Nickela-electrocatalyzed Mild C?H Alkylations at Room Temperature

Article abstract of DOI:10.1002/anie.202004958

Direct alkylations of carboxylic acid derivatives are challenging and particularly nickel catalysis commonly requires high reaction temperatures and strong bases, translating into limited substrate scope. Herein, nickel-catalyzed C?H alkylations of unactivated 8-aminoquinoline amides have been realized under exceedingly mild conditions, namely at room temperature, with a mild base and a user-friendly electrochemical setup. This electrocatalyzed C?H alkylation displays high functional group tolerance and is applicable to both the primary and secondary alkylation. Based on detailed mechanistic studies, a nickel(II/III/I) catalytic manifold has been proposed.

Full text of DOI:10.1002/anie.202004958

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Accepted Article
Title: Nickelaelectro-Catalyzed Mild C–H Alkylations at Room
Temperature
Authors: Ramesh C. Samanta, Julia Struwe, and Lutz Ackermann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202004958
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10.1002/anie.202004958
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Nickelaelectro-Catalyzed Mild C–H Alkylations at Room
Temperature
Ramesh C. Samanta,[a] Julia Struwe,[a] and Lutz Ackermann*[a,b]
Dedication ((optional))
[a]
[b]
Dr. Ramesh C. Samanta, Julia Struwe, Prof. Dr. Lutz Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Göttingen
Tammannstrasse 2, 37077 Göttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/:
Prof. Dr. Lutz Ackermann
Woehler Research Institute for Sustainable Chemistry (WISCh)
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.((Please delete this text if not appropriate))
Abstract: Direct alkylations of carboxylic acid derivatives are
challenging and particularly nickel catalysis commonly requires high
reaction temperatures and strong bases, translating into limited
substrate scope. Herein, nickel-catalyzed C–H alkylations of
unactivated 8-aminoquinoline amides has been realized under
exceedingly mild conditions, namely at room temperature, with a mild
base and a user-friendly electrochemical setup. This electrocatalyzed
C–H alkylation displays high functional group tolerance and is
applicable to both the primary and secondary alkylation. Based on
detailed mechanistic studies a nickel(II/III/I) catalytic manifold has
been proposed.
for mild C–H alkylations by nickel catalysis continue to be highly
desirable.
Recently electrosynthesis[15] has gained considerable momentum
due to the use of electricity as a sustainable alternative for toxic
chemical redox equivalents, thereby avoiding stoichiometric
waste product formation. In this regard, electrochemical C–H
activations[16] has resulted in a renaissance in this field with
notable contributions by Mei,[17] Ackermann,[18] Lei[19] and Xu.[20]
Despite the undisputable advances in metalla-electrooxidative C–
H
activation, net redox neutral transformations under
electrochemical conditions have barely been explored, while the
effect of electricity was beneficial for net redox-neutral nickel-
catalyzed Ullmann-type C–N forming reactions.[21] Moreover,
recently disclosed electrochemical net redox-neutral C–C
coupling by Sevov[22] and C–S couplings by Mei[23] and Wang[24]
represented key contribution for electrochemical cross-coupling
reactions.
Within our program on sustainable C–H activation,[25] we report
herein a nickel-catalyzed C–H alkylation using both primary and
more challenging secondary alkyl halides under particularly mild
electrochemical conditions. The key findings include a) nickel-
electrocatalyzed C–H activations at room temperature, b)
tolerance of sensitive functionalities, c) absence of additional
phosphine or amine ligands, d) mild bases for nickel-catalyzed C–
H activation, and e) detailed mechanistic insights.
