Abstract
Functional group interconversion, a pivotal synthetic technique for precise editing of molecular building blocks, is particularly rare when facilitated by energy transfer catalysis. Herein, we showcase two instances of photochemical rearrangement of isonitriles, facilitated by energy transfer catalysis under visible light. The di-π-ethane rearrangement and di-π-propane rearrangement proceed through a six-membered transition state, offering a fresh synthetic paradigm for constructing three- and five-membered molecular architectures. Notably, these open-shell rearrangements demonstrate a vast substrate scope, compatibility with diverse functional groups, and applicability to complex drug and natural product derivatives, thereby presenting a complementary strategy for advancing energy transfer-enabled functional group interconversion. Furthermore, the photochemical rearrangements of isonitriles have been supported by computational studies.
Introduction
Functional group interconversion is one of the fundamental synthetic steps1,2, which has been widely applied in organic chemistry, drug discovery and material science3,4,5. Radical rearrangement is one of the efficient synthetic tools, which has also become an established tool to achieve molecular rearrangement6,7,8,9,10,11,12,13,14, especially thanks to the resistance of radical chemistry15,16,17,18,19,20,21,22,23. For example, the versatile nitrile functional group24,25 has been widely explored in radical translocation reactions by Kalvoda26, Watt27,28, Beckwith29, Zhu30,31,32, Liu32 and many others7. Very recently, Xu and co-workers developed an innovative radical translocation of cyano functional groups by reversible C-H sampling33. However, these excellent examples all undergo an electron transfer mechanism. Inspired by the seminal work by Zimmerman and others regarding photochemical di-π-methane rearrangement (Fig. 1A)34,35,36,37, we developed the di-π-ethane (DPE) rearrangement of cyano functional groups via energy transfer catalysis through a five-membered ring transition state (Fig. 1B)38, which not only overcomes the limitation that cyano functional groups cannot be translocated in the classical photochemical di-π-methane (DPM) rearrangement, but also extends the concept of di-π-methane (DPM) rearrangement.
A Seminal work: photochemical di-π-methane rearrangement; B Previous work: di-π-ethane rearrangement via EnT catalysis; C This work: photochemical rearrangement of isonitriles via EnT catalysis.
The isonitrile functional group is another important functional group in synthetic chemistry39,40,41 and also a common radical acceptor in radical chemistry42. Unfortunately, the isonitrile group could also not be interconverted using classic di-π-methane (DPM) rearrangement. Based on the success of our previous work, we wonder whether the concept of di-π-ethane rearrangement could be applied to the interconversion of the isonitrile functional group. Radical cyclisation is well-documented to favor the 5-exo pathway, as the associated transition state exhibits a significantly lower kinetic barrier compared to the 6-endo alternative43,44. The challenge is that a six-membered transition state may need higher energy barrier compared to the five-membered ring in previous successful examples30,33,45. We hypothesized that a highly active isonitrile functional group may overcome the above limitation toward the atypical 6-endo-dig pathway. The radical intermediate preferentially adds to the terminal carbon of the isonitrile, forming a stabilized imidoyl radical42 and interconverts to the isonitrile functional group via a six-membered ring state, which will be particularly advantageous for the development of visible light-driven di-π-ethane (DPE) rearrangement38,46,47 and π, σ-methane rearrangement48,49 through energy transfer catalysis50,51,52,53,54. In this article, we report two types of photochemical rearrangement of isonitriles, facilitated by energy transfer catalysis under visible light via a six-membered transition state to build three-membered and five-membered architectures (Fig. 1C).
Results and discussion
Optimization of di-π-ethane rearrangement of isonitriles
To validate our concept, we synthesized substrate 1a and tested it with different photocatalysts. These included Eosin Y (Fig. 2, entry 1), Ru(bpy)3PF6 (entry 2), Ir(ppy)3 (entry 3), 4CzIPN (entry 4), Ir-F (entry 5), and thioxanthone (entry 6). We achieved an isolated yield of the desired product 2 of up to 91%. We also screened different organic solvents, finding trifluoromethyl benzene to be the optimal choice, yielding a 93% result (entry 7). Further investigations into the catalytic amounts of thioxanthone and reaction times revealed that a 92% isolated yield of product 2 could be obtained using just 1 mol% thioxanthone for a duration of 9 hours (entries 9-10). Control experiments confirmed that both the photocatalyst and visible light are crucial for facilitating the di-π-ethane rearrangement of isonitrile functional groups.
