Synthesis and Properties of 3,8-Diaryl-2H-cyclohepta[b]furan-2-ones

Abstract

Synthesis of 3,8-diaryl-2H-cyclohepta[b]furan-2-ones was accomplished by the one-pot procedure involving sequential iodation and Suzuki–Miyaura coupling reactions. The optical and structural characteristics of 3,8-diaryl-2H-cyclohepta[b]furan-2-ones prepared were scrutinized using UV/Vis spectroscopy, theoretical calculations, and single-crystal X-ray crystallography. The redox properties of the compounds were also evaluated through cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The findings reveal that the introduction of aryl groups at both the 3- and 8-positions significantly influences the electronic properties of the CHFs, resulting in distinct optical and electrochemical characteristics.

1. Introduction

2H-Cyclohepta[b]furan-2-one (CHF) is recognized as one of the heteroazulenes [1], and its functionalized derivatives are known to exhibit inotropic character [2]. In their utilization of these derivatives, Ando et al. have demonstrated that CHFs can be used as starting materials for the total synthesis of natural products [3,4,5]. On the other hand, Nitta and co-workers have reported the synthesis and properties of methylium or tropylium ions connected with CHF [6,7,8,9,10]. As a result, these ions were found to be highly stable and to exhibit an absorption band with a large molar absorption coefficient in the visible region of the UV-visible absorption spectrum. The CHFs can also be effectively converted to azulene derivatives through reactions with olefins [11,12,13] and reactive intermediates, such as enamines [14,15,16,17,18], silyl enol ether [19], and active methylene compounds [20]. Although numerous methods for the conversion of CHFs to azulene derivatives have been documented, the modification method of CHF itself has not been extensively explored. Over the past decade, we have made strides in the electrophilic substitution [21,22,23] and cross-coupling reactions [24,25,26] of CHFs, primarily targeting the highly reactive 3-position (Figure 1).

Nevertheless, the synthesis of CHF derivatives featuring functional groups other than alkyl ones at the seven-membered ring has been limited. In this regard, we have developed a novel synthetic pathway to 8-aryl-CHFs by Suzuki–Miyaura coupling of 8-trifluoromethanesulfonyl-CHF obtained by the reaction of 8-hydroxy-CHF with trifluoromethanesulfonic anhydride [27]. In our previous work, we reported the first synthesis of 8-aryl-CHFs 2a–2c by Suzuki–Miyaura coupling of triflate 1, which was derived from the 8-hydroxy-CHF precursor. This method is innovative for its ability to introduce an aryl group at the difficult 8-position, which is not easily established using traditional methods.

As an extension of our previous studies on the reactivity of 8-trifluoromethanesulfonyl- and 8-aryl-CHFs, we explored the incorporation of aryl groups at both the 3- and 8-positions of these molecules. The introduction of two aryl groups into CHF can effectively achieve a redshift of its absorption wavelength due to the extension of the conjugated system, leading to the development of its application in functional dyes. p-Methoxy and p-nitrophenyl groups were selected and introduced as the aryl groups to be introduced. The incorporation of these aryl groups with different electronic properties is anticipated to induce donor-acceptor-type contributions, thereby endowing the modified molecules with optical properties that are significantly different from those exhibited by conventional CHFs.

In this paper, we describe the synthesis and properties of 3,8-diaryl-CHFs, which were prepared via the Suzuki-Miyaura coupling reaction. The optical and structural properties of 3,8-diaryl-CHFs were investigated by UV/Vis spectroscopy, theoretical calculations, and single-crystal X-ray analysis. In addition, the redox behavior of these compounds was investigated by voltammetry experiments, i.e., cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The results indicate that the aryl groups at the 3- and 8-positions significantly affect the electronic properties of the CHFs, leading to unique optical and electrochemical properties contingent on the electronic nature of the aryl groups substituted.

