Cationic ruthenium(II) catalysts for oxidative C - H/N - H bond functionalizations of anilines with removable directing group: Synthesis of indoles in water

Article abstract of DOI:10.1021/ol203309y

Cationic ruthenium(II) complexes enabled oxidative C - H bond functionalizations with anilines bearing removable directing groups. The C - H/N - H bond cleavages occurred most efficiently in water as a sustainable solvent and provided general access to va

Full text of DOI:10.1021/ol203309y

ORGANIC
LETTERS
2012
Vol. 14, No. 3
764–767
Cationic Ruthenium(II) Catalysts for
Oxidative CÀH/NÀH Bond
Functionalizations of Anilines with
Removable Directing Group: Synthesis of
Indoles in Water
Lutz Ackermann* and Alexander V. Lygin
€
Institut fu€r Organische und Biomolekulare Chemie, Georg-August-Universitat,
€
Tammannstrasse 2, 37077 Gottingen, Germany
Lutz.Ackermann@chemie.uni-goettingen.de
Received December 11, 2011
ABSTRACT
Cationic ruthenium(II) complexes enabled oxidative CÀH bond functionalizations with anilines bearing removable directing groups. The CÀH/
NÀH bond cleavages occurred most efficiently in water as a sustainable solvent and provided general access to various bioactive indoles.
Mechanistic studies provided strong support for a novel reaction manifold.
Indoles are ubiquitous structural motifs in biologically
active compounds and natural products.1,2 Their central
importance in medicinal chemistry and drug discovery
has, thus, resulted in a continued strong demand for gen-
erallyapplicable, modular synthesesofthisheteroaromatic
moiety.3 In this context, transition-metal-catalyzed trans-
formations of ortho-halo-substituted aniline derivatives,
most notably Larock’s annulation,4,5 have proven partic-
ularly useful for the selective assembly of indole deri-
vatives.6 Unfortunately, this approach inherently relies
on the use of prefunctionalized starting materials, which
reduces the overall atom and step economy. Conversely, a
significantly more sustainable strategy is represented by
the direct use of easily available anilines for catalytic
oxidative indole syntheses.7 As of yet, these CÀH bond
functionalizations8 have predominantly been accom-
plished with palladium or rhodium catalysts.9 We, in
contrast, devised very recently inexpensive neutral ruthe-
nium complexes for oxidative annulations of alkynes
through CÀH bond cleavages.10 Key to success for the
development of these transformations was an effective
carboxylate-assisted11 CÀH bond ruthenation as the
rate-limiting reaction step.10 Hence, the chemoselecti-
vities and site selectivities of these processes were
governed by kinetic CÀH bond acidity, thereby rendering
(1) Eicher, T.; Hauptmann, S. The Chemistry of Heterocycles; Wiley-
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103, 893–930.
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Senanayake, C. H. Arkivoc 2010, 390–449.
(4) Larock, R. C. Top. Organomet. Chem. 2005, 14, 147–182.
(5) For multicatalytic reaction sequences with complementary re-
gioselectivity, see: (a) Ackermann, L.; Kaspar, L. T.; Gschrei, C. J. Chem.
Commun. 2004, 2824–2825. (b) Ackermann, L.; Sandmann, R.; Villar, A.;
Kaspar, L. T. Tetrahedron 2008, 64, 769–777.
(8) Selected recent reviews on CÀH bond functionalizations:(a) Cho,
S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068–
5083. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215–
1292. (c) Ackermann, L.; Potukuchi, H. K. Org. Biomol. Chem. 2010, 8,
4503–4513. (d) Daugulis, O. Top. Curr. Chem. 2010, 292, 57–84. (e)
Ackermann, L. Chem. Commun. 2010, 46, 4866–4877. (f) Fagnou, K.
Top. Curr. Chem. 2010, 292, 35–56. (g) Ackermann, L.; Vicente, R.;
Kapdi, A. Angew. Chem., Int. Ed. 2009, 48, 9792–9826. (h) Thansandote,
P.; Lautens, M. Chem.;Eur. J. 2009, 15, 5874–5883 and references cited
therein.
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€
(b) Vicente, R. Org. Biomol. Chem. 2011, 9, 6469–6480. (c) Kruger, K.;
Tillack, A.; Beller, M. Adv. Synth. Catal. 2008, 350, 2153–2167. (d)
Ackermann, L. Synlett 2007, 507–526. (e) Humphrey, G. R.; Kuethe,
J. T. Chem. Rev. 2006, 106, 2875–2911 and references cited therein.
r
10.1021/ol203309y
Published on Web 01/13/2012
2012 American Chemical Society