1a (0.2 mmol), Thioxanthone (TXT, 5 mol %), and MeCN (2 mL, 0.1 M) at room temperature under 30 W 405 nm LEDs with a cooling fan for 12 h under N2. a Isolated yield. b 450 nm LEDs are used instead of 405 nm LEDs. c PhCF3 as solvent. d Thioxanthone (TXT, 1 mol%) was used as photocatalyst.
Substrate scope of di-π-ethane rearrangement of isonitriles
With the optimal conditions established, we proceeded to explore the scope of the di-π-ethane rearrangement of isonitriles (Fig. 3). We found that various substitutions on the aromatic ring were well-tolerated, including methyl (3), fluorine (4), chloride (5), trifluoromethyl (6), sulfoxide (7), ester (8), nitrile (9), methoxy (10), amine (11), multi-substituted fluorine (12), and ortho-substituted fluorine (13). Subsequently, a range of heteroaromatic rings were also tested, such as pyrrole (14), thiophene (15), furan (16), indole (17), benzothiophene (18), and benzofuran (19), all yielding the desired products in good to excellent yields. Additionally, we examined various diene motifs for activating the substrate to generate the corresponding diradical species. Interestingly, different diene substrates, including both cyclic and acyclic dienes (20–26), were accommodated with good yields. Notably, enyne motifs were also found to be activatable, leading to the formation of radical intermediates, with products 27 and 28 obtained in moderate yields. Lastly, we explored the rearrangement’s applicability to complex architectures derived from L-citronellol (29), vitamin E (30), L-menthol (31), diacetone fructose (32), pregnenolone (33), and L-(-)-borneol (34). The desired products (29–34) were successfully synthesized in good yields, highlighting the broad applicability and generality of this photochemical rearrangement.
Reaction condition: 1a-1ag (0.2 mmol), Thioxanthone (TXT, 1 mol %), and PhCF3 (2 mL, 0.1 M) at room temperature under 30 W 405 nm LEDs with a cooling fan for 9 h under N2. a 27 h; b Ir-F (1 mol%) as photocatalyst; c DCE as solvent.
We conducted further investigations into the di-π-ethane rearrangement of isonitriles to gain deeper insights (Fig. 4). Under the optimized conditions, using substrate 1ah, we observed the formation of both products 35 and 35’, indicating that migration could occur on both the isonitrile and phenyl functional groups. Additional experiments with substrate 1ai also resulted in both migration products (36 & 36’). Interestingly, when the substrate 1aj or 1ak was subjected to the optimized condition, only the isonitrile functional group was interconverted, and the corresponding product 37 or 38 could be obtained smoothly. Furthermore, the substrates 1al and 1am containing two alkyl functional groups could also react under the optimized conditions, and the corresponding three-membered rings 39 and 40 could be obtained in high yields. Unfortunately, the substrate 1an, only containing one ester functional group or 1ao, containing only one alkyl functional group, could not afford the corresponding products 41 or 42. Our findings suggest that the migration of functional groups is influenced by the rate of the migration step and the stability of the newly formed radical intermediates. In comparison to our previous work on the di-π-ethane rearrangement of nitrile functional groups, we successfully managed to interconvert the isonitrile functional group triggered by secondary radical species, which was not successful in the previous work38. We obtained the desired product 43 with an 87% isolated yield. We further explored the reaction with tetra-substituted alkene 1aq, but unfortunately, the desired product 44 was not formed. Attempts to synthesize the four-membered product 45 were also unsuccessful. Similarly, when using an ester-substituted alkene 1as, we failed to detect the formation of the desired product 46.
