Ruthenium(II)-Catalyzed Double Annulation of Quinones: Step-Economical Access to Valuable Bioactive Compounds

Article abstract of DOI:10.1002/chem.202001434

Double ruthenium(II)-catalyzed alkyne annulations of quinones were accomplished. Thus, a strategy is reported that provides step-economical access to valuable quinones with a wide range of applications. C?H/N?H activations for alkyne annulations of naphthoquinones provided challenging polycyclic quinoidal compounds by forming four new bonds in one step. The singular power of the thus-obtained compounds was reflected by their antileukemic activity.

Full text of DOI:10.1002/chem.202001434

A Journal of
Accepted Article
Title: Ruthenium(II)-Catalyzed Double Annulation of Quinones: Step-
Economical Access to Valuable Bioactive Compounds
Authors: Eufrânio N. da Silva Júnior, Renato L. de Carvalho, Renata
G. Almeida, Luisa G. Rosa, Felipe Fantuzzi, Torben Rogge,
Pedro M. S. Costa, Claudia Pessoa, Claus Jacob, and Lutz
Ackermann
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.202001434
Link to VoR: http://dx.doi.org/10.1002/chem.202001434
Supported by

10.1002/chem.202001434
Chemistry - A European Journal
COMMUNICATION
Ruthenium(II)-Catalyzed Double Annulation of Quinones: Step-
Economical Access to Valuable Bioactive Compounds
Eufrânio N. da Silva Júnior,*[a,b] Renato L. de Carvalho,[a,b] Renata G. Almeida,[b] Luisa G. Rosa,[b]
Felipe Fantuzzi,[c] Torben Rogge,[a] Pedro M. S. Costa,[d] Claudia Pessoa,[d] Claus Jacob,[e] and Lutz
Ackermann*[a,f]
Abstract: Double ruthenium(II)-catalyzed alkyne annulations of
quinones were accomplished. Thus, we report a strategy that provides
step-economical access to valuable quinones with a wide range of
applications. C–H/N–H activations for alkyne annulations of
naphthoquinones provided challenging polycyclic quinoidal
compounds by forming four new bonds in one step. The singular
power of the thus-obtained compounds was reflected by their
antileukemic activity.
others have developed synthetic methods for preparing
functionalized quinones based on C‒H iodination,9 oxygenation,10
alkenylation,11 sequential C–H iodination/thiolation12 and
selenation.13 Most of these methods are limited to
functionalizations at the position C-5, while the construction
polycyclic quinoidal motifs remains a challenge. Thus, on the
basis of our experience in developing annulative reactions14 for
the construction of heterocyclic rings, we have identified C–H
activation/annulation as
a complementary method for the
construction of the desired cyclic systems.
Polycyclic quinones represent an important class of
substances with outstanding biological activities1 and diverse
applications for example as dyes.2 Consequently, there is a
continued strong demand for effective methods to access this
class of compounds in a direct and efficient fashion.3 Metal-
catalyzed reactions are an effective and reliable approach for the
construction of such compounds (Scheme 1A).4 Ruthenium-
alkylidene Grubbs catalysts have been used to perform ring-
closing metathesis to afford polycyclic compounds.5 Nitrogenated
quinones were also prepared by three-component reactions via
C‒H6 difunctionalization of naphthoquinones.7 The antitumor
potential of polycyclic quinonoid compounds prepared via
palladium catalysis was described by the Koketsu group.8 The
compounds exhibited important antileukemic activity and a
mechanism of action associated with the generation of reactive
oxygen species (ROS).
In this work, we report on the development and scope of a
new protocol for preparing polycyclic quinones, which provides for
the first time a versatile and efficient alternative for the synthesis
of molecules that represent a great synthetic challenge via
ruthenium(II)-catalyzed double annulation reaction (Scheme 1B).
