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Synlett 2009(5): 813-817  
DOI: 10.1055/s-0028-1087937
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Improved Synthesis of Diquinones

Brian E. Love*a, Jeffrey Bonner-Stewartb, Lori A. Forrestb
a Department of Chemistry, East Carolina University, Greenville, NC 27858, USA
Fax: +1(252)3286210; e-Mail: loveb@ecu.edu;
b PhytoMyco Research Corporation, 1800 N. Greene St., Suite H, Greenville, NC 27834, USA
Further Information

Publication History

Received 17 October 2008
Publication Date:
24 February 2009 (online)

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Abstract

Preparation of a series of substituted diquinones is reported. In most examples, inverse order of addition (addition of a dimethoxybenzene derivative to a CAN solution) has been found to produce higher yields of diquinones than the traditional protocol in which the oxidant is added to the arene.

Key words

quinones - dimerizations - oxidations - CAN - reaction protocols

    References and Notes

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13

Castagnoli6a reports an 85% yield of 6a and an 8% yield of 7a, while Maruyama¹¹ reports a 75% yield of 6a and does not report a yield for 7a.

14

Initially this was done unintentionally.

16

Applicability of the method to hydrophobic substrates becomes particularly relevant if the method is to be applied to the synthesis of popolohuanone E and related compounds, since the presumed precursor to popolohuanone E contains a large alicyclic side chain (in addition to an additional hydroxyl group; Scheme  [¹] ).

17

¹H NMR and ¹³C NMR spectra were obtained on crude products. These spectra indicated that compounds prepared by ‘inverse’ addition were typically devoid of any significant impurities. Products purified by recrystallization were used to obtain melting point data.

18

Typical Experimental Procedure: A sample of 2,5-dimethoxytoluene (0.79 g, 5.2 mmol) was dissolved in MeCN (15 mL) and added dropwise over 20 min to a stirred solution of ceric ammonium nitrate (9.38 g, 17.1 mmol) dissolved in distilled H2O (15 mL). The mixture was stirred at r.t. for 1 h, then diluted with H2O (75 mL). The precipitate was isolated by suction filtration, rinsed with H2O, and dried under reduced pressure, yielding the product (0.57 g, 91%) as a bright yellow solid; mp 186-187 ˚C (EtOH) (lit.6a 189-190 ˚C). ¹H NMR (CDCl3): δ = 6.82 (s, 2 H), 6.71 (q, J = 1.8 Hz, 2 H), 2.11 (d, J = 1.8 Hz, 6 H). ¹³C NMR (CDCl3): δ = 186.9, 184.7, 146.2, 139.5, 135.9, 133.6, 15.6. IR: 1652, 912 cm-¹.

