(1-Nosyl-5-nitroindol-3-yl)methyl ester: A novel protective group for carboxylic acids

Article abstract of DOI:10.1021/ol8008655

(Chemical Equation Presented) 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.

Full text of DOI:10.1021/ol8008655

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
fukuyama@mol.f.u-tokyo.ac.jp
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

Scheme 2
.
Attempted Cleavage of Indol-3-ylmethyl Ester
Scheme 4. Preparation of Alcohol 12 and Chloride 13
without any chromatographic separations. Alcohol 12 was
readily transformed into its chloride 13 by treatment with
thionyl chloride.
The esters of aryl, aliphatic, R,ꢀ-unsaturated, and R-amino
caboxylic acids with alcohol 12 were prepared by treatment
with EDCI and a catalytic amount of DMAP in dichlo-
romethane (Table 1, method A). Alkylation of the carboxylic
acids with chloride 13 also proceeded in the presence of
omethyl)indole (8) was also isolated, which might be formed
via a reaction of the intermediate 2 with thiophenol.
Although the high reactivity of (1-Ns-indol-3-yl)methyl
ester to liberate the corresponding carboxylic acid was
confirmed, it turned out that the ester is too labile under acidic
conditions to serve as a good protecting group. Upon
treatment with trifluoroacetic acid, for example, only a trace
amount of 4b could be recovered (Scheme 3). To increase
Table 1. Preparation of (1-Ns-5-nitroindol-3-yl)methyl Estersa
Scheme 3. Stability of the Esters under Acidic Conditions
the stability under acidic conditions, we attempted to
introduce an additional electron-withdrawing group4 and
found that a nitro group at the 5-position of indole greatly
increased the stability of the corresponding ester. Under the
aforementioned acidic conditions, 9b was recovered in 89%
yield. Hence, we decided to employ the (1-Ns-5-nitroindol-
3yl)methyl group as a protective group for carboxylic acids.
(1-Ns-5-Nitroindol-3-yl)methyl esters can be prepared
either by condensation with alcohol or by alkylation, as
described below. Preparation of the requisite alcohol 12 and
chloride 13 is shown in Scheme 4. Commercially available
5-nitroindole (10) was subjected to the Vilsmeier reaction
to give formylindole 11.5 Introduction of the Ns group on
the indole nitrogen followed by reduction with NaBH4
afforded (1-Ns-5-nitroindol-3yl)methanol (12) in good yield
a Method A: 12 (X ) OH, 1.2 equiv), EDCI (1.5 equiv), DMAP (cat),
CH2Cl2. Method B: 13 (X ) Cl, 1.2 equiv), Cs2CO3 (3.0 equiv), NaI (3.0
equiv), CH3CN, 40 °C.
(4) Schwarz, H.; Arakawa, K. J. Am. Chem. Soc. 1959, 81, 5691.
(5) Noland, W. W.; Rieke, R. D. J. Org. Chem. 1962, 27, 2250.
2602
Org. Lett., Vol. 10, No. 12, 2008