electron-deficient arenes most reactive in all studied
transformations.10 Given the prevalence of indoles in
medicinal chemistry and pharmaceutical industries, we
became interested in exploring the first ruthenium-
catalyzed oxidative annulations with simple aniline deri-
vatives, the development of which we report herein. Notable
features of the new protocol include the unprecedented use
of cationic ruthenium(II) complexes for oxidative annula-
tions of alkynes, along with an extraordinary chemoselec-
tivity that enabled CÀH bond transformations in water12,13
as an environmentally benign reaction medium. Impor-
tantly, mechanistic studies revealed electron-rich arenes
to be converted preferentially, thus highlighting a novel
reaction manifold to be operative in ruthenium-catalyzed
oxidative CÀH bond transformations.
for the generation of cationic ruthenium(II) complexes
with a weakly coordinating anion.16À18 Transformations
in the presence of the surfactant polyoxyethanyl R-toco-
pheryl sebacate (PTS) did not improve the yield of desired
product 3aa (entries 8 and 9), providing support for the
catalytic CÀH bond functionalization to take place in
water.12 Notably, the catalytic efficacy of our inexpensive
cationic ruthenium complex compared favorably to the one
of representative palladium or rhodium precursors (entries 3
and 4 vs 12 and 13). As to the catalytically active species,
it is noteworthy that a well-defined cationic ruthenium(II)
complex16 provided a yield comparable to the one obtained
with the in situ generated catalyst (entries 3 and 4 vs 14).
Our studies were initiated by probing various solvents
and cocatalytic additives for the envisioned ruthenium-
catalyzed oxidative preparation of N-substituted indoles.
Since the 2-pyrimidyl14 group was shown to be easily
removed from the indole nucleus,15 we focused our opti-
mization studies on the use of N-2-pyrimidyl-substituted
anilines (Table 1). Among a set of representative solvents,
water proved to be optimal (entries 1À4) and also fur-
nished higher yields as compared to reactions performed
in the absence of any solvent (entry 5). High catalytic
efficacy was accomplished with a complex generated from
[RuCl2(p-cymene)]2 and cocatalytic amounts of KPF6
(entries 4À7), reaction conditions previously established
Table 1. Optimization for the Synthesis of Indole 3aa in Watera
3aa
entry solvent t [°C]
additive (mol %)
(%)
1
t-AmOH 100 KPF6 (10)
44
19
92
94b
53
2
DMF
H2O
H2O
À
100 KPF6 (10)
3
100 KPF6 (10)
100 KPF6 (20)
100 KPF6 (10)
100 KPF6 (10)
(9) [Rh]: (a) Stuart, D. R.; Bertrand-Laperle, M.; Burgess, K. M. N.;
Fagnou, K. J. Am. Chem. Soc. 2008, 130, 16474–16475. (b) Stuart, D. R.;
Alsabeh, P.; Kuhn, M.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 18326–
18339. (c) Huestis, M. P.; Chan, L. N.; Stuart, D. R.; Fagnou, K. Angew.
Chem., Int. Ed. 2011, 50, 1338–1341. [Cu]: (d) Bernini, R.; Fabrizi, G.;
Sferrazza, A.; Cacchi, S. Angew. Chem., Int. Ed. 2009, 48, 8078–8081.
See also: (e) Guan, Z.-H.; Yan, Z.-Y.; Ren, Z.-H.; Liu, X.-Y.; Liang,
Y.-M. Chem. Commun. 2010, 46, 2823–2825. [Pd]: (f) Wurtz, S.;
Rakshit, S.; Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int.
Ed. 2008, 47, 7230–7233. (g) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.;
Cui, Y.; Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572–4576. (h) Chiba,
S.; Zhang, L.; Sanjaya, S.; Ang, G. Y. Tetrahedron 2010, 66, 5692–5700.
(i) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676–3677.
(j) Zhou, F.; Han, X.; Lu, X. Tetrahedron Lett. 2011, 52, 4681–4685.
(10) (a) Ackermann, L.;Lygin, A. V.; Hofmann, N.Angew. Chem., Int.
Ed. 2011, 50, 6379–6382. (b) Ackermann, L.; Lygin, A. V.; Hofmann, N.
Org. Lett. 2011, 13, 3278–3281. (c) Ackermann, L.; Wang, L.; Lygin, A. V.
Chem. Sci. 2012, 2, 177–180.
4
5
c
6
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
À
7
100
80
À
6
8
KPF6 (10)
KPF6 (10)
58
9
80
58d
43e
63e
16f
85g
10
11
12
13
14
100 KPF6 (10)
100 KPF6 (10), KOAc (200)
100 KPF6 (10)
100 KPF6 (10)
100 [Ru2Cl3(p-cymene)2][PF6] (2.5) 96
a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), [RuCl2(p-
cymene)]2 (2.5 mol %), Cu(OAc)2•H2O (2.0 equiv), solvent (2.0 mL);
yields of isolated product. b [RuCl2(p-cymene)]2 (5.0 mol %). c In the
absence of [RuCl2(p-cymene)]2. d With PTS (3 wt %). e Cu(OAc)2•H2O
(1.0 equiv). f [Pd(PPh3)2Cl2] (10 mol %). g [RhCp*Cl2]2 (5.0 mol %).
(11) (a) Ackermann, L. Chem. Rev. 2011, 111, 1315–1345. (b) See
ꢀ
also: Ackermann, L.; Novak, P.; Vicente, R.; Pirovano, V.; Potukuchi,
H. K. Synthesis 2010, 2245–2253. (c) Ackermann, L. Pure Appl. Chem.
2010, 82, 1403–1413.
(12) Recent reviews on metal-catalyzed reactions in or on water: (a)
Li, C.-J. Acc. Chem. Res. 2010, 43, 581–590. (b) Lipshutz, B. H.; Abela,
A. R.; Boskovic, Z. V.; Nishikata, T.; Duplais, C.; Krasovskiy, A. Top.
Catal. 2010, 53, 985–990. (c) Butler, R. N.; Coyne, A. G. Chem. Rev.
2010, 110, 6302–6337 and references cited therein.
(13) Recent ruthenium-catalyzed oxidative CÀH bond transforma-
tions in water: (a) Ackermann, L.; Pospech, J. Org. Lett. 2011, 13, 4153–
4155. (b) Ackermann, L.; Fenner, S. Org. Lett. 2011, 13, 6548–6551. See
also: (c) Li, B; Feng, H.; Xu, S.; Wang, B. Chem.;Eur. J. 2011, 17,
12573–12577.
(14) For very recent elegant reports on related rhodium- and palla-
dium-catalyzed transformations of anilines with difficult to remove 2-pyr-
idyl-substituents in organic solvents, including one example with a
2-pyrimidyl directing group, see: (a) Chen, J.; Song, G.; Pan, C.-L.;
Li, X. Org. Lett. 2010, 12, 5426–5429. (b) Chen, J.; Pang, Q.; Sun, Y.; Li,
X. J. Org. Chem. 2011, 76, 3523–3526.
With an optimized catalytic system in hand, we surveyed its
scope in the oxidative indole synthesis in water (Scheme 1).
Anilines displaying either 2-pyrimidyl or 2-pyridyl sub-
stituents were efficiently converted to the desired indoles
3aaÀ3cb, while the N-2-pyrimidyl group was easily cleaved
from the indole 3aa (Scheme 2). The cationic ruthenium-
(II) complex was not limited to tolane derivatives, but also
allowed the efficient annulation of alkyl-substituted deriv-
atives 2. Unsubstituted aniline 1c as well as derivatives 1
ꢀ
(17) Fernandez, S.; Pfeffer, M.; Ritleng, V.; Sirlin, C. Organometal-
lics 1999, 18, 2390–2394.
(15) Ackermann, L.; Lygin, A. V. Org. Lett. 2011, 13, 3332–3335.
(16) Bennett, M. A.; Smith, A. K. J. Chem. Soc., Dalton Trans. 1974,
233–241.
(18) (a) Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211–
229. See also: (b) Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.; Jutand, A.
J. Am. Chem. Soc. 2011, 133, 10161–10170.
Org. Lett., Vol. 14, No. 3, 2012
765

