A concise synthesis of 3-hydroxyindole-2-carboxylates by a modified Baeyer-Villiger oxidation

Article abstract of DOI:10.1016/S0040-4039(00)01456-8

Indole-2-carboxylates are converted in good yields to 3-hydroxyindole-2-carboxylates by use of a Vilsmeier-Haack/Baeyer-Villiger reaction sequence. A systematic examination of the various indole substituents revealed this route to be general in scope. (C) 2000 Published by Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01456-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8217–8220
A concise synthesis of 3-hydroxyindole-2-carboxylates by a
modified Baeyer–Villiger oxidation
Zachary L. Hickman, Claudio F. Sturino and Nicolas Lachance*
Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe Claire-Dorval, Que´bec, Canada, H9R 4P8
Received 28 July 2000; accepted 25 August 2000
Abstract
Indole-2-carboxylates are converted in good yields to 3-hydroxyindole-2-carboxylates by use of a
Vilsmeier–Haack/Baeyer–Villiger reaction sequence. A systematic examination of the various indole
substituents revealed this route to be general in scope. © 2000 Published by Elsevier Science Ltd.
3-Hydroxyindole-2-carboxylates have been used as intermediates in the synthesis of com-
pounds of medicinal value.1 A common route to prepare hydroxyindoles involves the
Dieckmann reaction of anthranilic acid with a-halogenoacetate.2 Due to the numerous steps
required by this approach to build this indole core, the yield is not generally higher than the 25%
yield observed for the direct oxidation of 1-methylindole-2-carboxylate with lead tetraacetate.3
Other methods, like Hawthorne’s procedure, to transform a t-butyl 3-bromo-1-methylindole-2-
carboxylate to the corresponding 3-hydroxyindole via a one pot reaction (reaction with n-BuLi,
(MeO)3B and H2O2 in acetic acid) also proceed in low yields.4 Finally, the Baeyer–Villiger
oxidation of the N-methyl-3-formylindole-2-carboxylate has been previously reported, although
this approach leads to poor yields of the corresponding alcohol.5 To date, an efficient procedure
to prepare 3-hydroxyindole-2-carboxylates from unprotected indoles is not available. As part of
our medicinal chemistry research program, we required an efficient route to hydroxyindoles and
we wish to report herein an improvement in the Baeyer–Villiger reaction conditions resulting in
good yields of the corresponding products.
* Corresponding author. Tel: (514) 428-8696; fax: (514) 428-4900; e-mail: nicolas lachance@merck.com
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0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01456-8

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The starting 3-formylindole 2 required for our studies was easily prepared in good yield by
exposing indole 1 to Vilsmeier–Haack reaction conditions (Scheme 1).6 At the outset, we treated
aldehyde 2 to reaction conditions described by Me´rour (dried m-CPBA in CH2Cl2 at 5°C)
originally developed to oxidize N-tosyl or acetyl 3-formylindoles.5 Under these conditions, the
oxidation was slow. When the reaction mixture was warmed to room temperature, a 90% yield
(after hydrolysis of the 3-formyloxy intermediate) of indole 3 was obtained after 30 h.
Performing the same reaction with 1 equiv. of PTSA to activate the aldehyde, a 77% yield of the
Baeyer–Villiger product was realized in only 40 min. The main side product in this reaction was
over oxidation of the indole moiety in approximately 15–20% yield. To avoid the formation of
this undesired oxidation product, the reaction was carried out at 10°C and the efficiency of the
reaction was improved to 90% (Scheme 1, Table 1, entry 1). For comparison, Me´rour et al.
reported a yield of 23% for the synthesis of the ethyl N-methyl-3-formyloxyindole-2-carboxylate.
O
OH
O
O
O
a
b, c
N
H
N
H
OEt
OEt
N
H
OEt
86%
90%
1
2
3
Scheme 1. Reagents and conditions: (a) POCl3 (1.5 equiv.), HCON(CH3)C6H5 (1.5 equiv.), ClCH2CH2Cl, reflux; (b)
m-CPBA, PTSA, CH2Cl2, 10°C; (c) Me2S, EtOH
Having established high yielding conditions for the oxidation of aldehyde 2 to hydroxyindole
3, we wanted to examine the scope of this method. Table 1 summarizes the results of this indole
oxidation reaction.7 Replacement of the ester substituent with a carboxamide (Table 1, entry 1)
gave similar yields of the hydroxyl product. Introduction of a bromine substituent at either the
4-, 5- or 6-position of the indole was well tolerated (Table 1, entries 2, 3 and 4).8 Also, the
presence of a second ester group on the indole did not affect the oxidation yield (Table 1, entry
5).9 However, with a strong electron-withdrawing group such as a methylsulfone at the
5-position of the indole ring completely shut down the oxidation process (Table 1, entry 6). We
speculate that this indole is too electron-poor to undergo the desired Baeyer–Villiger rearrange-
ment.10 On the other hand, electron-donating groups did not interfere with the efficiency of the
indole oxidation (Table 1, entry 7). Likewise, both N-methyl or benzyloxy substituents are
tolerated in this reaction (Table 1, entry 8). This last example, N-methyl-5-benzyloxy-3-hydroxy-
indole-2-carboxylate (Table 1, entry 8), has been previously prepared according to the
Hawthorne’s procedure in four to five steps with an overall yield of 28%.4 Using our method,
this product is now accessible in only two steps with an overall yield of 80%.
The importance of having at least one electron-withdrawing group in the Baeyer–Villiger
reaction was investigated by replacing the 2-carboxylate group of the indole with a methyl or a
phenyl substituent. Exposure of these analogs to our standard reaction conditions only lead to
recovery of starting material. Performing the reaction in refluxing ClCH2CH2Cl did not improve
the reaction, underscoring the importance of the 2-carboxylate substituent to the success of this
reaction.
In summary, an efficient procedure has been outlined for the preparation of 3-hydroxyindole-
2-carboxylates from the corresponding unprotected indole-2-carboxylates by use of a modified
Vilsmeier–Haack/Baeyer–Villiger reaction sequence. Work is currently underway to further
examine the scope of this indole oxidation reaction.

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Table 1
Synthesis of 3-formyl and 3-hydroxyindoles
References
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1
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1
indole-2,5-dicarboxylate (Table 1, entry 5). H NMR (400 MHz, acetone-d6) l 10.44 (br s, 1H), 8.42 (br s, 2H),
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