Nickela-electrocatalyzed C?H Alkoxylation with Secondary Alcohols: Oxidation-Induced Reductive Elimination at Nickel(III)

Article abstract of DOI:10.1002/anie.201913930

Nickela-electrooxidative C?H alkoxylations with challenging secondary alcohols were accomplished in a fully dehydrogenative fashion, thereby avoiding stoichiometric chemical oxidants, with H₂ as the only stoichiometric byproduct. The nickela-electrocatalyzed oxygenation proved viable with various (hetero)arenes, including naturally occurring secondary alcohols, without racemization. Detailed mechanistic investigation, including DFT calculations and cyclovoltammetric studies of a well-defined C?H activated nickel(III) intermediate, suggest an oxidation-induced reductive elimination at nickel(III).

Full text of DOI:10.1002/anie.201913930

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Accepted Article
Title: Nickellaelectro-Catalyzed C–H Alkoxylation with Secondary
Alcohols: Oxidation-Induced Reductive Elimination at Nickel(III)
Authors: Shou-Kun Zhang, Julia Struwe, Lianrui Hu, and Lutz
Ackermann
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201913930
Angew. Chem. 10.1002/ange.201913930
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10.1002/anie.201913930
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Nickellaelectro-Catalyzed C–H Alkoxylation with Secondary
Alcohols: Oxidation-Induced Reductive Elimination at Nickel(III)
Shou-Kun Zhang, Julia Struwe, Lianrui Hu and Lutz Ackermann*[a]
Abstract: Nickellaelectro-oxidative C–H alkoxylations with
challenging secondary alcohols were accomplished in fully
found that versatile nickel catalysts are uniquely effective for
challenging C–H electro-alkoxylations with sterically encumbered
secondary alcohols, on which we report herein. It is noteworthy
that complexes of cobalt, copper, and even precious palladium,
iridium, ruthenium and rhodium did not catalyze the difficult
secondary C–H alkoxylations. In addition, we disclose
mechanistic support for an oxidation-induced reductive
elimination nickel(III/IV) regime.
a
dehydrogenative fashion, thus avoiding stoichiometric chemical
oxidants with H2 as the only stoichiometric byproduct. The
nickellaelectro-catalyzed oxygenation proved viable with various
(hetero)arenes, including naturally occurring secondary alcohols
without racemization. Detailed mechanistic insights, including DFT
computation, and cyclovoltammetric studies of a well-defined C–H
activated nickel(III) intermediate, render an oxidation-induced
reductive elimination at nickel(III) likely to be operative.
C−O forming transformations[1] are of utmost importance to the
synthesis of bioactive pharmaceuticals,[2] natural products[3] and
functional materials.[4] Classical approaches for the synthesis of
aryl ethers, such as the palladium-catalyzed Buchwald−Hartwig
cross-couplings[5] and copper-catalyzed Ullmann−Goldberg[6] or
Chan−Evans−Lam reactions[7] rely on prefunctionalized
substrates, the preparation and use of which result in undesired
byproducts and solvent waste. In contrast, dehydrogenative
functionalizations of otherwise inert C–H bonds constitute more
sustainable strategies, which significantly reduce the footprint of
organic syntheses.[8] Despite of major advances in C–H activation,
C–H alkoxylations are less developed than typical
hydroxylations,[9] acetoxylations,[10] and phenoxylations,[11]
because competing β-hydride elimination or overoxidation
represent undesired side reactions. Specifically, C–H
alkoxylations with sterically encumbered secondary alcohols
continue to be difficult, which contrast the wealth of viable
methods for the use of primary alcohols.[12]
In recent years, electrosynthesis[13] has gained significant
attention through the use of waste-free and inexpensive electric
current as redox equivalent, thereby avoiding stoichiometric
amounts of toxic and costly chemical redox reagents.
Electrochemical C–H activations[14] have until recently largely
required expensive 5d and 4d metals, such as palladium,[15]
ruthenium,[16] rhodium,[17] and iridium.[18] In sharp contrast, major
recent momentum was gained by the use of earth-abundant, less
toxic 3d metals,[19] such as cobalt[20] and copper,[21] as reported by
Ackermann, Lei, and Mei, among others. In spite of the
indisputable progress, such cost-effective nickel electrocatalysis
has, until very recently proven, elusive, when we established the
nickellaelectro-catalyzed C–H aminations, which were however
restricted to morpholine−type amines.[22] In contrast, we have now
Figure 1. Nickellaelectro-catalyzed C–H alkoxylation with secondary alcohols:
Mechanistic insights by isolation, CV and DFT studies.
Our studies were initiated by optimizing reaction conditions
