Regioselective one-pot bromination of aromatic amines

Article abstract of DOI:10.1021/ol0259600

(Matrix Presented) Treatment of aniline with n-butyllithium and then trimethyltin chloride gave the tin amide (PhNH-SnMe₃) in situ. Without isolation of the tin amide reaction with bromine and workup with aqueous fluoride ion gave p-bromoaniline in 76% yield, with no dibromoaniline or o-bromoaniline. Application of this sequence to 11 different aromatic amines gave selective bromination in 36-91% yields, without formation of dibromides. This constitutes a good general method for the regioselective bromination of aromatic amines.

Full text of DOI:10.1021/ol0259600

ORGANIC
LETTERS
2002
Vol. 4, No. 14
2321-2323
Regioselective One-Pot Bromination of
Aromatic Amines1
,†
,‡
Michael B. Smith,* Lisa (Chen) Guo,†,2 Sherrad Okeyo,3 Jason Stenzel,*
James Yanella,‡ and Eric LaChapelle†,4
Departments of Chemistry, UniVersity of Connecticut, 55 North EagleVille Road,
Storrs, Connecticut 06269-3060, and Southern Connecticut State UniVersity,
501 Crescent Street, North HaVen, Connecticut 06515-1355
smith@nucleus.chem.uconn.edu
Received April 2, 2002
ABSTRACT
Treatment of aniline with n-butyllithium and then trimethyltin chloride gave the tin amide (PhNH-SnMe3) in situ. Without isolation of the tin
amide, reaction with bromine and workup with aqueous fluoride ion gave p-bromoaniline in 76% yield, with no dibromoaniline or o-bromoaniline.
Application of this sequence to 11 different aromatic amines gave selective bromination in 36−91% yields, without formation of dibromides.
This constitutes a good general method for the regioselective bromination of aromatic amines.
Electrophilic aromatic bromination is one of the older
reactions known to organic chemists. Aryl halides are
important synthetic intermediates for a variety of transforma-
tions that range from formation of functionalized aromatic
compounds to aryl organometallic reagents that are used in
other reactions. Despite the many halogenation methods that
are available, activated aromatic compounds such as aniline
derivatives remain a problem. Mixtures of ortho and para
products and polybromination are problems that limit the
synthetic utility of many procedures. There are a handful of
selective bromination procedures, and we now report another
that gives good yields of p-bromoaniline. The reaction is
rather general in scope, and many monobrominated aromatic
amines can be formed in good yield with high selectivity.
Tin amides such as 1 are known, formed by treating an
amine with a strong base such as LDA, followed by addition
of a trialkyltin halide (R3SnCl). We became interested in
these compounds as putative amino transfer agents in
palladium-catalyzed coupling reactions but found that they
also react with elemental bromine to give N-bromoamines
(2), as shown in Scheme 1. When diisopropylamine was
Scheme 1
† University of Connecticut.
‡ Southern Connecticut State University.
(1) Presented, in part, at the 221st National Meeting of the American
Chemical Society, May 4, 2001, San Diego, CA. Guo, C.; LaChapelle, E.;
Smith, M. B.; Stenzel, J.; Yanella, J. ORGN 492.
(2) Current address: Pfizer Central Research, Groton, CT.
(3) A National Science Foundation REU student, 2000.
(4) Pfizer PREPARE Summer Scholar, 2000-2001.
treated with butyllithium (ether, -78 °C) and then trimeth-
yltin chloride, i-Pr2N-SnMe3 was formed in situ. Simple
titration with elemental bromine at -78 °C gave 2 (R )
i-Pr). We obtained a 45% isolated yield of 2. N-Bromoamines
10.1021/ol0259600 CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/11/2002

are known compounds but are rather unstable upon isolation.
Although we prepared several different bromoamines 2, the
isolated yields were lower than those reported with other
procedures. This process was not amenable to making large
amounts, possibly as a result of residual tin compounds that
promoted decomposition. Although we knew that N-bromo-
aniline was reported to be an unstable compound, we
explored the possibility of generating this compound in situ
for possible use. We therefore treated aniline with n-butyl-
lithium and added trimethyltin chloride in ether, also at -78
°C. We presumably generated the tin amide in situ, and
addition of bromine at -78 °C followed by warming at
workup with aqueous KF to remove tin residues led to a
76% yield of p-bromoaniline, with no detectable o-bromo
or dibromo compounds. Although the aromatic bromination
is not surprising in itself, the selectivity of the reaction was
notable.
Table 1. Selective Bromination of Aromatic Amines via Tin
Amides
Examining the literature revealed several previous methods
for selective bromination of aniline. Tetrabutylammonium
6
tribromide,5 DBUH‚Br3 cetyltrimethylammonium tribro-
mide,7 and pyridinium bromide perbromide8 have been
reported as mild brominating agents. Aniline reacted with
tetrabutylammonium tribromide, for example, to give an 82%
yield of 3, along with some dibrominated products. However,
acetanilide and pyridine did not react with this reagent.9 This
contrasts with pyridinium bromide perbromide, which bro-
minated pyridine, aniline, and its derivatives, although
reaction with aniline gave a 19:68 ratio of o- to p-
bromoaniline.10 A recent study used LiBr/ceric ammonium
nitrate as a brominating agent, converting N,N-dimethyl-
aniline to a 2:3 mixture of o- and p-bromo derivatives in
70% yield.11 Majetich and co-workers, who showed that
aniline reacted with HBr/DMSO to give a 76% yield of 3
after 6 h, in a remarkably selective reaction, reported one of
the most useful methods.12
We were pleased to find that conversion of aniline to the
corresponding tin amide, followed by directed bromination,
led to good yields of monobrominated product, 4-bromo-
aniline,13 with excellent selectivity (entry 1 in Table 1). We
were interested in expanding this reaction to other aromatic
amines, with the hope that monobrominated products could
be obtained. Our results are presented in Table 1, and it is
clear that this technique is both general and selective.
We examined the reactivity of both 4-methylaniline and
2-methylaniline. 2-Methylaniline (entry 3) reacted much like
aniline, giving a 73% yield of 4-bromo-2-methylaniline.14
We were particularly interested in the reaction of 4-methyl-
aniline (entry 2), in which bromination was forced to the
ortho position or there would be no reaction. Although a
30% yield of 2-bromo-4-methylaniline15 was obtained, it is
clear that reactivity is greatly diminished. We have not clearly
determined the source of this para selectivity. Two possibili-
ties are a steric effect or an electronic effect of the N-Sn
unit. If the brominating agent were coordinated to the tin,
one might expect delivery of bromine to the ortho position.
This was not observed. We also observed that 2-methyl-
aniline reacted rapidly to give the 4-bromo product but
4-methylaniline reacted sluggishly to give a poor yield of
the 2-bromo derivative. These results are consistent with a
steric effect that inhibits delivery to the ortho position but
do not prove it. Another report involves coordination of
aniline to a metal, in which aniline was converted to the
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Org. Lett., Vol. 4, No. 14, 2002