In recent years, C–H activation has been recognized as a
transformative tool in molecular syntheses.[1] Although the vast
majority of C–H functionalization was predominantly realized by
precious 4d and 5d transition metals, recent focus has been
shifted to the less toxic Earth-abundant 3d transition metals.[2]
While increasing advances were accomplished in site-selective
C–H activation via chelation assistance, a direct C–H alkylation of
arenes remains challenging due to undesirable competitive -
hydride elimination. These approaches heavily rely on the
precious and rather toxic 4d metals ruthenium[3] and
palladium.[4],[5] Among the 3d transition metals, cobalt,[6] iron[7] and
manganese-catalyzed[8] reactions were developed. However,
their applications to functionalized substrates were severely
limited due to the use of an excess amount of highly reactive
Grignard reagents. To meet the continuous demand for a suitable
C–H alkylations, such nickel-catalysis was largely explored by
Chatani,[9] Ackermann[10] and Punji,[11] among others.[12] The N,N’-
bidentate 8-amino quinoline[13] that was previously introduced by
Daugulis,[14] enabled particularly efficient nickel-catalysis. Major
issues associated with and beyond known nickel-catalyzed C–H
alkylations are the requirement of high reaction temperatures and
the use of strong bases, such as lithium tert-butoxide (LiOtBu) or
lithium bis(trimethyl)silylamide (LiHMDS), thereby limiting
applications to sensitive functional groups. Therefore, strategies
Figure 1. Nickel-catalyzed electrochemical C–H alkylations at room
temperature.
We commenced our studies by probing various reaction
conditions to enable the nickel-catalyzed electrochemical C–H
1
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alkylation of benzamide 1a with the n-octyl iodide 2a in an
undivided cell set-up.[26] Zinc as anode material and nickel foam
as cathode delivered the desired alkylation product 3aa in 76%
yield at room temperature, notably with Et3N as a mild base (Table
1 and entry 1). Slow addition of the alkyl iodide 2a was required
to suppress its homocoupling, 3aa was otherwise obtained in a
lower yield of 41% (entry 2). Previous studies on nickela-
electrooxidative C–H activation have used graphite felt and nickel
foam as anode and cathode respectively,[27] however, it was not
suitable here (entry 3). The combination of zinc anode with
electricity was beneficial, and the nickel catalyst was essential for
this transformation (entries 4–6). The reaction was sluggish when
performed with stoichiometric amounts of zinc as the chemical
reductant (entry 7). DMF was also found to be a potent solvent
for this transformation with a slightly lower efficacy (entry 8). The
use of methanol in lieu of DMA and TBAI was found less efficient
(entry 9). It is noteworthy that a yield of 55% in product 3aa was
obtained in the absence of an additional base (entry 10). Notably,
no desired product was obtained when the reaction was
performed under air instead of N2 atmosphere.
3ha and 3ia with excellent chemo-selectivity. Aryl ethers and silyl
ether were smoothly converted to the products 3ea–3ha. A free
phenolic hydroxyl group was well tolerated with good yield of 3ja,
bypassing the inherent preference for O–alkylation. Electrophilic
functional groups, those are prone to nucleophiles or bases, such
as acetate, ketone and ester derivative 3na–3pa, were also well
tolerated. Oxidation labile thioether 3qa and arylamine 3ra were
viable under the nickel-electro catalysis. 3-Substituted amides
1h–1r delivered only mono-alkylation products and the selectivity
was governed by the steric-hindrance.
Table 1. Optimization of the nickel-catalyzed electrochemical C–H alkylation.[a]
Entry
Deviation from standard conditions
none
Yield [%]b
1
2
76
41
---
6
direct addition of 2a
graphite felt anode
3
4
Mg anode
5
with nickel catalyst but no current
without current or nickel catalyst
Zn dust instead of current
DMF instead of DMA
MeOH instead of DMA
without Et3N
---
---
8
Scheme 1. Nickellaelectro-catalyzed C–H alkylation of amides 1. [a]
Bisalkylation product (10%).
6
7
The scope of viable alkyl iodides 2 was next explored, on and
indeed, a slightly modified condition was equally applicable for
alkylation using secondary alkyl iodides (Scheme 2). In contrast
8
67
27c
55
9
o
to known procedures under harsh reaction conditions of 160 C
and LiOtBu, benzamide 1a was selectively C–H alkylated with
various secondary alkyl iodides 2 under this nickel-catalyzed
electrochemical manifold under extremely mild conditions with
Et3N as the base. Importantly, acyclic secondary alkyl iodides 2d–
2h reacted efficiently to deliver the products 3ad–3ah in good
yields without chain-walking,[28] thereby avoiding the formation of
isomerization products. Benzamides containing sensitive
functional groups, such as OTBS, OAc, CO2Me and COMe were
well tolerated under the nickelaelectro-catalyzed C–H alkylation
reaction conditions to furnish the products 3gh, 3lh, 3nh, 3oh and
3ph in moderate to good yields. Interestingly, the electrochemical
secondary alkylation method resulted in a better selectively and
the desired monoalkylation product 3gh was obtained in 53%
yield, with only trace of bisalkylation was detected. However, it is
noteworthy that previously reported methods for direct C–H
alkylation of benzamide 1a using a secondary alkyl bromide
10
[a] Reaction conditions: Undivided cell, 1a (0.30 mmol), 2a (1.05 mmol), [Ni] (10
mol %), Et3N (3.5 equiv), nBu4NI (2.0 equiv), solvent (3.2 mL), RT, constant
current at 4.0 mA, 8 h, zinc anode, nickel-foam cathode and 2a was added
slowly over 7 h. [b] Yield of isolated product. [c] No conducting salt was added.
