Generation and Capture of Both Sides of the 7-Norbornylidene — Bicyclo[2.2.2]oct-2-yne Fritsch–Buttenberg–Wiechell Rearrangement

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Generation and Capture of Both Sides of the 7-Norbornylidene — Bicyclo[2.2.2]oct-2-yne Fritsch–Buttenberg–Wiechell Rearrangement

https://doi.org/10.21203/rs.3.rs-3464061/v1

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The strained caged alkyne bicyclo[2.2.2]oct-2-yne, previously reported to be inaccessible, was generated via the Fritsch–Buttenberg–Wiechell rearrangement of 7-norbornylidene carbene. Computational experiments predict the alkyne to be more stable than its corresponding alkylidenecarbene, and both of these intermediates can be intercepted with the use of appropriate trapping agents.

Physical sciences/Chemistry/Organic chemistry/Reaction mechanisms

Physical sciences/Chemistry/Organic chemistry/Structure elucidation

Strained cyclic alkynes are of both theoretical and practical interest in organic chemistry. Incorporation of alkynes into constricted ring structures forces deviation from their ideal linear geometry, allowing chemists to probe the limits of distortion of these chemical bonds. The reactivity associated with the strain of cyclic alkynes has also been a subject of growing synthetic interest, and has been used in the generation of a number of complex molecular scaffolds.¹ Highly strained cycloalkynes are unstable, transient species, however, making their generation and study difficult under normal laboratory conditions.²

Alkylidene carbenes 1 undergo 1,2-shifts, known as Fritsch–Buttenberg–Wiechell (FBW) rearrangements, to yield alkynes 2 (Scheme 1).^3–4 In the case of exocyclic alkylidene carbenes 3, FBW rearrangements can provide access to highly reactive, conformationally strained cyclic alkynes 4 that are difficult to generate through other means (Scheme 1).^5–6 FBW rearrangements of alkylidene carbenes have been used for the generation of monocyclic alkynes^7–8 such as cyclopentynes^9–11 and cyclohexynes,^12,11,13 as well as a number of polycyclic alkynes.^14–16 Many of these strained alkynes are transient, non-isolable species under ambient temperature, and their formation is inferred through their reaction with various trapping agents.^10,2

The generation of alkynes via FBW rearrangements of alkylidene carbenes is generally considered to depend upon a thermodynamic equilibrium that favors the target alkyne over the corresponding carbene.^17–21 While this is the case for most monocyclic alkynes,^14,9,8 with the exceptions of cyclobutyne¹⁷ and cycloheptyne,^22–23 the additional geometric constriction present in many polycyclic alkynes can potentially tip equilibrium in favor the carbene. In such cases, even direct synthesis of the strained alkyne will result in rearrangement to the alkylidene carbene through the reverse 1,2-shift, known as the Roger Brown rearrangement.^17,24–25 Attempts to detect a number of polycyclic alkynes, including 6, 8, and 10, through the FBW rearrangement of their respective alkylidene carbenes have been unsuccessful, purportedly due to unfavorable differences in the relative stabilities of the two chemical species (Scheme 2).^18–21

A number of experimental factors affect the successful detection of a cycloalkyne that is in equilibrium with an alkylidenecarbene, factors that can confound subsequent interpretations of the relative thermodynamic stabilities of these intermediates. Preparation of alkylidene carbenes for the generation of polycyclic alkynes has primarily involved the deprotonation of bromoethylenecycloalkanes,^{14–15,26,16} or the lithiation of dibromomethylenecycloalkanes,^23,18–21 both of which initially generate an alkylidenecarbenoid species. Alkylidenecarbenoids exhibit different patterns of reactivity compared to free alkylidenecarbenes,²⁷ and can react through unique pathways³ that involve dimerization,²⁸ decomposition,^29–31 and FBW rearrangements.^32–34 This potential for alternative pathways of reactivity makes the use of alkylidenecarbenoids problematic for the study of carbene–alkyne equilibria.

Reaction temperature will also influence the degree to which the carbene–alkyne equilibrium is established. Typical preparations of alkylidenecarbenes require either high temperatures in the case of deprotonation of bromoethylenecycloalkenes,^{14–15,26,16} or low temperatures in the case of lithiation of dibromomethylenecycloalkanes.^23,18–21 Whereas trapping experiments utilizing high-temperature reactions have typically been successful in detecting the alkyne,^{14–15,26,16} a number of attempts under low temperature conditions have been unsuccessful.^18–21 While this outcome has generally been attributed to thermodynamic favorability of the carbene over the alkyne, low temperatures may also place the reaction outcome under kinetic control, thereby favoring consumption of the carbene before thermodynamic equilibrium is established between the two intermediates (Fig. 1A).