As part of a broad program focused on the development of
transition metal-catalyzed reactions involving quinones, we and
[a]
[b]
R. L. de Carvalho, Prof. Dr. E. N. da Silva Júnior,
Dr. T. Rogge, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie, Georg-August-
Universität Göttingen, Tammannstraße 2, 37077 Göttingen
(Germany). E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
R. L. de Carvalho, R. G. Almeida, L. G. Rosa,
Prof. Dr. E. N. da Silva Júnior
Institute of Exact Sciences, Department of Chemistry, Federal
University of Minas Gerais, UFMG, 31270-901, Belo Horizonte, MG
(Brazil). E-mail: eufranio@ufmg.br
[c]
[d]
[e]
[f]
Dr. F. Fantuzzi
Institute for Inorganic Chemistry, Julius-Maximilians-Universität
Würzburg, Am Hubland, 97074, Würzburg (Germany).
P. M. S. Costa, Prof. Dr. C. Pessoa
Department of Physiology and Pharmacology, Federal University of
Ceará, Fortaleza, CE, 60430-270 (Brazil).
Prof. Dr. C. Jacob
Division of Bioorganic Chemistry, School of Pharmacy, University of
Saarland, 66123 Saarbrücken (Germany).
Scheme 1. C–H activation/annulation for polycyclic quinone assembly.
Our initial attempts to achieve the double annulation process
focused on the reaction between naphthoquinone 1a and
diphenylacetylene (2a) (Table 1). [RuCl2(p-cymene)]2 in
combination with Cu(OAc)2 as the catalyst known for its efficiency
to perform annulation reactions,15 provided the desired product 3a
in only 44% yield with DCE as the solvent (entry 1). This initial
result was highly encouraging when considering the challenging
formation of four new bonds in only a single step. Despite the
successful preparation of product 3a, subsequent efforts have
Prof. Dr. L. Ackermann
German Center for Cardiovascular Research (DZHK), Potsdamer
Strasse 58,10785 Berlin (Germany)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001434
Chemistry - A European Journal
COMMUNICATION
been undertaken aiming at alternative ruthenium-based catalysts,
in order to improve the efficiency of the reaction. Accordingly,
Ru(O2CMes)2(p-cymene), Ru(OPiv)2(PPh3)2, RuCl3 and RuBr3
were also probed as the ruthenium source, but the efficacy was
not improved (entries 2-5). Increasing the catalyst loading of
H annulation reaction. The reaction with diphenylacetylenes
containing EDGs proceeded smoothly, affording the targets 3b,
3h and 3j in moderate yields. The exception here was product 3c,
which was obtained in somewhat lower yield. A decreased yield
of annulated quinolone 3k was observed with two methyl groups
[RuCl2(p-cymene)]2 did not lead to an improvement (entry 6). Next, being present in the respective alkyne 2k, probably due to the
we evaluates the effectiveness of different solvents for the
assembly of product 3a , albeit with limited success (entries 7-10).
However, further experimentation revealed DCE as the optimal
solvent for this transformation, and, consequently, we decided to
steric effect caused by the substituent groups. Then, we
evaluated the presence of EWGs and, as expected, the efficiency
of the process decreased as the alkyne becomes more electron-
deficient. The yields of all the compounds described here could
be increased when an additional 5 mol % of the catalyst was
added after 12h.
probe the presence of additives to generate
a cationic
ruthenium(II) catalyst. Here, KPF6, KOAc, NaOAc, and NaOPiv
were evaluated as additives (entries 11-14). Further refinement
led to the reaction conditions outlined in entries 15 and 18,
delivering product 3a 80% yield (See SI for experimental details).
Table
1.
Optimization
studies
for
ruthenium(II)-catalyzed
C–H
activation/annulation.[a]
Yield
3a
(%)
Additive
(Y equiv)
Cu(OAc)2
(X equiv)
Entry
[Ru] (mol %)
Solvent
CCDC: 1984922
1
2
[RuCl2(p-cymene)]2 (5)
Ru(O2CMes)2(p-cymene) (5)
Ru(OPiv)2(PPh3)2 (5)
RuCl3 (10)
DCE
DCE
-
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
4.0
2.0
44
16
NR
NR
NR
11
16
16
12
16
27
50
48
55
63
47
21
80
29
NR
-
3
DCE
-
4
DCE
-
5
RuBr3 (10)
DCE
-
6
[RuCl2(p-cymene)]2 (10)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (5)
[RuCl2(p-cymene)]2 (2 × 2.5)a
[RuCl2(p-cymene)]2 (2 × 5)a
[RuCl2(p-cymene)]2 (2 × 5)a
-
DCE
-
7
t-AmOH
DMF
CHCl3
o-xylene
DCE
-
8
-
9
-
10
11
12
13
14
15
16
17
18
19
20
-
KPF6 (0.2)
KOAc (0.2)
NaOAc (0.2)
NaOPiv (0.2)
NaOPiv (0.5)
NaOPiv (1.0)
NaOPiv (0.5)
NaOPiv (0.5)
NaOPiv (0.5)
-
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Reaction conditions: 1a (0.20 mmol), 2a (4.0 equiv), catalyst (5.0-10.0 mol %),
additive (0.20-1.00 equiv), Cu(OAc)2·H2O (2.0-4.0 equiv), solvent (2.0 mL), 120
°C, 24 h. NR = no reaction. In all cases, the starting material was recovered.