DMA = N,N-Dimethylacetamide. DMF = N,N-Dimethylformamide.
Having the optimized reaction conditions in hand, the versatility of
the nickel-catalyzed electrochemical C–H alkylation manifold was
examined for differently substituted benzamides 1 using n-octyl
iodide as the alkylation reagent (Scheme 1). Both, electron-
donating as well as electron-withdrawing substituents at the
benzamides 3aa–3ca were well suited. 3,4-Disubstituted amides
1d and 1e were also alkylated in good yield. In the case of
unsubstituted 1f or para-substituted benzamides 1g bis-alkylation
was also observed. Halogen containing amides were alkylated to
2
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delivered the product 3ah (58%) in diminished yield. More
importantly, for benzamides 1o and 1p bearing COMe and
CO2Me functional groups respectively, only traces of the desired
alkylation products 3oh and 3ph were detected.[10d]
Scheme 3. Mechanistic Investigations. a) Intermolecular competition
experiment. b) H/D exchange studies. c) Attempted use of organozinc halide as
alkylation reagent.
Scheme 2. Nickel-catalyzed electrochemical C–H activation with alkyl iodides
2. For comparison with chemical method using benzamide 1 (0.5 mmol), 2-
bromobutane
(1.0 mmol),
Ni(DME)Cl2
(10 mol%),
bis[2-(N,N-
dimethylamino)ethyl] ether (BDMAE) (40 mol%), LiOtBu (2.0 equiv) in toluene
at 160 °C for 20 h.
To gain insights into the reaction mechanism, an intermolecular
competition experiment between substrates 1a and 1b revealed
that the electron-deficient amide 1b reacted faster than the
electron rich-substrate 1a (Scheme 3a). No significant deuterium
scrambling was observed neither in the product nor the unreacted
starting material when the reaction was performed with [D]4-
MeOD as additive, which excludes reversibility in the C–H
cleavage step (Scheme 3b). When the reaction was performed
with alkylzinc iodide 4, product formation was not observed.
Hence, the in-situ generation of alkylzinc halides in the reaction
mechanism can be ruled out (Scheme 3c). In radical clock
experiments, both substrates 2i and 2j provided the cyclization
products 3ai and 3aj respectively, being suggestive of a homolytic
C–I bond cleavage for the nickelaelectro-catalyzed C–H alkylation
(Scheme 4a). The chiral alkyl iodide (+)-2e underwent
racemization under the developed reaction conditions to yield the
product rac-3ae (Scheme 4b). Moreover, the desired alkylation
reaction did not proceed in the presence of a typical radical
scavenger TEMPO, providing further support for a single electron
transfer (SET) regime (Scheme 4c).
Scheme 4. Mechanistic control experiments towards single electron transfer.
The cyclometalated nickel(III)-5[27a] complex was synthesized and
used as catalyst for the electrocatalytic alkylation reaction.
Interestingly, it was found catalytically incompetent in the absence
of electricity, albeit the desired C–H alkylation took place in the
presence of electricity (Scheme 5). This finding indicates that
cathodic reduction was necessary to generate the active catalyst.
Cyclic voltammetry studies of the nickel(III)-5 complex revealed
3
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the following reduction potentials in DMA: NiIII/NiII at –1.01 V,
NiII/NiI at –1.52 V and NiI/Ni0 at –2.40 V vs. Fc0/+ [26]
A fast
.
coordination of amide 1a with Ni(DME)Cl2 shifted the potentials,
NiII/NiI at –1.51 V and NiI/Ni0 at –2.28 V compared to the free
Ni(DME)Cl2. A sharp increase in the reductive current was
observed upon addition of 2a to Ni(DME)Cl2 with an onset
potential of –1.0 V and the peak potential of –2.21 V vs. Fc0/+. A
similar phenomenon was observed with the mixture of
Ni(DME)Cl2, 1a and 2a.[26]
Scheme 5. Catalytic activity of Ni(III)-5 complex.
