Practical synthesis and elaboration of methyl 7-chloroindole-4-carboxylate

Article abstract of DOI:10.1021/jo026434p

A synthesis of a previously unknown indole derivative is presented. The route reported herein allows for the preparation of multihundred gram quantities of material without any chromatographic purification. Conditions are presented for the Pd-catalyzed el

Full text of DOI:10.1021/jo026434p

P r a ctica l Syn th esis a n d Ela bor a tion of
Meth yl 7-Ch lor oin d ole-4-ca r boxyla te
Phil B. Alper* and KhanhLinh T. Nguyen
The Genomics Institute of the Novartis Foundation,
10675 J ohn J ay Hopkins, San Diego, California 92121-1125
palper@gnf.org
Received September 10, 2002
F IGURE 1. Representative indole-containing substances.
Abstr a ct: A synthesis of a previously unknown indole
derivative is presented. The route reported herein allows for
the preparation of multihundred gram quantities of material
without any chromatographic purification. Conditions are
presented for the Pd-catalyzed elaboration of one of the
“diversity generating elements” of this important pharma-
cophore.
F IGURE 2. Designed indole scaffold and proposed starting
material.
The prominence of the indole nucleus in medicinally
important natural products and synthetic pharmaceuti-
cals can hardly be overstated.1 As a result, the chemistry
of the substituted indole has received an enormous
amount of attention.2 The revolution of combinatorial
chemistry of small molecules3 assured that the synthesis
of indole-containing lead compounds would be accelerated
in a manner similar to all other scaffolds.4
It was the tremendous variety of biological activities
associated with indoles that made them a scaffold of
choice for a multiple assay high throughput screening
effort such as the one at our institute. We wanted to
design an indole core that would allow for synthesis of a
diverse set of molecules, which could elicit the greatest
possible variety of biological responses possible from a
single starting point.
When thinking about the design of such a scaffold, it
was desirable to leave the pyrrole ring unsubstituted
since this ring has a rich chemistry associated with it.
To introduce appropriate handles for diversification
chemistry, we needed to choose which positions of the
benzene ring were to be modified.
Figure 1 shows three natural products that have
nonrelated biological activities. Lysergic acid diethyl
amide (1) is a hallucinogen and CNS activator5 in
addition to a plethora of physiological effects.6 Hippadine
(2) causes reversible inhibition of fertility in male rats
without antimitotic activity.7 (-)-7-Octylindolactam V (3)
is a protein kinase C modulator.8 The structural proper-
ties that these molecules share is their substitution in
positions 4 and 7 of the indole nucleus. It was therefore
decided to equip our scaffold with chemically orthogonal
substituents at positions 4 and 7.
Figure 2 shows the structure of the scaffold 4 chosen
for further study along with the proposed starting mate-
rial 5. With the inherent alkylative, electrophilic, and
nucleophilic properties of positions 1, 2, and 3 and the
diverse chemistries available to the substituents at
(4) (a) Hutchins, S. M.; Chapman, K. T. Tetrahedron Lett. 1996,
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B. E. J . Org. Chem. 1997, 62, 1804. (g) Arumugam, V.; Routledge, A.;
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Maryanoff, B. E. Tetrahedron Lett. 1998, 39, 4449. (k) Smith, A. L.;
Stevenson, G. I.; Swain, C. J .; Castro, J . L. Tetrahedron Lett. 1998,
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Lett. 2000, 10, 2693. (t) Stevenson, G. I.; Smith, A. L.; Lewis, S.; Michie,
S. G.; Neduvelil, J . G.; Patel, Sm.; Marwood, R.; Patel, Sh.; Castro, J .
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Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: New
York, 1996; Vol. 2, p 207. (b) Ban, Y.; Murakami, Y.; Iwasawa, Y.;
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E. The Chemistry of Heterocyclic Compounds; Wiley: New York, 1983;
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10.1021/jo026434p CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/08/2003
J . Org. Chem. 2003, 68, 2051-2053
2051

