Redox isomerization via azomethine ylide intermediates: N-alkyl indoles from indolines and aldehydes

Article abstract of DOI:10.1021/ol1031359

Indolines react with aromatic and heteroaromatic aldehydes to yield N-alkyl indoles in a benzoic acid catalyzed redox isomerization reaction. Azomethine ylides are intermediates in this process which was established by intramolecular [3 + 2] trapping expe

Full text of DOI:10.1021/ol1031359

ORGANIC
LETTERS
2011
Vol. 13, No. 4
812–815
Redox Isomerization via Azomethine Ylide
Intermediates: N-Alkyl Indoles from
Indolines and Aldehydes
Indubhusan Deb, Deepankar Das, and Daniel Seidel*
Department of Chemistry and Chemical Biology, Rutgers, The State University of
New Jersey, Piscataway, New Jersey 08854, United States
seidel@rutchem.rutgers.edu
Received December 25, 2010
ABSTRACT
Indolines react with aromatic and heteroaromatic aldehydes to yield N-alkyl indoles in a benzoic acid catalyzed redox isomerization reaction.
Azomethine ylides are intermediates in this process which was established by intramolecular [3 þ 2] trapping experiments.
The ubiquity of the indole nucleus in natural products
and medicinal agents continues to inspire the development
Scheme 1. Tunge’s Redox Neutral Pyrrole Formation
of new synthetic approaches to this heterocyclic frame-
work.1,2 Here we report a redox neutral method for the
formation of N-alkyl indoles from indolines and aldehydes.
In a recent publication, Tunge et al. described the intrigu-
ing formation of N-alkyl pyrroles 2 via the reaction of
3-pyrroline (1) with aldehydes or ketones in the presence of
an acid catalyst (Scheme 1).3 As proposed by these authors,
this reaction proceeds via a redox isomerization process in
which 3 and 4 are likely intermediates in the sequence
leading up to the formation of pyrroles.
In the course of our studies aimed at developing redox
neutralamine functionalizations,4,5 we became interested in
the mechanism of this reaction and its possible application
(1) For selected reviews on indole chemistry, see: (a) Gribble, G. W. J.
Chem. Soc., Perkin Trans. 1 2000, 1045. (b) Cacchi, S.; Fabrizi, G. Chem.
Rev. 2005, 105, 2873. (c) Humphrey, G. R.; Kuethe, J. T. Chem. Rev.
2006, 106, 2875. (d) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed.
2009, 48, 9608. (e) Palmieri, A.; Petrini, M.; Shaikh, R. R. Org. Biomol.
Chem. 2010, 8, 1259.
(4) (a) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc.
2008, 130, 416. (b) Murarka, S.; Zhang, C.; Konieczynska, M. D.; Seidel,
D. Org. Lett. 2009, 11, 129. (c) Zhang, C.; Murarka, S.; Seidel, D. J. Org.
Chem. 2009, 74, 419. (d) Murarka, S.; Deb, I.; Zhang, C.; Seidel, D. J.
Am. Chem. Soc. 2009, 131, 13226. (e) Zhang, C.; Seidel, D. J. Am. Chem.
Soc. 2010, 132, 1798. (f) Deb, I.; Seidel, D. Tetrahedron Lett. 2010, 51,
2945. (g) Zhang, C.; Das, D.; Seidel, D. Chem. Sci. 2011, 2, Advance
Article DOI: 10.1039/C0SC00432D.
(2) For the importance of indoles in the context of medicinal chem-
istry, see for example: (a) Alves, F. R. D.; Barreiro, E. J.; Fraga, C. A. M.
Mini-Rev. Med. Chem. 2009, 9, 782. (b) Welsch, M. E.; Snyder, S. A.;
Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347. (c) Kochanowska-
Karamyan, A. J.; Hamann, M. T. Chem. Rev. 2010, 110, 4489.
(3) Pahadi, N. K.; Paley, M.; Jana, R.; Waetzig, S. R.; Tunge, J. A.
J. Am. Chem. Soc. 2009, 131, 16626.
r
10.1021/ol1031359
Published on Web 01/19/2011
2011 American Chemical Society

