Dehalogenation and barbier-type hydroxyalkylation of π-deficient haloheterocycles using indium

Article abstract of DOI:10.3987/COM-08-S(F)95

The reaction of π-deficient haloheterocycles with indium metal in water gave corresponding dehalogenated heterocycles. The use of diluted hydrochloric acid instead of water accelerated the reductive reactivity of indium metal. Furthermore, Barbier-type additions proceeded by reactions of α-iodoheterocycles with indium in the presence of pivalaldehyde.

Full text of DOI:10.3987/COM-08-S(F)95

HETEROCYCLES, Vol. 77, No. 2, 2009
1163
HETEROCYCLES, Vol. 77, No. 2, 2009, pp. 1163 – 1170. © The Japan Institute of Heterocyclic Chemistry
Received, 4th August, 2008, Accepted, 18th September, 2008, Published online, 22nd September, 2008
DOI: 10.3987/COM-08-S(F)95
DEHALOGENATION AND BARBIER-TYPE HYDROXYALKYLATION
OF π-DEFICIENT HALOHETEROCYCLES USING INDIUM
Eri Fukuda, Yukiko Takahashi, Natsumi Hirasawa, Osamu Sugimoto,* and
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
osamu@smail.u-shizuoka-ken.ac.jp; tanji@smail.u-shizuoka-ken.ac.jp
Abstract – The reaction of π-deficient haloheterocycles with indium metal in
water gave corresponding dehalogenated heterocycles. The use of diluted
hydrochloric acid instead of water accelerated the reductive reactivity of indium
metal. Furthermore, Barbier-type additions proceeded by reactions of
α-iodoheterocycles with indium in the presence of pivalaldehyde.
Indium (In, atomic number 49) is one of various rare metals discovered by Reich and Richter in 1863.
Recently, indium has been widely used in organic syntheses. For example, organic halides react with
1
2
acetylenes, or carbonyl compounds, in the presence of indium to create corresponding carbon-carbon
bonded products. Iodoalkanes or iodobenzenes are converted into bialkyls or biphenyls by reactions with
3
,4
indium in dry DMF. It has been reported that nitrogen-containing heterocycles, e. g. quinolines,
isoquinolines, quinoxalines, and indoles are reduced by indium in aqueous ethanolic ammonium chloride
5
in order to create dihydro- or tetrahydroheterocycles. To our knowledge, however, the study of
haloheterocycles as a substrate which uses indium has not been mentioned except in a sole report of the
5
conversion of 2-chloroquinoline into 1,2,3,4-tetrahydroquinoline using indium. Here we report the
6
deiodination of nitrogen-containing π-deficient haloheterocycles.
Pitts et al. have reported that the reaction of 2-chloroquinoline with excess indium in aqueous ethanolic
ammonium chloride under refluxing for several days creates 1,2,3,4-tetrahydroquinoline with a 79%
5
yield. In this reaction, it has been speculated that the substrate, 2-chloroquinoline is dechlorinated to
afford quinoline, which is further reduced to give 1,2,3,4-tetrahydroquinoline because quinoline is
converted into 1,2,3,4-tetrahydroquinoline under the same condition. So we planned a selective
dehalogenation of haloheterocycles using indium metal.
th
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75 birthday.

1164
HETEROCYCLES, Vol. 77, No. 2, 2009
Table 1. The reaction of 2-haloquinolines with indium under several conditions
In, solvent, reflux
N
X
N
N
H
1
2
(
X = I, Br, Cl )
hydrolysis
N
O
H
3
Indium
Time
(h)
48
24
2.5
2
Yields (%)
Entry
Solvent
X
(
eq)
10
1
1
2
3
Recovery
Trace
1
2
3
4
5
6
7
8
9
aq. NH
aq. NH
aq. NH
4
Cl
4
Cl
4
Cl
I
I
8
73
84
64
70
84
57
91
83
91
92
92
83
81
68
88
51
60
69
66
75
75
67
66
I
1
H
H
H
H
H
2
2
2
2
2
O
I
10
10
1
O
O
O
O
I
48
1
Trace
I
33
7
I
1
2
I
1
3
6
H O
2
I
1
5
2
1
0
H
H
H
H
2
O
2
O
2
O
2
O
I
1
11.5
5
4
11
I
2
4
12
13
14
15
16
17
18
19
20
21
22
23
I
2
10
10
2
3
I
3
6
Br
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
1
15
3
H
H
H
H
2
O
2
O
2
O
2
O
1
5
1
2
39
15
1
5
0.5 N HCl
0.25 N HCl
0.5 N HCl
0.5 N HCl
1 N HCl
1
5
21
3
2
2
3
4
1
12
2
5
2
2
10
17
5
2
2
Trace
0.5 N HCl
3
2.5
10
Initially, reactions of 2-haloquinolines with indium under several conditions were performed as shown in
Table 1. A mixture of 2-iodoquinoline and indium powder (10 eq) in aqueous ammonium chloride was
heated to reflux for 48 h and produced 1,2,3,4-tetrahydroquinoline (2) with a 73% yield and quinoline (1)
with an 8% yield (entry 1). These results are identical to the results reported by Pitts et al. Conversely and