SCHEME 1. Syn th esis of th e F ir st Cr ysta llin e
In ter m ed ia te
SCHEME 2. F in a l Step s to th e Desir ed Com p ou n d
alone or to do the reaction in the presence of both 6 and
7 led to unsatisfactory results. Activation of 6 using SO2-
Cl2 turned out to generate a very electrophilic species that
readily coupled with 7 at low temperature in the presence
of collidine. The resulting sulfilimine was directly treated
with excess triethylamine and heated to 70 °C to gener-
ate, after aqueous workup, the rearrangement product
8 as an oil, which was carried on without purification.
The next transformation required to make the indole
by the reported route13d,e was to make the p-toluene-
sulfonamide from 8, which would hopefully be crystalline.
In our hands, all attempts to effect this transformation
met with failure. An alternate pathway had to be taken,
and the first order of business was to find a crystalline
intermediate that could easily be purified.
Treatment of 8 with NaOMe in MeOH effected the
cleavage of the pivalate ester and subsequent spontane-
ous cyclization to the lactone (9), also an oil. Lactone 9
was treated with TFAA and pyridine, and the resulting
trifluoroacetamide 10 was crystalline and insoluble in
methylene chloride. These properties enabled isolation
of pure 10 in a single crystallization in 31% yield after
three steps.
To get 10 to 4, the sulfide had to be eliminated to the
double bond. This was accomplished by oxidizing to the
diastereomeric mixture of sulfoxides with a stoichiometric
amount of hydrogen peroxide and without isolation
eliminating methyl sulfinic acid by refluxing in AcOH to
generate the isocoumarin 11 as a solid (Scheme 2).
Finally, treatment of 11 with sulfuric acid in refluxing
methanol afforded 4 as a pure substance in nearly
quantitative yield after aqueous workup. In this way,
more than 250 g of 4 was prepared in the laboratory
without the need for a single chromatographic purifica-
tion.
We next focused our attention on functionalizing 4 to
generate useful derivatives. Palladium-catalyzed carbon-
carbon bond forming chemistry has become a mainstay
of the organic chemist because of its reliability and
tolerance of sensitive functional groups.14 The longstand-
ing condition of needing aromatic bromides or iodides in
order to effect C-C bond forming reactions has recently
been overcome,15 and it is now possible to use chlorides.
positions 4 and 7, this was thought to be a good starting
point for development of libraries of lead generating
compounds.
The synthesis of 4,7-disubstituted indoles with a car-
boxylate equivalent in the 4 position and a leaving group
or precursor in the 7 position has been explored by
several synthetic methods. However, most of these routes
suffered from either the probability of regiochemical
problems leading to isolation difficulties,9 the need for
chromatography,10 or the need for multistep manipula-
tions from the reported compound to get to the desired
material.11
In this paper, we report the development of a large
scale, practical synthesis of 4 from 5 along with a method
for functionalizing the chloride via Pd catalysis. The
chemistry that we chose to install the pyrrole ring was
the Sommelet-Hauser rearrangement of aryl sulfil-
imines.12 Since this chemistry had been applied to the
synthesis of indoles derivatives,13 and specifically 2-chloro-
substituted indoles,13e we felt that this would be a fruitful
pathway.
The synthesis (Scheme 1) started by coupling 2-meth-
ylthioethyl 1,1-dimethyl acetate 6 (available in 97% yield
from 2-methylthioethanol) with methyl 3-amino-4-chlo-
robenzoate (7) (available on large scale in 80% yield from
5) to form a sulfilimine (Scheme 1). The classical condi-
tions of activation using chlorine gas were quite incon-
venient, and the use of NCS either to activate the sulfide
(9) (a) Bowman, R. E.; Goodburn, T. G.; Reynolds, A. A. J . Chem.
Soc., Perkin Trans. 1 1972, 1121. (b) Ponticello, G. S.; Baldwin, J . J .;
Lumma, P. K.; McClure, D. E. J . Org. Chem. 1980, 45, 6. (c) Nagasaka,
T.; Yuge, T.; Ohki, S. Heterocycles 1977, 371.
(10) (a) Dobson, D.; Todd, A.; Gilmore, J . Synth. Commun. 1991,
611. (b) Santangelo, F.; Casagrande, C.; Norcini, G.; Gerli, F. Synth.
Commun. 1993, 2717. (c) Ohno, M.; Shimizu, S.; Eguchi, S. Heterocycles
1991, 1199. (d) Dobbs, A. J . Org. Chem. 2001, 66, 638.
(11) Cannon, J . G.; Lukszo, J .; Max, G. A. J . Heterocycl. Chem. 1983,
149.
(14) For a general review, see: (a) Metal Catalyzed Cross Coupling
Reactions; Diederich, F., Stang, P. J ., Eds.; Wiley-VCH: Wienheim,
Germany, 1998. For an outstanding monograph on the applications of
Pd chemsitry to heterocyclic synthesis, see: Li, J . J .; Gribble, G. W.
Palladium in Heterocyclic Chemistry: A Guide for the Synthetic
Chemist; Baldwin, J . E. et. al., Eds.; Pergamon: New York, 2000.
(15) (a) Old, D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 9722. (b) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed.
1998, 37, 3387. (c) Wolfe, J . P.; Buchwald, S. L. Angew. Chem., Int.
Ed. 1999, 38, 2413. (d) Zhang, C.; Huang, J .; Trudell, M. L.; Nolan, S.
P. J . Org. Chem. 1999, 64, 3804. (e) Wolfe, J . P.; Singer, R. A.; Yang,
B. H.; Buchwald, S. L. J . Am. Chem. Soc. 1999, 121, 9550. (f) Littke,
A. F.; Dai, C.; Fu, G. C. J . Am. Chem. Soc. 2000, 122, 4020.
(12) For reviews, see: (a) Claus, P. K.; Rieder, W.; Hofbauer, P.
Tetrahedron 1975, 31, 505. (b) Gilchrist, T. L.; Moody, C. J . Chem.
Rev. 1977, 77 (3), 409. (c) Oae, S. Sulfilimines and Related Derivatives;
American Chemical Society: Washington, DC, 1983; p 7.
(13) For the original references for the Gassman indole synthesis,
see: (a) Gassman, P. A.; van Bergen, T. J .; Gilbert, D. P.; Cue, B. W.,
J r. J . Am. Chem. Soc. 1974, 96(17), 5495. (b) Gassman, P. A.; van
Bergen, T. J . J . Am. Chem. Soc. 1974, 96(17), 5508. (c) Gassman, P.
A.; Gruetzmacher, G.; van Bergen, T. J . J . Am. Chem. Soc. 1974, 96(17),
5512. For another approach, see: (d) Murai, Y.; Masuda, G.; Inoue,
S.; Sato, K. Heterocycles 1991, 32(7), 1377. (e) Murai, Y.; Kobayashi,
S.; Inoue, S.; Sato, K. Heteocycles 1992, 34(5), 1017.
2052 J . Org. Chem., Vol. 68, No. 5, 2003

