Aromatization via a Dibromination-Double Dehydrobromination Sequence: A Facile and Convenient Synthetic Route to 2,6-Bis(trifluoroacetyl)phenols [1]

Abstract

An efficient and reliable method to synthesize 2,6-bis(trifluoroacetyl)phenols bearing various substituents in the 4-position was developed. These valuable fluorinated building blocks were obtained from the corresponding cyclohexanones in a facile and convenient procedure, demonstrated to be superior to the traditional approaches. The application of this methodology to cyclohexane-1,4-dione opened access to 2,5-bis(polyfluoroacyl)-1,4-hydroquinones. Structural peculiarities of the obtained phenols as well as their 1,3-dicarbonyl or 1,3,5-tricarbonyl precursors are discussed on the basis of multinuclear NMR spectroscopy.

Key words

fluorinated compounds - arenes - ketones - aromatization - phenols

1

This work was presented in part at the 18th International Symposium on Fluorine Chemistry, Bremen, Germany, 30 July-4 August 2006.

References

• 3a Welch JT. Tetrahedron  1987,  43:  3123 
• 3b Lin P. Jiang J. Tetrahedron  2000,  56:  3635 
• 3c Welch JT. Eswarakrishnan S. Fluorine in Bioorganic Chemistry   Wiley; New York: 1991. 
• 3d Organofluorine Chemistry - Principles and Commercial Applications   Banks RE. Smart BE. Tatlow JC. Plenum; New York: 1994. 
• 3e Bégué J.-P. Bonnet-Delpon D. Chimie bioorganique et médicinale du fluor   CNRS Editions; Paris: 2005. 
• 4a Hiyama T. Organofluorine Compounds. Chemistry and Application   Springer; Berlin: 2000. 
• 4b Kirsch P. Modern Fluoroorganic Chemistry, Synthesis, Reactivity, Applications   Wiley-VCH; Weinheim: 2004. 
• 4c Chambers RD. Fluorine in Organic Chemistry   Blackwell; Oxford: 2004. 
• 5 Mandal SK. Nag K. J. Chem. Soc., Dalton Trans.  1983,  2429 
• 6 Schoth R.-M. PhD Thesis   University of Bremen; Germany: 1996. 
• 7 Ansong O. Antoine MD. Nwokogu GC. Hergenrother PM. J. Org. Chem.  1994,  59:  2506 
• 8a Prelog V. Metzler O. Jeger O. Helv. Chim. Acta  1947,  30:  675 
• 8b Jones ECS. Kenner J. J. Chem. Soc.  1931,  1842 
• 8c Bertz SH. Synthesis  1980,  708 
• 8d Nishiwaki N. Tohda Y. Ariga M. Synthesis  1997,  1277 
• 9 Sevenard DV. Kazakova O. Chizhov DL. Röschenthaler G.-V. J. Fluorine Chem.  2006,  127:  983 
• 10a Openshaw HT. Robinson R. J. Chem. Soc.  1946,  912 
• 10b Coumbarides GS. Dingjan M. Eames J. Weerasooriya N. J. Chem. Res., Synop.  2000,  328 
• 11 Sevenard DV. Kazakova O. Chizhov DL. Yachevskii DS. Lork E. Poveleit J. Charushin VN. Röschenthaler G.-V. Helv. Chim. Acta  2007,  90:  369 
• 12a Sevenard DV. Khomutov OG. Kodess MI. Pashkevich KI. Russ. Chem. Bull.  1999,  48:  400 
• 12b Chizhov DL. Pashkevich KI. Röschenthaler G.-V. J. Fluorine Chem.  2003,  123:  267 
• 15 Archer S. Perianayagam C. J. Med. Chem.  1979,  22:  306 
• 16 Duan J. Zhang LH. Dolbier WR. Synlett  1999,  1245 
• 17 Kirsch P. Reiffenrath V. Bremer M. Synlett  1999,  389 
• 18 Linderman RJ. Jamois EA. J. Fluorine Chem.  1991,  53:  79 
• 19a Herrman F. Liebigs Ann. Chem.  1882,  211:  306 
• 19b Guha PC. Chem. Ber.  1939,  72:  1359 
• 19c Bagrov FV. Bagrov DF. Russ. J. Org. Chem. (Engl. Transl.)  1994,  30:  637 
• 20 The Chemistry of Enols   Rappoport Z. Wiley; Chichester: 1990. 
• 21 For the hydrogen bonding and equilibria in related non-fluorinated phenols, see: Koelle U. Forsén S. Acta Chem. Scand., Ser. A  1974,  28:  531 
• 22 Sevenard DV. Kazakova O. Lork E. Dülcks T. Chizhov DL. Röschenthaler G.-V. J. Mol. Struct.  2007,  846:  87 
• 23a Koltsov AI. Kheifets GM. Russ. Chem. Rev. (Engl. Transl.)  1971,  40:  773 
• 23b Emsley J. Struct. Bonding  1984,  57:  147 
• 23c Koltsov AI. J. Mol. Struct.  1998,  444:  1 
• 24 Sosnovskikh VY. Russ. Chem. Bull.  2001,  1223 
• 25 Neyland OY. Stradyn’ YaP. Silin’sh EA. Balode DR. Valtere SP. Kadysh VP. Kalnin’ SV. Kampar VE. Mazheyka IB. Taure LF. Stroenie i Tautomernye Prevrashcheniya β-Dikarbonil’nykh Soedineniy (in Russian)   Zinatne; Riga: 1977. 
• 26 Wustrow D. Belliotti T. Glase S. Kesten SR. Johnson D. Colbry N. Rubin R. Blackburn A. Akunne H. Corbin A. Davis MD. Georgic L. Whetzel S. Zoski K. Heffner T. Pugsley T. Wise L. J. Med. Chem.  1998,  41:  760 
• 27 Kohn M. Segel A. Monatsh. Chem.  1925,  46:  661 
• 29 Okada Y. Yokozava M. Akiba M. Oishi K. Okawa K. Akeboshi T. Kawamura Y. Inokuma S. Nakamura Y. Nishimura J. Org. Biomol. Chem.  2003,  1:  2506 

1

This work was presented in part at the 18th International Symposium on Fluorine Chemistry, Bremen, Germany, 30 July-4 August 2006.

2

Present address: Hansa Fine Chemicals GmbH, BITZ, Fahrenheit Str. 1, 28359 Bremen, Germany.

13

For the synthesis of related bridged dibromoketones from fluorinated 1,3,5-triketones, as well as for the stereochemis-try of 4, see ref. 11.

14

2,4-Dibromo-6-(trifluoroacetyl)phenol and 4-bromophenol 3j and its monohydrate could be identified (see experimental procedure), whereas the targeted acid 3g was not detected at all.

28

For freshly prepared CDCl₃ (3d,h,i,j and 5a,c,f,k), acetone-d ₆, or THF (5g) solns. It is notable that if the CDCl₃ soln of 5c is maintained at r.t. for 20 h, the [bis-enol]/[F]/[G] molar ratio changes from 53:24:23 to 89:6:5 (by NMR spectroscopy). Contact with silica gel leads to hydration of phenols 3. When a mixture of 3j is stirred with silica gel in CHCl₃, the concentration of the hydrate form increases from 11% to 70% after 14 h at r.t. Dehydration can be achieved if the substance is maintained in anhyd CHCl₃: for 3j the hydrate content changed from 70% to 11% after 7 d at r.t. The use of 4-Å MS accelerates dehydration. In this case, the content of the hydrate form decreases to 7% after 17 h at r.t. (by ¹⁹F NMR). Anhyd MgSO₄ appeared to be inefficient.