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was brominated ortho to the phenolic OH only when the
para position was occupied (entries 3, 4 and 7). Similar
results were observed for ethers (entries 11 and 12) or ani-
lines (entries 13–15) with the ZrBr4/diazene mixture under
similar reaction conditions. Two equivalents of this mix-
ture were required for the introduction of two bromine
atoms into the molecule (entries 12 and 14). This indicates
that the position of the electrophilic attack as well as the
number of entering bromine atoms can be regulated by
controlling the ratio of substrate: ZrBr4/diazene.
In conclusion, this Letter describes the first example of
the use of a ZrBr4/diazene mixture for the selective bromin-
ation of various phenols, aromatic ethers and anilines. The
method is completely regioselective thus offering numerous
22. De Almeida, L. S.; Esteves, P. M.; De Mattos, M. C. S. Synthesis
2006, 221–223.
synthetic applications. Mild reaction conditions,
a
23. De Almeida, L. S.; Esteves, P. M.; De Mattos, M. C. S. Synlett 2007,
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relatively rapid conversion, good-to-excellent yields, and
the selectivity profile are notable characteristics of
the described protocol. Studies concerning the reaction
pathway are now in progress.
26. Batt, S.; Nayak, S. K. Synth. Commun. 2007, 37, 1687–1690.
´
27. See, for example: (a) Imramovsky´, A.; Polanc, S.; Vinsˇova, J.;
Acknowledgements
´
ˇ
´
´
Kocˇevar, M.; Jampılek, J.; Reckova, Z.; Kaustova, J. Bioorg. Med.
Chem. 2007, 15, 2551–2559; (b) Pozˇgan, F.; Polanc, S.; Kocˇevar, M.
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The Ministry of Higher Education, Science and Tech-
nology of Slovenia and the Slovenian Research Agency
are gratefully acknowledged for their financial support
(P1-0230-103). We would like to thank Dr. Bogdan Kralj
28. For recent references, see: (a) Kovacˇ, A.; Majce, V.; Lenarsˇicˇ, R.;
Bombek, S.; Bostock, J.; Chopra, I.; Polanc, S.; Gobec, S. Bioorg.
Med. Chem. Lett. 2007, 17, 2047–2054; (b) Hren, J.; Kranjc, K.;
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ˇ
and Dr. Dusˇan Zigon (Mass Spectrometry Center, Jozˇef
Stefan Institute, Ljubljana, Slovenia) for recording the
mass spectra.
References and notes
ˇ
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29. Lenarsˇicˇ, R.; Kocˇevar, M.; Polanc, S. J. Org. Chem. 1999, 64, 2558–
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31. Aminated phenol 3: mp 117–118 °C (hexane/diethyl ether); IR (KBr)
3428, 2976, 1738, 1675, 1489, 1412, 1326, 1244, 1111 cmÀ1; 1H NMR
(CDCl3, 300 MHz) d 1.27 (6H, d, J 6.2 Hz), 1.28 (6H, d, J 6.2 Hz),
2.26 (3H, s), 5.00 (1H, h, J 6.2 Hz), 5.01 (1H, h, J 6.2 Hz), 5.57 (1H,
s), 6.80 (1H, s), 7.12 (1H, br), 7.28 (1H, br); 13C NMR (CDCl3,
75 MHz) d 16.4, 21.90, 21.93, 70.2, 71.0, 118.9, 122.9, 125.7, 126.3,
134.3, 148.2, 154.5, 156.0; MS (EI) m/z 344 (M+, 13), 258 (38), 216
(100), 171 (78). Anal. Calcd for C15H21ClN2O5 (344.79): C, 52.25; H,
6.14; N, 8.12. Found: C, 52.57; H, 6.20; N, 7.99.
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´
34. Typical procedure: A mixture of the substrate (1 mmol) and the
diazene (1 mmol) in anhydrous dichloromethane (5 mL) was added
over 30 min to a stirred suspension of ZrBr4 (419 mg, 1 mmol) in
anhydrous dichloromethane (7 mL) at room temperature. The reac-
tion was monitored by TLC until the substrate was consumed (Table
2). Then, water was added (5 mL), followed by a saturated solution of
NaHCO3 until pH 7 was reached. The two phases were separated and
the aqueous phase was extracted with dichloromethane (2 Â 5 mL).
The combined organic phases were dried over anhydrous Na2SO4,
filtered, evaporated to dryness and purified by radial chromatography
using petroleum ether/ethyl acetate (7:1) to separate dialkyl 1,2-
hydrazinedicarboxylate from the desired brominated product.
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