A facile debromination reaction: Can bromide now be used as a protective group in aromatic systems? [3]

Full text of DOI:10.1021/ja0164374

9202
J. Am. Chem. Soc. 2001, 123, 9202-9203
A Facile Debromination Reaction: Can Bromide
Now Be Used as a Protective Group in Aromatic
Systems?
Scheme 1
Han Young Choi and Dae Yoon Chi*
Department of Chemistry, Inha UniVersity
53 Yonghyundong Namgu, Inchon 402-751, Korea
2
ReceiVed June 17, 2001
ReVised Manuscript ReceiVed August 2, 2001
Bromine as an aromatic substituent is very useful as a site for
further substitution, using palladium-catalyzed and other aromatic
substitution strategies. However, because the replacement of an
aromatic bromine by hydrogen generally requires rather harsh
ionic, catalytic, or radical reduction conditions, this group is
generally not considered useful as a protecting group. During a
recent study of quinoline-5,8-dione chemistry,1 we have en-
countered a facile debromination reaction of an olefinic bromide
Scheme 2
Scheme 3
,2
(
shown in Scheme 1), that led to the investigations described
herein, through which we have developed useful methods by
which bromine can be used as a protective group in aromatic
systems.
In our first experience with this debromination process (Scheme
1
), we thought that the HBr, produced during the amination of
Table 1. Debrominations of 2,4-Diamino-3,5-dibromotoluene in
Various Reaction Conditions
dibromoquinaldine-5,8-dione, might be playing an important role
in the debromination process. In fact, when the debromination
of 6-bromo-7-piperidinoquinaldine-5,8-dione was tested in the
presence of concentrated HBr in dioxane (Scheme 2), we were
able to obtain the debrominated product in 85% yield, under
optimized conditions. When we tested the debromination reaction
of 2,4-dibromoaniline with concentrated HBr in refluxing acetic
acid for 4 h, disproportionation products (2,4,6-tribromoaniline,
yield (%)e
scavengerc
1
2
5.2%; 2,4,6-tribromoacetanilide, 0.6%; 2,4-dibromoaniline, 59.6%;
,4-dibromoacetanilide, 1.5%; 2,6-dibromoaniline, 0.6%; 4-bro-
entry solvent reagenta timeb
(equiv)
6d
7
8
9
total
moaniline, 17.9%; 2-bromoaniline, 2.2%) were isolated.
We have found only a few reports on these kinds of isomer-
1
2
3
4
5
6
7
8
9
MeOH
EtOH
AcOH
HBr
AcOH
AcOH
AcOH
AcOH
AcOH
HBr
HBr
HBr
HBr
HBr
HBr
HBr
HCl
HI
50 min
50 min
50 min
50 min
50 min
4 h
10 min
10 min
10 min
A (11)
A (11)
A (11)
A (11)
A (11)
A (11)
A (11)
A (11)
A (11)
A (11)
B (11)
0
54 40
55 27 16
0
94
98
95
98
97
95
87
100
0
0
0
0
izations and disproportionations of bromophenol, anisol,4
3
,4
47
22
0
0
48
76
3
95
28
0
0
0
70
4
5
aniline, and pyrrole systems in the literature. The process of
arene bromination and debromination is reversible, but typically,
bromination predominates over debromination to a very great
extent (Scheme 3). Questions that are key in assessing the potential
utility of reversing this bromination-debromination equilibrium
are: (1) is it possible to shift the equilibrium toward debromi-
nation by using a scavenger of bromine? and (2) if this reversal
can be achieved, can bromide then be used as a protecting group
in aromatic systems?
62 22 10
0
0
100
0
100
0
0
59
0
0
0
0
0
0
0
0
0
10 EtOH
11 AcOH
NaBr 30 min
HBr 4 h
100
70
0
a
b
Concentrated acid used except in entries 5 (dry HBr) and 10. At
reflux. c A ) Na , B ) aniline. d Recovered. e Isolated yield.
2 3
SO
To investigate the first issue, we tested the debromination of
the much more activated 2,4-diamino-3,5-dibromotoluene, using
either sodium sulfite, aniline, or phenol as a scavenger of bromine
result of these investigations, we selected concentrated HBr/AcOH
as a solvent and sodium sulfite as a scavenger for reducing
bromine to bromide.
(
Table 1). Under optimized conditions, one of the bromines was
removed within 10 min and the other bromine within 4 h (entry
). Debromination proceeded more rapidly with higher boiling
Regarding the potential of using aromatic bromine as a
protecting group, it is worth noting that generally aromatic
bromide is converted back to hydrogen by various reducing agents
6
and more strongly acidic solvents, but debromination was slower
with anhydrous HBr than with concentrated HBr (entries 1-5).
The debromination reaction did not proceed at all in concentrated
HCl (entry 8) or under a neutral condition (entry 10), and only
side products were obtained in concentrated HI (entry 9). As a
such as metal hydride6 or catalytic hydrogenation etc., and that
-8
9
these reductions have the following selectivities: (1) no selectivity
between bromide and NO , COOH, and other halogen,
2
2) I > Br > Cl,
arenes,
7
a,b,8a,9a-c
7b-e,8b-d,9a,d,e,10a,b
(
(3) X in EWG-arenes > EDG-
7b,c,f,10a,b
(4) o-X > p-X.7b,c,f,10a,b
(
1) Choi, H. Y.; Lee, B. S.; Chi, D. Y.; Kim, D. J. Heterocycles 1998, 48,
647-2652.
2) Yoon, E. Y.; Choi, H. Y.; Shin, K. J.; Yoo, K. H.; Chi, D. Y.; Kim, D.
2
(
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1
0.1021/ja0164374 CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/22/2001

