Nickel-catalyzed alkyne annulation by anilines: Versatile indole synthesis by C-H/N-H functionalization

Article abstract of DOI:10.1039/c3cc43915a

Versatile nickel catalysts enabled the step-economical synthesis of decorated indoles through alkyne annulations with anilines bearing removable directing groups. The C-H/N-H activation strategy efficiently occurred in the absence of any metal oxidants and with excellent selectivities.

Full text of DOI:10.1039/c3cc43915a

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Nickel-catalyzed alkyne annulation by anilines:
versatile indole synthesis by C–H/N–H
functionalization†
Cite this: Chem. Commun., 2013,
49, 6638
Received 24th May 2013,
Accepted 30th May 2013
Weifeng Song and Lutz Ackermann*
DOI: 10.1039/c3cc43915a
www.rsc.org/chemcomm
Versatile nickel catalysts enabled the step-economical synthesis of
decorated indoles through alkyne annulations with anilines bearing
removable directing groups. The C–H/N–H activation strategy
efficiently occurred in the absence of any metal oxidants and with
excellent selectivities.
Indoles are key structural motifs in bioorganic chemistry, drug
discovery and medicinal chemistry.1,2 Therefore, there is a
continuous strong demand for chemo- and site-selective syntheses
of this heteroaromatic scaffold. While palladium-catalyzed C–C
Scheme 1 Environmentally-benign indole synthesis.
Notable features of our strategy are not limited to (a) the use
and C–N bond forming reactions have been particularly proven of easily removable, monodentate directing groups, (b) a high
to be valuable for the preparation of indoles, these transforma- catalytic efficacy with challenging electron-rich anilines, and
tions largely relied on prefunctionalized starting materials.2 (c) in contrast to previous indole syntheses,4 oxidative alkyne
Significantly more step-economical strategies are represented annulations devoid of copper(II) or silver(I) salts as the sacrificial
by methods that capitalize upon unactivated C–H bonds as oxidants (Scheme 1).
latent functional groups.3 As of yet, solely expensive second-row
We commenced our studies by identifying the reaction
transition metal catalysts, such as rhodium, palladium, or conditions for the envisioned nickel-catalyzed indole synthesis
ruthenium complexes,4 have been utilized for indole syntheses with pyridyl-substituted aniline 1a (Table 1). Among a variety of
by oxidative alkyne annulation through C–H/N–H bond func- ligands, bidentate dppf, in combination with Ni(cod)2, proved
tionalizations.5 Furthermore, these methods relied on the use to be optimal (entries 1–9). We were pleased to find that
of copper(II) or silver(I) salts as the stoichiometric or cocatalytic stoichiometric amounts of copper(II) or silver(I) salts were not
oxidants. Recent notable progress in the use of naturally more required as sacrificial oxidants—a notable advantage over pre-
abundant nickel6 catalysts for C–H bond functionalizations7 viously developed protocols.4,9 Interestingly, the formation of
was accomplished by Chatani and coworkers with a versatile indole 3aa occurred most efficiently in the absence of solvents
isoquinolone synthesis from arenes bearing electron-withdrawing (entries 10–14), thereby further improving the environmentally-
amides.8 However, the atom-economical nature of this benign nature of our approach. Control experiments verified
approach was compromised by the need for a specific, less that the formation of indole 3aa was neither achieved in the
atom-economical bidentate directing group. In consideration absence of Ni(cod)2 nor without the dppf ligand (entries 15 and 16).
of the practical importance of modular indole syntheses, Moreover, our studies revealed that representative palladium or
we became interested in developing unprecedented nickel- cobalt complexes in lieu of the nickel(0) catalyst were ineffective
catalyzed alkyne annulations by electron-rich anilines, which (entries 17 and 18).
we wish to report herein.
With an optimized catalytic system in hand, we explored its
versatility in the oxidative annulation of alkyne 2a (Scheme 2).
Given that the N-2-pyrimidyl group is easily removed from
the indole nucleus, we focused our studies on the use of
N-pyrimidyl-substituted anilines 1. We were delighted to find
that the challenging pyrimidyl-substituted substrate 1b was
converted with a comparably high efficacy compared to reac-
tions with the more electron-rich aniline 1a. The optimized
Institut fuer Organische und Biomolekulare Chemie, Georg-August-Universitaet,
Tammannstrasse 2, 37077 Goettingen, Germany.
