Tandem organocatalysis and photocatalysis: An anthraquinone-catalyzed indole-c3-alkylation/photooxidation/1,2-shift sequence

Article abstract of DOI:10.1002/anie.201402920

Quinones exhibit orthogonal ground- and excited-state reactivities and are therefore highly suitable organocatalysts for the development of sequential catalytic processes. Herein, the discovery of an anthraquinone-catalyzed thermal indole-C3-alkylation with benzylamines is described, which can be combined sequentially with a new visible-light-driven catalytic photooxidation/1,2-shift reaction. The one-flask tandem process converts indoles into 3-benzylindole intermediates, which are further transformed into new fluorescent 2,2-disubstituted indoline-3-one derivatives.

Full text of DOI:10.1002/anie.201402920

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Chemie
DOI: 10.1002/anie.201402920
Tandem Catalysis
Hot Paper
Tandem Organocatalysis and Photocatalysis: An Anthraquinone-
Catalyzed Indole-C3-Alkylation/Photooxidation/1,2-Shift Sequence**
Stephanie Lerch, Lisa-Natascha Unkel, and Malte Brasholz*
Dedicated to Professor Hans-Ulrich Reissig on the occasion of his 65th birthday
Abstract: Quinones exhibit orthogonal ground- and excited-
state reactivities and are therefore highly suitable organo-
catalysts for the development of sequential catalytic processes.
Herein, the discovery of an anthraquinone-catalyzed thermal
indole-C3-alkylation with benzylamines is described, which
can be combined sequentially with a new visible-light-driven
catalytic photooxidation/1,2-shift reaction. The one-flask
tandem process converts indoles into 3-benzylindole inter-
mediates, which are further transformed into new fluorescent
2,2-disubstituted indoline-3-one derivatives.
Figure 1. Tandem process for the synthesis of 2,2-disubstituted indo-
line-3-ones 4 by an anthraquinone-catalyzed indole-C3-alkylation/pho-
tooxidation/1,2-shift sequence.
I
n tandem catalysis, several fundamentally different catalytic
reactions are combined in a one-flask protocol.[1] Ideally, one
precatalyst is present at the outset of the process and each
catalytic cycle is initiated by an external trigger such as
addition of a reagent or switch in reaction conditions. A major
challenge in this field is the precise separation of catalytic
activities between the individual reaction steps and when
a transition-metal catalyst is used, this is often achieved by in
situ modification of the metalꢀs ligand sphere,[2] or by
temporal separation.[3] Herein, we describe the development
of a tandem organocatalytic process which combines a thermal
reaction with a photochemical one. Thus, separation of
catalytic activities is achieved by exploiting a catalystꢀs
orthogonal ground- and excited-state reactivities.
indole-C3-alkylation with amines constitutes the first organo-
catalytic variant of this type of reaction, the quinone-
catalyzed photooxidation of substrates 3 was demonstrated
to proceed with selectivity opposite to that found in the self-
sensitized oxidation.
Initially, we were interested in the C3-alkylation of indoles
1 with benzylamines 2 (Scheme 1), a reaction previously
reported by Beller et al. using Shvoꢀs ruthenium catalyst.[6a]
The analogous process using benzyl and aliphatic alcohols has
also been described employing catalytic Pt nanoclusters[6b]
and stoichiometric hydroxide base.[6c] These high-temperature
reactions (140–1508C for 24 h) are initiated by dehydrogen-
ation of the amine or alcohol to give an imine or aldehyde
electrophile 5, followed by nucleophilic addition–elimination
of indoles 1 furnishing a putative 1-azadiene intermediate 6.
This is subsequently reduced to the saturated C3-alkylation
product 3, and the entire reaction can be regarded as
Quinones are among the most commonly used ground-
state oxidants in synthesis[4] with the distinction that they also
possess powerful and well-studied reactivity in the excited
state.[5] This orthogonal reactivity renders them interesting
candidate catalysts for the development of multistep sequen-
tial catalytic protocols. Our interest in quinone catalysis led to
the development of such a sequence by combining two new
catalytic reactions which we recently discovered. As depicted
in Figure 1, an anthraquinone-catalyzed C3-alkylation of
indoles 1 with benzylamines 2 was successfully sequenced
with a visible-light-driven photooxidation/1,2-shift reaction to
convert intermediate 3-benzylindoles 3 into new fluorescent
2,2-disubstituted indoline-3-one derivatives 4. While the
[*] Dipl.-Chem. S. Lerch, B. Sc. L.-N. Unkel, Juniorprof. Dr. M. Brasholz
Department of Chemistry/Institute of Organic Chemistry
University of Hamburg
Martin-Luther-King-Platz 6, 20146 Hamburg (Germany)
E-mail: malte.brasholz@chemie.uni-hamburg.de
[**] We thank the University of Hamburg and the Fonds der Chemischen
Industrie (FCI) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402920.