2. Results and Discussion

Synthesis: The preparation of 4a–4c began with the treatment of 1 or 2a–2c [11] using N-iodosuccinimide (NIS), followed by the Suzuki–Miyaura coupling [28] with phenylboronic acid (Figure 2). Owing to the instability and rapid decomposition of the iodide intermediate 3 during the purification process, we performed the subsequent Suzuki–Miyaura coupling without the isolation of 3 using PdCl₂(dppf) as a catalyst. As a result, the coupling product 4a at the 3- and 8-positions was obtained in a 50% yield in a one-pot procedure. The reaction of 2a with NIS also provided an unstable product; hence, the coupling reaction with phenylboronic acid was performed without a purification process to give 4a in a 60% yield. In a similar manner, iodation of 2b and 2c with NIS and the following Suzuki–Miyaura coupling with p-nitrophenylboronic or p-methoxyphenylboronic acids formed the corresponding coupling products 4b and 4c in 77% and 40% yields, respectively, in the two steps. The resulting 4a–4c demonstrated sufficient stability to be stored for several months under ambient conditions.

Spectroscopic properties: Newly prepared compounds 4a–4c were comprehensively characterized utilizing spectral data, as detailed in the “Materials and Methods” section. Charts of NMR and high-resolution mass spectra (HRMS) of 4a–4c were appeared in Supplementary Materials. The ¹H NMR spectroscopic assignments of 4a–4c were validated by the COSY experiment. The HRMS of 4a–4c, ionized through electrospray ionization (ESI), exhibited the expected molecular ion peaks, corroborating their molecular structures.

Due to the acquisition of suitable crystals by slow solvent evaporation, the molecular structures of 4a–4c were elucidated by X-ray crystallographic analysis, as depicted in Figure 3. Previously, we reported that the CHF moiety and substituted aryl groups of 8-aryl-CHFs have large dihedral angles and that the contribution of these conjugates is small based on their UV/Vis spectra. On the other hand, the dihedral angles between the CHF moiety and phenyl groups at the 3-position and at the 8-position of 4a were 39.58° and 34.78°, respectively, which are smaller than those of the 8-aryl-CHFs. Although the dihedral angle (40.26°) between the CHF moiety and the aryl group at the 3-position of 4b was similar to that of 4a, the angle with the aryl group at the 8-position (58.10°) was comparable to those in 8-aryl-CHFs. Similar to 4b, a larger dihedral angle (65.71°) between the CHF moiety and the aryl group at the 8-position was observed in 4c,even though that at the 3-position is relatively small (35.63°). This observation implies that the aryl group at the 3-position of 4b and 4c may extend the conjugated system, whereas the aryl group at the 8-position may not significantly contribute to the π-extension.

To evaluate the optical properties of the prepared compounds, measurements of their UV/Vis absorption spectra were performed. The absorption maxima and coefficients (log ε) of 4a–4c in CH₂Cl₂ and 2a–2c as a reference are shown in

Table 1. The longest absorption maxima [nm] and their coefficients (log ε) of 4a–4c in CH₂Cl₂ and 2a–2c in CH₂Cl₂ as a reference, and electronic transitions of 4a–4c derived from the computed values based on the TD-DFT calculations at the B3LYP/6-31+G* level.

	Experimental	Computed Values
Compound	λmax [nm] (log ε)	λmax (Oscillator Strength)	Composition of Band (Contribution)
4a	411 (4.26)	454 (0.0168)	H → L (0.6044) H → L + 1 (0.3550)
		366 (0.5569)	H − 1 → L (0.0863) H → L (0.2631) H → L + 1 (0.5405)
4b	443 (4.42)	446 (0.0517)	H → L (0.2436) H → L + 1 (0.6598) H → L + 2 (0.0471)
		421 (0.7559)	H → L (0.6154) H → L + 1 (0.2990)
4c	424 (4.25)	519 (0.1046)	H → L (0.7916) H → L + 1 (0.1354) H → L + 2 (0.0458)
		458 (0.1429)	H → L (0.1216) H → L + 1 (0.8431)
		379 (0.3522)	H − 1 → L (0.1842) H → L + 2 (0.7128)
2a	395 (4.06)	–	–
2b	396 (4.09)	–	–
2c	396 (4.10)	–	–

. The UV/Vis spectra of 4a–4c are represented in Figure 4.

