Ruthenaelectro-Catalyzed Domino Three-Component Alkyne Annulation for Expedient Isoquinoline Assembly

Article abstract of DOI:10.1002/anie.202014289

The electrochemical three-component assembly of isoquinolines has been accomplished by ruthenaelectro-catalyzed C?H/N?H functionalization. The robustness of the electrocatalysis was reflected by an ample substrate scope, an efficient electrooxidation, and an operationally friendly procedure. The isolation of key intermediates and detailed mechanistic studies, including unprecedented cyclovoltammetric analysis of a seven-membered ruthenacycle, provided support for an unusual ruthenium(II/III/I) regime.

Full text of DOI:10.1002/anie.202014289

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Ruthenaelectro-Catalyzed Domino Three-Component Alkyne
Annulation Expedient Isoquinoline Assembly
Authors: Xuefeng Tan, Xiaoyan Hou, Torben Rogge, 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: Angew. Chem. Int. Ed. 10.1002/anie.202014289
Link to VoR: https://doi.org/10.1002/anie.202014289

10.1002/anie.202014289
Angewandte Chemie International Edition
COMMUNICATION
Ruthenaelectro-Catalyzed Domino Three-Component Alkyne
Annulation Expedient Isoquinoline Assembly
Xuefeng Tan,[a] Xiaoyan Hou,[a] Torben Rogge,[a] and Lutz Ackermann*[a,b]
Dedicated to Prof. Dr. Paul Knochel on the occasion of his 65th birthday
[a]
Dr. X. Tan, X. Hou, Dr. T. Rogge, and 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
Prof. Dr. L. Ackermann
[b]
Wöhler Research Institute for Sustainable Chemistry
Georg-August-Universität Göttingen
Tammannstraße 2, 37077 Göttingen (Germany)
Supporting information for this article is given via a link at the end of the document.
Abstract: The electrochemical three-component assembly of
isoquinolines has been accomplished by ruthenaelectro-catalyzed C–
H/N–H functionalization. The robustness of the electrocatalysis was
reflected by an ample substrates scope, an efficient electrooxidation
and an operationally-friendly procedure. The isolation of key
intermediates and detailed mechanistic studies, including
unprecedented cyclovoltammetric analysis of a seven-membered
ruthenacycle, provided support for an unusual ruthenium(II/III/I)
regime.
mechanistic
insights
into
oxidation-induced
reductive
elimination[17] at ruthenium(II) by experiments and calculation.
Transition metal-catalyzed C–H activation has been recognized
as an increasingly viable transformative platform in molecular
syntheses.[1] Nitrogen-containing heterocycles are omnipresent in
bioactive molecules of interest to medicinal chemistry and
pharmaceutical industries.[2] Particularly, isoquinolines feature
diverse activities, such as cardiovascular,[3] anti-tumor,[4] anti-
inflammatory[5] or anti-malaria[6] properties. Transition metal-
catalyzed imino group-directed C–H activation, along with a
subsequent annulation of alkynes represents one of the most
efficient strategies to construct isoquinolines.[7,8] In the past
decade, considerable efforts have thus been devoted to the
development of oxidative C–H activations. These largely required
stoichiometric amounts of chemical oxidants, such as copper or
silver salts.[7,9] In addition, the imines largely needed to be isolated
prior to catalysis.[9]
Figure 1. Ruthenium-catalyzed electrochemical three-component synthesis of
isoquinoline.
At the outset of our studies, various reaction conditions were
explored for the envisioned ruthenium-catalyzed electrooxidative
three-component annulation of acetophenone 1a, alkyne 2a and
NH4OAc in an operationally simple undivided cell setup equipped
with a graphite felt (GF) anode and a platinum cathode (Table 1
and Table S1 in the Supporting Information). Ru(OAc)2(p-cymene)
was found to be superior as compared to [RuCl2(p-cymene)]2,
even without additives (Table 1, Entries 1-3). An increased
reaction temperature proved beneficial (Entries 3-5). An
evaluation of various solvents (Table S1) showed that alcoholic
solvents enabled a higher efficacy than aprotic solvents, while the
acidic trifluoroethanol (TFE) was proven best. These findings can
be rationalized in terms of a facile condensation and stabilization
of the imine through hydrogen bonding. The optimal current was
found as 2.5 mA (Entry 6). A variation in the stoichiometry of
NH4OAc did not show any significant difference (Entries 6-7).
