Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2026 Jan 30.
Published in final edited form as: J Am Chem Soc. 2025 Apr 23;147(18):14936–14944. doi: 10.1021/jacs.5c02425

Catalyst-Controlled Regiodivergent Synthesis of Bicyclo[2.1.1]hexanes via Photochemical Strain-Release Cycloadditions

Yu-Che Chang 1, María Martín 2, Kingsley Bortey 3, Quentin Lefebvre 4, Thomas Fessard 5, Christophe Salome 6, Ricardo Javier Vázquez 7, M Kevin Brown 8
PMCID: PMC12854239  NIHMSID: NIHMS2134988  PMID: 40266885

Abstract

Bicyclo[2.1.1]hexane is an emerging scaffold in various pharmaceutical settings, but the scarcity of approaches to target different regioisomers from a common starting material prevents targeting a broader range of chemical space. Herein, we demonstrate a new design for the photocatalyst-controlled regiodivergent synthesis of this scaffold. Of particular interest is that the synthesis of two distinct substitution patterns was achieved under photochemical conditions with catalyst control. This was possible due to the activating group, N-methylimidazole, not only playing an important role in guiding divergent pathways but also enabling transformation to various functional groups. Transient absorption spectroscopy discerned between the regiodivergent mechanisms, as assignable bands consistent with electron transfer and energy transfer processes were distinctively observed, depending on the identity of the photocatalyst.

Graphical Abstract

graphic file with name nihms-2134988-f0001.jpg

Saturated bicyclic scaffolds have gained significant attention in pharmaceutical and agricultural industries due to their promising nature as isosteres.1 These structures are candidates for replacing an aromatic ring due to their rigidity, allowing for the display of well-defined orientations. In addition, the increased sp3 content relative to an aromatic ring can improve physicochemical properties such as solubility and metabolic stability.2-5 Therefore, various methods have been demonstrated to construct diverse bicyclic skeletons.

Bicyclo[2.1.1]hexanes not only can be considered as isosteres of ortho- or meta-substituted aromatic rings but also are useful in cyclopentanes rigidification strategies.6 Due to the growing interest in bicyclo[2.1.1]hexanes, our group has initiated a program toward developing methods to access polysubstituted variants.7 Various approaches have been reported to gain access to the scaffold, such as crossed [2 + 2]-cycloaddition8-13 or ring contraction.7,14 In recent years, strain-release [2π+2σ]-cycloaddition with bicyclo[1.1.0]butanes (BCBs) has emerged as a powerful approach.15,16 Pioneering work from Wipf demonstrated thermal [2π+2σ]-cycloadditions with tethered alkenes.17 More recently, independent studies from our group/SpiroChem,18 the Glorius group,19 and the Procter group20 reported intermolecular strain-release cycloadditions with alkenes. Since these reports, many studies have disclosed strain-release cycloaddition of BCBs under a variety of activation modes (Scheme 1A).21-42

Scheme 1. Introduction.

Scheme 1.

Open in a new tab

Our team first reported the head-to-head synthesis of bicyclo[2.1.1]hexane initiated by energy transfer (Scheme 1B).18 Although the naphthalene is crucial as an “antenna” for Dexter energy transfer, conversion to a more synthetically useful ester does require Baeyer–Villiger oxidation under harsh conditions. More recently, independent studies from Glorius43 and Walker44 reported head-to-tail synthesis of bicyclo[2.1.1]hexanes through a photooxidation process (Scheme 1B). However, poor regioselectivity was observed for the reaction with the ketones. Controlled access to both regioisomers of a given product from a common starting material would be ideal for targeting a broader range of chemical space, but it remains a challenge. In this manuscript, we directly address this problem and report a catalyst-controlled regiodivergent method for the [2π+2σ]-cycloaddition of BCB with alkenes (Scheme 1C).