Reaction condition: 1ah-1as (0.2 mmol), Thioxanthone (TXT, 1 mol%), and PhCF3 (2 mL, 0.1 M) at room temperature under 30 W 405 nm LEDs with a cooling fan for 36 h under N2. a 9 h; b TXT (5 mol%); c TXT (10 mol%), 60 h, d 390 nm LEDs (0.479 W/cm2), 52 °C.
Optimization of di-π-propane rearrangement of isonitriles
A limitation of our recently developed di-π-ethane rearrangement for nitrile functional groups was our inability to synthesize the five-membered product38. To address this and extend our photochemical rearrangement toolkit, we successfully developed a di-π-propane rearrangement for isonitriles. We easily synthesized substrate 47a and applied the standard conditions, resulting in a 57% isolated yield of the five-membered product 48 with a diastereomeric ratio of 5:1 (Fig. 5). Both isomers were confirmed through X-ray analysis (CCDC 2417730 for trans-48 and CCDC 2419059 for cis-48). We further explored photocatalyst loading, different photocatalysts, and various organic solvents. The optimized condition demonstrated that the di-π-propane rearrangement is efficient with just 2 mol% of TXT photocatalyst using acetonitrile as the solvent, achieving a 71% isolated yield of the desired product 48 with a 6:1 dr (entry 7).
Reaction condition: 47a (0.2 mmol), Thioxanthone (TXT, 1 mol%), and PhCF3 (2 mL, 0.1 M) at room temperature under 30 W 405 nm LEDs with a cooling fan for 9 h under N2. a Isolated yield; b 450 nm LEDs is used instead of 405 nm LEDs. c 2 mol% of TXT.
Substrate scope of di-π-propane rearrangement of isonitriles
We proceeded to explore the substrate scope for the di-π-propane rearrangement of isonitrile functional groups (Fig. 6). This rearrangement demonstrated robust performance across a variety of functional groups, including methoxy (49), fluorine (50, 56, 57), chloride (51), bromide (52), trifluoromethyl (53, 58), nitrile (54) and ester (55). Interestingly, ortho-substituted substrates enhanced the diastereoselectivity of the resulting products (57, 58). Notably, heteroaromatic groups such as thiophene (59), furan (60), and naphthyl (61) were also well-tolerated in this newly developed rearrangement. Additionally, when testing substrate 47o, which contains a diene motif, we successfully obtained the desired product 62 with an 82% isolated yield, albeit with low diastereoselectivity.
Reaction condition: 43 (0.2 mmol), Thioxanthone (TXT, 2 mol%), and MeCN (2 mL, 0.1 M) at room temperature under 30 W 405 nm LEDs with a cooling fan for 9 h under N2. a TXT (10 mol%).
Mechanistic studies and synthetic applications
Following the successful development of two photochemical rearrangements, we conducted gram-scale experiments. Both the three-membered (2) and five-membered (48) products were obtained in good yields (Fig. 7A). The nitrile functional group in 2 could be converted to an ester functional group (63) in 56% isolated yield, and the 3-oxabicyclo[4.1.0]heptan-4-ol (64) could be obtained in 62% isolated yield using 6 equivalents of DIBAL-H. The nitrile group in 48 could be converted to primary amine 65 in 92% yield. Pleasingly, the nitrile group could also be transferred to aldehyde (66), ketone (67), ester (68), alkyne (69) and alkene (70) efficiently with good to excellent yields (Fig. 7B). Additionally, we carried out radical inhibitor and triplet energy quenching experiments. In these experiments, the formation of products 2 and 48 was significantly hindered, indicating the essential role of radical processes (Fig. 7C). An electron paramagnetic resonance (EPR) experiment with substrate 47a further confirmed the involvement of carbon radicals in the catalytic system (Fig. 7D). UV–Vis spectroscopy and Stern-Volmer quenching experiments were also conducted and demonstrating that the photocatalyst exclusively absorbs visible light, and substrates 1a or 47a are capable of quenching the photo-excited photocatalyst (Fig. 7E).