to other processes. The most direct pathway leading from 3
to 4 would involve a 1,3-hydride shift.6 However, orbital
symmetry considerations dictate that, in the case of a
migrating hydrogen, a 1,3-hydride shift would have to
occur antarafacially and thus represents an essentially
geometry-forbidden pathway.7 In addition, given the rela-
tively mild reaction conditions, a 1,3-hydride shift seems to
be unlikely to account for this transformation.
of azomethine ylide 5.8,9 Reprotonation of this dipolar
intermediate results in the new iminium ion 4. Subsequent
proton loss leads to aromatization and formation of pyrrole
2. As an alternative to benzoate, which is depicted as the
proposed base in this process, deprotonation could also be
promoted by unmodified 3-pyrroline.
Scheme 3. Evidence for Azomethine Ylide Intermediates
Scheme 2. Proposed Mechanism for Redox Isomerization
In considering alternative mechanisms, we proposed the
reaction sequence as outlined in Scheme 2. Deprotonation
of iminium ion 3 is envisioned to give rise to the formation
(5) For other selected examples of redox neutral amine functionaliza-
tions, see: (a) Ten Broeke, J.; Douglas, A. W.; Grabowski, E. J. J. J. Org.
Chem. 1976, 41, 3159. (b) Verboom, W.; Reinhoudt, D. N.; Visser, R.;
Harkema, S. J. Org. Chem. 1984, 49, 269. (c) De Boeck, B.; Jiang, S.;
Janousek, Z.; Viehe, H. G. Tetrahedron 1994, 50, 7075. (d) Pastine, S. J.;
McQuaid, K. M.; Sames, D. J. Am. Chem. Soc. 2005, 127, 12180. (e)
Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2006, 45, 1683. (f)
Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polonka-Balint, A.; Halasz-
Dajka, B. Synthesis 2006, 2625. (g) Indumathi, S.; Kumar, R. R.;
Perumal, S. Tetrahedron 2007, 63, 1411. (h) Ryabukhin, S. V.; Plaskon,
A. S.; Volochnyuk, D. M.; Shivanyuk, A. N.; Tolmachev, A. A. Synthe-
sis 2007, 2872. (i) Ryabukhin, S. V.; Plaskon, A. S.; Volochnyuk, D. M.;
Shivanyuk, A. N.; Tolmachev, A. A. J. Org. Chem. 2007, 72, 7417. (j)
Belskaia, N. P.; Deryabina, T. G.; Koksharov, A. V.; Kodess, M. I.;
Dehaen, W.; Lebedev, A. T.; Bakulev, V. A. Tetrahedron Lett. 2007, 48,
9128. (k) Oda, M.; Fukuchi, Y.; Ito, S.; Thanh, N. C.; Kuroda, S.
Tetrahedron Lett. 2007, 48, 9159. (l) Zheng, L.; Yang, F.; Dang, Q.; Bai,
X. Org. Lett. 2008, 10, 889. (m) Che, X.; Zheng, L.; Dang, Q.; Bai, X.
In order to establish the intermediacy of azomethine
ylides such as 5, we opted to investigate the reaction of
3-pyrroline (1) with aldehyde 6 (Scheme 3). The latter
reaction partner possesses a pendant dipolarophile and
has previously been used in intramolecular [3 þ 2] cyclo-
additions.10,11 Indeed, a reaction of 1 and 6, conducted in
the presence of catalytic amounts of benzoic acid under
microwave irradiation, led to the rapid formation of 7 in
53% yield.12 The expected [3 þ 2] cycloaddition product 7
was obtained in the form of a single diastereomer. This
strongly suggests the intermediacy of azomethine ylides in
this redox neutral reaction cascade.
Next we sought to apply this method to a related process,
namely the formation of N-alkyl indoles from indolines and
aldehydes. This approach would provide an efficient
alternative to the N-alkylation of preformed indoles which
sometimes suffers from issues of regioselectivity.13
Although iminium ions derived from aldehydes and indo-
line might be expected to be somewhat less acidic than
species such as 3, these reactions proceeded efficiently when
conducted under microwave irradiation. As outlined in
Figure 1, indoline readily underwent reactions with a
range of electronically diverse benzaldehydes.14 The use
of only 1.2 equiv of indoline proved sufficient to achieve
ꢀ
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A.; Ludanyi, K.; Matyus, P. Tetrahedron 2010, 66, 2331. (y) Zhou, G.;
Zhang, J. Chem. Commun. 2010, 46, 6593.
(6) A 1,3-hydride shift has been proposed to occur in a thermal,
uncatalyzed reaction between 3-pyrroline and cyclohexanone to yield
N-cyclohexylpyrrole: Cook, A. G.; Switek, K. A.; Cutler, K. A.; Witt,
A. N. Lett. Org. Chem. 2004, 1, 1.
(7) (a) Woodward, R. B.; Hoffman, R. J. Am. Chem. Soc. 1965, 78,
2511. (b) Berson, J. A. Acc. Chem. Res. 1968, 1, 152.
(8) Deprotonation of iminium ions is an established concept for the
generation of azomethine ylides. For examples, see: (a) Huisgen, R.;
Grashey, R.; Steingruber, E. Tetrahedron Lett. 1963, 1441. (b) Toth, G.;
Frank, J.; Bende, Z.; Weber, L.; Simon, K. J. Chem. Soc., Perkin Trans. 1
1983, 1961. (c) Ardill, H.; Grigg, R.; Sridharan, V.; Surendrakumar, S.;
Thianpatanagul, S.; Kanajun, S. J. Chem. Soc., Chem. Commun. 1986,
602. (d) Kanemasa, S.; Takenaka, S.; Watanabe, H.; Tsuge, O. J. Org.
Chem. 1989, 54, 420. (e) Ardill, H.; Fontaine, X. L. R.; Grigg, R.;
Henderson, D.; Montgomery, J.; Sridharan, V.; Surendrakumar, S.
Tetrahedron 1990, 46, 6449. (f) Grigg, R.; Sridharan, V.; Thornton-Pett,
M.; Wang, J.; Xu, J.; Zhang, J. Tetrahedron 2002, 58, 2627.
(10) See for instance ref 8e.
(11) For a review on intramolecular azomethine ylide cycloadditions,
see: Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765.
(12) Conventional thermal conditions were also evaluated briefly.
However, we found the use of microwave irradiation to be superior in
terms of overall efficiency. Consequently, microwave acceleration was
used as the method of choice throughout this study.
(13) For an example of efficient indole N-alkylation, see: Hayat, S.;
Attaur, R.; Choudhary, M. I.; Khan, K. M.; Schumann, W.; Bayer, E.
Tetrahedron 2001, 57, 9951 and references cited therein.
(14) During the preparation of this manuscript, Sun, Pan and cow-
orkers reported the formation of N-alkyl indoles under very similar but
reflux conditions, using 2 equiv of indoline. These authors proposed the
intervention of a 1,3-hydride shift: Mao, H.; Xu, R.; Wan, J.; Jiang, Z.;
Sun, C.; Pan, Y. Chem.;Eur. J. 2010, 16, 13352.
(9) See also: Kadas, I.; Szanto, G.; Toke, L.; Simon, A.; Toth, G. J.
Heterocycl. Chem. 2007, 44, 1373 and references cited therein.
Org. Lett., Vol. 13, No. 4, 2011
813