19

Characterization Data (copies of spectra are provided in the Supporting Information): 6b: mp 190-192 ˚C (EtOH-CHCl3) (lit.²4 195-197 ˚C). ¹H NMR (CDCl3): δ = 6.76 (s,
2 H), 6.69 (s, 2 H), 1.31 (s, 18 H). ¹³C NMR (CDCl3): δ = 186.6, 185.6, 156.3, 138.0, 137.6, 131.9, 35.3, 29.0. IR: 2957, 1658, 914 cm-¹. 6c: mp 157-159 (EtOH) ˚C. ¹H NMR (CDCl3): δ = 6.81 (s, 2 H), 6.65 (s, 2 H), 2.45 (t, J = 7.5 Hz, 4 H), 1.50-1.60 (m, 4 H), 1.20-1.40 (m, 16 H), 0.89 (t, J = 6.9 Hz, 6 H). ¹³C NMR (CDCl3): δ = 186.7, 185.0, 150.0, 139.2, 136.2, 132.6, 31.6, 29.2, 28.9, 28.8, 27.7, 22.6, 14.0. IR: 2917, 1661, 1644, 922 cm-¹. Anal. Calcd for C26H34O4: C, 76.06; H, 8.35. Found: C, 75.88; H, 8.29. 6d: mp 170-171 ˚C (EtOH). ¹H NMR (CDCl3): δ = 6.81 (s, 2 H), 6.65 (s, 2 H), 2.50 (q, J = 7.2 Hz, 4 H), 1.17 (t, J = 7.2 Hz, 6 H). ¹³C NMR (CDCl3): δ = 186.7, 185.0, 151.1, 139.3, 136.1, 131.9, 21.9, 11.5. IR: 2955, 1662, 1646, 914 cm-¹. Anal. Calcd for C16H14O4: C, 71.10; H, 5.22. Found: C, 71.00; H, 5.18. 6e: mp 153-154 ˚C (EtOH). ¹H NMR (CDCl3): δ = 6.81 (s, 2 H), 6.65 (s, 2 H), 2.44 (t, J = 7.5 Hz, 4 H), 1.50-1.60 (m, 4 H), 1.00 (t, J = 7.2 Hz, 6 H). ¹³C NMR (CDCl3): δ = 186.7, 185.0, 149.7, 139.2, 136.2, 132.7, 30.8, 21.0, 13.8. IR: 1660, 1644, 917 cm-¹. Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.36; H, 6.15. 6f: mp 167-168 ˚C (EtOH-CHCl3). ¹H NMR (CDCl3): δ = 6.81 (s, 2 H), 6.65 (s, 2 H), 2.46 (t, J = 6.9 Hz, 4 H), 1.40-1.60 (m, 8 H), 0.95 (t, J = 6.9 Hz, 6 H). ¹³C NMR (CDCl3): δ = 186.7, 185.0, 150.0, 139.2, 136.2, 132.6, 29.7, 28.5, 22.4, 13.7. IR: 2924, 1661, 1645, 922 cm-¹. Anal. Calcd for C20H22O4: C, 73.60; H, 6.79. Found: C, 73.50; H, 6.79. 6g: mp 158-159 ˚C (EtOH-CHCl3). ¹H NMR (CDCl3): δ = 6.81 (s, 2 H), 6.65 (s, 2 H), 2.45 (t, J = 6.9 Hz, 4 H), 1.50-1.60 (m, 4 H), 1.30-1.40 (m, 8 H), 0.93 (t, J = 6.9 Hz, 6 H). ¹³C NMR (CDCl3): δ = 186.7, 185.0, 150.0, 139.2, 136.2, 132.6, 31.4, 28.8, 27.4, 22.3, 13.9. IR: 2923, 1660, 1645, 922 cm-¹. Anal. Calcd for C22H26O4: C, 74.55; H, 7.39. Found: C, 74.47; H, 7.28. 6h: mp 190-192 ˚C (lit.9 194-195 ˚C). ¹H NMR (CDCl3): δ = 7.12 (s, 2 H), 7.00 (s, 2 H). ¹³C NMR (DMSO-d 6): δ = 180.6, 176.8, 141.0, 137.5, 133.9, 132.0. IR: 1670, 1652, 910 cm-¹. 6i: mp 181-183 ˚C (EtOH) (lit.9 187-188 ˚C). ¹H NMR (CDCl3): δ = 7.41 (s, 2 H), 7.04 (s, 2 H). ¹³C NMR (CDCl3): δ = 181.7, 178.4, 139.0, 138.2, 137.7, 135.6. IR: 1667, 914 cm-¹. 6j: mp 224-225 ˚C (CHCl3). ¹H NMR (CDCl3): δ = 7.76 (s, 2 H), 7.07 (s, 2 H). ¹³C NMR (CDCl3): δ = 181.4, 179.7, 146.4, 139.3, 134.6, 119.8. IR: 1666, 1642, 914 cm-¹. Anal. Calcd for C12H4I2O4: C, 30.93; H, 0.87. Found: C, 31.04; H, 0.93. 6k: mp 189-192 ˚C (EtOH). ¹H NMR (DMSO-d 6): δ = 6.92 (s, 2 H), 6.75 (s, 2 H), 5.46 (br s, 2 H), 4.36 (s, 4 H). ¹³C NMR (DMSO-d 6): δ = 187.2, 185.6, 150.2, 140.6, 136.4, 130.6, 57.6. IR: 3400, 1663, 923 cm-¹. Anal. Calcd for C14H10O6: C, 61.32; H, 3.68. Found: C, 61.26; H, 3.60. 