HETEROCYCLES, Vol. 77, No. 2, 2009
1165
interestingly, a selective deiodination proceeded to create 1 under mild conditions such as the use of a
stoichiometric amount of indium (entries 2,3), or the use of water as a solvent instead of aqueous
ammonium chloride (entries 4,5). Next, the deiodination of 2-iodoquinoline in water was performed with
various amounts of indium and the reaction times. It was discovered that 2-iodoquinoline was
successfully deiodinated to create 1 with the use of a stoichiometric amount of indium in water for 2 h
(
entry 7). Dehalogenation of 2-bromoquinoline and 2-chloroquinoline was performed (entries 14,15) in
order to discover the different reactivities with 2-iodoquinoline. Although both 2-bromoquinoline and
2
2
-chloroquinoline were dehalogenated to create 1, it was made clear that 2-bromoquinoline and
-chloroquinoline are less reactive compared to 2-iodoquinoline, and more drastic conditions would be
required to dehalogenate successfully. Subsequently, the dechlorination of 2-chloroquinoline using
indium in diluted hydrochloric acid was performed (entries 16-21) because it is known that the reactivity
of indium is accelerated in acidic solvent. As shown in entries 18 and 19, 2-chloroquinoline was smoothly
dechlorinated with 2 eq of indium in 0.5 N hydriodic acid and refluxing for 2-5 h to produce a 75% yield
of quinoline.
Table 2 shows the dehalogenation of some haloheterocycles using indium. Water or 0.5 N hydrochloric
acid was used as solvents to compare the effects on dehalogenation reactivity. In many cases, the use of
0
.5 N hydrochloric acid as a solvent accelerated the dehalogenation of halopyridines and haloquinolines.
Especially, chloroquinolines such as N,N-diethyl 2-chloroquinoline-4-carboxamide (entries 7,8) and
-chloroquinoline (entries 12,13), were dechlorinated smoothly, using 0.5 N hydrochloric acid to produce
4
corresponding dechlorinated products. It should be noted that a reaction of 7-chloro-4-iodoquinoline with
indium preceded deiodination at the 4-position of the quinoline ring selectively and dechlorination at the
7
-position did not proceed (entries 15,16). This result indicates that ring nitrogen of the quinoline ring
affects the reactivity of dehalogenation using indium. Deiodination of iododiazines,
4
0
-iodo-1-phenyl-1H-pyrazolo[3,4-d]pyrimidine (entries 17,18) and 2-iodoquinoxaline (entries 19,20), in
.5 N hydrochloric acid did not produce any corresponding deiodinated compounds whereas deiodination
in water created products in 30% and 44%, respectively. It was found that aqueous hydrochloric acid is
not suitable for indium mediated deiodination of iododiazines because diazines tend to dimerize under
acidic conditions.
Plausible mechanisms for the dehalogenation of haloheterocycles using indium were shown in Scheme 1.
Pitts et al. have reported that quinoline derivatives are reduced to give 1,2,3,4-tetrahydroquinolines under
drastic conditions, using excess indium in aqueous ammonium chloride for several days.

