Simple and Efficient Method for the Halogenation of Oxygenated Aromatic Compounds

Abstract

An efficient and mild method for the chlorination and bromination of oxygenated aromatics, with good regioselectivity and excellent yields, using a combination of HX/H₂O₂/AcOH in petroleum ether is presented. The effect of ultrasound was investigated.

Key words

halogenation - phenols - heterocycles - hydrogen peroxide - hydrohalic acid

References and Notes

• 2 Ullmann’s Encyclopedia of Industrial Chemistry   Electronic Release, 6th ed.:  Wiley-VCH; Weinheim: 1998. 
• 3a Beletskaya IP. Cheprakov AV. Chem. Rev.  2000,  100:  3009 
• 3b Franzén R. Xu Y. Can. J. Chem.  2005,  83:  266 
• 4 Ogata Y. Takag K. Kondo Y. Hsin SC. Woo WI. Chen FC. J. Chin. Chem. Soc.  1983,  30:  261 
• 5 Smith K. Butters M. Tetrahedron Lett.  1988,  29:  1319 
• 6 Leblanc JC. inventors; EP  196,260. 
• 7 Gnaim JM. Sheldon RA. Tetrahedron Lett.  1995,  36:  3893 
• 8 Gnaim JM. Sheldon RA. Tetrahedron Lett.  2004,  45:  8471 
• 9 Jacquesy J. Jouannetaud M. Makani S. J. Chem. Soc., Chem. Commun.  1980,  110 
• 10 Coburn CE. Anderson DK. Swenton JS. J. Org. Chem.  1983,  48:  1455 
• 11 Gnaim JM. Sheldon RA. Tetrahedron Lett.  2005,  46:  4465 
• 12 Kim YH. Park MY. Yang SG. Phosphorus, Sulfur Silicon Relat. Elem.  2005,  180:  1235 
• 13 Barhate NB. Gajare AS. Wakharkar RD. Bedekar AV. Tetrahedron Lett.  1998,  39:  6349 
• 14 Duan J. Zhang LH. Dolbier WR. Synlett  1999,  1245 
• 15 Auerbach J. Weissman SA. Blacklock TJ. Tetrahedron Lett.  1993,  34:  931 
• 16 Oberhauser T. J. Org. Chem.  1997,  62:  4504 
• 17 Konishi H. Aritomi K. Okano T. Kijii J. Bull. Chem. Soc. Jpn.  1989,  62:  591 
• 18 Paul V. Sudalai A. Daniel T. Srinivasan KV. Tetrahedron Lett.  1994,  35:  7055 
• 19 Ganguly NC. De P. Dutta S. Synthesis  2005,  1103 
• 20 Das B. Venkateswarlu K. Krishnahiah M. Holla H. Tetrahedron Lett.  2006,  47:  8693 
• 21 Das B. Venkateswarlu K. Majhi A. Siddaiah V. Reddy KV. J. Mol. Catal. A: Chem.  2007,  267:  30 
• 22 Bovonsombat P. Khanthapura P. Krause MM. Leykajarakul J. Tetrahedron Lett.  2008,  49:  7008 
• 23 Chaudhuri SK. Roy S. Saha M. Bhar S. Synth. Commun.  2007,  37:  1381 
• 24 Menini L. Parreira LA. Gusevskaya EV. Tetrahedron Lett.  2007,  48:  6401 
• 25 Chiappe C. Leandri E. Pieraccini D. Chem. Commun.  2004,  2536 
• 26 Viroopakshappa J. Jagannadham V. Indian J. Chem., Sect A: Inorg., Bio-inorg. Phys., Theor. Anal. Chem.  2004,  43:  532 
• 27 Bovicelli P. Bernini R. Antonioletti R. Mincione E. Tetrahedron Lett.  2002,  43:  5563 
• 28 Narender N. Sriniva P. Ramakrishna M. Kilkarmi SJ. Reghaven KV. Synth. Commun.  2002,  32:  2313 
• 29 Tsoukala A. Liguori L. Occhipinti G. Bjørsvik H.-R. Tetrahedron Lett.  2009,  50:  831 
• 30 Koini EN. Papazafiri P. Vassilopoulos A. Koufaki M. Horváth Z. Koncz I. Virág L. Papp GJ. Varró A. Calogeropoulou T. J. Med. Chem.  2009,  52:  2328 
• 31 Koufaki M. Detsi A. Theodorou E. Kiziridi C. Calogeropoulou T. Vassilopoulos A. Kourounakis A. Rekka E. Kourounakis P. Gaitanaki C. Papazafiri P. Bioorg. Med. Chem.  2004,  12:  4835 
• 32 Koufaki M. Calogeropoulou T. Rekka E. Chryselis M. Papazafiri P. Gaitanaki C. Makriyannis A. Bioorg. Med. Chem.  2003,  11:  5209 
• 33 Krishna Mohan KVV. Narender N. Srinivasu P. Kulkarni SJ. Raghavan KV. Synth. Commun.  2004,  34:  2143 
• 34 Narender N. Suresh Kumar Reddy K. Krishna Mohan KVV. Kulkarni SJ. Tetrahedron Lett.  2007,  48:  6124 
• 35 Suresh Kumar Reddy K. Narender N. Rohitha CN. Kulkarni SJ. Synth. Commun.  2008,  38:  3894 
• 36 Bhatkhande BS. Adhikari MV. Samant SD. Ultrason. Sonochem.  2002,  9:  31 
• 37 Podgoršek A. Zupan M. Iskra J. Angew. Chem. Int. Ed.  2009,  48:  8424 
• 40 Guy A. Lemaire M. Guette J.-P. Tetrahedron  1982,  38:  2347 
• 41 Joseph AR. Kumbhar VB. Ranade AA. Paradkar MV. J. Chem. Res., Synop.  2007,  91 
• 44 Zhang Y.-N. Zhong X.-G. Zheng Z.-P. Hu X.-D. Zuo J.-P. Hu L.-H. Bioorg. Med. Chem.  2007,  15:  988 
• 47 Rosenau T. Adelwöhrer C. Kloser E. Mereiter K. Netscher T. Tetrahedron  2006,  62:  1772 

