible":true,"origin":"","legend":"checkcif_Int IIa","description":"","filename":"checkcifIntIIa.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5669760/v1/0b27913d7cc189332d44acdc.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Iron-catalyzed carbene and carbene radical cascade reactions: Mechanistic study and synthetic applications","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe development of sustainable and eco-friendly methodologies constitutes a pivotal long-term research endeavor in synthetic chemistry\u003csup\u003e1-3\u003c/sup\u003e. In this context, transition metal-catalyzed carbene transfer reactions have exhibited remarkable efficacy across a broad spectrum of catalytic applications that otherwise inaccessible chemistry\u003csup\u003e4-12\u003c/sup\u003e. The carbene chemistry has matured into a fruitful area over the past decades\u003csup\u003e13\u003c/sup\u003e\u003csup\u003e-18\u003c/sup\u003e. However, since these advantages generally rely on the use of precious metal catalysts,\u0026nbsp;there persists an urgent need to explore readily available, cost-effective, and environmentally benign catalysts in light of economy and environmental concerns\u003csup\u003e19-21\u003c/sup\u003e. In this respect, complexes based on abundantly available iron have attracted sustained attention because of their low cost and potential for distinct and complementary models of reactivity, offering opportunities to explore diverse catalytic synthetic transformations\u003csup\u003e22-32\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eIron porphyrin complexes have a low toxicity, are easy-to-handle and inexpensive catalysts for carbene transfer reactions\u003csup\u003e33-35\u003c/sup\u003e. Despite the captivating benefits of introducing these iron catalysts, the scope of reaction types remains constrained, such as Csp\u003csup\u003e3\u003c/sup\u003e-H bond alkylation\u003csup\u003e36,37\u003c/sup\u003e, cyclopropanation\u003csup\u003e38-42\u003c/sup\u003e, and few others\u003csup\u003e43-46\u003c/sup\u003e.\u0026nbsp;One shortcoming, which obstructs the development of iron complexes compared to other types of carbene transfer reactions, is that surprisingly little is known about the mechanistic aspects, in particular the structures of the reactive intermediates.\u003csup\u003e47\u003c/sup\u003e Iron porphyrin carbenes (IPCs) are generally suggested as the key intermediates in these Fe(II)/Fe(III) promoted transformations. Over the past decades, only a handful IPC intermediates have been isolated and confirmed by X-ray crystallography (Fig. 1a)\u003csup\u003e48-53\u003c/sup\u003e. For example, Mansuy and co-workers reported the first IPC crystal structure in 1978\u003csup\u003e48\u003c/sup\u003e. This pioneering discovery shed light on the following study on carbene transfer reactions. Later, Chi\u0026rsquo;s group isolated a donor-donor IPC complex [Fe(TFPP)CPh\u003csub\u003e2\u003c/sub\u003e] (TFPP = tetrakis(\u003cem\u003emeso\u003c/em\u003e-pentafluorophenyl)porphyrin), which provided solid mechanistic information for understanding cyclopropanation and C-H insertion reactions\u003csup\u003e50\u003c/sup\u003e. Thoroughly identifying and characterizing the authentic structure of proposed reactive intermediates is a pivotal task in carbene chemistry, which is not only indispensable for understanding the detailed reaction mechanism, but also crucial for the development of new selective synthetic methodologies\u003csup\u003e54,55\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eCatalytic carbene/alkyne metathesis (CAM) has emerged as a practical method for the straightforward construction of polycyclic frameworks (Fig. 1b)\u003csup\u003e56,57\u003c/sup\u003e. This cascade process is initiated by formation of a metal carbene intermediate, followed by a metathesis process with the alkyne moiety to generate a hypothetic vinyl metallocarbene intermediate and finalized by a distinct carbene transfer reaction\u003csup\u003e58,59\u003c/sup\u003e. In these advancements, vinyl metallocarbene species, which are the proposed key intermediates derived from the CAM process, have hitherto remained a hypothetical entity\u0026nbsp;and has never been isolated yet\u003csup\u003e60\u003c/sup\u003e. Considering the fact that the\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003ein situ\u003c/em\u003e formed vinyl carbene species is a prototypical donor-donor metal carbene, if it does indeed exist, we envisioned that there might be a chance to isolate and characterize this key intermediate by employing an iron porphyrin as the metal catalyst. To the best of our knowledge,\u0026nbsp;no reports have been published thus far on the porphyrin iron-catalyzed CAM process, let alone the isolation or characterization of carbene intermediate derived from alkyne (Fig. 1b). It should be mentioned that isolation of reactive intermediates has historically provided a great deal of insight into the mechanisms of chemical reactions, but several challenges remains in this area\u003csup\u003e61\u003c/sup\u003e. For example, iron porphyrin carbenes (IPC) have been generally proposed in early studies\u003csup\u003e36-46\u003c/sup\u003e, but [Fe(Por)X] and [Fe(Por)] catalysts could potentially steer the reaction along distinct pathways\u003csup\u003e62-64\u003c/sup\u003e (Fig. 1c). According to the work of White, a stepwise radical mechanism might be involved in\u0026nbsp;Csp\u003csup\u003e3\u003c/sup\u003e-H bond alkylation by using [FePc]Cl as the metal catalyst\u003csup\u003e62\u003c/sup\u003e, which is similar to the Co(II)-MRC (Co(II)-based metalloradical catalysis) system established by the groups of Zhang\u003csup\u003e63\u003c/sup\u003e and de Bruin\u003csup\u003e47,64,65\u003c/sup\u003e. Recently Zhang and co-workers suggested that also [Fe(Por)Cl] might act as a metalloradical catalyst for stereoselective olefin cyclopropanation reactions\u003csup\u003e66\u003c/sup\u003e. While mechanistic questions about oxidation states and spin states remain partially unanswered, control experiments pointed to the involvement of radical-type intermediates in these reactions. However, in view of recently reported high-level multiconfigurational computational studies the proposed involvement of discrete \u0026ldquo;carbene radical\u0026rdquo; intermediates in these reactions seems rather controversial, because for related Fe(II)-porphyrin complexes CASSCF calculations have shown that such carbene complexes are best regarded as classical Fischer-type carbenes (in contrast to earlier results obtained by DFT calculations pointing to carbene radical intermediates for such species)\u003csup\u003e67,68\u003c/sup\u003e. Remaining both puzzled and motivated by these results, we wondered if iron porphyrin complexes could facilitate the CAM process, and we were thus keen to elucidate the intricate reaction mechanism involving either [Fe\u003csup\u003eIII\u003c/sup\u003e(Por)X] or [Fe\u003csup\u003eII\u003c/sup\u003e(Por)] catalysts.