A Gram-scale experiments; B Synthetic applications; C Radical inhibitor & triplet energy quenching experiments; D EPR experiment of substrate 47a; E Stern-Volmer quenching experiments. Reaction conditions: [a] EtOH/AcCl = 2/1 (0.4 M), 60 °C, 10 h. [b] DIBAL-H (6.0 equiv.), DCM (0.2 M), −78 °C, 12 h; then Rochelle salt (aq.). [c] LiAlH4 (1.2 equiv.), THF (0.2 M), 0 °C, overnight. [d] DIBAL-H (2.0 equiv.), DCM (0.2 M), −78 °C, 12 h; then Rochelle salt (aq). [e] (i) PhLi (3.0 equiv.), Et2O (0.2 M), 0 °C to RT, 4 h; (ii) Acetone/HCl = 1/1 (0.1 M), 70 °C, overnight. [f] MeOH/AcCl = 2/1 (0.4 M), 60 °C, 10 h. [g] Ohira-Bestmann reagent (2.4 equiv.), K2CO3 (3.0 equiv.), MeOH (0.2 M), RT, 6 h. [h] MTPPB (1.2 equiv.), t-BuOK (1.2 equiv.), THF (0.2 M), 0 °C to RT, 12 h.
Computational studies of photochemical rearrangement of isonitriles
To gain deeper insights into the photochemical rearrangement of isonitriles, we performed density functional theory (DFT) calculations (Fig. 8). As shown in Fig. 8A, the adiabatic triplet π, π* reactant 1a* is 53.3 kcal/mol radiative to the ground state of 1a. The transition sate TS1 (9.5 kcal/mol) was obtained, leading to intermediate I (−11.4 kcal/mol), which is a 1,3-diradical. The intermediate I can undergo isonitrile migration via TS2 (ΔΔG‡rel = 9.6 kcal/mol) to form the more stable diradical intermediate II (-33.2 kcal/mol). A minimum-energy crossing point (MECP) was located, which furnishes the final coupled product 2. The di-π-propane rearrangement of isonitrile functional groups was also calculated (Fig. 8B). Energy transfer from the excited photosensitizer to substrate 47a yields the triplet 47a* (50.8 kcal/mol uphill in energy which can be accessed by triplet–triplet EnT with excited TXT), the diradical intermediate III (−14.7 kcal/mol) could be formed via TS3 with a small energy barrier (ΔΔG‡rel = 8.6 kcal/mol). The newly generated diradical intermediate III undergoes isonitrile migration to form the diradical species IV (−38.1 kcal/mol) via an energy barrier (ΔΔG‡rel = 9.0 kcal/mol). Compared to a relatively high energy barrier (ΔΔG‡rel = 30.0 kcal/mol) for the hydrogen atom transfer (HAT) process, the diradical intermediate IV prefers to undergo the MECP2 process to form the singlet intermediate VI, which can lead to the final coupling product 48. The trans-48 product (−84.3 kcal/mol) is preferred than cis-48 product (−80.2 kcal/mol) with a lower trans-VI singlet intermediate (−37.2 kcal/mol), which is consistent with the experimental results.
A DFT calculation of di-π-ethane rearrangement of isonitriles; B DFT calculation of di-π-propane rearrangement of isonitriles.
In summary, we successfully demonstrated two types of photochemical rearrangements: di-π-ethane and di-π-propane rearrangements of isonitrile functional groups, facilitated by energy transfer catalysis under visible light conditions. These rearrangements exhibit a broad substrate scope and functional group tolerance, producing three- or five-membered cyclic architectures in high to excellent yields. The key to two photochemical rearrangements is the efficient formation of a six-membered transition state, supported by computational studies that align with the proposed mechanism. We anticipate that these novel rearrangements will expand the concept of di-π-ethane rearrangement and functional group interconversion enabled by photochemical rearrangements.
Methods
General procedure A to synthesize products 2–17, 19–32, 34, 39–46
Step 1: An oven-dried 40 mL vial equipped with a magnetic stir bar was charged with TXT (4.2 mg, 0.02 mmol). The vial was pumped into a glovebox, and then PhCF3 (20 mL) was added via a syringe to prepare a photocatalyst solution (1.0 mM).
