Preparation of ethyl 5-iodo-1H-indole-2-carboxylate

Article abstract of DOI:10.1081/SCC-120021830

A facile, two step procedure for the preparation of ethyl 5-iodo-1H-indole-2-carboxylate (1) from commercially available ethyl 1H-indole-2-carboxylate is described herein, employing a regioselective C3, C5-bisiodination followed by zinc-mediated C3-dehalogenation.

Full text of DOI:10.1081/SCC-120021830

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Preparation of Ethyl 5-Iodo-1H-indole- 2-carboxylate
a
a
Douglas C. Beshore & Christopher J. Dinsmore
a
Merck Research Laboratories, Department of Medicinal Chemistry , West Point,
Pennsylvania, USA
Published online: 20 Aug 2006.
To cite this article: Douglas C. Beshore & Christopher J. Dinsmore (2003) Preparation of Ethyl 5-Iodo-1H-indole- 2-
carboxylate, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
33:14, 2423-2427, DOI: 10.1081/SCC-120021830
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 14, pp. 2423–2427, 2003
Preparation of Ethyl 5-Iodo-1H-indole-
2-carboxylate
Douglas C. Beshore* and Christopher J. Dinsmore
Merck Research Laboratories, Department of
Medicinal Chemistry, West Point, Pennsylvania, USA
ABSTRACT
A facile, two step procedure for the preparation of ethyl 5-iodo-
1H-indole-2-carboxylate (1) from commercially available ethyl 1H-
indole-2-carboxylate is described herein, employing a regioselective
C3, C5-bisiodination followed by zinc-mediated C3-dehalogenation.
Key Words: Indole; Regioselective halogenation; Dehalogenation.
*
Correspondence: Douglas C. Beshore, Research Chemist, Merck Research
Laboratories, Department of Medicinal Chemistry, Sumneytown Pike, West
Point, PA 19486, USA; Fax: (215) 652-7310; E-mail: douglas_beshore@ merck.
com.
2
423
DOI: 10.1081/SCC-120021830
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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424
Beshore and Dinsmore
In the course of a recent drug discovery program, we required access
to 5-substituted indole-2-carboxylic acids or esters. While several are
commercially available, our requirementsfor wide ts ructural diver ist y
led usto engage 5-halo derivativesin metal-catalyzed cro ss coupling
reactions. While ethyl 5-bromo-1H-indole-2-carboxylate isavailable, we
were surprised to discover that a synthesis of the more reactive and
versatile 5-iodo-1H-indole-2-carboxylate (1) wasa be ns t from the
[1]
literature. We have therefore devised a simple, direct route to 1 from
commercially available ethyl 1H-indole-2-carboxylate (Sch. 1).
Iodination of indolesisknown to proceed regio es lectively at
C3
[
2]
under relatively mild conditions. However, further halogenation of
the benzo portion of the indole moiety hasoften re us lted in mixtures
of halogenation products, which vary depending on the reaction condi-
[
3]
tionsemployed.
[4,5]
Recent work by Erra-Balsells and coworkers on the
[6]
[7]
chlorination,
carbolines, and by Billimoria and Cava on the regioselective C3,C5-
dibromination of indolo[1,2-c]quinazoline,
bromination and iodination of carbazolesand b-
[
8]
provided precedent for
regioselective bishalogenation of indole-2-carboxylate derivatives. In
fact, upon treatment with in situ generated periodic acid (I /NaIO /
2
4
[9]
H SO /EtOH/reflux), ethyl indole-2-carboxylate (2) wasregioeslec-
4
2
tively C3,C5-bishalogenated to provide diiodide 3 in quantitative yield
1
after workup. The structure of 3 wasconfirmed by
H NMR nOe
correlations (see Experimental section). The reaction was found to
proceed sequentially; initial treatment resulted in immediate C3-iodina-
tion, which wasfollowed by C5-iodination upon heating in ethanol over
the next 90 min. Other attemptsat bi si odination (i.e., NIS or I /H SO )
2
2
4
provided only C3-monoiodination, leaving the benzo portion of the
indole unfunctionalized.
[10]
In order to access the desired compound 1, selective dehalogenation
of 3 wasinve st igated. C3-Protonation of indolesisfacile under st rongly
[11]
acidic conditions,
and thisproceswasexploited by Murakami and
colleaguesto affect the es lective C3-protodebromination of substituted
ethyl 3-bromoindole-2-carboxylatesui sn g LiBr in aqueousacid, with
I
I
I
I2, NaIO4
2
Zn
CO Et
2
CO Et
2
CO Et
2
N
EtOH/H SO4
N
EtOH/ HCl
N
H
H
H
2
3
1
Scheme 1.