\u003c/p\u003e\n\u003cp\u003eHerein, we report our endeavors in this direction. We developed an iron porphyrin-catalyzed\u0026nbsp;cascade reaction of alkyne-tethered diazo compounds, which offers an expeditious and efficient approach for the synthesis of carbocyclic molecules with structural diversity and flexibility under mild conditions. Control experiments and density functional theory calculations reveal two distinct reaction pathways catalyzed by Fe(II) and Fe(III) complexes, which involves carbene and carbene radical intermediates, respectively (Fig. 1d). Solid evidence was obtained from the X-ray crystal structure of the key vinyl iron carbene intermediate derived \u003cem\u003evia\u003c/em\u003e a CAM process. This study not only extends the horizon of iron-catalyzed carbene transfer reactions by formal carbene radical/alkyne metathesis processes, but also provides solid mechanistic information. The synthetic utility of these reactions is demonstrated by gram-scale preparation and synthesis of poly-substituted arenes in a streamlined one-pot process.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eReaction development\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo achieve the designed cascade reaction, we began our investigation by using alkyne tethered diazo compound \u003cstrong\u003e1a\u003c/strong\u003e as the model substrate. After the extensive screening of the reaction parameters (see Supplementary Table 1-6 for details), we identified the following optimal reaction conditions: 5.0 mol% \u003cstrong\u003eFe3\u003c/strong\u003e [Fe(\u003cem\u003ep\u003c/em\u003e-OMeTPP)Cl] and 5.0 mol% NaBArF\u003csup\u003e4\u003c/sup\u003e in1,2-dichloroethane (DCE) at 25 ℃ under argon atmosphere for 24 h, wherein the desired carbocyclic product \u003cstrong\u003e2a\u003c/strong\u003e was obtained in 80% yield (Fig. 2a, entry 1). To illustrate the impact of different parameters on the reaction outcomes, a set of reactions under conditions deviating from the optimized one have been conducted (Fig. 2a). No reaction occurred either in the absence of \u003cstrong\u003eFe3\u003c/strong\u003e or NaBArF\u003csup\u003e4\u003c/sup\u003e (entries 2-3), and neither FeCl\u003csub\u003e3\u003c/sub\u003e nor FeCl\u003csub\u003e2\u003c/sub\u003e was effective to initiate this reaction under otherwise identical conditions (entries 4-5). Even the Fe(II) porphyrin complex, \u003cem\u003ein situ\u003c/em\u003e derived from a combination of \u003cstrong\u003eFe3\u003c/strong\u003e with iron powder, failed to promoted the transformation (entry 6), however, after a brief optimization of the reaction temperature and solvent using \u003cem\u003ein situ\u003c/em\u003e formed Fe(II) catalyst (see Supplementary Table 7 for details), the product \u003cstrong\u003e2a\u003c/strong\u003e was furnished in 51% yield (entry 7). Subsequently, a variety of Fe(III) porphyrin complexes (entries 8-11) and other metal porphyrin catalysts were evaluated (entries 12-14). In general, iron complex contains electronic-rich porphyrin system showed higher efficiency, leading to product \u003cstrong\u003e2a\u003c/strong\u003e with compatible high yields (entry 1 vs 9), and only attenuated results were obtained in other cases in term of yield (Fig. 2b).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubstrate scope\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWith the optimal reaction conditions established, we started to evaluate the substrate scope of this iron porphyrin-catalyzed cascade transformation (Fig. 3a). Substrates with aromatic rings containing electron-neutral, electron-donating, and electron-withdrawing groups on different positions all reacted smoothly to give the corresponding products \u003cstrong\u003e2a\u003c/strong\u003e-\u003cstrong\u003e2k\u0026nbsp;\u003c/strong\u003ein generally good to high yields. Moderate yield was observed for the ortho-substituted one, which might be due to the steric effect. Moreover, 1-naphthyl, 3-thienyl, and alkyl groups were also found to be compatible, the reaction with these materials performed well, achieving the products \u003cstrong\u003e2l\u003c/strong\u003e-\u003cstrong\u003e2n\u003c/strong\u003e in 55-70% yields. The substitutions on the aromatic ring tethered to the olefinic part have little influence on the reaction efficiency, all the tested materials were successfully transformed into the desired products in \u0026gt;72% yields. The structure of the product \u003cstrong\u003e2g\u003c/strong\u003e was determined by X-ray crystallography, and the other products were tentatively assigned by analogy.\u003c/p\u003e\n\u003cp\u003eFurthermore, this Fe(III)-catalyzed cascade reaction could be extend to the benzyl Csp\u003csup\u003e3\u003c/sup\u003e-H bond alkylation by replacing the terminating allylic Csp\u003csup\u003e3\u003c/sup\u003e-H unit with a benzyl Csp\u003csup\u003e3\u003c/sup\u003e-H motif. After a brief optimization\u0026nbsp;(see Supplementary Table 8-12 for details), substrate \u003cstrong\u003e3a\u003c/strong\u003e could be successfully converted to product \u003cstrong\u003e4a\u003c/strong\u003e in 82% yield using the same \u003cstrong\u003eFe3\u003c/strong\u003e catalyst at elevated temperature (90 \u003csup\u003eo\u003c/sup\u003eC) in DCE. Notably, only slowly decomposition of diazo compounds was observed when this reaction was conducted in the absence of iron catalyst \u003cstrong\u003eFe3\u003c/strong\u003e, which ruled out the possibility of thermal condition initiated free carbene transformation. Under the optimized conditions, we next evaluated the generality of this benzyl Csp\u003csup\u003e3\u003c/sup\u003e-H bond alkylation reaction (Fig. 3b). In general, diazo compounds containing a variety of substitutions on the two tethering aromatic rings, including methyl, methoxy, fluoro, chloro, bromo, and\u0026nbsp;naphthyl, exert a negligible effect on the reaction\u0026rsquo;s progress, all affording the desired products \u003cstrong\u003e4a\u003c/strong\u003e-\u003cstrong\u003e4q\u003c/strong\u003e in good to high yield (64-89% yield).\u0026nbsp;The structure of the product \u003cstrong\u003e4h\u003c/strong\u003e was determined by X-ray crystallography, and the other products were tentatively assigned by analogy.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSynthetic applications\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo demonstrate the synthetic utility of the current method, the scale-up experiments were first conducted. Products \u003cstrong\u003e2a\u003c/strong\u003e and \u003cstrong\u003e4a\u003c/strong\u003e were obtained in 72% and 77% yields, respectively (Fig. 4a, 2.0 mmol scale). Given that the polysubstituted aromatic structure represents a key motif in natural products and bioactive molecules\u003csup\u003e69,70\u003c/sup\u003e, an oxidative aromatization process of these resulting carbocyclic products has been established under mild conditions using DDQ as oxidant, leading to isobenzofuranones \u003cstrong\u003e5\u003c/strong\u003e and \u003cstrong\u003e6\u003c/strong\u003e in 86-95% yields (Fig. 4b). The structures of the products \u003cstrong\u003e5f\u003c/strong\u003e and \u003cstrong\u003e6f\u003c/strong\u003e was determined by X-ray crystallography, and the other products were tentatively assigned by analogy. Moreover, these aromatization products could be obtained directly from the corresponding diazo compounds through a one-pot operation in good yields (Fig. 4c).