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Y.-Q. WU ET AL.
monobromination and regioselectivity can be challenging, especially for highly activated
aromatic substrates, such as phenol and its derivatives.
Many selective monobromination reagents have been reported, including pyridinium
tribromide,[1–3] tetrabutylammonium tribromide,[4] tetrapropylammonium nonabro-
mide,[5] 1-butyl-3-methylimidazolium tribromide,[6] f[K.18-Crown-6]Br3gn,[7] dioxane
dibromide,[8] hexamethylenetetramine-bromine complex,[9] a DABCO-derived bromine
complex,[10] N,N,N0,N0-tetrabromobenzene-1,3-disulfonylamide,[11] ammonium bromide
and oxone,[12] and a ZrBr4/diazene mixture.[13] However, these reagents are expensive
or difficult to use.
N-Bromosuccinimide (NBS) is a readily available, cheap reagent that provides a pre-
cise stoichiometric amount of the bromonium ion and allows easy reaction handling
because the by-product, succinimide, is soluble in water. Several selective monobromi-
nation methods using NBS have been developed. Typical examples are NBS/
HBF4ꢁEt2O,[14] NBS/silica gel,[15,16] NBS/HZSM-5,[17] NBS/NaOH,[18] NBS/p-toluenesul-
fonic acid,[19] NBS/NH4OAc,[20] NBS/Amberlyst-15,[21] NBS/thioamide,[22] NBS/ionic
liquid,[23] NBS/CF3COOH/H2SO4,[24] NBS/UV irradiation,[25] and solvent-controlled
regioselective bromination using NBS.[26] However, these methods still use reagents that
are expensive, not commercially available, or corrosive acids, and the scope of substrates
in some reactions is restricted. Thus, the development of a selective monobromination
method using cheap, commercially available and environmentally friendly reagents is
still required.
5-Bromo-4-fluoro-2-hydroxybenzoic acid (1a) has become an important starting
material for us to construct a small molecule library for biological screening. However,
1a is not readily available on a large scale and is expensive as well. This prompted us to
develop a facile method to synthesize 5-bromo-4-fluoro-2-hydroxybenzoic acid.
According to a literature method,[27] we prepared 1a from 4-fluoro-2-hydroxybenzoic
acid (1) in DMF using NBS (Scheme 1A). However, in contrast to the literature, a
nearly equal mixture of 1a and dibrominated product 1b was obtained, and the mixture
was difficult to be separated. The amount of 1b could not be decreased, even at the
reaction temperatures of ꢂ40 and ꢂ70 ꢃC. The dibrominated compound 2b was the
major product when methyl 4-fluoro-2-hydroxybenzoate (2) was used as the starting
material in DMF (Scheme 1B). To decrease the amount of dibrominated product, we
increased the steric hindrance at the ortho hydroxyl group in 3, but the bromination
reaction did not occur (Scheme 1C).
The combination of NBS/H2SO4 had been used for the monobromination of highly
deactivated aromatic compounds under harsh reaction condition (conc. H2SO4 as a
solvent, 60 ꢃC).[28] Thomas Oberhauser also reported the synthesis of 3-bromo-4-
hydroxybenzonitrile using H2SO4 and NBS in CH3CN, however, the selectivity was only
71% and the reaction time was long up to 24 h.[14] Based on these results, we tried to
use NBS and H2SO4 in CH3CN to prepare 1a. To our delight, the desired monobromi-
nated product was obtained in excellent yield (Scheme 1D). In consideration of the lim-
ited research of NBS and H2SO4 as the regioselective monobromination reagents, in the
present work, we further investigate the application of the combination of NBS/H2SO4
in the regioselective monobromination of salicylic acid derivatives and other
phenol analogs.