Figure 2. Proposed catalytic cycle for nickelaelectro-catalyzed C–H alkylation.
Based on our mechanistic studies we propose a nickel(II/III/I)
manifold for the electrocatalysis. The catalytic cycle is initiated by
a cathodic reduction to deliver intermediate [Ni(I)-A], which in turn
reacts with alkyl iodide 2 and upon C–H cleavage forms the
cyclometalated intermediate [Ni(III)-B]. Note that [Ni(III)-B]
(Ni(III)-5) was shown to be catalytically competent under the
electrochemical reaction conditions (vide supra). Subsequent
cathodic reduction initially generates [Ni(II)-C] intermediate. Next,
a single-electron-transfer (SET) generates the intermediate
[Ni(III)-D], which next forms [Ni(III)-E] and subsequently delivers
the desired product 3. At the same time, coordination of substrate
1 regenerates the catalytically competent species [Ni(I)-A]. To
compensate the cathodic reduction, anodic zinc oxidation takes
place, while the role of zinc as redox mediator is unlikely to
operative.[29]
In conclusion, we have developed
a
nickel-catalyzed
electrochemical direct C–H alkylation of quinoline amides under
unprecedentedly mild reaction conditions, namely at room
temperature with the mild base Et3N. This strategy enabled the
conversion of a wide range of primary and secondary alkyl iodides,
while tolerating various sensitive functional groups. Detailed
mechanistic studies provided strong support for a Ni(II/III/I)
catalytic cycle through SET processes. We believe that our
findings overcome the difficulties in typical nickel-catalyzed C–H
alkylations, for which harsh reaction conditions of 160 oC
temperature and LiOtBu are thus far prevalent.
Acknowledgements
Generous support by the DFG (Gottfried-Wilhelm-Leibniz award
to L.A.) and the Alexander-von-Humboldt foundation (fellowship
to R.C.S.) is gratefully acknowledged.
Keywords: C–H alkylation • ambient temperature • mild base •
electrosynthesis • nickel
[1]
a) S. Rej, Y. Ano, N. Chatani, Chem. Rev. 2020, 120, 1788–
1887; b) Y. Park, Y. Kim, S. Chang, Chem. Rev. 2017, 117,
9247–9301; c) J. He, M. Wasa, K. S. L. Chan, Q. Shao, J.-Q.
Yu, Chem. Rev. 2017, 117, 8754–8786; d) T. Cernak, K. D.
Dykstra, S. Tyagarajan, P. Vachal, S. W. Krska, Chem. Soc.
Rev. 2016, 45, 546–576; e) L. Ackermann, Org. Process Res.
Dev. 2015, 19, 260–269; f) J. Wencel-Delord, F. Glorius, Nat.
Chem. 2013, 5, 369–375; g) J. Yamaguchi, A. D. Yamaguchi,
K. Itami, Angew. Chem. Int. Ed. 2012, 51, 8960–9009; h) D. A.
Colby, A. S. Tsai, R. G. Bergman, J. A. Ellman, Acc. Chem. Res.
2012, 45, 814–825; i) L. McMurray, F. O'Hara, M. J. Gaunt,
Chem. Soc. Rev. 2011, 40, 1885–1898; j) L. Ackermann, Chem.
Rev. 2011, 111, 1315–1345; k) L. Ackermann, R. Vicente, A. R.
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202004958
Angewandte Chemie International Edition
COMMUNICATION
Kapdi, Angew. Chem. Int. Ed. 2009, 48, 9792–9826; l) R. G.
Bergman, Nature 2007, 446, 391–393.
3350; e) A. Wiebe, T. Gieshoff, S. Möhle, E. Rodrigo, M. Zirbes,
S. R. Waldvogel, Angew. Chem. Int. Ed. 2018, 57, 5594–5619;
f) S. Tang, Y. Liu, A. Lei, Chem 2018, 4, 27–45; g) M. Yan, Y.
Kawamata, P. S. Baran, Chem. Rev. 2017, 117, 13230–13319;
h) R. Feng, J. A. Smith, K. D. Moeller, Acc. Chem. Res. 2017,
50, 2346–2352; i) R. Francke, R. D. Little, Chem. Soc. Rev.