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMechanistic studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo shed light on the mechanism of iron-catalyzed cascade reactions, we undertook a set of control experiments (Fig. 5). Initially, the model reaction of \u003cstrong\u003e1a\u003c/strong\u003e was conducted in the presence of the radical trap TEMPO (5 equiv.), trying to probe the carbene or carbene radical intermediates in this reaction (Fig. 5a)\u003csup\u003e62,63\u003c/sup\u003e. Notably, no desired product \u003cstrong\u003e2a\u003c/strong\u003e was observed when the reaction was catalyzed by Fe(III) porphyrin complex \u003cstrong\u003eFe3\u003c/strong\u003e; whereas, under the combination of \u003cstrong\u003eFe5\u003c/strong\u003e and Fe powder catalysis conditions, \u003cstrong\u003e2a\u003c/strong\u003e was formed in 53% yield. These results suggest that both Fe(III) and Fe(II) porphyrin complexes can catalyze the reaction, and that they follow different reaction pathways. Competitive intermolecular cyclopropanation reactions were investigated. However, above used substrates (\u003cstrong\u003e1a\u003c/strong\u003e-\u003cstrong\u003e1q\u003c/strong\u003e and \u003cstrong\u003e3a-3q\u003c/strong\u003e) only led to the corresponding intramolecular cyclization products \u003cstrong\u003e2\u003c/strong\u003e and \u003cstrong\u003e4\u003c/strong\u003e, rather than generating the cyclopropanation product with external alkenes. Thus, the equivalent cyclopropanation reactions of diazo compounds \u003cstrong\u003e3r\u003c/strong\u003e without alkyne motif and \u003cstrong\u003e3s\u003c/strong\u003e containing an \u003cem\u003eortho\u003c/em\u003e-substitution steric hindrance were performed (Fig. 5b and 5c). In the reaction of \u003cstrong\u003e3r\u003c/strong\u003e with (\u003cem\u003eZ\u003c/em\u003e)-akene \u003cstrong\u003e7\u003c/strong\u003e, cyclopropane product \u003cstrong\u003e8\u003c/strong\u003e with both \u003cem\u003ecis\u003c/em\u003e- and \u003cem\u003etrans\u003c/em\u003e- diastereoisomers was furnished (see Supplementary Figure 1 and 2 for details) when the reaction was catalyzed by \u003cstrong\u003eFe3\u003c/strong\u003e (Fig. 5b)\u003csup\u003e66\u003c/sup\u003e. Moreover, the \u003cstrong\u003eFe3\u003c/strong\u003e-catalyzed reaction of \u003cstrong\u003e3s\u003c/strong\u003e with \u003cem\u003ep\u003c/em\u003e-trifluoromethyl styrene or \u003cem\u003ep\u003c/em\u003e-methoxy styrene, two alkenes with different electronic properties, gave the corresponding cyclopropanation products \u003cstrong\u003e9a\u003c/strong\u003e and \u003cstrong\u003e9b\u003c/strong\u003e in comparable yields. However, a much lower yield was obtained with \u003cem\u003ep\u003c/em\u003e-trifluoromethyl styrene when the reaction was promoted by the Fe(II) system (Fig. 5c, \u003cstrong\u003e9a\u003c/strong\u003e = 8% \u003cem\u003evs\u003c/em\u003e \u003cstrong\u003e9b\u003c/strong\u003e = 37%). These divergent reaction outcomes suggest different reaction pathways, perhaps indicating a radical pathway for the iron(III) system. In the absence of iron catalyst, majority of the diazo compounds remain intact in all these tested reactions, which ruled out the influence of thermal-induced free carbene transformations.\u003c/p\u003e\n\u003cp\u003eGiven the fact that Fe(II) porphyrin carbene species might be stable enough for isolation, efforts have been directed towards observing and characterizing the key intermediates involved in this iron carbene cascade transformation. To our delight, when substrate \u003cstrong\u003e1a\u003c/strong\u003e was treated with 1 equivalent of \u003cstrong\u003eFe5\u003c/strong\u003e and 2 equivalent Fe powder in DCM and MeOH (9:1) mixed solvent at 25 \u003csup\u003eo\u003c/sup\u003eC under argon atmosphere, the iron carbene intermediate \u003cstrong\u003eInt II\u003c/strong\u003e\u003cstrong\u003ea\u003c/strong\u003e was formed in 58% yield, which could convert to the final product \u003cstrong\u003e2a\u003c/strong\u003e in 87% yield upon heated at 70 \u003csup\u003eo\u003c/sup\u003eC for 6 h (Fig. 5d). This combination system of Fe(II) catalysis also work well for the carbene/alkyne metathesis reaction, delivering the carbocyclic products \u003cstrong\u003e2\u003c/strong\u003e in synthetic useful yields (Fig. 5e). The isolated key iron carbene intermediate \u003cstrong\u003eInt II\u003c/strong\u003e\u003cstrong\u003ea\u003c/strong\u003e was confirmed by \u003csup\u003e1\u003c/sup\u003eH NMR, \u003csup\u003e13\u003c/sup\u003eC NMR\u003csup\u003e53\u003c/sup\u003e, and X-ray crystallography analysis\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e(Fig. 5f and 5g), which is the first identified vinyl metallocarbene intermediate derived from a\u003cem\u003e\u0026nbsp;\u003c/em\u003eCAM process.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo shine more light on the divergent mechanisms, density functional theory (DFT) calculations were conducted to further elucidated the details of both the Fe(III) and Fe(II) porphyrin catalyzed pathways (Fig. 6). The DFT investigations were performed at the /B3-LYP/SDD// OPBE/def2TZVP/ level of theory on unsubstituted model systems (R = H) starting at with the carbene species assuming that their formation was readily established. For the Fe(II) reaction pathway the electronic structure of the donor-acceptor carbene species \u003cstrong\u003eI\u0026rsquo;\u003c/strong\u003e shows the typical pseudo-octahedral d\u003csup\u003e6\u003c/sup\u003e configuration of an ML\u003csub\u003e5\u003c/sub\u003e-Fe(II) low-spin complex without unpaired electrons (Fig. 6a). Decreasing the distance between C\u003csub\u003e2\u003c/sub\u003e and (carbene)-C\u003csub\u003e5\u003c/sub\u003e leads to formation of the 5 membered furanone ring with an activation barrier \u0026Delta;G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e of modest 22.3 kcal/mol (\u003cstrong\u003eTS1\u0026rsquo;\u003c/strong\u003e, C\u003csub\u003e2\u003c/sub\u003e-C\u003csub\u003e5\u003c/sub\u003e=1.740 \u0026Aring;). Upon ring formation, the iron-C\u003csub\u003e5\u003c/sub\u003e bond is broken and the newly formed carbene function at C\u003csub\u003e1\u003c/sub\u003e coordinates to the iron-moiety without any intermediate to form the donor-donor vinyl carbene intermediate\u0026nbsp;\u003cstrong\u003eII\u003c/strong\u003e\u0026rsquo;, which is exergonic by -59.2 kcal /mol with respect to\u003cstrong\u003e\u0026nbsp;I\u0026rsquo;\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eFormation of the six membered-ring may occur by a concerted C-H insertion of the C\u003csub\u003e1\u003c/sub\u003e carbene into the C\u003csub\u003e8\u003c/sub\u003e-H bond \u003cem\u003evia\u003c/em\u003e a triangular transition structure \u003cstrong\u003eTS2\u0026rsquo;\u0026nbsp;\u003c/strong\u003erevealing a C\u003csub\u003e1\u003c/sub\u003e-C\u003csub\u003e8\u003c/sub\u003e bond distance of 2.141 \u0026Aring; (C\u003csub\u003e1\u003c/sub\u003e-H= 1.177 \u0026Aring;, C\u003csub\u003e8\u003c/sub\u003e-H= 1.460 \u0026Aring;). This pathway shows a high energy barrier of \u0026Delta;G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = +36.9 kcal/mol, which seems not viable under the current reaction conditions. Alternatively, the formal C-H insertion may proceed in a stepwise manner. First, a 1-6 Hydrogen atom transfer (HAT) takes place with a moderate barrier of \u0026Delta;G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = +27.3 kcal/mol for \u003cstrong\u003eTS3\u0026rsquo;\u003c/strong\u003e, which shows an almost linear geometry depicting a C\u003csub\u003e1\u003c/sub\u003e-C\u003csub\u003e8\u003c/sub\u003e bond distance of 2.614 \u0026Aring; with the \u003cem\u003eH\u003c/em\u003e-atom in between (C\u003csub\u003e1\u003c/sub\u003e-H= 1.344 \u0026Aring;, C\u003csub\u003e8\u003c/sub\u003e-H= 1.349 \u0026Aring;). Interestingly, the geometry of \u003cstrong\u003eTS3\u0026rsquo;\u003c/strong\u003e resembles a structure with some biradical character at the B3-LYP/SDD level.\u0026nbsp;However, the OPBE/def2TZVP single point calculations resulted exclusively in the closed shell solution and hence we resorted to CASSCF (8,10) calculations, which confirmed an increased multireference character (b=40%) compared to the carbene precursor (b=12%). The significant biradical contribution to\u0026nbsp;\u003cstrong\u003eTS3\u0026rsquo;\u003c/strong\u003e is points\u0026nbsp;to a hydrogen atom transfer (HAT) process, but a hydride transfer process with some HAT character is also legible.\u0026nbsp;Upon C\u003csub\u003e1\u003c/sub\u003e-H bond formation, the carbon-iron bond is released while the \u003cem\u003etrans\u003c/em\u003e-hexatriene \u003cstrong\u003eIII\u0026rsquo;\u003c/strong\u003e is formed. This process is slightly endergonic by \u0026Delta;G\u0026deg; = 11.0 kcal/mol with respect to the open shell singlet Fe(II) porphyrin, which may relax to its triplet ground state and re-enter the catalytic cycle while the six membered ring of the substrate is easily formed by disrotatory ring closure of the 6-electron system \u003cem\u003evia\u003c/em\u003e \u003cstrong\u003eTS4\u0026rsquo;\u003c/strong\u003e with a low barrier of \u0026Delta;G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = 16.8 kcal/mol (Fig. 6a).\u003c/p\u003e\n\u003cp\u003eAs for the reaction sequence of the Fe(III) porphyrin (without reduction by Fe powder, Fig. 6b), based on the neglectable multi-refence character of the CASSCF (5,10 def2-TZVP,\u0026nbsp;b=1%) results, carbene \u003cstrong\u003eI\u003c/strong\u003e can be described as a traditional Fischer-type carbene complex with a formal Fe(III) centre containing a single unpaired metal-d electron. Formation of the 5-membered furanone ring proceeds very similar to the Fe(II) system by decreasing the C5-C2 distance (\u003cstrong\u003eTS1\u003c/strong\u003e, C\u003csub\u003e2\u003c/sub\u003e-C\u003csub\u003e5\u003c/sub\u003e=2.019 \u0026Aring;), giving rise to a modest activation barrier \u0026Delta;G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = 21.8 kcal/mol to form donor-donor vinyl Fe(III) carbene \u003cstrong\u003eII\u003c/strong\u003e (\u0026Delta;G\u0026deg; = -60.5). Interestingly, based on the (7.8)-CASSCF calculations the electronic structure of carbene \u003cstrong\u003eII\u003c/strong\u003e is very different from carbene\u0026nbsp;\u003cstrong\u003eI\u003c/strong\u003e and clearly bears a ligand radical. It is best viewed as a delocalized \u0026ldquo;carbene radical complex\u0026rdquo; with the single electron delocalized over the carbene ligand\u0026nbsp;p-system, with non-negligible\u0026nbsp;p-overlap between the carbene p-orbital at C5 with a d\u003csub\u003ep\u003c/sub\u003e-type orbital (d\u003csub\u003exz\u003c/sub\u003e or d\u003csub\u003eyz\u003c/sub\u003e) at the formal Fe(IV)-center in an antiferromagnetic coupling arrangement, giving rise to the overall doublet state (Fig. 6c). Obviously, the\u0026nbsp;p-donor Cl\u003csup\u003e-\u003c/sup\u003e-substituent pushes the d\u003csub\u003exz\u003c/sub\u003e orbital up in energy resulting in a better interaction with the carbene\u0026nbsp;p-system.\u003c/p\u003e\n\u003cp\u003eConcerted C-H insertion of the C\u003csub\u003e1\u003c/sub\u003e carbene into the C\u003csub\u003e8\u003c/sub\u003e-H bond to form the six membered ring through triangular transition structure \u003cstrong\u003eTS2\u0026nbsp;\u003c/strong\u003ehas an activation barrier of \u0026Delta;G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = +27.4 kcal/mol, which is quite a bit lower than the barrier for the Fe(II) case. However, the stepwise mechanism has an even lower barrier (\u003cstrong\u003eTS3\u003c/strong\u003e, \u0026Delta;G\u003csup\u003e\u0026Dagger;\u003c/sup\u003e = 22.3 kcal/mol) for the 1-6 hydrogen transfer, which shows a similar multireference contribution (derived from (7.8)-CASSCF calculations;\u0026nbsp;b=42%) as was observed for the reduced\u0026nbsp;\u003cstrong\u003eTS3\u0026rsquo;\u003c/strong\u003e. Ring closure of the six membered ring is of course identical to the reduced system (Fig. 6a).\u003c/p\u003e\n\u003cp\u003eFrom the theoretical point of view, both systems, the Fe(III)-porphyrin as well as the reduced Fe(II) form, show very similar reactivity. This holds for the formation of the 5-membered furanone ring in addition to the C-H insertion by a preferred stepwise mechanism. Surprisingly, the ground state of the Fe(III) ring carbene compound\u0026nbsp;\u003cstrong\u003eII\u003c/strong\u003e is almost 100% a Fe(IV)-carbene radical (delocalized). In the\u0026nbsp;\u003cstrong\u003eTS3\u003c/strong\u003e that follows, the HAT has apparently already progressed quite strongly (late TS) so that the radical character on the organic fragment is considerably disappearing and iron has largely been reduced back to Fe(III) in that transition state. The Fe(II) variant\u0026nbsp;\u003cstrong\u003eTS3\u0026rsquo;\u003c/strong\u003e appears to have a similar multireference character as the Fe(III) variant\u0026nbsp;\u003cstrong\u003eTS3\u003c/strong\u003e (Fig. 6d), but the initial situation is different for Fe(II). Whereas carbene complex \u003cstrong\u003eII\u003c/strong\u003e is best described as a nearly 100% Fe(IV)-carbene radical complex, the Fe(II) carbene analog \u003cstrong\u003eII\u0026rsquo;\u003c/strong\u003e surprisingly has hardly any multireference character and is best describe as a classical Fischer-type carbene complex of Fe(II). This may well be the cause of the higher \u003cstrong\u003eTS3\u0026rsquo;\u003c/strong\u003e DFT barrier for Fe(II) compared to Fe(III). Anyhow, the CASSCF results of both transition states \u003cstrong\u003eTS3\u0026rsquo;\u003c/strong\u003e and \u003cstrong\u003eTS3\u003c/strong\u003e, so Fe(II) as well as Fe(III), show quite some multireference character which might explain that not only in the Fe(III) case some radical character is imposed on the carbene-carbon, but also for the Fe(II) in the form of the open shell singlet electronic structure of \u003cstrong\u003eTS3\u0026rsquo;\u003c/strong\u003e, resulting in similar reactivity for both oxidation states of iron.