Facile synthesis of azaarene-substituted 3-hydroxy-2-oxindoles via Bronsted acid catalyzed sp3 C - H functionalization

Article abstract of DOI:10.1021/ol2030982

Bronsted acid catalyzed functionalization of sp³ C - H bonds in 2-methyl azaarenes has been achieved in the reaction with isatins. This method provides facile synthesis of biologically important azaarene-substituted 3-hydroxy-2-oxindoles in one

Full text of DOI:10.1021/ol2030982

ORGANIC
LETTERS
2012
Vol. 14, No. 3
676–679
Facile Synthesis of Azaarene-Substituted
3-Hydroxy-2-oxindoles via Brønsted Acid
Catalyzed sp3 CÀH Functionalization
Rui Niu,†,‡ Jian Xiao,*,† Tao Liang,† and Xingwei Li*,†
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
P. R. China, and Key Laboratory of Marine Environment and Ecology,
Ministry of Education, and College of Environmental Science and Engineering,
Ocean University of China, Qingdao 266100, P. R. China
xiaojian@dicp.ac.cn; xwli@dicp.ac.cn
Received November 19, 2011
ABSTRACT
Brønsted acid catalyzed functionalization of sp3 CÀH bonds in 2-methyl azaarenes has been achieved in the reaction with isatins. This method
provides facile synthesis of biologically important azaarene-substituted 3-hydroxy-2-oxindoles in one step in moderate to good yields.
3-Substituted-3-hydroxy-2-oxindoles are key structural
motifs which recurrently appear in a large array of alka-
loids and natural products with diverse biological activities
such as potent antioxidant, anticancer, anti-HIV, and
neuroprotective properties.1 Representative examples
are convolutamydines, maremycins, donaxaridine,
SM-130686, dioxibrassinine, and welwitindolinone C
(Figure 1). Consequently, the 3-substituted-3-hydroxy-
2-oxindole framework has been an intensively investigated
synthetic target, and some elegant methods emerged such
as transition-metal-catalyzed cyclization of ortho-
prefunctionalized R-ketoanilides2 (boronate or halide) or
R-ketoamides3 as well as direct hydroxylation of oxin-
doles.4 In contrast, direct addition of nucleophiles to
isatins represents the most straightforward manner to con-
struct this motif. Thus direct catalytic arylation,5 alkyl-
ation,6 FriedelÀCrafts reactions,7 and organocatalyzed
aldol8 or MoritaÀBaylisÀHillman9 reactions have been
employed using isatins as electrophiles. However, all
the known methods deal with the synthesis of aryl or
alkyl substituted 3-hydroxy-2-oxindoles. As far as we
know, no method for the synthesis of azaarene-substi-
tuted 3-hydroxy-2-oxindoles has been reported, although
† Chinese Academy of Sciences.
‡ Ocean University of China.
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r
10.1021/ol2030982
Published on Web 01/24/2012
2012 American Chemical Society

