Manganese-catalyzed aerobic dehydrogenative cyclization toward ring-fused indole skeletons

Article abstract of DOI:10.1039/c3ob40855h

We describe the first example of manganese(iii)-catalyzed aerobic dehydrogenative cyclization producing ring-fused indole skeletons. This catalytic system converts from two C-H bonds of indole and malonate to a C-C bond and produces water as the sole side product. This operationally easy method was extended to an intermolecular cross-dehydrogenative coupling of indole and α-substituted malonate with complete C2-selectivity.

Full text of DOI:10.1039/c3ob40855h

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Manganese-catalyzed aerobic dehydrogenative
cyclization toward ring-fused indole skeletons†
Cite this: DOI: 10.1039/c3ob40855h
Received 25th April 2013,
Accepted 17th May 2013
Kounosuke Oisaki,*a Junpei Abea and Motomu Kanai*a,b
DOI: 10.1039/c3ob40855h
www.rsc.org/obc
We describe the first example of manganese(III)-catalyzed aerobic
dehydrogenative cyclization producing ring-fused indole skele-
tons. This catalytic system converts from two C–H bonds of
indole and malonate to a C–C bond and produces water as the
sole side product. This operationally easy method was extended
to an intermolecular cross-dehydrogenative coupling of indole
and α-substituted malonate with complete C2-selectivity.
Catalytic dehydrogenative carbon–carbon (C–C) bond-for-
mation converting two C–H bonds to a C–C bond is an ideal
process contributing to streamlined complex molecule syn-
thesis. The reaction eliminates the need for cumbersome pre-
activations and functional group manipulations, thereby
minimizing the number of synthetic steps and chemical
waste.1,2 The recent worldwide concern for the environment
has inspired chemists to utilize aerobic oxygen as an ideal stoi-
chiometric oxidant for oxidative transformations, because it is
abundant and produces H2O as the sole side product.3
Polycyclic indole skeletons are ubiquitously observed in bio-
active natural products and medicinal leads.4 A number of syn-
thetic methods for substituted indoles have been developed
over the long history of organic synthesis.5 Most of these,
however, require specific functionalities (requiring multistep
preparation) and skillful operations (keeping out air and
moisture), and produce waste. A dehydrogenative cyclization
strategy can solve these long-standing problems (Fig. 1).
Several such examples have been applied to polycyclic indole
syntheses.6–8 A base metal-catalysis using molecular oxygen as
the terminal oxidant, however, has not been reported.
Fig. 1 Waste-minimized, general catalytic approach toward the polycyclic core
of bioactive indole alkaloids.
produce ring-fused indole skeletons, which is potentially
extensible to concise and versatile syntheses of polycyclic
indole alkaloids. We also established a practical method to
utilize aerobic oxygen as the terminal oxidant for an operation-
ally easy, environmentally benign synthetic process.
Here we report a manganese-catalyzed dehydrogenative
cyclization protocol between indole and malonate ester to
Our catalysis design was based on the generation of carbon
radicals by one-electron oxidation. Addition of the thus-gener-
ated radicals to a Δ2,3-double bond of indole, followed by
further one-electron oxidation would produce the ring-fused
indole product after aromatization (Fig. 2). If the reduced form
of a catalyst can be re-oxidized by a terminal oxidant, catalyst
turnover would be realized. There are many precedents of
free-radical cyclizations via α-carbon radicals generated from
aGraduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo,
Bunkyo-ku, Tokyo 113-0033, Japan. E-mail: kanai@mol.f.u-tokyo.ac.jp,
oisaki@mol.f.u-tokyo.ac.jp
bJapan Science and Technology Agency, ERATO, Kanai Life Science Catalysis Project,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
†Electronic supplementary information (ESI) available: Experimental details
including procedures, synthesis and characterization of all new products. See
DOI: 10.1039/c3ob40855h
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Table 1 Optimization of conditions
Mn cat. Oxidant
Entry (mol%) (equiv.)
Temp. Time Yielda
Solvent (°C)
(h)
(%)
1
2
3
4
5
6
7
8
30
30
30
30
30
30
10
10
0
10
10
10
10
10
10
TBP(1)
TBP(1)
TBP(1)
TBP(1)
TBP(1)
TBP(1)
TBP(1)
TBP(1)
TBP(1)
CH3CN
DMSO
CHCl3
Dioxane 70
AcOH 70
Toluene 70
Toluene 70
Toluene 100
Toluene 100
70
70
70
24
23
23
24
21
22
86
13
31
19
24
55
40
12
15
40
0
9
16
0
50
31
77
0
74
6
28
40
77b
84b
9
10
11
12
13
14
15
None (argon balloon) Toluene 100
None (in glovebox)
O2 (1 atm)
Toluene 100
Toluene 100
Toluene 100
Toluene 100
xylenes 130
Air, open
Air, CaCl2 tubec
Air, CaCl2 tubec
a The yield was determined by 1H NMR of a crude mixture in the
presence of an internal standard. b Isolated yield. c See the ESI for the
detailed reaction setup.
