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Copper cayalysed nucleophilic substitution of an electron rich bromoarene; 2,3,4,5-tetramethoxytoluene: 

SyntheticPage 592
DOI: 10.1039/SP592
Submitted Apr 07, 2013, published Apr 15, 2013
WANG JIN (jaxdon@126.com)
A contribution from M.WANG Jin
Reaction Scheme: <IMG src="/images/empty.gif">Copper cayalysed nucleophilic substitution of an electron rich bromoarene<IMG src="/images/empty.gif">

Chemicals Used

Sodium methoxide (Sigma-Aldrich)
methanol (Sigma-Aldrich)
Copper(I) Chloride(Sigma-Aldrich)
Dimethylformamide(Sigma-Aldrich)

     

    Procedure

    To a 50 mL round bottom flask equipped with stir bar  containing a solution of CH3ONa (11.2 g, 0.20 mol) in 10 ml dry methanol  was added rapidly CuCl (1 g, 0.01 mol) 2-bromo-3,4,5-trimethoxy-1-methylbenzene (26.0 g, 0.1 mol) and dry DMF (3 ml) in sequence under an N2 atmosphere . The reaction mixture was raised to 120 ℃  and maintained at this temperature for 8 h (solution turns blue in colour). After cooling to ambient temperature, a solution of 5M HCl(40ml) was added, and the mixture was refluxed for another 0.5 h , The mixture was cooled and extracted with petroleum ether (3×80 ml), and the combined extracts were washed with brine (4×80 ml). The solution are dried over anhydrous sodium sulfate and solvent was removed in vacuo to afford a slightly yellow oil 2,3,4,5-tetramethoxytoluene (19.6 g) in 92.5% yield

    Author's Comments

    1 This method use CuCl as catalist instead of CuI,CuCN , the reaction temperature(120℃) is mild than literature , and is less expensive, more practical, and environmentally friendly.
    2 Use of nitrogen atmosphere during the reaction slightly gives better colour product. 
    3 Use solution of 5M HCl and petroleum ether is better for extraction of product

    Data

    1H NMR (500MHz, CDCl3): 2.24 (s，3H，-CH3), 3.74 (s, 3H, -OCH3), 3.78 (s, 3H, -OCH3), 3.85 (s, 3H, -OCH3), 3.92 (s, 3H, -OCH3), 6.40 (s, 1H, Ar-H).

    Lead Reference

    1.Jin Wang,Jian Yang*, Bo Yang, Jia-Qiang Sun and Tao Yang. Alternative synthesis of 5-chloromethyl-2,3-dimethoxy-6-methyl-1,4-benzoquinone: a key intermediate for preparing coenzyme Q analogues. Journal of Chemical Research 2010, 34(12), 724-725.
    http://dx.doi.org/10.3184/030823410X12857507693464

    2. Jin Wang, Jian Yang*, Bo Yang, Xiao Hu, Jia-Qiang Sun and Tao Yang. A green and efficient synthesis of 1-chloromethyl-2,3,4,5-tetramethoxy-6-methylbenzene. Journal of Chemical Research 2010, 34(12), 717-718.
    http://dx.doi.org/10.3184/030823410X12857507693437

    Other References

    3. Jin Wang, Jian Yang*, Rong-Guang Zhou*, Bo Yang and Yuan-Shuang Wu. Alternative synthesis of 2-(4-benzoyl-piperazin-1-ylmethyl)-5, 6-dimethoxy-3-methyl-[1, 4]benzoquinone. Journal of Chemical Research 2011, 35 (7), 431-432.
    http://dx.doi.org/10.3184/174751911X13099411630089

    4. Jin Wang, Jian Yang*, Rong-Guang Zhou*, Bo Yang and Yuan-Shuang Wu. A facile synthesis of 2, 3-dimethoxy-5-methyl-1, 4-benzoquinones. Journal of Chemical Research 2011, 35(7), 428-430.

    http://dx.doi.org/10.3184/174751911X13099377293263

    5. Jin Wang, Rong-Guang Zhou, Ting Wu, Tao Yang, Qi-Xue Qin, li Li, Bo Yang and Jian Yang. Total synthesis of apigenin. Journal of Chemical Research, 2012, 36(3):121-122.

    http://dx.doi.org/10.3184/174751912X13285269293913

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    Keywords: coenzyme Q analogus