Concise preparation of daldiquinone via palladium-catalyzed regioselective peri- C-H oxygenation of the naphthalene ring

Abstract

A total synthesis of the natural polycyclic phenolic compound daldiquinone was reported derived from 1-naphthaldehyde. The synthesis utilizes regioselective peri-C-H oxidation as a key step, proceeding through a longest linear sequence of seven steps with an overall yield of 40%. The binaphthol intermediate is obtained via Baeyer-Villiger oxidative rearrangement in 81% yield, followed by IBX oxidation to produce naphthoquinone. The binaphthalene core is constructed using Suzuki coupling. This strategy, which relied on direct oxidation of the C-H bond of the naphthalene ring, significantly truncated the synthetic pathway and boosted efficiency. The regiospecific approach offers a promising pathway for obtaining a wide array of daldiquinone derivatives.

Introduction

Naphthalene-containing compounds represent a distinct class of molecules characterized by their unique structure and significant biological importance, found in numerous natural products and pharmaceuticals.^1–5 The distinctive structure and properties of naphthalene provide broad opportunities for drug discovery.^6–9 The aromatic polycyclic phenolic compounds with naphthalene skeletons, such as naphthols and naphthoquinones, have garnered attention for their wide-ranging pharmacological activities, including antioxidant,^10,11 anti-inflammatory,^12–16 antitumor,^17–20 as well as their roles in regulating blood glucose levels^21–24 and improving the intestinal microenvironment.^25,26 Daldiquinone, a binaphthoquinone, was isolated by Koyama’s group in 2018 from Daldinia concentrica, and was discovered to possess potent anti-angiogenesis activity. ²⁷ The first total synthesis was reported by Türkmen, ²⁸ who employed 1,8-dihydroxynaphthalene as the starting material. However, the limited variety of 1,8-dinaphthol constrains the diversity of daldiquinone analogs and the synthesis of peri-naphthol is mostly relied on the substituted precursors of benzene containing C-O bonds, resulting in lengthy reaction sequences.

The development of C-H activation techniques^29–31 has enabled efficient natural product synthesis through direct cleavage of inert C-H bonds and subsequent functionalization.^32–34 It is recognized that natural polycyclic phenolic compounds would be obtained via direct C-H oxygenation of naphthalene material. Our previous studies demonstrated hydroxylation of the peri-position of naphthalene rings using aldehyde groups as directing groups, showcasing broad substrate applicability. ³⁵ Herein, we presented the synthesis of daldiquinone via C-H oxidation as the central step, directly introducing the OH group at the peri-position of naphthalene. This approach facilitated the synthesis of 1,8-dinaphthol through Baeyer-Villiger oxidative rearrangement, enriching the diversity of dihydroxynaphthalene species and expanding the scope of daldiquinone derivatives (Figure 1).

Figure 1.

(a) Natural products and drug molecules with a polyphenol structure. (b) Regioselective C-H oxidation of 1-naphtaladehyde with tunable TDGs. (c) This work is for synthesis of daldiquinone.

Results and discussion

Structural analysis of daldiquinone revealed that it was constructed by a Suzuki–Miyaura cross-coupling between naphthoquinone 4 and naphthalenol 7. Both naphthoquinone and naphthol involved the construction of C-O bonds on the naphthalene core (Scheme 1). It coincided with our previous work on regioselective C-H oxidation of naphthalene rings. ³⁵ The naphthoquinone 4 and naphthalenol 7 could be regarded as the peri-C-H oxidation products of 4-bromo-1-naphthaldehyde 1. Based on this retrosynthetic strategy, we successfully achieved the total synthesis of daldiquinone.

Scheme 1.

Retrosynthetic analysis of daldiquinone.

The synthesis began with commercially available 4-bromo-1-naphthaldehyde. A hydroxyl group was smoothly installed at the peri-position of naphthaldehyde 1 in a good yield using Pd-catalyzed regioselective C-H oxidation. ³⁵ Methylation of the hydroxyl group with iodomethane produced compound 2, an overall yield of 74% in two steps. Next, in the presence of m-CPBA, the aryl aldehyde 2 was subjected to Baeyer-Villiger oxidation and subsequently hydrolyzed to give naphthol 3. Chloromethyl ethyl ether was employed to protect naphthol 3, which was later removed under mild conditions to avoid compromising other functional groups. Boronic ester 6 was then synthesized from naphthol 3 using B₂Pin₂ and Pd(dppf)Cl₂ as the catalyst, with an 89% yield. Meanwhile, oxidation of naphthol 3 with 2-iodoxybenzoic acid (IBX) furnished naphthoquinone 4. The Suzuki–Miyaura reaction between 4 and 6 was efficiently accomplished to afford the unsymmetrical binaphthalene product. Final deprotection of the ethoxymethyl ether group using HCl completed the synthesis of daldiquinone in a total of seven steps. Compared with the previously reported route, the current method is one step shorter with maintaining the original yield. In addition, the C-H activation strategy offered a novel approach to synthesizing polyhydroxylated naphthalenes, thereby enhancing the diversity of daldiquinone derivatives (Scheme 2).

