A convenient synthesis of 1,4-benzoquinones

Abstract

A series of 1,4-benzoquinones was prepared in a high yield by a two-step reaction starting from 2,3,4,5-tetramethoxytoluene by a Blanc reaction and subsequent oxidation.

Introduction

Coenzyme Q₁₀ (CoQ₁₀, Figure 1) is a 1,4-benzoquinone molecule with a side chain of 10 isoprenyl units, occurs naturally in human and most bacteria and acts as an electron carrier in mitochondrial respiratory chains. ¹ CoQ₁₀ is widely used in the treatment of mitochondrial disorders and neurodegenerative movement disorders, ² such as Parkinson’s disease, Alzheimer’s disease, and Friedreich’s ataxia. ³ Synthetic CoQ analogues (3, Figure 1) with mimics of the alkyl chain by other functional groups show good antioxidant properties and could be used as potent antioxidants for combating oxidative stress. ⁴

Figure 1.

CoQ₁₀ and compounds 3a–3d.

Among the published syntheses of CoQ₁₀, Lipshutz et al. ⁵ and Negishi et al. ⁶ developed efficient procedures based on metal-catalyzed cross-coupling between a chloromethyl-CoQ₀ (compound 3a, Figure 1) and organoaluminum or organozinc reagents. In our previous study, ⁷ we found N-heterocyclic-substituted coenzyme Q compounds which exhibited good biological activities. ⁸ There are several methods reported for the synthesis of alkyl-CoQ₀. Crozet et al. ⁹ reported a five-step synthesis of 3a in an overall yield of 44%. Lipshutz et al. ¹⁰ utilized zirconocene catalysts which are not readily available to form CoQ compounds in multiple steps. However, most of these methods are time consuming, complex, and low yielding.

We now present an efficient and reproducible synthesis of compounds 3a–3d starting from easily available 2,3,4,5-tetramethoxytoluene 1 by a Blanc reaction and subsequent oxidation. The synthetic route is described in Scheme 1 .

Scheme 1.

Reagents and conditions: (a) paraformaldehyde and 37% HCl, 47% HBr, morpholine, or piperidine (35 °C) and (b) CAN and THF/H₂O (25 °C).

Results and discussion

As shown in Table 1, a two-step method for the synthesis of 1,4-benzoquinones is described. In the first step, Blanc reaction of compound 1 with paraformaldehyde in different solvents (37% HCl, 47% HBr, morpholine, and piperidine) at 35 °C for 2 h gave compounds 2a–2d, respectively, in high yields. The solvents were also employed as a reagent in this transformation and the reaction is clean. The final step was achieved in each case by oxidation of compounds 2a–2d with ceric ammonium nitrate (CAN) at room temperature to give the desired compounds 3a–3d in good yields (Table 1). Compared with the existing methods for synthesis of 1,4-benzoquinones, this procedure is short, high yield, and involves easy work-up.

Table 1.

Two-step synthesis of 1,4-benzoquinones (3).

Entry	Solvent	R	2 (yield)	3 (yield)
1	37% HCl	Cl	2a (99%)	3a (85%)
2	47% HBr	Br	2b (98%)	3b (82%)
3	Morpholine		2c (95%)	3c (65%)
4	Piperidine		2d (97%)	3d (70%)

Conclusion

In summary, a two-step route for the synthesis of 1,4-benzoquinones 3a–3d has been achieved in good yield. This protocol has the features of high yield, mild conditions, and simple work-up procedure. In addition, this economical and environmentally friendly method provides a potential new synthesis of an intermediate for the gram-scale synthesis of CoQ₁₀. It should also provide a general method for the synthesis of other CoQ analogues.

Experimental

All reactions were monitored by thin layer chromatography (TLC; SiO₂, petroleum ether (boiling range in 60–90^oC)/EtOAc 5:1); nuclear magnetic resonance (NMR) and mass spectra were recorded on a Bruker AVANCE III-HD 400 NMR spectrometer and a TripleTOF mass spectrometer, respectively. Elemental analyses were performed on a Perkin-Elmer PE2400 Elemental Analyzer. All reagents, for example, paraformaldehyde and CAN, were purchased from Adamas, P.R. China, and used without further purification. 2,3,4,5-Tetramethoxytoluene 1 was prepared by the literature method. ¹¹

General procedure for compounds 2a–2d

Different solvents (37% HCl, 47% HBr, morpholine, and piperidine) were added dropwise at room temperature to stirred mixtures of compound 1 (2.12 g, 0.01 mol) and paraformaldehyde (0.45 g, 0.015 mol). The mixtures were stirred at room temperature for 2 h. The reactions were then quenched with water and extracted with CH₂Cl₂. The extracts were washed with brine, dried over anhydrous Na₂SO₄, and evaporated under reduced pressure to afford compounds 2a–2d. In all cases, the spectroscopic data (see in the following) accorded with those in the literature.

