Simple and efficient method for the halogenation of oxygenated aromatic compounds

Article abstract of DOI:10.1055/s-0030-1260792

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. Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0030-1260792

LETTER
1537
Simple and Efficient Method for the Halogenation of Oxygenated Aromatic
Compounds
S
imple and Effi
f
cient
H
a
t
logenat
y
ion of
O
xyge
c
nate
d
A
ren
h
es ia N. Koini,1 Nicolaos Avlonitis,1 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
Received 10 February 2011
oxygenated aromatic rings. Thus, in this communication
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 pe-
troleum ether is presented. The effect of ultrasound was investigat-
ed.
we wish to present the use of a combination of hydrogen
peroxide and hydrohalic acid, in petroleum ether as sol-
vent, in the presence of acetic acid, for the halogenation of
oxygenated aromatic compounds (Scheme 1).
Key words: halogenation, phenols, heterocycles, hydrogen perox-
ide, hydrohalic acid
OR'
OR´
HX, H2O2, ACOH
PE
R
R
X
R' = H, Me
X = Cl, Br
Halogenated aromatic compounds find important applica-
tions in the synthesis of natural products, bioactive com-
Y
Y
HX, H2O2, ACOOH
PE
A
A
R1
R2
R1
R2
R
R
pounds,
materials,
and
industrial
chemicals.
O
O
Chlorophenols are useful intermediates for the manufac-
ture of insecticides, dyestuffs, preservatives, and disinfec-
tants.2 In turn, bromoaromatics have assumed increasing
importance in organic synthesis as versatile starting mate-
rials in metal-catalyzed cross-coupling reactions such as
the Heck, Suzuki, Negishi, and Sonogashira reactions.3
X
R1, R2 = H, Alk, Ph, COOEt
Y = CH2, A = CH2
Y = NH, A = C(O)
X = Cl, Br
19 examples
Scheme 1
The commercial significance of halogenated compounds
has led to the investigation of a wide variety of reagents
and conditions for their preparation. Direct ortho chlori-
nation of phenols is effected using of tert-butyl hypochlo-
rite,4 N,N-dichlorobutylamine,5 N-chlorodialkylamines/
silica gel,6 Cl2 or sulfuryl chloride catalysed by amines,7,8
and sulfuryl chloride in the presence of tert-butylaminom-
ethyl polysterene as a heterogeneous amine catalyst.9
Conventional methods for the synthesis of bromoaromat-
ics involve use of Br2/SbF5/HF,10 Br2 in acetic acid,11 Br2/
SO2Cl2 over microporous catalyst,12 Br2/tetrabutylammo-
nium peroxydisulfate,13 TBHP (70%)/HBr,14 NBS/
Oxyhalogenations have been previously reported using
acetic acid as solvent and hydrogen peroxide as the oxi-
dant. However, this is the first report of the use of HX (1
or 2 equiv)/H2O2 (30%, 6.5 equiv)/AcOH (6.5 equiv) in an
oxidative halogenation reaction using a nonpolar organic
solvent. The molar ratios of H2O2 (30%, 6.5 equiv) and
AcOH (6.5 equiv) vs. the substrate (1 equiv) afforded the
best yields of halogenated products during our optimisa-
tion efforts, which involved varying the relative reagent
ratios, temperature, and substrate concentration. More-
over, our method is superior to other oxidative chlorina-
tion and bromination approaches because it can be applied
both to phenols and anisoles, hindered or not, substituted
by electron-donating or electron-withdrawing substitu-
ents, with excellent control of mono- vs. bishalogenation
and high yields.
H2SO4/TFA,15
NBS/dibromodimethyl
hydantoin/
NaOH,16 NBS/HBF4·OEt2,17 NBS/SiO2,18 NBS/over
HZSM-5,19 NBS/TBAB,20 NBS/SO3H-functionalised sil-
ica,21 NBS/ammonium acetate,22 NBS/PTSA,23 dioxane
dibromide,24 LiBr/Cu(OAc)2/O2,25 3-methylimidazolium
tribromide,26 quinolinium bromochromate in glacial ace-
tic acid, hypobromites,27 Oxone® with NaBr28 or KBr,29
and KBr/acetic anhydride/HNO3.
More specifically, the previously reported chlorination of
anisole and N,N-dimethyl(3,4,5-trimethoxy)benzamide
using HCl and H2O2 afforded 2,4-dichloroanisole and
N,N-dimethyl(2,4-dichloro-3,4,5-trimethoxy)benzamide,
respectively.14 Since hydrochloric acid is difficult to oxi-
dise with dilute hydrogen peroxide, an excess of HCl and
a higher temperature were required for the oxidative chlo-
rination, which resulted in poor selectivity.14 The reported
ring bromination using NH4Br/H2O2 in acetic acid was
effected only when anilines and methoxy derivatives of
benzene or naphthalene were used as substrates.33 Fur-
thermore, acetic acid has been previously employed as the
In the course of our research involving the synthesis of
1,4-benzoxazine and benzopyran analogues with activity
against reperfusion arrhythmia30–32 we were prompted to
search for a mild methodology to affect halogenations of
SYNLETT 2011, No. 11, pp 1537–1542
x
x
.x
x
.2
0
1
1
Advanced online publication: 15.06.2011
DOI: 10.1055/s-0030-1260792; Art ID: D04411ST
© Georg Thieme Verlag Stuttgart · New York

