Preparation of aryl-substituted 2-oxyindoles by superelectrophilic chemistry

Article abstract of DOI:10.1016/j.tetlet.2013.04.011

A series of pyridyl-substituted 3-hydroxy-2-oxyindoles have been prepared and reacted with arenes in superacid promoted Friedel-Crafts reactions. The product aryl-substituted 2-oxyindoles are formed in generally good yields. With substituted arenes such as toluene, bromobenzene, or ethyl salicylate, the Friedel-Crafts reactions occur with excellent regioselectivity. A mechanism is proposed involving dicationic, superelectrophilic species leading to the electrophilic aromatic substitution chemistry.

Full text of DOI:10.1016/j.tetlet.2013.04.011

Tetrahedron Letters 54 (2013) 3245–3247
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Preparation of aryl-substituted 2-oxyindoles by superelectrophilic chemistry
⇑
Rajasekhar Reddy Naredla, Erum K. Raja, Douglas A. Klumpp
Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of pyridyl-substituted 3-hydroxy-2-oxyindoles have been prepared and reacted with arenes in
superacid promoted Friedel–Crafts reactions. The product aryl-substituted 2-oxyindoles are formed in
generally good yields. With substituted arenes such as toluene, bromobenzene, or ethyl salicylate, the
Friedel–Crafts reactions occur with excellent regioselectivity. A mechanism is proposed involving
dicationic, superelectrophilic species leading to the electrophilic aromatic substitution chemistry.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 16 March 2013
Revised 2 April 2013
Accepted 3 April 2013
Available online 10 April 2013
Keywords:
Heterocycle
Oxyindole
Superacid
Friedel–Crafts
Superelectrophile
Introduction
Results and discussion
Substituted oxyindoles are known to have a variety of biological
activities. The aryl-substituted oxyindole sub-structure is present
in natural products1 and in several biologically active compounds,
such as the anti-cancer (1),2 cardiovascular (2),3 and laxative (3)4
agents. The aryl-substituted oxyindoles
Our studies began with the reactions of 2-picoline with isatins
to provide a series of (2-pyridyl)methyl-substituted 2-oxyindoles.8
For example, 5-bromoisatin is reacted with 2-picoline in dioxane
with catalytic CF3SO3H to provide a good yield of the addition
product (4, Eq. (1)). Previous work from our group and others has
demonstrated the ability of pyridinium groups to strongly activate
adjacent electrophiles.9 This suggested to us that ionization of
alcohol 4 would give a highly reactive dicationic – or superelectr-
ophilic – species,10 an intermediate likely to be useful in Friedel–
Craft-type reactions.
may be prepared by a number of synthetic routes,5 including the
condensation of isatins with arenes in acid-promoted conversions.6
Similarly, Friedel–Craft-type reactions have recently been done
with 3-hydroxy-2-oxyindoles to provide aryl-substituted 2-oxyin-
doles.7 Nevertheless, new synthetic routes to aryl-substituted
2-oxyindoles are highly sought after, especially those producing
novel structures. In the following letter, we describe a synthetic
methodology leading to highly functionalized 2-oxyindoles. A
mechanism is proposed involving dicationic, superelectrophilic
intermediates.
ð1Þ
Thus, reaction of compound 4 in a mixture of CF3SO3H and
C6H6 leads to product 5 in 74% yield (Table 1). The same conver-
sion may be accomplished in 69% yield with H2SO4 as a catalyst.
Trifluoroacetic acid (CF3CO2H) does not promote the reaction. In
the CF3SO3H promoted conversion, 10 equiv of acid is necessary
to obtain high yields of product within several hours.11 With
substituted arenes, alcohol 4 reacts regioselectively in CF3SO3H
promoted reactions (Table 1). Toluene, bromobenzene,
2,6-dimethylphenol, 4-(3-phenylpropyl)pyridine, ethyl salicylate,
and anisole provide the respective Friedel–Crafts products (5–
11) in good yields. In all cases, the reaction shows excellent
⇑
Corresponding author. Tel.: +1 815 753 1959; fax: +1 815 753 4802.
E-mail address: dklumpp@niu.edu (D.A. Klumpp).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.04.011