Step 2: An oven-dried 8 mL vial equipped with a magnetic stir bar was charged with the isocyanide 1 (0.2 mmol, 1.0 equiv.). The vial was pumped into a glovebox, and then the TXT solution (2.0 mL, 0.1 M) was added via a syringe. The vial was sealed and removed from the glovebox and irradiated with 405 nm LEDs (with a stream of air blowing over vials in a water bath to keep the reaction at 25–30 °C). After 9 h, the reaction was concentrated under reduced pressure and then purified by flash column chromatography to provide the corresponding products.
General procedure B to synthesize product 18
An oven-dried 8 mL vial equipped with a magnetic stir bar was charged with the substrate 1q (0.2 mmol, 71.4 mg, 1.0 equiv.) and Ir-F (0.002 mmol, 2.2 mg, 1.0 mol%). The vial was pumped into a glovebox, and then PhCF3 (2.0 mL, 0.1 M) was added via a syringe. The vial was sealed and removed from the glovebox and irradiated with 405 nm LEDs (with a stream of air blowing over vials in a water bath to keep the reaction at 25–30 °C). After 9 h, the reaction was purified by flash column chromatography (PE/Acetone = 30/1 to 20/1) to provide 18 as a colorless light liquid.
General procedure C to synthesize product 33
Step 1: An oven dried 40 mL vial equipped with a magnetic stir bar was charged with TXT (4.2 mg, 0.02 mmol). The vial was pumped into a glovebox and then DCE (20 mL) was added via a syringe to prepare a photocatalyst solution (1.0 mM).
Step 2: An oven-dried 8 mL vial equipped with a magnetic stir bar was charged with the substrate 1af (136.7 mg, 0.2 mmol, 1.0 equiv.). The vial was pumped into a glovebox, and then the TXT solution (1.0 mM TXT in DCE, 2.0 mL) was added via a syringe. The vial was sealed and removed from the glovebox and irradiated with 405 nm LEDs (with a stream of air blowing over vials in water bath to keep reaction at 25 ~ 30 °C). After 9 h, the reaction was purified by flash column chromatography (PE/Acetone = 15/1 to 3/1) to provide 33 as a colorless light liquid.
General procedure D to synthesize products 35–38
Step 1: An oven-dried 40 mL vial equipped with a magnetic stir bar was charged with TXT (4.2 mg, 0.02 mmol). The vial was pumped into a glovebox and then PhCF3 (20 mL) was added via a syringe to prepare a photocatalyst solution (1.0 mM).
Step 2: An oven-dried 8 mL vial equipped with a magnetic stir bar was charged with the isocyanide 1 (0.2 mmol, 1.0 equiv.). The vial was pumped into a glovebox, and then the TXT solution (2.0 mL) was added via a syringe. The vial was sealed and removed from the glovebox and irradiated with 405 nm LEDs (with a stream of air blowing over vials in a water bath to keep the reaction at 25–30 °C). After 36 h, the reaction was concentrated under reduced pressure and then purified by flash column chromatography to provide the corresponding products.
General procedure E to synthesize products 48–51, 53–57, 61
Step 1: An oven-dried 40 mL vial equipped with a magnetic stir bar was charged with TXT (8.4 mg, 0.04 mmol). The vial was pumped into a glovebox, and then MeCN (20 mL) was added via a syringe to prepare a photocatalyst solution (2.0 mM).
Step 2: An oven-dried 8 mL vial equipped with a magnetic stir bar was charged with the isocyanide 47 (0.2 mmol, 1.0 equiv.). The vial was pumped into a glovebox, and then the TXT solution (2.0 mL, 0.1 M) was added via a syringe. The vial was sealed and removed from the glovebox and irradiated with 405 nm LEDs (with a stream of air blowing over the vials in a water bath to keep the reaction at 25–30 °C). After 9 h, the reaction was concentrated under reduced pressure and then purified by flash column chromatography to provide the corresponding products.
