4,7-Dimethoxy-6-propyl-2H-1,3-benzodioxole-5-carbaldehyde

Abstract

A simple intermediate for the synthesis of methoxy-analogues of coenzymes Q with substituents having various chain lengths based on natural polyalkoxyallylbenzene apiol has been developed.

1. Introduction

1,4-Quinones and hydroquinones with various functional substituents alongside the isoprenoid and long chains is an important cancer-related class of coenzymes Qn. Simple coenzyme Q₀ was found to possess antitumor properties, in particular, it inhibits the metastasis of breast [1], skin (melanoma) [2], and ovarian [3] cancer in mice. The majority of the syntheses of Qn coenzymes are based on the incorporation of hydrocarbon chains into an already prepared quinone, coenzyme Q₀, by oxidative radical reactions, which have a number of drawbacks [4].

2. Results and Discussion

We found an easy method for synthesizing the intermediates of Q₀ and its analogues with methoxy, methylenedioxy, methyl and alkyl substituents in the ring based on allylpolymethoxybenzenes (like apiol 1) that are easily isolated in large quantities from CO₂ extracts of parsley and dill seeds [5]. Previously, it was shown that apiol aldehyde 2 is oxidized by the Baeyer–Villiger reaction to the corresponding phenol 3 and then to quinone 4 [6] (Scheme 1). Recently, it was shown that apiole 1, dihydroapiol 5, and a number of other derivatives [7,8] inhibited colon cancer cells COLO 205.

The oxidative rearrangement of apiol aldehyde derivatives (like 6) with various substituents in the ortho position would make coenzyme Q analogs available, where a methoxy group is present instead of a methyl group. In this work, we developed a procedure for obtaining one of the key intermediates 6 for the future synthesis of a series of coenzyme Q analogues through intermediate phenol 7 and quinone 8 from apiol 1, which we isolated from parsley essential oil, in the amount of several kg. Aldehyde 6 was obtained by the formylation of dihydroapiol 5, according to a previously developed procedure, in the presence of SnCl₄ [8] with a yield of 90% (Scheme 1). The hydrogenation of apiol 1 to dihydroapiol 5 was carried out on highly porous ceramic block Pd-catalyst according to our procedure [9]. The target 6 was obtained during 1 h at 0 °C in high yield with the help of simple separation and crystallization from EtOH. Mass spectrum 6 confirmed the molecular weight and the presence of the fragment (MW–HCO = 233). The IR spectrum showed a clear band of the carbonyl group (1609, 1674 cm⁻¹). The ¹H; and ¹³C; spectra of compound 6 contained the aldehyde group (10.25 and 189.8 ppm, respectively), as well as all the corresponding signals of the methoxy, methylenedioxy, and propyl groups (See experiment and Supplementary Materials).

As a result of this work, the simple synthesis of an important intermediate for the preparation of coenzyme methoxy analogues based on the available Apiol was developed.

3. Materials and Methods

Melting points were measured using a Boetius melting point apparatus and were uncorrected. ¹H NMR and ¹³C NMR spectra were recorded on a Bruker DRX-500 instrument (working frequencies of 500.13 MHz (¹H) and of 125.76 MHz (¹³C), respectively). Chemical shift values were reported in parts per million (ppm) and referenced to the appropriate NMR solvent peaks (see Supplementary Materials). Spin–spin coupling constants (J) were reported in hertz (Hz). Mass spectra (m/z) were recorded on a Finnigan MAT/INCOS 50 mass spectrometer at 70 eV using direct-probe injection. Elemental analysis was performed on the automated Perkin-Elmer 2400 CHN microanalyzer. All solvents and reagents were purified according to standard procedures.

Synthesis of 4,7-Dimethoxy-6-propyl-2H-1,3-benzodioxole-5-carbaldehyde 6

• Preparation of the formylation mixture: Ethyl formate as a single portion (11.0 g, 148 mmol) was added to a suspension of PCl₅ (26.7 g, 128 mmol) in dry CH₂Cl₂ (40 mL) and refluxed for 4 h (CaCl₂ tube). A solution of dichloromethyl methyl ether (128 mmol) was obtained.
• A solution of 4,7-dimethoxy-5-propyl-1,3-benzodioxole 5 [9] (2.1 g, 9.3 mmol) in formylation mixture (12.8 mmol) and dry CH₂Cl₂ (15 mL) was added dropwise to a solution of SnCl₄ (7.0 g, 27 mmol) in dry CH₂Cl₂ (15 mL) at −10 °C. The reaction mixture was kept for 1 h at 0 °C and poured into water (100 mL). The organic layer was separated, washed with water (3 × 50 mL), and dried over MgSO₄. After removal of the solvent, the product was recrystallized from EtOH. White powder; 2.1 g (90%); mp 69–71 °C (EtOH); ¹H NMR (DMSO-d₆) δ: 0.90 (t, 3H, Me, J 7.3 Hz), 1.34–1.42 (m, 2H, CH₂), 2.815 (t, 2H, ArCH₂, J 7.7 Hz), 3.83 (s, 3H, OMe), 3.95 (s, 3H, OMe), 6.16 (s, 2H, OCH₂ O), 10.25 (s, ¹H, CHO). ¹³C NMR (DMSO-d₆) δ: 14.12, 23.85, 27.01, 60.08, 60.68, 102.60, 120.04, 132.35, 136.33, 136.90, 142.59, 143.93, 189.79. EIMS m/z: 252 ([M]⁺, 90%), 251 (38), 237 (30), 235 (18), 223 (100), 209 (57), 208 (31), 207 (17), 193 (18), 179 (18), 151 (12), 121 (11), 92 (19), 91 (28), 79 (34), 77 (50), 69 (22), 67 (25), 66 (29), 65 (35), 64 (22), 63 (29), 53 (43), 51 (39), 41 (26). IR (KBr) ν_max: 1609, 1674 (CO), calculated for C₁₃H₁₆O₅ C, 61.90; H, 6.39; found C, 61.96; H, 6.42.