Scheme 1. Indole-C3-alkylation with amines or alcohols by catalytic H2-
transfer.
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a catalytic hydrogen-transfer process. As quinone derivatives
are known to catalyze the dehydrogenation of amines to
imines both thermally[7] and photochemically,[8] we speculated
they might also be suitable catalysts in the indole-C3-
alkylation with benzylamines, provided the reduction of
azadiene 6 by a second H2-transfer step occurs. As shown in
Scheme 2, we attempted the C3-alkylation of 1H-indole (1a)
Scheme 2. Benzoquinone-mediated C3-alkylation of indole (1a) with
benzylamine (2a) and hydroquinone-mediated reaction of 1a with
imine 8.
with benzylamine (2a) in the presence of K2CO3 using p-
benzoquinone as the catalyst. The reaction furnished 3-
benzylindole (3a) with 37% conversion using 20 mol% of
benzoquinone and a fourfold excess of benzylamine 2a under
solvent-free conditions and when the mixture was heated to
2008C for 24 h and under air (sealed vial). On the other hand,
reacting indole 1a with preformed imine 8 and replacing
benzoquinone by hydroquinone led to full conversion and
product 3a was isolated in 42% yield. These results demon-
strated that benzoquinone acted as a hydrogen shuttle in the
overall process, which appears to proceed by a hydrogen-
borrowing mechanism analogous to the known metal-based
protocols.[6a,b,9]
Scheme 3. DCAQ-catalyzed C3-alkylation of indoles 1 with amines 2.
Reaction conditions: 0.50 mmol indole 1, 2.00 mmol amine 2, 5 mol%
DCAQ, 5 mol% K2CO3, sealed vial, air, 2258C, 24 h. [a] 30 mol%
DCAQ and no K2CO3 used. [b] 20 mol% DCAQ used. [c] N-alkylation:
NaH, 1-bromopentane, DMF, RT. [d] N-benzoylation: NaH, 4-chloro-
benzoyl chloride, DMF, 808C.
cannabinoid receptor ligand 3l[11] was obtained in 83% yield
after N-alkylation and low-micromolar tyrosine kinase inhib-
itor 3m[12] was prepared by N-benzoylation in 63% over two
steps. The only byproducts generally observed in these
reactions were bisindolylmethanes 7 (Scheme 1). Kinetic
analysis[10a] showed that their formation is initially fast, but
since this side reaction is reversible 7 is subsequently
converted into products 3.
A distinct feature of the indole-C3-alkylation using
DCAQ as the catalyst is the deep-red coloration of the
resulting reaction mixtures. The benzylation of 2-phenyl-
indole (1b) with benzylamine (2a) and catalytic DCAQ
(10 mol%) was chosen as a model reaction for UV/Vis
analysis (Figure 2). The absorption spectrum of the reaction
mixture in acetic acid, after complete conversion of substrate
1b (16 h), showed absorption bands characteristic for 3-
benzyl-2-phenylindole (3n; lmax = 304 nm) as well as a band in
the visible region centered around 491 nm. This could be
assigned to 1,5-bis(dibenzylamino)anthraquinone anil (9a)
and was confirmed by comparison with a reference sample.
Thus, DCAQ undergoes twofold chloride substitution by
benzylamine 2a during the process and anthraquinone anil 9a
appears as the key intermediate in the amine dehydrogen-
ation step of the catalytic cycle, as well as the catalyst resting
state after complete consumption of substrate 1b. With this
information at hand, we investigated possible photochemical
reactions that could be performed sequentially with the
indole-C3-alkylation. We found that irradiation of the crude
Upon optimization,[10a] various benzo- and anthraquinone
derivatives were found to catalyze the alkylation of indole 1a
with benzylamine (2a), of which 1,5-dichloroanthraquinone
(DCAQ) offered the best results. When the reaction was
conducted at the elevated temperature of 2258C for 24 h,
a reduced catalyst loading of 5 mol% was sufficient to
achieve complete conversion and to afford product 3a in
64% yield. A small library of 3-alkylated indole derivatives
prepared by our method is depicted in Scheme 3. While 2-
unsubstituted indoles were benzylated with moderate yields
ranging from 50 to 60% (products 3b–e), yields for 2-
substituted derivatives were generally higher (products 3 f–h).
