Acid-Mediated Halogen Exchange in Heterocyclic Arenes: A Highly Effective Iodination Method

Article abstract of DOI:10.1055/s-2003-41405

Heterocyclic arenes including pyridyl, quinolyl, and isoquinolyl chlorides have been converted to their corresponding iodides in good to high yields via acid-mediated nucleophilic halogen exchange with sodium iodide. This procedure avoids the use of transition metals, harsh reaction conditions, and affords highly regioselective halide exchange. Chloride substituents in position 2 and 4 of pyridines and quinolines are readily substituted by iodide in 75-91% and conversion of 1-chloroisoquinoline to its iodide derivative was found to proceed with 90% yield. Positions that are not activated for nucleophilic aromatic substitution proved to be inert to halide exchange. Regioselective chloride/iodide exchange in 4,7-dichloroquinoline hydrochloride gave 7-chloro-4-iodoquinoline, an important precursor of anti-malaria drugs, in almost 90% yield.

Full text of DOI:10.1055/s-2003-41405

LETTER
1801
Acid-Mediated Halogen Exchange in Heterocyclic Arenes: A Highly Effective
Iodination Method
A
C
cid-Mediated
H
h
alogenExch
r
ange in
i
s
yclic
A
re
t
nes ian Wolf,* Gilbert E. Tumambac, Cristina N. Villalobos
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
E-mail: cw27@georgetown.edu
Received 30 July 2003
Common strategies for the synthesis of aryl iodides are
limited to metal-promoted halide exchange or electro-
Abstract: Heterocyclic arenes including pyridyl, quinolyl, and iso-
quinolyl chlorides have been converted to their corresponding
iodides in good to high yields via acid-mediated nucleophilic halo-
philic aromatic substitution reactions using iodonium
4
gen exchange with sodium iodide. This procedure avoids the use of salts. Recently, Buchwald et al. reported high yields for
transition metals, harsh reaction conditions, and affords highly the 1,2-diamine-accelerated copper-catalyzed conversion
5
regioselective halide exchange. Chloride substituents in position 2
of aryl bromides to aryl iodides. This elegant approach is
and 4 of pyridines and quinolines are readily substituted by iodide
in 75–91% and conversion of 1-chloroisoquinoline to its iodide
derivative was found to proceed with 90% yield. Positions that
are not activated for nucleophilic aromatic substitution proved
to be inert to halide exchange. Regioselective chloride/iodide ex-
6
also applicable to the formation of aryl cyanides. Howev-
er, it is limited to aryl bromides as starting materials and
requires the use of a transition metal catalyst. Schlosser et
al. introduced iodotrimethylsilane for the preparation of
change in 4,7-dichloroquinoline hydrochloride gave 7-chloro-4- heterocyclic aryl iodides from their corresponding chlo-
7
iodoquinoline, an important precursor of anti-malaria drugs, in rides. A drawback of this silyl-mediated transformation
almost 90% yield.
is that corrosive chlorotrimethylsilane is formed as a
Key words: chloride/iodide exchange, aryl iodides, nucleophilic volatile by-product reducing the applicability of this
aromatic substitution, cross-coupling reactions.
approach to industrial scale synthesis. Furthermore, low
yields were obtained with chloropyridines, which in the
case of 4-chloropyridine was attributed to decomposition
Aryl iodides are frequently used starting materials for a under the reaction conditions employed.
variety of organic transformations. Through metal/halide
exchange the iodide can easily be reductively replaced or
transformed to a nucleophilic Grignard or organolithium
reagent for reaction with a suitable electrophile. Further-
more, aryl iodides are excellent starting materials for
transition metal catalyzed Suzuki, Negishi, Hiyama,
Because heterocyclic aryl iodides derived from pyridine8
or quinoline exhibit key pharmacophores and important
9
intermediates for the synthesis of biologically active com-
pounds, we decided to investigate a convenient, metal-
free venue toward heterocyclic iodides from their readily
available and stable chloride derivatives. We assumed that
protonated chloropyridines or chloroquinolines might be
susceptible to nucleophilic substitution by sodium iodide.
Initial attempts to convert 4-chloroquinoline (1) in the
presence of glacial acetic acid into 4-iodoquinoline (2)
using various solvents including dichloromethane, aceto-
nitrile or DMF were not successful. We were pleased to
find that formation of the hydrochloride salt of 1 followed
by treatment with NaI in acetonitrile provides hetero-
cyclic aryl iodide 2 in 91% yield, see Figure 1.