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HETEROCYCLES, Vol. 77, No. 2, 2009
Table 2. Dehalogenation of various haloheterocycles using indium metal
In, solvent, reflux
Het-X
Indium
Het-H
Product
(Het-H)
CO H
Substrate
Het-X)
CO H
Time
(h)
Yields (%)
Entry
Solvent
(
(eq)
1
Het-H Recovery
1
2
3
4
2
H
2
O
5
2
2
60
80
64
2
1
2
0.5 N HCl
I
N
N
N
CO Et
CO Et
2
H O
2
10
2
2
1
0.5 N HCl
8
I
N
I
5
6
1
2
H O
10
10
49
53
20
24
2
0.5 N HCl
N
NEt2
N
NEt2
CONEt2
CONEt2
7
8
1
2
H
2
O
2
2
24
55
55
0.5 N HCl
N
Cl
N
CONEt2
CONEt2
9
1
H
H
2
O
O
2
91
N
I
N
I
1
0
1
2
2
8
52
80
36
19
11
0.5 N HCl
5.5
N
N
Cl
1
2
3
1
2
H
2
O
5
2
60
86
1
0.5 N HCl
N
N
N
N
I
1
4
1
H
H
2
O
O
5
69
N
I
1
1
5
6
1
2
2
15
2
59
55
16
0.5 N HCl
Cl
Cl
N
I
1
1
7
8
1
2
H O
2
2
N
N
30
0
9
2
N
N
N
N
N
N
Ph
0.5 N HCl
Ph
1
2
9
0
N
1
2
H
2
O
2
2
N
N
56
0
14
0.5 N HCl
N
I
1
. Nicotinic acid was obtained

HETEROCYCLES, Vol. 77, No. 2, 2009
1167
There was also speculation that a single electron transfer would proceed from indium to the
carbon-nitrogen bond of the quinoline ring. Thus we have speculated that the dehalogenation would
proceed through a similar mechanism, that is, a single electron transfer from indium to the
carbon-nitrogen bond.
Scheme 1. Plausible mechanisms for dehalogenation of haloheterocycles
-
-
e , H O
e , H O
2
2
- HI
.
N
X
N
I
N
H
I
N
H
α-haloheterocycles
X
I
I
.
-
-
e , H O
e , H O
- HI
2
2
N
N
H
N
H
N
γ-haloheterocycles
.
.
X
I
I
I
-
-
e , H O
e , H O
2
2
-
HI
N
N
N
N
N
H
β-haloheterocycles
7
-9
Since π-deficient heterocycles are less reactive with electrophiles, lithiation are frequently used to
introduce electrophiles into π-deficient heterocycles. However, metalation of π-deficient heterocycles
usually requires low temperature to avoid some side reactions. Through the examination of this study, we
planned the novel introduction of electrophiles into π-deficient heterocycles via a reaction of
iodoheterocycles with carbonyl compounds in the presence of indium without protonic solvents such as
water. Table 3 shows the reaction of iodopyridines and iodoquinolines with indium in the presence of
pivalaldehyde. The reaction of 2-iodoquinoline with indium in the presence of pivalaldehyde under
refluxing created the corresponding adduct, 2,2-dimethyl-1-(2-quinolinyl)-1-propanol in moderate yields
as well as the deiodinated product, quinoline (entries 1-5). 2-Iodopyridine was also converted to
2
,2-dimethyl-1-(2-pyridinyl)-1-propanol using a similar method (entries 6-12). Interestingly, a
Barbier-type hydroxyalkylation was facilitated using α-iodoheterocycles (entries 13,14). It is evident that
more studies using various kinds of iodoheterocycles are necessary in order to clarify the potentiality and
limitation of this reaction.
In conclusion, we have found a novel method of the deiodination of π-deficient haloheterocycles using
indium in water to create corresponding dehalogenated heterocycles. The use of diluted hydrochloric acid
instead of water accelerated the reductive reactivity of indium. Barbier-type coupling reactions were
preceded by the reaction of α-iodoheterocycles with indium in the presence of pivalaldehyde.

1168
HETEROCYCLES, Vol. 77, No. 2, 2009
Table 3. The reaction of iodopyridines and iodoquinolines with indium in the presence of pivalaldehyde
In, tBuCHO (excess)
I
CH(OH)tBu
+
7
5 °C (solvent-free)
N
N
N
Substrate
Product
In
eq)
1
Time
(h)
18
3
Yields (%)
Entry
Substrate
Product
(
Product
47
Quinoline Recovery
42
1
2
3
4
5
6
7
8
9
4
33
23
37
36
43
30
4
6
59
N
I
N
CH(OH)tBu
4
24
30
4.5
8
51
4
46
2
7
45
14
2
23
3
8
38
18
3
24
66.5
8
41
Trace
Trace
33
N
N
I
I
N
N
CH(OH)tBu
1
0
3
27
11
4
29
1
2
4
24
56
CH(OH)tBu
1
3
1
1
18
18
2
0
9
I
CH(OH)tBu
1
4
76
N
N
EXPERIMENTAL
1
All melting points were not corrected. H-NMR spectra was measured with Hitachi R-90H spectrometer
(
90 MHz) using tetramethylsilane as an internal standard.
The dehalogenation of haloheterocycles using In in aqueous media (General procedure 1) : A mixture of
In, haloheterocycles, and solvent was heated to reflux. The reaction mixture was alkalinized with 1 N
NaOH and extracted with EtOAc. The organic layer was dried over Na
column chromatography to give the corresponding product.
2
SO
4
and treated with silica gel
1
1
1
,2,3,4-Tetrahydroquinoline : Eluted with hexane - EtOAc (2:1). Yellow liquids. H-NMR (CDCl
3
), δ :
3
4
2
.72-2.13 (2H, m, C -H), 2.60-2.91 (2H, m, C -H), 3.15-3.47 (2H, m, C -H), 3.70 (1H, brs, NH),

