The Desymmetrisation of Resorcinol: The Synthesis of Resorcinol Monoalkyl Ethers

Abstract

The desymmetrisation of resorcinol to give 3-alkoxyresorcinol derivatives can be achieved in excellent yields either from resorcinol monobenzoate and alcohols using Mitsunobu reactions followed by hydrolysis using a strong base or by using 3-iodophenylbenzyl ether as a resorcinol monobenzyl ether equivalent in reactions with alcohols catalysed by copper(I)-9,10-phenanthroline followed by ammonium formate-palladium catalysed hydrogenolysis.

caesium carbonate - copper(I) iodide - hydrolyses - Mitsunobu reactions - 9,10-phenanthroline

References

1 Hoarau C. Pettus TRR. Synlett  2003,  127 

2a Klarmann E. Gatyas LW. Shternov VA. J. Am. Chem. Soc.  1931,  53:  3397 

2b Hodgson HH. Clay H. J. Chem. Soc.  1932,  869 

2c Gardner JH. Stevens JR. J. Am. Chem. Soc.  1947,  69:  3086 

2d Gregory RA. Tomlinson ML. J. Chem. Soc.  1956,  795 

3 von Freudenberg K. Alonso de Lama JM. Liebigs Ann. Chem.  1958,  612:  78 

4a Fitton AO. Ramage GR. J. Chem. Soc.  1962,  4870 

4b Schuda PF. Phillips JL. J. Heterocycl. Chem.  1984,  21:  669 

4c Weber E. Köhler H.-J. Panneerselevam K. Chacko K. J. Chem. Soc., Perkin Trans. 2  1990,  1599 

4d Wissner A. Carroll ML. Green KE. Kerwar SS. Pickett WC. Schaub RE. Torley LW. Wrenn S. Hohler CA. J. Med. Chem.  1992,  35:  1650 

4e El Hadri A. Nicolle E. Guillaume MC. Leclerc G. Pietri-Rouxel F. Strosberg AD. Archimbault P. Pharmazie  2001,  56:  517 

5a Mauleón D. Pujol MD. Minguillón C. Miquel J. J. Heterocycl. Chem.  1989,  26:  693 

5b Majumdar KC. Jana GH. Ghosh SK. Saha S. Monatsh. Chem.  1997,  128:  641 

5c Suh Y.-G. Min K.-H. Baek S.-Y. Chai J.-H. Heterocycles  1998,  48:  1527 

5d Kalinin AV. Bower JF. Riebel P. Sniekus V. J. Org. Chem.  1999,  64:  2986 

5e Bowman WR. Mann E. Parr J. J. Chem. Soc., Perkin Trans. 1  2000,  2991 

5f Palmacci ER. Seeberger PH. Org. Lett.  2001,  3:  1547 

5g Plante OJ. Palmacci ER. Andrade RB. Seeberger PH. J. Am. Chem. Soc.  2001,  123:  9545 

6 Simas ABC. Coelho AL. Costa PRR. Synthesis  1999,  1017 

7 Amabilino DB. Ashton PR. Boyd SE. Gómez-López M. Hayes W. Stoddart JF. J. Org. Chem.  1997,  62:  3062 

8 Maleski RJ. Kluge M. Sicker D. Synth. Commun.  1995,  25:  2327 

9a El Gihani MT. Heaney H. Slawin AMZ. Tetrahedron Lett.  1995,  36:  4905 

9b Page PCB. Heaney H. Sampler EP. J. Am. Chem. Soc.  1999,  121:  6751 

10 Wolter M. Nordmann G. Job GE. Buchwald SL. Org. Lett.  2002,  4:  973 

11a Mitsunobu O. Synthesis  1981,  1 

11b Hughes DL. Org. React.  1992,  42:  335 

11c Hughes DL. Org. Prep. Proced. Int.  1996,  28:  129 

11d Bittner S. Assaf Y. Chem. Ind. (London)  1975,  281 

11e Manhas MS. Hoffman WH. Lai B. Bose AK. J. Chem. Soc., Perkin Trans. 1  1975,  461 

11f Dirlam NL. Moore BS. Urban FJ. J. Org. Chem.  1987,  52:  3587 

11g Danishefski S. Berman EM. Ciufolini M. Etheredge SJ. Segmuller BE. J. Am. Chem. Soc.  1985,  107:  3891 

