Indium-mediated dehalogenation of haloheteroaromatics in water

Article abstract of DOI:10.1016/j.tetlet.2007.12.116

It turned out that indium metal was applicable to the dehalogenation of aromatic halides in water. This method is facile and safe compared with the conventional methods such as Pd-C, Raney Ni, or halogen-metal exchange.

Full text of DOI:10.1016/j.tetlet.2007.12.116

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1492–1494
Indium-mediated dehalogenation of haloheteroaromatics in water
Natsumi Hirasawa, Yukiko Takahashi, Eri Fukuda, Osamu Sugimoto *, Ken-ichi Tanji *
Laboratory of Organic Chemistry, School of Food and Nutritional Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Received 30 October 2007; revised 13 December 2007; accepted 21 December 2007
Available online 25 December 2007
Abstract
It turned out that indium metal was applicable to the dehalogenation of aromatic halides in water. This method is facile and safe
compared with the conventional methods such as Pd–C, Raney Ni, or halogen–metal exchange.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Indium; Dehalogenation; Heteroaromatics
Table 1
In recent years, indium derivatives have been increas-
Reaction of 2-haloquinolines with indium under several conditions
ingly recognized as an important reagent in organic synthe-
sis. It is known that the reaction of aromatic halides with
indium derivatives afford functionalized aromatic com-
In, Solvent, reflux
N
X
pounds by several methods such as a cross-coupling reac-
tion with triorganoindium compounds,1–3 introduction of
alkenyl4,5 or alkyl6 group by hydroindation, indium-medi-
ated radical cyclization,7 palladium/indium/indium (III)
chloride-mediated cross-coupling reaction,8 and reductive
homocoupling reaction.9,10 This time we directed our atten-
tion to the reductive ability of indium. In this Letter, we
report the novel indium-mediated dehalogenation of aro-
matic halides using water as a cheap and safe solvent.
At first, the reaction of 2-haloquinolines with indium
using various kinds of solvents was carried out as shown
in Table 1. Interestingly, deiodination proceeded to afford
the deiodinated product, quinoline, in 91% yield using
water as a solvent (entry 4) whereas 2-iodoquinoline was
recovered quantitatively when organic solvents such as eth-
anol, dioxane, or toluene were used (entries 1–3). Both 2-
bromoquinoline and 2-chloroquinoline reacted with
indium to give quinoline in 68% and 51% yields, respec-
tively (entries 5 and 6). It was found that the reactivity of
N
Entry Solvent
X
In (equiv) Time (h)
Yields (%)
Product Recovery
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
a
Ethanol
Dioxane
Toluene
H2O
H2O
H2O
H2O
H2O
H2O
H2O
I
I
I
I
Br
Cl
I
I
I
I
I
I
I
I
I
I
I
1
1
2
2
0
0
0
95
98
95
7
15
39
33
6
3
0
4
3
1
2
1
2
91
68
51
57
83
91
92
92
83
81
70
84
64
84
8a
1
2
1
2
1
1
1
3
1
5
1
2
10
5
H2O
H2O
H2O
H2O
2
3
10
10
1
10
10
2
48
2.5
6
Trace
0
H2O
aq NH4Cl
aq NH4Cl
aq NH4Cl
0
0
0
1
10
24
48
I
1,2,3,4-Tetrahydroquinoline (73%) was obtained.
*
Corresponding authors.
bromo and chloro compounds was inferior to that of iodo
compounds.
E-mail addresses: osamu@smail.u-shizuoka-ken.ac.jp (O. Sugimoto),
tanji@smail.u-shizuoka-ken.ac.jp (K. Tanji).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.116