HETEROCYCLES, Vol. 77, No. 2, 2009
1169
6
8
5
7
6
.32-6.72 (2H, m, C and C -H), 6.78-7.11 (2H, m, C and C -H).
1
Quinoline : Eluted with hexane - EtOAc (2:1). Yellow oil. H-NMR (CDCl
3
), δ : 7.38 (1H, dd, J = 8.3 Hz,
3
5
6
7
4
8
4
.2 Hz, C -H), 7.45-7.90 (3H, m, C , C , and C -H), 8.13 (2H, d, J = 8.3 Hz, C and C -H), 8.90 (1H, dd, J
2
=
4.2 Hz, 1.4 Hz, C -H).
1
0
2
1
(1H)-Quinolinone : Eluted with EtOAc-EtOH (20:1). White solids. Mp 199.5-200.5 °C (lit.,
1
3
6
96-197 °C). H-NMR (CDCl
3
), δ : 6.72 (1H, d, J = 9.5 Hz, C -H), 7.02-7.32 (1H, m, C -H), 7.32-7.68
5
7
8
4
(
3H, m, C , C , and C -H), 7.81 (1H, d, J = 9.5 Hz, C -H), 12.50 (1H, brs, NH).
11
Nicotinic acid : Eluted with EtOAc-EtOH (4:1). Yellow solids. Mp 237.7-239.1 °C (lit., 236-239 °C).
1
5
4
6
H-NMR (DMSO-d ), δ : 7.50 (1H, dd, J = 7.6 Hz, 4.7 Hz, C -H), 8.25 (1H, d, J = 7.6 Hz, C -H), 8.74
6
2
(
1H, d, J = 4.7 Hz, C -H), 9.08 (1H, s, C -H).
1
Ethyl nicotinate : Eluted with hexane - EtOAc (1:1). Pale yellow liquids. H-NMR (CDCl ), δ : 1.41 (3H,
3
5
t, J = 7.1 Hz, CH
3
), 4.42 (2H, q, J = 7.1 Hz, CH
2
), 7.38 (1H, dd, J = 7.9 Hz, 4.8 Hz, C -H), 8.29 (1H, dt, J
4
6
2
=
7.9 Hz, 1.7 Hz, C -H), 8.76 (1H, dd, J = 4.8 Hz, 1.7 Hz, C -H), 9.22 (1H, d, J = 1.7 Hz, C -H).
1
2
1
3
-Diethylaminopyridine : Eluted with hexane - EtOAc (15:1). Slight violet liquids. H-NMR (CDCl ), δ :
3
5
.18 (6H, t, J=7.0 Hz, CH
3
x 2), 3.51 (4H, q, J=7.0 Hz, CH
2
x 2), 6.32-6.57 (2H, m, C and C -H), 7.38
4
6
(
1H, td, J=7.8 Hz, 1.9 Hz, C -H), 8.13 (1H, dd, J=5.5 Hz, 1.9 Hz, C -H).
1
N,N-Diethyl-4-quinolinecarboxamide : Eluted with EtOAc. White oil. H-NMR (CDCl
3
), δ : 1.02 (3H, t, J
=
7.1 Hz, CH
3
), 1.38 (3H, t, J = 7.1 Hz, CH
3
), 3.09 (2H, q, J = 7.1 Hz, CH
2
), 3.43-3.95 (2H, m, CH
2
), 7.29
3
5
6
7
8
(
1H, d, J = 4.4 Hz, C -H), 7.41-7.90 (3H, m, C , C , and C -H), 8.14 (1H, dd, J = 8.4 Hz, 1.5 Hz, C -H),
2
8
7
.94 (1H, d, J = 4.4 Hz, C -H).
1
3
-Chloroquinoline : Eluted with hexane - EtOAc (2:1). Yellow liquids. H-NMR (CDCl ), δ : 7.25-7.60
3
6
5
4
8
(
2H, m, C and C -H), 7.74 (1H, d, J = 8.8 Hz, C -H), 7.95-8.24 (2H, m, C and C -H), 8.90 (1H, dd, J =
2
4
1
7
8
.2 Hz, 1.6 Hz, C -H).
-Phenyl-1H-pyrazolo[3,4-d]pyrimidine : Eluted with hexane - EtOAc (2:1). Pale yellow solids. Mp
1
2
1
5-79 °C (lit., 80 °C). H-NMR (CDCl
3
), δ : 7.25-7.70 (3H, m, phenyl-H), 8.08-8.38 (2H, m, phenyl-H),
3
6
4
.32 (1H, s, C -H), 9.12 (1H, s, C -H), 9.26 (1H, s, C -H).
13
1
Quinoxaline : Eluted with hexane - EtOAc (2:1). Brown needles. Mp 28.5 °C (lit., 29-30 °C). H-NMR
5
8
6
7
2
3
(
3
CDCl ), δ : 7.66-7.91 (2H, m, C and C -H), 7.91-8.22 (2H, m, C and C -H), 8.85 (2H, s, C and C -H).
The reaction of iodoheterocycles with In in the presence of pivalaldehyde (General procedure 2) : A
mixture of iodoheterocycles, In, and excess pivalaldehyde was heated to reflux. The reaction mixture was
diluted with EtOAc, and insoluble solids were filtered off. After the filtrate was diluted with water, the
mixture was neutralized with 1 N NaOH and extracted with EtOAc. The organic layer was dried over
Na SO and treated with silica gel column chromatography to give the corresponding product.
2
4

