A New Bromination Method for Phenols and Anisoles: NBS/HBF4*Et2O in CH3CN

Full text of DOI:10.1021/jo9622993

4504
J . Org. Chem. 1997, 62, 4504-4506
ylamine for the selective ortho-bromination of phenols.17
A New Br om in a tion Meth od for P h en ols
Benzene reacts with NBS only in the presence of sto-
ichiometric amounts of Lewis acids or concd H2SO4.18
Other acidic catalysts that were used with NBS for the
bromination of activated aromatic substrates are aqueous
a n d An isoles: NBS/HBF 4‚Et2O in CH3CN
Thomas Oberhauser
H2SO4 or catalytic amounts of concd H2SO4,20 TsOH,21
F. Hoffmann-La Roche Ltd, Pharmaceuticals Division,
Chemical Process Research, CH-4070 Basel, Switzerland
19
silica gel,22 and the zeolite HZSM-5.23
Herein we report a new method for the selective
monobromination of phenols and anisoles with NBS in
CH3CN promoted by HBF4‚Et2O or other strong acids.24
The results are summarized in Table 1. In the course of
process research directed towards a technical synthesis
of the potassium channel opener Ro 31-6930,25 we
required 2-bromo-4-hydroxybenzonitrile. Bromination of
4-hydroxybenzonitrile with NBS in CH3CN gave a mix-
ture of starting material, the desired ortho-monobromi-
nated phenol, and the corresponding dibromo compound
(entry 1f). With stoichiometric H2SO4, selective mono-
bromination was observed, but even after 24 h the
reaction was not complete (entry 1e). CF3SO3H, FSO3H,
and HBF4‚Et2O on the other hand resulted in selective
monobrominations within 3-24 h (entries 1a,b,d) whereas
ClSO3H gave about 9% dibromophenol (entry 1c). Even
when 4-hydroxybenzonitrile was treated with 2 equiv of
NBS and 2 equiv of HBF4‚Et2O, only 6% dibromophenol
was detected. This nicely demonstrates the high selec-
tivity of this reagent. For all subsequent bromination
experiments HBF4‚Et2O was used. The bromination is
highly para-selective for phenol itself (entry 7a) as well
as for ortho- and meta-substituted phenols (entries 2a,
3a, 5a, 6a, 9a). Para-substituted phenols were bromi-
nated in the ortho-position (entries 4a, 8a). The yields
were generally good to excellent. 4-Nitrophenol and
2-nitroanisole required FSO3H for complete bromination
(entries 10a, 12a). HBF4‚Et2O led only to incomplete
conversion (entries 10b, 12b). In the absence of acid,
mixtures of compounds were obtained, often with the
dibrominated compound dominating (entries 2-9b, 10c).
The only exceptions were 2-methylphenol and 2-meth-
oxyphenol (entries 13, 14). With these substrates, selec-
tive monobromination was achieved with and without
acid. 2-Nitroanisole and 4-methoxybenzoic acid methyl
ester were virtually inert toward NBS in the absence of
acid (entries 12c, 11b).
Received December 10, 1996
For the bromination of phenols, bromine in haloge-
nated hydrocarbons1 or HOAc2 is often the reagent of
choice. However, with many substrates, mixtures of
mono- and polybrominated compounds are obtained.3 For
the selective monobromination of phenols and other
activated aromatics, milder and also less hazardous
reagents like dioxane dibromide,4 pyridinium hydrobro-
mide perbromide,5 DBU hydrobromide perbromide,6 tet-
rabromocyclohexadienone,7 tetraalkylammonium tribro-
mides,8 and hexamethylenetetramine tribromide9 have
been developed. These reagents yield selectively para-
brominated phenols unless the para-position is substi-
tuted. A reagent which brominates phenol selectively in
the ortho-position is Br2/t-BuNH2.10
Another popular and inexpensive reagent for aromatic
brominations is N-bromosuccinimide (NBS) in CCl4.11
Alkylated aromatics are either brominated in the side
chain with NBS and benzoyl peroxide (Wohl-Ziegler
reaction) or in the aromatic nucleus when no radical
initiator is present.12 The nuclear bromination of acti-
vated aromatic compounds (alkylbenzenes, phenols, ani-
soles) with NBS is clearly favored by polar solvents like
propylene carbonate,13 DMF,14 and CH3CN.15 NBS has
also been used in aqueous NaOH for the bromination of
methoxy benzoic acids16 and in the presence of diisoprop-
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NBS and HBF4‚Et2O in CH3CN is not suited for the
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S0022-3263(96)02299-2 CCC: $14.00 © 1997 American Chemical Society

Notes
J . Org. Chem., Vol. 62, No. 13, 1997 4505
Ta ble 1
acetophenone, a small amount of the R-brominated
compound was isolated.
lowed by a slow cleavage of the N-Br bond under
formation of succinimide and possibly bromonium tet-
rafluoroborate. To our knowledge, BrBF4 has not yet
been reported in the literature.26
In conclusion we developed an efficient new method
for the selective monobromination of phenols and anisoles
using NBS/HBF4‚Et2O in CH3CN. Bromonium tetrafluo-
roborate might be the actual brominating species. Fur-
ther work regarding the halogenation of other activated
To gain insight into the nature of the active brominat-
ing species, 13C NMR measurements were performed.
