Electroremovable Traceless Hydrazides for Cobalt-Catalyzed Electro-Oxidative C-H/N-H Activation with Internal Alkynes

Article abstract of DOI:10.1021/jacs.8b03521

Electrochemical oxidative C-H/N-H activations have been accomplished with a versatile cobalt catalyst in terms of [4 + 2] annulations of internal alkynes. The electro-oxidative C-H activation manifold proved viable with an undivided cell setup under exceedingly mild reaction conditions at room temperature using earth-abundant cobalt catalysts. The electrochemical cobalt catalysis prevents the use of transition metal oxidants in C-H activation catalysis, generating H₂ as the sole byproduct. Detailed mechanistic studies provided strong support for a facile C-H cobaltation by an initially formed cobalt(III) catalyst. The subsequent alkyne migratory insertion was interrogated by mass spectrometry and DFT calculations, providing strong support for a facile C-H activation and the formation of a key seven-membered cobalta(III) cycle in a regioselective fashion. Key to success for the unprecedented use of internal alkynes in electrochemical C-H/N-H activations was represented by the use of N-2-pyridylhydrazides, for which we developed a traceless electrocleavage strategy by electroreductive samarium catalysis at room temperature.

Full text of DOI:10.1021/jacs.8b03521

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Article
Electro-Removable Traceless Hydrazides for Cobalt-Catalyzed
Electro-Oxidative C–H/N–H Activation with Internal Alkynes
Ruhuai Mei, Nicolas Sauermann, João C. A. Oliveira, and Lutz Ackermann
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b03521 • Publication Date (Web): 29 May 2018
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Electro-Removable Traceless Hydrazides for Cobalt-Catalyzed Elec-
tro-Oxidative C–H/N–H Activation with Internal Alkynes
Ruhuai Mei,[a] Nicolas Sauermann,[a] João C. A. Oliveira,[a] and Lutz Ackermann*[a,b,c]
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[a] Institut für Organische und Biomolekulare Chemie, Georg-August-Universität Göttingen, Tammannstraße 2,
37077, Göttingen (Germany).
[b] Department of Chemistry, University of Pavia, Viale Taramelli, 10, 27100 Pavia, Italy
[c] International Center for Advanced Studies of Energy Conversion (ICASEC), Georg-August-Universität Göttingen
Supporting Information Placeholder
ABSTRACT: Electrochemical oxidative C–H/N–H activations have been accomplished with a versatile cobalt catalyst in terms of
[4+2] annulations of internal alkynes. The electro-oxidative C–H activation manifold proved viable with an undivided cell set-up
under exceedingly mild reaction conditions at room temperature using earth-abundant cobalt catalysts. The electrochemical
cobalt catalysis prevents the use of transition metal oxidants in C–H activation catalysis, generating H2 as the sole byproduct.
Detailed mechanistic studies provided strong support for a facile C–H cobaltation by an initially formed cobalt(III) catalyst. The
subsequent alkyne migratory insertion was interrogated by mass spectrometry and DFT calculations, providing strong support
for a facile C–H activation and the formation of a key seven-membered cobalta(III)cycle in a regio-selective fashion. Key to suc-
cess for the unprecedented use of internal alkynes in electrochemical C–H/N–H activations was represented by the use of N-2-
pyridylhydrazides, for which we developed a traceless electro-cleavage strategy by electro-reductive samarium catalysis at room
temperature.
Introduction
earth-abundant 3d transition metals for electro-oxidative70-73
C–H activation catalysis.74 Thus, cost-effective base metal75-81
cobalt(II) catalysts82-94 enabled sustainable C–H oxygenations
in the absence of any chemical oxidants.74 Based on key
mechanistic insights into the working mode of these C–H
alkoxylations, we unraveled C–H/N–H activations for the
step-economical [4+2] annulation of alkynes.95 In spite of
major progress in the field,95-96 the cobalt-catalyzed alkyne
annulation regime continues to be severely restricted to
exclusively include terminal alkynes. Thus, synthetically
meaningful internal acetylenes were thus far completely inert
(Scheme 1).