Increasing the amount of alkyne 2a and changing the cathode
material to nickel foam yielded 3aa in a slightly improved
efficiency (Entries 8-9). Careful GC-MS analysis revealed that the
alkyne was fully consumed after the reaction when nickel foam
was used as the cathode material, generating the corresponding
E/Z-alkenes through hydrogenation with molecular H2 formed at
the cathode by paired electrolysis. Therefore, we employed a
larger reaction flask, facilitating the H2 dispersion into the
expanded volume (Entry 10). Further, we employed an oil bubbler,
In recent years, the use of electricity as a formal redox
reagent has been recognized as an increasingly viable,
environmentally-friendly strategy to empower chemical
reactions.[10] Significant recent impetus was gained by the merger
of electrocatalysis with oxidative C–H activation, thus avoiding the
use of often toxic metal oxidants.[11] Compared with rhodium[12]
and
iridium[13]
electrocatalysis,
economically-attractive
ruthenaelectrocatalysis continues to be underdeveloped.[14]
Within our program on electrochemical C–H activation,[15] we have
now devised
a sustainable ruthenaelectro-catalyzed three-
component reaction to assemble versatile isoquinolines in a
Domino manner.[16] Salient features of our findings include 1)
multi-component assembly in a one-pot fashion with a cost-
effective ruthenium catalyst,[8f] 2) isolation and full
characterization of ruthenacycle intermediates, and 3)
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202014289
Angewandte Chemie International Edition
COMMUNICATION
which allowed for the H2 release, benefiting the chemo-selectivity
for product 3aa formation (Entries 11, 12, and the SI). With air,
oxygen or with Cu(OAc)2 as the oxidant, unsatisfactory results
were obtained, reflecting the unique efficacy of the
electrocatalysis (Entries 13-15).
meta-substituted ketones 1t and 1v was governed by steric
hindrance, while meta-methoxy-substituted acetophenone 1d
delivered the less congested product 3da preferentially.
Table 1. Optimization of the ruthenium-catalyzed three-component annulation.
[a]
Entry
Current
t (h)
T (°C)
Yield (%)
1
2
4 mA
4 mA
4 mA
4 mA
4 mA
2.5 mA
2.5 mA
2.5 mA
2.5 mA
2.5 mA
2.5 mA
1.2 mA
--
14
14
14
14
14
20
20
20
20
20
20
36
20
20
20
95
22[b]
33[b,c]
33
95
3
95
4
80
19
5
110
110
110
110
110
110
110
110
110
110
110
47
6
50
7
50[d]
8
55[e]
9
63[e,f]
72[e,f,g]
82[e,f,g,h]
65[e,f,g,h,i]
12[j]
10
11
12
13
14
15
--
19[k]
--
NR[l]
[a] 1a (0.3 mmol), 2a (0.45 mmol), [Ru(OAc)2(p-cymene)] (10 mol %), NH4OAc
(4.0 equiv.), trifluoroethanol (3.5 mL), graphite felt anode (GF) (10 x 10 x 6 mm3),
platinum plate cathode (10 x 15 x 0.25 mm3), under N2 in a 10 mL vessel. [b]
[RuCl2(p-cymene)]2 (5 mol %) instead of [Ru(OAc)2(p-cymene)]. [c] KPF6 (20
mol %) added. [d] NH4OAc (2.0 equiv.). [e] 2a (0.6 mmol). [f] Nickel foam as
cathode. [g] In a 25 mL vessel. [h] Vessel equipped with an oil bubbler. [i]
[Ru(OAc)2(p-cymene)] (5 mol %). [j] Under air. [k] Under oxygen (O2 balloon). [l]
Cu(OAc)2 (2 equiv.).
Scheme 1. Ruthena-domino-electrocatalysis with ketones 1. [a] Starting
material is 4-acetoxyl acetophenone.
We then turned our attention to different alkynes 2 for the
ruthenaelectro-catalyzed three-component annulation (Scheme
2). Electron-rich or electron-deficient alkynes
2 efficiently
delivered the desired products 3, while electron-rich alkynes
exhibited a slightly higher innate reactivity. Due to the poor
solubility of para-substituted alkynes 2b and 2c in TFE, we
employed here a solvent mixture consisting of TFE and toluene.
