Abstract
5-bromo-2,3-dimethoxy-6-methyl-1,4-benzoquinone 3, a key intermediate for preparing coenzyme Q compounds, was readily synthesized in two steps by a reaction sequence starting from the commercially available 3,4,5-trimethoxytoluene 1 via bromination and oxidation reactions. Persulfate salts were first employed as oxidants to synthesize 1,4-benzoquinone, the overall yield of title compound 3 was 65%.
1 Introduction
In synthetic chemistry, researchers are always seeking new methods for synthesising a specific compound that are important in many areas such as pharmaceutical industry. 5-bromo-2,3-dimethoxy-6-methyl-1,4-benzoquinone (3) [1], is an important coenzyme Q compound [2], which facilitates electron-transfer activity [3] and radical properties in mitochondria [4]. In addition, compound 3 is also a key intermediate [5] in the preparation of other biologically active coenzyme Q analogues [6]. In 2000, Jung and co-workers [7] reported that coupling of compound 3 with isoprenylstannanes could efficiently produce coenzyme Q10 and its analogues, as shown in Scheme 1. CoQ10 is a lipid-soluble benzoquinone with a side-chain of 10 isoprenoid units (Scheme 1), acts as a free radical scavenging antioxidant [3]. CoQ10 has been widely used in the treatment of mitochondria disorders [8].
To date, methods for the synthesis of compound 3 are limited [9]. Most of the methods used CoQ0 as starting material, compound 3 was obtained by reaction with toxic bromine [10], and few syntheses leading to compound 3 have been disclosed [11]. Hence, based on our previous work on the synthesis of CoQ analogues [12, 13, 14, 15, 16], we now report an efficient synthetic path for compound 3 as shown in Scheme 2. The reaction is operationally simple and could be used in the preparation of other coenzyme Q analogues.
2 Experimental
All reactions were monitored by TLC (SiO2, petrol ether/ EtOAc 5:1). Melting points were measured on Melting Point M-565 (BuChi). NMR and mass spectra were recorded on a Bruker Avance III-HD 400 NMR and TripleTOF mass spectrometers, respectively. GC-Mass spectra were recorded on Triple Quadrupole GC/MS of Agilent 7890B-7000C. All reagents: e.g. NaBr, Na2S2O8, K2S2O8, (NH4)2S2O8 were purchased from Adamas, P. R. China, and used without further purification.
2.1 Synthetic procedure for 2-bromo-3,4, 5-trimethoxytoluene (2)
A mixture of 3,4,5-trimethoxytoluene 1 (0.72 g, 4 mmol) and NaBr (0.42 g, 4 mmol) were dissolved in acetic acid (4 mL). A solution of 30% H2O2 (2 mL, 18 mmol) was added dropwise at 40°C over a period of 1 h. The resulting mixture was quenched with water and extracted with petroleum ether. Combined the organic layers and evaporated in vacuo to afford a yellow oil 2 (1.04 g) in 100% yield. 1H NMR (400MHz, CDCl3): δ 6.61 (s, 1H, ArH), 3.89 (s, 3H, OCH3), 3.86 (s, 3H, OCH3), 3.84 (s, 3H, OCH3), 2.37 (s, 3H, CH3). 13C NMR (101MHz, CDCl3): δ 152.2, 150.8, 141.1, 133.4, 110.8, 109.5, 61.1 (OCH3), 60.9 (OCH3), 56.1 (OCH3), 23.2 (CH3).
Compound 3 and coenzyme Q10.
Reagents and conditions: (a) NaBr, 30% H2O2, HOAc, 40°C, 1 h, 100%; (b) Sodium persulfate, HOAc/H2SO4, 80°C, 2 h, 65%.
The data is consistent with the literature [13].
2.2 Synthesis of compound 3
Method (1): Compound 2 (0.44 g, 1.7 mmol) was dissolved in a mixture solvent of acetic acid (2.5 mL) and H2SO4 (0.25 mL), then a solution of Na2S2O8 (0.80 g, 3.4 mmol) in H2O (5 mL) was added dropwise over 5 min. The mixture was stirred and heated at 80°C for another 2 h and extracted with dichloromethane. Combined organic layers, and washed with H2O and NaHCO3, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue was purified by a flash column (PE/EtOAc 6:1) to give red solid 3 (0.28 g, 65% yield).