1
Kumada, Stille, and Heck reactions. Unlike aryl chlo-
rides, iodides are usually quite expensive or not commer-
cially available. This can partly be attributed to the
reduced stability and shelf life of aryl iodides. The low
availability of aryl iodides also stems from the lack of ef-
fective methods for their preparation, which is an impor-
tant limitation to some of the reactions mentioned above.
Accordingly, highly active transition metal complexes
that catalyze aryl-aryl coupling reactions utilizing readily
available but less reactive chlorides have been devel-
2
oped. The remaining problem is that some of these cata-
Cl
I
lysts are expensive and need to be prepared prior to use.
In addition to their synthetic use, aryl iodides play an
important role in radiopharmaceutical chemistry. Radio-
1
. 4M HCl in Et2O
91 %
2. 10eq. NaI, ACN,
o
N
80 C, 24h
N
1
2
1
25
active I-labeled arenes have been employed in radio-
immunoassay and nuclear imaging studies.3 The
Scheme 1 Acid-mediated halogen exchange using 4-chloro-
quinoline (1)
development of effective methods for the synthesis of aryl
iodides thus continues to be highly desirable.
Further studies proved that our procedure is applicable to
a variety of heterocyclic aryl chlorides, Table 1. As one
would expect for a nucleophilic aromatic substitution
reaction, unactivated chlorides are not replaced under
the mild reaction conditions employed. Thus, commer-
cially available 4,7-dichloroquinoline (3) was converted
SYNLETT 2003, No. 12, pp 1801–1804
Advanced online publication: 28.08.2003
DOI: 10.1055/s-2003-41405; Art ID: S06103st.pdf
2
9
.0
9
.2
0
0
3
10
©
Georg Thieme Verlag Stuttgart · New York

1
802
C. Wolf et al.
LETTER
to 7-chloro-4-iodoquinoline (4) in 88% yield, entry 2. consequence of decomposition of the iodopyridines as
7
This is most remarkable because 4 is a versatile starting was previously described by others. It should be noticed
material for the synthesis of 4-substituted 7-chloroquino- that iodides 4, 12, and 14 are not accessible in high
lines and can not be prepared via silyl-mediated halide ex- yields via previously developed halide exchange methods.
7
change. The synthesis of anti-malaria drugs, in particular As expected, our procedure also allows conversion of
chloroquine derivatives exhibiting a 7-chloroquinoline 1-chloro-isoquinoline (15) to its iodo derivative 16 in
moiety, has received considerable attention because of the 90% yield, entry 8.
1
1
global rise of resistant malarial parasites. The facile syn-
thesis of 4 via acid-mediated halide exchange from inex-
pensive 3 is thus believed to be very useful for future drug
development efforts. We observed that introduction of
alkyl groups into position 2 of 4-chloroquinoline results
in slightly reduced yields which may be attributed to
reduced reactivity of 4-chloro-2-methylquinoline (5) and
In summary, we have developed a convenient method for
the preparation of heterocyclic aryl iodides from their
corresponding chlorides. Various pyridyl, quinolyl and
isoquinolyl iodides have been prepared in good to high
yields. In contrast to common chloride/iodide exchange
reactions, our procedure avoids harsh conditions, the use
of transition metals, and polar solvents such as DMF or
HMPA that might constitute a waste disposal problem on
an industrial scale. Chloride substituents in position 2 and
4
-chloro-2-isopropylquinoline (7) toward nucleophilic
1
2
aromatic substitution, entries 3 and 4. We obtained
-iodo-2-methylquinoline (6) and 4-iodo-2-isopropyl-
quinoline (8) in 80% and 84% yield, respectively, whereas
-phenyl-4-iodoquinolines (10) was obtained in 90%
4
4
of the heterocyclic aryls are readily replaced, whereas
chlorides in non-activated positions proved to be inert.
We believe that our acid-mediated chloride/iodide
exchange procedure will prove helpful for a variety of
organic transformations of electron-deficient heterocyclic
aryls such as Stille and Suzuki reactions which are well
known to afford better yields with aryl iodides than with
chlorides.
2
yield from its chloride derivative 9, entry 5.
Table 1 Acid-Mediated Halogen Exchange in Electron-Deficient
Heterocyclic Aryl Halides
Entry Aryl halide
Product
Yield (%)
91
Cl
I
1
All chemicals were purchased from Aldrich or Acros and used
without further purification. All reactions were carried out under
anhydrous conditions. Products were purified by flash chromato-
1
2
N
N
2
3
4
5
6
Cl
I
88
80
84
90
84
graphy on SiO (Merck Kieselgel 60, particle size 0.032–0.063
2
1
mm). NMR spectra were obtained at 300 MHz ( H NMR) and 75
MHz ( C NMR) on a Varian FT-NMR spectrometer using CDCl
3
4
13
3
Cl
N
Cl
N
as the solvent. Chemical shifts are reported in ppm relative to TMS.