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data, and 1H and 13C NMR spectra of products. See
DOI: 10.1039/c3cc43915a
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Table 1 Optimization of the nickel-catalyzed oxidative annulationa
Entry
[TM]
Ligand
Solvent
Yield (%)
1
2
3
4
5
6
7
8
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2
Ni(cod)2c
Ni(cod)2c
Ni(cod)2c
Ni(cod)2c
Ni(cod)2c
Ni(cod)2
TMEDA
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
m-Xylene
o-Xylene
—
—
—
40
—
21
30
30
43
48
63
45
35
65
82
—
—
—
—
Terpyridine
b
PPh3
dcype
rac-BINAP
dppp
DPEphos
Xantphos
dppf
9
10
11
12
13
14
15
16
17
18
dppf
dppf
dppf
PPh3
b
Scheme 3 Catalyzed C–H/N–H bond functionalization with alkynes 2.
dppf
dppf
—
dppf
dppf
—
—
PhMe
PhMe
PhMe
c
—
Ni(cod)2
c
c
Pd2(dba)3
Co2(CO)8
c
a
Reaction conditions: 1a (0. 50 mmol), 2a (1.5 mmol), [TM] (10 mol%),
b
c
ligand (20 mol%), 160 1C, 20 h, isolated yields. PPh3 (40 mol%). 2a
(2.5 mmol).
Scheme 4 Removal of the directing group.
bond functionalization with the unsymmetrical alkyne 2f10 yielded
the corresponding indole 3bf with an excellent regioselectivity.
For future practical applications it is important to note that
the 2-pyrimidyl group was easily removed from indole 3ba to
deliver the corresponding NH-free indole 4 (Scheme 4).
Considering the remarkable reactivity of the nickel(0) catalyst,
we became interested in rationalizing its mode of action. To this
end, we conducted intramolecular competition experiments with
meta-substituted anilines 1m–o. Here, the site-selectivity of the
C–H bond functionalization was largely governed by steric
interactions, while a fluoro-substituent11 led to significant
amounts of product 3oa00 through C–H bond functionalization
at the C-2 position (Scheme 5).
Furthermore, intermolecular competition experiments with
differently substituted alkynes 2 highlighted arylacetylenes to be pre-
ferentially converted (Scheme 6a),12 while electron-deficient arenes
were found to be more reactive (Scheme 6b). These experimental
Scheme 2 Nickel-catalyzed oxidative annulation with anilines 1.
nickel(0) catalyst proved to be widely applicable, and allowed
for the use of functionalized as well as sterically hindered ortho-
substituted anilines 1, thereby furnishing the desired indoles
3ba–3ia. It is particularly notable that reactive electrophilic
functional groups, such as the chloro, acetyl or cyano substi-
tuents, were well tolerated, which should prove instrumental
for further derivatization of the thus obtained products 3ja–3la.
Subsequently, we tested the scope of the nickel catalyst with
a representative set of substituted alkynes 2 (Scheme 3). We
observed that tolane derivatives 2b–2d featuring either electron-
donating or electron-withdrawing groups were efficiently con-
verted by the optimized nickel complex. However, the catalytic
system was not restricted to tolanes. Indeed, dialkylalkyne 2e
provided the desired product as well. Importantly, the C–H/N–H Scheme 5 Experiments with meta-substituted arenes 1m–o.
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Notes and references
1 J. Alvarez-Builla, J. J. Vaquero and J. Barluenga, Modern
Heterocyclic Chemistry, Wiley-VCH, Weinheim, 2011.
2 Select reviews on the preparation of indoles: (a) S. Cacchi, G. Fabrizi
and A. Goggiamani, Org. React., 2012, 76, 281; (b) S. Cacchi,
G. Fabrizi and A. Goggiamani, Org. Biomol. Chem., 2011, 9, 641;
(c) K. Kru¨ger, A. Tillack and M. Beller, Adv. Synth. Catal., 2008,
350, 2153; (d) L. Ackermann, Synlett, 2007, 507; (e) D. A. Horton,
G. T. Bourne and M. L. Smythe, Chem. Rev., 2003, 103, 893 and
references cited therein.