Method (2): A solution of K2S2O8 (3.4 mmol) in H2O (8 mL) was added dropwise to a mixture of compound 2 (0.44 g, 1.7 mmol) in acetic acid (2.5 mL) and H2SO4 (0.25 mL). The reaction mixture was heated at 80°C for 2 h, quenched with water and extracted with dichloromethane. The organic phases were washed with H2O and Brine, dried over anhydrous Na2SO4, and evaporated in vacuo. The residue oil was purified by a flash column to give red solid 3 (0.26 g, 60% yield).
Method (3): To a mixture of Compound 2 (0.44 g, 1.7 mmol) in HOAc (2.5 mL) and H2SO4 (0.25 mL) was added dropwise by a solution of (NH4)2S 2O 8 (3.4 mmol) in H2O (6 mL) over 5 min. The reaction mixture was heated at 80°C for 2 h and extracted with dichloromethane. The combined organic phases were washed with H2O and NaHCO3, dried over Na2SO4, and evaporated in vacuo. The residue oil was purified by a flash column to give red solid 3 (0.17 g, 40% yield). m.p. 68 - 69°C (lit. 67-69°C [10]). 96% purity by HPLC. 1H NMR (400 MHz, CDCl3): δ 4.04 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 2.21 (s, 3H, CH3). 13C NMR (101MHz, CDCl3): δ 181.0 (C=O), 176.7 (C=O), 145.2, 144.1, 143.8, 133.6, 61.58 (OCH3), 61.33 (OCH3), 16.75 (CH3). GC-MS (EI): m/z = 260.
Synthesis of compound 3 under different persulfate. 
| Entry | Oxidant | Time (h) | Temp (°C) | Yield (%) |
|---|---|---|---|---|
| 1 | Na2S2O8 | 2 | 80 | 65 |
| 2 | K2S2O8 | 2 | 80 | 60 |
| 3 | (NH4)2S2O8 | 2 | 80 | 40 |
Conditions: 2 (1.7 mmol), persulfate (3.4 mmol), HOAc-H2SO4 (v/v = 10:1).
The data is consistent with the literature [4].
3 Results and discussion
As shown in Scheme 2, treatment of 3,4,5-trimethoxytoluene (1) with NaBr and 30% in acetic acid at 40°C gave compound 2 in 100% yield. Finally, compound 2 was oxidized with a persulfate compound in HOAc-H2SO4 mixed solvent (v/v = 10:1) to afford compound 3 (Table 1). The reaction is conducted without using any metal catalyst. This environmentally friendly procedure is based on the persulfate oxidant as an oxygen atom donor, and the HOAc-H2SO4 solvent as proton atom in this transformation [2]. The use of (NH4)2S2O8 as oxidant in HOAc-H2SO4 (10:1) mixed solvent gave 3 in a yield of 40% (entry 3, Table 1). When utilized K2S2O8 as oxidant in the same mixed solvent HOAc-H2SO4 (10:1) can improve the reaction yield to 60% (entry 2, Table 1). The best yield was obtained using Na2S2O8 as oxidant in HOAc-H2SO4 (10:1) solvent system, which gave the desired compound 3 in 65% yield (entry 1, Table 1).
4 Conclusion
In summary, we developed a two-step synthetic protocol for the preparation of 5-bromo-2,3-dimethoxy-6-methyl-1,4-benzoquinone (3) from the cheap and readily available 3,4,5-trimethoxytoluene (1). The bromination reaction utilize NaBr–H2O2 system as a green brominating agent instead of bromine and NBS, the reaction is clean and easy work up without purification. Persulfate salts were first employed as oxidants to synthesize 1,4-benzoquinone under mild condisitons, the chemistry was clean and easy work up. This method is potentially applicable for the the synthesis of a wide variety of coenzyme Q compounds [14,15].
Acknowledgments
We thank the National Natural Science Foundation of China (Nos. 31600740 and 81803353), the Natural Science Foundation of Jiangsu Province (BK20160443), the Six Talent Peaks Project in Jiangsu Province (SWYY-094), the Jiangsu Provincial Key Laboratory for Bioresources of Saline Soils (Nos. JKLBS2016013 and JKLBS2017010) for financial support.