C–H activation has been recognized as a powerful tool in
molecular synthesis,1-16 with enabling applications to material
sciences,17 natural product synthesis,18 and pharmaceutical
industries,19-20 among others. Particularly, oxidative C–H
transformations have proven instrumental for the develop-
ment of step-economical organic syntheses.21-24 Despite of
considerable advances, these oxidative C–H functionaliza-
tions largely rely on stoichiometric amounts of costly and/or
toxic transition metal oxidants that generate undesired met-
al-containing byproducts, thereby compromising the atom-
economical nature of the C–H activation approach.25
In the meantime, electrosynthesis has emerged as an increas-
ingly viable platform for molecular synthesis.26-37 Specifically,
electrocatalysis holds great potential for avoiding the use of
cost-intensive chemical reagents in redox-processes, thereby
reducing the footprint of undesirable byproducts.28-29, 35, 38-42
Thus, in recent years, electrosynthesis was illustrated to
significantly improve the sustainability of molecular trans-
Scheme 1. [4+2] Annulation with Terminal Alkynes.
formations.43-44
A considerable recent momentum was
gained by merging organometallic electrosynthesis and cata-
lyzed C–H activation.28-29, 39-42 In this context, major advances
were accomplished by innate reactivity guidance under met-
al-free conditions, as reported by Barran, Waldvogel, and Xu,
among others.45-59 Alternatively, the power of precious palla-
dium catalysts has been unraveled at elevated temperatures
(70-90 °C), as elegantly developed by Kakiuchi, and Mei,
among others.60-69 In contrast, we have introduced in 2017
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On the one hand this represents a major limitation in the
electrochemical C–H activation with internal alkyne 2a was
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synthesis of diversely substituted heterocycles by electroca-
talysis. On the other hand, these findings feature important
mechanistic implications in that two viable reaction path-
ways could not unambiguously be discriminated. Thus, the
two scenarios involving (a) a migratory insertion/reductive
best accomplished with TFE as the solvent and NaOPiv as
the key additive in a most user-friendly undivided cell (en-
tries 1-4). The catalytic efficacy of the electro-oxidation was
reflected by efficient C–H/N–H activation occurring at an
ambient temperature of 23 °C (entries 4-6). The catalytic
performance could be further improved with pivalic acid as
the additive (entries 7-11), which can be rationalized by im-
proved solubility and chemo-selectivity as well as a more
effective cathodic reduction. Control experiments confirmed
the essential role of the cobalt catalyst, the carboxylate addi-
tive (entries 13-15), and the electricity (entry 16).
elimination manifold, or (b)
a
C–H alkynyla-
tion/hydroamidation regime continue to be viable options
for the electrochemical [4+2] alkyne annulation. With our
continued interest in sustainable C–H activation,97-98 we have
now devised conditions for the first base metal-catalyzed
electro-chemical C–H activation with internal alkynes, on
which we report herein. Thus, pyridyl-benzhydrazides 199
underwent effective electrochemical C–H/N–H activations
with internal alkynes to provide expedient access to diversely
decorated isoquinolones – key structural motifs of relevance
to natural product chemistry, medicinal chemistry, and
pharmaceutical industries.100-102 Herein, we report the devel-
opment of cobalt-catalyzed electro-oxidative C–H/N–H acti-
vation with internal alkynes, employing electricity as the sole
oxidant, which avoid the use of stoichiometric metal salts as
sacrificial oxidants (Figure 1). Salient features of our strategy
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Table 1. Electro-Oxidative C–H/N–H Activa-
tion with Internal Alkyne 2a.[a]
include (i) electrochemical C–H activation with internal
103-104
alkynes, (ii) earth-abundant cobalt76-77,
catalysis, (iii)
Entry
1
Solvent
MeOH
Additive
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
Na2CO3
K3PO4
T [°C]
Yield [%]
trace
trace
---
high levels of position- and chemo-selectivity, (iv) an user-
friendly undivided cell set-up, and (v) exceedingly mild room
temperature conditions. It is also noteworthy that we have
established reaction conditions for the electro-reductive
removal of the benzhydrazide directing groups by samarium
catalysis, setting the stage for the first electro-cleavable di-
recting group strategy in C–H activation catalysis. We, fur-
thermore, disclose detailed mechanistic insights on the C–
H/N–H activation, including experimental spectrometric and
computational DFT studies on the selectivity control in co-
balt-catalyzed electro-oxidation catalysis.
23
2
EtOH
H2O
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
TFE
23
23
23
60
80
23
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3
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48
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34
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39
7
trace
---
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9
NaOAc
n-Bu4NPF6
PivOH
---
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63
79
37
---
---[b]
71[b]
---[c]
---[d]
PivOH
PivOH
PivOH
Figure 1. Electro-Oxidative Cobalt-Catalyzed C–H/N–H
Activation Featuring Electro-Reductive Hydrazide Cleavage.
[a] Reaction conditions: Undivided cell, 1a (0.5 mmol), 2a (0.6
mmol), Co(OAc)2 (10 mol %), additive (2.0 equiv), solvent (3.0 mL),
5.0 mA, 16 h, RVC anode (1.0 × 1.5 cm), Pt-plate cathode (1.0 × 1.5
cm), under N2. [b] CoCl2 (10 mol %). [c] Without cobalt. [d] Without
electricity.