for the envisioned nickellaelectro-catalyzed C–H oxygenation of
amide 1a with the challenging secondary alcohol 2a in an
undivided cell set-up (Table 1 and Table S1–S7 in the Supporting
Information). After considerable experimentation, the desired
product 3aa was obtained with Ni(DME)Cl2 as the catalyst and
bulky carboxylate NaO2CAd as the additive, whilst RVC and
nickel foam electrodes were found to be beneficial (entries 1–4).
Here, C–H acetoxylations were not observed. The catalysts’
performance was improved by adjusting the alcohol concentration
(Table S4). Control experiments confirmed that the
eletrooxidative C–H transformation could not be realized in the
absence of the electricity, the nickel complex or the additive
(entries 7–9). Other nickel compounds, such as Ni(COD)2,
Ni(acac)2 or Ni(OAc)2 furnished the desired product 3aa (entry 10,
and Table S3). It is particularly noteworthy that nickel catalysts
featured proved uniquely effective for the challenging C–H
activation with secondary alcohols, while other transition metals,
including cobalt, copper, and even precious palladium, iridium,
ruthenium or rhodium, fell short under otherwise identical reaction
conditions (entries 11–17 and Table S7). Indeed, while palladium,
copper and cobalt catalysts were highly effective for primary
alcohols, no or very minor catalytic turnover was accomplished
with the secondary alcohol 2a (Table S9).
Table 1. Optimization of the nickellaelectro-catalyzed secondary alkoxylation.[a]
[a]
Shou-Kun Zhang, Julia Struwe, Dr. Lianrui Hu, and 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/
Supporting information for this article is given via a link at the end of the
document.((Please delete this text if not appropriate))
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2q–2s were identified as viable substrates, notably without
Entry
[TM]
Additive
3aa [%]
racemization at the stereogenic centers (Figure S1 and S2).
1
2
Ni(DME)Cl2
Ni(DME)Cl2
NaOPiv
45[b]
55[b]
NaO2CAd
3
Ni(DME)Cl2
Ni(DME)Cl2
Ni(DME)Cl2
Ni(DME)Cl2
---
KOAc
24[b]
---[b]
74
4
K2HPO4
5
NaO2CAd
NaO2CAd
NaO2CAd
---
6
69[c]
---
7
8
Ni(DME)Cl2
Ni(DME)Cl2
Ni(COD)2
---
9
NaO2CAd
NaO2CAd
NaO2CAd
NaO2CAd
NaO2CAd
NaO2CAd
NaO2CAd
NaO2CAd
NaO2CAd
---[d]
67
10
11
12
13
14
15
16
17
Co(OAc)2·4H2O
Mn(OAc)2
---
---
Cu(OAc)2·H2O
Ru(OAc)2(PPh3)2
[Cp*RhCl2]2
Pd(OAc)2
---
---
---[e]
---
[Cp*IrCl2]2
---[e]
[a] Reaction conditions: 1a (0.25 mmol), 2a (2.5 mmol), 1-AdCO2H (20 mol %),
[TM] (10 mol %), additive (1.0 equiv), nBu4NClO4 (0.5 mmol), DMA (3.0 mL),
CCE = 8.0 mA, 12 h, N2, RVC anode and Ni foam cathode, isolated yield. [b] 2a
(1.25 mmol). [c] DMPU as solvent. [d] No current. [e] [TM] (5.0 mol %).
The efficacy of the nickellaelectro-oxidation was considerably
affected by the substitution pattern of the quinoline moiety
(Scheme 1). Analysis by computation at the PEB0/Def2TZVP
level of theory[23] unraveled the key importance of increased
electron-density at the quinolinyl nitrogen, while decreased
electron-density at the amide nitrogen was beneficial (Figure S16
in the Supporting Information). These findings indicate the
importance of increased σ-donation at the sp2-hybridized
quinolinyl nitrogen in concert with an anionic amide nitrogen.
Scheme 2. Electrooxidative C–H alkoxylation of arenes with secondary alcohols.
Moreover, we evaluated the robustness of the
nickellaelectro-catalyzed C–H alkoxylation with a variety of
functionalized benzamides 1 (Scheme 3). Thus, the reactions
proceeded efficiently with arenes 1 bearing valuable functional
groups, such as halo, sulfido, and cyano substituents. For the
meta-substituted substrates 1b and 1c the reaction occurred with
high position-selectivity by repulsive steric interactions. The
nickellaelectrocatalysis was not limited to arenes, but the
heteroarene 1o was also selectively transformed. It is noteworthy
that the strongly-coordinating pyridine was fully tolerated to give
bidentate amide-guided C–H functionalization (3pa). Likewise,
the gram-scale synthesis was realized without compromising the
efficacy on scale (3ba).
Scheme 1. Directing group power for nickellaelectro-oxidative alkoxylation.
[a]
Yields of recovered starting materials in parenthesis.
In addition, we carried out electricity on/off experiments to
probe a radical chain scenario (Scheme 4a). Hence, the reaction
was haltered without electrochemistry. Yet, the C–H alkoxylation
continued when switching the electric current back on, ruling out
a radical chain process.
With the optimized reaction conditions in hand, we probed
the versatility of the nickellaelectro-catalyzed C–H alkoxylation
with various secondary alcohols 2 (Scheme 2). Not only benzylic
alcohols 2b and 2c were well accepted, but also alicyclic, cyclic
and heterocyclic alcohols were successfully converted with
