Practical One-Pot C-H Activation/Borylation/Oxidation: Preparation of 3-Bromo-5-methylphenol on a Multigram Scale

Abstract

A practical one-pot C-H activation/borylation/oxidation sequence for the generation of 3,5-disubstituted phenols is presented. Specifically, 3-bromo-5-methylphenol is prepared from 3-bromotoluene, without isolation of intermediates, on a multigram scale, and in high yield. The process proceeds under mild conditions and can be completed within one day.

Key words

phenol - C-H activation - borylation - oxidation - boronic ester

References

• 1 Tyman JP. Synthetic and Natural Phenols   Elsevier; New York: 1996. 
• 2 Davidson JP. Sarma K. Fishlock D. Welch MH. Sukhtankar S. Lee GM. Martin M. Cooper GF. Org. Process Res. Dev.  2010,  477 
• 3a Hodgson HH. Wignall JS. J. Chem. Soc.  1926,  2077 
• 3b Also see: Kohn M. Zandman A. Montsh. Chem.  1926,  47:  357 
• 4a Cho J.-Y. Tse MK. Holmes D. Maleczka RE. Smith MR. Science  2002,  295:  305 
• 4b Boller TM. Murphy JM. Hapke M. Ishiyama T. Miyaura N. Hartwig JF. J. Am. Chem. Soc.  2005,  127:  14263 
• 4c For a review see: Mkhalid IAI. Barnard JH. Marder TB. Murphy JM. Hartwig JF. Chem. Rev.  2010,  110:  890 
• 5 Maleczka RE. Shi F. Holmes D. Smith MR. J. Am. Chem. Soc.  2003,  125:  7792 
• 6 C-H Acidities can also influence regiochemical outcomes, see: Vanchura BA. Preshlock SM. Roosen PC. Kallepalli VA. Staples RJ. Maleczka RE. Singleton DA. Smith MR. Chem. Commun.  2010,  46:  7724 
• 7 Webb KS. Levy D. Tetrahedron Lett.  1995,  36:  5117 
• 8 Marshall LJ. Cable KM. Botting NP. Tetrahedron Lett.  2010,  51:  2690 
• 9 For a Pd-catalyzed borylation/oxidation approach to similar phenols see: Lee Y. Kelly MJ. Tetrahedron Lett.  2006,  47:  4897 
• 10 For a multigram borylation of 1-chloro-3-iodobenzene with [Ir(OMe)(cod)]₂-dtbpy and B₂pin₂ see: Ishiyama T. Takagi J. Nobuta Y. Miyaura N. Org. Synth.  2005,  82:  126 
• 12 Merola JS. Kacmarcik RT. Organometallics  1989,  8:  778 
• 13a

  Whereas (Ind)Ir(cod) and H-BPin are relatively air stable, dmpe is ‘moderately sensitive to air’^¹³b and should be handled under an inert atmosphere. Herein, the flask into which the initial set of reagents was charged was in a glovebox. Once charged, the flask was moved to a fume hood where the actual reaction was run

• 13b Burt RJ. Chatt J. Hussain W. Leigh GJ. J. Organomet. Chem.  1979,  182:  203 

11

So as to establish a benchmark yield herein, the starting 3-bromotoluene was distilled over CaH₂ under reduced pressure and degassed before use. In most cases the starting arene can be used as received, but yields are dependent on starting material quality, which can vary by vendor and batch. A use test prior to scale up is recommended.

14

WARNING: As with any oxidation of this type, one should be watchful for exotherms and control the rate of addition accordingly.