A convenient preparation of 4-iodoindoles from indoles: Application to the chemical synthesis of hapalindole alkaloids

Article abstract of DOI:10.1016/S0040-4039(00)02194-8

4-Iodoindoles were synthesized via regioselective chloromercuration and subsequent iodination of a series of N-p-toluenesulfonyl indoles bearing a variety of substituents at the 3-position. This procedure allows rapid access to 3,4-dihaloindoles which may be used as synthetic precursors to indole alkaloids.

Full text of DOI:10.1016/S0040-4039(00)02194-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 983–985
A convenient preparation of 4-iodoindoles from indoles:
application to the chemical synthesis of hapalindole alkaloids
Martyn A. Brown and Michael A. Kerr*
Department of Chemistry, The University of Western Ontario, London, Ontario, Canada N6A 5B7
Received 23 November 2000; accepted 29 November 2000
Abstract—4-Iodoindoles were synthesized via regioselective chloromercuration and subsequent iodination of a series of N-p-tolue-
nesulfonyl indoles bearing a variety of substituents at the 3-position This procedure allows rapid access to 3,4-dihaloindoles which
may be used as synthetic precursors to indole alkaloids. © 2001 Elsevier Science Ltd. All rights reserved.
The regioselective functionalization of aromatic systems
is an ongoing challenge in organic synthesis.1 Advances
in directed metallation2 and the use of cross-coupling
methodology3 has allowed the organic chemist access to
a wide variety of multi-functionalized benzenoid and
heteroaromatic compounds. The functionalization of
polyaromatic (both carbocyclic and heteroaromatic)
molecules is more complex.
the pyrrole ring from a suitably adorned benzenoid
precursor. It is rare that a direct fuctionalization of the
4-position can be achieved. A thallation reaction has
been used to generate an organometallic species which
was subsequently iodinated.6 Semmelhack has
employed a chromium carbonyl adduct of indoles in
order to nucleophilicity functionalize the benzopyrrole
system.7 Herein we report a simple and direct halogena-
tion protocol which allows for the preparation of a
variety of 3-substituted-4-iodoindoles.
Recently we have undertaken a chemical synthesis of a
series of alkaloids of the hapalindole class.4 Scheme 1
illustrates our retrosynthetic analysis using hapalindole
J as an example. The penultimate target would be a
suitably functionalized tetracyclic compound such as 1,
which is an intramolecular Diels–Alder cyclization
product of 2. The formation of 2 would arise from
sequential cross-coupling reactions which would install
the dienophilic and diene moieties (necessary for the
cycloaddition onto the 3,4-dihaloindole 3).
During a synthesis of a 3-iodoindole using the mercura-
tion protocol of Hegedus,8 we were intrigued by the
fact that when a tosylated substrate which already bore
a substituent in the 3-position was subjected to these
conditions (Hg(OAc)2/CH3CO2H/catalytic HClO4), a
precipitate formed which was the 4-(acetoxymercurio)
derivative (see Table 1). Stirring in aqueous NaCl
effected an exchange reaction to the chloromercurioin-
dole which could be isolated in good yield. Titration of
the organomercurio species with a solution of iodine in
CH2Cl2 resulted in the smooth conversion to the 4-
3,4-Disubstitued indoles are well known compounds5
but their formation usually relies on the formation of
Scheme 1. Retrosynthesis of hapalindole J.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02194-8

984
M. A. Brown, M. A. Kerr / Tetrahedron Letters 42 (2001) 983–985
Table 1. The preparation of 4-iodoindoles by mercuration/iodination
Entry
R1
R2
R3
R4
Yield of 5
Yield of 6
a
b
c
d
e
f
g
h
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Me
H
H
H
H
Br
CHO
CHꢀCH-C(O)Me
CO2Me
Me
Me
Br
Me
H
H
H
H
H
H
OMe
H
83
85
0
71
76
74
49
0
75
67
–
75
70
69
17
–
H
Me
Me
Me
iodoindole. We were pleasantly surprised by the efficacy
of the procedure and sought to probe its generality. To
this end, a series of 3-substitued indoles was subjected
to the above conditions; the results are presented in
Table 1.9
The filtrate was washed with 5 M sodium thiosulfate
solution, water, stirred with decolorizing charcoal, and
dried over anhydrous MgSO4. Filtration of the drying
agent and removal of the solvent yielded a pale yellow
oil which was crystallized from hexanes. The yield of
3-bromo-4-N-p-toluenesulfonylindole 6a was 0.35 g
(75%).
A typical procedure is as follows. Preparation of 5a:
3-Bromo-N-p-toluenesulfonylindole 4a (0.35 g,
1
mmol) was stirred in glacial acetic acid (20 mL) at
ambient temperature. Mercury(II) acetate (0.35 g, 1.1
mmol) was added along with one drop of 70% perchlo-
ric acid. The reaction was stirred for 48 h after which
time a precipitate formed. The reaction mixture was
poured into a saturated NaCl solution (30 mL) with
stirring. Stirring was continued for 15 min and the solid
material (6a) was isolated by filtration, washed liberally
with water and dried under vacuum to a constant mass
(0.58 g, 92%). Preparation of 6a: The organomercury
compound 5a (0.58 g, 0.99 mmol) was added at ambi-
ent temperature to dry methylene chloride (30 mL) and
iodine (0.26 g, 1.01 mmol) was added with strirring.
The reaction was stirred form 16 h after which time the
mixture was filtered to remove the inorganic material.
Several items from Table 1 are worthy of note. In the
absence of a tosyl group on the indolic nitrogen, the
reaction failed to give a clean product. It is suspected
that the tosyl group serves to deactivate the benzopy-
rrole double bond and remove it from competition for
the electrophilic mercury reagent. Even with an electron
withdrawing group in the 3-position, the presence of a
tosyl group is required. For example, indole 3-carbox-
aldehyde failed to produce reasonable yields of the
4-mercurioindole. Note that an alkenyl substituent
(even a relatively electron poor one as in 4c) serves to
complicate the reaction. In cases where the indole nitro-
gen was not protected with an electron-withdrawing
group, reaction occurred but the exact nature of the
reaction mixture was not determined.
Scheme 2. Synthesis of a hapalindole model via a cross-coupling/Diels–Alder strategy.