3246
R. R. Naredla et al. / Tetrahedron Letters 54 (2013) 3245–3247
Table 1
Products (5–20) and isolated yields from the reactions of arenes and 3-hydroxy-2-oxyindoles in CF3SO3H
Product
Yield (%)
Product
Yield (%)
74
94
80
81
71
58
78
70
69
70
77
81
60
96
75
74
regioselectivity, an observation previously made with the conden-
sation of isatins and arenes in superacid.6 Likewise, reaction of ni-
tro- and chloro-substituted 2-oxyindoles gives regioselective
product formation (12–13) with toluene. Similar products (14–
20) are prepared by reactions of C- or N-functionalized substrates
with C6H6 and CF3SO3H.
tethered pyridyl ring should be fully protonated in the superacidic
media, leading to a highly reactive dicationic electrophile. Thus,
substrate 4 is initially ionized to the pyridyl-oxonium dication
21, which undergoes dehydration to form the superelectrophilic
carbocation 22. Although the carbocation center is somewhat sta-
bilized by the indolyl ring, it is also activated by both the pyridi-
num ring and the adjacent carbonyl group. Further protonation
or hydrogen bonding at the carbonyl oxygen (by the superacid)
As Friedel–Craft-type reactions, the conversions involve the for-
mation of a carbocation intermediate (Scheme 1). Moreover, the

R. R. Naredla et al. / Tetrahedron Letters 54 (2013) 3245–3247
3247
References and notes
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Scheme 1.
would provide increasing electrophilic activation at the carbocat-
ionic site. The need for strong or superacidic conditions is consis-
tent with the formation of dicationic, superelectrophiles.12
Conclusions
In summary, we have found that pyridyl-aryl disubstituted
2-oxyindoles may be prepared in good yields from Friedel–
Craft-type reactions involving 3-hydroxyl-2-oxyindoles.13,14 The
reactions may be accomplished with H2SO4 or CF3SO3H and a
mechanism is proposed involving dicationic electrophiles.
10. Olah, G. A.; Klumpp, D. A. Superelectrophiles and Their Chemistry; Wiley & Sons:
New York, 2008.
11. Triflic acid may be quantitatively recycled, see: Booth, B. L.; El-Fekky, T. A. J.
Chem. Soc., Perkin Trans. I 1979, 2441–2448.
Acknowledgments
12. Olah, G. A.; Prakash, G. K. S.; Molnar, A.; Sommer, J. Superacid Chemistry, 2nd
ed.; Wiley: New York, 2009.
We gratefully acknowledge the support of the NIH-National
Institute of General Medical Sciences (GM085736-01A1) and the
Northern Illinois University for Great Journeys Fellowship (R.R.N.).
13. General synthetic method: The 3-hydroxy-2-oxindoles (1 mmol) are dissolved
in 2 ml of C6H6 and triflic acid (CF3SO3H, 0.9 mL, 10 mmol) is then added. The
mixture is stirred for 2 h at 60 °C and then poured over several grams of ice. To
the resulting solution, CHCl3 (ca. 30 mL) is added and the aqueous phase is
made basic (pH paper) with drop-wise addition of NaOH (10 M). Following
product extraction, the organic phase is separated and washed successively
with H2O and twice with brine. The solution is dried with MgSO4 and the crude
product is isolated by filtration and removal of solvent. Further purification is
accomplished with column chromatography (silica gel; hexanes:ethyl acetate).
14. Triflic acid may be quantitatively recycled, see: Booth, B. L.; El-Fekky, T. A. J.
Chem. Soc., Perkin I 1979, 2441–2443.
Supplementary data
Supplementary data (analytical data and copies of 1H and
13C NMR spectra.) associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
04.011.