2-Substituted 4-(Trifluoromethyl)phenols by Directed ortho-Lithiation

Abstract

A broad variety of 2-substituted 4-(trifluoromethyl)phenols can be prepared in a large scale by o-lithiation and reaction with electrophiles in good to excellent yields. The key for the selectivity is the superior ortho-directing effect of the THP-protected hydroxy group (OTHP) as compared to the CF₃-group.

Key Words

arylations - electrophilic aromatic substitutions - lithiation - protecting groups - 4-(trifluoromethyl)phenol

References

• 1a Sakai TT. Santi DV. J. Med. Chem.  1973,  16:  1079 
• 1b Grinter R. Heilbronner E. Petrzilka T. Seiler P. Tetrahedron Lett.  1968,  35:  3845 
• 2a Jones RG. J. Am. Chem. Soc.  1947,  69:  2346 
• 2b Pettit MR. Tatlow JC. J. Chem. Soc.  1954,  3852 
• 3a Matthews DP. Witten JP. McCarthy JR. J. Org. Chem.  1986,  51:  3228 
• 3b Kimoto H. Cohen LA. J. Org. Chem.  1979,  44:  2902 
• 5 Dyer RG. Turnbull KD. J. Org. Chem.  1999,  64:  7988 
• 2-Hydroxy-5-(trifluoromethyl)benzaldehyde:
• 6a Wishart N, and Birch AM. inventors; WO Patent  98/29411. 
• 6c Bansleben DA, Friedrich SK, Younkin TR, Grubbs RH, Wang C, and Li RT. inventors; WO Patent  98/42664. 
• [2-Hydroxy-5-(trifluoromethyl)phenyl]alkan-1-ones:
• 7a Jiménez MC. Leal P. Miranda MA. Tormos R. J. Chem. Soc., Chem. Commun.  1995,  2009 
• 7b Galindo F. Jiménez MC. Miranda MA. Tormos R. J. Photochem. Photobiol., A  1996,  97:  151 
• 7c Meussdoerffer JN, and Niederpruem H. inventors; German Patent  2653601. 
• 2-Hydroxy-4-(trifluoromethyl)benzoic acid:
• 8a Metivier P, Dos Santos E, Michel M, and Bigouraux JC. inventors; French Patent  2735771. 
• 8c Biller SA, Dickson JK, Lawrence RM, Magnin DR, Poss MA, Robl JA, Sulsky RB, and Tino JA. inventors; US Patent  5712279. 
• 8e Yamamoto S. Hashiguchi S. Miki S. Igata Y. Watanabe T. Shiraishi M. Chem. Pharm. Bull.  1996,  44:  734 
• 8f Alexander J. Org. Prep. Proceed. Int.  1986,  18:  213 
• 8g

  Caution: Chloromethyl methyl ether is a cancer suspect reagent (bp 55-57 °C)

• 8h Marzi E. Mongin F. Spitaleri A. Schlosser M. Eur. J. Org. Chem.  2001,  2911 
• 2-Chloro-4-(trifluoromethyl)phenol:
• 9a Wakselman C, and Tordeux M. inventors; EP  206951. 
• 9c Blazejewski J.-C. Dorme R. Wakselman C. J. Chem. Soc., Perkin Trans. 1  1987,  1861 
• 9d Briner PH, and Mason RF. inventors; EP  188031. 
• 9f Horst O, Swithenbank C, and Yih RY. inventors; German Patent  2311638. 
• 9h Veracini S. inventors; French patent  2529197. 
• 9j Johnson WO. inventors; EP  19388. 
• 9l inventors; Japanese Patent  59139336. Asahi Chemical Industries Co Ltd.;
• 9n Aly EA. inventors; US Patent  4548640. 
• 10a Kaplan JP, and Raizon BM. inventors; German Patent  2907379. Aryl-(2-hydroxy-5-(trifluoromethyl)phenyl)ketones:
• Previous applications of OTHP as ortho-directing group for the metalation:
• 11a Parham WE. Anderson EL. J. Am. Chem. Soc.  1948,  70:  4187 
• 11b Stern R. English J. Cassidy HG. J. Am. Chem. Soc.  1957,  79:  5797 
• 11c Santucci L. Gilman H. J. Am. Chem. Soc.  1958,  80:  4537 
• 11d Schäfer W. Leute R. Chem. Ber.  1966,  99:  1632 
• 11e Schäfer W. Leute R. Schlude H.  Chem. Ber.  1971,  104:  3211 
• 11f Bunce RA. Moore JD. Org. Prep. Proc. Int.  1997,  29:  293 
• 12a van Eikema Hommes NJR. von Ragué Schleyer P. Angew. Chem. Int. Ed. Engl.  1992,  31:  755 
• 12b van Eikema Hommes NJR. von Ragué Schleyer P. Tetrahedron  1994,  50:  5903 
• 13 Ouedraogo A. Lessard J. Can. J. Chem.  1991,  69:  474 
• 14 For a discussion about the ortho-directing effect of the CF₃ group, see for example: Mongin F. Maggi R. Schlosser M. Chimia  1996,  50:  650 ; and references cited therein
• 15 See for example: Christensen HJ. Synth. Commun.  1975,  5:  65 
• 16 Krizan TD. Martin JC. J. Org. Chem.  1982,  47:  2681 
• 17 Caron S. Hawkins JM. J. Org. Chem.  1998,  63:  2054 

4

DSC: onset temperature: 130 °C, decomposition energy: 760 J/g. Caution: After several months on storage 4-(trifluoromethyl)phenol decomposes spontaneously.