Fig. 2 Catalytic strategy toward polycyclic indole skeletons via sequential one-
electron oxidations.
1,3-dicarbonyl compounds,9 but re-oxidation of the catalyst is much lower than that in entry 10. On the other hand, open-
not a trivial problem. Furthermore, electron-rich indole rings air conditions afforded a better yield (entry 13). The concen-
are rather sensitive to strongly oxidative conditions.
tration of oxygen seems crucial for catalyst turnover. We also
Based on this idea, we began by applying metal catalysts speculated that a small amount of water under open-air con-
that prefer a one-electron redox process (Cu, Fe, Mn, Ce, Co, ditions would affect the catalyst performance. To capture
etc.) with weak peroxides as terminal oxidants to the dehydro- external moisture and in situ-generated water via azeotropic
genative cyclization of 1a. Extensive screening revealed that removal, attachment of a CaCl2 tube to the top of a test tube
only Mn(acac)3 exhibited catalyst turnover in the presence of significantly improved the result (entry 14). A higher reaction
di-tert-butylperoxide (TBP) (Table 1, entry 1).10 Encouraged by temperature in xylenes further improved the yield up to 84%
this initial finding, further optimization studies were per- (entry 15).
formed. Solvent studies (entries 1–6) revealed that generally
Under these optimized conditions, we next investigated the
non-polar solvents, especially toluene, afforded better results substrate scope (Table 2). From substrates possessing electron-
and improved the yield (entry 6). Reducing the catalyst loading withdrawing or electron-donating groups on the benzene ring
(10 mol%) decreased the reaction rate (entry 7), but raising (1b–1d), the corresponding products were obtained in moder-
the reaction temperature (100 °C) produced 2a in 77% yield ate to good yield (entries 2–4). N-Methyl protection of the
(entry 8).
As a control, we conducted the reaction without a manga-
indole moiety (1e) had little effect on the efficiency (entry 5).
The present system was not efficient for ring systems of
nese catalyst or TBP (entries 9–11). Although the reaction did other sizes (5 and 7-membered ring-formation, 1f and 1g;
not proceed at all in the absence of the Mn(acac)3 catalyst, entries 6 and 7).11 These results were attributed to the inher-
the reaction unexpectedly proceeded with a similar efficiency ently difficult cyclization mode. In the case of 1f, cyclization
in the absence of TBP in an argon atmosphere (entry 10). We proceeds in a Baldwin-forbidden manner (5-endo-trig). In the
doubted the gas-tightness of the attached rubber balloon case of 1g, 7-membered ring-formations are entropically
filled with argon gas. Molecular oxygen possibly permeated disfavored.
into the reaction vessel through the rubber balloon, acting as
Instead of C3 to C2 cyclization, N1 to C2 cyclization was
the actual terminal oxidant. Based on this consideration, we investigated. Both 5-membered and 6-membered ring-for-
conducted the reaction under strictly oxygen-free conditions mation occurred in moderate to good yield (entries 8 and 9).
(inside a glovebox) and obtained a poor yield of 2a as
As a preliminary extension of the current catalytic system,
expected (entry 11). Contaminated molecular oxygen is more an intermolecular catalytic cross-dehydrogenative coupling2,8
likely to be the terminal oxidant. We then conducted the reac- between indole and dimethyl 2-methylmalonate (3) was con-
tion under 1 atm of oxygen gas (entry 12), but the yield was ducted. C–C bond formation occurred exclusively at the
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with a quaternary carbon attached to an indole ring, which is
difficult to achieve under conventional electrophilic substi-
tution conditions.
Table 2 Substrate scope
Conclusions
In conclusion, we developed an inexpensive Mn(acac)3-cata-
lyzed aerobic dehydrogenative cyclization. This catalytic system
can convert from two C–H bonds (C(2)–H of indole and α-C–H
bond of malonate ester) to a C–C bond as a part of a polycyclic
indole skeleton in synthetically useful yield. In this method,
aerobic oxygen can be used as the stoichiometric oxidant, and
H2O is the sole stoichiometric side-product. This is the first
example of base metal-catalyzed aerobic dehydrogenative cycli-
zation producing ring-fused indole skeletons. This operation-
ally easy method was preliminarily extended to an
intermolecular cross-dehydrogenative coupling reaction of
indole and α-substituted malonate, toward selective C2-
functionalization of an indole with maximized convergency.
Entry Substrate Product
Time (h) Yieldb (%)
1
2
3
1a
1b
1c
15
19
18
84
74
74
Acknowledgements
This work was supported by a Grant in-Aid for Young Scientists
B from JSPS (K. O.) and ERATO from JST (M. K.).
4
5
1d
1e
19
19
67
80
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