3 Selected reviews on C–H functionalizations: (a) N. Kuhl, M. N.
Hopkinson, J. Wencel-Delord and F. Glorius, Angew. Chem., Int. Ed.,
2012, 51, 10236; (b) J. Yamaguchi, A. D. Yamaguchi and K. Itami,
Angew. Chem., Int. Ed., 2012, 51, 8960; (c) K. M. Engle, T.-S. Mei,
M. Wasa and J.-Q. Yu, Acc. Chem. Res., 2012, 45, 788; (d) L. McMurray,
F. O’Hara and M. J. Gaunt, Chem. Soc. Rev., 2011, 40, 1885;
Scheme 6 Intermolecular competition experiments.
¨
(e) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius, Chem. Soc.
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P. Alsabeh, M. Kuhn and K. Fagnou, J. Am. Chem. Soc., 2010,
132, 18326. Activated alkynes: ( f ) R. Bernini, G. Fabrizi,
A. Sferrazza and S. Cacchi, Angew. Chem., Int. Ed., 2009, 48, 8078.
[Pd]: (g) Z. Shi, C. Zhang, S. Li, D. Pan, S. Ding, Y. Cui and N. Jiao,
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14, 764 and references cited therein.
Scheme 7 Alkyne annulation with labeled arene [D]5-1b.
findings are in good agreement with a rate-determining migratory
alkyne insertion.
5 Recent reviews: (a) L. Ackermann, Acc. Chem. Res., 2013, 46, DOI:
10.1021/ar3002798; (b) G. Song, F. Wang and X. Li, Chem. Soc. Rev.,
2012, 41, 3651; (c) T. Satoh and M. Miura, Chem.–Eur. J., 2010,
16, 11212.
6 Reviews on the use of inexpensive first-row transition metal catalysts
for C–H functionalization: (a) N. Yoshikai, Synlett, 2011, 1047;
(b) Y. Nakao, Chem. Rec., 2011, 11, 242; (c) E. Nakamura and
N. Yoshikai, J. Org. Chem., 2010, 75, 6061; (d) A. Kulkarni and
O. Daugulis, Synthesis, 2009, 4087.
7 Nickel-catalyzed C–H functionalizations: (a) Y. Aihara and
N. Chatani, J. Am. Chem. Soc., 2013, 135, 5308; (b) K. Muto,
J. Yamaguchi and K. Itami, J. Am. Chem. Soc., 2012, 134, 169;
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M. Miura, Org. Lett., 2009, 11, 1737; (i) J. Canivet, J. Yamaguchi,
I. Ban and K. Itami, Org. Lett., 2009, 11, 1733.
Furthermore, we performed oxidative annulations with iso-
topically labeled substrate [D]5-1b (Scheme 7), revealing a con-
siderable H/D exchange. Notably, scrambling with the free N–H
functionality exclusively occurred at the ortho-positions of the
arene. These results, thus, provide strong support for an initial
reversible C–H/N–H bond activation event to be operative.
Based on our mechanistic studies we consequently propose
the catalytic cycle to involve an initial reversible C–H/N–H bond
activation of aniline 1. Subsequent migratory insertion and
reductive elimination furnish the desired indole 3 and regenerate
the catalytically active nickel complex.
In summary, we have reported an unprecedented nickel-
catalyzed oxidative alkyne annulation by electron-rich anilines
with removable directing groups. The C–H/N–H bond function-
alizations proceeded with excellent chemo-, regio- and site-
selectivities in the absence of metal salts as oxidants, thereby
furnishing substituted indoles with a broad scope. Experimental
mechanistic studies provided support for reversible C–H/N–H
bond activation, and are suggestive of a rate-limiting migratory
alkyne insertion.
8 H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto and N. Chatani, J. Am.
Chem. Soc., 2011, 133, 14952.
9 Careful analysis of the reaction mixtures revealed the alkyne to serve
as the formal hydrogen acceptor.
10 The oxidative annulation of 1-phenylpropyne by substrate 1a gave a
low conversion of 25% as judged by GC analysis.
Support by the European Research Council under the European 11 (a) D. Balcells, E. Clot and O. Eisenstein, Chem. Rev., 2010, 110, 749;
(b) E. Clot, C. Megret, O. Eisenstein and R. N. Perutz, J. Am. Chem.
Soc., 2009, 131, 7817.
12 Catalytic annulations of 1-octyne or a TMS-substituted internal
Community’s Seventh Framework Program (FP7 2007–2013)/ERC
Grant agreement no. 307535 and the Chinese Scholarship Council
alkyne were thus far unsuccessful.
(fellowship to W.S.) is gratefully acknowledged.
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6640 Chem. Commun., 2013, 49, 6638--6640
This journal is The Royal Society of Chemistry 2013