The alcohol-containing product 3aj should prove valuable for late-
stage derivatization.
With the optimized reaction conditions in hand, we next
examined the viable substrate scope of the ruthenaelectro-
catalyzed three-component annulation with diverse ketones 1
(Scheme 1). Electron-rich as well as electron-deficient aromatic
ketones 1a-1x were amenable to the ruthenaelectro-catalyzed
Domino multi-component synthesis of isoquinolines 3. Notably, a
diverse array of valuable functional groups, including halogens
(3ea-3ga), ester (3ha), amide (3ia), acetoxyl (3ja) and cyano (3ka)
groups, were tolerated under the electrochemical conditions,
highlighting a notable potential for further late-stage diversification.
The amino ester-containing product 3ma indicated the power for
the synthesis of bio-fluorescent probes. The site-selectivity for
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202014289
Angewandte Chemie International Edition
COMMUNICATION
Scheme 2. Ruthena-domino-electrocatalysis with alkynes 2. [a] Toluene/TFE =
6:1.
Intrigued by the versatility of the ruthenaelectro-catalyzed
three-component annulation, we became interested in delineating
the catalyst’s mode of action. Competition experiments revealed
that the substitution pattern on the ketone 1 did not have a
significant influence on the reactivity, whereas electron-donating
substituents on the alkynes 2 resulted in a higher reactivity than
electron-withdrawing substituents (Scheme 3a). Reactions
conducted with deuterated methanol as a co-solvent revealed the
reversibility of a fast C–H activation step (Scheme 3b). In good
agreement with this finding, kinetic studies provided strong
support for a fast C–H metalation with a minor kinetic isotope
effect (KIE) of kH/kD ≈ 1.2 (Scheme 3c).
Scheme 3. Summary of key mechanistic experiments.
Next, we intended the isolation of key intermediates. Three
ruthenacycle complexes 5q, 5v and 5w were thereby isolated and
complex 5w was unambiguously characterized by X-ray
diffraction analysis (Scheme 4a). It is noteworthy that the 1H NMR
resonances of the ruthenacycle complexes in methanol-d4 were
1
split into two sets of resonances in contrast to the H NMR in
CDCl3, which showed only one set of resonances.[18] This is likely
caused by an equilibrium of the ruthenacycles and the OAc
disassociation from the metal center, which facilitates the alkyne
coordination to the ruthenium. Notably, the metallacycle 5q was
found to be competent under stoichiometric and catalytic reaction
conditions (Scheme 4b).
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202014289
Angewandte Chemie International Edition
COMMUNICATION
Figure 2. Relative Gibbs free energy profile in kcal mol–1 at the ωB97X-V/def2-
QZVP+SMD(TFE)//TPSS-D3(BJ)/def2-TZVP level of theory. The given
potential (red) corresponds to the half-wave potential versus Fc0/+
.
Inspired by the DFT calculations, we intended to isolate the
key intermediate of the reaction of ruthenacycle 5 with alkyne 2.
We were pleased to obtain the seven-membered ring
intermediate 6 through a stoichiometric reaction of ruthenacycle
5v with alkyne 2a, and ruthena(II)cycle 6 was unambiguously
characterized by X-ray diffraction analysis (Scheme 5a). Direct
electrolysis of intermediate 6 in TFE delivered the desired
isoquinoline product 3va, irrespective of the reaction temperature
(Scheme 5b).
Scheme 4. Study on C–H activation ruthenacycle complexs and X-ray analysis
of 5w.[19]
To gain insights into the catalyst’s working mode, we
performed density functional theory (DFT) studies at the ωB97X-
V/def2-QZVP+SMD(TFE)//TPSS-D3(BJ)/def2-TZVP level of
theory.[18] Initial one-electron oxidation of seven-membered
ruthenacycle A with an oxidation potential of 0.7 V versus Fc0/+
takes place and leads to the formation of ruthenium(III) complex
A+ (Figure 2). Afterwards, reductive elimination occurs to
generate B+, which subsequently undergoes a second one-
electron oxidation to ruthenium(II) with a calculated oxidation
potential of 0.5 V. Finally, facile deprotonation and decoordination
of acetic acid takes place to deliver the 18-electron ruthenium
sandwich-type complex D2+.