Yields refer to the isolated product. aAn additional amount of 2.5 or 5.0 mol %
of catalyst was added after 12 h.
To investigate the viable scope of the ruthenium-catalyzed
double annulation process, our method was employed for the
synthesis of various naphthoquinoidal compounds. Initially, we
explored the influence of the alkyne substitution pattern (Scheme
2). Thus, 2-acetylamino-1,4-naphthoquinone (1a) was used as
quinone component and both electron-donating (EDG) as well as
electron-withdrawing (EWG) substituents were probed in the C‒
Scheme 2. Double annulation reaction between quinone 1a and alkynes 2.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001434
Chemistry - A European Journal
COMMUNICATION
The effectiveness of the annulation process herein developed
was also proven with the use of A-ring substituted quinones 1b-g
(Scheme 3). Naphthoquinone 1b possessing C-7 and C-8
substitution underwent an efficient annulation reaction with 71%
yield. Quinone 1c with a methoxy group at C-5 delivered the
product in 39% yield. As expected, a more electron-deficient
benzenoid ring decreased the reactivity of the quinoidal system
and, consequently, nitro-substituted quinone 4c was produced in
only 12% yield. When the corresponding quinone 1e bearing a
hydroxyl group was used, the expected products 4d and 4e were
obtained in 18% and 19% yield, respectively. The reaction in the
absence NaOPiv allowed the preparation of product 4d as a
single product. Surprisingly, when sulphur-containing quinone 1f
and 2-acetamide-1,4-antraquinone (1g) were used, only the
products 4f and 4g via the first C‒H/N‒H annulation process were
isolated. The products were unambiguously characterized by X-
ray crystallographic analysis.
analysis and ORTEP-3 projections for both compounds are
presented in the Scheme 4.
CCDC: 1984934
CCDC: 1984935
Scheme 4. Double annulation reaction between quinone 1a and asymmetric
alkyne 2l. aAn additional 5.0 mol % of catalyst was added after 12 h.
Based on previous mechanistic studies,14,16 we propose a
plausible catalytic cycle to commence with sequential C–H/N–H
activation steps to form key intermediate 6 (Scheme 5).
Coordination of 2a followed by migratory insertion leads to the first
C–C coupling and the formation of B. The next step is the
reductive elimination of the intermediate 3a’ after ruthenium-
mediated C–N coupling and regeneration of the active catalytic
ruthenium(II) species by reoxidation. Intermediate 3a’, which
bears
a terminal pyrrole ring, undergoes a subsequent
transformation, where a new sequence of C–H/N–H activation
steps leads to intermediate 7. After coordination of 2a and
migratory insertion, a seven-membered metallacycle is formed
(intermediate E). Product 3a is then generated after ruthenium-
mediated C–N coupling followed by reductive elimination.
Given the remarkable formation of four new bonds by our
strategy, we became attracted to better understand the C–C and
C–N coupling steps through density functional theory (DFT)
calculations (Figure 1). Geometry optimizations and frequency
calculations were performed at the ωB97XD/def2-DZVPP17 level
of theory and single point energies at the SMD-ωB97XD/def2-
TZVPP17,18 level of theory. The energy barrier for the first
migratory insertion starting from the alkyl-coordinated
intermediate A is merely 10.7 kcal mol-1, while intermediate B is
stabilized by 31.6 kcal mol-1 in comparison to A. However, the
initial C–N coupling is achieved through an energy barrier of 25.9
kcal mol-1. In the second catalytic cycle, the energy barrier of the
migratory insertion step is 14.5 kcal mol-1 and the following
intermediate E is favorable by 12.6 kcal mol-1 in comparison to D.