M. A. Brown, M. A. Kerr / Tetrahedron Letters 42 (2001) 983–985
985
ing, I. Eds.; Pergamon Press: Oxford, 1991; Vol. 3, pp.
436–478; (c) Comprehensive Organometallic Chemistry,
2nd Ed.; Abel, E. W.; Stone, G. A.; Wilkinson, G., Eds.;
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Chem. Soc. 1984, 106, 6456–6457; (b) Moore, R. E.;
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344–347; (d) Kruse, L. I; Meyer, M. D. J. Org. Chem.
1984, 49, 4761–4768.
To demonstrate the feasibility of our cross-coupling/
Diels–Alder approach to the synthesis of the tetracyclic
hapalindoles, we prepared a simple model system
(Scheme 2). Using dihaloindole 6a, the allyl
(dienophilic) moiety was installed using a Stille cou-
pling to produce 7 in 76% yield. A subsequent Heck
reaction employing methyl vinyl ketone gave enone 8 in
81% yield. Methylenation in 55% yield produced the
Diels–Alder substrate 9 which when heated at 100°C
for 12 h in toluene and produced an inseparable mix-
ture of cis and trans adducts 10 and 11 in a combined
yield of 15%.10
In summary we have developed a convenient method
for the direct mercuration and subsequent iodination of
3-substitued indoles having an N-tosyl protecting
group. The method appears to be very general and
promises to be extremely useful for the preparation of
synthetic precursors to a wide range of indole alkaloids
and other non-natural indole containing molecules. It is
our intention to utilize this method in combination with
cross-coupling methodology in our efforts to prepare
hapalindoles and other indole alkaloids. Details of the
cross-coupling/Diels–Alder methodology presented in
Scheme 2 will be reported in due course.
6. Somei, M.; Yamkada, F.; Kunimoto, M.; Kaneko, C.
Heterocycles 1984, 22, 7801–7970.
7. (a) Semmelhack, M. F.; Wulff, W.; Garcia, J. L. J.
Organomet. Chem. 1982, 260, C5; (b) Semmelhack, M. F.;
Rhee, H. Tetrahedron 1993, 49, 1395–1398.
8. Harrington, P. J.; Hegedus, L. S. J. Org. Chem. 1984, 49,
2658–2662.
9. Physical data for 5a: 1H NMR (CDCl3) d=7.97 (d,
J=7.1 Hz, 1H), 7.71 (d=8.9 Hz, 2H), 7.41–7.22 (m, 5H),
2.37 (s, 3H). 13C NMR (CDCl3) l=146.1, 136.9, 134.9,
130.5, 129.9, 127.0, 126.8, 126.4, 120.4, 114.0, 99.3, 21.9.
IR (thin film) w=3110–3020, 1595, 1372, 1173. HRMS
(70 ev) for C15H11O2SNHgBr (M+−Cl) calcd:584.5088,
Acknowledgements
We thank MedMira Laboratories and the Natural Sci-
ences and Engineering Research Council (NSERC) of
Canada for generous financial support of this research.
1
found: 584.5098. Physical data for 6a: H NMR (CDCl3)
l=8.35 (d, J=7.9 Hz, 1H), 7.75 (d, J=8.4 Hz, 2 H), 7.43
(d, J=9.0 Hz, 1 H), 7.35–7.22 (m, 2H), 7.20 (d, J=8.3
Hz, 2H), 2.39 (s, 3H). 13C NMR (CDCl3) l=146.3,
138.2, 134.1, 133.8, 130.0, 127.8, 126.1, 125.1, 124.2,
116.2, 91.0, 89.1, 21.9. IR (thin film): w=3115–3050,
1594, 1370, 1175. HRMS (70 ev) for C15H11O2SNBrI
(M+) calcd: 474.8733, found: 474.8739.
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yield using Lewis acids both alone and in concert with
high pressures (ꢀ13 kbar).
.