Scheme 5. Isolation of key intermediate ruthenacycle 6.[19]
Furthermore, we probed the electrochemical C–H activation
by means of cyclovoltammetric analysis (Figure 3). At ambient
temperature in TFE, substrates 1v and 2a as well as product 3va
showed onset potentials of Eonset > 1.2V versus ferrocene. In
contrast, two irreversible oxidation events were observed for the
C–H activated ruthenacycle 5v with an onset potential of Eonset
=
0.60 V versus ferrocene (Figure 3b). The seven-membered
ruthenacycle 6 showed a significantly lower oxidation potential,
with an onset potential of Eonset = 0.20 V versus ferrocene. Since
the direct electrolysis of 6 efficiently delivered the desired product
3va (Scheme 5b), these findings are supportive of an oxidation-
induced reductive elimination within a ruthenium(II/III) regime.
Alternatively, ruthenium (II/IV) or ruthenium (II/0) pathways
appear less likely to be operative.[18]
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202014289
Angewandte Chemie International Edition
COMMUNICATION
(a) Cyclic voltammetry of 1v, 2a and 3va
1.5x10-4
1.0x10-4
1v
2a
3va
5.0x10-5
0.0
-0.4
0.0
0.4
0.8
1.2
1.6
2.0
2.4
Potential vs Ferrocene (V)
(b) Cyclic voltammetry of 5v and 6
7.0x10-5
6.0x10-5
Figure 4. Proposed catalytic cycle.
5.0x10-5
4.0x10-5
3.0x10-5
2.0x10-5
5v
6
In conclusion, we have reported on the unprecedented three-
component electrochemical Domino-assembly of isoquinolines
with electricity as the sole oxidant, generating only H2 as
byproduct. Well-defined ruthenacycles of C–H activation and a
seven-membered ring intermediate were isolated and fully
characterized by X-ray diffraction analysis, DFT calculations and
cyclovoltammetric analysis, providing strong support for a fast C–
H activation and a ruthenium(II/III) manifold.
1.0x10-5
0.0
-1.0x10-5
-0.4
0.0
0.4
0.8
1.2
1.6
2.0
2.4
Potential vs Ferrocene (V)
Figure 3. Cyclic voltammetry measurements in TFE under N2 with 0.1 M
nBu4NBF4 at RT with 100 mVs-1.
Acknowledgements
Generous support by the DFG (Gottfried-Wilhelm-Leibniz award
to L.A.) is gratefully acknowledged. We thank Dr. Christopher
Golz (Göttingen University) for assistance with the X-ray
diffraction analysis.
Based on these detailed mechanistic studies, we propose
the catalytic cycle to commence by in situ generation of the imine
4 and a fast organometallic C–H activation (Figure 4). Thereby,
ruthena(II)cycle 5 is generated. Thereafter, migratory insertion
occurs to furnish intermediate 6. Then, anodic oxidation-induced
reductive elimination by a ruthenium(II/III/I) manifold generates
intermediate 9. Further anodic oxidation and deprotonation of
intermediate 9 generates intermediate 10, which delivers the final
product through ligand exchange, thus regenerating ruthenium(II)
catalyst.
Keywords: electrocatalysis • ruthenium • domino reactions •
annulation • C–H activation
[1] a) Ł. Woźniak, J.-F. Tan, Q.-H. Nguyen, A. Madron du Vigné, V.
Smal, Y.-X. Cao, N. Cramer, Chem. Rev. 2020, 120, 10516-
10543; b) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz,
L. Ackermann, Chem. Rev. 2019, 119, 2192-2452; c) A. Dey, S.
K. Sinha, T. K. Achar, D. Maiti, Angew. Chem. Int. Ed. 2019, 58,
10820-10843; d) P. Nareddy, F. Jordan, M. Szostak, ACS Catal.
2017, 5721-5745; e) Y. Park, Y. Kim, S. Chang, Chem. Rev.
2017, 117, 9247-9301; f) O. Daugulis, J. Roane, L. D. Tran, Acc.
Chem. Res. 2015, 48, 1053-1064; g) J. Wencel-Delord, F.