To achieve a regiodivergent reaction, we chose a C-acyl imidazole BCB as substrate.45-47 Depending on the presence or absence of a Lewis/Bronsted acid, photoinduced reduction, photoinduced oxidation, or energy transfer might occur to generate a reactive intermediate that may engage alkenes with different regioselectivity. Moreover, the C-acyl imidazole can readily be cleaved to the corresponding ester or amide.47

We initiated our investigation with C-acyl imidazole BCB 1 with various acid catalysts. Based on precedent from Yoon and Meggers on reactions of C-acyl imidazole cinnamates,47 we tested Ir-based photocatalysts in combination with (PhO)2P-(O)OH, but an unsatisfactory regioisomer ratio (rr) of 10:1 was obtained. In contrast, rac-RhS gave excellent regioselectivity but a lower yield (Table 1, entries 1 and 2). After screening different acids in combination with Ir-based photocatalysts, we identified Zn(OTf)2 as a promising additive forming 2 in 52% yield with >20:1 regioselectivity (Table 1, entry 3). Upon testing various Zn salts, the yield could be improved to 65% with ZnI2, while maintaining high selectivity (Table 1, entry 5). Finally, the reaction time could be reduced to 3 h (see the SI for details).

Table 1.

Reaction Optimizationa

graphic file with name nihms-2134988-t0008.jpg
Entry Ir Catalyst Additive Solvent Yield Ratio 2:3
1 [Ir(ppy)2(dtbbpy)](PF6) (PhO)2P(O)OH THF 54% 10:1
2 – rac-RhS THF 42% >20:1
3 [Ir(ppy)2(dtbbpy)](PF6) Zn(OTf)2 THF 52% >20:1
4 [Ir(ppy)2(dtbbpy)](PF6) ZnCI2 THF 20% >20:1
5 [Ir(ppy)2(dtbbpy)](PF6) ZnI2 THF 65% >20:1
6 [Ir(ppy)2(dtbbpy)](PF6) – THF 9% 1:8
7 [Ir(dFCF3ppy)2(dtbbpy)](PF6) – THF 20% 1:9
8 Ir(pCF3ppy)3 – THF 32% 1:10
9 Ir(ppy)3 – THF 61% 1:7
10 ITXb – THF 17% 1:5
11 Ir(ppy)3 – EtOAc 50% <1:20
12 Ir(ppy)3 – MeCN 90% 1:3
13 c Ir(ppy)3 – EtOAc 96% <1:20
14 Ir(ppy)3 ZnI2 THF 40% >20:1
Open in a new tab
a

All reactions are performed on 0.1 mmol scale. Yield and regioisomer ratio were determined by 1H NMR analysis of the unpurified reaction mixture using CH2Br2 as internal standard. NMI = N-methyl imidazole

b

10 mol % ITX (i-Prthioxanthone) with 395 nm LEDs.

c

Kessil 440 nm lamp is used.

Remarkably, in the absence of the Lewis acid catalyst, the other regioisomer of product 3 was formed in 8:1 rr, albeit in low yield, thus partially confirming our hypothesis (Table 1, entry 6). It was suspected that this reaction pathway might involve Dexter energy transfer; thus, photocatalysts with increased triplet energy were evaluated. Ir(ppy)3 (ET = 58.1 kcal/mol)48 allowed for product formation in 61% yield (Table 1, entry 9). Screening various solvents led to further improvement with EtOAc being identified as optimal as the product was formed in high regioselectivity (>20:1 rr). Finally, changing the light source from LED strips to Kessil 440 nm lamps improved the yield while maintaining the same regioselectivity (Table 1, entry 13). As a control experiment, the significance of ZnI2 with Ir(ppy)3 was evaluated and revealed that the head-to-head regioisomer was exclusively generated (Table 1, entry 14).

With a set of optimal conditions in hand, the scope under the ZnI2-catalyzed reaction conditions was first investigated (Scheme 2). In most cases, the reaction led to the formation of the head-to-head regioisomer as the only observable product by 1H NMR analysis.49 Various para-substituted styrenes such as OMe, ester, Cl, acetate, and Bpin were tolerated in the reaction with moderate yields observed (products 4–8). A more sterically demanding styrene was also tolerated in the system with a similar outcome (product 9). Heterocycles such as benzodioxole and indole could be installed with moderate yield (products 10, 11). 1,1-Disubstituted alkenes allowed the formation of quaternary carbon, carbocycle, and spirocarbocycle (products 12, 13). Polysubstituted bicyclo[2.1.1]hexanes formed with (E)- and (Z)-β-methyl styrene in high regio- and diastereoselectivity, albeit in low yield (product 15). Additional heterocycles were also investigated. Thiophene, furan, pyrrole, pyrazole, and pyridine were all well-tolerated to form products 16–20 in a good yield. In addition to styrenes, electron-deficient alkenes such as acrylate and methacrylate performed moderately well (products 21, 22). Dienes also work similarly well as styrene (23, 24). It is worth noting that the reaction with isoprene gave rise to a 4:1 mixture of regioisomers from reaction with each end of the diene. Moreover, variation of the aromatic group on the BCB N-methyl imidazole substrate was evaluated. The electronic and steric nature of the phenyl group did not greatly affect the reaction outcome (product 25–27). The phenyl group could be substituted by a simple methyl group, which led to the formation of the desired product 28. Finally, use of an imine allowed for synthesis of azabicyclo[2.1.1]hexane 29 in 46% yield.50

Scheme 2. Substrate Scope of Head-to-Head Reactiona.