11h Valentine DH. Hillhouse JH. Synthesis  2003,  317 

11j Yoakim C. Guse I. O’Meara JA. Thavonekham B. Synlett  2003,  473 

12a Kaufman KD. J. Org. Chem.  1961,  26:  117 

12b Kaufman KD. Russey WE. J. Org. Chem.  1965,  30:  1320 

13a Hurd CD. Greengard H. Pilgrim FD. J. Am. Chem. Soc.  1930,  52:  1700 

13b Nikiforova IS. Mel’kanovitskaya SG. J. Org. Chem U.S.S.R.  1966,  2:  1234 ; Zhur. Org. Khim. 1966, 2, 1240

13c Ponpipom MM. Yue BZ. Bugianesi RL. Brooker DR. Chang MN. Shen TY. Tetrahedron Lett.  1986,  27:  309 

13d Ponpipom MM. Bugianesi RL. Brooker DR. Yue B.-Z. Hwang S.-B. Shen T.-Y. J. Med. Chem.  1987,  30:  136 

13e Gates BD. Dalidowicz P. Tebben A. Wang S. Swenton JS. J. Org. Chem.  1992,  57:  2135 

14 Zaugg H. E.; J. Org. Chem.; 1976, 41: 3419

15 Matsumoto T. Hosoya T. Suzuki K. J. Am. Chem. Soc.  1992,  114:  3568 

16

Boxhall, J. Y.; Page, P. C. B.; Elsegood, M. R. J.; Chan, Y.; Heaney, H.; Holmes, K. E.; McGrath, M. J. Synlett 2003, following letter.

17 In some reactions we isolated a yellow crystalline solid, see: Anderson NG. Lust DA. Colapret KA. Simpson JH. Malley MF. Gougoutas JZ. J. Org. Chem.  1996,  61:  7955 

18

MS: m/z found M⁺ 256.10991; C₁₆H₁₆O₃ requires 256.10995. IR: ν_max = 3069, 2976, 2932, 1735, 1606, 1589, 1485, 1465, 1451, cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.40 (d, 6 H, J = 6.4 Hz), 4.59 (sept., 1 H, J = 6.4 Hz), 6.88 (m, 3 H), 7.35 (m, 1 H), 7.54 (m, 2 H), 7.66 (m, 1 H), 8.28 (m, 2 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 24.23 (Me), 72.29 (CH), 111.67 (CH), 115.71 (CH), 115.89 (CH), 130.86 (2 × Me), 131.83 (C), 132.16 (CH), 132.39 (2 × CH), 135.87 (CH), 154.24 (C), 161.17 (C), and 167.26 (C=O) ppm.

19

MS: m/z found M⁺ 152.08346; C₉H₁₂O₂ requires 152.08346. IR: ν_max = 3385, 2976, 2932, 1595, 1490 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 1.32 (d, 6 H, J = 6.0 Hz), 4.51 (sept., 1 H, J = 6.0 Hz), 6.40 (m, 2 H), 6.47 (m, 1 H), 7.11 (m, 1 H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 22.43 (2 × Me), 70.36 (CH), 103.71 (CH), 107.95 (CH), 108.69 (CH), 130.48 (CH), 157.15 (C), and 159.66 (C) ppm.

20

Mp 118 ºC. MS (FAB): m/z (%) = 202 (100) [M + H⁺] found 202.0868, C₁₂H₁₂NO₂ requires 202.0868. Found: C, 71.61; H, 5.47; N, 6.88%. C₁₂H₁₁NO₂ requires C, 71.63; H, 5.51; N, 6.96%. IR (KBr): ν_max = 3058 (br), 2731, 2611, 1617, 1600, 1572, 1439, 1380, 1300, 1243, 1179, 1157, 1061, 749 cm^-1. ¹H NMR (400 MHz, d ₆-acetone): δ = 5.14 (s, 2 H), 6.46 (ddd, 1 H, J = 1.0, 2.2, 8.0 Hz), 6.50-6.52 (m, 2 H), 7.07-7.12 (m, 1 H), 7.28-7.32 (m, 1 H), 7.52, (br d, 1 H, J = 9.2 Hz), 7.81 (ddd, 1 H, J = 1.8, 7.7, 7.7 Hz), 8.45 (br s, 1 H,), and 8.57 (ddd, 1 H, J = 1.0, 1.7, 4.8 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 71.3 (CH₂), 103.1 (CH), 106.8, (CH), 109.1 (CH), 122.1 (CH), 123.5 (CH), 130.8 (CH), 137.5 (CH), 150.0 (CH), 158.4 (C), 159.6 (C), and 160.8 (C) ppm.