Scheme 4. Redox Isomerization vs Intermolecular Hydride
Transfer
Scheme 5. Reaction of Indoline and Salicylaldehyde
hyde (Scheme 5). While the N-alkyl indole 11r was still the
major product (50% yield), the corresponding N-alkylated
indoline 14 was obtained in 15% isolated yield.17 We
attribute this observation to the presence of an acidic
phenol proton. The latter makes it likely more challenging
to regioselectively deprotonate the initially formed iminium
ion to generate the required azomethine ylide intermediate.
Consequently, the intermolecular reduction pathway as
illustrated in Scheme 4 becomes more predominant than
in reactions of indoline with other aldehydes lacking such
an acidic functionality.16
Figure 1. Synthesis of N-alkylated indoles.
full conversion of the aldehydes. Interestingly, reactions
of indoline with aminobenzaldehydes also gave rise to
N-alkylated indoles.15 Thiophene, furan, and pyridine
aldehydes led to the formation of alkylated indoles in good
yields. Substituted indolines such as 2-phenylindoline and
3-methylindoline were also viable substrates in this redox
isomerization. Enolizable aldehydes failed to yield indoles,
presumably due to the facile formation of enamines.
Interestingly, in a reaction between 2-methylindoline
and p-chlorobenzaldehyde, in addition to the expected
indole product 11q which was isolated in 35% yield, we
observed the formation of N-alkylated 2-methylindoline
13 in 20% yield (Scheme 4). An additional product of this
reaction was identified as 2-methylindole. Given the ob-
servation of the latter, we propose that the formation of 13
is the result of an intermolecular hydride transfer as out-
lined in Scheme 4.16
Scheme 6. Intramolecular [3 þ 2] vs Indole Formation
A substantial amount of reduced product (14) was also
observed in the reaction between indoline and salicylalde-
To establish the intermediacy of azomethine ylides in
the formation of N-alkyl-indoles, we conducted a similar
trapping experiment as discussed earlier in the case of
(15) In related cases where aromatization is not possible, we have
previously observed the formation of aminals upon trapping of azo-
methine ylides. See refs 4a and 4g.
(16) In most reactions leading to the formation of products shown in
Chart 1, small amounts of the corresponding N-alkyl indolines were also
observed. These compounds were typically recovered in less than 3%
yield.
(17) Interestingly, in a reaction of indoline and salicylaldehyde
conducted under thermal conditions, Sun, Pan and co-workers observed
the exclusive formation of the reduced product 14 (ref 14). They
attributed this to a potential involvement of the phenolic OH group in
an intramolecular hydrogen bonding interaction that was thought to
interfere with the redox isomerization.
814
Org. Lett., Vol. 13, No. 4, 2011