Scheme 2.

Open in a new tab

aReaction run on 0.2 mmol scale. Yield represents the average of two separate experiments.

We then switched our attention to reactivity without ZnI2 (Scheme 3).49 Similar to the above scope, different electron-donating (products 30, 34, and 35) or electron-withdrawing substituents (products 31–33) were well-tolerated. Indene worked well and allowed for the formation of fused bicyclo[2.1.1]hexane (36). In addition, the spirocyclic product was formed by reaction with 1,1-disubstituted styrene (37). Interestingly, sterically hindered ortho-methylstyrene resulted in an erosion of the regioselectivity probably due to the repulsion between the methyl group and phenyl unit on the BCB (38). In addition to styrene, various heterocycles were also tolerated. Pyridine, thiophene, furan, pyrazole, and pyrrole all allowed for the formation of the desired products in good yields (products 40–44). Dienes also worked well and led to product formation in high regioselectivity (products 45, 46). Additionally, different aromatic groups on the BCB N-methyl imidazole substrate were explored. As previously observed, the electronic nature of the aryl unit does not greatly affect the reactivity (products 47, 48). However, the ortho-methyl substituent lowers the rr likely due to the steric repulsion with styrene (product 49). Pyridyl BCB also worked smoothly in the reaction (product 50). Finally, methyl BCB imidazole reacted poorly under these conditions and led to the formation of the other regioisomer as the major product (28). This is likely due to initial bond formation with the more reactive tertiary radical versus the ketyl radical.

Scheme 3. Substrate Scope of Head-to-Tail Reactiona.

Scheme 3.

Open in a new tab

aReaction run on 0.2 mmol scale. Yield represents the average of two separate experiments.

Both processes were run on a gram scale to showcase the robustness of this protocol (Scheme 4). With access to preparative amounts of both regioisomers in hand, two distinct methods to remove N-methyl imidazole were carried out. Alkylation of the imidazole moiety with methyl triflate followed by nucleophilic addition yielded the benzylamide and carboxylic acid products (51, 53, 58).51 Alternatively, following a procedure by Ohshima and Morimoto,52 simple heating of 3 with benzyl alcohol, followed by hydrogenolysis, led to carboxylic acid (56). The acids can be derivatized by a Curtius rearrangement to access amine products 54 and 59. In addition, redox-active esters 52 and 57 were prepared from the acid followed by decarboxylative borylation to allow the synthesis of 55 and 60 respectively.53

Scheme 4. Larger Scale Synthesis and Derivatization.

Scheme 4.

Open in a new tab

Reaction conditions: a(i) MeOTf, DCM, rt, 24 h; (ii) 2 M NaOH, DCM, rt, 24 h. b(i) MeOTf, DCM, rt, 24 h; (ii) BnNH2, DBU, DCM, rt, 24 h. c(i) DPPA, Et3N, PhMe, 110 °C, 24 h; (ii) 3 M HCl, AcOH, 0 °C to rt, 16 h. dNHPI, DCC, 10 mol % DMAP, DCM, rt, 12 h. eB2cat2, DMAc, rt, 16 h, blue LED; then pinacol, Et3N. f(i) BnOH, 150 °C, 24 h; (ii) Pd/C, H2, MeOH. rt, 16 h.

To probe the mechanism of both pathways, several control experiments were performed (Scheme 5A). Under conditions reported by Glorius and Walker, the reaction was low yielding and led to a mixture of regioisomers. This indicates that photooxidation is unlikely to occur in either process described herein.43,44 Next, we explored the role of the imidazole. Under the Lewis acid catalyzed conditions, the BCB methyl ester 61 and BCB phenyl ketone 62 react poorly (products 63, 64), which establishes the unique activating ability of the imidazole unit. In the absence of a Lewis acid, BCB methyl ester 61 leads to the formation of product 65 in low yield. Though BCB phenyl ketone 62 reacts to give 66 in good yield, the regioselectivity is low.