Scheme 1. Proposed Brønsted Acid Catalyzed sp3 Functional-
ization of 2-Methylazaarenes
Figure 1. Representative natural products and pharmaceuticals
possessing 3-substituted 3-hydroxy-2-oxindoles.
Table 1. Screening of the Catalysta
azaarene-substituted 3-hydroxy-2-oxindoles hold great
potential for biological activities and pharmaceutical
utility.10 The biological effects are known to vary with
the substituent at the C3 position of oxindoles.1e Thus
development of an efficient synthetic route to this archi-
tecture is highly desirable.
Quite recently, activation of the sp3 CÀH bond in
2-methyl azaarenes has been achieved using Lewis acids
as the sole catalyst.11 However, only sporadic examples
were reported and functionalization of the sp3 CÀH bond
in 2-methylazaarenes remains largely unexplored despite
its synthetic utility.12 To the best of our knowledge, no
entry
catalyst
CH3SO3H
solvent
yield (%)b
1
2
3
4
5
6
7
dioxane
dioxane
dioxane
dioxane
dioxane
THF
76
71
44
70
85
38
41
p-CH3C6H4SO3H
CF3COOH
Tf2NH
TfOH
TfOH
(7) (a) Hanhan, N. V.; Sahin, A. H.; Chang, T. W.; Fettinger, J. C.;
Franz, A. K. Angew. Chem., Int. Ed. 2010, 49, 744. (b) Deng, J.; Zhang,
S.; Ding, P.; Jiang, H.; Wang, W.; Li, J. Adv. Synth. Catal. 2010, 352, 833.
(c) Chauhan, P.; Chimni, S. S. Chem.;Eur. J. 2010, 16, 7709.
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shima, H.; Kubo, K.; Shibata, N.; Toru, T. Chem.;Eur. J. 2008, 14,
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Asian J. 2009, 4, 1664. (c) Itoh, T.; Ishikawa, H.; Hayashi, Y. Org. Lett.
2009, 11, 3854. (d) Hara, N.; Nakamura, S.; Shibata, N.; Toru, T.
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Wei, Y.; Shi, M. Chem.;Eur. J. 2010, 16, 13617. (e) Zhong, F.; Chen,
G. Y.; Lu, Y. Org. Lett. 2011, 13, 82.
TfOH
toluene
a Reactions were conducted with 1a (0.75 mmol), 2a (0.3 mmol),
catalyst I (0.03 mmol) in 1 mL of solvent at 120 °C for 48 h. b Isolated
yield.
example of Brønsted acid catalyzed sp3 CÀH bond func-
tionalization of azaarenes has been reported although
Brønsted acids have been used to effect a wide variety of
transformations.13 As part of our ongoing interest in CÀH
bond activation as well as synthesis of diversity-oriented
structures,14 we now report the first Brønsted acid cata-
lyzed sp3 CÀH functionalization of 2-methylazaarenes,
leading to facile CÀC formation.
(10) (a) Campeau, L.-C.; Fagnou, K. Chem. Soc. Rev. 2007, 36, 1058.
(b) Bagley, M. C.; Glover, C.; Merritt, E. A. Synlett 2007, 2459.
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Tetrahedron 2004, 60, 6043. (e) Michael, J. P. Nat. Prod. Rep. 2005, 22,
627.
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Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683. (b) Campos, K. R.
Chem. Soc. Rev. 2007, 36, 1069. (c) Jazzar, R.; Hitce, J.; Renaudat, A.;
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Chem. Soc. Rev. 2003, 32, 289. (b) Pihko, P. M. Angew. Chem., Int. Ed.
2004, 43, 2062. (c) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew.
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Org. Lett., Vol. 14, No. 3, 2012
677

Table 2. Scope of 2-Methylazaarenesa
Scheme 2. Scope of Isatinsa
a Reactions were conducted with 2,6-lutidine 1 (0.75 mmol), isatins 2
(0.3 mmol), TfOH (0.03 mmol) in 1 mL of dioxane at 120 °C for 48 h. The
yields indicated are the isolated yield by column chromatography.
Scheme 3. Reaction of 1a with Other Dicarbonyls
As outlined in Scheme 1, we envision that protonation of
2-methyl-substituted azaarenes 1 should give pyridinium A.
As a result of the enhanced acidity of the benzylic protons
and the endogenous proton abstraction, CÀH cleavage
should occur to give enamine B. Synergistically, protonation
of the carbonyl group of isatin renders it more electrophilic
such that enamine B can nucleophilically add via transition
state C (Scheme 1) to afford the coupled product 3.
a Reactions were conducted with 1 (1.2 mmol), 2 (0.3 mmol), TfOH
(0.03 mmol) in 1 mL of dioxane at 120 oC for 48 h. b Isolated yield by
column chromatography. c Not determined.
To test this hypothesis, our initial studies were
conducted on the reaction of 2,6-lutidine (1a) and
1-methylindoline-2,3-dione (2a) in 1,4-dioxane catalyzed
by Brønsted acids (10 mol %) at 120 °C. It was found that
678
Org. Lett., Vol. 14, No. 3, 2012