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Ethyl 5-Iodo-1H-indole-2-carboxylate
2425
[
12]
N-methylpyrrole asa bromine cs avenger.
In an effort to extend this
methodology to the protodeiodination of 3, we subjected 3 to analogous
conditions(LiI/ N-methylpyrrole/H SO /AcOH, reflux). Disappointingly,
2
4
the extreme reaction conditionsthat were required re su lted in polymer-
ization and poor yieldsof 1. Tashiro and Fukata have shown that selec-
tive reductive dehalogenation of iodo- and bromo-substituted phenols
[
13]
occurswith zinc powder in the pre se nce of aqueousacid.
[
Taken with
thisprecedent prompted usto us bject 3 to
12]
the work of Murakami,
acidic, reductive conditionsto effect C3-deiodination. Under standard
reductive conditions(powdered zinc/HCl/EtOH/ambient temperature),
a clean transformation ensued to produce 1 with no detectable C5-
deiodination. Thus, over two steps, a 57% isolated yield of crystalline 1
[
14]
wasobtained from ethyl indole-2-carboxylate.
A simple two-step procedure involving regioselective C3,C5-bisiodi-
nation of ethyl 1H-indole-2-carboxylate, followed by C3-selective reduc-
tive dehalogenation readily providesaccesto the previou sl y unreported
ethyl 5-iodo-1H-indole-2-carboxylate (1). In addition to the high regio-
selectivity achieved in the halogenation reaction, this method also opens
the potential for using the C3-iodide asa blocking group that can be
[
15]
easily removed under mild reductive conditions.
EXPERIMENTAL
Ethyl 3,5-diiodo-1H-indole-2-carboxylate (3). To a stirring solution of
ethyl-1H-indole-2-carboxylate (5.00 g, 26.4 mmol, 1.0 equiv.) in 50 mL of
absolute EtOH was added I2 (6.71 g, 26.4 mmol, 1.0 equiv.), NaIO4
(
2.83 g, 13.2 mmol, 0.50 equiv.) and H SO (2.94 mL, 52.8 mmol,
2 4
2.0 equiv.). The vessel was heated to reflux for 90 min, cooled to ambient
temperature and poured into saturated aqueous Na SO . The mixture
2
3
wasextracted three timeswith EtOAc and the combined organic extracts
were washed once with brine, dried (Na SO ), filtered and concentrated
2
4
1
in vacuo to provide the titled compound 3 (11.7 g, 100%). H-NMR
500 MHz, CDCl ) ꢀ 9.27 (br s, 1H), 7.93 (s, 1H), 7.62 (dd, J ¼ 8.5,
(
3
0
.9 Hz, 1H), 7.18 (d, J ¼ 8.5 Hz, 1H), 4.46 (q, J ¼ 7.1 Hz, 2H) and 1.48
þ þ
1
(
t, J ¼ 7.1 Hz, 3H) ppm; m/z (ES ) ¼ 441.8 (MH ). H-NMR nOe studies
were performed to confirm the structural assignment of compound 3.
Irradiations of the proton resonances at 9.27 and 7.18 ppm showed
nOe enhancements to the resonances at 7.18 and 7.62 ppm, respectively,
confirming the C5 location of the iodo group.
Ethyl 5-iodo-1H-indole-2-carboxylate (1). To a stirring suspension
of 3 (11.7 g, 26.4 mmol, 1.0 equiv.) in 250 mL of EtOH wasadded