Scheme 5. Mechanistic Insights.

Scheme 5.

Open in a new tab

The lack of a change in the UV/vis spectrum upon mixing the substrates in the presence or absence of the zinc additive indicates that the formation of an electron donor–acceptor complex is unlikely (Scheme 5B).54 Stern–Volmer quenching experiments also supported that both 1 and its zinc complex quench the excited state of the Ir-complex more effectively compared to styrene (Scheme 5C).

Transient absorption spectroscopy (TAS) was performed to elucidate the nature of the excited state catalyst quenching event. Measurements were conducted at higher concentrations than the reaction conditions while maintaining equivalent ratios between the photocatalyst and substrates. As shown in Scheme 5D-a and Scheme 5D-b, a long-lived excited state absorption (ESA) band spanning the microsecond time scale, consistent with triplet states, was detected for Ir(ppy)3 under O2-free conditions.55 Notably, the ESA profile of Ir(ppy)3 exhibited similar photophysical trends in the presence of O2 and 1 under O2-free conditions, with minimal ESA quenching and a robustly shortened ESA lifetime. This photophysical profile is consistent with a photocatalytic mechanism governed by Dexter energy transfer (EnT), as described by McCusker and co-workers.56

As observed in Scheme 5D-c and Scheme 5D-d, [Ir(ppy)2(dtbbpy)](PF6) also exhibits a long-lived ESA consistent with triplet states under the O2-free conditions. As expected, this photocatalyst undergoes quenching of the ESA via an EnT mechanism upon exposure to O2, with minimal ESA quenching and a shortened ESA lifetime observed under these conditions. However, a different photophysical profile was obtained when [Ir(ppy)2(dtbbpy)](PF6) was exposed to the zinc complex of 1 in O2-free conditions. Notably, a significant loss of the ESA band was observed, indicative of photocatalyst consumption and consistent with an oxidative quenching electron-transfer (ET) mechanism, as described by McCusker and co-workers.56 The significant loss of the ESA band, concomitant with its lengthening, suggests the formation of a new chemical species, presumably a reduced Zn-based chemical substrate. These clearly distinct photophysical profiles are in line with our hypothesis regarding the regiodivergent synthesis of bicyclo[2.1.1]hexanes.

The studies outlined in Scheme 5 suggest the reaction mechanisms shown in Scheme 6. First, in the absence of Lewis acid, 1 is sensitized via Dexter energy transfer with Ir(ppy)3* (ET = 59.2 kcal/mol, see SI for details) to form a triplet excited state (ET = 62 kcal/mol, see SI for details). Ring cleavage can then occur to generate triplet II. This intermediate reacts with styrene by first forming a bond with the more electrophilic α-carbonyl radical (as opposed to the benzylic radical), followed by ISC and bond formation to generate product 3. In the presence of ZnI2, coordination likely occurs with the C-acyl imidazole unit. Next, IV is reduced by [Ir]*, generating ketyl radical intermediate V. The BCB then undergoes C─C bond cleavage to generate a benzylic radical and a zinc enolate. The addition of the alkene to the benzylic radical, followed by oxidation and ring closure, leads to the formation of product 2. The benzylic carbocation formation was supported by the electronic nature of styrene. Since the carbocation could be stabilized with electron-donating aromatics, the yields were generally higher (products 4, 6, 7, and 9).

Scheme 6. Proposed Reaction Mechanism.

Scheme 6.

Open in a new tab

In conclusion, a catalyst controlled regiodivergent strategy to access structurally diverse bicyclo[2.1.1]hexane is presented. Under catalyst control, diverse reactions enabled the formation of the products in good yield and high regioselectivity. The activating group can be easily transformed into a variety of functional groups. Finally, transient absorption spectroscopy suggests the energy transfer process and photoreduction mechanisms of each pathway.

Supplementary Material

Supporting Info

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c02425.

  • Experimental procedures, analytical data for all new compounds. (PDF)

ACKNOWLEDGMENTS

We thank Indiana University, the NIH (R35GM131755), and Spirochem AG for financial support. This project was partially funded by the Vice Provost for Research through the Research Equipment Fund and the NSF MRI program, CHE-1726633 and CHE-1920026. We thank Dr. Maren Pink and Dr. Nobu Yamamoto of the IU Molecular Structure Center for the acquisition of X-ray crystal structure data. We thank Professor Ryan Van Hoveln from Indiana State University and Alec Sanchez from Indiana University Bloomington for the helpful discussions regarding DFT calculations. Support for the acquisition of the Bruker Venture D8 diffractometer through the Major Scientific Research Equipment Fund from the President of Indiana University and the Office of the Vice President for Research is gratefully acknowledged. M.M. thanks Ministerio de Universidades for FPU (FPU20/06320) and Mobility (EST24/00610) fellowships.

