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Synlett 2008(13): 1993-1998  
DOI: 10.1055/s-2008-1077949
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Microwave-Assisted Cleavage of Aryl Methyl Ethers with Lithium Thioethoxide (LiSEt)

Ján Cvengroš, Stefan Neufeind, Anne Becker, Hans-Günther Schmalz*
Institut für Organische Chemie, Universität zu Köln, Greinstr. 4, 50939 Köln, Germany
Fax: +49(221)4703064; e-Mail: schmalz@uni-koeln.de;
Further Information

Publication History

Received 1 May 2008
Publication Date:
15 July 2008 (online)

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Abstract

Lithium thioethoxide (LiSEt), a white solid easily prepared from EtSH and n-BuLi in hexane, was identified as a highly efficient reagent for the cleavage (O-demethylation) of aryl methyl ethers, i.e. methyl-protected phenols. Of particular synthetic value are applications in the double deprotection of 1,2-dimethoxyarenes (to give catechols) and in the selective monodeprotection of di- and trimethoxyarenes. The thermal reactions, which are usually performed in DMF as a solvent, can be greatly accelerated through microwave irradiation. In this case, the monodemethylated products are usually formed in high (80-99%) yield within only 15 minutes.

Key words

lithium - thioethanolate - phenol protecting groups - ­microwave irradiation - SN2 reactions - demethylation