However, the second C–N coupling has an energy barrier of 43.3
kcal mol-1, with E and F being nearly equiergic. This value
indicates the reductive elimination to be rate-determining, and is
in line with the reaction proceeding at 120 °C, while in select
cases only the first annulation was thus observed (vide supra).
Comparable results were obtained using Truhlar’s M06
functional19 with D3 correction.20
CCDC: 1984932
Scheme 3. Double annulation reaction between quinones 1 and alkyne 2b.
Finally, the use of unsymmetrically-substituted alkynes was
also explored. Compound 1a was reacted with 1-phenyl-1-
propyne (2l) affording compounds 5a and 5b in a 1:1 ratio. The
product structures were also unambiguously confirmed by X-ray
In order to investigate the electronic structure of the polycyclic
quinones synthesized, we furthermore performed additional
computational studies for the species 1a, 3a' and 3a at the
B3LYP21-D3(BJ)22/def2-TZVPP+SMD(DCE)17 level of theory
This article is protected by copyright. All rights reserved.

10.1002/chem.202001434
Chemistry - A European Journal
COMMUNICATION
(Figure 2). Our calculations show that, while the HOMO of
naphthoquinone 1a is mainly localized on the C=C bonds of the
quinoidal ring, for product 3a' it is delocalized through the π-space
of the pyrrole ring and its aryl substituents. After the second
annulation and formation of the final product 3a, the HOMO
delocalizes only through the pyrrole ring and the newly formed π-
extended system. In contrast, the LUMO is localized on the
quinoidal ring for all compounds irrespective of the level of π-
extension. The HOMO-LUMO gap decreases systematically as
the π-system is extended in a similar fashion as in n-acenes.23
Thus, we expect that adapting our synthetic strategy for preparing
high-order polycyclic quinones could eventually lead to the
development of novel organic semiconducting materials.
Scheme 5. Proposed catalytic cycle.
Figure 1. Relative Gibbs free energy profile for the C–C and C–N coupling steps of the reaction of 1a with 2a at the ωB97XD/def2-TZVPP+SMD(DCE) (―) and
M06-D3/def2-TZVPP+SMD(DCE) (―) levels of theory.
Finally, we evaluated the novel quinoidal compounds against
cancer cell lines (Table S20 in the SI). Compounds 3d and 4g
exhibited antitumor activity against leukaemia cancer cells (HL-
60) with IC50 values of 2.92 and 3.17 µM, respectively. We
evaluated the compounds against five other tumour cell lines
(NCI-H460, HCT-116, SNB-19, MCF-7 and PC3) and against one
normal cell line (L-929) and the compounds were not active in
these cell lines. These results are indicative of the substances
featuring considerable potential selectivity for leukaemia cells.
More detailed studies are in progress in our laboratories to
understand the aspects related to the cytotoxicity presented by
these compounds against leukaemia cancer cells.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001434
Chemistry - A European Journal
COMMUNICATION
We thank Dr. Christopher Golz (Göttingen University) for
assistance with the Xray diffraction analysis.
Conflict of interest
The authors declare no conflict of interest.
Keywords: alkynes • annulation • C‒H activation • quinones •
ruthenium • cancer
[1]
(a) T. Rodrigues, M. Werner, J. Roth, E. H. G. da Cruz, M. C. Marques,
P. Akkapeddi, S. A. Lobo, A. Koeberle, F. Corzana, E. N. da Silva Júnior,
O. Werz, G. J. L. Bernardes, Chem. Sci. 2018, 9, 6899-6903; (b) S. L. de
Castro, F. S. Emery, E. N. da Silva Júnior, Eur. J. Med. Chem. 2013, 69,
678-700; (c) D. Kallifidas, H.-S. Kang, S. F. Brady, J. Am. Chem. Soc.