Footnotes

Accession Codes

Deposition Numbers 2422484–2422485 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via the joint Cambridge Crystallographic Data Centre (CCDC) and Fachinformationszentrum Karlsruhe Access Structures service.

The authors declare no competing financial interest.

Contributor Information

Yu-Che Chang, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

María Martín, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

Kingsley Bortey, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

Quentin Lefebvre, SpiroChem AG, Basel 4058, Switzerland.

Thomas Fessard, SpiroChem AG, Basel 4058, Switzerland.

Christophe Salome, SpiroChem AG, Basel 4058, Switzerland.

Ricardo Javier Vázquez, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

M. Kevin Brown, Department of Chemistry, Indiana University, Bloomington, Indiana 47405, United States.

REFERENCES

  • (1).Subbaiah MAM; Meanwell NA Bioisosteres of the Phenyl Ring: Recent Strategic Applications in Lead Optimization and Drug Design. J. Med. Chem 2021, 64, 14046–14128. [DOI] [PubMed] [Google Scholar]
  • (2).Lovering F; Bikker J; Humblet C Escape from Flatland: Increasing Saturation as an Approach to Improving Clinical Success. J. Med. Chem 2009, 52, 6752–6756. [DOI] [PubMed] [Google Scholar]
  • (3).Lovering F. Escape from Flatland 2: complexity and promiscuity. Med. Chem. Commun 2013, 4, 515–519. [Google Scholar]
  • (4).Mykhailiuk PK Saturated Bioisosteres of Benzene: Where to go Next? Org. Biomol. Chem 2019, 17, 2839–2849. [DOI] [PubMed] [Google Scholar]
  • (5).Tse EG; Houston SD; Williams CM; Savage GP; Rendina LM; Hallyburton I; Anderson M; Sharma R; Walker GS; Obach RS; Todd MH Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of novel Open-Source Antimalarials. J. Med. Chem 2020, 63, 11585–11601. [DOI] [PubMed] [Google Scholar]
  • (6).Tsien J; Hu C; Merchant RR; Qin T Three-dimensional Saturated C(sp3)-rich Bioisosteres for Benzene. Nat. Rev. Chem 2024, 8, 605–627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (7).Paul S; Adelfinsky D; Salome C; Fessard T; Brown MK 2,5-Disubstituted Bicyclo[2.1.1]hexanes as Rigidified Cyclopentane Variants. Chem. Sci 2023, 14, 8070–8075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (8).Denisenko A; Garbuz P; Shishkina SV; Voloshchuk NM; Mykhailiuk PK Saturated Bioisosteres of ortho-Substituted Benzenes. Angew. Chem., Int. Ed 2020, 59, 20515–20521. [DOI] [PubMed] [Google Scholar]
  • (9).Rigotti T; Bach T Bicyclo[2.1.1]hexanes by Visible Light-Driven Intramolecular Crossed [2 + 2] Photocycloadditions. Org. Lett 2022, 24, 8821–8825. [DOI] [PubMed] [Google Scholar]
  • (10).Herter L; Koutsopetras I; Turelli TL; Fessard TF; Salome C Preparation of new bicyclo[2.1.1]hexane compact modules: an opening towards novel sp3-rich chemical space. Org. Biomol. Chem 2022, 20, 9108–9111. [DOI] [PubMed] [Google Scholar]
  • (11).Reinhold M; Steinebach J; Golz C; Walker JCL Synthesis of polysubstituted bicyclo[2.1.1]hexanes enabling access to new chemical space. Chem. Sci 2023, 14, 9885–9891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (12).Denisenko A; Garbuz P; Makovetska Y; Shablykin O; Lesyk D; Al-Maali G; Korzh R; Sadkova IV; Mykhailiuk PK 1,2-Disubstituted bicyclo[2.1.1]hexanes as saturated bioisosteres of ortho-substituted benzene. Chem. Sci 2023, 14, 14092–14099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (13).Posz JM; Sharma N; Royalty PA; Liu Y; Salome C; Fessard TC; Brown MK Synthesis of Borylated Carbocycles by [2 + 2]-Cycloadditions and Photo-Ene Reactions. J. Am. Chem. Soc 2024, 146, 10142–10149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (14).Wiberg KB; Lowry BR; Colby TH Bicyclo [2.1.1]hexane Derivatives. J. Am. Chem. Soc 1961, 83, 3998–4006. [Google Scholar]