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, we have developed an iron porphyrin-catalyzed cascade reaction that terminated by benzylic and allylic Csp\u003csup\u003e3\u003c/sup\u003e-H bond functionalization, providing an expeditious and efficient protocol for the synthesis of carbocyclic molecules with structural diversity and flexibility under mild conditions. Control experiments and density functional theory calculations unambiguously reveal two distinct reaction pathways catalyzed by Fe(II) and Fe(III) complexes. Interestingly, and counterintuitively, CASSCF data revealed that the conjugated carbene complex \u003cb\u003eII\u003c/b\u003e is best described as a delocalized Fe(IV)-carbene radical complex with an antiferromagnetic coupling between the ligand and Fe-centered unpaired electrons, while the Fe(II) analog \u003cb\u003eII\u0026rsquo;\u003c/b\u003e is best described as a classical Fischer-type carbene complex of Fe(II).\u003c/p\u003e \u003cp\u003eThe gram-scale preparation and synthesis of poly-substituted arenes, achieved either \u003cem\u003evia\u003c/em\u003e oxidation of the resulting products or through a streamlined one-pot process, have further augmented the synthetic utility and value. This study not only extended the horizon of iron-catalyzed carbene transfer reactions by encompassing formal carbene/alkyne metathesis process, but also provides solid evidence on the mechanistic aspects. Notably, the key donor-donor type vinyl iron carbene intermediate has been isolated and characterized by X-ray crystallography analysis for the first time. With these detailed mechanistic insights, novel iron-promoted carbene transfer reactions can be envisioned in the foreseeable future.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eGeneral procedure for the formal allylic Csp\u003csup\u003e3\u003c/sup\u003e-H bond insertion reaction\u003c/h2\u003e \u003cp\u003eTo a 10-mL oven-dried vial equipped with a magnetic stir bar, was charged with [Fe(\u003cem\u003ep\u003c/em\u003e-OMeTPP)Cl] (\u003cb\u003eFe3\u003c/b\u003e, 5 mol%, 4.1 mg) and NaBArF\u003csup\u003e4\u003c/sup\u003e (5 mol%, 4.4 mg) in glovebox. Then, the vial was capped and took out from the glovebox, and DCE (0.5 mL) was injected into vial under argon atmosphere. The resulting reaction mixture was stirred at 25 ℃ for 0.5 h. A solution of diazo compound \u003cb\u003e1\u003c/b\u003e (0.1 mmol) in DCE (1.0 mL) was added into the reaction vessel through syringe in 3.5 h, then the new mixture was stirred under these conditions for 20 h. After the reaction was completed, the reaction mixture was purified directly by column chromatography on silica gel without any additional treatment (eluent: PE: EA\u0026thinsp;=\u0026thinsp;10:1 to 6:1) to afford the corresponding products \u003cb\u003e2\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eGeneral procedure for the formal benzyl Csp\u003csup\u003e3\u003c/sup\u003e-H bond insertion reaction\u003c/h2\u003e \u003cp\u003eTo a 10-mL vial equipped with a magnetic stir bar, was charged with [Fe(\u003cem\u003ep\u003c/em\u003e-OMeTPP)Cl] (\u003cb\u003eFe3\u003c/b\u003e, 10 mol%, 8.2 mg) and 4\u0026Aring; MS (100 mg). Then, the capped vial was evacuated and back-filled with argon (3 times). A solution of diazo compound 3 (0.1 mmol) in DCE (2.0 mL) was added into the reaction vessel in one-time and the reaction mixture was stirred at 90 ℃ for 12 h. After the reaction was completed, the reaction mixture was purified directly by column chromatography on silica gel without any additional treatment (eluent: PE: EA\u0026thinsp;=\u0026thinsp;10:1 to 5:1) to afford the corresponding products \u003cb\u003e4\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data supporting the findings of this study are available within the paper and its Supplementary Information or from the corresponding author upon request. The X-ray crystallographic coordinates for structures \u003cstrong\u003e2g\u003c/strong\u003e, \u003cstrong\u003e4h\u003c/strong\u003e, \u003cstrong\u003e5f\u003c/strong\u003e, \u003cstrong\u003e6f\u003c/strong\u003e, and \u003cstrong\u003eInt\u003c/strong\u003e \u003cstrong\u003eIIa\u0026nbsp;\u003c/strong\u003ereported in this article have been deposited at the Cambridge Crystallographic Data Centre (CCDC). These data can be obtained free of charge from the CCDC via www.ccdc.cam.ac.uk/data_request/cif.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by the National Natural Science Foundation of China (22371309) and the Guangdong Basic and Applied Basic Research Foundation (2024B1515040025).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eX.Z. and X.X. devised the project. X.Z., M.Y., K.C., and Y.W. synthesized and characterized all products. X.Z. and Y.W. both got the crystal and collected the X-ray crystallographic data for \u003cstrong\u003eInt\u003c/strong\u003e \u003cstrong\u003eIIa\u003c/strong\u003e. A.E. and B.B. performed the computational work. X.X supervised the project and drafted the manuscript. X.Z., A.E., B.B., and X.X. revised the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence and requests for materials\u0026nbsp;\u003c/strong\u003eshould be addressed to Bas de Bruin or Xinfang Xu.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKar, S., Sanderson, H., Roy, K., Benfenati, E. \u0026amp; Leszczynski, J. Green chemistry in the synthesis of pharmaceuticals. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e122\u003c/strong\u003e, 3637\u0026ndash;3710 (2022).\u003c/li\u003e\n\u003cli\u003eGuillemard, L., Kaplaneris, N., Ackermann, L. \u0026amp; Johansson, M. J. Late-stage C-H functionalization offers new opportunities in drug discovery. \u003cem\u003eNat. Rev. Chem.\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 522\u0026ndash;545 (2021).\u003c/li\u003e\n\u003cli\u003eGrover, J., Prakash, G., Goswami N. \u0026amp; Maiti, D. Traditional and sustainable approaches for the construction of C-C bonds by harnessing C-H arylation. \u003cem\u003eNat. Commun.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 1085 (2022).\u003c/li\u003e\n\u003cli\u003eBergstrom, B. D., Nickerson, L. A., Shaw, J. T. \u0026amp; Souza, L. W. Transition metal catalyzed insertion reactions with donor/donor carbenes. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e \u003cstrong\u003e60\u003c/strong\u003e, 6864\u0026ndash;6878 (2021).\u003c/li\u003e\n\u003cli\u003eLiu, Z. H., Sivaguru, P., Zanoni, G. \u0026amp; Bi, X. H. \u003cem\u003eN\u003c/em\u003e-Triftosylhydrazones: a new chapter for diazo-based carbene chemistry. \u003cem\u003eAcc. Chem. Res.\u003c/em\u003e \u003cstrong\u003e55\u003c/strong\u003e, 1763\u0026ndash;1781 (2022).\u003c/li\u003e\n\u003cli\u003eXia, Y., Qiu, D. \u0026amp; Wang, J. B. Transition-metal-catalyzed cross-couplings through carbene migratory insertion. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e117\u003c/strong\u003e, 13810\u0026ndash;13889 (2017).\u003c/li\u003e\n\u003cli\u003eYe, L. W. et al. Nitrene transfer and carbene transfer in gold catalysis. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e121\u003c/strong\u003e, 9039\u0026ndash;9112 (2021).\u003c/li\u003e\n\u003cli\u003eCheng, Q. Q., Deng, Y. M., Lankelma, M. \u0026amp; Doyle, M. P. Cycloaddition reactions of enoldiazo compounds. \u003cem\u003eChem. Soc. Rev.\u003c/em\u003e \u003cstrong\u003e46\u003c/strong\u003e, 5425\u0026ndash;5443 (2017).\u003c/li\u003e\n\u003cli\u003eDavies, H. M. L. \u0026amp; Manning, J. R. Catalytic C-H functionalization by metal carbenoid and nitrenoid insertion. \u003cem\u003eNature\u003c/em\u003e \u003cstrong\u003e451\u003c/strong\u003e, 417\u0026ndash;424 (2008).\u003c/li\u003e\n\u003cli\u003eYao, M. H., Dong, S. L. \u0026amp; Xu, X. F. Asymmetric carbene transformations for the construction of all-carbon quaternary centers. \u003cem\u003eChem. Eur. J.\u003c/em\u003e \u003cstrong\u003e30\u003c/strong\u003e, e202304299 (2024).\u003c/li\u003e\n\u003cli\u003eWang, T. \u0026amp; Hashmi, A. S. K. 1,2-Migrations onto gold carbene centers. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e121\u003c/strong\u003e, 8948\u0026ndash;8978 (2021).\u003c/li\u003e\n\u003cli\u003eFord, A. et al. Modern organic synthesis with \u0026alpha;-diazocarbonyl compounds. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e115\u003c/strong\u003e, 9981\u0026ndash;10080 (2015).\u003c/li\u003e\n\u003cli\u003eCandeias, N. R., Paterna, R. \u0026amp; Gois, P. M. P. Homologation reaction of ketones with diazo compounds. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e116\u003c/strong\u003e, 2937\u0026ndash;2981 (2016).\u003c/li\u003e\n\u003cli\u003eCho, H. J. \u0026amp; Kim, J. H. Accessing functionalized furans from reacting enynones and enynals through furyl metal carbenes. \u003cem\u003eAsian J. Org. Chem.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, e202300616 (2024).\u003c/li\u003e\n\u003cli\u003eEmpel, C., Pham, Q. H. \u0026amp; Koenigs, R. M. Spin states matter-from fundamentals toward synthetic methodology development and drug discovery. \u003cem\u003eAcc. Chem. Res.\u003c/em\u003e \u003cstrong\u003e57\u003c/strong\u003e, 2717\u0026ndash;2727 (2024).\u003c/li\u003e\n\u003cli\u003eZhao, X. M., Rudolph, M., Asiri, A. M. \u0026amp; Hashmi, A. S. K. Easy access to pharmaceutically relevant heterocycles by catalytic reactions involving \u0026alpha;-imino gold carbene intermediates. \u003cem\u003eFront. Chem. Sci. Eng.\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 317\u0026ndash;349 (2020)\u003c/li\u003e\n\u003cli\u003eMato, M., Garc\u0026iacute;a-Morales, C. \u0026amp; Echavarren, A. M. Generation of gold(I) carbenes by retro-buchner reaction: from cyclopropanes to natural products synthesis. \u003cem\u003eChemCatChem\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 53\u0026ndash;72 (2019).\u003c/li\u003e\n\u003cli\u003eLiu, S. P. et al. Tunable molecular editing of indoles with fluoroalkyl carbenes. \u003cem\u003eNat. Chem.\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, 988\u0026ndash;997 (2024).\u003c/li\u003e\n\u003cli\u003eJazzar, R., Soleilhavoup, M. \u0026amp; Bertrand, G. Cyclic (alkyl)- and (aryl)-(amino)carbene coinage metal complexes and their applications. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e120\u003c/strong\u003e, 4141\u0026ndash;4168 (2020).\u003c/li\u003e\n\u003cli\u003eLiu, Z. \u0026amp; Arnold, F. H. New-to-nature chemistry from old protein machinery: carbene and nitrene transferases. \u003cem\u003eCurr. Opin. Biotechnol.\u003c/em\u003e \u003cstrong\u003e69\u003c/strong\u003e, 43\u0026ndash;51, (2021).\u003c/li\u003e\n\u003cli\u003eMu\u0026ntilde;oz-Molina, J. M., Belderrain, T. R. \u0026amp; P\u0026eacute;rez, P. J. Group 11 tris(pyrazolyl)methane complexes: structural features and catalytic applications. \u003cem\u003eDalton. Trans.\u003c/em\u003e \u003cstrong\u003e48\u003c/strong\u003e, 10772\u0026ndash;10781 (2019).\u003c/li\u003e\n\u003cli\u003eEnthaler, S., Junge, K. \u0026amp; Beller, M. Sustainable metal catalysis with iron: From rust to a rising star? \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e \u003cstrong\u003e47\u003c/strong\u003e, 3317\u0026ndash;3321 (2008).\u003c/li\u003e\n\u003cli\u003eBolm, C., Legros, J., Le Paih, J. \u0026amp; Zani, L. Iron-catalyzed reactions in organic synthesis. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e104\u003c/strong\u003e, 6217\u0026ndash;6254 (2004).\u003c/li\u003e\n\u003cli\u003eBauer, I. \u0026amp; Kn\u0026ouml;lker, H.J. Iron catalysis in organic synthesis. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e115\u003c/strong\u003e, 3170\u0026ndash;3387 (2015).\u003c/li\u003e\n\u003cli\u003eWei, D. \u0026amp; Darcel, C. Iron catalysis in reduction and hydrometalation reactions. \u003cem\u003eChem. Rev.\u003c/em\u003e \u003cstrong\u003e119\u003c/strong\u003e, 2550\u0026ndash;2610 (2019).\u003c/li\u003e\n\u003cli\u003eChen, M.S. \u0026amp; White, M.C. A predictably selective aliphatic C-H oxidation reaction for complex molecule synthesis. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e318\u003c/strong\u003e, 783\u0026ndash;787 (2007).\u003c/li\u003e\n\u003cli\u003eHennessy, E.T. \u0026amp; Betley, T.A. Complex N-heterocycle synthesis \u003cem\u003evia\u003c/em\u003e iron-catalyzed, direct C-H bond amination. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e340\u003c/strong\u003e, 591\u0026ndash;595 (2013).\u003c/li\u003e\n\u003cli\u003eCheng, L. et al. Iron-catalyzed arene C-H hydroxylation. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e374\u003c/strong\u003e, 77\u0026ndash;81 (2021).\u003c/li\u003e\n\u003cli\u003eLiu, L. et al. General method for iron-catalyzed multicomponent radical cascades-cross-couplings. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e374\u003c/strong\u003e, 432\u0026ndash;439 (2021).\u003c/li\u003e\n\u003cli\u003eGan, X.C. et al. Carbon quaternization of redox active esters and olefins by decarboxylative coupling. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e384\u003c/strong\u003e, 113\u0026ndash;118 (2024).\u003c/li\u003e\n\u003cli\u003eKaur, P. \u0026amp; Tyagi, V. Recent advances in iron-catalyzed chemical and enzymatic carbene-transfer reactions. \u003cem\u003eAdv. Synth. Catal.\u003c/em\u003e \u003cstrong\u003e363\u003c/strong\u003e, 877\u0026ndash;905 (2021).\u003c/li\u003e\n\u003cli\u003eDamiano, C., Sonzini, P. \u0026amp; Gallo, E. Iron catalysts with N-ligands for carbene transfer of diazo reagents. \u003cem\u003eChem. Soc. Rev.\u003c/em\u003e \u003cstrong\u003e49\u003c/strong\u003e, 4867\u0026ndash;4905 (2020).\u003c/li\u003e\n\u003cli\u003eZhu, S.F. \u0026amp; Zhou, Q.L. Iron-catalyzed transformations of diazo compounds. \u003cem\u003eNatl. Sci. Rev.\u003c/em\u003e \u003cstrong\u003e1\u003c/strong\u003e, 580\u0026ndash;603 (2014).\u003c/li\u003e\n\u003cli\u003eBatista, V.F., Pinto, D. \u0026amp; Silva, A.M.S. Iron: a worthy contender in metal carbene chemistry. \u003cem\u003eACS Catal.