GC-MS was performed using a Fison Instruments MD800 capillary
GC-Mass spectrometer using a 15 m DB-1 column. Elemental
analysis data were collected using a Perkin Elmer 2400 CHN.
Cl
I
5
6
N
Me
N
I
Me
Cl
General Halide Exchange Procedure
To a solution of 1.0 g heterocyclic aryl chloride in 10 mL THF was
added 2 mL 4 M HCl in 1,4-dioxane. After 5 min, the solvent was
removed and the precipitate dried under reduced pressure. The
hydrochloride salt and 4.0 g NaI previously dried at 120 °C under
vacuum were suspended 30 mL anhyd MeCN and refluxed for 24 h.
After cooling to r.t., an aq solution of 10% K CO and 5% NaHSO
7
8
N
i-Pr
N
I
i-Pr
Cl
9
10
2
3
3
(10 mL) was added and the mixture was extracted with CH Cl . The
N
Ph
N
Ph
2 2
combined organic layers were dried over MgSO and the solvents
Cl
N
I
4
were evaporated under reduced pressure. The residue was purified
by chromatography on silica gel using hexanes:EtOAc:Et N
11
12
3
(100:10:1) as the mobile phase if not stated otherwise.
N
7
8
75
90
4
-Iodoquinoline (2)13
1
3
14
Chromatography purification of the residue gave a colorless oil (1.4
g, 91%).
N
Cl
Cl
N
I
15
16
N
N
7
-Chloro-4-iodoquinoline (4)
Purification by flash chromatography using hexanes:EtOAc (5:1)
afforded white crystals (1.3 g, 88%).
I
1
H NMR: d = 7.42 (dd, J = 1.8 Hz, J = 9.1 Hz, 1 H), 7.81 (d,
One would expect that electron-deficient 2- and 4-chloro-
J = 9.1 Hz, 1 H), 7.84 (d, J = 4.6 Hz, 1 H), 7.92 (d, J = 1.8 Hz, 1 H)
pyridine (11, 13) are more reactive than chloroquinolines. 8.32 (d, 7.84, J = 4.6 Hz, 1 H).
However, the corresponding iodopyridines 12 and 14
were obtained in lower yields, i.e. 84% and 75%, entries
13
C NMR: d = 111.7, 129.0, 129.1, 129.2, 132.9, 133.3, 136.6,
48.2, 150.8.
1
6
and 7. We assume that the reduced yields are a
Synlett 2003, No. 12, 1801–1804 © Thieme Stuttgart · New York

LETTER
Acid-Mediated Halogen Exchange in Heterocyclic Arenes
1803
+
+
EI-MS (70 eV): m/z (%) = 289 (100) [M ], 162 (94) [M – I], 127
W. H.; Guram, A. S. J. Org. Chem. 1999, 64, 6797.
+
+
(
70) [M – I, Cl], 99 (73) [M – I, – Cl, – C H ].
(k) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L.
J. Am. Chem. Soc. 1999, 121, 9550. (l) Huang, J.; Nolan, S.
P. J. Am. Chem. Soc. 1999, 121, 9889. (m) Bohm, V. P. W.;
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A. S.; Zim, D.; Ebeling, G.; Monteiro, A. L.; Dupont, J. Org.
Lett. 2000, 1287. (o) Morales-Morales, D.; Redon, R.;
Yung, C.; Jensen, C. M. Chem. Commun. 2000, 1619.
2
4
Anal. Calcd for C H ClIN: C, 37.34; H, 1.74; N, 4.84. Found: C,
9
5
3
7.62; H, 1.88; N, 4.68.
4
-Iodo-2-methylquinoline (6)
Chromatography purification of the residue using hexanes:
EtOAc:Et N (100:20:1) as the mobile phase gave a white solid
3
(
p) Bohm, V. P. W.; Weskamp, T.; Gstottmayr, C. W. K.;
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(1.2 g, 80%).
1
H NMR: d = 2.70 (s, 3 H), 7.56 (ddd, J = 1.4 Hz, J = 6.9 Hz,
J = 8.2 Hz, 1 H), 7.71 (ddd, J = 1.4 Hz, J = 6.9 Hz, J = 8.4 Hz, 1 H),
.91 (s, 1 H), 7.94 (dd, J = 1.4 Hz, J = 8.4 Hz, 1 H), 7.97 (dd,
(
1
7
Soc. 2000, 122, 4020. (s) Zapf, A.; Ehrentraut, A.; Beller,
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Chem. Commun. 2002, 2610.