2012, 134, 19552-19555; (d) R. H. Thomson, Naturally Occurring
Quinones, Academic Press, London, 1971, 2nd edn.; (e) R. H. Thomson,
Naturally Occurring Quinones III Recent Advances, Chapman and Hall,
London, 1987, 3rd edn; (f) G. Powis, Pharmacol. Ther. 1987, 35, 57; (c)
P. J. O’Brien, Chem. Biol. Interact. 1991, 80, 1; (g) E. A. Hillard, F. C.
Abreu, D. C. Ferreira, G. Jaouen, M. O. F. Goulart, C. Amatore, Chem.
Commun. 2008, 23, 2612.
[2]
[3]
Z. Chen, T. M. Swager, Org. Lett. 2007, 9, 997-1000.
J. M. Wood, E. N. da Silva Júnior, J. F. Bower, Org. Lett. 2020, 22, 265-
269.
Figure 2. Energies and shapes of frontier orbitals (HOMO and LUMO) of 1a, 3a’
and 3a calculated at the B3LYP-D3(BJ)/def2-TZVPP+SMD(DCE) level of theory.
[4]
[5]
[6]
(a) B. R. Ambler, B. W. H. Turnbull, S. R. Suravarapu, M. M. Uteuliyev,
N. O. Huynh, M. J. Krische, J. Am. Chem. Soc. 2018, 140, 9091-9094;
(b) M. Bender, B. W. H. Turnbull, B. R. Ambler, M. J. Krische, Science
2017, 357, 779-781.
In summary, we have reported on the first ruthenium(II)-
catalyzed C‒H/N‒H double annulation of quinones with various
alkynes. We have described an effective and robust method for
the formation of four bonds in an expedient and versatile fashion,
affording quinoidal compounds with value in medicinal chemistry,
with potential application in the treatment of cancer. Thus, the
annulation reaction is viable with ample scope and formation of
challenging compounds in just one step. Additionally, we
performed computational studies in order to provide more
information about the catalytic cycle of this reaction and the
electronic structure of the intermediates and products. Finally, we
also conducted antitumor studies against cancer cells,
highlighting the biological activity of the compounds obtained
herein.
(a) M. Arisawa, Y. Fujii, H. Kato, H. Fukuda, T. Matsumoto, M. Ito, H. Abe,
Y. Ito, S. Shuto, Angew. Chem. Int. Ed. 2013, 52, 1003-1007; (b) Y. Fujii,
T. Takehara, T. Suzuki, H. Fujioka, S. Shuto, M. Arisawa, Adv. Synth.
Catal. 2015, 357, 4055-4062.
For selected reviews, see: (a) S. Rej, Y. Ano, N. Chatani, Chem. Rev.
2020, DOI: 10.1021/acs.chemrev.9b00495; (b) S. M. Khake, N. Chatani,
Trends Chem. 2019, 1, 524–539; (c) A. Dey, S. K. Sinha, T. K. Achar, D.
Maiti, Angew. Chem. Int. Ed. 2019, 58, 10820-10843; (d) P. Gandeepan,
T. Müller, D. Zell, G. Cera, S. Warratz, L. Ackermann, Chem. Rev. 2019,
119, 2192–2452; (e) C. S. Wang, P. H. Dixneuf, J. F. Soule, Chem. Rev.
2018, 118, 7532–7585; (f) P. Gandeepan, L. Ackermann, Chem 2018, 4,
199–222; (g) J. C. K. Chu, T. Rovis, Angew. Chem. Int. Ed. 2018, 57,
62–101; (h) K. Murakami, S. Yamada, T. Kaneda, K. Itami, Chem. Rev.
2017, 117, 9302–9332; (i) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017,
117, 9247–9301; (j) J. He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q. Yu,
Chem. Rev. 2017, 117, 8754-8786; (k) J. F. Hartwig, M. A. Larsen, ACS
Cent. Sci. 2016, 2, 281–292; (l) P. B. Arockiam, C. Bruneau, P. H.
Dixneuf, Chem. Rev. 2012, 112, 5879–5918.
Acknowledgements
[7]
[8]
Y. Liu, J.-W. Sun, J. Org. Chem. 2012, 77, 1191-1197.
N. Suematsu, M. Ninomiya, H. Sugiyama, T. Udagawa, K. Tanaka, M.
Koketsu, Bioorg. Med. Chem. Lett. 2019, 29, 2243-2247.