3-pyrroline (1). As outlined in Scheme 6, reaction of indoline
with aldehyde 6 resulted in the formation of the expected
cycloaddition product 15a as a single diastereomer in 50%
yield. In addition, the N-alkylated indole 16a was obtained in
43% yield. These observations are again consistent with the
proposed intermediacy of azomethine ylides.
A reaction of 5-bromoindoline with aldehyde 6
resulted in the formation of the crystalline cycloaddition
product 15b as a single diastereomer in 63% yield. The
X-ray crystal structure of 15b is shown in Figure 2. In
this instance, none of the N-alkylated indole 16b was
isolated. Instead, a small amount (5%) of the correspond-
ing N-alkylated indoline was recovered (product not
shown).
In summary, we have reported a facile redox neutral
method for the synthesis of N-alkylated indoles from
indolines and aldehydes. Rather than proceeding through
a deceptively apparent (but orbital-symmetry forbidden)
1,3-hydride shift mechanism, this reaction involves the
intermediacy of azomethine ylides as established by intra-
molecular trapping experiments. This observation has
implications for the future development of related trans-
formations.
Acknowledgment. We thank the National Science
Foundation for partial support of this research (Grant
CHE-0911192). We thank Dr. Tom Emge (Rutgers
University) for crystallographic analysis.
Supporting Information Available. Experimental pro-
cedures, characterization data, and X-ray crystal struc-
ture of 15b. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 2. ORTEP view (50% probability thermal ellipsoids) of
the molecular structure of 15b.
Org. Lett., Vol. 13, No. 4, 2011
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