An alkyne that is thermodynamically favored over its corresponding carbene can still evade detection, even after establishment of equilibrium, depending on the particular trapping agent in use. The reaction of carbene or alkyne with a trapping agent may be expected to follow a Curtin–Hammett scenario,³⁵ in which the distribution of products is determined not by the thermodynamic stability of the intermediates, but by the relative energetic barriers to the trapping of these intermediates. If the absolute barrier to carbene trapping is lower than that of alkyne trapping, the carbene will be preferentially selected regardless of thermodynamic stability (Fig. 1B).

Our laboratory has a developed a photolytic approach to the generation of free alkylidenecarbenes that proceeds under mild conditions and ambient temperatures.^{36–37,12,11,38} Herein, we demonstrate the utility of this method toward the generation of a highly strained, bridged, polycyclic alkyne bicyclo[2.2.2]oct-2-yne (13), previously thought to be thermodynamically inaccessible,¹⁹ via the FBW rearrangement of 7-norbornylidenecarbene 12 (Scheme 3).¹⁹ The choice of trapping agent was found to have a decisive effect on reaction outcome, one that could be predicted through computational experiments (vide infra). The photochemical generation of alkylidenecarbenes demonstrated herein provides a means to investigate alkylidenecarbene–alkyne equilibria without the complications introduced by alternative reaction pathways that are characteristic of alkylidenecarbenoids,³ nor the use of exceedingly low or high reaction temperatures that are required for alternative methods of carbene generation.

Our investigation into the generation of bicyclo[2.2.2]octyne (13) via FBW rearrangement of 7-norbornylidenecarbene 12 was prompted by calculations at the DLPNO-CCSD(T)/def2-TZVPP//PBE0/def2-TZVP^39–46 level of theory, which predicted 13 to be lower in energy than 12 by 1.6 kcal/mol (Fig. 2). The activation energy of the rearrangement was predicted to be 9.4 kcal/mol, a barrier that is comparable to those predicted for previously investigated alkylidene carbenes that undergo FBW rearrangement.¹³ Bicyclo[2.2.2]oct-2-yne (13) has been previously considered to be thermodynamically less stable than the corresponding 7-norbornylidenecarbene 12 based on trapping experiments with norbornadiene.¹⁹

Precursor 11, from which 7-norbornylidenecarbene can be photochemically generated, was synthesized from 7-norbornanone (22)^47–49 and dichlorocyclopropyl phenanthrene derivative 23⁵⁰ (Scheme 4). The synthesis of 7-norbornanone (22) was achieved in four steps starting from norbornadiene (18) following previously reported procedures.^47–49 Precursor 11 was then made via reaction with the dichlorocyclopropyl phenanthrene derivative 23 by adapting a procedure previously reported by Takeda et al.⁵¹

The strained alkyne bicyclo[2.2.2]octyne (13) was successfully generated following irradiation of the norbornylphenanthrene derivative 11 in benzene (280–400 nm, 6 h) and intercepted with cyclopentadienone 15 as the trapping agent. Photolysis of 11 is expected to initially extrude norbornylidenecarbene 12 with the concomitant release of phenanthrene (Scheme 5).^12,52,13 Subsequent FBW rearrangement of 12 generates bicyclo[2.2.2]octyne (13), which can then undergo a Diels–Alder cycloaddition to the trapping agent 15, yielding the adduct 24. Loss of carbon monoxide from 24 leads to the observed product 17. The structure of 17 was confirmed by X-ray crystallography (Scheme 5).

The use of cyclopentadienone 15 as a trapping agent was expected to preferentially detect alkyne 13, with which it can undergo Diels–Alder cycloaddition, over carbene 12, which can only undergo a [1 + 2] cyclopropanation reaction. Irradiation of precursor 11 in the presence of cyclohexene (14, 280–400 nm, 4 h), which is expected to be capable of trapping both carbene and alkyne,^9,18,21 yielded the cyclopropanation product 16 exclusively (Scheme 5). The reaction outcome was not affected by concentration, yielding 16 selectively when cyclohexene was used as solvent, or when the reagents were diluted to 0.1 M or 0.01 M in benzene. The identity of 16 was determined by derivatization to spirocyclopropane 26 and subsequent resolution by X-ray crystallography (Scheme 6).