Immediately after the addition of 1 (or 2) equiv of
HBF4‚Et2O to NBS in CD3CN, the signal of the carbonyl
group shifted from 176.27 to 177.33 ppm. After 5 h,
however, the CO signal occurred at 184.16 ppm which
corresponds to protonated succinimide (succinimide + 1
equiv of HBF4‚Et2O: 183.98 ppm). The CO signal of
neutral succinimide in CD3CN is at 180.17 ppm. These
results suggest protonation of NBS by HBF4‚Et2O, fol-
(26) The isolation of tribromine tetrafluoroborate (Br3BF4) has been
reported: Sˇmalc, A. Inst. J ozef Stefan Rep. 1972, R-612, 1-7.

4506 J . Org. Chem., Vol. 62, No. 13, 1997
Notes
4-Br om o-3-ch lor op h en ol: mp 67-68 °C (lit.32 mp 67.5-69
aromatics with similar reagents is in progress and will
be reported in due course.
1
°C); H NMR 5.50 (s, 1H), 6.63 (dd, J ) 8.7, 2.8, 1H), 6.97 (d, J
) 2.8, 1H), 7.43(d, J ) 8.7, 1H); MS 210, 208, 206 (M+, 24, 100,
82).
Exp er im en ta l Section
1
4-Br om op h en ol: mp 66-68 °C; H NMR 5.42 (s, 1H), 6.72
(dm, J ) 8.9, 2H), 7.32 (dm, J ) 8.9, 2H).
Gen er a l. Unless otherwise indicated, all starting materials
and reagents were obtained from commercial suppliers and used
without further purification. Solvents for reactions, extraction,
and chromatography were analytical grade. 1H and 13C NMR
spectra were recorded in CDCl3 at 250 MHz. Low resolution
EI mass spectra were obtained with an ionization voltage of 70
eV. GC analyses were performed on a crosslinked 5% Ph Me
Silicone capillary column (0.25 µM, 30 m). Analytical HPLC
employed a RP-18 column (250 × 4 mm) and a potassium
phosphate buffer (0.03 M, pH 6)/CH3CN gradient (1.2 mL/min,
50 °C). TLC was performed on precoated Merck glass plates
(0.25 mm) with silica gel 60 F254. Compound visualization was
effected by UV light (254 nm).
Meth yl 3-br om o-4-h yd r oxyben zoa te:33 mp 105 °C (lit.39 mp
106-107 °C); 1H NMR 3.89 (s, 3H), 5.92 (s, 1H), 7.05 (d, J )
8.5, 1H), 7.92 (dd, J ) 8.5, 2.0, 1H), 8.19 (d, J ) 2.0, 1H); MS
232, 230 (M+, 32, 33), 201, 199 (99, 100).
5-Br om o-2-h yd r oxyben zoic a cid : mp 167 °C (lit.34 mp 166
1
°C); H NMR 6.92 (d, J ) 8.9, 1H), 7.60 (dd, J ) 8.9, 2.5, 1H),
8.03 (d, J ) 2.5, 1H), 10.39 (s, br, 1H).
2-Br om o-4-n itr op h en ol: mp 114-115 °C (lit.4 mp 112-114
1
°C); H NMR 6.20 (s, br, 1H), 7.13 (d, J ) 9.0, 1H), 8.16 (dd, J
) 9.0, 2.6, 1H), 8.44 (d, J ) 2.6, 1H); MS 219, 217 (M+, 98, 100),
189, 187 (49, 51).
Meth yl 3-br om o-4-m eth oxyben zoa te: mp 97-98 °C (lit.35
mp 99-100 °C); 1H NMR 3.90 (s, 3H), 3.96 (s, 3H), 6.92 (d, J )
8.7, 1H), 7.99 (dd, J ) 8.7, 2.1, 1H), 8.23 (d, J ) 2.1, 1H); MS
246, 244 (M+, 73, 72), 215, 213 (97, 100).