6l: mp 162-166 ˚C (EtOH). ¹H NMR (CDCl3): δ = 6.89 (t, J = 1.8 Hz, 2 H), 6.81 (s, 2 H), 4.34 (d, J = 1.8 Hz, 4 H), 3.48 (s, 6 H). ¹³C NMR (CDCl3): δ = 186.1, 184.6, 145.9, 139.4, 135.9, 131.6, 67.4, 59.2. IR: 1659, 920 cm-¹. Anal. Calcd for C16H14O6: C, 63.57; H, 4.67. Found: C, 62.67; H, 4.52. 6m: mp 195-196 ˚C (EtOH). ¹H NMR (CDCl3): δ = 6.88 (s, 2 H), 6.83 (s, 2 H), 3.05 (br s, 2 H), 1.56 (s, 12 H). ¹³C NMR (CDCl3): δ = 187.6, 185.2, 152.6, 138.1, 137.5, 131.0, 71.3, 29.0. IR: 3416, 1646, 939 cm-¹. Anal. Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 65.29; H, 5.44. 6n: mp 184-186 ˚C (EtOH). ¹H NMR (DMSO-d 6): δ = 6.95 (s, 2 H), 6.81 (s, 2 H), 4.76 (t, J = 5.4 Hz, 2 H), 3.59 (dt, J = 5.4, 6.0 Hz, 4 H), 2.55 (t, J = 6.0 Hz, 4 H). ¹³C NMR (DMSO-d 6): δ = 187.5, 185.7, 147.4, 140.5, 136.4, 134.3, 59.4, 32.6. IR: 3418, 1662, 1646, 920 cm-¹. Anal. Calcd for C16H14O6: C, 63.57; H, 4.67. Found: C, 63.29; H, 4.56. 6o: mp 115-117 ˚C (EtOH). ¹H NMR (CDCl3): δ = 6.86 (s, 2 H), 6.73 (s, 2 H), 4.29 (t, J = 6.0 Hz, 4 H), 2.81 (t, J = 6.0 Hz, 4 H), 2.05 (s, 6 H). ¹³C NMR (CDCl3): δ = 186.0, 184.4, 170.7, 145.7, 139.3, 136.1, 134.1, 61.4, 28.6, 20.8. IR: 1739, 1661, 1241, 1041, 922 cm-¹. Anal. Calcd for C20H18O8: C, 62.17; H, 4.70. Found: C, 62.17; H, 4.64. 6p: mp 116-117 ˚C (EtOH). ¹H NMR (CDCl3): δ = 6.82 (s, 2 H), 6.77 (s, 2 H), 3.60 (t, J = 6.0 Hz, 4 H), 3.35 (s, 6 H), 2.73 (t, J = 6.0 Hz, 4 H). ¹³C NMR (CDCl3): δ = 186.5, 184.7, 146.6, 139.1, 136.2, 134.1, 69.6, 58.6, 29.1. IR: 1662, 1364, 1123, 922 cm-¹. Anal. Calcd for C18H18O6: C, 65.45; H, 5.49. Found: C, 64.29; H, 5.42. 6q: mp 227-233 ˚C (EtOH-CHCl3). ¹H NMR (CDCl3): δ = 8.39 (br s, 2 H), 7.67 (s, 2 H), 6.89 (s, 2 H), 1.32 (s, 18 H). ¹³C NMR (CDCl3): δ = 185.0, 182.3, 177.8, 139.4, 138.4, 133.7, 114.8, 40.6, 27.2. IR: 3375, 1706, 1664, 1643, 1505 cm-¹. Anal. Calcd for C22H24N2O6: C, 64.07; H, 5.87; N, 6.79. Found: C, 63.66; H, 5.85; N, 6.65. 6r: mp 234-244 ˚C (EtOH-CHCl3). ¹H NMR (DMSO-d 6): δ = 9.87 (s, 2 H), 7.47 (s, 2 H), 6.96 (s, 2 H), 2.21 (s, 6 H). ¹³C NMR (DMSO-d 6): δ = 185.6, 182.1, 171.4, 140.3, 140.0, 133.5, 113.9, 24.4. IR: 3317, 1682, 1634, 1520 cm-¹. Anal. Calcd for C16H12N2O6: C, 58.54; H, 3.68; N, 8.53. Found: C, 58.48; H, 3.53; N, 8.51. 6s: mp 256-260 ˚C (EtOH-DMSO). ¹H NMR (DMSO-d 6): δ = 10.20 (s, 2 H), 7.44 (s, 2 H), 6.98 (s, 2 H), 4.52 (s, 4 H). ¹³C NMR (DMSO-d 6): δ = 185.3, 181.7, 167.3, 140.2, 139.7, 133.7, 114.9, 43.4. IR: 3340, 1703, 1670, 1638 cm-¹. Anal. Calcd for C16H10Cl2N2O6: C, 48.39; H, 2.54; N, 17.85. Found: C, 48.40; H, 2.51; N, 6.98.

20

Dimethyl acetals of 2,5-dimethoxybenzaldehyde and 2′,5′-dimethoxyacetophenone both returned only the unprotected carbonyl compounds under these reaction conditions.

22

Typical reaction conditions utilized approximately 3 mL of MeCN per mmol of substrate (see typical experimental procedure). ‘Dilute’ reaction conditions utilized approximately 10 mL of MeCN-H2O (2:1) per mmol of substrate. Both employed CAN solutions that were approximately 1 M.