References
[1] Pei Z., Gustavsson T., Roth R., Frejd T., Hägerhäll C., Photolabile ubiquinone analogues for identification and characterization of quinone binding sites in proteins. Bioorg. Med. Chem., 2010, 18(10), 3457-3466.10.1016/j.bmc.2010.03.075Search in Google Scholar PubMed
[2] Wang J., Hu X., Yang J., Two-Step Synthesis of 2-(9-Hydroxynonyl)-5,6-dimethoxy-3-methyl-1,4- benzoquinone. Synthesis-Stuttgart, 2014, 46(17), 2371-2375.10.1055/s-0033-1338643Search in Google Scholar
[3] Wang J., Li S., Yang T., Yang J., Single-step synthesis of idebenone from coenzyme Q0 via free-radical alkylation under silver catalysis. Tetrahedron, 2014, 70(47), 9029-9032.10.1016/j.tet.2014.10.017Search in Google Scholar
[4] Ma W., Zhou H., Ying Y.L., Li D.W., Chen G.R., Long Y.T., In situ spectroeletrochemistry and cytotoxic activities of natural ubiquinone analogues. Tetrahedron, 2011, 67(33), 5990-6000.10.1016/j.tet.2011.06.026Search in Google Scholar
[5] Lu S., Li W.W., Rotem D., Mikhailova E., Bayley H., A primary hydrogen–deuterium isotope effect observed at the single-molecule level. Nat. Chem., 2010, 2(11), 921-922.10.1038/nchem.821Search in Google Scholar PubMed
[6] Liu X.Y., Long Y.T., Tian H., New insight into photo-induced electron transfer with a simple ubiquinone-based triphenylamine model. RSC Adv., 2015, 5(71), 57263-57266.10.1039/C5RA09324DSearch in Google Scholar
[7] Jung Y.S., Joe B.Y., Seong C.M., Park N.S., Synthesis of ubiquinones utilizing Pd(0)-catalyzed Stille coupling. B. Kor. Chem. Soc., 2000, 21(5), 463-464.10.1002/chin.200043222Search in Google Scholar
[8] Wang J., Li S., Yang T., Yang J., Synthesis and antioxidant activities of coenzyme Q analogues. Eur. J. Med. Chem., 2014, 86, 710-713.10.1016/j.ejmech.2014.09.042Search in Google Scholar PubMed
[9] Davis B.M., Tian K., Pahlitzsch M., Brenton J., Ravindran N., Butt G., et al., Topical coenzyme Q10 demonstrates mitochondrial-mediated neuroprotection in a rodent model of ocular hypertension. Mitochondrion, 2017, 36, 114-123.10.1016/j.mito.2017.05.010Search in Google Scholar PubMed PubMed Central
[10] Lu L., Chen F., A novel and convenient synthesis of coenzyme Q1. Synthetic Commun., 2004, 34(22), 4049-4053.10.1081/SCC-200036578Search in Google Scholar
[11] Düz B., Yüksel D., Ece A., Sevin F., The first example of tungsten-based carbene generation from WCl6 and atomic carbon and its use in olefin metathesis. Tetrahedron Lett., 2006, 47(29), 5167-5170.10.1016/j.tetlet.2006.05.054Search in Google Scholar
[12] Hu X., Qiu Q., Wang W.L., Wang J., Practical synthesis of 2-(4-benzyl-piperazin-1-ylmethyl)-5, 6-dimethoxy-3-methyl-[1,4] benzoquinone hydrochloride. Res. Chem. Intermediat., 2017, 43(1), 57-61.10.1007/s11164-016-2605-9Search in Google Scholar
[13] Wang J., Li S., Hu X., Yang J., A Convenient Synthesis of N-Benzylpiperazine, 1-Aralkyl-4-benzylpiperazines and an Isostere of Idebenone. Org. Prep. Proced. Int., 2014, 46(5), 469-474.10.1080/00304948.2014.944409Search in Google Scholar
[14] Wang J., Yang J., Yang B., Hu X., Yang T., A green and efficient synthesis of 1-chloromethyl-2,3,4,5-tetramethoxy-6-methyl-benzene. J. Chem. Res., 2010, 34(12), 717-718.10.3184/030823410X12857507693437Search in Google Scholar
[15] Hu X., Chen H., Wu W.J., Wang W.L., Wang J., A convenient synthesis of 1-aralkyl-4-benzylpiperazine derivatives. J. Chem. Res., 2016, 40(9), 519-529.10.3184/174751916X14683176211054Search in Google Scholar
[16] Wang J., Xia F., Jin W.B., Guan J.Y., Zhao H., Efficient synthesis and antioxidant activities of N-heterocyclyl substituted coenzyme Q analogues. Bioorg. Chem., 2016, 68, 214-218.10.1016/j.bioorg.2016.08.008Search in Google Scholar PubMed
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