The differences in product specificity when cyclopentadienone 15 or cyclohexene 14 are used as trapping agents are consistent with calculations at the DLPNO-CCSD(T)/def2-TZVPP//PBE0/def2-TZVP^39–46 level of theory. Upon generation of norbornylidenecarbene 12, at least three pathways of reactivity are possible: dimerization, addition to the trapping agent, or FBW rearrangement. Dimerization, a pathway generally associated with carbenoids,^19,3 has also been observed following the photochemical generation of free 2-adamantylidenecarbene.⁵³ In the case of norbornylidenecarbene 12, dimerization to triene 28 is predicted to be an energetically barrierless process (Fig. 3), similar to the dimerization of methylenecarbene.^54–56

With the use of diene 15 as a trapping agent, the activation energy of FBW rearrangement of norbonylidenecarbene 12 to bicyclo[2.2.2]octyne (13) is predicted to be higher than, though comparable to, trapping of the carbene to form cyclopropylidene 27 (Fig. 3). Despite having the highest activation energy of the three pathways, the first-order, intramolecular FBW rearrangement of norbonylidenecarbene 12 could potentially outcompete the second-order, intermolecular processes of trapping and dimerization (Fig. 1A).⁵⁷ Bicyclo[2.2.2]octyne (13), which exhibits a lower absolute and relative energetic barrier to trapping with diene 15 compared to that of 12, would thereby be favored in the trapping experiment, first forming adduct 24 then product 17 via decarbonylation.

A similar difference in activation energies between the trapping of norbonylidenecarbene 12 versus the FBW rearrangement to bicyclo[2.2.2]octyne (13) is predicted with the use of cyclohexene (14) as a trapping agent as was predicted with diene 15 (Fig. 4). As was the case with diene 15 the FBW rearrangement may be expected to outcompete trapping, despite a slightly higher barrier to reaction, due to a smaller dependence on the concentration of reactants. The strained alkyne 13, however, which likely reacts as a dicarbene,^58–61 faces a substantially larger barrier to trapping compared to the alkylidene carbene 12 (18.0 kcal/mol vs 7.4 kcal/mol).⁶² Thus, even at the lower concentration of carbene 12 at equilibrium, trapping of 12 will be favored over trapping of 13. The cyclobutylated product 25, and likewise the presence of bicyclo[2.2.2]octyne (13), will thus not be detected under these experimental conditions, regardless of the relative thermodynamic stabilities of the two intermediates (Fig. 4).

In conclusion, we have demonstrated that the photochemical generation of polycyclic alkylidenecarbenes provides a useful strategy for generating highly strained caged alkynes, and have employed this method for the generation of bicyclo[2.2.2]octyne 13, an alkyne that was previously considered to be thermodynamically inaccessible.¹⁹ While prior investigations into alkyne–carbene equilibria in FBW rearrangements have used chemical trapping to infer thermodynamic relationships, this is a problematic interpretation. The results of trapping experiments reflect the differences in the absolute energetic barriers to trapping of the two intermediates, rather than the thermodynamic relationships of the intermediates themselves. With the use of different traps, both norbornylidene carbene 12 and bicyclo[2.2.2]octyne (13) could be intercepted in the present work. The relative stabilities of the two intermediates is less consequential, in regards both to their trapping and their potential synthetic utility, than the reactive partner used, and the corresponding barriers to reaction of the two intermediates.

General Notes

Tetrahydrofuran was degassed by purging with nitrogen, and dried by passage through two activated alumina columns (2 ft × 4 in). Other solvents and reagents were used as obtained from commercial sources. Medium pressure flash chromatography was performed on an automated system using prepacked silica gel columns (70 − 230 mesh), or by hand using Sorbtech silica gel 60A (35 x 70 mesh) with the indicated eluents. AgNO₃-treated silica gel was prepared as follows: To a solution of AgNO₃ (12.0 g) in acetonitrile (100 mL) was added silica gel (40 g). The mixture was stirred, and the resulting slurry was heated at 80°C in vacuo on a rotary evaporator for 2 h, then allowed to cool to room temperature and stored in a foil-covered flask. Proton (¹H) and proton-decoupled carbon ¹³C{¹H} NMR spectra were recorded in CDCl₃ at 500 and 126 MHz, respectively. The data are reported as follows: chemical shift in ppm referenced to residual solvent (¹H NMR: CDCl₃ δ 7.26; ¹³C NMR: CDCl₃ δ 77.2, multiplicity, coupling constants (Hz), and integration. Structures were determined using COSY, HSQC, and HMBC experiments. Overlapping carbon peaks were identified using HSQC experiments and integration of ¹³C NMR spectra. High resolution mass spectra (HRMS) data were obtained on an Agilent 6230 TOF Mass Spectrometer. Infrared spectra (resolution 4.0 cm^− 1) were acquired on solid samples with an FTIR instrument equipped with an attenuated total reflectance (ATR) accessory. Photolysis experiments were conducted with a Newport 200 W Xe-Hg arc lamp (model # 6290; horizontal intensity 600 cd) with a Newport 280–400 dichroic mirror (model # 66245) fitted in a Newport 67005 Housing with a Newport 69907 Universal Arc Lamp Power Supply. All photolysis reactions were conducted in quartz glassware positioned 30 cm away from the light source. All reactions were performed under an atmosphere of argon in glassware that had been dried in an oven at 120°C unless otherwise stated.