1

New address: E. N. Koini and N. Avlonitis, School of Chemistry, University of Edinburgh, West Mains Rd, Edinburgh, EH9 3JJ, UK.

38

Method A
To a solution/slurry of substrate (1 mmol) in PE (40-60, 10 mL) was added a mixture of AcOH (6.5 mmol), 30% H₂O₂ (6.5 mmol), and the appropriate amount of HCl (37%, Table  [¹] ), and the resulting mixture was refluxed for 1-96 h until completion of the reaction (cf. Table  [¹] ). The reaction was cooled to r.t., diluted with EtOAc, the organic layer was extracted with H₂O and brine, dried over anhyd Na₂SO₄, and filtered. The solvent was evaporated in vacuo, and the residue was purified by flash column chromatography (silica gel) using PE (40-60)-EtOAc as eluent to afford the desired chlorinated compounds.
Method B
To a solution/slurry of substrate (1 mmol) in PE (40-60, 50 mL) was added a mixture of AcOH (6.5 mmol), 30% H₂O₂ (6.5 mmol), and the appropriate amount of HCl (37%) or HBr (48%, Table  [¹] ), and the resulting mixture was sonicated until completion of the reaction (cf. Table  [¹] ). The reaction mixture was diluted with EtOAc, the organic layer was extracted with H₂O and brine, dried over anhyd Na₂SO₄, and filtered. The solvent was evaporated in vacuo, and the residue was purified by flash column chromatography (silica gel) using PE (40-60)-EtOAc as eluent to afford the desired chlorinated compounds.
Method C
To a solution/slurry of substrate (1 mmol) in PE (40-60, 50 mL) was added a mixture of AcOH (6.5 mmol), 30% H₂O₂ (6.5 mmol), and the appropriate amount of HBr (48%, cf. Table  [¹] ), and the resulting mixture was stirred at r.t. until completion of the reaction (Table  [¹] ). The reaction mixture was diluted with EtOAc, the organic layer was extracted with H₂O and brine, dried over anhyd Na₂SO₄, and filtered. The solvent was evaporated in vacuo, and the residue was purified by flash column chromatography (silica gel) using PE (40-60)-EtOAc as eluent to afford the desired brominated compounds.

39

Compounds 1a-3a, 13a, and 14a are commercially available

42

Spectroscopic Data for Compound 6a
^¹H NMR (300 MHz, CDCl₃): δ = 6.59 (s, 1 H), 4.02 (s, 2 H), 3.92 (s, 6 H).

43

Spectroscopic Data for Compound 12a ^¹H NMR (300 MHz, CDCl₃): δ = 3.72 (s, 3 H), 2.73 (t, J = 7.0 Hz, 2 H), 2.19 (s, 3 H), 2.06 (s, 3 H), 1.77 (t, J = 7.0 Hz, 2 H). 1.29 (s, 6 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 148.5, 146.9, 129.3, 124.4, 124.1, 117.0, 72.6, 60.4, 32.5, 26.7, 21.5, 12.8, 11.9.

45

Spectroscopic Data for Compound 16a
^¹H NMR (300 MHz, CDCl₃): δ = 9.64 (s, 1 H), 2.60 (s, 3 H), 2.46 (s, 3 H), 2.29 (s, 3 H). ^¹³C NMR (75.5 MHz, CDCl₃):
δ = 150.4, 144.7, 135.5, 131.6, 125.4, 120.6, 22.0, 13.3.

46

Spectroscopic Data for Compound 17a ^¹H NMR (300 MHz, CDCl₃): δ = 8.38 (br s, 1 H), 4.54 (s, 2 H), 2.35 (s, 6 H), 2.21 (s, 3 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 165.9, 141.1, 132.3, 124.0, 123.1, 121.2, 120.9, 67.0, 20.3, 17.2, 12.9.

48

Spectroscopic Data for Compound 19a ^¹H NMR (300 MHz, CDCl₃): δ = 3.72 (s, 3 H), 2.72 (t, J = 7.0 Hz, 2 H), 2.24 (s, 3 H), 2.07 (s, 3 H), 1.78 (t, J = 7.0 Hz, 2 H), 1.29 (s, 6 H). ^¹³C NMR (75.5 MHz, CDCl₃): δ = 148.7, 147.9, 129.3, 124.9, 118.5, 116.4, 73.6, 60.3, 32.8, 26.6, 24.4, 13.1, 11.9.