2014, 43, 2492–2521; j) A. Jutand, Chem. Rev. 2008, 108,
2300–2347.
[2]
a) P. Gandeepan, T. Müller, D. Zell, G. Cera, S. Warratz, L.
Ackermann, Chem. Rev. 2019, 119, 2192–2452; b) Y. Hu, B.
Zhou, C. Wang, Acc. Chem. Res. 2018, 51, 816–827; c) T.
Yoshino, S. Matsunaga, Adv. Synth. Catal. 2017, 359, 1245–
1262; d) D. Wei, X. Zhu, J.-L. Niu, M.-P. Song, ChemCatChem
2016, 8, 1242–1263; e) W. Liu, L. Ackermann, ACS Catal. 2016,
6, 3743–3752; f) K. Hirano, M. Miura, Chem. Lett. 2015, 44,
868–873; g) K. Gao, N. Yoshikai, Acc. Chem. Res. 2014, 47,
1208–1219; h) J. Yamaguchi, K. Muto, K. Itami, Eur. J. Org.
Chem. 2013, 19−30; i) A. A. Kulkarni, O. Daugulis, Synthesis
2009, 2009, 4087–4109.
[16] a) H. Wang, X. Gao, Z. Lv, T. Abdelilah, A. Lei, Chem. Rev.
2019, 119, 6769–6787; b) Y. Qiu, J. Struwe, L. Ackermann,
Synlett 2019, 30, 1164–1173; c) T. H. Meyer, L. H. Finger, P.
Gandeepan, L. Ackermann, Trends Chem. 2019, 1, 63–76; d)
Q.-L. Yang, P. Fang, T.-S. Mei, Chin. J. Chem. 2018, 36, 338–
352; e) N. Sauermann, T. H. Meyer, Y. Qiu, L. Ackermann, ACS
Catal. 2018, 8, 7086–7103; f) N. Sauermann, T. H. Meyer, L.
Ackermann, Chem. Eur. J. 2018, 24, 16209–16217; g) C. Ma,
P. Fang, T.-S. Mei, ACS Catal. 2018, 8, 7179–7189.
[17] a) K.-J. Jiao, Y.-K. Xing, Q.-L. Yang, H. Qiu, T.-S. Mei, Acc.
Chem. Res. 2020, 53, 300–310; b) Q.-L. Yang, X.-Y. Wang, J.-
Y. Lu, L.-P. Zhang, P. Fang, T.-S. Mei, J. Am. Chem. Soc. 2018,
140, 11487–11494; c) Q.-L. Yang, Y.-Q. Li, C. Ma, P. Fang, X.-
J. Zhang, T.-S. Mei, J. Am. Chem. Soc. 2017, 139, 3293–3298.
[18] a) T. H. Meyer, J. C. A. de Oliveira, D. Ghorai, L. Ackermann,
Angew. Chem. Int. Ed. 2020, DOI: 10.1002/anie.202002258; b)
C. Zhu, M. Stangier, J. C. A. Oliveira, L. Massignan, L.
Ackermann, Chem. Eur. J. 2019, 25, 16382–16389; c) Y. Qiu,
C. Tian, L. Massignan, T. Rogge, L. Ackermann, Angew. Chem.
Int. Ed. 2018, 57, 5818–5822; d) Y. Qiu, M. Stangier, T. H.
Meyer, J. C. A. Oliveira, L. Ackermann, Angew. Chem. Int. Ed.
2018, 57, 14179–14183; e) Y. Qiu, W.-J. Kong, J. Struwe, N.
Sauermann, T. Rogge, A. Scheremetjew, L. Ackermann, Angew.
Chem. Int. Ed. 2018, 57, 5828–5832; f) N. Sauermann, T. H.
Meyer, C. Tian, L. Ackermann, J. Am. Chem. Soc. 2017, 139,
18452–18455.
[19] a) Y. Yuan, A. Lei, Acc. Chem. Res. 2019, 52, 3309–3324; b) S.
Tang, L. Zeng, A. Lei, J. Am. Chem. Soc. 2018, 140, 13128–
13135.
[20] 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.