1538
E. N. Koini et al.
LETTER
solvent for the oxyiodination of aromatic compounds us- observed chlorination of the activated 1,4-benzoxazine
ing ammonium iodide and hydrogen peroxide. However, ring and not of the phenyl substituent at C2, which is an
methoxy benzene derivatives, despite their marked reac- indication that our method is selective for oxygenated ar-
tivity in electrophilic reactions, were not iodinated.34 This omatics. In addition, we observed that, under our condi-
was also the case for phenols substituted by electron-with- tions, we obtain only the halogenated product in excellent
drawing substituents.35 Finally, iodination of phenols with yield without concomitant oxidative halogenations, which
KI and H2O2 in acetic acid resulted in a mixture of the is usually observed as a side reaction upon treatment of
ortho- and para-halogenated products accompanied by phenols with HX and H2O2. Furthermore, we did not ob-
dihalogenation.35
serve side-chain halogenation in the case of alkyl-substi-
tuted substrates (entries 2, 7–13, 16–19).
A number of different aromatic substrates was subjected
to our halogenation conditions to test the scope and gen- Ultrasound has been previously employed for the chlori-
erality of the method, and the results are summarised in nation of phenol, 2-nitrophenol, and thymol using HCl–
Table 1. In a typical procedure, to a solution of aromatic H2O2 to afford polychlorinated or mixtures of monochlo-
substrate in petroleum ether was added the mixture of ridated products.36 Conversely, 1-naphthol and 1-hy-
AcOH/H2O2 (30%)/HX. Using 1 equivalent of substrate, droxy-2-naphthoic acid gave chlorinated quinones as the
AcOH (6.5 equiv), 30% H2O2 (6.5 equiv), and 1 equiva- major products.36 Therefore, we were interested to exploit
lent of HCl or HBr we obtained the corresponding mono- the effect of ultrasound using our reaction conditions. In
halogenated compound while, with 2 equivalents of HCl the oxychlorination reaction (entries 7 and 12), even
or HBr, two halogen atoms are introduced (cf. Table 1). though we observed a marked reduction of the reaction
As shown in Table 1 the reaction gives high yields and time, the respective product yields were lower. In con-
ortho selectivity for a range of activated benzenes. Fur- trast, in the case of oxybromination the product yield was
thermore, we observe good control of mono- vs. dichlori- similar to conventional heating with concomitant reduc-
nation using our method (entries 1–5 and 6, respectively). tion by half of the reaction time (entry 16).
Even in the case of more reactive substrates, monochlori-
Halogenation of phenols is one of the key reactions in
nation or monobromination is observed (entries 5 and 15,
their functionalisation and in the synthesis of different de-
respectively). In contrast, exclusive dichlorination was
rivatives, including synthesis on an industrial scale.
previously observed using hydrogen peroxide and HCl.14
Therefore, the search for effective halogenating reagents
HBr possesses a lower oxidation potential thus oxybromi-
suitable for ecologically safe technology is of interest.37
nation requires milder conditions and smaller excess of re-
From a ‘green-oxidant’ perspective one of the best is hy-
agents. However, selective monobromination of reactive
drogen peroxide since water is the only side product.
aromatic compounds such as oxygenated arenes remains
Herein, we have reported an efficient and mild method for
problematic. Employing our methodology we obtained
the chlorination and bromination of activated aromatics
the monobrominated derivatives at room temperature, in
(phenols, substituted phenols, methoxyarenes, and 1,4-
excellent yields (entries 13–15). Introduction of an elec-
benzoxazines), with good regioselectivity and excellent
yields, using a combination HX/H2O2 (30%)/AcOH in pe-
troleum ether as solvent. The use of ultrasound did not
tron-withdrawing group ortho or para to the phenolic hy-
droxyl substantially decreased the rate of ring chlorination
(entries 3 and 7 vs. entry 1) without affecting the product
confer any additional advantage in comparison to conven-
yield. In the cases of simple phenols ortho halogenation is
tional heating.
favoured vs. para (entries 1 and 4). Introduction of an
electron-donating group ortho to the phenolic hydroxyl
(entry 2) results in both the ortho- and para-chlorinated
derivatives in a 1:1 ratio. Interestingly, in entry 11 we only
Table 1 Halogenated Oxygenated Aromatic Compounds 1a–19a Produced via Scheme 1
Entry Substrate
HX (equiv) Methoda,38 Time (h)
Productb
Isolated yield (%)c
OH
OH
Cl
1
1
1
A
A
24
12
8539
1a
OH
Cl
OH
OH
2a 4139
2b 4739
Cl
2
2a
2b
Synlett 2011, No. 11, 1537–1542 © Thieme Stuttgart · New York