Compound 2a , ⁴ yellow oil, 99% yield: ¹H NMR (400 MHz, CDCl₃): δ 4.69 (s, 2H, CH₂Cl), 3.93 (s, 3H, OCH₃), 3.92 (s, 3H, OCH₃), 3.90 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃), 2.29 (s, 3H, CH₃).

Compound 2b , ² yellow oil, 98% yield: ¹H NMR (500 MHz, CDCl₃): δ 4.68 (s, 2H, CH₂Br), 3.93 (s, 3H, OCH₃), 3.92 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 3.78 (s, 3H, OCH₃), 2.28 (s, 3H, CH₃).

Compound 2c , ¹² yellow oil, 95% yield: ¹H NMR (400 MHz, CDCl₃): δ 3.93 (s, 3H, OCH₃), 3.89 (s, 3H, OCH₃), 3.83 (s, 3H, OCH₃), 3.79 (s, 3H, OCH₃), 3.65 (t, J = 8.0 Hz, 4H), 3.46 (s, 2H, CH₂N), 2.46 (t, J = 8.0 Hz, 4H), 2.26 (s, 3H, CH₃).

Anal. calcd for C₁₆H₂₅NO₅: C, 61.72; H, 8.09; N, 4.50; O, 25.69; found: C, 61.70; H, 8.10; N, 4.52; O, 25.71%.

Compound 2d , ¹² yellow oil, 97% yield: ¹H NMR (400 MHz, CDCl₃): δ 3.91 (s, 3H, OCH₃), 3.88 (s, 3H, OCH₃), 3.81 (s, 3H, OCH₃), 3.77 (s, 3H, OCH₃), 3.37 (s, 2H, CH₂N), 2.36 (s, 4H), 2.24 (s, 3H, CH₃), 1.51–1.46 (m, 4H), 1.40–1.39 (m, 2H).

Anal. calcd for C₁₇H₂₇NO₄: C, 65.99; H, 8.80; N, 4.53; O, 20.68; found: C, 66.00; H, 8.81; N, 4.50; O, 20.69%.

General procedure for compounds 3a-3d

A solution of CAN (0.002 mol) in water (5 mL) was added dropwise to a solution of each compound 2a–2d (0.001 mol) in tetrahydrofuran (THF; 10 mL) at 25 °C. Each mixture was stirred at room temperature for another 1 h. The progress of the reactions was monitored by TLC. After completion of the reaction, the crude was extracted in each case with three portions of CH₂Cl₂ (10 mL). The orange CH₂Cl₂ extracts were washed with brine until neutrality and then dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude products were purified by silica gel column chromatography (petroleum ether/EtOAc 4:1) to give compounds 3a–3d. In each case, the spectroscopic data (see the following) accorded with those in the literature.

Compound 3a , ⁷ red oil, 85% yield. ¹H NMR (500 MHz, CDCl₃): δ 4.29 (s, 2H, CH₂Cl), 3.88 (s, 3H, OCH₃), 3.86 (s, 3H, OCH₃), 1.99 (s, 3H, CH₃); ¹³C NMR (101 MHz, CDCl₃): 183.7 (C=O), 181.6 (C=O), 144.7, 144.2, 142.3, 136.7, 61.2 (OCH₃), 61.1 (OCH₃), 35.0 (CH₂Cl), 11.8 (CH₃); mass spectrometry (MS; electrospray ionization (ESI)): m/z = 253 [M + Na]⁺.

Compound 3b , ⁴ red oil, 82% yield. ¹H NMR (500 MHz, CDCl₃): δ 4.39 (s, 2H, CH₂Br), 3.97 (s, 3H, OCH₃), 3.96 (s, 3H, OCH₃), 2.09 (s, 3H, CH₃); MS (ESI): m/z = 275 [M + H]⁺.

Compound 3c , ¹³ red oil, 65% yield. ¹H NMR (400 MHz, CDCl₃): δ 3.96 (s, 3H, OCH₃), 3.94 (s, 3H, OCH₃), 3.65 (t, J = 4.0 Hz, 4H), 3.38 (s, 2H, CH₂), 2.44 (t, J = 4.0 Hz, 4H), 2.16 (s, 3H, CH₃); MS (ESI): m/z = 282 [M + H]⁺.

Compound 3d , ² red oil, 70% yield. ¹H NMR (400 MHz, CDCl₃): δ 4.01 (s, 3H, OCH₃), 3.99 (s, 3H, OCH₃), 3.32 (s, 2H, CH₂), 2.36 (t, J = 4.0 Hz, 4H), 2.12 (s, 3H, CH₃), 1.53 (quint, J = 4.0 Hz, 4H), 1.37–1.42 (m, 2H); MS (ESI): m/z = 280 [M + H]⁺.