[21] a) Y. Kawamata, J. C. Vantourout, D. P. Hickey, P. Bai, L. Chen,
Q. Hou, W. Qiao, K. Barman, M. A. Edwards, A. F. Garrido-
Castro, J. N. deGruyter, H. Nakamura, K. Knouse, C. Qin, K. J.
Clay, D. Bao, C. Li, J. T. Starr, C. Garcia-Irizarry, N. Sach, H. S.
White, M. Neurock, S. D. Minteer, P. S. Baran, J. Am. Chem.
Soc. 2019, 141, 6392–6402; b) C. Li, Y. Kawamata, H.
Nakamura, J. C. Vantourout, Z. Liu, Q. Hou, D. Bao, J. T. Starr,
J. Chen, M. Yan, P. S. Baran, Angew. Chem. Int. Ed. 2017, 56,
13088–13093.
[3]
a) A. J. Paterson, S. St John-Campbell, M. F. Mahon, N. J.
Press, C. G. Frost, Chem. Commun. 2015, 51, 12807–12810;
b) J. Li, S. Warratz, D. Zell, S. De Sarkar, E. E. Ishikawa, L.
Ackermann, J. Am. Chem. Soc. 2015, 137, 13894–13901; c) L.
Ackermann, N. Hofmann, R. Vicente, Org. Lett. 2011, 13, 1875–
1877; d) L. Ackermann, P. Novák, R. Vicente, N. Hofmann,
Angew. Chem. Int. Ed. 2009, 48, 6045–6048; e) L. Ackermann,
P. Novák, Org. Lett. 2009, 11, 4966–4969.
[4]
[5]
[6]
a) Y. Zhao, G. Chen, Org. Lett. 2011, 13, 4850–4853; b) Y.-H.
Zhang, B.-F. Shi, J.-Q. Yu, Angew. Chem. Int. Ed. 2009, 48,
6097–6100.
a) Z. Dong, Z. Ren, S. J. Thompson, Y. Xu, G. Dong, Chem.
Rev. 2017, 117, 9333–9403; b) L. Ackermann, Chem. Commun.
2010, 46, 4866–4877.
a) B. Punji, W. Song, G. A. Shevchenko, L. Ackermann, Chem.
Eur. J. 2013, 19, 10605–10610; b) K. Gao, N. Yoshikai, J. Am.
Chem. Soc. 2013, 135, 9279–9282; c) W. Song, L. Ackermann,
Angew. Chem. Int. Ed. 2012, 51, 8251–8254; d) For a review,
see; L. Ackermann, J. Org. Chem. 2014, 79, 8948–8954.
a) G. Cera, T. Haven, L. Ackermann, Angew. Chem. Int. Ed.
2016, 55, 1484–1488; b) B. M. Monks, E. R. Fruchey, S. P.
Cook, Angew. Chem. Int. Ed. 2014, 53, 11065–11069; c) E. R.
Fruchey, B. M. Monks, S. P. Cook, J. Am. Chem. Soc. 2014,
136, 13130–13133.
a) Z. Shen, H. Huang, C. Zhu, S. Warratz, L. Ackermann, Org.
Lett. 2019, 21, 571–574; b) T. Sato, T. Yoshida, H. H. Al Mamari,
L. Ilies, E. Nakamura, Org. Lett. 2017, 19, 5458–5461; c) W. Liu,
G. Cera, J. C. A. Oliveira, Z. Shen, L. Ackermann, Chem. Eur.
J. 2017, 23, 11524–11528.
a) T. Uemura, M. Yamaguchi, N. Chatani, Angew. Chem. Int.
Ed. 2016, 55, 3162–3165; b) T. Kubo, N. Chatani, Org. Lett.
2016, 18, 1698–1701; c) Y. Aihara, M. Tobisu, Y. Fukumoto, N.
Chatani, J. Am. Chem. Soc. 2014, 136, 15509–15512; d) Y.
Aihara, N. Chatani, J. Am. Chem. Soc. 2013, 135, 5308–5311;
e) H. Shiota, Y. Ano, Y. Aihara, Y. Fukumoto, N. Chatani, J. Am.
Chem. Soc. 2011, 133, 14952–14955.
[7]
[8]
[9]
[22] B. R. Walker, C. S. Sevov, ACS Catal. 2019, 9, 7197–7203.
[23] D. Liu, H.-X. Ma, P. Fang, T.-S. Mei, Angew. Chem. Int. Ed.