    References and Notes

  • 1a Wuts PGM. Greene TW. Greene’s Protective Groups in Organic Synthesis   4th ed.:  Wiley; Hoboken, NJ: 2006. 
    Google Scholar
  • 1b Kocienski PJ. Protecting Groups   3rd ed.:  Georg Thieme Verlag; Stuttgart: 2004. 
    Google Scholar
  • For selected examples, see:
  • 2a Wu Q. Fu D.-X. Hou A.-J. Lei G.-Q. Liu Z.-J. Chen J.-K. Zhou T.-S. Chem. Pharm. Bull.  2005,  53:  1065 
    Google Scholar
  • 2b Adams M. Pacher T. Greger H. Bauer R. J. Nat. Prod.  2005,  68:  83 
    Google Scholar
  • 2c Kanchanapoom T. Noiarsa P. Tiengtham P. Otsuka H. Ruchirawat S. Chem. Pharm. Bull.  2005,  53:  579 
    Google Scholar
  • 3a Kawasaki I. Matsuda K. Kaneko T. Bull. Chem. Soc. Jpn.  1971,  44:  1986 
    Google Scholar
  • 3b Landini D. Montanari F. Rolla F. Synthesis  1978,  771 
    Google Scholar
  • 3c Kamal A. Gayatri NL. Tetrahedron Lett.  1996,  37:  3359 
    Google Scholar
  • 3d Hwang K. Park S. Synth. Commun.  1993,  23:  2845 
    Google Scholar
  • 4a Jung ME. Lyster MA. J. Org. Chem.  1977,  42:  3761 
    Google Scholar
  • 4b Minamikawa J. Brossi A. Tetrahedron Lett.  1978,  3085 
    Google Scholar
  • 4c Olah GA. Narang SC. Tetrahedron  1982,  38:  2225 
    Google Scholar
  • 4d Groutas WC. Felker D. Synthesis  1980,  861 
    Google Scholar
  • 5 Morita T. Okamoto Y. Sakurai H. J. Chem. Soc., Chem. Commun.  1978,  874 
    CrossrefGoogle Scholar
  • 6a McOmie JFW. West DE. Org. Synth., Coll. Vol. V   Wiley; New York: 1973.  p.412 
    Google Scholar
  • 6b Vickery EH. Pahler LF. Eisenbraun EJ. J. Org. Chem.  1979,  44:  4444 
    Google Scholar
  • 6c Demuynck M. Clercq P. Vandewalle M. J. Org. Chem.  1979,  44:  4863 
    Google Scholar
  • 6d Meier H. Dullweber U. J. Org. Chem.  1997,  62:  7667 
    Google Scholar
  • 6e Ryu I. Matsubara H. Yasuda S. Nakamura H. Curran D. J. Am. Chem. Soc.  2002,  124:  12946 
    Google Scholar
  • 7a Williard PG. Fryhle CB. Tetrahedron Lett.  1980,  21:  3731 
    Google Scholar
  • 7b Konieczny MT. Maciejewski G. Konieczny W. Synthesis  2005,  1575 
    Google Scholar
  • 8a Nagaoka H. Schmid G. Iio H. Kishi Y. Tetrahedron Lett.  1981,  22:  899 
    Google Scholar
  • 8b Gerecke M. Borer R. Brossi A. Helv. Chim. Acta  1976,  59:  2551 
    Google Scholar
  • 9a Lansinger JM. Ronald RC. Synth. Commun.  1979,  9:  341 
    Google Scholar
  • 9b Narayana C. Padmanabhan S. Kabalka GW. Tetrahedron Lett.  1990,  21:  6977 
    Google Scholar
  • 10a Grieco PA. Ferrino S. Vidari G. J. Am. Chem. Soc.  1980,  102:  7586 
    Google Scholar
  • 10b Node M. Hori H. Fujita E. J. Chem. Soc., Perkin. Trans. 1  1976,  2237 
    Google Scholar
  • 11a Parker KA. Petraitis JJ. Tetrahedron Lett.  1981,  22:  397 
    Google Scholar
  • 11b Li T.-T. Wu YL. J. Am. Chem. Soc.  1981,  103:  7007 
    Google Scholar
  • 11c Kawamura Y. Takatsuki H. Torii F. Horie T. Bull. Chem. Soc. Jpn.  1994,  67:  511 
    Google Scholar
  • 12 Horie T. Kobayashi T. Kawamura Y. Yoshida I. Tominaga H. Yamashita K. Bull. Chem. Soc. Jpn.  1995,  68:  2033 
    CrossrefGoogle Scholar
  • 13a Fürstner A. Seidel G. J. Org. Chem.  1997,  62:  2332 
    Google Scholar
  • 13b Köster R. Seidel G. Organometallic Syntheses  1988,  4:  440 