Glorius, Nat. Chem. 2013, 5, 369-375; h) B. Li, P. H. Dixneuf,
Chem. Soc. Rev. 2013, 42, 5744-5767; i) D. A. Colby, A. S. Tsai,
R. G. Bergman, J. A. Ellman, Acc. Chem. Res. 2012, 45, 814-
825; j) L. Ackermann, R. Vicente, A. R. Kapdi, Angew. Chem.
Int. Ed. 2009, 48, 9792-9826.
[2] N. Kerru, L. Gummidi, S. Maddila, K. K. Gangu, S. B.
Jonnalagadda, Molecules 2020, 25, 1909.
[3] Y. Zhang, M. Li, X. Li, T. Zhang, M. Qin, L. Ren, Front.
Pharmacol. 2018, 9, 602.
[4] M. C. Sharma, S. Sharma, P. Sharma, A. Kumar, Med. Chem.
Res. 2013, 22, 5772-5788.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202014289
Angewandte Chemie International Edition
COMMUNICATION
[5]
[6]
[7]
T.-Y. Jin, S.-Q. Li, C.-R. Jin, H. Shan, R.-M. Wang, M.-X. Zhou,
A.-L. Li, L.-Y. Li, S.-Y. Hu, T. Shen, L. Xiang, J. Nat. Prod. 2018,
81, 768-777.
Y. Nishiyama, K. Iwasa, S. Okada, S. Takeuchi, M. Moriyasu,
M. Kamigauchi, J. Koyama, A. Takeuchi, H. Tokuda, H. S. Kim,
Heterocycles 2010, 81, 1193-1229.
Chem. Res. 2017, 50, 2346-2352; q) R. Francke, R. D. Little,
Chem. Soc. Rev. 2014, 43, 2492-2521; r) A. Jutand, Chem. Rev.
2008, 108, 2300-2347.
[11] a) R. C. Samanta, T. H. Meyer, I. Siewert, L. Ackermann, Chem.
Sci. 2020, 11, 8657-8670; b) P. Gandeepan, L. H. Finger, T. H.
Meyer, L. Ackermann, Chem. Soc. Rev. 2020, 49, 4254-4272;
c) H. Wang, X. Gao, Z. Lv, T. Abdelilah, A. Lei, Chem. Rev.
2019, 119, 6769-6787. d) T. H. Meyer, L. H. Finger, P.
Gandeepan, L. Ackermann, Trends Chem. 2019, 1, 63-76; e)
Q.-L. Yang, P. Fang, T.-S. Mei, Chin. J. Chem. 2018, 36, 338-
352; f) C. Ma, P. Fang, T.-S. Mei, ACS Catal. 2018, 8, 7179-
7189; g) N. Sauermann, T. H. Meyer, Y. Qiu, L. Ackermann,
ACS Catal. 2018, 8, 7086-7103.
For selected reviews, see: a) R. Gujjarappa, N. Vodnala, C. C.
Malakar,
Adv.
Synth.
Catal.
2020,
https://doi.org/10.1002/adsc.202000658. b) J. S. S. Neto, G.
Zeni, Tetrahedron 2020, 76, 130876; c) G. Duarah, P. P.
Kaishap, T. Begum, S. Gogoi, Adv. Synth. Catal. 2019, 361,
654-672;
[8]
For selected examples, see: a) F. Yang, J. Yu, Y. Liu, J. Zhu,
Org. Lett. 2017, 19, 2885-2888; b) X. Yu, K. Chen, F. Yang, S.
Zha, J. Zhu, Org. Lett. 2016, 18, 5412-5415; c) H. Wang, J.
Koeller, W. Liu, L. Ackermann, Chem. Eur. J. 2015, 21, 15525-
15528; d) B. Sun, T. Yoshino, M. Kanai, S. Matsunaga, Angew.
Chem. Int. Ed. 2015, 54, 12968-12972; e) M. Sen, D. Kalsi, B.
Sundararaju, Chem. Eur. J. 2015, 21, 15529-15533; f) J. Zhang,
H. Qian, Z. Liu, C. Xiong, Y. Zhang, Eur. J. Org. Chem. 2014,
8110-8118; g) C. Kornhaaß, C. Kuper, L. Ackermann, Adv.