Communications to the Editor
J. Am. Chem. Soc., Vol. 123, No. 37, 2001 9203
Scheme 4
Scheme 6
Scheme 5
selective processes for the preparation of ortho- or para-substituted
aromatic compounds are of great interest in organic chemistry.
However, there is always a chance of getting an isomeric mixture
of ortho- or para-substituted products. To avoid this intrinsic
problem, protective groups such as sulfonic acid and carboxylic
acid are typically used, thus allowing a substituted compound in
the desired position to be obtained after desulfonylation or
decarboxylation.11
We tried to apply our bromine protecting-reductive debro-
mination deprotecting approach to the synthesis of some com-
pounds which are normally considered difficult to prepare. As
shown in Scheme 6, we found that 2,6-dichloroaniline, which is
generally prepared from an aminocarboxylic acid by dichlorination
We investigated the substituent selectivities of debromination
in some compounds, and the results, shown in Scheme 4, illustrate
one of the most attractive aspects of HBr as a reducing agent:
by our method, we can remove bromine without affecting other
reducible groups, such as the nitro group or chloride. To the best
of our knowledge, this has not been reported before.
Scheme 5 shows another attractive aspect of HBr as a reducing
agent: in a highly brominated aniline, only the o,p-bromines were
selectively reduced; the bromine that was meta with respect to
the electron-donating group was unaffected. To our knowledge,
such a regioselective debromination has not been achieved. The
10
followed by decarboxylation, could be readily prepared by
substituent-selective debromination. In a second example, 5-hy-
droxyquinaldine was prepared from protected dibromohydroxy-
aniline with bromine using a Skraup reaction, followed by
deprotection of bromine with HBr. Since the Skraup reaction of
3-hydroxyaniline with crotonaldehyde produces 7-hydroxyquinal-
dine as the major product along with 5-hydroxyquinaldine as the
minor one, it has not been easy to prepare 5-hydroxyquinaldine.
In the last example, 3-bromoaniline, which cannot be prepared
directly from aniline, was prepared by regioselective debromi-
nation from p-dibromobenzene.
In conclusion, although this acid-catalyzed, bromine-scavenging
debromination requires a high temperature and a stability of
compounds toward HBr, it should prove to be very useful. The
method is inexpensive, easy to handle, selective against another
reducible groups, and regioselective (with o,p-debromination
proceeding in preference to m-bromination with electron-donating
systems). It is hoped that this work, which demonstrates that the
bromination-debromination equilibrium can be shifted toward
debromination using a scavenger of bromine, will lead to the
greater use of bromine as a protecting group in aromatic systems
and will facilitate the preparation of many aromatic systems.
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Acknowledgment. This work was supported by Korea Research
Foundation Grant (KRF-2000-015- DP0274), and we thank Professor John
A. Katzenellenbogen for helpful discussions.
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