J = 1.4 Hz, J = 8.2 Hz, 1 H).
1
3
C NMR: d = 24.6, 112.1, 127.1, 128.4, 129.1, 130.3, 131.32,
1
33.3, 147.3, 158.6.
+
+
EI-MS (70 eV): m/z (%) = 269 (100) [M ], 142 (93) [M – I], 127
+
(
33) [M – I, – Me].
Anal. Calcd for C H IN: C, 44.64; H, 3.00; N, 5.21. Found: C,
1
0
8
4
4.98; H, 2.78; N, 5.09.
4
-Iodo-2-isopropylquinoline (8)
Purification by flash chromatography afforded a yellow oil (1.1 g,
8
4%).
(3) Seevers, R. H.; Counsell, R. E. Chem Rev. 1982, 82, 575.
(4) (a) Meyer, G.; Rollin, Y.; Perichon, J. Tetrahedron Lett.
1
H NMR: d = 1.39 (d, J = 6.9 Hz, 6 H), 3.19 (sept, J = 6.9 Hz, 1 H),
1986, 27, 3497. (b) Yang, S. H.; Li, C. S.; Cheng, C. H. J.
7
.55 (ddd, J = 1.4 Hz, J = 6.9 Hz, J = 8.3 Hz, 1 H), 7.70 (ddd,
Org. Chem. 1987, 52, 691. (c) Bozell, J. J.; Vogt, C. E. J.
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J = 1.4 Hz, J = 6.9 Hz, J = 8.3 Hz, 1 H), 7.95–7.98 (m, 2 H).
1
3
C NMR: d = 22.5, 36.8, 112.2, 127.1, 128.8, 129.5, 130.1, 130.9,
30.9, 131.3, 147.4, 167.3.
1
+
+
EI-MS (70 eV): m/z (%) = 297 (21) [M ], 282 (60) [M – Me], 170
+
+
+
(
3) [M – I], 155 (20) [M – I, – Me], 127 (18) [M – I, – i-Pr].
(
(
5) Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
Anal. Calcd for C H IN: C, 48.51; H, 4.07; N, 4.71. Found: C,
4
12
12
1
4844.
6) Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc.
003, 125, 2890.
8.91; H, 3.91; N, 4.64.
2
4
-Iodo-2-phenylquinoline (10)13
(
(
7) Schlosser, M.; Cottet, F. Eur. J. Org. Chem. 2002, 4181.
8) (a) Couve-Bonnaire, S.; Carpentier, J.-F.; Castanet, Y.;
Mortreux, A. Tetrahedron Lett. 1999, 40, 3717. (b) Koseki,
Y.; Omino, K.; Anzai, S.; Nagasaka, T. Tetrahedron Lett.
Purification by flash chromatography using hexanes:CH Cl :Et N
2
2
3
(100:50:1) as the mobile phase afforded a yellow oil (1.24 g, 90%).
4
-Iodopyridine (12)13
2
2
000, 41, 2377. (c) Song, J. J.; Yee, N. K. J. Org. Chem.
001, 66, 605. (d) Couve-Bonnaire, S.; Carpentier, J.-F.;
Flash chromatography gave brown crystals (1.5 g, 84%).
Mortreux, A.; Castanet, Y. Tetrahedron Lett. 2001, 42,
2
-Iodopyridine (14)13
3689. (e) Mello, J. V.; Finney, N. S. Org. Lett. 2001, 3,
After purification by chromatography, a red oil was obtained (1.4 g,
7
4263. (f) Hanrahan, J. R.; Mewett, K. N.; Chebib, M.;
5%).
Burden, P. M.; Johnston, G. A. R. J. Chem. Soc., Perkin
Trans. 1 2001, 2389. (g) Bach, T.; Heuser, S. Synlett 2002,
1
-Iodoisoquinoline (16)13
2089. (h) Yue, W. S.; Li, J. J. Org. Lett. 2002, 4, 2201.
Flash chromatography using CH Cl :hexanes:Et N (100:25:2) as
the mobile phase afforded a yellow solid (1.5 g, 90%).
2
2
3
(
i) Mongin, F.; Trecourt, F.; Gervais, B.; Mongin, O.;
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355. (k) Schlosser, M.; Bobbio, C. Eur. J. Org. Chem.
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1
804
C. Wolf et al.
LETTER
(
(
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2
Synlett 2003, No. 12, 1801–1804 © Thieme Stuttgart · New York