The maximum absorption wavelengths of 4a–4c displayed a redshift from those of the corresponding 2a–2c. For instance, the absorption maxima of 4a (λ_max = 411 nm) exhibit a redshift of 16 nm compared to that of 2a (λ_max = 395 nm), suggesting that the aryl group introduced at the 3-position effectively extends the conjugated system as predicted by the single-crystal X-ray analysis. Compounds 4b (λ_max = 443 nm) and 4c (λ_max = 424 nm), which incorporate both an electron-donating p-methoxyphenyl and an electron-withdrawing p-nitrophenyl group within their structures, exhibit absorption at the longer wavelength region, compared to that of 4a. However, the maximum absorption wavelength of 4b displayed a redshift of 19 nm compared to that of 4c. These results suggest that the introduction of an electron-withdrawing group (EWG), i.e., the p-nitrophenyl group, at the 3-position of CHF leads to a longer wavelength of maximum absorption than at the 8-position.

To theoretically elucidate the variations in absorption wavelengths observed in the UV/Vis spectra of 4a–4c, the electronic transitions within the absorption band and the energies of the HOMO and LUMO of these compounds were examined using time-dependent density functional theory (TD-DFT) calculations at the B3LYP/6-31G* level [30]. These methods are employed to optimize the molecular geometries, calculate the electronic excitation energies, and determine the UV/Vis absorption spectra. The electronic transitions of 4a–4c, as determined from the calculations, are summarized in Table 1. Figure 5 represents the frontier Kohn–Sham orbitals of 4a–4c along with their corresponding energy levels.

Theoretical calculations indicated that the absorption bands in the visible region for 4a–4c result from the superposition of multiple transitions. The longest wavelength absorption band of 4a was revealed as the transitions between HOMO, HOMO−1, and LUMO, LUMO+1, and in these, there is hardly any orbital coefficient involved in the LUMOs of the phenyl groups at the 3- and 8-positions. Therefore, this absorption band in 4a is considered to be dominated by the π-π* transition of CHF itself. The absorption band of 4b was also revealed as transitions from HOMO, in which the orbital coefficients are distributed in the aryl groups at the 3- and 8-positions and in the CHF moiety, to LUMO, LUMO+1, and LUMO+2. Among these transitions, the HOMO–LUMO transition, specifically the π-π* transition and the intramolecular charge transfer between the two aryl groups, was identified as the dominant contribution based on the calculation results. The longest absorption band of 4c can be attributed to the overlap of several transitions from HOMO, HOMO−1 to LUMO, LUMO+1, and LUMO+2. The maximum absorption wavelength of 4c shows a hypochromic shift compared to that of 4b, but the absorption onset wavelength was observed to be on the longer side, which could be attributed to the HOMO to LUMOs transitions, i.e., both of π-π* transitions, and the intramolecular charge transfer between the p-methoxyphenyl and p-nitrophenyl groups at the 3- and 8-positions, i.e., transition from HOMO to LUMO and LUMO+2.

To elucidate the electrochemical properties, the redox potentials of 4a–4c were assessed by CV and DPV. The redox potentials derived from DPV measurements are summarized in

Table 2. Redox potentials measured by DPV ^a of 4a–4c.

Compound	E1OX [V]	E2OX [V]	E3OX [V]	E1RED [V]	E2RED [V]	E3RED [V]
4a	+0.91	–	–	−1.72	–	–
4b	+1.02	+1.30	+1.43	−1.38	−1.71	−1.88
4c	+0.84	+1.50	–	−1.34	−1.48	−1.86

V vs. Ag/AgNO₃, 1 mM in benzonitrile containing Et₄NClO₄ (0.1 M), Pt electrode (internal diameter: 1.6 mm), scan rate: 20 mVs⁻¹, and internal reference Fc/Fc⁺ = +0.15 V.