This research was funded by grants from CNPq (404466/2016-8
and PQ 305741/2017-9), FAPEMIG (PPM-00638-16 and PPM-
00635-18), CAPES and INCT-Catálise. ENSJ thanks Capes-
Humboldt research fellowship for experienced researchers (Proc.
No. 88881.145517/2017-01) and Return Fellowship of the
Alexander-von-Humboldt foundation. LA acknowledges funding
from the DFG (Gottfried-Wilhelm-Leibniz prize). ENSJ and CJ
thank CAPES and DAAD for research cooperation project under
the PROBRAL programme (Proc. No. 99999.008126/2015-01).
FF acknowledges Capes-Humboldt research fellowship for
postdoctoral researchers and JMU Würzburg for HPC resources.
[9]
G. A. M. Jardim, E. N. da Silva Júnior, J. F. Bower, Chem. Sci. 2016, 7,
3780-3784.
[10] G. G. Dias, T. Rogge, R. Kuniyil, C. Jacob, R. F. S. Menna-Barreto, E. N.
da Silva Júnior, L. Ackermann, Chem. Commun. 2018, 54, 12840-12843.
[11] G. G. Dias, T. A. do Nascimento, A. K. A. de Almeida, A. C. S. Bombaça,
R. F. S. Menna-Barreto, C. Jacob, S. Warratz, E. N. da Silva Júnior, L.
Ackermann, Eur. J. Org. Chem. 2019, 2344-2353.
[12] G. A. M. Jardim, W. X. C. Oliveira, R. P. de Freitas, R. F. S. Menna-
Barreto, T. L. Silva, M. O. F. Goulart, E. N. da Silva Júnior, Org. Biomol.
Chem. 2018, 16, 1686-1691.
[13] G. A. M. Jardim, I. A. O. Bozzi, W. X. C. Oliveira, C. Mesquita-Rodrigues,
R. F. S. Menna-Barreto, R. A. Kumar, E. Gravel, E. Doris, A. L. Braga, E.
N. da Silva Júnior, New J. Chem. 2019, 43, 13751-13763.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001434
Chemistry - A European Journal
COMMUNICATION
[14] For selected references, see: (a) L. Ackermann, Acc. Chem. Res. 2014,
47, 281-295; (b) G. Rouquet, N. Chatani, Angew. Chem. Int. Ed. 2013,
52, 11726-11743; (c) S. Peng, S. Liu, S. Zhang, S. Cao, J. Sun, Org. Lett.
2015, 17, 5032-5035; (d) J. Jayakumar, K. Parthasarathy, Y.-H. Chen,
T.-H. Lee, S.-C. Chuang, C.-H. Cheng, Angew. Chem. Int. Ed. 2014, 53,
9889-9892; (e) S. Rakshit, F. W. Patureau, F. Glorius, J. Am. Chem. Soc.
2010, 132, 9585-9587; (f) G. Song, D. Chen, C.-L. Pan, R. H. Crabtree,
X. Li, J. Org. Chem. 2010, 75, 7487-7490; (g) M. Satoshi, U. Nobuyoshi,
H. Koji, S. Tetsuya, M. Masahiro, Chem. Lett. 2010, 39, 744-746. For
representative examples from our laboratories, see: (h) W.-J. Kong, L. H.
Finger, A. M. Messinis, R. Kuniyil, J. C. A. Oliveira, L. Ackermann, J. Am.
Chem. Soc. 2019, 141, 17198-17206; (i) C. Zhu, R. Kuniyil, L.
Ackermann, Angew. Chem. Int. Ed. 2019, 58, 5338-5342; (j) E. Gońka,
L. Yang, R. Steinbock, F. Pesciaioli, R. Kuniyil, L. Ackermann, Chem.
Eur. J. 2019, 25, 16246-16250; (k) C. Tian, U. Dhawa, A. Scheremetjew,
L. Ackermann, ACS Catal. 2019, 9, 7690-7696; (l) R. Mei, J. Koeller, L.
Ackermann, Chem. Commun. 2018, 54, 12879-12882; (m) R. Mei, H.