LETTER
Simple and Efficient Halogenation of Oxygenated Arenes
1539
Table 1 Halogenated Oxygenated Aromatic Compounds 1a–19a Produced via Scheme 1 (continued)
Entry Substrate
HX (equiv) Methoda,38 Time (h)
Productb
Isolated yield (%)c
OH
OH
Cl
3
1
A
48
9539
COOMe
COOMe
3a
OH
OH
Cl
4
5
1
1
A
A
1
8840
4a
CN
CN
Cl
20
9741
MeO
OMe
MeO
MeO
OMe
5a
CN
CN
Cl
MeO
6a
6
7
2
A
4
8742
OMe
OMe
Cl
OH
Cl
OH
NO2
2.5
2.5
A
B
96
1.5
8530
65
NO2
7a
H
N
H
N
Cl
O
O
O
O
8
9
2.5
2.5
2.5
2.5
A
A
A
A
12
12
12
12
8530
9830
8930
8930
O
O
8a
H
N
H
N
Cl
O
O
9a
H
N
H
N
Cl
O
O
10
11
O
COOEt
O
COOEt
10a
H
N
H
N
Cl
O
O
O
Ph
O
Ph
11a
Synlett 2011, No. 11, 1537–1542 © Thieme Stuttgart · New York

1540
E. N. Koini et al.
LETTER
Table 1 Halogenated Oxygenated Aromatic Compounds 1a–19a Produced via Scheme 1 (continued)
Entry Substrate
HX (equiv) Methoda,38 Time (h)
Productb
Isolated yield (%)c
Cl
MeO
MeO
2.5
2.5
A
B
12
72
8743
47
12
O
O
12a
OH
OH
Br
Br
13
1
C
1
1
8539
13a
OH
OH
14
1
1
C
C
9539
COOMe
COOMe
14a
CN
CN
Br
15
0.5
9644
MeO
OMe
MeO
OMe
15a
OH
Br
OH
NO2
2.5
2.5
B
C
1.5
3
6845
64
NO2
16
16a
H
N
H
N
Br
O
O
17
2.5
2.5
2.5
C
C
C
1
8546
7247
7548
O
O
17a
Br
HO
HO
18
1
O
O
18a
Br
MeO
MeO
19
0.5
O
O
19a
a Methods:38 A: substrate (1 mmol), AcOH (6.5 mmol), 30% H2O2 (6.5 mmol), HCl (37%), PE 40–60 °C (10 mL), reflux. B: substrate (1 mmol),
AcOH (6.5 mmol), 30% H2O2 (6.5 mmol), HCl (37%) or HBr (48%), PE 40–60 °C (50 mL), sonication. C: substrate (1 mmol), AcOH (6.5
mmol), 30% H2O2 (6.5 mmol), HBr (48%), PE 40–60 °C (50 mL), r.t.
b Compounds were characterised by 1H NMR and 13C NMR spectroscopy and mass spectrometry
c Isolated yields after flash column chromatography
supervised by the Greek General Secretariat for Research and Tech-
nology EPAN 3.3.1. (2006-2009) ‘Design and synthesis of bio-
Acknowledgment
This work was supported in part by the Greek General Secretariat
active molecules’.
for Research and Technology-Excellence in the Research Institutes
Synlett 2011, No. 11, 1537–1542 © Thieme Stuttgart · New York