4-Br om o-1-m eth oxy-2-n itr oben zen e: mp 84-85 °C (lit.36
mp 85-85.5 °C); 1H NMR 3.96 (s, 3H), 6.99 (d, J ) 8.9, 1H),
7.64 (dd, J ) 8.9, 2.5, 1H), 7.98 (d, J ) 2.5, 1H); MS 233, 231
(M+, 100, 97), 203, 201 (29, 30), 186, 184 (92, 87), 172, 170 (58,
59), 157, 155 (46, 43).
4-Br om o-2-m eth ylp h en ol: mp 63-64 °C (lit.37a mp 62-64
°C); 1H NMR 2.22 (s, 3H), 4.67 (s, 1H), 6.64 (d, J ) 8.5, 1H),
7.17 (dd, J ) 8.5, 2.4, 1H), 7.24 (d, J ) 2.4, 1H); MS 188, 186
(M+, 99, 100), 107 (60), 77 (30).
4-Br om o-2-m eth oxyp h en ol:38 1H NMR 3.89 (s, 3H), 5.55 (s,
1H); 6.79 (d, J ) 8.0, 1H), 6.96 (d, J ) 2.1, 1H), 6.98 (dd, J )
8.0, 2.1, 2H); Diff-NOE irradiation at 3.89 results in 11% pos
NOE at 6.96. MS 204, 202 (M+, 100, 98), 189, 187 (74, 72), 161,
159 (42, 41).
Gen er a l P r oced u r e for th e Br om in a tion of P h en ols a n d
An isoles. To a cold (-20 °C) solution of phenol or anisole (2
g)27 in CH3CN (20 mL) under argon was added acid (1.0-1.1
equiv) and then slowly NBS (1.0-1.2 eq) such that the temper-
ature did not rise above -10 °C. After the addition, the cooling
bath was removed and the reaction mixture allowed to warm
up to rt. The progress of the reaction was followed by TLC, GC,
or HPLC. Stirring was continued for the time indicated in Table
1. NaHSO3 (38%, 10 mL) was added, and the reaction mixture
was extracted with t-BuOMe (2 × 25 mL). Each organic layer
was washed with H2O (2 × 25 mL) and brine (25 mL). The
combined organic extracts were dried over MgSO4 and concen-
trated under reduced pressure with a rotary evaporator. If
necessary, the crude products were purified by crystallization
or flash chromatography (230-400 mesh silica gel 60).
3-Br om o-4-h yd r oxyben zon itr ile: mp 155-156 °C (lit.28 mp
1
154-155 °C); H NMR 6.06 (s, 1H), 7.09 (d, J ) 8.5, 1H), 7.54
(dd, J ) 8.5, 1.9, 1H), 7.80 (d, J ) 1.9, 1H); MS 199, 197 (M+,
100, 98).
5-Br om o-2-h yd r oxyben zon itr ile: mp 157-158 °C (lit.29 mp
1
Ack n ow led gm en t. Mrs. Sandra Mu¨ller and Mr.
Guy Zielinski are thanked for their excellent technical
assistance.
158-159 °C); H NMR 6.05 (s, 1H), 6.89 (d, J ) 8.8, 1H), 7.57
(dd, J ) 8.8, 2.4, 1H), 7.62 (d, J ) 2.4, 1H); MS 199, 197 (M+,
98, 100), 171, 169 (61, 63).
2-Br om o-5-h yd r oxyben zon itr ile: 1H NMR 5.20 (s, 1H),
6.97 (dd, J ) 8.8, 2.8, 1H), 7.13 (d, J ) 2.4, 1H), 7.53 (d, J ) 8.8,
1H); MS 199, 197 (M+, 100, 92).
J O9622993
2-Br om o-4-ch lor op h en ol: mp 31-32 °C (lit.30 mp 33-34
°C); 1H NMR 5.56 (s, 1H), 6.95 (d, J ) 8.7, 1H), 7.19 (dd, J )
8.7, 2.4, 1H), 7.46 (d, J ) 2.4, 1H); MS 210, 208, 206 (M+, 23,
100, 75).
(31) Smith, K; J ames, D. M.; Matthews I.; Bye, M. R. J . Chem Soc.,
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4-Br om o-2-ch lor op h en ol:31 mp 49-50 °C (lit.30 mp 48-49
°C); 1H NMR 5.51 (s, 1H), 6.91 (d, J ) 8.7, 1H), 7.29 (dd, J )
8.7, 2.3, 1H), 7.47 (d, J ) 2.3, 1H); MS 210, 208, 206 (M+, 22,
100, 78).
(27) The bromination of 4-hydroxybenzonitrile with NBS/CF3SO3H
was performed at a 200 g scale (entry 1a).
(28) Geratz, J . D.; Whitmore, A. C.; Cheng, M. C.-F.; Piantadosi, C.
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