Synthetic Procedures

7- t -butoxynorbornadiene (19): Following the procedure of Kozel et al.,⁴⁸ to a stirred refluxing mixture of norbornadiene (18, 45.3 g, 492 mmol) and cuprous bromide (0.109 g, 0.756 mmol) in benzene (150 mL) under argon atmosphere was added a solution of t-butylperoxybenzoate (36 mL, 189 mmol) in benzene over 20 min. The reaction mixture was stirred an additional 30 min, then cooled to room temperature and washed with 10% aqueous sodium carbonate (3 x 100 mL), followed by water (2 x 100 mL). The organic phase was then dried (Na₂SO₄), and the benzene was removed in vacuo. Distillation under reduced pressure afforded 7-t-butoxynorbornadiene (19) as a colorless oil (10.5 g, 34%). The spectroscopic data are in agreement with those previously reported:^{63 1}H NMR (500 MHz, CDCl₃) δ 6.54 (t, J = 2.2 Hz, 2H), 6.49 (t, J = 2.2 Hz, 2H), 6.50–6.48 (m, 2H), 3.68 (s, 1H), 3.32–3.28 (m, 2H), 1.04 (s, 9H). ¹³C NMR (126 MHz, CDCl₃) δ 139.9, 137.4, 104.4, 73.7, 55.6, 28.4. HRMS (ESI) m/z: [M• – t-Bu]⁺ Calcd for C₁₁H₁₆O 107.0497; Found 107.0499.

7- t -butoxynorbornane (20): Following the procedure of Felpin and Fouquet,⁴⁷ to a stirring solution of diene 19 in methanol (75 mL) was added a mixture of palladium acetate (0.013 g, 0.058 mmol) and charcoal (0.117 g). The reaction mixture was flushed with hydrogen gas, then stirred under an atmosphere of hydrogen until diene 19 was fully consumed, as determined by GC-MS. The reaction mixture was then filtered through Celite, and the solvent was removed in vacuo. Purification by flash column chromatography (3:97 Et₂O:pentane) afforded 7-t-butoxynorbornane (20) as a colorless oil (4.09 g, 43%). The spectroscopic data are in agreement with those previously reported:^{47 1}H NMR (500 MHz, CDCl₃) δ 3.69 (s, 1H), 1.89–1.80 (m, 4H), 1.56–1.49 (m, 2H), 1.21–1.15 (m, 11H), 1.13–1.09 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 79.4, 72.8, 40.2, 28.6, 27.4, 26.5. HRMS (ESI) m/z: [M• – t-Bu]⁺ Calcd for C₁₁H₂₀O 111.0810; Found 111.0808.

7-norbornol (21): Following the procedure of Rosenkoetter et al.,⁴⁹ iodotrimethylsilane (3.7 mL, 26 mmol) was added to a solution of 7-t-butoxynorbornane (20) in chloroform (45 mL). The reaction mixture was stirred 20 min at room temperature, then poured into a slurry of sodium carbonate (7.4 g) in methanol (150 mL) and stirred an additional 10 min. The suspension was then filtered, and the filtered solid was washed with methanol (150 mL). The combined filtrates were concentrated in vacuo, then suspended in 10% aqueous sodium thiosulfate (185 mL) and stirred 1 h. The mixture was then extracted with diethyl ether (3 x 100 mL), and the combined organic phases were dried (Na₂SO₄), filtered, and concentrated in vacuo to afford 7-norbornol (21) as an orange waxy solid (2.20 g, 98%): ¹H NMR (500 MHz, CDCl₃) δ 3.99 (s, 1H), 3.75–3.67 (m, 1H), 1.96–1.93 (m, 2H), 1.88–1.83 (m, 2H), 1.58–1.53 (m, 2H), 1.30–1.25 (m, 2H), 1.19–1.14 (m, 2H). ¹³C NMR (126 MHz, CDCl₃) δ 79.9, 40.4, 26.9, 26.7. HRMS (ESI) m/z: [M• – H]⁺ Calcd for C₇H₁₂O 111.0810; Found 111.0810.