ketone, being well tolerated by the cationic ruthenium(II)
complex.
Scheme 1. Scope of Ruthenium-Catalyzed Oxidative Synthesis
of Indoles 3
Scheme 2. Removal of Directing Group
Given the remarkable chemoselectivity of the ruthe-
nium catalysis in water, we became interested in probing
its mode of action. To this end, intermolecular competi-
tion experiments with differently substituted alkynes 2
revealed aryl-substituted derivatives to be converted pre-
ferentially (Scheme 3).
Scheme 3. Competition Experiments with Alkynes 2
with electron-donating or -withdrawing substituents
furnished the desired indoles 3 in synthetically useful
isolated yields. Intramolecular competition experiments
with meta-substituted aniline 1h led to the site-selective
functionalization at the less sterically encumbered CÀH
bond, thereby delivering indole 3hb as the sole product.
Moreover, unsymmetrically substituted alkynes 2cÀ2l
were converted with high regioselectivity,19 placing the
aliphatic substituents distal to the nitrogen. Generally,
the optimized catalytic system proved to be widely
applicable, as illustrated by valuable functional groups,
such as an unprotected alcohol, esters, or an enolizable
Interestingly, intermolecular competition experiments
between anilines 1 highlighted arene 1a to be converted
preferentially (Scheme 4). This selectivity pattern con-
trasts all previously observed chemoselectivities of
ruthenium-catalyzed oxidative annulations of alkynes,10
thus being suggestive of a novel mode of activation to be
operative.
Additionally, we observed an H/D exchange when
employing D2O as the solvent (Scheme 5). This scrambling
occurred exclusively in the ortho-position of substrates 1a
and 1c. More importantly, deuterium incorporation took
place both in the absence (a) and in the presence of alkynes
(19) For detailed information see the Supporting Information.
766
Org. Lett., Vol. 14, No. 3, 2012