commonly used Brønsted acids such as methanesulfonic
acid (MsOH) and p-toluenesulfonic acid gave good yields
(Table 1, entries 1À2). A lower yield was obtained for
trifluoroacetic acid, a weaker acid (Table 1, entry 3).
Trifluoromethanesulfonimide (Tf2NH), a widely used
strong Brønsted acid in synthetic organic chemistry,15
also gave good yield (Table 1, entry 4). Eventually, the
best result was obtained (85% yield) with trifluorometh-
anesulfonic acid (TfOH) in dioxane (Table 1, entry 5).
However, other solvents gave inferior results (Table 1,
entries 6À7).
Gratifyingly, when diketone 4a was allowed to react with
1a, the corresponding product 5a was isolated in 77%
yield. However, other acyclic 1,2-dicarbonyls such as ethyl
glyoxylate 4b and methyl pyruvate 4c failed to react under
the same conditions (Scheme 3).
To probe the selectivity of 1,2 addition versus 1,4
addition of enones, the reaction of (E)-methyl 2-oxo-4-
phenylbut-3-enoate (6) and 1a was carried out (20 mol %
TfOH). Interestingly, only the 1,2 addition product 7 was
isolated (33% yield, Scheme 4). This observed exclusive 1,2
addition selectivity agrees with the proposed mechanism in
Scheme 1.
With the optimized conditions in hand, we examined a
variety of N-substituted isatins in the reaction with 2,6-
lutidine (Scheme 2). Both electron-donating and -with-
drawing substituents, including halogen groups, in the
isatin phenyl ring are well-tolerated, affording the desired
products in yields ranging from 60% to 84% (Scheme 2,
3aÀ3e), where there seems no direct correlation between
the efficiency of this reaction and the electronic effects
of these substituents. Next, a range of N-alkylated isatins
were allowed to react with 1-methylindoline-2,3-dione
(2a). N-Ethyl, -propyl, and -benzyl isatins are suitable
substrates, and 3fÀh were isolated in good yields
(70À80%). However, the reaction of simple NH protic
isatin afforded product 3i in only 33% yield, which prob-
ably resulted from the decomposition of isatin. The scope
of 2-methylazaarenes was theninvestigated, and the results
are given in Table 2. The 2-methyl group in pyridine,
quinoline, and quinoxaline rings can smoothly add to
N-methylisatin to afford the corresponding 3-hydroxy-2-
oxindoles in moderate to good yields (Table 2, 3jÀ3m).
Notably, when 2-methylquinoline was used as the sub-
strate, the analogous product 3na was not detected. In-
stead, the 1,2 addition product 3nb was isolated in 34%
yield. Thus in situ generated 3na is proposed to undergo a
subsequent acid-catalyzed dehydrative coupling reaction
to furnish product 3nb. In sharp contrast, this selectivity
was not observed in the reported Lewis acid catalyzed
addition of 2-methylquinoline to imines and enones.12
Notably when 2,4-lutidine was employed as a substrate,
two isometric products (3pa and 3pb) were isolated in
essentially the same yield. This implies that the 2- and
4-methyl groups are of comparable reactivity. Indeed,
when only a 4-methyl group is present as in 4-picoline,
product 3o was also obtained in 58% yield.
Scheme 4. 1,2 Addition vs 1,4 Addition
In summary, we present the first Brønsted acid catalyzed
sp3 CÀH functionalization of 2-methyl-substituted azaar-
enes for the efficient construction of substituted 3-hydro-
xy-2-oxindoles. A relatively broad scope of isatins and
azaarenes has been defined, and the coupled products were
isolated in moderate to good yields. This method provides
an efficient and new protocol to construct this biologically
important architecture in a single step. The success of this
reaction should broaden the synthetic utility of Brønsted
acids in the catalytic functionalization of sp3 CÀH bonds
in organic synthesis.
Acknowledgment. Financial support from the Dalian
Institute of Chemical Physics, Chinese Academy of
Sciences and the National Natural Science Foundation
of China (No. 21102142) is gratefully acknowledged.
Supporting Information Available. Additional experi-
mental procedures and spectroscopic data of new pro-
ducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
Encouraged by the success in isatin substrates, we
attempted to extend the scope to other 1,2-dicarbonyls.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 3, 2012
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