Synth. Catal. 2014, 356, 1619-1624; g) D.-G. Yu, F. de
Azambuja, T. Gensch, C. G. Daniliuc, F. Glorius, Angew. Chem.
Int. Ed. 2014, 53, 9650-9654; h) R. K. Chinnagolla, S. Pimparkar,
M. Jeganmohan, Chem. Commun. 2013, 49, 3703-3705; i) C.
Kornhaaß, J. Li, L. Ackermann, J. Org. Chem. 2012, 77, 9190-
9198; j) P. C. Too, S. H. Chua, S. H. Wong, S. Chiba, J. Org.
Chem. 2011, 76, 6159-6168; k) B. Li, H. Feng, S. Xu, B. Wang,
Chem. Eur. J. 2011, 17, 12573-12577; l) T. K. Hyster, T. Rovis,
Chem. Commun. 2011, 47, 11846-11848; m) N. Guimond, S. I.
Gorelsky, K. Fagnou, J. Am. Chem. Soc. 2011, 133, 6449-6457;
n) L. Ackermann, S. Fenner, Org. Lett. 2011, 13, 6548-6551; o)
P. C. Too, Y.-F. Wang, S. Chiba, Org. Lett. 2010, 12, 5688-
5691; p) N. Guimond, C. Gouliaras, K. Fagnou, J. Am. Chem.
Soc. 2010, 132, 6908-6909; s) K. Parthasarathy, C.-H. Cheng,
J. Org. Chem. 2009, 74, 9359-9364; and references therein.
a) J. Li, M. John, L. Ackermann, Chem. Eur. J. 2014, 20, 5403-
5408; b) Y.-F. Wang, K. K. Toh, J.-Y. Lee, S. Chiba, Angew.
Chem. Int. Ed. 2011, 50, 5927-5931; c) N. Guimond, K. Fagnou,
J. Am. Chem. Soc. 2009, 131, 12050-12051; d) T. Fukutani, N.
Umeda, K. Hirano, T. Satoh, M. Miura, Chem. Commun. 2009,
5141-5143; and references therein.
[12] a) Y. Zhang, J. Struwe, L. Ackermann, Angew. Chem. Int. Ed.
2020, 59, 15076-15080; b) W.-J. Kong, Z. Shen, L. H. Finger, L.
Ackermann, Angew. Chem. Int. Ed. 2020, 59, 5551-5556; c) Z.-
J. Wu, F. Su, W. Lin, J. Song, T.-B. Wen, H.-J. Zhang, H.-C. Xu,
Angew. Chem. Int. Ed. 2019, 58, 16770-16774; d) Y. Qiu, A.
Scheremetjew, L. Ackermann, J. Am. Chem. Soc. 2019, 141,
2731-2738; e) W.-J. Kong, L. H. Finger, J. C. A. Oliveira, L.
Ackermann, Angew. Chem. Int. Ed. 2019, 58, 6342-6346; f) 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; g)
Y. Qiu, W.-J. Kong, J. Struwe, N. Sauermann, T. Rogge, A.
Scheremetjew, L. Ackermann, Angew. Chem. Int. Ed. 2018, 57,
5828-5832.
[13] a) X. Ye, C. Wang, S. Zhang, J. Wei, C. Shan, L. Wojtas, Y. Xie,
X. Shi, ACS Catal. 2020, 11693-11699. b) Q.-L. Yang, Y.-K.
Xing, X.-Y. Wang, H.-X. Ma, X.-J. Weng, X. Yang, H.-M. Guo,
T.-S. Mei, J. Am. Chem. Soc. 2019, 141, 18970-18976; c) Y.
Qiu, M. Stangier, T. H. Meyer, J. C. A. Oliveira, L. Ackermann,
Angew. Chem. Int. Ed. 2018, 57, 14179-14183.
[14] a) L. Yang, R. Steinbock, A. Scheremetjew, R. Kuniyil, L. H.
Finger, A. M. Messinis, L. Ackermann, Angew. Chem. Int. Ed.
2020, 59, 11130-11135; b) L. Massignan, X. Tan, T. H. Meyer,
R. Kuniyil, A. M. Messinis, L. Ackermann, Angew. Chem. Int. Ed.
2020, 59, 3184-3189; c) Z.-Q. Wang, C. Hou, Y.-F. Zhong, Y.-
X. Lu, Z.-Y. Mo, Y.-M. Pan, H.-T. Tang, Org. Lett. 2019, 21,
9841-9845; d) M.-J. Luo, T.-T. Zhang, F.-J. Cai, J.-H. Li, D.-L.