1170
HETEROCYCLES, Vol. 77, No. 2, 2009
2
7
,2-Dimethyl-1-(2-quinolinyl)-1-propanol : Eluted with hexane - EtOAc (5:1). Pale yellow solids. Mp
1
2
1
t
3
0-72 °C (lit., 73-75 °C). H-NMR (CDCl ), δ : 0.98 (9H, s, Bu), 4.50 (1H, brs, CH), 4.52-4.85 (1H, br,
3
6
5
7
OH), 7.32 (1H, d, J = 8.6 Hz, C -H), 7.38-7.66 (1H, m, C -H), 7.66-7.90 (2H, m, C and C -H), 8.08 (2H,
4
8
d, J = 8.6 Hz, C and C -H).
2
5
7
3
,2-Dimethyl-1-(2-pyridinyl)-1-propanol : Eluted with hexane - EtOAc (1:1). Pale yellow solids. Mp
1
t
3
5
3
3-57 °C. H-NMR (CDCl ), δ : 0.92 (9H, s, Bu), 4.32 (2H, brs, CHOH), 7.06-7.35 (2H, m, C and C -H),
4
6
.61 (1H, ddd, J = 7.5 Hz, 7.5 Hz, 1.8 Hz, C -H), 8.57 (1H, dd, J = 5.0 Hz, 1.8 Hz, C -H).
1
-Pivaloylpyridine : Eluted with hexane - EtOAc (5:1). Pale yellow liquids. H-NMR (CDCl
3
), δ : 1.36
t
5
(
9H, s, Bu), 7.35 (1H, ddd, J = 8.1Hz, 5.2 Hz, 0.5 Hz, C -H), 8.00 (1H, ddd, J = 7.9 Hz, 2.0 Hz, 2.0 Hz,
4
6
2
+
C -H), 8.69 (1H, dd, J = 5.8 Hz, 1.5 Hz, C -H), 8.97 (1H, d, J = 1.8 Hz, C -H). MS 163 (M ).
1
2
0
,2-Dimethyl-1-(3-pyridinyl)-1-propanol : Eluted with EtOAc. Pale yellow liquids. H-NMR (CDCl
3
), δ :
t
5
.93 (9H, s, Bu), 4.42 (1H, s, CH), 7.24 (1H, dd, J = 7.8 Hz, 4.7 Hz, C -H), 7.69 (1H, d, J = 10.0 Hz,
4
2
6
+
C -H), 8.38-8.63 (2H, m, C and C -H). MS 165 (M ).
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