N-magnesium compound (PhNHMgBr), and upon reaction
with oxygen, p-bromoaniline was obtained.16 It was sug-
gested that Br+ was formed in situ, but no o-bromoaniline
was reported. The authors did not comment on the selectivity,
and we believe that bromination of the tin amides proceeds
by a different mechanism.
carbazole with N-bromosuccinimide has been reported, but
with only modest selectivity for monobromination.24
We were also interested in the scope of this halogenation
reaction. When iodine replaced bromine in the sequence,
shown in Scheme 2 using aniline as the starting material,
The bromination of aminonaphthalenes shows that the
steric argument may be too simplistic. While 2-aminonaph-
thalene (entry 8) gave a 91% yield of 1-bromo-2-amino-
naphthalene,17 1-aminonaphthalene (entry 7) gave only a 40%
yield of 4-bromo-1-aminonaphthalene.18 Although the “para”
position is blocked in entry 8, there are two ortho positions,
with bromination at C1 favored. Although ortho attack is
forced, the reaction proceeds in excellent yield in contrast
to that of 4-methylaniline (entry 2). 1-Aminonaphthalene has
an open para position, but the reaction is very sluggish and
gives a poor yield of product. Without additional work,
including internal competition experiments, we cannot further
speculate on a mechanism.
Scheme 2
we obtained a 45-50% yield of 4-iodoaniline, 4.25 Although
the reaction was selective, showing no 2-iodoaniline or
diiodination products, the yield was poor. In addition, we
found that iodine (or iodide) attacked the methyl group
attached to tin, producing iodomethane. This was confirmed
when we used tri-n-butyltin chloride to form the tin amide.
Subsequent reaction with iodine led to 4 as well as a good
yield of iodobutane. We did not attempt the reaction with
chorine gas.
We have discovered a remarkably selective bromination
technique that works well for a variety of aromatic amines,
including substituted aniline derivatives. Although there are
four distinct steps, including the aqueous fluoride workup,
it is a one-pot reaction. The tin byproducts are easily removed
and separable from the brominated products by using the
fluoride ion workup, making this an excellent synthetic route
to monobrominated aromatic amines.
The bromination proceeded normally when there were
substituents on nitrogen. N-Methylaniline gave an 83% yield
of 4-bromo-N-methylaniline.19 Acetanilide gave a 58% yield
of the 4-bromo derivative,14b without formation of other
isomers.
Attempts to extend this methodology to other useful
aromatic systems were successful. The tin amide vehicle for
bromination showed great selectivity for the reaction of
indole, 3-aminoquinoline, carbazole, and 2-aminopyrazole.
In all cases, the bromination gave a single product in good
yield. Indole (entry 10) gave an 80% yield of 3-bromo-
indole,20 and 3-aminoquinoline (entry 9) gave 2-bromo-3-
aminoquinoline21 but in only 36% yield. Presumably, this is
due to the difficulty inherent to electrophilic substitution on
a pyridine ring. Carbazole (entry 11) gave a 69% yield of
4-bromocarbazole,22 and 2-aminopyrazole (entry 6) gave an
88% yield of 4-bromo-1-aminopyrazole.23 Bromination of
Acknowledgment. We thank the National Science Foun-
dation REU program for providing support to Mr. Okeyo in
2000. We also thank Pfizer Central Research for providing
a Pfizer PREPARE summer scholarship to Mr. LaChapelle
in 2000 and 2001.
Supporting Information Available: Experimental pro-
cedures and characterization data for new compounds
prepared. This material is available free of charge via the
Internet at http://pubs.acs.org.
(16) Newman, M. S.; MacDowell, D.; Swaminathan, S. J. Org. Chem.
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OL0259600
(19) Ando, W.; Tsumaki, H. Synthesis 1982, 263-264.
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Kno¨chel, A.; Koch, K. U.; Kopf, J.; Merlzer, D.; Rudolph, G. J. Am. Chem.
Soc. 1983, 105, 6568-6577. (b) Yasuhara, A.; Kasano, A.; Sakamoto, T.
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1995, 25, 2401-2406.
(22) Paudler, W. W.; Jovanovic, M. V. J. Org. Chem. 1983, 48, 1064-
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