  • (15).Golfmann M; Walker JCL Bicyclobutanes as unusual building blocks for complexity generation in organic synthesis. Commun. Chem 2023, 6, 9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (16).Kelly CB; Milligan JA; Tilley LJ; Sodano TM Bicyclobutanes: from curiosities to versatile reagents and covalent warheads. Chem. Sci 2022, 13, 11721–11737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (17).Wipf P; Walczak MAA Pericyclic Cascade Reactions of (Bicyclo[1.1.0]butylmethyl)amines. Angew. Chem., Int. Ed 2006, 45, 4172–4175. [DOI] [PubMed] [Google Scholar]
  • (18).Guo R; Chang Y-C; Herter L; Salome C; Braley SE; Fessard TC; Brown MK Strain-Release [2π + 2σ] Cycloadditions for the Synthesis of Bicyclo[2.1.1]hexanes Initiated by Energy Transfer. J. Am. Chem. Soc 2022, 144, 7988–7994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (19).Kleinmans R; Pinkert T; Dutta S; Paulisch TO; Keum H; Daniliuc CG; Glorius F Intermolecular [2π+2σ]-Photocycloaddition Enabled by Triplet Energy Transfer. Nature 2022, 605, 477–482. [DOI] [PubMed] [Google Scholar]
  • (20).Agasti S; Beltran F; Pye E; Kaltsoyannis N; Crisenza GEM; Procter DJ A Catalytic Alkene Insertion Approach to Bicyclo[2.1.1]hexane Bioisosteres. Nat. Chem 2023, 15, 535–541. [DOI] [PubMed] [Google Scholar]
  • (21).Bellotti P; Glorius F Strain-Release Photocatalysis. J. Am. Chem. Soc 2023, 145, 20716–20732. [DOI] [PubMed] [Google Scholar]
  • (22).Liu X; He J; Lin K; Wang X; Cao H State-of-the-art strategies for Lewis acid-catalyzed strain-release cycloadditions of bicyclo[1.1.0]butanes (BCBs). Org. Chem. Front 2024, 11, 6942–6957. [Google Scholar]
  • (23).Feng J-J Recent Progress in [3 + 3] Cycloadditions of Bicyclobutanes to Access Bicyclo[3.1.1]heptane Derivatives. Synlett 2025, 36, 621. [Google Scholar]
  • (24).Yang H; Chen J; Zhou L Lewis Acid Catalyzed Cycloaddition Reaction of Bicyclo[1.1.0]butanes. Synlett 2025, 36, 788. [Google Scholar]
  • (25).Zhou X; Hu Y; Huang Y; Xiong Y Recent advances in photochemical strain-release reactions of bicyclo[1.1.0]butanes. Chem. Commun 2024, 61, 23–32. [DOI] [PubMed] [Google Scholar]
  • (26).Dhake K; Woelk KJ; Becica J; Un A; Jenny SE; Leitch DC Beyond Bioisosteres: Divergent Synthesis of Azabicyclohexanes and Cyclobutenyl Amines from Bicyclobutanes. Angew. Chem., Int. Ed 2022, 61, No. e202204719. [DOI] [PubMed] [Google Scholar]
  • (27).Liang Y; Kleinmans R; Daniliuc CG; Glorius F Synthesis of Polysubstituted 2-Oxabicyclo[2.1.1]hexanes via Visible-Light-Induced Energy Transfer. J. Am. Chem. Soc 2022, 144, 20207–20213. [DOI] [PubMed] [Google Scholar]
  • (28).Zheng Y; Huang W; Dhungana RK; Granados A; Keess S; Makvandi M; Molander GA Photochemical Intermolecular [3σ + 2σ]-Cycloaddition for the Construction of Aminobicyclo[3.1.1]-heptanes. J. Am. Chem. Soc 2022, 144, 23685–23690. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (29).Kleinmans R; Dutta S; Ozols K; Shao H; Schäfer F; Thielemann RE; Chan HT; Daniliuc CG; Houk KN; Glorius F ortho-Selective Dearomative [2π + 2σ] Photocycloadditions of Bicyclic Aza-Arenes. J. Am. Chem. Soc 2023, 145, 12324–12332. [DOI] [PubMed] [Google Scholar]