SCHEME 3. P d -Ca ta lyzed Ar yla tion of 4
In summary, a nine-step synthesis has been developed
that delivers a previously unknown indole scaffold in an
overall yield of 17.8% from commercially available start-
ing material. The synthesis is robust and scalable to
deliver hundreds of grams of material. It was also shown
that the halide on 4 can be readily substituted using Pd
chemistry.
The production of chemical libraries starting from this
scaffold and the screening of these libraries for biological
activity are currently ongoing. The results of these
studies will be reported in due course.
Ack n ow led gm en t. This work was supported by the
Novartis Charitable Foundation.
We wanted to make use of this chemistry to make an
sp2-sp2 C-C bond at position 7 of 4.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and experimental procedures for the preparation of 4-12.
This material is available free of charge via the Internet at
http://pubs.acs.org.
After screening several different reaction conditions,
the biaryl indole acid 12 was generated from 4 (Scheme
3), showing that the scaffold can effectively be substituted
and made into interesting derivatives. Because it is
known that the indole NH can function in a Pd-mediated
arylation,16 we used CsHCO3 as a base instead of Cs2-
CO3 to avoid indole NH deprotonation.
J O026434P
(16) Old, D. W.; Harris, M. C.; Buchwald, S. L. Org. Lett. 2000, 2(10),
1403.
J . Org. Chem, Vol. 68, No. 5, 2003 2053