.

Cyclic voltammograms of 4a–4c displayed irreversible redox waves under CV measurement conditions, suggesting the formation of unstable cationic and anionic species. The first oxidation potential (E₁^OX) in the DPV of 4b (+1.02 V) showed an anodic shift compared to that of 4a (+0.91 V). On the other hand, a cathodic shift was observed in the E₁^OX of 4c (+0.84 V) relative to 4a. These results imply the EWG at the 3-position of 4b, i.e., the p-nitrophenyl group, is accountable for the reduction in the energy level of HOMO, as anticipated by DFT calculations. The first reduction potential (E₁^RED) of 4a displayed −1.72 V, while those of 4b (−1.38 V) and 4c (−1.34 V) were almost the same. These identical E₁^RED values were attributed to the reduction in the substituted p-nitrophenyl group of 4b and 4c, rather than CHF moiety, under the electrochemical reduction conditions. These results indicate that the LUMO energy level, unlike that of HOMO, is decreased by the EWG at the 3- or 8-positions, as expected from the DFT calculations. Since the value of E₂^RED in 4b (−1.71 V) is similar to E₁^RED of 4a, this peak potential can be corresponded to the electrochemical reduction in the CHF moiety. Meanwhile, the E₂^RED of 4c (−1.48 V) revealed a pronounced cathodic shift compared to that of 4b. This outcome implies that the substitution of a p-nitrophenyl group at the 8-position effectively reduces the reduction potential of the CHF moiety more than the substitution at the 3-position.

3. Materials and Methods

Melting points were determined with a Yanagimoto MPS3 micro-melting apparatus and are uncorrected. High-resolution mass spectra were obtained with a Waters Xevo G2-XS QTof instrument. The UV/Vis spectra were recorded with a Shimadzu UV-2550 spectrophotometer (Shimadzu Corporation, Kyoto, Japan). Voltammetry measurements were carried out with a BAS 100B/W electrochemical workstation (BAS Corporation, Tokyo, Japan). ¹H and ¹³C NMR spectra were recorded in CDCl₃ with a JEOL ECA500 at 500 MHz and 125 MHz or a JEOL ECZ400 at 400 MHz and 100 MHz (JEOL Ltd., Tokyo, Japan), respectively.

5-Isopropyl-3,8-diphenyl-2H-cyclohepta[b]furan-2-one (4a): Synthesis from 1: To a solution of 1 (168 mg, 0.50 mmol) in CH₂Cl₂ (2.5 mL) was added N-iodosuccinimide (169 mg, 0.75 mmol) at room temperature. The resulting mixture was stirred at the same temperature for 1 h. After the solvent was removed under reduced pressure, the crude product was passed through the short silica gel column with CHCl₃ to give crude iodide 3 (113 mg). To a degassed solution of the crude iodide 3, phenylboronic acid (92 mg, 0.754 mmol), K₃PO₄ (317 mg, 1.49 mmol) in 1,4-dioxane (1.2 mL) and H₂O (0.2 mL) were added PdCl₂(dppf) (11 mg, 0.01 mmol). The resulting mixture was stirred at 100 °C for 13 h. The reaction mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with CHCl₃/AcOEt (50:1) as an eluent to give 4a (85 mg, 50% from 1) as yellow solid.