    Google Scholar
  • 13c Bhatt MV. J. Organomet. Chem.  1978,  156:  221 
    Google Scholar
  • 14 Yamaguchi S. Nedachi M. Yokoyama H. Hirai Y. Tetrahedron Lett.  1999,  40:  7363 
    CrossrefGoogle Scholar
  • 15a Feutrill GI. Mirrington RN. Tetrahedron Lett.  1970,  1327 
    Google Scholar
  • 15b Feutrill GI. Mirrington RN. Aust. J. Chem.  1972,  25:  1719 
    Google Scholar
  • 15c Dodge JA. Stocksdale MG. Fahey KJ. Jones CD. J. Org. Chem.  1995,  60:  739 
    Google Scholar
  • 15d Smith ABIII. Schow SR. Bloom JD. Thompson AS. Winzenberg KN. J. Am. Chem. Soc.  1982,  104:  4015 
    Google Scholar
  • 15e Myers AG. Tom NJ. Fraley ME. Cohen SB. Mader DJ. J. Am. Chem. Soc.  1997,  119:  6072 
    Google Scholar
  • 16 Huffman JW. Joyner H. Lee MD. Jordan D. Pennington WT. J. Org. Chem.  1991,  56:  2081 
    CrossrefGoogle Scholar
  • 17 Ahmad R. Saá JM. Cava MP. J. Org. Chem.  1977,  42:  1228 
    CrossrefGoogle Scholar
  • 18 Hansson C. Wickberg B. Synthesis  1976,  191 
    Article in Thieme ConnectGoogle Scholar
  • 19 Bernard AM. Ghiani MR. Piras PP. Rivoldini A. Synthesis  1989,  287 
    Article in Thieme ConnectGoogle Scholar
  • 20a Mechoulam R. Gaoni Y. J. Am. Chem. Soc.  1965,  87:  3273 
    Google Scholar
  • 20b Alonso E. Ramon DJ. Yus M. J. Org. Chem.  1997,  62:  417 
    Google Scholar
  • 20c Wilds AL. McCormack WB. J. Am. Chem. Soc.  1948,  70:  4127 
    Google Scholar
  • 21 Kirschke K. Wollf E. J. Prakt. Chem./Chem.-Ztg.  1995,  337:  405 
    CrossrefGoogle Scholar
  • 22 Harrison IT. J. Chem. Soc., Chem. Commun.  1969,  616 
    Google Scholar
  • 23 McCarthy JR. Moore JL. Crege RJ. Tetrahedron Lett.  1978,  5183 
    CrossrefGoogle Scholar
  • 24 Ireland RE. Walba D. Org. Synth.   Coll. Vol. VI:  Wiley; New York: 1988.  p.567 
    Google Scholar
  • 25a Newman MS. Sankaran V. Olson DR. J. Am. Chem. Soc.  1976,  98:  3237 
    Google Scholar
  • 25b Newman MS. Sankaran V. Olson DR. J. Am. Chem. Soc.  1976,  98:  3237 
    Google Scholar
  • 26 Kelly TR. Dali HM. Tsang WG. Tetrahedron Lett.  1977,  3859 
    CrossrefGoogle Scholar
  • 27 Welch SC. Rao ASCP. Tetrahedron Lett.  1977,  505 
    CrossrefGoogle Scholar
  • 28 Hwu JR. Tsay S.-C. J. Org. Chem.  1990,  55:  5987 
    CrossrefGoogle Scholar
  • 29a Driver G. Johnson KE. Green Chem.  2003,  5:  163 
    Google Scholar
  • 29b Chauhan SMS. Jain N. J. Chem. Res.  2004,  693 
    Google Scholar
  • 30a Melillo DG. Larsen RD. Mathre DJ. Shukis WF. Wood AW. Collelouri JR. J. Org. Chem.  1987,  52:  5143 
    Google Scholar
  • 30b Fujii N. Irie H. Yajima H. J. Chem. Soc., Perkin Trans. 1  1977,  2288 
    Google Scholar
  • 31a Boger DL. Miyazaki S. Kim SH. Wu JH. Castle SL. Loiseleur O. Jin Q. J. Am. Chem. Soc.  1999,  121:  10004 
    Google Scholar
  • 31b Boger DL. Kim SH. Mori Y. Weng J.-H. Rogel O. Castle SL. McAtee JJ. J. Am. Chem. Soc.  2001,  123:  1862 
    Google Scholar
  • 31c Node M. Nishide K. Fuji K. Fujita E. J. Org. Chem.  1980,  45:  4275 
    Google Scholar
  • 32 Evans DA. Dinsmore CJ. Ratz AM. Evrard DA. Barrow JC. J. Am. Chem. Soc.  1997,  119:  3417 
    CrossrefGoogle Scholar
  • 33 Inaba T. Umezawa I. Yuasa M. Inoue T. Mihashi S. Itokawa H. Ogura K. J. Org. Chem.  1987,  52:  2957 
