A short and efficient synthesis of N-substituted indol-2-ones (oxindoles)

Article abstract of DOI:10.1016/S0040-4039(01)01413-7

A short and high yielding process has been developed for the synthesis of N-(4-piperidinyl)-indol-2-ones. This strategy also constitutes a general route to N-substituted indol-2-ones.

Full text of DOI:10.1016/S0040-4039(01)01413-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6943–6945
A short and efficient synthesis of N-substituted indol-2-ones
(oxindoles)
Ian T. Forbes*
GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK CM19 5AD
Received 5 July 2001; accepted 27 July 2001
Abstract—A short and high yielding process has been developed for the synthesis of N-(4-piperidinyl)-indol-2-ones. This strategy
also constitutes a general route to N-substituted indol-2-ones. © 2001 Elsevier Science Ltd. All rights reserved.
Literature routes to 3a involve either a Friedel–Crafts
cyclisation step5 or involve reductive alkylation of an
ortho-aminophenylacetic acid or ortho-aminophenyl-
acetamide followed by cyclisation (Scheme 1).6 In our
hands, the Friedel–Crafts approach was low yielding
and not reproducible, while the main disadvantages of
the other (also low yielding) approaches were unwanted
cyclisation to the indol-2-one prior to reductive alkyla-
tion, or the harsh conditions required for complete
cyclisation onto the primary amide.6
The
1-piperidin-4-yl-1,3-dihydro-benzimidazol-2-one
ring system 1 is well known in pharmaceutical research
as a template for ligands at numerous G-protein cou-
pled receptors, e.g. dopamine receptors and 5-hydroxy-
trypamine (5-HT) receptor subtypes.1 Indeed, various
derivatives of 1 are currently marketed as drugs for the
treatment of psychiatric and/or gastrointestinal disor-
ders.2 In-house calculations on various structures con-
taining the template 1 indicated potential low brain
penetration for these compounds, due primarily to the
presence of the polar benzimidazolone NH group.3
Thus, we became interested in the less polar O and CH2
isosteres, 2 and 3, which were predicted to confer
greater brain penetration in a wide range of analogues.
There are numerous high yielding syntheses of the
benzoxazol-2-one 2,4 but very few references to the
corresponding 1,3-dihydro-indol-2-one (oxindole) 3a.5,6
We have developed a simple, flexible, and high yielding
synthetic route to 3a, as well as substituted analogues
3b and 3c (Scheme 3). This methodology also consti-
tutes a general syntheses of N-substituted indol-2-ones
as it is capable of introducing a wide variety of sub-
stituents onto the indolone nitrogen atom.
We envisaged that the general process outlined in
Scheme 2 would offer numerous advantages to existing
routes. The t-butyl ester of ortho-aminophenylacetic
acid, 4, is a stable compound,7 which should readily
allow reductive amination, prior to effecting ring
closure.
In practice, we developed the route summarised in
Scheme 3. Addition of di-t-butyl malonate, under basic
conditions, to the ortho-fluoronitrobenzene derivatives
5 afforded the adducts 6. The use of di-t-butyl mal-
onate serves two functions: it allows facile anion forma-
Keywords: heterocyclic compounds; indol-2-ones; oxindoles; synthesis.
* Tel.: (+) 44 1279 622126; fax: (+) 44 1279 627841; e-mail: ian t forbes@sbphrd.com
– –
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01413-7

6944
I. T. Forbes / Tetrahedron Letters 42 (2001) 6943–6945
Scheme 1. Literature routes to 3.
Scheme 2. Outline of synthetic strategy.
Scheme 3. Synthetic route to substituted indol-2-ones: (a) R=H; (b) R=5-F, (c) R=6-F.
gratifyingly showed no propensity to cyclise. Reductive
tion prior to nucleophilic aromatic substitution, and use
of the t-butyl esters prevents unwanted cyclisation at
the next stage. Thus, the nitro adducts 6 were hydro-
genated in quantitative yield to the anilines 7, which
alkylation of 7 using N-benzyloxycarbonyl-4-piperi-
done proceeded under standard literature conditions8 to
provide the key di-esters 8. In a highly efficient manner,

I. T. Forbes / Tetrahedron Letters 42 (2001) 6943–6945
6945
the di-esters 8 were converted into the desired indol-2-
References
ones 9, by treatment with 4-toluenesulfonic acid (ptsa)
in refluxing toluene for 1 h. Thus, in a single step, the
di-t-butyl esters 8 were deprotected, allowing concomit-
ant intramolecular cyclisation to the indol-2-one to
occur, in addition to the facile decarboxylation of the
redundant carboxyl group. Removal of the benzyloxy-
carbonyl protecting group on the piperidine nitrogen
was accomplished by standard hydrogenation, afford-
ing compounds of generic structure 3.9
1. A search of Chemical Abstracts gave ꢀ6,000 references
to substituted 1-piperidin-4-yl-1,3-dihydro-benzimidazol-
2-ones mainly in the patent literature. For examples see
WO 0127104, WO 0125200, WO 9955694, WO 9936421,
US 5789402, EP 739891.
2. For example, Pimozide is marketed as a neuroleptic and
Domperidone is marketed as an antiemetic agent.
A wide range of substituted ortho-fluoro and ortho-
chloro nitrobenzenes are commercially available, in
addition to various heteroaryl analogues, thus opening
up pathways to the synthesis of a wide range of substi-
tuted and heterocyclic indol-2-ones. Additionally, this
route is also a versatile process for the synthesis of
indol-2-ones having a diverse range of N-substituents,
by appropriate choice of aldehyde or ketone in the
reductive alkylation of 7.
For example, reductive alkylation of 7a with benzalde-
hyde followed by treatment with ptsa in refluxing tolu-
ene afforded the N-benzylindol-2-one 10 in 70% overall
yield.
3. GlaxoSmithkline, unpublished data.
4. For examples see WO 9932481, US 5665719, WO
9502405.
5. US 3325499.
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Arch. Pharm. (Weinheim, Ger.) 1975, 308, 910–916.
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Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61,
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9. NMR and mass spectra of all compounds were fully
consistent with the structures shown.
In summary, a short, versatile and high yielding process
for the synthesis of N-substituted 1,3-dihydroindol-2-
ones has been developed. The high yields and ready
availability of starting materials distinguish this
approach from other routes to N-substituted indol-2-
ones.10
10. Comprehensive Heterocyclic Chemistry 1984, 4, 364–366;
Comprehensive Heterocyclic Chemistry II 1996, 2, 146.