Synthesis from 2a: To a solution of 2a (267 mg, 1.01 mmol) in CH₂Cl₂ (5 mL) was added N-iodosuccinimide (338 mg, 1.50 mmol) at room temperature. The resulting mixture was stirred at the same temperature for 1 h. After the solvent was removed under reduced pressure, the crude product was passed through the silica gel column with CHCl₃/AcOEt (20:1) to give crude iodide (383 mg). To a degassed solution of the crude iodide, phenylboronic acid (177 mg, 1.45 mmol), K₃PO₄ (616 mg, 2.90 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) were added PdCl₂(dppf) (37 mg, 0.05 mmol). The resulting mixture was stirred at 100 °C for 13 h. The reaction mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with CHCl₃/AcOEt (50:1) as an eluent to give 4a (206 mg, 60% from 2a) as yellow solid. M.p. 190–191 °C; UV/Vis (CH₂Cl₂): λ_max (log ε) = 236 (4.32), 250 (4.35), 293 (4.19), 410 (4.26) nm; ¹H NMR (500 MHz, CDCl₃): δ_H = 7.64 (dd, J = 8.0, 1.1 Hz, 2H, Ph), 7.55–7.54 (m, 3H, H₄, Ph), 7.45–7.51 (m, 4H, Ph), 7.36–7.43 (m, 2H, Ph), 7.08 (d, J = 12.1 Hz, 1H, H₇), 6.77 (dd, J = 12.1, 1.6 Hz, 1H, H₆), 2.80 (sept, J = 6.9 Hz, 1H, i-Pr), 1.25 (d, J = 6.9 Hz, 6H, i-Pr) ppm; ¹³C NMR (125 MHz, CDCl₃): δ_C = 168.45, 154.99, 152.97, 146.53, 137.66, 136.33, 131.41, 130.96, 129.45, 128.85, 128.59, 128.53, 127.90, 127.32, 123.54, 110.05, 38.66, 23.05 ppm; HRMS (ESI-TOF): calcd for C₂₄H₂₀O₂ + Na⁺ [M + Na]⁺ 363.1355, found: 363.1375.

5-Isopropyl-3-(4-nitrophenyl)-8-(4-methoxyphenyl)-2H-cyclohepta[b]furan-2-one (4b): To a solution of 2b (301 mg, 1.02 mmol) in CH₂Cl₂ (5 mL) was added N-iodosuccinimide (345 mg, 1.54 mmol) at room temperature. The resulting mixture was stirred at the same temperature for 1 h. After the solvent was removed under reduced pressure, the crude product was passed through the silica gel column with CHCl₃/AcOEt (20:1) to give crude iodide (397 mg). To a degassed solution of the crude iodide, p-methoxyphenylboronic acid (237 mg, 1.42 mmol), K₃PO₄ (605 mg, 2.85 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) were added PdCl₂(dppf) (39 mg, 0.05 mmol). The resulting mixture was stirred at 100 °C for 12.5 h. The reaction mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with CHCl₃/AcOEt (20:1) as an eluent to give 4b (328 mg, 77% from 2b) as orange solid. M.p. 227–229 °C; UV/Vis (CH₂Cl₂): λ_max (log ε) = 344 (4.09), 443 (4.42) nm; ¹H NMR (500 MHz, CDCl₃): δ_H = 8.32 (d, J = 8.9 Hz, 2H, 3-(m-Bz)), 7.84 (d, J = 8.9 Hz, 2H, 3-(o-Bz)), 7.61 (s, 1H, H₄), 7.53 (d, J = 8.9 Hz, 2H, 8-(m-Bz)), 7.25 (d, J = 12.2 Hz, 1H, H₇), 7.00 (d, J = 8.9 Hz, 2H, 8-(o-Bz)), 6.92 (dd, J = 12.2, 1.6 Hz, 1H, H₆), 3.87 (s, 3H, OMe), 2.88 (sept, J = 6.9 Hz, 1H, i-Pr), 1.28 (d, J = 6.9 Hz, 6H, i-Pr) ppm; ¹³C NMR (125 MHz, CDCl₃): δ_C = 167.63, 160.21, 156.89, 152.89, 147.47, 146.53, 138.48, 137.56, 132.33, 131.01, 129.47, 129.21, 128.97, 124.10, 123.26, 114.15, 106.53, 77.36, 55.49, 38.83, 23.16 ppm; HRMS (ESI-TOF): calcd for C₂₅H₂₁NO₅ + H⁺ [M + H]⁺ 416.1493, found: 416.1479.