Scheme 2.

The synthesis of daldiquinone.

Conclusion

We have devised an efficient synthetic route for the natural product daldiquinone, achieving an overall yield of 40% through a linear sequence of seven steps. This process begins with commercially available 4-bromo-1-naphthaldehyde and leverages Pd-catalyzed regioselective peri-C-H oxidation as a pivotal step. The application of regioselective C-H oxygenation proved critical for constructing the hydroxylated naphthalene core, facilitating access to active naphthols and their derivatives. This method establishes a versatile platform for the rapid synthesis of diverse natural polycyclic phenolic compounds. Ongoing research in our group focuses on expanding the synthesis of daldiquinone derivatives and exploring their biological activities.

Experiment

General information

¹ H (500 MHz) and ¹³ C (125 MHz) NMR spectra were examined on Bruker AV-500 instruments at ambient temperature, using CDCl₃ and DMSO-d₆ as the solution with TMS as the interior label. Chemical shifts were reported as δ values and j (Hz). HRMS experiments were conducted in the positive mode using a Thermo Fisher Scientific Q Exactive Plus in ESI mode. Unless otherwise stated, all reagents were commercially sourced and utilized without further purification. The reaction progress was monitored by TLC from Jiangyou Chemical Co., Ltd. (Yantai, China), visualized using UV irradiation (254 nm). Silica gel (100–200 mesh) from Haiyang Chemical Co., Ltd (Qingdao, China) was used.

Procedure for synthesis of daldiquinone

4-Bromo-8-methoxy-1-naphthaldehyde (2)

4-bromo-1-naphthal-dehyde 1 (10 mmol), Pd(dba)₂ (0.3 mmol), 2-aminobenzenesulfonic acid (1.0 mmol), and PhI(OTFA)₂ (20 mmol) were dissolved in DCE (50 mL). The reaction was refluxed at 80°C and stirred for 12 h, then cooled down to ambient temperature and concentrated to give a crude product without further purification. K₂CO₃ (30 mmol) and CH₃I (30 mmol) were added to the above crude product in DMF (100 mL) at ambient temperature. After stirring for 3 h, the mixture was terminated by addition of H₂O and extracted twice with EtOAc. The organic phases were combined, concentrated under vacuum, and subsequently purified by column chromatography to obtain compound 2 as yellow solid (1.95 g, 74% yield in two-step total yield). R_f 0.50 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 10.97 (s, 1H), 7.97 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.57 (t, J = 8.5 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 4.04 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 194.7, 156.4, 135.1, 133.7, 130.5, 128.6, 128.1, 127.2, 124.5, 120.8, 107.7, 56.2. HRMS (ESI) m/z [M+H]⁺calcd for C₁₂H₁₀BrO₂ 264.9864, found 264.9857.

4-bromo-8-methoxynaphthalen-1-ol (3)

NaOAc (3.6 mmol) and 3-chloroperoxybenzoic acid (3.6 mmol, technical ~70%) were added to compound 2 (3.0 mmol) in CHCl₃ (15 mL). The mixture was stirred at ambient temperature for 16 h, then neutralized with saturated NaHCO₃ solution, and extracted twice with DCM. The organic phases were combined, concentrated in vacuo to obtained the crude formyl ester. NaOCH₃ (3.0 mmol, 1.0 M in MeOH) was added slowly to the above crude formyl ester in THF (300 mL) for 10 min at ambient temperature. The mixture was detected by TLC. Once the reaction was completed, the reaction was neutralized with aqueous citric acid solution and extracted twice with EtOAc. The organic phases were combined, concentrated under vacuum, and subsequently purified to afford compound 3 as a yellow solid (605 mg, 81% yield), which showed identical characterization profiles as in the literature. ²⁸ R_f 0.50 (10:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 9.47 (s, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 4.09 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 156.2, 154.6, 134.2, 131.7, 127.0, 121.3, 116.2, 111.3, 111.2, 104.9, 56.4. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₁H₁₀BrO₂ 252.9864, found 252.9853.

4-Bromo-8-methoxynaphthalene-1,2-dione (4)

Compound 3 (1.0 mmol) dissolved in DMF (10 mL) was treated with 2-iodoxybenzoic acid (1.1 mmol). The mixture was stirred at ambient temperature and monitored by TLC. Until complete conversion, the mixture was neutralized with H₂O and extracted twice with EtOAc. The organic phases were combined, concentrated under vacuum, and subsequently purified to afford compound 4 as a yellow solid (245 mg, 92% yield). R_f 0.20 (5:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 7.68 (t, J = 8.5 Hz, 1H), 7.57 (dd, J = 8.0, 1.0 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.04 (s, 1H), 4.02 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 178.5, 177.4, 162.9, 145.2, 136.7, 135.4, 132.3, 124.0, 118.7, 116.8, 56.8. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₁H₈BrO₃ 266.9657, found 266.9661.