moderate to excellent yields (3ab–3ap). Remarkably, the
naturally-occurring alcohols menthol, cholesterol and β-estradiol
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10.1002/anie.201913930
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COMMUNICATION
C–H activation.[24] Head-space gas-chromatographic analysis
identified H2 as the only stoichiometric byproduct (Figure S14).
The electrocatalysis was inhibited by the typical radical
scavengers TEMPO, BHT and BQ, being indicative of single-
electron-transfer (SET) steps (Scheme 5d). A minor kinetic
isotope effect of kH/kD ≈ 1.4 by independent experiments gave
support for a facile C–H scission (Figure S13). H/D exchange was
not found when using isotopically labeled tBuOD as the additive
(Figure S11). An irreversible nickelation[25] was further found by
DFT calculations to generate the substrate-coordinated nickel(II)
intermediate Ni(II)-II (Figure S20). Thus, the combined analysis
by DFT and CV studies provided strong support for a viable
nickel(II/III) oxidation (purple, Figure S22).
Scheme 3. Electrooxidative C–H alkoxylation of arenes. [a] Gram-scale testing
with 1b (4.0 mmol,1.32 g). [b] 3.0 mA, 32 h.
The clear benefits of electricity were not restricted to being a
green and inexpensive oxidant. Indeed, the electrocatalysis was
characterized by significantly improved levels of performance as
compared to the chemical oxidants AgOAc, Cu(OAc)2, molecular
oxygen, PhI(OAc)2 or K2S2O8 (Scheme 4b).
Scheme 5. Summary of selected mechanistic findings. Conversions determined
by 1H-NMR analysis with 1,3,5-(MeO)3C6H3 as the internal standard.
To rationalize the elementary process of C–O formation, the
well-defined nickel(III) complex Ni(III)-I was independently
synthesized, and fully characterized, including X-ray diffraction
analysis (Scheme 6a).[26] The well-defined nickel(III) complex
Ni(III)-I was competent in a catalytic and stoichiometric setting,
provided that electricity was applied (Scheme 6b and 6c). Cyclic
voltammetric studies of Ni(III)-I showed a facile oxidation at a
potential of 0.50 V vs. Fc0/+ (red, Scheme 6e), suggesting the
formation of a formal nickel(IV) complex.
Scheme 4. a) On/off experiment. b) Electrochemical vs. chemical oxidants.
Given the unique performance of the nickellaelectro-
catalyzed C–H activation,
a series of experiments were
conducted to gain insights into the reaction mechanism.
Intermolecular competition experiments between secondary
alcohol 2p and amine 2t, or with primary alcohol 2u highlighted
the particular challenge of the nickellaeletrooxidative secondary
C–H alkoxylations (Scheme 5a and 5b). In contrast to
cobaltaelectro-catalysis by a BIES mechanism, an intermolecular
competition experiment showed electron-deficient arenes 1 to be
inherently more reactive (Scheme 5c). This finding is indicative of
a concerted-metalation-deprotonation (CMD) mechanism for the
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As to the synthetic utility, it is noteworthy that the 6-
methylquinuoline was easily removed in a traceless fashion to
provide efficient access to benzamide 4, benzoic acid 5, or
aromatic aldehyde 6 (Scheme S15–S17).
In summary, we have reported on a carboxylate-enabled
nickellaelectro-catalyzed
alkoxylations
with
challenging
secondary alcohols. The robust electrochemical C–H activation
was accomplished with broad substrate scope through traceless
removable quinoline amides. The most user-friendly nickel
electrocatalyst ensured high levels of chemo- and position-
selectivities. The C–H oxygenation was more effective with
electricity than with any other chemical oxidant. Detailed
mechanistic studies by experiment, cyclovoltammetry and
computation provided strong support for an oxidation-induced
reductive elimination nickel(III/IV) manifold.
Acknowledgements
Generous support by the DFG (Gottfried-Wilhelm-Leibniz award
to LA) and the CSC (fellowship to SKZ) is gratefully acknowledged.
Keywords: Electrochemistry • C–H Alkoxylation • Mechanism •
Nickel • Oxygenation • Electrocatalysis
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This article is protected by copyright. All rights reserved.

10.1002/anie.201913930
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Shou-Kun Zhang, Julia Struwe, Lianrui
Hu and Lutz Ackermann*
Page No. – Page No.
Nickellaelectro-Catalyzed C–H
Alkoxylation with Secondary
Alcohols: Oxidation-Induced
Reductive Elimination at Nickel(III)
Text for Table of Contents
II, III or IV: Challenging secondary C–H alkoxygenations were accomplished by a versatile nickel electrocatalyst. Mechanistic studies
by experiment and computation provide support for an oxidation-induced reductive elimination regime.
This article is protected by copyright. All rights reserved.