  • (30).Liang Y; Paulus F; Daniliuc CG; Glorius F Catalytic Formal [2π+2σ] Cycloaddition of Aldehydes with Bicyclobutanes: Expedient Access to Polysubstituted 2-Oxabicyclo[2.1.1]hexanes. Angew. Chem., Int. Ed 2023, 62, No. e202305043. [DOI] [PubMed] [Google Scholar]
  • (31).Radhoff N; Daniliuc CG; Studer A Lewis Acid Catalyzed Formal (3 + 2)-Cycloaddition of Bicyclo[1.1.0]butanes with Ketenes. Angew. Chem., Int. Ed 2023, 62, No. e202304771. [DOI] [PubMed] [Google Scholar]
  • (32).Ni D; Hu S; Tan X; Yu Y; Li Z; Deng L Intermolecular formal cycloaddition of indoles with bicyclo[1.1.0]butanes by Lewis acid catalysis. Angew. Chem., Int. Ed 2023, 62, No. e202308606. [DOI] [PubMed] [Google Scholar]
  • (33).Xu M; Wang Z; Sun Z; Ouyang Y; Ding Z; Yu T; Xu L; Li P Diboron(4)-Catalyzed Remote [3 + 2] Cycloaddition of Cyclopropanes via Dearomative/Rearomative Radical Transmission through Pyridine. Angew. Chem., Int. Ed 2022, 61, No. e202214507. [DOI] [PubMed] [Google Scholar]
  • (34).Liu Y; Lin S; Li Y; Xue J-H; Li Q; Wang H Pyridineboryl radical-catalyzed [2π + 2σ] cycloaddition of bicyclo[1.1.0]butanes with alkenes. ACS Catal. 2023, 13, 5096–5103. [Google Scholar]
  • (35).Wang X; Gao R; Li X Catalytic Asymmetric Construction of Chiral Polysubstituted 3-Azabicyclo[3.1.1]heptanes by Copper-Catalyzed Stereoselective Formal [4π+2σ] Cycloaddition. J. Am. Chem. Soc 2024, 146, 21069–21077. [DOI] [PubMed] [Google Scholar]
  • (36).Wu F; Wu W-B; Xiao Y; Li Z; Tang L; He H-X; Yang X-C; Wang J-J; Cai Y; Xu T-T; Tao J-H; Wang G; Feng J-J Zinc-Catalyzed Enantioselective Formal (3 + 2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes. Angew. Chem., Int. Ed 2024, 63, No. e202406548. [DOI] [PubMed] [Google Scholar]
  • (37).Chintawar CC; Laskar R; Rana D; Schäfer F; Van Wyngaerden N; Dutta S; Daniliuc CG; Glorius F Photoredox-catalysed amidyl radical insertion to bicyclo[1.1.0]butanes. Nat. Catal 2024, 7, 1232–1242. [Google Scholar]
  • (38).Zhang X-G; Zhou Z-Y; Li J-X; Chen J-J; Zhou Q-L Copper-Catalyzed Enantioselective [4π + 2σ] Cycloaddition of Bicyclobutanes with Nitrones. J. Am. Chem. Soc 2024, 146, 27274–27281. [DOI] [PubMed] [Google Scholar]
  • (39).Dutta S; Daniliuc CG; Mück-Lichtenfeld C; Studer A Formal [2σ + 2σ]-Cycloaddition of Aziridines with Bicyclo[1.1.0]butanes: Access to Enantiopure 2-Azabicyclo[3.1.1]heptane Derivatives. J. Am. Chem. Soc 2024, 146, 27204–27212. [DOI] [PubMed] [Google Scholar]
  • (40).Qin T; He M; Zi W Palladium-catalysed [2σ + 2π] cycloaddition reactions of bicyclo[1.1.0]butanes with aldehydes. Nat. Synth 2025, 4, 124–133. [Google Scholar]
  • (41).Jeong J; Cao S; Kang H-J; Yoon H; Lee J; Shin S; Kim D; Hong S Divergent Enantioselective Access to Diverse Chiral Compounds from Bicyclo[1.1.0]butanes and α,β-Unsaturated Ketones under Catalyst Control. J. Am. Chem. Soc 2024, 146, 27830–27842. [DOI] [PubMed] [Google Scholar]
  • (42).Li Y-J; Wu Z-L; Gu Q-S; Fan T; Duan M-H; Wu L; Wang Y-T; Wu J-P; Fu F-L; Sang F; Peng A-T; Jiang Y; Liu X-Y; Lin J-S Catalytic Intermolecular Asymmetric [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes: Practical Synthesis of Enantioenriched Highly Substituted Bicyclo[2.1.1]hexanes. J. Am. Chem. Soc 2024, 146, 34427–34441. [DOI] [PubMed] [Google Scholar]