1-Bromo-4-(ethoxymethoxy)-5-methoxynaphthalene (5)

NaH (1.8 mmol) was added to compound 3 (1.5 mmol) in anhydrous DMF (3.0 mL) in an ice-water bath and maintained at 0°C with continuous stirring for 1 h. Chloromethoxyethane (2.25 mmol) was added at 0°C, then slowly warmed to ambient temperature and stirred continuously for another 2 h. The reaction was neutralized with H₂O and extracted twice with EtOAc. The organic phases were combined, concentrated under vacuum, and subsequently purified to afford compound 5 as a colorless oil (428 mg, 92% yield). R_f 0.70 (5:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 7.84 (dd, J = 8.5, 1.0 Hz, 1H), 7.67 (d, J = 8.0 Hz, 1H), 7.48 (t, J = 8.0 Hz, 1H), 6.96 (d, J = 8.5 Hz, 1H), 6.92 (d, J = 7.5 Hz, 1H), 5.30 (s, 2H), 3.96 (s, 3H), 3.85 (q, J = 7.0 Hz, 2H), 1.28 (t, J = 7.0 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 157.1, 154.2, 135.1, 130.5, 127.7, 120.4, 119.9, 115.8, 113.5, 107.2, 95.5, 64.8, 56.6, 15.3. HRMS (ESI) m/z [M+H]⁺ calcd for C₁₄H₁₆BrO₃ 311.0283, found 311.0292.

2-(4-(Ethoxymethoxy)-5-methoxynaphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6)

Under an inert N₂ atmosphere, B₂Pin₂ (1.2 mmol), Pd(dppf)Cl₂·CH₂Cl₂ (0.1 mmol), KOAc (4.0 mmol), and compound 5 (1.0 mmol) were dissolved in toluene and refluxed at 110°C stirring for 2 h Then cooled down to ambient temperature, the mixture was quenched with H₂O and subsequently extracted twice with EtOAc. The organic phases were combined, concentrated under vacuum, and purified to obtain compound 6 as a colorless oil (318 mg, 89 % yield). R_f 0.30 (20:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 8.40 (dd, J = 8.5, 1.0 Hz, 1H), 7.99 (d, J = 7.5 Hz, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.87 (d, J = 7.5 Hz, 1H), 5.36 (s, 2H), 3.95 (s, 3H), 3.85 (q, J = 7.0 Hz, 2H), 1.40 (s, 12H), 1.26 (t, J = 7.0 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 157.2, 157.1, 141.4, 137.1, 126.8×2, 121.5, 118.4, 111.2, 106.5, 94.8, 83.6×2, 64.7, 56.6, 25.1×4, 15.26. HRMS (ESI) m/z [M+H]⁺calcd for C₂₀H₂₈BO₅ 359.2030, found 359.2038.

Daldiquinone

Under an inert N₂ atmosphere, compound 4 (0.5 mmol), compound 6 (0.75 mmol), Pd(PPh₃)₄ (0.075 mmol), and K₂CO₃ (2.0 M in H₂O, 1.0 mL) were dissolved in 1,4-dioxane (5 mL) and stirred at 60°C for 1 h. Then cooled to ambient temperature, the mixture was quenched with H₂O and subsequently extracted twice with EtOAc. The organic phases were combined and concentrated under vacuum to afford a crude product. HCl (1.0 M in H₂O, 5 mL) was added to the crude product in THF (5 mL) and stirred for 1 h at ambient temperature. The mixture was completely terminated by addition of H₂O and extracted twice with EtOAc. The organic phases were combined, concentrated under vacuum, and purified to afford daldiquinone as a brown solid (147 mg, 82% yield in two-step total yield), which showed identical characterization profiles as in the literature. ²⁷ R_f 0.40 (1:1 hexane/EtOAc). ¹H NMR (500 MHz, CDCl₃) δ 9.63 (s, 1H), 7.35-7.31 (m, 2H), 7.27 (t, J = 8.5 Hz, 1H), 7.24 (t, J = 7.5 Hz, 1H), 7.07 (d, J = 8.5 Hz, 1H), 6.96 (d, J = 7.5 Hz, 1H), 6.84 (d, J = 7.5 Hz, 1H), 6.48 (s, 1H), 6.47 (d, J = 7.5 Hz, 1H), 4.11 (s, 3H), 4.02 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 181.2, 178.9, 163.1, 157.1, 156.9, 156.0, 138.4, 136.5, 134.4, 129.4, 128.5, 126.8, 125.6, 123.2, 119.9, 119.5, 115.4, 115.2, 110.3, 104.8, 56.6, 56.5. HRMS (ESI) m/z [M+H]⁺ calcd for C₂₂H₁₇O₅ 361.1076, found 361.1078.

Supplemental Material

sj-docx-1-chl-10.1177_17475198251316139 – Supplemental material for Concise preparation of daldiquinone via palladium-catalyzed regioselective peri-C-H oxygenation of the naphthalene ring

Supplemental material, sj-docx-1-chl-10.1177_17475198251316139 for Concise preparation of daldiquinone via palladium-catalyzed regioselective peri-C-H oxygenation of the naphthalene ring by Jing Jiang, Yue Gao, Chenqi Wu, Suqin Zhang and Shuyang Hu in Journal of Chemical Research