A green N-detosylation of indoles and related heterocycles using phase transfer catalysis

Article abstract of DOI:10.1021/op700274v

A practical method for the N-detosylation of indoles and related heterocycles with KOH in THF and water in the presence of a phase transfer catalyst is described. Using a nonalcoholic solvent, this method prevents the formation of toxic alkyl p-toluene-sulfonate and consequently eliminates the formation of even traces of N-alkyl byproduct. This green method is particularly useful for indoles bearing electron-withdrawing groups and for azaindoles.

Full text of DOI:10.1021/op700274v

Organic Process Research & Development 2008, 12, 778–780
Communications to the Editor
A Green N-Detosylation of Indoles and Related Heterocycles Using Phase Transfer
Catalysis
Yugang Liu,* Lichun Shen, Mahavir Prashad,* Jessica Tibbatts,‡ Oljan Repicˇ, and Thomas J. Blacklock
Process Research & DeVelopment, NoVartis Pharmaceuticals Corporation, One Health Plaza, East HanoVer,
New Jersey 07936, U.S.A.
Scheme 1
Abstract:
A practical method for the N-detosylation of indoles and related
heterocycles with KOH in THF and water in the presence of a
phase transfer catalyst is described. Using a nonalcoholic solvent,
this method prevents the formation of toxic alkyl p-toluene-
sulfonate and consequently eliminates the formation of even traces
of N-alkyl byproduct. This green method is particularly useful for
indoles bearing electron-withdrawing groups and for azaindoles.
sonication (Mg/MeOH).3 Deprotections under nucleophilic
conditions, such as PhMe2SiLi, HSCH2CO2H/LiOH, tetra-n-
butlyammonium fluoride,6 sodium or potassium hydroxide/
alcohol, and Cs2CO3/THF/MeOH4 have also been reported.
Despite the many N-detosylation methods, very few are
really useful in industries where safety, simplicity and reliability
are desired. While making an azaindole-containing active
pharmaceutical ingredient, we needed to cleave the N-tosyl
group without producing impurities that were difficult to
remove. We tried several methods reported in the literature,
and none of them gave satisfactory results. The best results were
obtained using KOH/MeOH or Cs2CO3/THF/MeOH, but they
generated an N-methylated impurity, which was very difficult
to remove by crystallization or by chromatography. Methanol
as solvent led to the formation of toxic methyl p-toluene-
sulfonate as the byproduct in this detosylation reaction, as a
consequence of esterification of liberated p-toluenesulfonic acid,
which acted as the N-alkylating agent on the deprotected indole5
(Scheme 1). When difficult to remove, even 1-2% of such an
N-alkylated byproduct could be a serious problem in achieving
the desired purity specifications of drug substances. Addition-
ally, special measures are required on large scale due to the
carcinogenic nature of these alkyl p-toluenesulfonates.
Introduction
Indoles and related structures are widely found in many
active pharmaceutical ingredients. The NH groups are often
protected as p-toluenesulfonamides along the synthetic pathways
when incompatibilities with other functionalities or reagents
arise. One has to deal with the eventual removal of the tosyl
group, usually at a later stage of the synthesis. Not surprisingly,
many protocols for the N-detosylation of indoles have been
reported, such as reductive cleavage by dissolving metals in
ammonia, HMPA, or alcohol,1 single-electron transfer reagents
including sodium naphthalenide, sodium amalgam, and
Bu3SnH,2 and those involving the use of special devices, for
example, electrolysis, microwave activation (KF/Al2O3), and
* To whom correspondence should be addressed. E-mail: yugang.liu@
novartis.com. Telephone: 862-778-3470. Fax: 973-781-4384.
‡ Summer Intern (2007) from Pennsylvania State University, University Park,
PA.
(1) (a) du Vigneaud, V.; Behrens, O. K. J. Biol. Chem. 1937, 117, 27. (b)
Kovacs, J.; Ghatak, U. R. J. Org. Chem. 1966, 31, 119. (c) Heathcock,
C. H.; Smith, K. M.; Blumenkopf, T. A. J. Am. Chem. Soc. 1986, 108,
5022. (d) Schultz, A. G.; McCloskey, P. J.; Court, J. J. J. Am. Chem.
Soc. 1987, 109, 6493. (e) Yamazaki, N.; Kibayashi, C. J. Am. Chem.
Soc. 1989, 111, 1396. (f) Wittig, G.; Joos, W.; Rathfelder, P. Liebigs
Ann. Chem. 1957, 610, 180. (g) Howard, C. C.; Marckwald, W. Chem.
Ber. 1899, 32, 2031. (h) Cuvigny, T.; Larcheveˆque, M. J. Organomet.
Chem. 1974, 64, 315. (i) Ohsawa, T.; Takagaki, T.; Ikehara, F.;
Takahashi, Y.; Oishi, T. Chem. Pharm. Bull. 1982, 30, 3178.
(2) (a) Ji, S.; Gortler, L. B.; Waring, A.; Battisti, A.; Bank, S.; Closson,
W. D.; Wriede, P. J. Am. Chem. Soc. 1967, 89, 5311. (b) Closson,
W. D.; Ji, S; Schulenberg, S. J. Am. Chem. Soc. 1970, 92, 650. (c)
Quaal, K. S.; Ji, S.; Kim, Y. M.; Closson, W. D.; Zubieta, J. A. J. Org.
Chem. 1978, 43, 1311. (d) Nagashima, H.; Ozaki, N.; Washiyama, M;
Itoh, K. Tetrahedron Lett. 1985, 26, 657. (e) McIntosh, J. M.; Matassa,
L. C. J. Org. Chem. 1988, 53, 4452. (f) Henry, J. R.; Marcin, L. R.;
McIntosh, M. C.; Scola, P. M.; Harris, G. D, Jr.; Weinreb, S. M.
Tetrahedron Lett. 1989, 30, 5709. (g) Birkinshaw, T. N.; Holmes, A. B.
Tetrahedron Lett. 1987, 28, 813. (h) Chavez, F.; Sherry, A. D. J. Org.
Chem. 1989, 54, 2990. (i) Parsons, A. F.; Pettifer, R. M. Tetrahedron
Lett. 1996, 37, 1667.
Therefore, we needed to develop a convenient and practical
method for the N-detosylation that avoided the formation of
toxic alkyl p-toluenesulfonate, and subsequently formation of
even traces of N-alkylated byproduct. Herein, we describe our
results on the development of a green method for this
(3) (a) Fleming, I.; Frackenpohl, J.; Ila, H. J. Chem. Soc., Perkin Trans. 1
1998, 1229. (b) Horner, L.; Neumann, H. Chem. Ber. 1965, 98, 3462.
(c) Moriwake, T.; Saito, S.; Tamai, H.; Fujita, S.; Inaba, M. Heterocycles
1985, 23, 2525.
(4) (a) MacCoss, R. N.; Henry, D. J.; Brain, C. T.; Ley, S. V. Synlett 2004,
675. (b) Haskins, M. C.; Knight, D. W. Tetrahedron Lett. 2004, 45,
599. (c) Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997,
1017. (d) Muratake, H.; Natsume, M. Hetrocycles 1989, 29, 783. (e)
Bajwa, J. S.; Chen, G-P.; Prasad, K.; Repicˇ, O.; Blacklock, T. J.
Tetrahedron Lett. 2006, 47, 6425.
(5) Shirley, D. A.; Roussel, P. A. J. Am. Chem. Soc. 1953, 75, 375.
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2003, 5, 4301.
778
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Vol. 12, No. 4, 2008 / Organic Process Research & Development
10.1021/op700274v CCC: $40.75
2008 American Chemical Society
Published on Web 05/30/2008

