A new route to indolines by the cu-catalyzed cyclization reaction of 2-ethynylanilines with sulfonyl azides

Article abstract of DOI:10.1021/ol800049b

It is revealed that 2-sulfonyliminoindolines can be efficiently synthesized by the Cu-catalyzed cyclization reaction of N-alkyl-or aryl-substituted 2-ethynylanilines with sulfonyl azides. This new route to the indoline derivatives is characterized by mild

Full text of DOI:10.1021/ol800049b

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1163-1166
A New Route to Indolines by the
Cu-Catalyzed Cyclization Reaction of
2-Ethynylanilines with Sulfonyl Azides
Eun Jeong Yoo and Sukbok Chang*
Center for Molecular Design and Synthesis (CMDS), Department of Chemistry and
School of Molecular Science (BK21), Korea AdVanced Institute of Science and
Technology (KAIST), Daejeon 305-701, Republic of Korea
sbchang@kaist.ac.kr
Received January 9, 2008
ABSTRACT
It is revealed that 2-sulfonyliminoindolines can be efficiently synthesized by the Cu-catalyzed cyclization reaction of N-alkyl- or aryl-substituted
2-ethynylanilines with sulfonyl azides. This new route to the indoline derivatives is characterized by mild reaction conditions, facile introduction
of functional groups at the 2-position of the indoline ring, and the wide substrate scope. Selective transformation of indoline to oxindole and
isatin analogs is also demonstrated.
Indolines and their oxidized derivatives including indoles and
oxindoles are highly important pharmacophores that appear
in numerous biologically active natural products.1 Because
of the ubiquitous presence of the bicyclic heterocycles in
both natural and synthetic bioactive compounds,2 develop-
ment of new synthetic methods to the core skeleton is of
great interest. As a result, a range of transition metal-
mediated procedures using Pd, Ni, or Rh species have been
documented.3 Despite this advance, there is still a great need
to develop more convenient and diversity-oriented catalytic
systems that can accommodate such attractive features as
easily accessible starting materials, mild reaction conditions,
and nontoxic side products.
Although some examples of tandem reactions are known
to afford heterocyclic compounds with a high degree of
molecular complexity,4 most of these approaches do not
fulfill all of the desired features mentioned above. Addition-
ally, to the best of our knowledge, no synthetic routes aimed
at preparing indoline derivatives have been reported using
tandem processes with the concomitant introduction of
2-functional groups.
1,n-Aminoalkynes are regarded as versatile reactants for
the generation of cyclic amino compounds, mainly through
the catalytic hydroamination pathway.5 Along this line, we
recently reported a novel catalytic approach to cyclic
amidines upon the reaction of 1,3- or 1,4- aminoalkynes with
electron-deficient azides under mild conditions (Scheme 1,
eq 1).6 It was proposed that the reaction proceeded via a
tandem manner; metal-mediated intramolecular hydroami-
nation followed by [3+2] cycloaddition of the resulting cyclic
(1) Southon, I. W.; Buchingham, D. J. In Dictionary of Alkaoids; Cordell,
G. A., Saxton, J. E., Shmma, M., Eds.; Chapman and Hall: New York,
1989.
(2) Chang, J.; Heieh, H.; Chang, C.; Hsu, K.; Chiang, Y.; Chen, C.; Kuo,
C.; Liou, J. J. Med. Chem. 2006, 49, 6656-6659.
(3) For selected recent example, see (a) Omar-Amrani, R.; Thomas, A.;
Brenner, E.; Schneider, R.; Fort, Y. Org. Lett. 2003, 5, 2311-2314. (b)
Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35-37. (c) Shintani, R.;
Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8, 4799-4801. (d) Lira, R.;
Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906-13907.
(4) For selected recent examples, see: (a) Poondra, R. R.; Tumer, N. J.
Org. Lett. 2005, 7, 863-866. (b) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc.
2004, 126, 13906-13907. (c) Michael, D. G.; Kerr, M. A. Org. Lett. 2005,
7, 4777-4779.
10.1021/ol800049b CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/21/2008

