ORGANIC
LETTERS
2008
Vol. 10, No. 12
2601-2604
(1-Nosyl-5-nitroindol-3-yl)methyl Ester: A
Novel Protective Group for Carboxylic
Acids
Takuya Nishimura, Kouhei Yamada, Tohru Takebe, Satoshi Yokoshima, and
Tohru Fukuyama*
Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan
Received April 15, 2008
ABSTRACT
The usefulness of (1-nosyl-5-nitroindol-3-yl)methyl esters as a novel protective group for carboxylic acid is fully demonstrated. The novel
protective group is stable under a broad range of conditions and can easily be deprotected under the mild conditions used for removal of the
nosyl (Ns) group. It is orthogonal to the existing protective groups for carboxylic acids such as t-butyl and allyl esters.
Indole is known to show a variety of reactivities due to its
electron-rich 10π-electron system.1 N,N-Dimethyl-(1H-indol-
Scheme 1. Reaction of Gramine
3-yl)methylamine (1), also known as gramine, is a useful
unit to synthesize 3-substituted indoles. Reactions of gramine
or its methiodide with nucleophiles, such as cyanides,
malonates, nitroalkanes, or boronic acid, proceed via the
elimination of the dimethylamine or trimethylamine and
subsequent addition to the resulting intermediate 2 to give
the corresponding “substitution” product 3 (Scheme 1).2 We
reasoned that introduction of an electron-withdrawing group
on the indole nitrogen would substantially slow down the
elimination process. This led us to develop a novel protective
method for carboxylic acids as (indol-3-yl)methyl esters.
We first prepared a model compound 4a and tested its
potential as a protective group for carboxylic acids (Scheme
2). 2-Nitrobenzensulfonyl (Ns) group,3 which can be re-
moved under mild conditions such as exposure to thiolates,
was selected as the electron-withdrawing group on the indole
nitrogen. As expected, subjection of 4a to the standard
conditions for cleaving the Ns group gave the corresponding
carboxylic acid 6a in good yield. In addition, 3-(phenylthi-
(1) (a) For recent representative reviews, see: Joule, J. A. In Science of
Synthesis; Thomas, E. J., Ed.; Georg Thieme Verlag: Stuttgart, 2000; pp
361-652. (b) Jones, G. B.; Chapman, B. J.; Black, D. St. C.; Sundberg,
R. J.; Gribble, G. W. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., Rees, C. W., Scriven, E. F., Eds.; Pergamon, Elsevier
Science Ltd: Oxford, 1996; pp 1-258..
(2) (a) For recent examples of gramines, see: Artman, G. D., III; Grubbs,
A. W.; Williams, R. M. J. Am. Chem. Soc. 2007, 129, 6336. (b) de la Herra´n,
G.; Segura, A.; Csa´ky, A. G. Org. Lett. 2007, 9, 961. (c) Wada, Y.;
Nagasaki, H.; Tokuda, M.; Orito, K. J. Org. Chem. 2007, 72, 2008. (d)
Jones, D. T.; Artman, G. D., III; Williams, R. M. Tetrahedron Lett. 2007,
48, 1291. (e) Grubbs, A. W.; Artman, G. D., III; Tsukamoto, S.; Williams,
R. M. Angew. Chem., Int. Ed. 2007, 46, 2257. (f) Shchekotikhin, A. E.;
Dezhenkova, L. G.; Susova, O. Y.; Glazunova, V. A.; Luzikov, Y. N.;
Sinkevich, Y. B.; Buyanov, V. N.; Shtil, A. A.; Preobrazhenskaya, M. N.
Bioorg. Med. Chem. 2007, 15, 2651. (g) Attia, M. I.; Gu¨clu¨, D.; Hertlein,
B.; Julius, J.; Witt-Enderby, P. A.; Zlotos, D. P. Org. Biomol. Chem 2007,
5, 2129.
(3) (a) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995,
36, 6373. (b) Kan, T.; Fukuyama, T. Chem. Commun. 2004, 353. (c) Kan,
T.; Fukuyama, T. J. Synth. Org. Chem., Jpn. 2001, 59, 779.
10.1021/ol8008655 CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society