to undergo coordination and migratory insertion with
alkyne 2 to furnish ruthenacycle 7. Finally, reductive
elimination delivers desired product 3, and reoxi-
dation regenerates the catalytically active cationic
complex 5.
Scheme 4. Competition Experiment with Anilines 1
Scheme 6. Proposed Catalytic Cycle
2 (b), a significant difference from a rhodium-catalyzed
oxidative synthesis of N-acetyl indoles.9a,b
Scheme 5. Reversible CÀH bond Functionalizations in D2O
In summary, we have reported on the first ruthenium-
catalyzed oxidative annulation of alkynes by aniline deri-
vatives. The most efficient catalysis was accomplished with
a cationic ruthenium(II) complex in water as a sustainable
solvent, thereby setting the stage for an expedient synthe-
sis of bioactive indoles with ample scope. Mechanistic
studies indicated a novel reaction manifold through the
reversible formation of six-membered ruthenacycles as
key intermediates.
Based on these experimental findings we propose
a catalytic cycle relying on initial reversible cyclo-
metalation with cationic ruthenium(II) complex 5
(Scheme 6). Thereby, six-membered ruthenacycle 6 is
formed as a key intermediate. Note that all ruthenium-
catalyzed oxidative annulations of alkynes10 were thus
far limited to substrates that form five-membered
ruthenacycles. Subsequently, complex 6 is proposed
Acknowledgment. Support by the Georg-August-
Universitaet Goettingen is gratefully acknowledged.
Supporting Information Available. Experimental pro-
1
cedures, characterization data, and H and 13C NMR
spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 14, No. 3, 2012
767