Scheme 1
Table 1. Cascade Reaction for Indoline Derivative in Various
Reaction Conditionsa
entry catalyst (mol %)
additive
solvent
THF
THF
THF
THF
THF
yield (%)b
1
2
3
PdCl2 (10)
Ru3(CO)12 (10)
CuI (10)
-
-
-
<1c
<1c
46
<1
<1c
76
4
CuI (10)
Et3N
K2CO3
2,6-lutidine THF
enamines with azides, and then subsequent rearrangement
of the triazoline intermediates upon release of nitrogen or
diazomethane molecule.
5
CuI (10)
6
CuI (10)
7
8
9
10
11
12
13d
CuI (10)
CuI (10)
CuCl (10)
CuOAc (10)
Cu(OAc)2 (10)
CuI (20)
2,6-lutidine 1,4-dioxane
2,6-lutidine CHCl3
2,6-lutidine CHCl3
2,6-lutidine CHCl3
2,6-lutidine CHCl3
2,6-lutidine CHCl3
2,6-lutidine CHCl3
67
81
68
11
41
91
64
During our studies, we were wondering whether the
reaction of 2-ethynylanilines with azides might follow a
different initial step rather than hydroamination. This surmise
was based on our previous work on the Cu-catalyzed three-
component additions between 1-alkynes, sulfonyl- or phos-
phoryl azides, and amines, alcohols, or water.7 Herein, we
report results on the three-functional group coupling reaction,
from which indoline derivatives can be readily obtained
under mild conditions (Scheme 1, eq 2).
CuI (20)
a 2-Aminoalkyne (0.5 mmol), tosyl azide (1.2 equiv), additive (1.2 equiv),
and catalyst were stirred in the indicated solvent (1.0 mL) at 25 °C for 12
h. b 1H NMR yield (internal standard: 1,1,2,2-tetrachloroethane). c No
conversion. d CHCl3 (2.0 mL) was used.
At the outset of our studies, we examined various reaction
conditions using 2-ethynyl-N-methylaniline (1a) and p-
toluenesulfonyl azide (2a) as representative reacting partners
(Table 1). No conversion was observed in the presence of
Pd or Ru catalysts in THF (entries 1-2), strongly suggesting
that the hydroamination-initated process does not operate in
this case.6
In a sharp contrast, the reaction was catalyzed by CuI
species to afford 1-methyl-2-(p-toluenesulfonyl)imino-indo-
line (3a) although with a moderate yield (entry 3). It turned
out that reaction efficiency was significantly dependent on
the reaction conditions employed. For example, base addi-
tives (entries 4-6), reaction media (entries 6-8), the source
of the copper catalysts (entries 8-11), the amounts of
catalysts (entries 8 and 12), and substrate concentrations all
affected the reaction outcome (entries 12 and 13). When
phosphoryl- or acyl azides were allowed to react with 1a,
only poor conversion into corresponding indoline (<5%) was
observed under various reaction conditions.
methoxy)benzyl, or N-allyl group were readily employed
resulting in comparable product yields (entries 3-5). Some
functional groups such as cyano or ester moieties were also
tolerated under the conditions (entries 6-7).
The scope of sulfonyl azides that could be used was also
broad, and a wide range of derivatives readily afforded the
corresponding 2-sulfonyliminoindolines in good to excellent
yields. In fact, reaction efficiency was not significantly
affected by the electronic variation of the arenesulfonyl
azides (entries 8-11). Not only aryl- but also alkylsulfonyl
azides reacted smoothly with 2-aminoalkynes (entries 12-
13).
3-Alkynyl-2-aminopyridines also participated in the reac-
tion with tosyl azide leading to 2-sulfonylimino-1H-pyrrol-
opyridine in good yield (eq 3). A fused tricyclic benzoin-
doline derivative was obtained in a moderate yield when
1-amino-2-ethynylnaphthalene was allowed to react with
sulfonyl azides (eq 4).8
The optimized reaction conditions for the formation of 3a
were subsequently applied to a wide range of 2-ethynyla-
nilines and sulfonyl azides, and the results are summarized
in Table 2. It turns out that variation of N-substituents in
the 2-ethynylanilines does not alter efficiency of the reac-
tions. For example, substrates bearing N-methyl or N-phenyl
groups react smoothly with similar efficiency (entries 1-2).
Notably, removable N-substituents such as N-benzyl, N-(p-
(5) (a) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873-2920. (b)
Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126-1136.
(c) Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Perez, M.; Garcia-
Martin, M. A.; Gonzalez, J. M. J. Org. Chem. 1996, 61, 5804-5812. (d)
Cacchi, S.; Fabrizi, G.; Parisi, L. M. Org. Lett. 2003, 5, 3843-3846.
(6) Chang, S.; Lee, M. J.; Jung, D. Y.; Yoo, E. J.; Cho, S. H.; Han, S.
K. J. Am. Soc. Chem. 2006, 128, 12366-12367.
Interestingly, we found that the progress of the present
tandem reactions could be controlled by the nature of the
1164
Org. Lett., Vol. 10, No. 6, 2008