Table 1. N-Detosylationa of N-tosyl-7-azaindole (1a)
Table 2. N-Detosylationa of indoles and related heterocycles
rxn temp
(°C)
rxn time (h)/
conversion (%)
entry
base
catalyst
1
2
KOH
none
20
65
20
65
65
20
65
20
65
20
65
20
65
20
65
20
65
20/0.3
48/95.0
20/2.0
10/100
20/100
20/2.2
15/100
20/0.3
20/78.0
20/2.0
20/100
20/0.1
20/0.1
20/0.1
20/5.0
20/0.1
20/6.0
KOH
none
3
KOH
CTAB
CTAB
Me4NCl
Bu4NBr
Bu4NBr
TDA-1
TDA-1
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
CTAB
4
KOH
KOH
5
6
KOH
7
KOH
8
KOH
9
KOH
10
11
12
13
14
15
16
17
NaOH
NaOH
Na2CO3
Na2CO3
K2CO3
K2CO3
Cs2CO3
Cs2CO3
a Conditions: 1 mmol of N-tosyl-7-azaindole, 5 mmol of base, 1.5 mL of THF and
0.5 mL of water were mixed and treated with or without phase transfer catalyst at 20
°C or at reflux. The conversion was determined by HPLC @ 280 nm.
transformation using KOH in THF and H2O under phase
transfer catalysis (PTC) conditions.
Results and Discussion
We first investigated the N-detosylation of N-tosyl-7-
azaindole in THF and water using KOH (Table 1). The reaction
mixture showed two clear layers when settled, and almost no
detosylation was observed (entry 1) under vigorous stirring at
room temperature. The reaction did occur at 65 °C, but took
48 h to achieve 95% conversion (entry 2). However, the use of
a phase transfer catalyst cetyltrimethylammonium bromide
(CTAB) was found to significantly accelerate the reaction,
leading the completion of reaction in only 10 h (entry 4). Other
phase transfer catalysts, e.g., tetramethylammonium chloride,
tetramethylammonium bromide and tris(dioxa-3,6-heptyl)amine
(TDA-1) were not as effective as CTAB (entries 5-9). The
reason for the rate differences was probably due to the fact that
CTAB has a more lipophilic cetyl group, as suggested by the
trend going from tetramethylammonium chloride to CTAB. No
emulsion was observed with either of the catalysts. Interestingly,
the N-detosylation took much longer if the base was changed
to NaOH (entries 10-11). As expected, weaker bases such as
Na2CO3, K2CO3 and Cs2CO3 led to negligible N-detosylation
(entries 12-17).
To test the scope and limitations of this N-detosylation
method, a variety of indole derivatives were subjected to the
above reaction conditions. The results are summarized in Table
2. A complete N-detosylation of N-tosyl indole (1b) was
achieved in 72 h in the presence of CTAB, whereas only 15%
conversion was observed without CTAB under identical condi-
tions (entry 2). Again CTAB accelerated the N-detosylation
reaction. The N-detosylation of N-tosyl indoles bearing an
electron-withdrawing group, e.g., aza (1a), 5-nitro (1c), and
a Conditions: 1 mmol of substrate, 5 mmol of KOH, 1.5 mL of THF and 0.5
mL of water were mixed and treated with or without 0.05 mmol of CTAB at
reflux.7 The conversion was determined by HPLC
temperature.
@ 280 nm. rt ) room
5-bromo (1d), were relatively faster compared to N-tosyl indole
(1b) itself, and went to completion in 10, 1.5, and 26 h,
respectively (entries 1, 3-4). Without CTAB, the conversions
were 53, 90, and 39%, respectively. However, the reactions of
N-tosyl indoles bearing an electron-donating group, such as
3-methyl (1e) and 5-methoxy indoles (1f) (entries 5-6), were
quite slow, giving only 35% and 73% conversion, respectively,
after 120 h in the presence of CTAB, and 1.5% and 8% without
CTAB. Deprotection of N-tosyl imidazoles, indazoles, and
triazoles was significantly faster compared to N-tosyl indole
(1b). However, the reactions without CTAB were also quite
fast. Detosylation of 2-phenylimidazole (1g) proceeded to
completion in 7 h with the catalyst, while only 61% conversion
was observed without CTAB (entry 7). For N-tosyl indazole
(1 h), the deprotection was complete in 3.5 h with CTAB and
Vol. 12, No. 4, 2008 / Organic Process Research & Development
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779