General procedure F to synthesize products 52, 58–60, 62
An oven-dried 8 mL vial equipped with a magnetic stir bar was charged with the d isocyanide 47 (0.2 mmol, 1.0 equiv.) and TXT (0.02 mmol, 4.2 mg, 10 mol%). The vial was pumped into a glovebox, and then MeCN (2.0 mL, 0.1 M) was added via a syringe. The vial was sealed and removed from the glovebox and irradiated with 405 nm LEDs (with a stream of air blowing over vials in a water bath to keep the reaction at 25–30 °C). After 9 h, the reaction was concentrated under reduced pressure and then purified by flash column chromatography to provide the corresponding products.
Data availability
Materials and methods, detailed optimization studies, experimental procedures, mechanistic studies, NMR spectra and computational data are available in the Supplementary Information and from the corresponding authors upon request. Source data are provided with this paper. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Center (CCDC), under deposition numbers 2417730 and 2419059. These data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif. Source data are provided with this paper.
References
Campos, K. R. et al. The importance of synthetic chemistry in the pharmaceutical industry. Science 363, eaat0805 (2019).
Rojas, C. M. Molecular Rearrangements in Organic Synthesis. (John Wiley & Sons, Inc., 2015).
Boström, J., Brown, D. G., Young, R. J. & Keserü, G. M. Expanding the medicinal chemistry synthetic toolbox. Nat. Rev. Drug Discov. 17, 709–727 (2018).
Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).
Jurczyk, J. et al. Single-atom logic for heterocycle editing. Nat. Synth. 1, 352–364 (2022).
Robertson, J., Pillai, J. & Lush, R. K. Radical translocation reactions in synthesis. Chem. Soc. Rev. 30, 94–103 (2001).
Wu, X., Ma, Z., Feng, T. & Zhu, C. Radical-mediated rearrangements: past, present, and future. Chem. Soc. Rev. 50, 11577–11613 (2021).
Li, W., Xu, W., Xie, J., Yu, S. & Zhu, C. Distal radical migration strategy: an emerging synthetic means. Chem. Soc. Rev. 47, 654–667 (2018).
Wu, X. & Zhu, C. Radical-mediated remote functional group migration. Acc. Chem. Res. 53, 1620–1636 (2020).
Studer, A. & Bossart, M. Radical aryl migration reactions. Tetrahedron 57, 9649–9667 (2001).
Holden, C. M. & Greaney, M. F. Modern aspects of the smiles rearrangement. Chem. A Eur. J. 23, 8992–9008 (2017).
Chen, Z. M., Zhang, X. M. & Tu, Y. Q. Radical aryl migration reactions and synthetic applications. Chem. Soc. Rev. 44, 5220–5245 (2015).
Sivaguru, P., Wang, Z., Zanoni, G. & Bi, X. Cleavage of carbon-carbon bonds by radical reactions. Chem. Soc. Rev. 48, 2615–2656 (2019).
Wu, X. & Zhu, C. Radical functionalization of remote C(sp3)–H bonds mediated by unprotected alcohols and amides. CCS Chem. 2, 813–828 (2020).
Twilton, J. et al. The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052 (2017).
Yan, M., Lo, J. C., Edwards, J. T. & Baran, P. S. Radicals: reactive intermediates with translational potential. J. Am. Chem. Soc. 138, 12692–12714 (2016).
Studer, A. & Curran, D. P. The electron is a catalyst. Nat. Chem. 6, 765–773 (2014).
Skubi, K. L., Blum, T. R. & Yoon, T. P. Dual catalysis strategies in photochemical synthesis. Chem. Rev. 116, 10035–10074 (2016).
Kärkäs, M. D., Porco, J. A. & Stephenson, C. R. J. Photochemical approaches to complex chemotypes: applications in natural product synthesis. Chem. Rev. 116, 9683–9747 (2016).
Xuan, J. & Xiao, W. J. Visible-light photoredox catalysis. Angew. Chem. Int. Ed. 51, 6828–6838 (2012).
Wang, F., Chen, P. & Liu, G. Copper-catalyzed radical relay for asymmetric radical transformations. Acc. Chem. Res. 51, 2036–2046 (2018).