N-substituents on the 2-ethynylaniline substrates.9 Unlike
N-alkyl- and aryl reactants, N-sulfonyl- or N-acyl substituted
2-ethynylanilines did not convert completely to indolines.
Rather, we isolated, with moderate to high yields, 1-(N-
sulfonyl)-1,2,3-triazole compounds (5a-c) when N-sulfonyl-
or N-acylaminoalkynes (4) were applied to the same reaction
conditions (Scheme 2). This result is readily explained by
Table 2. Cu-Catalyzed Synthesis of Indoline Derivativesa
Scheme 2
the previously proposed pathways in the Cu-catalyzed three-
component coupling reactions,10 in which triazole initially
forms upon the [3+2] cycloaddition of azide and Cu-
acetylide. The ring-opening of the N-sulfonyl triazolyl
intermediate followed by release of N2 might be subsequently
carried out leading to another key intermediate, ketenimine
(6). It is reasonable to assume that the low nucleophilicity
of amide in the substrates (4) does not drive the succeeding
process to ketenimine intermediate into which the tethered
secondary amino group adds to afford 2-sulfonyliminoin-
doline.
The present catalytic route to indolines was successfully
applied to a large scale reaction. For instance, the reaction
of 1.0 g of 2-ethynyl-N-phenylaniline with p-toluenesulfonyl
azide provided the desired indoline product in 72% yield
(Scheme 3). The indoline compounds obtained in this study
were found to be quantitatively oxidized to the corresponding
isatin analogs (e.g., 7) upon treatment of 2-sulfonyliminoin-
dolines with cerium(IV) ammonium nitrate (CAN).11 It
(7) (a) Bae, I.; Han, H.; Chang, S. J. Am. Chem. Soc. 2005, 127, 2038-
2039. (b) Yoo, E. J.; Bae, I.; Cho, S. H.; Han, H.; Chang, S. Org. Lett.
2006, 8, 1347-1350. (c) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am.
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(8) When 4-(N-benzylamino)-1-butyne was employed as a substrrate, the
reaction did not proceed and we could not observe desired product. In
addition, the reaction of N-methyl-2-[(trimethylsilyl)ethynyl]aniline, as one
representative internal alkynyl substrate, did not take place.
(9) Whereas reactions of 1,3- or 1,4-aminoalkynes were postulated to
proceed through the catalytic hydroamination route (Ref 6), those of
2-ethynylanilines are proposed here to form triazoles first followed by ring-
opening process.
(10) (a) Cassidy, M. P.; Raushel, J.; Fokin, V. V. Angew. Chem., Int.
Ed. 2006, 45, 3154-3157. (b) Yoo, E. J.; Ahlquist, M.; Kim, S. H.; Bae,
I. H.; Fokin, V. V.; Sharpless, K. B.; Chang, S. Angew. Chem., Int. Ed.
2007, 46, 1730-1733.
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a 2-Ethynylaniline (0.5 mmol), sulfonyl azide (1.2 equiv), 2,6-lutidine
(1.2 equiv), and CuI (20 mol %) in chloroform (1.0 mL) at 25 °C for 12 h.
b Isolated yield. c PMB: p-methoxybenzyl.
Org. Lett., Vol. 10, No. 6, 2008
1165

Scheme 3. Cerium(IV) Ammonium Nitrate (CAN)-mediated
Scheme 4. Hydrolysis of 2-Iminoindoline to Oxindole
Conversion of Indolines to Isatin Analog
should be noted that the isatin skeleton has been known to
have highly interesting bioactivities.12
Acknowledgment. This research was supported by the
KOSEF grant (No. R01-2007-000-10618-0) and CMDS at
KAIST. We acknowledge the Korea Basic Science Institute
(KBSI) for the mass analysis.
The synthetic utility of 2-sulfonyliminoindolines was
additionally demonstrated in the conversion of these mol-
ecules to oxindole derivatives. When indoline 3a was
hydrolyzed in acidic conditions, 1-methyloxindole (8) was
produced in good yield (Scheme 4). The oxindole species
are considered to be important building blocks in both
organic synthesis13 and medicinal chemistry.14 In fact, it is
known that oxindoles are readily derivatized into 2,3-
disubstituted indoles14 or 3-alkylideneoxindoles,15 which are
interesting metabolic intermediates.16
Supporting Information Available: Experimental details
1
and H and 13C NMR spectra of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL800049B
In summary, we have developed a new synthetic route to
2-sulfonyliminoindolines using the reaction of 2-ethynyla-
nilines with sulfonyl azides in the presence of CuI catalyst.
Significantly, it offers important pharmacophores in good
yields with a wide substrate scope under mild reaction
conditions.
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