Scheme 5
.
Heck Reaction
Table 2. Cleavage of (1-Ns-5-nitroindol-3-yl)methyl Estersa
cesium carbonate and sodium iodide in acetonitrile to furnish
the corresponding (1-Ns-5-nitroindol-3yl)methyl esters in
good yields (method B). In addition, we found that acrylate
14 is a suitable substrate for the Mizoroki-Heck reaction.6,7
Treatment with aryl iodide 15e-g under the standard
conditions furnished the corresponding R,ꢀ-unsaturated esters
9e-g in moderate to high yields (Scheme 5).
With a variety of (1-Ns-5-nitroindol-3-yl)methyl esters in
hand, we next tried to cleave the esters.8 Upon treatment
with 2-(dimethylamino)ethanethiol hydrochloride (16, 2 eq)
and DBU (4 eq) in acetonitrile at room temperature, the esters
underwent a facile cleavage of the Ns group to give the
deprotected carboxylic acids by way of elimination. The
whole process was completed within 15 min. As shown in
Scheme 2, two byproducts 7 and 8, which arose from the
Ns group and the indole core, respectively, were obtained
in the deprotection with thiophenol. Using aminothiol 16 as
a nucleophile, all the byproducts and the reagents can easily
be removed by washing with aqueous hydrochloric acid,
leaving the practically pure carboxylic acids in the organic
phase.
The cleavage of the aryl, aliphatic, and R,ꢀ-unsaturated
esters proceeded in good yields (Table 2, entries 1-7). The
deprotection of the R,ꢀ-unsaturated esters occurred without
forming the Michael adducts. A variety of protective groups,
such as Ac, THP, Boc, Alloc, and Cbz, remained intact under
these conditions (entries 6-10). Racemization of amino acids
was not observed during the deprotection.9 Although the
base-labile Fmoc group did not tolerate the above conditions,
treating 9k with thiophenol and potassium carbonate in
acetonitrile gave the desired product in good yield (entry
a Reaction conditions: HSCH2CH2NMe2·HCl (2.1 equiv), DBU (4.2
equiv), CH3CN, rt. b PhSH (2.0 equiv), K2CO3 (3.0 equiv), CH3CN, rt.
(6) (a) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971,
11). Typical esters of carboxylic acids, including t-butyl,
allyl, and benzyl esters, were also stable under these
conditions (entries 12-14).
Next, we examined the stability of (1-Ns-5-nitroindol-3-
yl)methyl esters. Removal of the protective groups on
nitrogen, such as Boc, Alloc, and Fmoc, could be conducted
under the standard conditions (Table 3, entries 1, 2 and 4).10
Additionally, the Cbz group was also removed by treatment
44, 581. (b) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320
.
(7) Ester 14 was prepared by a reaction of 12 with acryloyl chloride
.
(8) Esters 9i-k were prepared by condensation of the corresponding
carboxylic acids with 12 or by acylation of amine 17. On the other hand,
Esters 9l-n were obtained by reaction of 12 with succinic anhydride,
followed by esterification of the resulting carboxylic acid. For experimental
details, see the Supporting Information.
(9) The optical purity of the product 6j was determined as 99% ee by
HPLC (CHIRALCEL OD, hexane/2-propanol ) 90:10, 1.0 mL/min) after
transformation into its methyl ester (SOCl2, MeOH, rt).
Org. Lett., Vol. 10, No. 12, 2008
2603

a
Table 3. Compatibility of (1-Ns-5-nitroindol-3-yl)methyl Esters
entry
substrate
conditions
product
yield (%)
1
2
3
4
5
6
7
8
9h: R ) Boc
9i: R ) Alloc
9j: R ) Cbz
9k: R ) Fmoc
9l: R ) t-Bu
9m: R ) Allyl
9n: R ) Bn
20% TFA CH2Cl2
17
17
17
17
18
18
-
91
87
86
90
98
71
Pd(PPh3)4 TMSNEt2 CH2Cl2
TMSCl, NaI CH3CN
20% piperidine DMF
HCO2H
Pd(PPh3)4 Pyrrolidine CH3CN
-
b
-
9g: R ) THP
CSA MeOH-CH2Cl2
19
quant
a Reactions were performed under the conditions provided in the Table. b The desired product was not obtained.
with TMSCl and sodium iodide in acetonitrile without using
hydrogenolysis conditions (entry 3).11 Although selective
For further application of (1-Ns-5-nitroindol-3-yl)metha-
nol, trapping an isocyanate was attempted. Reaction of
isocyanate 20, derived from carboxylic acid 6c, with (1-Ns-
5-nitroindol-3-yl)methanol (12) proceeded to furnish car-
bamate 21 in good yield. Upon treatment with thiolate, the
carbamate was smoothly cleaved to generate the correspond-
ing amine 22, which was isolated in good yield as its Boc
amide (Scheme 6).
Scheme 6
In summary, we have demonstrated the utility of (1-Ns-
5-nitroindol-3-yl)methyl esters as a novel protective method
for carboxylic acids. Cleavage of the Ns group under mild
conditions liberated the corresponding carboxylic acids in
excellent yields. This novel protective group is stable under
acidic or basic conditions and is orthogonal to existing
protective groups for carboxylic acid, such as t-butyl and
allyl esters.
Acknowledgment. This work was financially supported
in part by a Grant-in-Aid (15109001, 16073205 and 19590004)
from the Ministry of Education, Culture, Sports, Science,
and Technology of Japan.
cleavage of benzyl ester could not be achieved even by
employing Lewis acids, t-butyl and allyl esters were cleaved
under the typical conditions (entries 5-7). On the other hand,
a THP ether was easily removed by treatment with CSA in
methanol (entry 8).
Supporting Information Available: Experimental details
and spectroscopic data. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL8008655
(10) Merzouk, A.; Guibe´, F.; Loffet, A. Tetrahedron Lett. 1992, 477,
35.
(11) Jung, M. E.; Lyster, M. A. J. Chem. Soc., Chem. Commun. 1978,
315.
2604
Org. Lett., Vol. 10, No. 12, 2008