7-norbornone (22): Following the procedure of Rosenkoetter et al.,⁴⁹ to a suspension of pyridinium chlorochromate (5.39 g, 25 mmol) in dichloromethane (300 mL) was added a solution of 7-norbornol (21, 1.12 g, 10.0 mmol) in dichloromethane (150 mL). The reaction mixture was stirred until 7-norbornol (21) was completely consumed, as determined by GC-MS. Diethyl ether (150 mL) was then added and the mixture was stirred 30 min, then transferred to a separatory funnel and extracted with diethyl ether (150 mL). The organic phase was washed with water (3 x 400 mL), dried (Na₂SO₄), filtered, and concentrated in vacuo. Purification by column chromatography (Et₂O) yielded 7-norbornone (22) as a pale oil (0.588 g, 53%): ¹H NMR (500 MHz, CDCl₃) δ 1.96–1.89 (m, 4H), 1.87–1.84 (m, 2H), 1.60–1.54 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 217.9, 38.1, 24.3. HRMS (ESI) m/z: [M• – H]⁺ Calcd for C₇H₁₀O 109.0653, Found 109.0652.

Precursor 11: According to the procedure of Takeda et al.,⁵¹ to a round-bottom flask charged with magnesium turnings (0.729 g, 30.0 mmol) and 4 Å molecular sieves (1.50 g) was added bis(cyclopentadienyl)titanium(IV) dichloride (7.47 g, 30.0 mmol) followed by anhydrous THF (60 mL). Triethyl phosphite (10.3 mL, 60.0 mmol) was added and the reaction mixture was stirred for 3 h, during which the color of the mixture turned from red to dark green. A solution of dichlorocyclopropyl phenanthrene 23 (2.62 g, 10.0 mmol) dissolved in THF (20 mL) was added and the reaction mixture was stirred for an additional 30 min. 7-norbornone (22, 0.55 g, 5.0 mmol) in THF (10 mL) was then added, and the reaction mixture was stirred for an additional 16 h. Hexanes (200 mL) was added, and the resulting suspension was transferred to a plug of silica and eluted with hexanes (200 mL) followed by a solution of hexanes and ethyl acetate (10:90, 100 mL). The elution was concentrated in vacuo, and purification by flash column chromatography with silica gel (2:98 ethyl acetate:hexanes) followed by flash column chromatography with AgNO3-treated silica gel (30%, 2:98◊20:80 ethyl acetate:hexanes) afforded precursor 11 (0.330 g, 23%) as a white solid: mp = 130–133°C. ¹H NMR (500 MHz, CDCl₃) δ 7.97–7.90 (m, 2H), 7.41–7.35 (m, 2H), 7.26–7.19 (m, 4H), 3.16 (s, 2H), 2.41 (s, 2H), 1.73–1.65 (m, 2H), 1.37–1.30 (m, 2H), 1.11–0.97 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 139.2, 134.8, 129.2, 128.6, 127.7, 125.8, 123.3, 108.1, 38.4, 29.3, 28.7, 22.3. IR (ATR) 2954, 2862, 1486, 1441, 763, 730, 615 cm^− 1. HRMS (ESI) m/z: [M• – H]⁺ Calcd for C₂₂H₂₀ 283.1487; Found 283.1499.

Adduct 17: Precursor 11 (0.135 g, 0.475 mmol) and 2-oxo-4,5-diphenyl-cyclopenta-3,5-diene-1,3-dicarboxylic acid dimethylester (15, 0.188 g, 0.54 mmol) were combined in deuterated benzene (5 mL) in a quartz cuvette. The reaction mixture was placed in front of a mercury lamp and irradiated until the starting material was consumed, as determined by ¹H NMR analysis of the reaction mixture (6 h). The solvent was removed in vacuo, and purification by flash column chromatography (0:100◊10:90 ethyl acetate:hexanes) afforded adduct 17 as a white solid (0.065 g, 32%): mp = 193–195°C. ¹H NMR (500 MHz, CDCl₃) δ 7.14–7.07 (m, 6H), 7.04–6.99 (m, 4H), 3.49 (s, 6H), 3.14 (s, 2H), 1.90–1.77 (m, 4H), 1.57–1.48 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 169.5, 140.9, 138.9, 136.2, 131.5, 130.2, 127.5, 126.8, 52.0, 31.8, 25.7. IR (ATR) 2948, 1726, 1233, 1197, 1077, 699 cm^− 1. HRMS (ESI) m/z: [M + H]⁺ calcd for C₂₈H₂₆O₄ 427.1904; Found 427.1911.