Li, Z. L., Fang, G. C., Gu, Q. S. & Liu, X. Y. Recent advances in copper-catalysed radical-involved asymmetric 1,2-difunctionalization of alkenes. Chem. Soc. Rev. 49, 32–48 (2020).
Murray, P. R. D. et al. Photochemical and electrochemical applications of proton-coupled electron transfer in organic synthesis. Chem. Rev. 122, 2017–2291 (2022).
Wang, F., Chen, P. & Liu, G. Copper-catalysed asymmetric radical cyanation. Nat. Synth. 1, 107–116 (2022).
Zhang, W. et al. Enantioselective cyanation of benzylic C–H bonds via copper-catalyzed radical relay. Science 353, 1014–1018 (2016).
Kalvoda, J. A new type of intramolecular group-transfer in steroid photochemistry. A contribution to the mechanism of the oxidative cyanohydrin-cyano-ketone rearrangement. J. Chem. Soc. D Chem. Commun. 1970, 1002–1003 (1970).
Watt, D. S. A reiterative functionalization of unactivated carbon-hydrogen bonds. Photolysis of.alpha.-peracetoxynitriles. J. Am. Chem. Soc. 98, 271–273 (1976).
Freerksen, R. W. et al. Photolysis of.alpha.-peracetoxynitriles. 2. A comparison of two synthetic approaches to 18-cyano-20-ketosteroids. J. Am. Chem. Soc. 99, 1536–1542 (1977).
Beckwith, A. L. J., O’Shea, D. M., Gerba, S. & Westwood, S. W. Cyano or acyl group migration by consecutive homolytic addition and β-fission. J. Chem. Soc., Chem. Commun. 1987, 666–667 (1987).
Wu, Z., Ren, R. & Zhu, C. Combination of a cyano migration strategy and alkene difunctionalization: the elusive selective azidocyanation of unactivated olefins. Angew. Chem. Int. Ed. 55, 10821–10824 (2016).
Wang, M., Huan, L. & Zhu, C. Cyanohydrin-mediated cyanation of remote unactivated C(sp3)-H bonds. Org. Lett. 21, 821–825 (2019).
Wang, N. et al. Catalytic diverse radical-mediated 1,2-cyanofunctionalization of unactivated alkenes via synergistic remote cyano migration and protected strategies. Org. Lett. 18, 6026–6029 (2016).
Chen, K. et al. Functional-group translocation of cyano groups by reversible C–H sampling. Nature 620, 1007–1012 (2023).
Zimmerman, H. E., Binkley, R. W., Givens, R. S. & Sherwin, M. A. Mechanistic organic photochemistry. XXIV. The mechanism of the conversion of barrelene to semibullvalene. A general photochemical process. J. Am. Chem. Soc. 89, 3932–3933 (1967).
Hixson, S. S., Mariano, P. S. & Zimmerman, H. E. Di-.pi.-methane and oxa-di-.pi.-methane rearrangements. Chem. Rev. 73, 531–551 (1973).
Zimmerman, H. E. & Armesto, D. Synthetic aspects of the Di-π-methane rearrangement. Chem. Rev. 96, 3065–3112 (1996).
Riguet, E. & Hoffmann, N. in Comprehensive Organic Synthesis: Second Edition. Vol. 5 (Elsevier Ltd., 2014).
Zheng, Y., Dong, Q.-X., Wen, S.-Y., Ran, H. & Huang, H.-M. Di-π-ethane rearrangement of cyano groups via energy-transfer catalysis. J. Am. Chem. Soc. 146, 18210–18217 (2024).
Qiu, G., Ding, Q. & Wu, J. Recent advances in isocyanide insertion chemistry. Chem. Soc. Rev. 42, 5257 (2013).
Zhu, J. Recent developments in the isonitrile-based multicomponent synthesis of heterocycles. Eur. J. Org. Chem. 2003, 1133–1144 (2003).
Dömling, A. Recent developments in isocyanide based multicomponent reactions in applied chemistry. Chem. Rev. 106, 17–89 (2006).
Zhang, B. & Studer, A. Recent advances in the synthesis of nitrogen heterocycles via radical cascade reactions using isonitriles as radical acceptors. Chem. Soc. Rev. 44, 3505–3521 (2015).