    CrossrefGoogle Scholar
  • 34 For a review, see: Schmalz H.-G. Gotov B. Böttcher A. In Arene Metal Complexes. Topics in Organometallic Chemistry   Vol. 7:  Kündig EP. Springer; Berlin: 2004.  p.157 
    Google Scholar
  • 35a Geller T. PhD Dissertation   TU-Berlin; Germany: 1998. 
    Google Scholar
  • 35b Majdalani A. Schmalz H.-G. Synlett  1997,  1303 
    Google Scholar
  • 35c Majdalani A. Schmalz H.-G. Tetrahedron Lett.  1997,  38:  4545 
    Google Scholar
  • 35d Geller T. Schmalz H.-G. Bats JW. Tetrahedron Lett.  1998,  39:  1537 
    Google Scholar
  • 35e Dehmel F. Schmalz H.-G. Org. Lett.  2001,  3:  3579 
    Google Scholar
  • 35f Dehmel F. Lex J. Schmalz H.-G. Org. Lett.  2002,  4:  3915 
    Google Scholar
  • 36 For an efficient entry to stilbene 5 by cross-metathesis, see: Velder J. Ritter S. Lex J. Schmalz H.-G. Synthesis  2006,  273 
    Article in Thieme ConnectGoogle Scholar
  • 37a Polunin KE. Polunina IA. Schmalz H.-G. Mendeleev Commun.  2002,  12:  178 
    Google Scholar
  • 37b Polunin KE. Schmalz H.-G. Russ. J. Coord. Chem.  2004,  30:  252 
    Google Scholar
  • 38a For synthetic approaches towards pestatone, see: Cueto M. Jensen PR. Kaufmann C. Fenical W. Lobkovsky E. Clardy J. J. Nat. Prod.  2001,  64:  1444 
    Google Scholar
  • 38b Kaiser F. Schmalz H.-G. Tetrahedron  2003,  59:  7345 
    Google Scholar
  • 38c Iijima D. Tanaka D. Hamada M. Ogamino T. Ishikawa Y. Nishiyama S. Tetrahedron Lett.  2004,  45:  5469 
    Google Scholar
  • For a review on colchicine total synthesis, see:
  • 39a Graening T. Schmalz H.-G. Angew. Chem. Int. Ed.  2003,  42:  2580 ; Angew. Chem. 2003, 115, 2684
    Google Scholar
  • 39b For a recent work from this laboratory, see: Graening T. Bette V. Neudörfl J. Lex J. Schmalz H.-G. Org. Lett.  2005,  7:  4317 
    Google Scholar
  • For previous examples of selective O-demethylation reactions with thiolate-based reagents which, however, require harsh reaction conditions, long reaction times and/or the use of HMPT as a toxic additive, see:
  • 40a Moos WH. Gless RD. Rapoport H. J. Org. Chem.  1982,  47:  1831 
    Google Scholar
  • 40b Lal K. Zarate EA. Youngs WJ. Salomon RG. J. Am. Chem. Soc.  1986,  108:  1311 
    Google Scholar
  • 40c Dodge JA. Stocksdale MG. Fahey KJ. Jones CD. J. Org. Chem.  1995,  60:  739 
    Google Scholar
  • 40d Loubinoux B. Coudert G. Guillaumet G. Synthesis  1980,  638 
    Google Scholar
  • 40e Lal K. Ghosh S. Salomon RG. J. Org. Chem.  1987,  52:  1072 
    Google Scholar
  • 41a Kappe CO. Stadler A. Microwaves in Organic and Medicinal Chemistry   Wiley-VCH; Weinheim: 2005. 
    Google Scholar
  • 41b Kappe CO. Angew. Chem. Int. Ed.  2004,  43:  6250 
    Google Scholar
  • 41c Kappe CO. Dallinger D. Nat. Rev. Drug Discovery  2006,  5:  51 
    Google Scholar
  • For the use of microwave irradiation in the cleavage or trans protection of aryl methyl ether using different reagents, see:
  • 42a Fredriksson A. Stone-Elander S. J. Labelled Compd. Radiopharm.  2002,  45:  529 
    Google Scholar
  • 42b Marette C. Larrouquet C. Tisne’s P. Deloyeb J.-B. Grasa E. Tetrahedron Lett.  2006,  47:  6947 
    Google Scholar
43