N. Hirasawa et al. / Tetrahedron Letters 49 (2008) 1492–1494
1493
Table 2
Next, deiodination of 2-iodoquinoline under a variety of
Deiodination of haloheteroaromatics using indium metal in water
amount of indium and reaction time was carried out to
optimize the condition (entries 7–18). It was clarified that
the use of equimolecular amounts of indium for 2 h or
above suffice for deiodination of 2-iodoquinoline. It is
reported by Pitts et al.11 that the reaction of quinoline with
9 equiv of indium in aq NH4Cl and ethanol under reflux
gave 1,2,3,4-tetrahydroquinoline in 52% yield. It should
be noted that the reaction of 2-iodoquinoline with 10 equiv
of indium in water under reflux for 48 h afforded quinoline
in 84% yield (entry 15), whereas similar reaction using
water as a solvent instead of aq NH4Cl gave 1,2,3,4-
tetrahydroquinoline in 73% yield (entry 18). From these
results, it was found that the use of water as a solvent in
the reaction is effective against the deiodination of
2-iodoquinoline.
The typical procedure is shown as follows: a mixture of
indium powder (À100 mesh, 99.99%, Aldrich), 2-iodoquin-
oline, and water was heated under reflux for 2 h. After the
reaction mixture was neutralized with 1 N NaOH, the mix-
ture was extracted with ethyl acetate and the organic layer
was dried over sodium sulfate. After ethyl acetate was
removed under reduced pressure, the residue was treated
with silica gel column chromatography (eluted with hex-
ane–ethyl acetate (2:1)) to give quinoline in 91% yield.
Slight yellow liquids. 1H NMR (90 MHz, in CDCl3): d
7.38 (1H, dd, J = 8.3 Hz, 4.2 Hz, C3–H), 7.45–7.90 (3H,
m, C5, C6, and C7–H), 8.13 (1H, d, J = 8.3 Hz, C4 and
C8–H), 8.90 (1H, dd, J = 4.2 Hz, 1.4 Hz, C2–H).
Reaction of some iodoheteroaromatics with indium in
water was carried out to clarify the generality of the deio-
dination (Table 2). All substrates were deiodinated to
afford the corresponding products in high to moderate
yields. It is noteworthy that the chloro group substituted
at the 7-position of quinoline ring was inert to indium
(entry 7), whereas the reaction of 2-chloroquinoline with
indium gave the corresponding dechlorinated product,
quinoline as shown in Table 1. Some of the substrates were
recovered when b-iodoheteroaromatics, 2-diethylamino-5-
iodopyridine (entry 3), or 3-iodoquinoline (entry 5) was
used as a substrate.
Speculated mechanisms of deiodination of iodoquino-
lines are shown in Scheme 1. When a- or c-iodoquinoline
is used as a substrate, the dihydroquinoline radical gener-
ates smoothly since the radical is stabilized by iodine atom.
On the other hand, b-iodoquinoline reacts with indium in
water more slowly than a- or c-iodoquinoline because the
dihydroquinoline radical is not stabilized by iodine atom.
Deiodination of iodobenzene using InCl3 and Et3SiH is
the sole report6 for the indium-mediated dehalogenation of
halobenzenes. So the In–H2O system was applied to the
deiodination of iodobenzene derivatives as shown in Table
3. When ethyl 4-iodobenzoate, 4-iodoaniline, and 3-iodo-
aniline were used as substrates, 24%, 19%, and 0% of the
product were obtained, and 63%, 54%, and 38% of the sub-
strates were recovered, respectively. From these results, it
was found that iodobenzenes are less reactive to indium
In (1 eq), H2O
Het-I
Het-H
reflux
Entry Substrate (Het-I)
Time (h)
Yields (%)
Product (Het-H) Recovery
CO2H
1
2
5
57
64
0
0
I
N
N
CO2Et
10
I
I
3
4
10
49
91
20
N
NEt2
CONEt2
2
0
N
I
I
5
6
8
5
52
69
36
0
N
I
N
I
I
7
8
9
15
59
30
44
0
9
0
Cl
N
N
N
2
N
Ph
N
N
N
5.5
I
compared with iodoheteroaromatics such as 2-
iodoquinoline.
In conclusion, deiodination of iodoheteroaromatics
using indium in water was accomplished. Removal of hal-
ogen from an aromatic ring is an important technique in
organic synthesis. Several methods are known and widely
used, however, some of these methods are troublesome to
execute. For example, a metal catalyst, Pd–C12,13 or Raney
Ni14 ignites easily. Halogen–metal exchange reaction15,16
requires a dehydrated condition and low reaction tempera-

1494
N. Hirasawa et al. / Tetrahedron Letters 49 (2008) 1492–1494
α-(2-)Iodoquinoline
e-, H2O
e-, H2O
- HI
.
(fast)
N
I
N
N
H
I
N
H
I
(stable)
γ-(4-)Iodoquinoline
I
I
I
.
e-, H2O
(fast)
e-, H2O
- HI
N
H
N
N
N
H
(stable)
β-(3-)Iodoquinoline : less reactive with In than α -or γ -Iodoquinolines
.
.
I
I
I
I
e-, H2O
e-, H2O
- HI
(slow)
N
N
H
N
N
N
Scheme 1. Speculated mechanisms of dehalogenation of haloquinolines using indium in water.
4. Takami, K.; Yorimitsu, H.; Oshima, K. Org. Lett. 2002, 4, 2993–
2995.
5. Wang, C.; Yan, L.; Zheng, Z.; Yang, D.; Pan, Y. Tetrahedron 2006,
62, 7712–7717.
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Table 3
Deiodination of iodobenzene derivatives
R
R
In, H2O
I
reflux
Entry
R
In (equiv)
Time (h)
Yields (%)
8. Lee, P. H.; Seomoon, D.; Lee, K.; Kim, S.; Kim, H.; Kim, H.; Shim,
E.; Lee, M.; Lee, S.; Kim, M.; Sridhar, M. Adv. Synth. Catal. 2004,
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9558.
Product
Recovery
1
2
3
4-CO2Et
4-NH2
3-NH2
3
1
2
24
6
8
24
19
0
63
54
38
10. Chang, Y. M.; Lee, S. H.; Cho, M. Y.; Yoo, B. W.; Rhee, H. J.; Lee,
S. H.; Yoon, C. M. Synth. Commun. 2005, 35, 1851–1857.
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Trans. 1 2001, 955–977.
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ture. Thus, the development of a facile method for the
dehalogenation of heteroaromatic halide is of great value.
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