5-Isopropyl-3-(4-methoxyphenyl)-8-(4-nitrophenyl)-2H-cyclohepta[b]furan-2-one (4c): To a solution of 2c (235 mg, 0.76 mmol) in CH₂Cl₂ (5 mL) N-iodosuccinimide (280 mg, 1.24 mmol) was added at room temperature. The resulting mixture was stirred at the same temperature for 1 h. After the solvent was removed under reduced pressure, the crude product was passed through the silica gel column with CHCl₃/AcOEt (50:1) to give crude iodide (312 mg). To a degassed solution of the crude iodide, p-nitrophenylboronic acid (167 mg, 1.01 mmol), K₃PO₄ (471 mg, 2.22 mmol) in 1,4-dioxane (5 mL) and H₂O (0.5 mL) were added PdCl₂(dppf) (37 mg, 0.04 mmol). The resulting mixture was stirred at 100 °C for 15 h. The reaction mixture was poured into water and extracted with AcOEt. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel with CHCl₃ as an eluent to give 4c (127 mg, 40% from 2c) as red solid. M.p. 234–235 °C; UV/Vis (CH₂Cl₂): λ_max (log ε) = 258 (4.42), 293 (4.37), 424 (4.25) nm; ¹H NMR (400 MHz, CDCl₃): δ_H = 8.30 (d, J = 8.7 Hz, 2H, 8-(m-Bz)), 7.70 (d, J = 8.7 Hz, 2H, 8-(o-Bz)), 7.55 (d, J = 8.7 Hz, 2H, 3-(o-Bz)), 7.48 (d, J = 1.4 Hz, 1H, H₄), 7.02 (d, J = 9.1 Hz, 2H, 3-(m-Bz)), 6.92 (d, J = 12.3 Hz, 1H, H₇), 6.74 (dd, J = 12.3, 1.4 Hz, 1H, H₆), 3.86 (s, 3H, OMe), 2.79 (sept, J = 6.9 Hz, 1H, i-Pr), 1.25 (d, J = 6.9 Hz, 6H, i-Pr) ppm; ¹³C NMR (100 MHz, CDCl₃): δ_C = 168.07, 159.51, 154.81, 153.26, 147.47, 145.40, 144.14, 134.34, 131.82, 130.47, 129.79, 123.83, 123.68, 122.62, 114.37, 111.09, 55.40, 38.63, 22.92 ppm; HRMS (ESI-TOF): calcd for C₂₅H₂₁NO₅ + H⁺ [M + H]⁺ 416.1493, found: 416.1519.

4. Conclusions

In this study, we have successfully prepared and characterized a series of 3,8-diaryl-2H-cyclohepta[b]furan-2-ones 4a–4c using a one-pot procedure involving sequential iodation and Suzuki–Miyaura coupling.

The introduction of aryl groups at both the 3- and 8-positions of CHFs has been shown to influence their electronic properties, resulting in distinct optical and electrochemical behaviors. The optical properties of 4a–4c, evaluated through UV/Vis spectroscopy, indicated that the substitution of aryl groups extends the conjugated system, leading to a bathochromic shift in the absorption maxima. In particular, the introduction of a p-nitrophenyl group at the 3-position of CHF led to a redshift of the maximum absorption wavelength. This was corroborated by theoretical calculations, which revealed that the absorption bands of these compounds are primarily due to π-π* transitions and intramolecular charge transfer between the aryl groups.

Electrochemical analysis of 4a–4c via CV and DPV demonstrated that these compounds exhibit irreversible redox waves, indicative of the formation of unstable cationic and anionic species under the redox conditions. The redox potentials of 4a–4c were also found to be influenced by the nature of the aryl substituents, with electron-donating and EWG affecting the HOMO and LUMO energy levels as predicted by DFT calculations.

As mentioned in the introduction, 2H-cyclohepta[b]furan-2-ones are useful precursors of azulene derivatives. Thus, 4a–4c could also be convertible to novel azulene derivatives. Therefore, we currently investigate the efficient synthesis of azulene derivatives using 4a–4c as starting materials.