DMF (99.8%, Fluka) was stored over molecular sieves. GC-MS measurements were carried out on an Agilent HP6890 instrument with MS detector 5937 N using an Optima 1 MS (Macherey-Nagel) 30 m × 0.25 mm capillary column with H2 as carrier gas. NMR data were measured on Bruker DPX 300 and AC 250 instruments. Chemical shifts (δ) are given in ppm relative to the solvent reference as the internal standard. Reactions under microwave irradiation were performed in a CEM Discover instrument (300 W) in glass tubes with temperature and pressure control.
Preparation of the Reagent (LiSEt): In a dry 500-mL Schlenk flask a solution of n-BuLi (1.3 M) in hexane (120 mL, 160 mmol) was diluted with hexane (150 mL) under an argon atmosphere. The solution was cooled to 0 ˚C and under rapid stirring EtSH (200 mmol, 1.25 equiv, 15 mL) was added dropwise, whereupon a white precipitate formed. The reaction mixture was stirred at 0 ˚C for 10 min and at r.t. for 30 min. After removal of the solvent (always ensuring inert conditions) the residue was dried in vacuo to give LiSEt as a white solid (10.6 g, 156 mmol, 97%). The product was stored under argon at ambient temperature. C2H5SLi; M = 68.06 g/mol. ¹H NMR (250 MHz, DMSO): δ = 1.06 (t, ³ J = 7.2 Hz, 3 H, H2), 2.27 (q, ³ J = 7.3 Hz, 2 H, H1).
General Procedure: The substrate (0.6 mmol, 1 equiv) and LiSEt (1.2 mmol, 2 equiv) were weighed into the reaction vessel (either a Schlenk tube or a microwave reactor), which was then evacuated and flushed with argon three times before DMF (5 mL) was added and the reaction mixture was heated/irradiated as specified in Table  [¹] . Reactions were monitored by TLC and/or GC-MS. For workup, the mixture was cooled to r.t. and partitioned between 2 N aq HCl (5 mL) and MTBE (5 mL). The aqueous layer was re-extracted with MTBE (3 × 10 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4, filtered through a pad of silica and solvents were evaporated. The residue was flash chromatographed on silica gel with c-hexane-EtOAc (4:1).
3-Methoxyphenol (10): colorless oil. ¹H NMR (CDCl3): δ = 3.76 (s, 3 H), 5.03 (br s, 1 H), 6.40-6.43, 6.46-6.50 (m, 3 H), 7.09-7.14 (m, 1 H). ¹³C NMR (CDCl3): δ = 55.3 (q), 101.5, 106.4, 107.9 (3 × d), 130.1 (d), 156.7 (s), 160.9 (s). HRMS (EI, 70 eV): m/z calcd for C7H8O2: 124.0524; found: 124.053.
3-Methoxy-2-methylphenol (12): white solid; mp 42-43 ˚C. ¹H NMR (CDCl3): δ = 2.11 (s, 3 H), 3.81 (s, 3 H), 4.80 (s, 1 H), 6.44 (d, ³ J = 8.5 Hz, 1 H), 6.47 (d, ³ J = 8.5 Hz, 1 H), 7.02 (ψt, ³ J = 8.5 Hz, 1 H). ¹³C NMR (CDCl3): δ = 7.9 (q), 55.6 (q), 103.0 (d), 108.0 (d), 112.1 (s), 126.4 (d), 154.3 (q), 158.6 (q). HRMS (EI, 70 eV): m/z calcd for C8H10O2: 138.0681; found: 138.068.
2-Hydroxy-6-methoxybenzonitrile (14): white solid; mp 163-164 ˚C. ¹H NMR (CD3OD): δ = 3.87 (s, 3 H), 6.50 (d, ³ J = 8.4 Hz, 1 H), 6.52 (d, ³ J = 8.4 Hz, 1 H), 7.34 (ψt, ³ J = 8.5 Hz, 1 H). ¹³C NMR (CD3OD): δ = 56.7 (q), 90.6 (s), 102.9 (d), 109.0 (d), 115.4 (s), 136.1 (d), 163.0 (s), 163.9 (s). IR (ATR): 3220 (br m), 2230 (s), 1607 (s), 1594 (s), 1476 (s) cm-¹. HRMS (EI, 70 eV): m/z calcd for C8H7NO2: 149.0477; found: 149.047.
3,5-Dimethoxybenzoic acid (16): GC-MS and NMR data matched those of an authentic(commercial) sample.
1-(4-Hydroxy-3,5-dimethoxyphenyl)ethanone (20): colorless oil. ¹H NMR (CDCl3): δ = 2.54 (s, 3 H), 3.92 (s, 6 H), 6.03 (br s, 1 H), 7.22 (s, 2 H). ¹³C NMR (CDCl3): δ = 26.2 (q), 56.4 (q), 105.7 (d), 128.8 (s), 139.7 (s), 146.7 (s), 200.3 (s). IR (ATR): 3350 (br m), 1728 (s) cm-¹. HRMS: m/z calcd for C10H12O4: 196.0736; found: 196.074.
5-Bromo-2,3-dimethoxyphenol (22a): white solid; mp 68-70 ˚C. ¹H NMR (CDCl3): δ = 3.82 (s, 3 H), 3.85 (s, 3 H), 5.83 (br s, 1 H), 6.59 (d, 4 J = 2.1 Hz, 1 H), 6.75 (d, 4 J = 2.1 Hz, 1 H). ¹³C NMR (CDCl3): δ = 56.5 (q), 60.9 (q), 107.9 (d), 111.6 (d), 116.4 (s), 134.8 (s), 149.9 (s), 152.8 (s). MS (EI, 70 eV; isotope pattern reflected a molecule with one bromine atom): m/z (%) = 234 (95) [M]+, 232 (100) [M]+, 219 (95), 217 (97), 191 (46), 189 (55), 173 (29), 171 (31), 110 (14), 67 (41). HRMS: m/z calcd for C8H9O3 79Br: 231.9735; found: 231.974.
4-Bromo-2,6-dimethoxyphenol (22b): white solid; mp 90-92 ˚C. ¹H NMR (CDCl3): δ = 3.86 (s, 6 H), 5.42 (br s, 1 H), 6.70 (s, 2 H). ¹³C NMR (CDCl3): δ = 56.4 (q), 108.4 (d), 111.04 (s), 138.9 (s), 147.5 (s). MS (EI, 70 eV; isotope pattern reflected a molecule with one Br atom): m/z (%) = 234 (93) [M]+, 232 (100) [M]+, 219 (37), 217 (41), 191 (27), 189 (30), 176 (16), 174 (16), 110 (13), 67 (19), 50 (16). HRMS: m/z calcd for C8H9 79BrO3: 231.9735; found: 231.974.
2-Bromo-4,6-dichloro-3-methoxy-5-methylphenol (24): white solid; mp 128 ˚C. ¹H NMR (CDCl3): δ = 2.44 (s, 3 H), 3.85 (s, 3 H), 5.91 (s, 1 H). ¹³C NMR (CDCl3): δ = 18.1 (q), 60.6 (q), 103.7 (s), 117.0 (s), 121.2 (s), 134.9 (s), 148.0 (s), 152.5 (s). MS (EI, 70 eV; isotope pattern reflected a molecule with one Br and two Cl atoms): m/z (%) = 290 (6) [M]+, 288 (44) [M]+, 286 (100) [M]+, 284 (63) [M]+, 273 (14), 271 (31), 269 (20), 245 (23), 243 (56), 241 (34), 179 (15), 177 (14). HRMS: m/z calcd for C8H7O2 79Br³5Cl2: 283.9006; found: 283.901.