LETTER
Simple and Efficient Halogenation of Oxygenated Arenes
1541
(33) Krishna Mohan, K. V. V.; Narender, N.; Srinivasu, P.;
References and Notes
Kulkarni, S. J.; Raghavan, K. V. Synth. Commun. 2004, 34,
2143.
(1) New address: E. N. Koini and N. Avlonitis, School of
Chemistry, University of Edinburgh, West Mains Rd,
Edinburgh, EH9 3JJ, UK.
(2) Ullmann’s Encyclopedia of Industrial Chemistry, Electronic
Release, 6th ed.; Wiley-VCH: Weinheim, 1998.
(3) (a) Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000,
100, 3009. (b) Franzén, R.; Xu, Y. Can. J. Chem. 2005, 83,
266.
(4) Ogata, Y.; Takag, K.; Kondo, Y.; Hsin, S. C.; Woo, W. I.;
Chen, F. C. J. Chin. Chem. Soc. 1983, 30, 261.
(5) Smith, K.; Butters, M. Tetrahedron Lett. 1988, 29, 1319.
(6) Leblanc, J. C. EP 196,260, 1986.
(7) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 1995, 36,
3893.
(8) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 2004, 45,
8471.
(9) Jacquesy, J.; Jouannetaud, M.; Makani, S. J. Chem. Soc.,
Chem. Commun. 1980, 110.
(10) Coburn, C. E.; Anderson, D. K.; Swenton, J. S. J. Org.
Chem. 1983, 48, 1455.
(11) Gnaim, J. M.; Sheldon, R. A. Tetrahedron Lett. 2005, 46,
(34) Narender, N.; Suresh Kumar Reddy, K.; Krishna Mohan,
K. V. V.; Kulkarni, S. J. Tetrahedron Lett. 2007, 48, 6124.
(35) Suresh Kumar Reddy, K.; Narender, N.; Rohitha, C. N.;
Kulkarni, S. J. Synth. Commun. 2008, 38, 3894.
(36) Bhatkhande, B. S.; Adhikari, M. V.; Samant, S. D. Ultrason.
Sonochem. 2002, 9, 31.
(37) Podgoršek, A.; Zupan, M.; Iskra, J. Angew. Chem. Int. Ed.
2009, 48, 8424.
(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.
4465.
Method B
(12) Kim, Y. H.; Park, M. Y.; Yang, S. G. Phosphorus, Sulfur
Silicon Relat. Elem. 2005, 180, 1235.
(13) Barhate, N. B.; Gajare, A. S.; Wakharkar, R. D.; Bedekar,
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.
A. V. Tetrahedron Lett. 1998, 39, 6349.
(14) Duan, J.; Zhang, L. H.; Dolbier, W. R. Jr. Synlett 1999, 1245.
(15) Auerbach, J.; Weissman, S. A.; Blacklock, T. J. 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, K. V.
Tetrahedron Lett. 1994, 35, 7055.
Method C
(19) Ganguly, N. C.; 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,
K. V. J. Mol. Catal. A: Chem. 2007, 267, 30.
(22) Bovonsombat, P.; Khanthapura, P.; Krause, M. M.;
Leykajarakul, J. Tetrahedron Lett. 2008, 49, 7008.
(23) Chaudhuri, S. K.; Roy, S.; Saha, M.; Bhar, S. Synth.
Commun. 2007, 37, 1381.
(24) Menini, L.; Parreira, L. A.; Gusevskaya, E. V. 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, S. J.;
Reghaven, K. V. Synth. Commun. 2002, 32, 2313.
(29) Tsoukala, A.; Liguori, L.; Occhipinti, G.; Bjørsvik, H.-R.
Tetrahedron Lett. 2009, 50, 831.
(30) Koini, E. N.; Papazafiri, P.; Vassilopoulos, A.; Koufaki, M.;
Horváth, Z.; Koncz, I.; Virág, L.; Papp, G. J.; 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.
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
(40) Guy, A.; Lemaire, M.; Guette, J.-P. Tetrahedron 1982, 38,
2347.
(41) Joseph, A. R.; Kumbhar, V. B.; Ranade, A. A.; Paradkar,
M. V. J. Chem. Res., Synop. 2007, 91.
(42) Spectroscopic Data for Compound 6a
1H NMR (300 MHz, CDCl3): d = 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): d = 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): d =
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.
(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.
(45) Spectroscopic Data for Compound 16a
1H NMR (300 MHz, CDCl3): d = 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):
d = 150.4, 144.7, 135.5, 131.6, 125.4, 120.6, 22.0, 13.3.
(32) Koufaki, M.; Calogeropoulou, T.; Rekka, E.; Chryselis, M.;
Papazafiri, P.; Gaitanaki, C.; Makriyannis, A. Bioorg. Med.
Chem. 2003, 11, 5209.
Synlett 2011, No. 11, 1537–1542 © Thieme Stuttgart · New York

1542
E. N. Koini et al.
LETTER
(46) Spectroscopic Data for Compound 17a
1H NMR (300 MHz, CDCl3): d = 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): d = 165.9, 141.1, 132.3, 124.0, 123.1, 121.2, 120.9,
67.0, 20.3, 17.2, 12.9.
(47) Rosenau, T.; Adelwöhrer, C.; Kloser, E.; Mereiter, K.;
Netscher, T. Tetrahedron 2006, 62, 1772.
(48) Spectroscopic Data for Compound 19a
1H NMR (300 MHz, CDCl3): d = 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): d =
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.
Synlett 2011, No. 11, 1537–1542 © Thieme Stuttgart · New York