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Beshore and Dinsmore
concentrated aqueoushydrogen chloride (22.0 mL, 264 mmol). Zinc dust
26.9 g, 410 mmol) was added portionwise over 90 min. After stirring for
0 min, the mixture wasdiluted with water and extracted four timeswith
(
3
EtOAc. The combined extracts were washed once with aqueous saturated
NaHCO and brine, dried (Na SO ), filtered and concentrated in vacuo.
3
2
4
The crude residue was crystallized thrice from EtOAc/hexanes (1.60 g,
.20 g and 0.710 g), which provided a total of 3.51 g of the title product.
1
The remaining mother liquor wasconcentrated in vacuo and purified by
flash chromatography (0% to 8% ethyl acetate in hexanes) to provide an
additional 1.24 g of the titled compound (combined yield of 1: 4.75 g,
1
5
7%). H-NMR (500 MHz, CDCl ) ꢀ 8.98 (br s, 1H), 8.04 (d,
3
J ¼ 1.0 Hz, 1H), 7.56 (dd, J ¼ 8.7, 1.6 Hz, 1H), 7.21 (d, J ¼ 8.8 Hz, 1H),
7
3
1
.12 (d, J ¼ 1.9 Hz, 1H), 4.41 (q, J ¼ 7.2 Hz, 2H) and 1.42 (t, J ¼ 7.2 Hz,
1
H) ppm; C-NMR (100 MHz, CDCl ) ꢀ 161.9, 135.9, 133.8, 131.6,
3
3
30.2, 128.4, 114.0, 107.7, 61.5, and 14.6 ppm. Anal. calcd. for
C H INO : C, 41.93; H, 3.20; N, 4.45; Found: C, 41.88; H, 2.97; N,
2
1
1
10
4.28. Exact mass calculated for C H INNaO : 337.9648; Found:
11 10 2
3
37.9649 (ESI, M þ Na).
ACKNOWLEDGMENTS
We thank B. Wesley Trotter for helpful suggestions and Joan S.
Murphy for NMR analysis to confirm the structure of 3.
REFERENCES
1
. Ethyl 5-iodo-1H-indole-2-carboxylate [99066-64-5] iscommercially
available only in milligram quantities, as of this writing. Neither
the corresponding acid nor alternative esters are known.
. Joule, J.A.; Mills, K. Chapter 16: Typical reactivity of indoles,
benzo[b]thiophenes, benzo[b]furans, isoindoles, benzo[b]thiophenes
and isobenzofurans and Chapter 17: Indoles: Reaction and synthesis.
In: Heterocyclic Chemistry, 4th Ed.; Blackwell Science Ltd., 2000,
pp. 319–379.
2
3
. Somei, M.; Tanimoto, A.; Yamada, F.; Ohta, T. Synthesis of wasabi
phytoalexin (methyl 1-methoxyindole-3-carboxylate) and its5-indo
derivative. Heterocycles 2001, 54, 425–432.
4
. Bonesi, S.M.; Erra-Balsells, R. On the synthesis and isolation of
chlorocarbazolesobtained by chlorination of carbazo l. es J.
Heterocyclic Chem. 1997, 34, 877–889.

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Ethyl 5-Iodo-1H-indole-2-carboxylate
2427
5
6
7
. Bonesi, S.M.; Erra-Balsells, R. On the synthesis and isolation of
chlorocarbazolesobtained by chlorination of N-substituted carba-
zoles. J. Heterocyclic Chem. 1997, 34, 891–900.
. Ponce, M.A.; Erra-Balsells, R. Synthesis and isolation of bromo-b-
carbolinesobtained by bromination of b-carboline alkaloids. J.
Heterocyclic Chem. 2001, 38, 1087–1095.
. Bonesi, S.M.; Erra-Balsells, R. Synthesis and isolation of iodocar-
bazoles. Direct iodination of carbazoles by N-iodosuccinimide and
N-iodosuccinimide-silica gel system. J. Heterocyclic Chem. 2001, 38,
77–87.
8. Billmoria, A.D.; Cava, M.P. Chemistry of indolo[1,2-c]quinazoline:
an approach to the marine alkaloid hinckdentine A. J. Org. Chem.
1994, 59, 6777–6782.
9. Lulinski, P.; Skulski, L. Iodination of both deactivated and acti-
´
vated arenes with sodium periodate or sodium iodate as the
oxidants. Bull. Chem. Soc. Jpn. 2000, 951–956.
0. Butler, A.R. Textbook errors. 104. Mechanism of aromatic iodina-
tion. J. Chem. Ed. 1971, 48, 508.
1. Hinman, R.L.; Whipple, E.B. The protonation of indoles: position
of protonation. J. Am. Chem. Soc. 1962, 84, 2534–2539.
2. Tani, M.; Gato, M.; Shimizu, M.; Mochimaru, Y.; Amemiya, J.;
Mizuno, N.; Sato, R.; Murakami, Y. Regioselective and non-
1
1
1
reductive C -debromination of indole nucleus. Synlett 1996, 931–932.
3
1
1
1
3. Tashiro, M.; Fukata, G. Studies on selective preparation of aro-
matic compounds. 12. Selective reductive dehalogenation of some
halophenolswith zinc powder in ba is c and acidic media. J. Org.
Chem. 1977, 42, 835–838. For a recent review of reductive
dehydrohalogenation see: Alonso, F.; Beletskaya, I.P.; Yus, M.
Metal-mediated reductive hydrodehalogenation of organic halides.
Chem. Rev. 2002, 102, 4009–4092.
4. A similar reaction sequence to produce ethyl 5-bromo-1H-indole-
2
-carboxylate from 2 wasdeveloped: (a) Br 2 (2.8 equiv.), AcOH,
then 508C, 90 min (93%); (b) Zn (50 equiv.), 10% HCl in EtOH,
58C, 72 h (78%). The reduction in step (b) was substantially slower
5
than the corresponding reaction of 3, necessitating reaction
temperature elevation. Thisr eus lted in a 9:1 mixture of ethyl
5-bromo-1H-indole-2-carboxylate and 2.
5. Choi, H.Y.; Chi, D.Y. A facile debromination reaction: can bromide
now be used as a proactive group in aromatic systems? J. Am.
Chem. Soc. 2001, 123, 9202–9203.
Received in the USA November 19, 2002

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