90% conversion without catalyst (entry 8). In case of N-tosyl
benzimidazole (1i) (entry 9), the deprotection was carried out
at room temperature and was complete in 4 h, while 15%
conversion occurred without CTAB. Deprotection of N-tosyl-
1H-benzotriazole (1j) (entry 10) was complete in 40 min at
room temperature with CTAB and in 1 h without CTAB. Thus,
CTAB consistently accelerated the N-detosylation reaction in
all cases.
In summary, we demonstrated that the N-detosylation of a
wide range of indole derivatives was accomplished with KOH
in THF and water in the presence of a phase transfer catalyst.
This method eliminates the formation of toxic alkyl p-toluene-
sulfonates and, consequently, even traces of N-alkyl byproduct
formed in alcoholic solvents. This green method is particularly
useful for indoles bearing electron-withdrawing groups and for
azaindoles.
A Typical Procedure of N-Detosylation. To a solution of
N-tosyl-7-azaindole (100 g, 367 mmol) in THF (540 mL) and
water (180 mL) was added CTAB (6.7 g, 0.05 equiv) and KOH
(103.0 g, 5 equiv). The mixture was heated at refluxing until
HPLC indicated the completion of the reaction. Water (300 mL)
and i-PrOAc (500 mL) were added to the reaction mixture upon
cooling to room temperature. The organic layer was separated
and washed with water (2 × 300 mL). It was then concentrated
under reduced pressure to a batch volume of ∼100 mL.
Heptanes (400 mL) was added to the residue. The resulting
suspension was distilled under reduced pressure to a batch
volume of ∼300 mL. The suspension was cooled to room
temperature and filtered. The filtered cake was washed with
heptanes (50 mL) and dried under reduced pressure at 55 °C
for 2 h to afford 7-azaindole (39.0 g, 90% yield).
Experimental Section
All products are catalogued compounds and have been
verified to be identical with the commercial materials.
Received for review November 28, 2007.
OP700274V
780
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