Efficient indole N-detosylation using thioglycolate

Article abstract of DOI:10.1016/j.tetlet.2003.10.154

The dilithium salt of thioglycolic acid in DMF can be used for the very efficient and convenient removal of N-p-toluenesulfonyl (tosyl) groups from a range of indoles at ambient temperature.

Full text of DOI:10.1016/j.tetlet.2003.10.154

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 599–601
Efficient indole N-detosylation using thioglycolate
Charlotte M. Haskins and David W. Knight*
Cardiff School of Chemistry, Cardiff University, PO Box 912, Cardiff CF10 3TB, UK
Received 10 October 2003; revised 17 October 2003; accepted 24 October 2003
Abstract—The dilithium salt of thioglycolic acid in DMF can be used for the very efficient and convenient removal of N-p-tolu-
enesulfonyl (tosyl) groups from a range of indoles at ambient temperature.
ꢀ
2003 Elsevier Ltd. All rights reserved.
The very stability of sulfonamides, while rendering them
attractive candidates for general amine protection,
clearly poses the conundrum of their eventual removal,
usually at a late stage in a synthetic scheme. A range of
dissolving metal reductions of a more or less appealing
nature can be effective such as sodium or lithium in
ammonia, an alcohol or HMPA and potassium and 18-
crown-6. Other single electron transfer reagents include
sodium naphthalenide, sodium amalgam and tributyltin
hydride, while photolysis and exposure to Red-Al pro-
phile-based method uses fluoride, provided in the form of
either potassium fluoride on alumina and requiring
microwave activation or tetrabutylammonium fluoride
7
(TBAF) in refluxing THF. Clearly, while effective in a
number of cases, applications of such reagent combina-
tions can be precluded because of the strongly basic
conditions, which are incompatible with some function-
ality or which may epimerise stereogenic centres.
6
8
These constraints led Fukuyama to develop a range of
1
vide contrasting alternatives.
nitrophenylsulfonyl groups as alternatives for general
amine protection. While clearly more vulnerable than
tosyl groups to various conditions and reagents such as
catalytic hydrogenation or nucleophiles, this latter
reactivity was exploited in a very selective and mild
method for their removal by ipso attack of thiopheno-
late followed by disintegration of the resulting nitronate
to give a phenyl(nitrophenyl)sulfide, sulfur dioxide and
the free amine. An even neater method employs thio-
glycolate as the sulfur nucleophile; clearly, the presence
of the carboxylate group allows simple by-product re-
moval during an aqueous work-up.
R
R
N
N
Ts
H
1
2
In the specific case of the N-detosylation of indoles 1,
other methods featuring nucleophilic attack at the sul-
fonyl group have proven viable, by reason of the lower
a
pK value associated with the nitrogen function in this
Herein, we report that thioglycolate can also be used for
the N-detosylation of indoles, thereby adding a partic-
ularly mild and relatively selective reagent to the fore-
going methods. The results of experiments with a variety
heterocycle 2 and hence its enhanced ability to act as a
leaving group. These include L-selectride, amongst a
2
number of hydride sources in some specific examples,
various concentrations of ethanolic hydroxide, which
9
of substituted indoles are presented in Table 1.
3;4
can require prolonged reflux, and the highly nucleo-
1
2
philic Gilman reagent, PhMe SiLi. A recently reported
Both N-tosylindole itself 3 and the 2-phenyl derivative
[
protocol features an alternative dissolving metal method,
5
that of magnesium in methanol, while another nucleo-
3; R ¼ Ph] were deprotected to give purified yields of the
corresponding free indoles 4 of just under 90% in 3 h at
ambient temperature. Similarly, the tetrahydrocarbazole
derivative 5 gave the NH derivative 6 in 80% yield in a
similar time, while N-tosylcarbazole 7 itself took a little
longer to react fully (5 h), but still the method delivered
*
0
Corresponding author. Fax: +44-2920-874210; e-mail: knightdw@
cf.ac.uk
040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.154