Wang, S. Warratz, S. A. Macgregor, L. Ackermann, Chem. Eur. J. 2016,
22, 6759-6763; (n) W. Ma, L. Ackermann, Synthesis 2014, 2297-2304;
(o) J. Li, L. Ackermann, Tetrahedron 2014, 70, 3342-3348; (p) W. Song,
L. Ackermann, Chem. Commun. 2013, 49, 6638-6640; (q) C. Kornhaaß,
J. Li, L. Ackermann, J. Org. Chem. 2012, 77, 9190-9198, and references
cited therein.
[15] W. Ma, K. Graczyk, L. Ackermann, Org. Lett. 2012, 14, 6318-6321.
[16] (a) J. Mo, T. Müller, J. C. A. Oliveira, S. Demeshko, F. Meyer, L.
Ackermann, Angew. Chem. Int. Ed. 2019, 58, 12874-12878; (b) W.-J.
Kong, L. H. Finger, J. C. A. Oliveira, L. Ackermann, Angew. Chem. Int.
Ed. 2019, 58, 6342-6346; (c) I. Funes-Ardoiz, F. Maseras, Chem. Eur. J.
2018, 24, 12383-12388; (d) R. Mei, N. Sauermann, J. C. A. Oliveira, L.
Ackermann, J. Am. Chem. Soc. 2018, 140, 7913-7921; (e) G. Rouquet,
N. Chatani, Chem. Sci. 2013, 4, 2201-2208; (f) B. Li, H. Feng, N. Wang,
J. Ma, H. Song, S. Xu, B. Wang, Chem. Eur. J. 2012, 18, 12873-12879;
(g) B. Li, T. Roisnel, C. Darcel, P. H. Dixneuf, Dalton Trans. 2012, 41,
10934-10937; (h) L. Ackermann, A. V. Lygin, N. Hofmann, Angew. Chem.
Int. Ed. 2011, 50, 6379-6382.
[17] (a) J.-D. Chai, M. Head-Gordon, Phys. Chem. Chem. Phys. 2008, 10,
6615-6620. (b) F. Weigend, R. Ahlrichs, Phys. Chem. Chem. Phys. 2005,
7, 3297-3305.
[18] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. B 2009, 113,
6378–6396.
[19] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215–241.
[20] S. Grimme, J. Antony, S. Ehrlich, H. Krieg, J. Chem. Phys. 2010, 132,
154104.
[21] (a) S. H. Vosko, L. Wilk, M. Nusair, Can. J. Phys. 1980, 58, 1200–1211.
(b) C. Lee, W. Yang, R. G. Parr, Phys. Rev. B 1988, 37, 785–789. (c) A.
D. Becke, J. Chem. Phys. 1993, 98, 5648–5652. (d) P. J. Stephens, F. J.
Devlin, C. F. Chabalowski, M. J. Frisch, J. Phys. Chem. 1994, 98, 11623–
11627.
[22] S. Grimme, S. Ehrlich, L. Goerigk, J. Comput. Chem. 2011, 32, 1456–
1465.
[23] (a) J. E. Anthony, Angew. Chemie Int. Ed. 2008, 47, 452–483. (b) M.
Kitamura, Y. Arakawa, J. Phys. Condens. Matter 2008, 20, 184011. (c)
M. Watanabe, Y. J. Chang, S.-W. Liu, T.-H. Chao, K. Goto, M. M. Islam,
C.-H. Yuan, Y.-T. Tao, T. Shinmyozu, T. J. Chow, Nat. Chem. 2012, 4,
574–578. (d) M. Pinheiro, L. F. A. Ferrão, F. Bettanin, A. J. A. Aquino, F.
B. C. Machado, H. Lischka, Phys. Chem. Chem. Phys. 2017, 19, 19225–
19233.
This article is protected by copyright. All rights reserved.

10.1002/chem.202001434
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Eufrânio N. da Silva Júnior,* Renato L.
de Carvalho, Renata G. Almeida, Luisa
G. Rosa, Felipe Fantuzzi, Torben
Rogge, Pedro M. S. Costa, Claudia
Pessoa, Claus Jacob, and Lutz
Ackermann*
Page No. – Page No.
Ruthenium(II)-catalyzed C‒H/N‒H double annulation were realized for the formation
of polycyclic quinones enabling the assembly of antitumor compounds.
Ruthenium(II)-Catalyzed Double
Annulation of Quinones: Step-
Economical Access to Valuable
Antitumor Compounds
This article is protected by copyright. All rights reserved.