He, Chem. Commun. 2019, 55, 7251-7254; e) M.-J. Luo, M. Hu,
R.-J. Song, D.-L. He, J.-H. Li, Chem. Commun. 2019, 55, 1124-
1127; f) F. Xu, Y.-J. Li, C. Huang, H.-C. Xu, ACS Catal. 2018, 8,
3820-3824; g) Y. Qiu, C. Tian, L. Massignan, T. Rogge, L.
Ackermann, Angew. Chem. Int. Ed. 2018, 57, 5818-5822; h) R.
Mei, J. Koeller, L. Ackermann, Chem. Commun. 2018, 54,
12879-12882.
[9]
[10] a) K. Yamamoto, M. Kuriyama, O. Onomura, Acc. Chem. Res.
2020, 53, 105-120; b) F. Wang, S. S. Stahl, Acc. Chem. Res.
2020, 53, 561-574; c) J. C. Siu, N. Fu, S. Lin, Acc. Chem. Res.
2020, 53, 547-560; d) J. L. Röckl, D. Pollok, R. Franke, S. R.
Waldvogel, Acc. Chem. Res. 2020, 53, 45-61; e) G. M. Martins,
G. C. Zimmer, S. R. Mendes, N. Ahmed, Green Chem. 2020,
22, 4849-4870; f) Q. Jing, K. D. Moeller, Acc. Chem. Res. 2020,
53, 135-143; g) K.-J. Jiao, Y.-K. Xing, Q.-L. Yang, H. Qiu, T.-S.
Mei, Acc. Chem. Res. 2020, 53, 300-310; h) T. Fuchigami, S.
Inagi, Acc. Chem. Res. 2020, 53, 322-334; i) P. Xiong, H.-C. Xu,
Acc. Chem. Res. 2019, 52, 3339-3350; j) M. Elsherbini, T. Wirth,
Acc. Chem. Res. 2019, 52, 3287-3296; k) S. R. Waldvogel, S.
Lips, M. Selt, B. Riehl, C. J. Kampf, Chem. Rev. 2018, 118,
6706-6765; l) S. Tang, Y. Liu, A. Lei, Chem 2018, 4, 27-45; m)
G. S. Sauer, S. Lin, ACS Catal. 2018, 8, 5175-5187; n) J. E.
Nutting, M. Rafiee, S. S. Stahl, Chem. Rev. 2018, 118, 4834-
4885; o) M. Yan, Y. Kawamata, P. S. Baran, Chem. Rev. 2017,
117, 13230-13319; p) R. Feng, J. A. Smith, K. D. Moeller, Acc.
[15] a) L. Ackermann, Acc. Chem. Res. 2020, 53, 84-104; b) Y. Qiu,
C. Zhu, M. Stangier, J. Struwe, L. Ackermann, CCS Chem. 2020,
2, 1529–1552.
[16] L. F. Tietze, Chem. Rev. 1996, 96, 115-136.
[17] a) J. Kim, K. Shin, S. Jin, D. Kim, S. Chang, J. Am. Chem. Soc.
2019, 141, 4137-4146; b) K. Shin, Y. Park, M.-H. Baik, S. Chang,
Nat. Chem. 2018, 10, 218-224; c) L. Li, W. W. Brennessel, W.
D. Jones, J. Am. Chem. Soc. 2008, 130, 12414-12419.
[18] For detailed information, see the Supporting Information.
[19] CCDC 2035831 (5w) and 2035832 (6) contain the
supplementary crystallographic data for this paper. These data
can beobtained free of charge from Cambridge Crystallographic
Data Centre.
6
This article is protected by copyright. All rights reserved.

10.1002/anie.202014289
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Ruthenium-catalyzed electrooxidative three-component syntheses of isoquinolines proved viable with ample scope. The isolation of
key intermediates, along with DFT calculations revealed an unusual ruthenium(II/III/I) catalytic cycle.
Institute and/or researcher Twitter usernames: @aztul
7
This article is protected by copyright. All rights reserved.