600
C. M. Haskins, D. W. Knight / Tetrahedron Letters 45 (2004) 599–601
Table 1. Detosylation of representative N-tosylindoles using thiogly-
colate
nucleophilic attack. For example, N-tosyl indole-3-car-
boxaldehyde 9 is converted into the free indole 10 in
essentially quantitative yield in only 1.5 h. No products
arising from other processes such as Cannizzaro reac-
tions were detected. Ester groups remain very largely
unattacked by thiogylcolate; thus, the 3-acetate deriva-
tive 11 is converted into the free indole ester 12 in 79%
isolated yield. In this case, activation to nucleophilic
attack was obviously much lower than that in the
foregoing example and complete reaction took 3 h.
Despite the basic conditions, there was no evidence for
the formation of Claisen condensation products. In
contrast, the indole-4-carboxylate 13 reacted a little
faster to give the free indole 14 in 2.5 h and in an isolated
R
R
S
CO2 2.Li
N
N
Ts
DMF, 20 ˚C,1.5–5 h
H
R
R
N
N
Ts
H
3
R ¼ H [3 h; 86%];
R ¼ Ph [3 h; 87%]
4
10
yield of 80%.
N
N
Ts
H
[3 h; 80%]
6
5
That the thiolate does indeed play a vital role in the
detosylations was established by exposing the indole-3-
carboxaldehyde derivative 9 to lithium hydroxide in
DMF but in the absence of thioglycolic acid. After 24 h
9
at ambient temperature, the usual work-up delivered
N
N
Ts
H
the free indole-3-aldehyde 10 in 82% yield. Hence, hy-
droxide alone in DMF is capable of removing N-tosyl
groups from indoles at ambient temperature, but at a
much slower rate (24 h compared with 1.5 h) in this case
of a relatively activated example. Less activated sub-
strates would clearly require even more prolonged re-
action times. This observation seems consistent with the
requirement for heating for extended periods when
[5 h; 87%]
7
8
O
O
N
N
H
Ts
[1.5 h; 95%]
10
9
3;4
ethanolic hydroxide is employed.
CO
2
Et
2
CO Et
Inevitably, almost any synthetic method has its limita-
tions, especially ones using nucleophiles. Thiolates in
general are well known to be good Michael nucleophiles,
so it did not come as much of a surprise to find that
detosylation of the unsaturated ester derivative 15 gave
a poor 41% purified yield of the free indole 16. The
material balance appeared to consist of Michael addi-
tion product(s) which, if derived from attack by thiolate,
could perhaps be converted back into the unsaturated
ester function by sequential oxidation and base treat-
ment. Finally, a probably unrecoverable example was
the attempted deprotection of the indole derivative 17
containing an a-keto-ester function. This resulted in no
identifiable products and little evidence for the forma-
tion of any free indole 18, presumably because of the
electrophilicity of the central carbonyl group.
N
N
H
Ts
11
[3 h; 79%]
12
2
CO Me
CO
2
Me
N
N
H
14
Ts
13
[2.5 h; 81%]
CO
2
Et
2
CO Et
N
N
H
16
Ts
5
1
[1 h; 41%]
We have also examined similar detosylations of two
imidazole derivatives 19. In view of the relatively good
leaving ability of the imidazole nucleus, it came as little
surprise that the corresponding free heteroaromatics
O
O
CO
2
Et
2
CO Et
20 were formed rapidly in around 90% purified
yields.
10
N
[1 h; 0%]
N
H
Ts
17
18
N
S
CO
2
2.Li
N
R
R
DMF, 20˚ C, 2~2.5 h
an excellent 87% return of the unprotected heterocycle 8.
Understandably, N-tosyl indoles having electron with-
drawing substituents are more prone to this type of
N
N
H
Ts
R = H [2 h; 92%]
R = Ph [2.5 h; 88%]
1
9
20

C. M. Haskins, D. W. Knight / Tetrahedron Letters 45 (2004) 599–601
601
In conclusion, we suggest that this relatively very mild
method will be useful for the N-detosylation of a very
wide range of indole derivatives, within some fairly
obvious constraints. Imidazoles can also be similarly
deprotected and possibly some other nitrogen-based
heteroaromatics. A particular advantage, certainly on a
small scale, is that the other products are so easy
removed from the free indoles using a simple wash with
mild aqueous base.
5. Muratake, H.; Natsume, M. Heterocycles 1989, 29, 783;
Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun.
1
997, 1017.
6
7
8
. Sabitha, G.; Abraham, S.; Subba Reddy, B. V.; Yadav,
J. S. Synlett. 1999, 1, 1745.
. Witulski, B.; Alayrac, C. Angew. Chem., Int. Ed. 2002, 41,
3
281.
. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett.
995, 36, 6373; Fukuyama, T.; Cheung, M.; Jow, C.-K.;
1
Hidai, Y. Tetrahedron Lett. 1997, 38, 5831; Kobayashi, S.;
Peng, G.; Fukuyama, T. Tetrahedron Lett. 1999, 40, 1519;
Kan, T.; Fujiwara, A.; Kobayashi, H.; Fukuyama, T.
Tetrahedron 2002, 58, 6267; Kunosawa, W.; Kan, T.;
Fukuyama, T. J. Am. Chem. Soc. 2003, 125, 8112, and
references cited therein.
Acknowledgements
9
. A representative procedure is as follows: The N-tosyl
indole or imidazole (0.5 mmol) was dissolved in DMF
We thank the EPSRC Mass Spectrometry Service,
University College Swansea for the provision of high
resolution Mass Spectrometric data and the EPSRC for
generous financial support.
(
2 mL). Lithium hydroxide (48 mg, 2.0 mmol) was added
followed by thioglycolic acid (30 ll, 0.6 mmol). The
resulting solution was stirred at ambient temperature
and monitored by TLC (1.5–5 h). When the reaction was
complete, the solution was diluted with ethyl acetate
(
4 mL) and water (2 mL) and the layers separated. The
References and Notes
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1
2
3
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aqueous sodium carbonate (3 · 5 mL) then dried (MgSO
4
),
filtered and evaporated. The residue was usually essen-
tially pure indole or imidazole. Additional purification, if
necessary, was then carried out by standard means
(crystallisation, chromatography etc.).
10. All N-tosyl derivatives and the corresponding free indoles
or imidazoles were identified by comparisons with
authentic materials.
2
002, 124, 13179.