\u003c/em\u003e \u003cstrong\u003e10\u003c/strong\u003e, 10096\u0026ndash;10116 (2020).\u003c/li\u003e\n\u003cli\u003eLewis, R.D. et al. Catalytic iron-carbene intermediate revealed in a cytochrome \u003cem\u003ec\u003c/em\u003e carbene transferase. \u003cem\u003ePNAS\u003c/em\u003e \u003cstrong\u003e115\u003c/strong\u003e, 7308\u0026ndash;7313 (2018).\u003c/li\u003e\n\u003cli\u003eMbuvi, H. M., Klobukowski, E. R., Roberts, G. M. \u0026amp; Woo, L. K. O-H insertion and tandem N-H insertion/cyclization reactions using an iron porphyrin as catalyst with diazo compounds as carbene sources. \u003cem\u003eJ. Porphyr. Phthalocya.\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 284\u0026ndash;292 (2010).\u003c/li\u003e\n\u003cli\u003eAviv, I. \u0026amp; Gross, Z. Iron(III) corroles and porphyrins as superior catalysts for the reactions of diazoacetates with nitrogen- or sulfur-containing nucleophilic substrates: Synthetic uses and mechanistic insights. \u003cem\u003eChem. Eur. J.\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 3995\u0026ndash;4005 (2008).\u003c/li\u003e\n\u003cli\u003eWolf, J. R., Hamaker, C. G., Djukic, J. P., Kodadek, T. \u0026amp; Woo, L. K. Shape and stereoselective cyclopropanation of alkenes catalyzed by iron porphyrins. \u003cem\u003eJ. Am. Chem.\u003c/em\u003e Soc. \u003cstrong\u003e117\u003c/strong\u003e, 9194\u0026ndash;9199 (1995).\u003c/li\u003e\n\u003cli\u003eAggarwal, V.K., de Vicente, J. \u0026amp; Bonnert, R.V. Catalytic cyclopropanation of alkenes using diazo compounds generated in situ. A novel route to 2-arylcyclopropylamines. \u003cem\u003eOrg. Lett.\u003c/em\u003e \u003cstrong\u003e3\u003c/strong\u003e, 2785\u0026ndash;2788 (2001).\u003c/li\u003e\n\u003cli\u003eNicolas, I., Le Maux, P. \u0026amp; Simonneaux, G. Synthesis of chiral water-soluble metalloporphyrins (Fe, Ru,): new catalysts for asymmetric carbene transfer in water. \u003cem\u003eTetrahedron Lett.\u003c/em\u003e \u003cstrong\u003e49\u003c/strong\u003e, 5793\u0026ndash;5795 (2008).\u003c/li\u003e\n\u003cli\u003eCarminati, D.M. et al. Designing \u0026apos;totem\u0026apos; C\u003csub\u003e2\u003c/sub\u003e-symmetrical iron porphyrin catalysts for stereoselective cyclopropanations. \u003cem\u003eChem. Eur. J.\u003c/em\u003e \u003cstrong\u003e22\u003c/strong\u003e, 13599\u0026ndash;13612 (2016).\u003c/li\u003e\n\u003cli\u003eBartels, K., Schinor, B. \u0026amp; Haufe, G. Diastereoselectivity of cyclopropanation of substituted \u0026alpha;-fluorostyrenes versus styrenes by different methods. \u003cem\u003eJ. Fluorine Chem.\u003c/em\u003e \u003cstrong\u003e203\u003c/strong\u003e, 200\u0026ndash;205 (2017).\u003c/li\u003e\n\u003cli\u003eChen, Y., Huang, L. Y. \u0026amp; Zhang, X. P. Acid-promoted olefination of ketones by an iron(III) porphyrin complex. \u003cem\u003eOrg. Lett.\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 2493\u0026ndash;2496 (2003).\u003c/li\u003e\n\u003cli\u003eBaumann, L.K., Mbuvi, H.M., Du, G. \u0026amp; Woo, L.K. Iron porphyrin catalyzed N-H insertion reactions with ethyl diazoacetate. \u003cem\u003eOrganometallics\u003c/em\u003e \u003cstrong\u003e26\u003c/strong\u003e, 3995\u0026ndash;4002 (2007).\u003c/li\u003e\n\u003cli\u003eLiu, C. R. et al. Highly diastereroselective synthesis of dihydrofurans and dihydropyrroles \u003cem\u003evia\u003c/em\u003e pyridine catalyzed formal 4\u0026thinsp;+\u0026thinsp;1 annulation. \u003cem\u003eChem. Commun.\u003c/em\u003e \u003cstrong\u003e47\u003c/strong\u003e, 1342\u0026ndash;1344 (2011).\u003c/li\u003e\n\u003cli\u003eDay, J., McKeever-Abbas, B. \u0026amp; Dowden, J. Stereoselective synthesis of tetrahydroindolizines through the catalytic formation of pyridinium ylides from diazo compounds. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e \u003cstrong\u003e55\u003c/strong\u003e, 5809\u0026ndash;5813 (2016).\u003c/li\u003e\n\u003cli\u003eEpping, R. F. J., Vesseur, D., Zhou, M. H. \u0026amp; de Bruin, B. Carbene radicals in transition-metal-catalyzed reactions. \u003cem\u003eACS Catal.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 5428\u0026ndash;5448 (2023).\u003c/li\u003e\n\u003cli\u003eMansuy, D. et al. Dichlorocarbene complexes of iron(II)-porphyrins-crystal and molecular structure of Fe(TPP)(CCl\u003csub\u003e2\u003c/sub\u003e)(H\u003csub\u003e2\u003c/sub\u003eO). \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e \u003cstrong\u003e17\u003c/strong\u003e, 781\u0026ndash;782 (1978).\u003c/li\u003e\n\u003cli\u003eCollman, J. P., Rose, E. \u0026amp; Venburg, G. D. Reactivity of ruthenium 5,10,15,20-tetramesitylporphyrin towards diazoesters: formation of olefins. \u003cem\u003eJ. Chem. Soc., Chem. Commun.\u003c/em\u003e 934\u0026ndash;935 (1993).\u003c/li\u003e\n\u003cli\u003eLi, Y., Huang, J. S., Zhou, Z. Y., Che, C. M. \u0026amp; You, X. Z. Remarkably stable iron porphyrins bearing nonheteroatom-stabilized carbene or (alkoxycarbonyl) carbenes: Isolation, X-ray crystal structures, and carbon atom transfer reactions with hydrocarbons. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e \u003cstrong\u003e124\u003c/strong\u003e, 13185\u0026ndash;13193 (2002).\u003c/li\u003e\n\u003cli\u003eLu, H. J. et al. Experimental evidence for cobalt(III)-carbene radicals: key intermediates in cobalt(II)-based metalloradical cyclopropanation. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e \u003cstrong\u003e133\u003c/strong\u003e, 8518\u0026ndash;8521 (2011).\u003c/li\u003e\n\u003cli\u003eMa, C. Q. et al. Synthesis and characterization of donor-acceptor iron porphyrin carbenes and their reactivities in N-H insertion and related three-component reaction. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e \u003cstrong\u003e145\u003c/strong\u003e, 4934\u0026ndash;4939 (2023).\u003c/li\u003e\n\u003cli\u003eKornecki, K. P. et al. Direct spectroscopic characterization of a transitory dirhodium donor-acceptor carbene complex. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e342\u003c/strong\u003e, 351\u0026ndash;354 (2013).\u003c/li\u003e\n\u003cli\u003eHu, C. P., Wang, X. F., Li, J. C., Chang, X. Y. \u0026amp; Liu, L. L. A stable rhodium-coordinated carbene with a \u0026sigma;\u003csup\u003e0\u003c/sup\u003e\u0026pi;\u003csup\u003e2\u003c/sup\u003e electronic configuration. \u003cem\u003eScience\u003c/em\u003e \u003cstrong\u003e383\u003c/strong\u003e, 81\u0026ndash;85 (2024).\u003c/li\u003e\n\u003cli\u003eBenitez, D. et al. A bonding model for gold(I) carbene complexes. \u003cem\u003eNat. Chem.\u003c/em\u003e \u003cstrong\u003e1\u003c/strong\u003e, 482\u0026ndash;486 (2009).\u003c/li\u003e\n\u003cli\u003eTorres, O. \u0026amp; Pla-Quintana, A. The rich reactivity of transition metal carbenes with alkynes. \u003cem\u003eTetrahedron Lett.\u003c/em\u003e \u003cstrong\u003e57\u003c/strong\u003e, 3881\u0026ndash;3891 (2016).\u003c/li\u003e\n\u003cli\u003ePei, C., Zhang, C., Qian, Y. \u0026amp; Xu, X. F. Catalytic carbene/alkyne metathesis (CAM): a versatile strategy for alkyne bifunctionalization. \u003cem\u003eOrg. Biomol. Chem.