Adduct 16: Precursor 11 (0.172 g, 0.605 mmol) was dissolved in cyclohexene (14, 6 mL) and transferred to an argon-flushed quartz cuvette. The reaction mixture was placed in front of a mercury lamp and irradiated until the starting material was consumed, as determined by ¹H NMR analysis of the reaction mixture (4 h). The reaction mixture was concentrated in vacuo, and purification by flash chromatography (1:99 ethyl acetate:hexanes) afforded adduct 16 as a colorless oil (0.040 g, 40%): ¹H NMR (500 MHz, CDCl₃) δ 2.54–2.49, (m, 2H), 1.80–1.72 (m, 2H), 1.70–1.60 (m, 6H), 1.59–1.53 (m, 2H), 1.40–1.34 (m, 4H), 1.24–1.17 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 137.3, 113.4, 38.4, 29.5, 29.4, 23.4, 21.6, 12.8. IR (ATR) 2924, 2856, 1490, 1546, 745, 720 cm-1. HRMS (ESI) m/z: [M• – H]⁺ calcd for C₁₄H₂₀ 187.1487; Found 187.1459.

Dichlorospirocyclopropane 26: To a mixture of alkene 16 (0.40 g, 0.21 mmol) and benzyl-triethylammonium chloride (0.001 g, 0.004 mmol) in chloroform (5 mL) was added 50% aqueous sodium hydroxide (5 mL) slowly. The mixture was heated under reflux overnight, then concentrated in vacuo. Purification by flash chromatography (1:99 ethyl acetate:hexanes) afforded dichlorospirocyclopropane 26 as a white solid (0.038 g, 66%): mp = 87–89°C. ¹H NMR (500 MHz, CDCl₃) δ 2.17–2.13 (m, 2H), 2.10–2.05 (m, 2H), 1.98–1.89 (m, 2H), 1.88–1.83 (m, 2H), 1.62–1.54 (m, 4H), 1.49–1.40 (m, 4H), 1.37–1.20 (m, 4H). ¹³C NMR (126 MHz, CDCl₃) δ 70.4, 52.0, 41.0, 37.2, 30.9, 29.0, 21.8, 21.6, 20.4. IR (ATR) 2924, 2851, 1456, 880, 812, 791 cm^− 1. HRMS (CI) m/z: [M + Hl]⁺ calcd for C₁₅H₂₀C_l2 271.1015; Found 271.1015.

Data Availability

Additional information, including X-ray crystallographic data, computational information, and NMR spectra are provided in the Supplementary Information for this manuscript. The X-ray crystallographic coordinates for compounds 17 and 26 have been deposited at the Cambridge Crystallographic Data Centre (CCDC) with accession codes 2301554 (17) and 2301553 (26). These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via https://www.ccdc.cam.ac.uk/structures/.

Acknowledgements

We thank the NSF (CHE-1955874), the Colby College Division of Natural Sciences, and the David Lee Phillips Postdoctoral Fellow-ship for funding our work.

Author Contributions

The manuscript was written through contributions of all authors, who have given approval to the final version of the manuscript.

Competing Interests

The authors declare no competing interests.

Materials & Correspondence

Dasan M. Thamattoor — Department of Chemistry, Colby College, 5765 Mayflower Hill, Waterville, ME 04901 (USA); E-mail: [email protected]

David Lee Phillips — Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong S.A.R. 999077; E-mail: [email protected]

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The pathway of addition of bicyclo[2.2.2]octyne (13) to cyclohexene (14) depicted in Fig. 4 is predicted to be the lowest in energy among a number of possible pathways. A full analysis of the potential energy surface for the generation of 26 is depicted in Figure S1
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Generation and Capture of Both Sides of the 7-Norbornylidene — Bicyclo[2.2.2]oct-2-yne Fritsch–Buttenberg–Wiechell Rearrangement

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