When methyl 1H-indole-2-carboxylate was employed in the
reaction, C3-benzylation was accompanied by formation of
the C2-carboxyamide to provide products 3i and 3j with 60%
and 65% overall yield, respectively. As expected, reactivity
was lower for N-substituted indole substrates and also when
benzylamines were replaced by aliphatic amines. In these
cases, preparatively useful results were obtained with
increased catalyst loading (20–30 mol% for products
3d,e,k). The utility of the method was further demonstrated
by the preparation of bioactive indoles 3l and 3m. Nanomolar
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Thus, photooxidation 3n!4a catalyzed by quinone anil 9a
overrides the inherent Type II reactivity of substrate 3n
offering a highly useful selectivity in favor of pseudo-indoxyl
product 4a. Using green LED light [l = (560 ꢀ 25) nm]
instead of blue fluorescent lamps [l = (450 ꢀ 50) nm) leads
to complete suppression of the formation of oxazinone 10
through the Type II path;[15] however, conversion 3n!4a was
much slower with the commercial LED assembly (5.4 W
total) than with the blue fluorescent lamps (2 ꢁ 18 W) as the
former have considerably lower power than the latter.
Despite the many factors influencing the course of the
tandem reaction, such as the type of the anthraquinone anil
9 formed by variation of the benzylamine, the 1,2-migration
propensity of the C3-substituent in intermediates 3, and the
more or less stabilizing contribution by the C2-substituent,
a number of indoline-3-one derivatives 4 could be synthesized
in a sequential fashion with consistently good yields over two
steps (Scheme 5). For 2-aryl-substituted 1H-indole deriva-
tives, yields ranged from 43 to 71% (examples 4a–g).
Changing the C2-substituent to a methyl group slows down
the photooxidation reaction. However, when irradiation was
extended to a duration of 48 h, also these substrates provided
appreciable yields of 52–56% of indoline-3-one products
(4h–j). Even when 2-tert-butyl-1H-indole was employed in
the sequence, product 4k could be isolated in 24% yield.
Figure 2. a) UV/Vis spectrum of the crude mixture obtained from the
reaction of 2-phenylindole (1b) with benzylamine (2a) catalyzed by
10 mol% DCAQ; c=10ꢁ4 m in HOAc with respect to the indole
component; b) absorption spectrum of 2-phenyl-3-benzylindole (3n;
c=10ꢁ4 m in HOAc); c) absorption spectrum of anthraquinone anil 9a
(c=10ꢁ5 m, HOAc).
reaction mixture containing intermediate 3n and quinone anil
9a in acetic acid, under oxygen atmosphere and using blue
fluorescent lamps, led to a photooxidation/1,2-shift reaction
converting indole 3n into 2-benzyl-2-phenylindoline-3-one
(4a) with a high overall yield of 71% over two steps
(Scheme 4). In this process, acetic acid traps excess benzyl-
amine 2a as its unreactive ammonium salt, and irradiation
with blue light ensures selective excitation of the catalyst
9a.[13]
A side product formed in this reaction is 2-phenylbenz-
oxazinone 10, which was isolated with 12% yield. Its origin
could be identified as a competing self-sensitized photo-
oxidation:[14] Despite its very faint absorption in the visible
region > 400 nm (Figure 2), when a sample of indole 3n was
reacted under similar photooxidation conditions but in the
absence of quinone anil 9a, oxazinone 10 was isolated as the
major product along with a minor amount of indoline-3-one
4a, both of which were obtained in low yields (Scheme 4).
Scheme 5. Tandem indole-C3-alkylation/photooxidation/1,2-shift reac-
tion. Conditions: step 1: 0.25 mmol indole 3, 4 equiv benzylamine 2,
10 mol% DCAQ, 10 mol% K2CO3, sealed vial, air, 2258C, 16 h; step 2:
O2, HOAc, hn 450 nm, RT, 24 h. [a] Irradiation for 48 h in step 2.