\u003c/em\u003e \u003cstrong\u003e16\u003c/strong\u003e, 8677\u0026ndash;8685 (2018).\u003c/li\u003e\n\u003cli\u003eHong, K. M. et al. Catalytic 4-exo-dig carbocyclization for the construction of furan-fused cyclobutanones and synthetic applications. \u003cem\u003eNat. Commun.\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 6378 (2023).\u003c/li\u003e\n\u003cli\u003eZhang, C. et al. Generation and utility of cyclic dienyl gold carbene intermediates. \u003cem\u003eACS Catal.\u003c/em\u003e \u003cstrong\u003e13\u003c/strong\u003e, 4646\u0026ndash;4655 (2023).\u003c/li\u003e\n\u003cli\u003eZhang, C. et al. Gold(I)-catalyzed intramolecular cyclization/intermolecular cycloaddition cascade as a fast track to polycarbocycles and mechanistic insights. \u003cem\u003eNat. Commun.\u003c/em\u003e \u003cstrong\u003e12\u003c/strong\u003e, 1182 (2021).\u003c/li\u003e\n\u003cli\u003eCaballero, A. \u0026amp; P\u0026eacute;rez, P. J. Dimensioning the term carbenoid. \u003cem\u003eChem. Eur. J.\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 14389\u0026ndash;14393 (2017).\u003c/li\u003e\n\u003cli\u003eGriffin, J. R., Wendell, C. I., Garwin, J. A. \u0026amp; White, M. C. Catalytic C(sp\u003csup\u003e3\u003c/sup\u003e)-H alkylation \u003cem\u003evia\u003c/em\u003e an iron carbene intermediate. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e \u003cstrong\u003e139\u003c/strong\u003e, 13624\u0026ndash;13627 (2017).\u003c/li\u003e\n\u003cli\u003eCui, X., Xu, X., Jin, L. M., Wojtas, L. \u0026amp; Zhang, X. P. Stereoselective radical C-H alkylation with acceptor/acceptor-substituted diazo reagents \u003cem\u003evia\u003c/em\u003e Co(II)-based metalloradical catalysis. \u003cem\u003eChem. Sci.\u003c/em\u003e \u003cstrong\u003e6\u003c/strong\u003e, 1219\u0026ndash;1224 (2015).\u003c/li\u003e\n\u003cli\u003eEpping, R. F. J., Hoeksma, M. M., Bobylev, E. O., Mathew, S. \u0026amp; de Bruin, B. Cobalt(II)\u0026ndash;tetraphenylporphyrin-catalyzed carbene transfer from acceptor-acceptor iodonium ylides \u003cem\u003evia\u003c/em\u003e N-enolate carbene radicals. \u003cem\u003eNat. Chem.\u003c/em\u003e \u003cstrong\u003e14\u003c/strong\u003e, 550\u0026ndash;557 (2022).\u003c/li\u003e\n\u003cli\u003eZhou, M., Wolzak, L. A., Li, Z., de Zwart, F. J., Mathew, S. \u0026amp; de Bruin, B. Catalytic synthesis of 1\u003cem\u003eH\u003c/em\u003e-2-benzoxocins; Cobalt(III)-carbene radical approach to 8-membered heterocyclic enol ethers. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e \u003cstrong\u003e143\u003c/strong\u003e, 20501\u0026ndash;20512 (2021).\u003c/li\u003e\n\u003cli\u003eLee, W. C. C., Wang, D. S., Zhu, Y. L. \u0026amp; Zhang, X. P. Iron(III)-based metalloradical catalysis for asymmetric cyclopropanation via a stepwise radical mechanism. \u003cem\u003eNat. Chem.\u003c/em\u003e 15, 1569\u0026ndash;1580 (2023).\u003c/li\u003e\n\u003cli\u003eSharon, D. A., Mallick, D., Wang, B. \u0026amp; Shaik, S. Computation Sheds Insight into Iron Porphyrin Carbenes\u0026rsquo; Electronic Structure, Formation, and N-H Insertion Reactivity. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e \u003cstrong\u003e138\u003c/strong\u003e, 9597\u0026ndash;9610 (2016).\u003c/li\u003e\n\u003cli\u003eGr\u0026auml;fenstein, J. \u0026amp; Cremer, D. Can Density Functional Theory Describe Multi-Reference Systems? Investigation of Carbenes and Organic Biradicals. \u003cem\u003ePhys. Chem. Chem. Phys.\u003c/em\u003e \u003cstrong\u003e2\u003c/strong\u003e, 2091\u0026ndash;2103 (2000).\u003c/li\u003e\n\u003cli\u003eNilova, A., Campeau, L. C., Sherer, E. C. \u0026amp; Stuart, D. R. Analysis of benzenoid substitution patterns in small molecule active pharmaceutical ingredients. \u003cem\u003eJ. Med. Chem.\u003c/em\u003e \u003cstrong\u003e63\u003c/strong\u003e, 13389\u0026ndash;13396 (2020).\u003c/li\u003e\n\u003cli\u003eSubbaiah, M. A. M. \u0026amp; Meanwell, N. A. Bioisosteres of the phenyl ring: recent strategic applications in lead optimization and drug design. \u003cem\u003eJ. Med. Chem.\u003c/em\u003e \u003cstrong\u003e64\u003c/strong\u003e, 14046\u0026ndash;14128 (2021).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-5669760/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5669760/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eTransition metal-catalyzed carbene transfer reactions are some of the most widely used methods that facilitate a range of otherwise inaccessible chemistry. However, these advantages generally promoted by precious metal catalysts, using inexpensive and less toxic iron complexes as catalysts is under development. Moreover, surprisingly little is known about the mechanistic aspects, in particular the structures of these intermediates. Herein, we report an iron-catalyzed cascade reaction of alkyne-tethered diazo compounds, offering an efficient approach for the synthesis of carbocyclic molecules with structural diversity and flexibility under mild conditions. Control experiments and density functional theory calculations unambiguously reveal two distinct reaction pathways catalyzed by either Fe(II) or Fe(III) porphyrin complexes, which involves carbene and carbene radical intermediates, respectively. The structure of the key vinyl iron carbene intermediate has been determined by X-ray diffraction. The synthetic utility has been demonstrated by gram-scale preparation and synthesis of poly-substituted arenes \u003cem\u003evia\u003c/em\u003e a streamlined one-pot process.\u003c/p\u003e","manuscriptTitle":"Iron-catalyzed carbene and carbene radical cascade reactions: Mechanistic study and synthetic applications","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-30 05:40:41","doi":"10.21203/rs.3.rs-5669760/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-catalysis","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natcatal","sideBox":"Learn more about [Nature Catalysis](http://www.nature.com/natcatal/)","snPcode":"","submissionUrl":"","title":"Nature Catalysis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"bb1efc72-c91b-45c1-9b54-ea0e76ee0b91","owner":[],"postedDate":"January 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":43568885,"name":"Physical sciences/Chemistry/Catalysis/Catalytic mechanisms"},{"id":43568886,"name":"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology"},{"id":43568887,"name":"Physical sciences/Chemistry/Green chemistry/Sustainability"},{"id":43568888,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2026-02-21T08:07:02+00:00","versionOfRecord":{"articleIdentity":"rs-5669760","link":"https://doi.org/10.1038/s41929-026-01496-w","journal":{"identity":"nature-catalysis","isVorOnly":false,"title":"Nature Catalysis"},"publishedOn":"2026-02-20 05:00:00","publishedOnDateReadable":"February 20th, 2026"},"versionCreatedAt":"2025-01-30 05:40:41","video":"","vorDoi":"10.1038/s41929-026-01496-w","vorDoiUrl":"https://doi.org/10.1038/s41929-026-01496-w","workflowStages":[]},"version":"v1","identity":"rs-5669760","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5669760","identity":"rs-5669760","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}