2019, 58, 5033–5037.
[10] a) D. Ghorai, L. H. Finger, G. Zanoni, L. Ackermann, ACS Catal.
2018, 8, 11657–11662; b) Z. Ruan, D. Ghorai, G. Zanoni, L.
Ackermann, Chem. Commun. 2017, 53, 9113–9116; c) Z. Ruan, [24] Y. Wang, L. Deng, X. Wang, Z. Wu, Y. Wang, Y. Pan, ACS Catal.
S. Lackner, L. Ackermann, Angew. Chem. Int. Ed. 2016, 55,
3153–3157; d) W. Song, S. Lackner, L. Ackermann, Angew.
Chem. Int. Ed. 2014, 53, 2477–2480; e) L. Ackermann, B. Punji,
W. Song, Adv. Synth. Catal. 2011, 353, 3325–3329.
2019, 9, 1630–1634.
[25] L. Ackermann, Acc. Chem. Res. 2014, 47, 281–295.
[26] For detailed information, see the Supporting Information.
[27] a) S.-K. Zhang, J. Struwe, L. Hu, L. Ackermann, Angew. Chem.
Int. Ed. 2020, 59, 3178–3183; b) S.-K. Zhang, R. C. Samanta,
N. Sauermann, L. Ackermann, Chem. Eur. J. 2018, 24, 19166–
19170.
[28] a) K.-J. Jiao, D. Liu, H.-X. Ma, H. Qiu, P. Fang, T.-S. Mei,
Angew. Chem. Int. Ed. 2020, 59, 6520–6524; b) G. S. Kumar,
A. Peshkov, A. Brzozowska, P. Nikolaienko, C. Zhu, M.
Rueping, Angew. Chem. Int. Ed. 2020, 59, 6513–6519.
[29] The reduction potential of Zn2+ to Zn (ZnBr2 in DMA) was
reported as Ep = –1.41 V vs. SHE and Ep/2 = –1.26 V vs. SHE,
which is considerable higher than the reduction potential of
NiII/NI that we have observed. Q. Lin, T. Diao, J. Am. Chem.
Soc. 2019, 141, 17937–17948.
[11] a) D. K. Pandey, S. B. Ankade, A. Ali, C. P. Vinod, B. Punji,
Chem. Sci. 2019, 10, 9493–9500; b) V. Soni, S. M. Khake, B.
Punji, ACS Catal. 2017, 7, 4202–4208; c) V. Soni, R. A. Jagtap,
R. G. Gonnade, B. Punji, ACS Catal. 2016, 6, 5666–5672.
[12] S. M. Khake, N. Chatani, Trends Chem. 2019, 1, 524–539.
[13] G. Rouquet, N. Chatani, Angew. Chem. Int. Ed. 2013, 52,
11726–11743.
[14] a) V. G. Zaitsev, D. Shabashov, O. Daugulis, J. Am. Chem. Soc.
2005, 127, 13154–13155; b) O. Daugulis, H.-Q. Do, D.
Shabashov, Acc. Chem. Res. 2009, 42, 1074–1086; c) D.
Shabashov, O. Daugulis, J. Am. Chem. Soc. 2010, 132, 3965–
3972.
[15] a) J. C. Siu, N. Fu, S. Lin, Acc. Chem. Res. 2020, 53, 547–560;
b) C. Kingston, M. D. Palkowitz, Y. Takahira, J. C. Vantourout,
B. K. Peters, Y. Kawamata, P. S. Baran, Acc. Chem. Res. 2020,
53, 72–83; c) L. Ackermann, Acc. Chem. Res. 2020, 53, 84–
104; d) P. Xiong, H.-C. Xu, Acc. Chem. Res. 2019, 52, 3339–
5
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10.1002/anie.202004958
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Ramesh C. Samanta, Julia Struwe and
Lutz Ackermann*
Page No – Page No
Nickelaelectro-Catalyzed Mild C–H
Alkylations at Room Temperature
Electrochemically enabled nickel-catalyzed C–H alkylations with primary and secondary alkyl halides have been accomplished under
exceedingly mild reaction conditions with Et3N at room temperature. Detailed mechanistic studies provided support for a nickel(II/III/I)
manifold.
Institute and/or researcher Twitter usernames: aztul
6
This article is protected by copyright. All rights reserved.