Synthesis of Halogenated Phenols by Directed ortho-Lithiation and ipso-Iododesilylation Reactions of O-Aryl N-Isopropylcarbamates

Abstract

The regioselective synthesis of halogenated phenols via directed ortho-lithiation reactions of in situ N-silylated O-aryl N-isopropylcarbamates is reported. This protocol is complemented by ipso-iododesilylation reactions of C-silylated carbamates and iodine-magnesium exchange reactions, which are facilitated by the adjacent carbamoyl group. These methods provide an entry into a series of o-fluoro-, o-iodo-, and o,o′-diiodophenols in high yields which are otherwise difficult to obtain.

Key words

electrophilic aromatic substitution - Grignard reactions - halides - lithiation - phenols

References

• Reviews:
• 1a Metal-Catalyzed Cross-Coupling Reactions   2nd ed.:  de Meijere A. Diederich F. Wiley-VCH; Weinheim: 2004. 
• 1b Volume on Cross-coupling Reactions, Top. Curr. Chem.  2002,  219:  1-241  
• 2a Shimizu M. Hiyama T. Angew. Chem. Int. Ed.  2005,  44:  214 
• 2b Special issue on Fluorine in the Life Sciences, ChemBioChem  2004,  5:  557-726  
• 3 Larock RC. Comprehensive Organic Transformations   2nd ed.:  Wiley; New York: 1999.  p.607 
• 4a Nyffeler PT. Durón SG. Burkart MD. Vincent SP. Wong C.-H. Angew. Chem. Int. Ed.  2005,  44:  192 
• 4b Lal GS. Pez GP. Syvret RG. Chem. Rev.  1996,  96:  1737 
• For reviews, see:
• 5a Snieckus V. Chem. Rev.  1990,  90:  879 
• 5b Hartung CG. Snieckus V. In Modern Arene Chemistry   Astruc D. Wiley-VCH; Weinheim: 2002.  p.330 
• 5c Clayden J. In The Chemistry of Organolithium Compounds   Rappoport Z. Marek I. Wiley; Chichester: 2004.  p.495 
• 5d Gribble GW. In Science of Synthesis   Vol. 8a:  Majewski M. Snieckus V. Thieme; Stuttgart: 2006.  p.357 
• 6a Kauch M. Hoppe D. Can. J. Chem.  2001,  79:  1736 
• 6b Kauch M. Snieckus V. Hoppe D. J. Org. Chem.  2005,  70:  7149 
• 7 Christensen H. Synth. Commun.  1975,  5:  65 
• 8 Sibi MP. Snieckus V. J. Org. Chem.  1983,  48:  1935 
• For metalation studies of MOM protected mono- and difluorophenols, see:
• 9a Marzi E. Mongin F. Spitaleri A. Schlosser M. Eur. J. Org. Chem.  2001,  2911 
• 9b Marzi E. Gorecka J. Schlosser M. Synthesis  2004,  1609 
• 10 Baker AW. Shulgin AT. Can. J. Chem.  1965,  43:  650 
• General reviews on arylsilanes and their application in organic synthesis:
• 11a Keay BA. In Science of Synthesis   Vol. 4:  Fleming I. Thieme; Stuttgart: 2002.  p.685 
• 11b Bassindale AR. Glynn SJ. Taylor PG. In The Chemistry of Organic Silicon Compounds   Vol. 2:  Rappoport Z. Apeloig Y. Wiley; Chichester: 1998.  p.355 
• 12 Kauch M. Hoppe D. Synthesis  2006,  xxx 
• Compounds 13a and 13b have been synthesized previously in low yields by direct formylation of the 2-halophenols:
• 13a Feldman KS. Eastman KJ. Lessene G. Org. Lett.  2002,  4:  3525 
• 13b Mcgarrigle EM. Murphy DM. Gilheany DG. Tetrahedron: Asymmetry  2004,  15:  1343 
• For alternative routes via ozonolysis of benzofurans, see:
• 13c Crich D. Grant D. J. Org. Chem.  2005,  70:  2384 
• 13d Ishii H. Ohta S. Nishioka H. Hayashida N. Harayama T. Chem. Pharm. Bull.  1993,  41:  1166 
• 14 For ipso-substitutions of DoM-derived arylsilanes including O-aryl N,N-diethylcarbamates, see: Zhao Z. Snieckus V. Org. Lett.  2005,  7:  2523 ; and references cited therein
• 15 Greene TW. Wuts PGM. Protective Groups in Organic Synthesis   3rd ed.:  Wiley; New York: 1999.  p.249 
• 16 Similar results were reported for a related system: Takahashi M. Hatano K. Kimura M. Watanabe T. Oriyama T. Tetrahedron Lett.  1994,  35:  579 
• For 26a, see:
• 17a Weeratunga G. Horne S. Rodrigo R. J. Chem. Soc., Chem. Commun.  1988,  721 
• For 26c, see:
• 17b Cambie RC. Rutledge PS. Smith-Palmer T. Woodgate PD. J. Chem. Soc., Perkin Trans. 1  1976,  1161 
• 18 For 28a, see: Vasil’ev AA. Engman L. J. Org. Chem.  1998,  63:  3911 
• 19a Boymond L. Rottländer M. Cahiez G. Knochel P. Angew. Chem. Int. Ed.  1998,  37:  1701 
• For reviews, see:
• 19b Knochel P. Dohle W. Gommermann N. Kneisel FF. Kopp F. Korn T. Sapountzis I. Vu VA. Angew. Chem. Int. Ed.  2003,  42:  4302 
• 19c Jensen AE. Dohle W. Sapountzis I. Lindsay DM. Vu VA. Knochel P. Synthesis  2002,  565