Preparation of 3-bromo-L-tyrosine and 3,5-dibromo-L-tyrosine
O
Furthermore, no chromatography is necessary to isolate the
product, and the isolated yield of 4 after crystallization of
the crude product from water is about 65 %. Small amounts
of contaminating 5 in the product are easily removed by
recrystallization at pH 6, taking advantage of the lower
pI for the dibrominated product. On the other hand, reac-
tion with 2.2 equiv. of DMSO under identical conditions
provides a good isolated yield (53 %) of 5 (Scheme 2),
which can be easily separated from any residual contami-
nating 4 by recrystallization from water at pH 5. The
excess of HBr presumably acts to protect the a-amino
group from oxidation by formation of the salt. The future
extension of this approach to tyrosine derivatives such as
L-Dopa or L-tyrosinol may be possible, since the amount of
oxidant can be easily controlled by the limited addition of
DMSO, and catechol is cleanly brominated in glacial acetic
acid with Br2 to give 4,5-dibromocatechol (Kohn 1951).
The mechanism of bromination under these conditions
has been proposed to involve the formation of bro-
modimethylsulfonium bromide by the reaction of DMSO
with 2 mol of HBr (Eq. 1) (Majetich et al. 1997). The
resulting bromodimethylsulfonium cation serves as the
selective source of Br? for the aromatic bromination, thus
allowing for the preparation of 4 in good yield. Further-
more, this reaction uses economical reagents, and avoids
the health and environmental hazards associated with the
use of Br2 for the preparation of 5. The extension of this
procedure to preparation of chloro and iodotyrosines can
be envisioned. However, Majetich et al. (1997) found
chlorination with HCl/DMSO to be much less effective,
and iodination with HI/DMSO fails completely. This is
likely due to different redox properties of the halogens. In
the case of chlorine, the equilibrium lies toward the side
of HCl, while for iodine, the iodosulfonium iodide
undergoes competing decomposition to elemental iodine.
Only for bromine is the bromosulfonium reagent rela-
tively stable.
O
HBr, 1.2 eq. DMSO Br
OH
OH
OH
NH2
CH3CO2H
NH2
HO
HO
O
O
Br
HBr, 2.2 eq. DMSO
CH3CO2H
OH
NH2
HO
NH2
HO
Br
Scheme 2 Bromination of L-tyrosine with HBr/DMSO
the yield of 4 was only 29 % after chromatography
(Yokoyama et al. 2006). The best procedure published to
date for selective monobromination of L-tyrosine uses a
relatively dilute solution (9 g L-tyrosine/2.15 L water) to
reduce the likelihood of dibromination, reacting with a
mixture of KBrO3 and KBr in 0.5 M HCl (Sano et al.
1986), and resulting in 88 % yield. However, product iso-
lation with this method requires inconvenient evaporation of
a large volume of water, followed by chromatography.
A recent paper described a procedure for selective mono-
bromination of N-acetyltyrosine with N-bromosuccinimide
in acetonitrile in the presence of p-toluenesulfonic acid
(Bovonsombat et al. 2008). However, these authors did not
report hydrolysis of the resultant N-acetyl-3-bromo-L-tyrosine
to give the free amino acid. None of these published proce-
dures lend themselves readily to the convenient production of
multigram-scale quantities of 4. Hence, we decided to apply
the mild and selective HBr/DMSO brominating system
(Majetich et al. 1997) to the problem of 4 and 5 synthesis.
To our delight, we found that L-tyrosine can indeed be
selectively monobrominated with aqueous HBr in glacial
acetic acid using 1.2 equiv. of DMSO, as shown in
Scheme 2. We made some modifications of the published
conditions in order to optimize yields. Under the standard
conditions in the paper (Majetich et al. 1997) (large excess
ð1Þ
of DMSO, room temperature) the reaction gave mixtures of
unreacted tyrosine, 4, and 5. Limiting the amount of
DMSO to a slight stoichiometric excess and raising the
temperature at the beginning of the reaction resulted in
nearly complete conversion of tyrosine to the desired mono
or dibromo product. This reaction is not performed at high
dilution (5 g L-tyrosine in 50 mL AcOH), so it is unnec-
essary to evaporate large volumes of solvent in the workup.
In conclusion, the bromination of L-tyrosine by HBr/
DMSO in glacial acetic acid provides a convenient and
practical method for the synthesis of either 3-bromo-L-
tyrosine (4) or 3,5-dibromo-L-tyrosine (5), by simply
changing the L-tyrosine/DMSO molar ratio. The prod-
uct is isolated simply by crystallization of the crude
product from water, without any need for time-con-
suming and inefficient chromatography. This process is
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