Synlett 2011(11): 1537-1542  
DOI: 10.1055/s-0030-1260792
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Simple and Efficient Method for the Halogenation of Oxygenated Aromatic Compounds

Eftychia N. Koini, Nicolaos Avlonitis, Theodora Calogeropoulou*
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Av., 11635 Athens, Greece
Fax: +30(210)7273831; e-Mail: tcalog@eie.gr;
Further Information

Publication History

Received 10 February 2011
Publication Date:
15 June 2011 (online)

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.

    References and Notes

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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.