Beckwith, A. L. J. Regio-selectivity and stereo-selectivity in radical reactions. Tetrahedron 37, 3073–3100 (1981).
Beckwith, A. L. J. & Schiesser, C. H. Regio- and stereo-selectivity of alkenyl radical ring closure: A theoretical study. Tetrahedron 41, 3925–3941 (1985).
Xu, Y., Huang, J., Pang, T., Wu, G. & Zhong, F. Norrish-Yang-type cyclopropanation via functional group migration with photosensitizer at ppb loading. Chem. Catal. 4, 101099 (2024).
Wen, S.-Y., Chen, J.-J., Zheng, Y., Han, J.-X. & Huang, H.-M. Energy-transfer enabled 1,4-Aryl migration. Angew. Chem. Int. Ed. 64, e202415495 (2025).
Wen, S.-Y., Chen, J.-J., Zheng, Y. & Huang, H.-M. Energy-transfer-enabled rearrangement involving pyridines. CCS Chem. 7, 2721–2730 (2025).
Wang, Q.-Z., Zheng, Y., Wu, W.-T. & Huang, H.-M. Oxa-π, σ-methane rearrangement approach for epoxide synthesis. J. Am. Chem. Soc. 147, 16248–16254 (2025).
Chen, S.-S., Zheng, Y., Xing, Z.-X. & Huang, H.-M. Borylated strain rings synthesis via photorearrangements enabled by energy transfer catalysis. Nat. Commun. 16, 3724 (2025).
Dutta, S., Erchinger, J. E., Strieth-Kalthoff, F., Kleinmans, R. & Glorius, F. Energy transfer photocatalysis: exciting modes of reactivity. Chem. Soc. Rev. 53, 1068–1089 (2024).
Zhou, Q., Zou, Y., Lu, L. & Xiao, W. Visible-light-induced organic photochemical reactions through energy-transfer pathways. Angew. Chem. Int. Ed. 58, 1586–1604 (2019).
Großkopf, J., Kratz, T., Rigotti, T. & Bach, T. Enantioselective photochemical reactions enabled by triplet energy transfer. Chem. Rev. 122, 1626–1653 (2022).
Zhu, M., Zhang, X., Zheng, C. & You, S.-L. Energy-transfer-enabled dearomative cycloaddition reactions of indoles/pyrroles via excited-state aromatics. Acc. Chem. Res. 55, 2510–2525 (2022).
Neveselý, T., Wienhold, M., Molloy, J. J. & Gilmour, R. Advances in the E → Z Isomerization of alkenes using small molecule photocatalysts. Chem. Rev. 122, 2650–2694 (2022).
Acknowledgements
We are grateful for financial support from the National Natural Science Foundation of China (22201179 & 22471168 to H.-M.H.), the startup funding from ShanghaiTech University (H.-M. H.). We thank the HPC Platform of ShanghaiTech University for computing time. We also sincerely thank Prof. Hong Yi (Wuhan University), Prof. Pengxin Liu, Fan Wu, Prof. Chaodan Pu, Zhuo Zhao and Kai-Dian Li (all in ShanghaiTech University) for help with EPR analysis, mechanistic studies and X-ray analysis.
Author information
Authors and Affiliations
Contributions
H.-M.H. conceived and directed the research; Q.-X.D., Y.-H.K., and Y.-H.T. performed the experiments and analyzed the data. H.-M.H., Y.-H.T., and S.Y. performed the DFT calculation and drafted the computation section. H.-M.H. wrote the manuscript with contributions from all authors.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Peer review
Peer review information
Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Website: https://sites.google.com/view/the-huang-group-shanghaitech
Supplementary information
Source data
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
About this article
Cite this article
Dong, QX., Ke, YH., Tang, YH. et al. Photochemical rearrangement of isonitriles via energy transfer catalysis. Nat Commun 16, 9417 (2025). https://doi.org/10.1038/s41467-025-64460-5
Received:
Accepted:
Published:
Version of record:
DOI: https://doi.org/10.1038/s41467-025-64460-5