Scheme 4. One-pot sequential conversion of 2-phenylindole (1b) into
indoline-3-one 4a and Type II photooxidation of 3-benzyl-2-phenyl-
indole (3n).
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Novel pseudo-indoxyls 4a–k all displayed blue fluorescence
around 430 nm, a property of these materials which may find
future applications.[10a,b]
A tentative mechanism for the photooxidation of sub-
strates 3 is depicted in Scheme 6. The anthraquinone anil
(AQA)-catalyzed reaction (path I) is initiated by H-abstrac-
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& Photobiology, 3rd ed., Vol. 1 (Eds. A. Griesbeck, M. Oelge-
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[8] J.-M. Kim, D.-K. Han, C.-W. Lee, S.-H. Kim, M.-S. Gong, K.-D.
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The resulting benzylic radical 13 reacts with molecular oxygen
to generate indole-3-peroxyradical 14, which is converted into
3-hydroperoxyindolenine 15 by H-abstraction, possibly from
acetic acid.[17] Reduction of 15 by the semiquinone radical 12
furnishes 3-hydroxyindolenine 16 by cleavage of the peroxide
bond and regenerates catalyst 9. Indolenine 16 subsequently
undergoes acid-assisted 1,2-migration to product 4.[18] In
contrast to path I, path II involves reaction of substrate 3 with
self-sensitized singlet oxygen generating keto amide 17
through dioxetane formation and scission of the C2–C3
bond.[19] Intramolecular cyclization to intermediate 18 fol-
lowed by acid-catalyzed elimination[20] leads to 4-alkylidene
oxazine 19 which is converted into benzoxazinone derivative
10 by [2+2] cycloaddition with singlet oxygen and subsequent
dioxetane cleavage.[21]
[9] a) The H2-transfer mechanism is further supported by the
presence of dibenzylamine (Bn2NH) in the crude product
mixture which was produced by hydrogenation of intermediary
imine 8; b) for a proposed complete mechanism, see the
Supporting Information.
[10] a) Please refer to the Supporting Information section for details;
b) fluorescence properties of some 2,2-dialkyl-substituted
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[11] J. W. Huffman, R. Mabon, M.-J. Wu, J. Lu, R. Hart, D. P. Hurst,
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[13] A ground-state reaction of substrate 3n with molecular oxygen
in a Witkop–Winterfeldt-type mechanism was excluded by
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KOH, DMSO, DT, light exclusion).
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Hu, J.-H Xu, J. Org. Chem. 2004, 69, 2332 – 2339.
In summary, two new anthraquinone-catalyzed reactions
were combined in a tandem process leading to pseudo-
indoxyls 4 by way of a photooxidation/1,2-shift reaction of the
intermediate 3-benzylindoles 3, which proceeds with selec-
tivity that is opposite that of a competing Type II reaction.
[15] Hence, singlet oxygen sensitization by catalyst 9a did not occur.
[16] a) F. Wilkinson, A. Garner, Photochem. Photobiol. 1978, 27,
659 – 670; b) M. V. Encinas, C. M. Previtali, S. Bertolotti, J.
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Received: March 3, 2014
Published online: && &&, &&&&
Keywords: indoles · organocatalysis · photocatalysis ·
quinones · tandem catalysis
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4
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[18] M. Colonna, L. Greci, M. Poloni, J. Chem. Soc. Perkin Trans. 2
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[21] a) This is supported by the presence of aryl aldehydes in crude
NMR spectra; b) overview on [2+2] photooxygenation: M. R.
Iesce, F. Cermola in Handbook of Organic Photochemistry &
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Communications
Tandem Catalysis
S. Lerch, L.-N. Unkel,
M. Brasholz*
&&&& — &&&&
Tandem Organocatalysis and
Photocatalysis: An Anthraquinone-
Catalyzed Indole-C3-Alkylation/
Photooxidation/1,2-Shift Sequence
Orthogonal reactivities: Anthraquinone
derivatives catalyze the thermal C3-alky-
lation of indoles with benzylamines in
sequence with a visible-light-driven pho-
tooxidation/1,2-shift reaction to provide
new fluorescent 2,2-disubstituted indo-
line-3-one derivatives. Quinones function
as H2 shuttles in the indole C3-alkylation
with amines and the subsequent photo-
oxidation of the intermediate 3-aryl-
methyl-1H-indoles is remarkably selec-
tive.
6
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