  • (43).Tyler JL; Schäfer F; Shao H; Stein C; Wong A; Daniliuc CG; Houk KN; Glorius F Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π+2σ] Cycloaddition Reactions. J. Am. Chem. Soc 2024, 146, 16237–16247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (44).Golfmann M; Reinhold M; Steen JD; Deike MS; Rodemann B; Golz C; Crespi S; Walker JCL Photocatalytic Oxidative Activation of Bicyclo[1.1.0]butanes for Formal [2σ+2π] Cycloadditions. ACS Catal. 2024, 14, 13987–13998. [Google Scholar]
  • (45).Huang X; Quinn TR; Harms K; Webster RD; Zhang L; Wiest O; Meggers E Direct Visible-Light-Excited Asymmetric Lewis Acid Catalysis of Intermolecular [2 + 2] Photocycloadditions. J. Am. Chem. Soc 2017, 139, 9120–9123. [DOI] [PubMed] [Google Scholar]
  • (46).Amador AG; Sherbrook EM; Yoon TP A Redox Auxiliary Strategy for Pyrrolidine Synthesis via Photocatalytic [3 + 2] Cycloaddition. Asian J. Org. Chem 2019, 8, 978–985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (47).Sherbrook EM; Jung H; Cho D; Baik M-H; Yoon TP Brønsted acid catalysis of photosensitized cycloadditions. Chem. Sci 2020, 11, 856–861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (48).Strieth-Kalthoff F; James MJ; Teders M; Pitzer L; Glorius F Energy Transfer Catalysis Mediated by Visible Light: Principles, Applications, Directions. Chem. Soc. Rev 2018, 47, 7190–7202. [DOI] [PubMed] [Google Scholar]
  • (49).The moderate yields are due to competitive polymerization of the BCB. This is indicated by broad signals in the 1H NMR spectrum of the unpurified reaction mixture.
  • (50).Chang Y-C; Salome C; Fessard T; Brown MK Synthesis of 2-Azanorbornanes via Strain-Release Formal Cycloadditions Initiated by Energy Transfer. Angew. Chem., Int. Ed 2023, 62, No. e202314700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (51).Plachinski EF; Qian RZ; Villanueva R; Poole DL; Rosenthal T; Yoon TP Enantioselective [2π + 2σ] Photocycloaddition Enabled by Brønsted Acid Catalyzed Chromophore Activation. J. Am. Chem. Soc 2024, 146, 31400–31404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (52).Xin H-L; Pang B; Choi J; Akkad W; Morimoto H; Ohshima T C-C Bond Cleavage of Unactivated 2-Acylimidazoles. J. Org. Chem 2020, 85, 11592–11606. [DOI] [PubMed] [Google Scholar]
  • (53).Fawcett A; Pradeilles J; Wang Y; Mutsuga T; Myers EL; Aggarwal VK Photoinduced decarboxylative borylation of carboxylic acids. Science 2017, 357, 283–286. [DOI] [PubMed] [Google Scholar]
  • (54).Crisenza GEM; Mazzarella D; Melchiorre P Synthetic Methods Driven by the Photoactivity of Electron Donor–Acceptor Complexes. J. Am. Chem. Soc 2020, 142, 5461–5476. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (55).Mehata MS; Yang Y; Qu Z-J; Chen J-S; Zhao F-J; Han K-L Spin Mixed Charge Transfer States of Iridium Complex Ir(ppy)3: Transient Absorption and Time-Resolved Photoluminescence. RSC Adv. 2015, 5, 34094–34099. [Google Scholar]
  • (56).Arias-Rotondo DM; McCusker JK The Photophysics of Photoredox Catalysis: a Roadmap for Catalyst Design. Chem. Soc. Rev 2016, 45, 5803–5820. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supporting Info
NIHMS2134988-supplement-Supporting_Info.pdf (11.4MB, pdf)

RESOURCES