RESULTS AND DISCUSSION
Optimization Studies
We initiated our studies by exploring reaction conditions for
the envisioned electro-oxidative [4+2] annulation of internal
alkyne 2a by 2-pyridyl-benzhydrazide 1a (Table 1 and Table
S-1 in the Supporting Information).105 After considerable
preliminary experimentation, we observed that the desired
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Thereafter, we probed the effect exerted by the N-substituent
Scheme 3. Electrochemical C–H/N–H Activation:
[4+2] Annulation of Internal Alkynes 2.
1
2
3
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7
of the benzamide motif in substrates 1 (Scheme 2). Interest-
ingly, none of the frequently used N-directing groups, such
as the omnipresent 8-quinolinyl106 or the previously em-
95
ployed74,
2-N-oxypyridyl substituents, allowed for the
transformation of the internal alkyne 2a. In sharp contrast,
solely the 2-pyridylhydrazide 1a proved amenable to the
desired C–H/N–H activation.
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Scheme 2. Effect of N-Substituents on Electrochemical
C–H/N–H Activation.
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Versatility
With the optimized cobalt-catalyzed electro-oxidative C–H
activation in hand, we probed its robustness with a variety of
internal alkynes 2 (Scheme 3a). Thus, disubstituted acety-
lenes 2b-2f bearing electron-donating or electron-
withdrawing aryl-, alkyl, and even ester groups were smooth-
ly converted within the [4+2] alkyne annulation regime.
Generally, the electrochemical C–H/N–H activation occurred
efficiently at room temperature. Detailed NMR spectroscopic
studies revealed that the annulation of unsymmetrically
substituted alkynes 2g-2i proceeded with synthetically useful
levels of regio-control (Scheme 3b), generally placing the
alkyl-group distal, and the -containing motif proximal to
nitrogen (vide infra). As to unsymmetrical diarylalkynes 2j-21,
the cobalt-catalyzed C–H/N–H activation placed the elec-
tron-deficient oligofluoroaryl moiety preferentially distal to
nitrogen, as was elaborated by NMR spectroscopic analysis
and single crystal X-ray diffraction.105 This observation is
indicative of attractive π-π dispersion interactions control-
ling the key migratory insertion step. Moreover, the versatile
cobalt catalyst was applicable to the site-selective functional-
ization of arenes 1b-1m displaying para-, meta- and ortho-
substituents (Scheme 3c). Thereby, synthetically meaningful
electrophilic functional groups were fully tolerated, including
ester, chloro, bromo, iodo and, cyano substituents, which
should prove invaluable for the further late-stage diversifica-
tion of the thus-obtained products 3jc-3mc.
The broadly applicable electro-oxidative C–H/N–H activation
manifold was not limited to internal alkynes 2. Indeed, vari-
ous terminal alkynes 7 proved to be viable substrates as well
(Scheme 4). Hence, a wealth of aryl-decorated alkynes 7 was
found to be suitable as well. Likewise, the aryl bromide and
heteroaryl alkyne 7h and 7l, respectively, were efficiently
converted, leaving the oxidation-sensitive thiophene moiety
untouched. Generally, the hydrogen was placed distal to
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nitrogen with excellent levels of regio-control. The sterically
ducted with isotopically labeled D2O as the co-solvent did
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congested tert-butyl alkyne 7q was also a competent sub-
strate, while the alkyl nitrile 7r was fully tolerated without
any signs for a nucleophilic attack. The electro-oxidative C–
H/N–H activation further enabled the late-stage diversifica-
tion to deliver erlotinib derivative 8at in a step-economical
manner.
not lead to any H/D scrambling (Scheme 5b). In good
agreement with this finding, kinetic studies provided support
for a facile C–H cleavage with a minor kinetic isotope effect
(KIE) of only kH/kD  1.1 (Scheme 5c). Gas-chromatographic
headspace analysis confirmed the formation of molecular
hydrogen as the sole byproduct (Scheme 5d and the Support-
ing Information).
Scheme 4. Electrochemical C–H/N–H Activation: Termi-
nal Alkynes 2.
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Scheme 5. Summary of Key Mechanistic Findings.
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Thereafter, we interrogated viable key intermediates of the
electrochemical C–H activation for the first time by means of
mass spectrometry (Scheme 6). Thus, careful analysis by
electrospray ionization (ESI) analysis provided strong sup-
port for the formation of the putative seven-membered co-
balta(III)cycle88, 115-116 9 as the key intermediate.
Mechanistic Studies by Experiment
Intrigued by the unique performance of the electro-oxidative
C–H activation with internal alkynes 2, we became attracted
to probing its modus operandi. To this end, intermolecular
competition experiments revealed electron-rich arenes 1 to
be inherently superior (Scheme 5a). This observation is not
in good agreement with competition experiments for a con-
certed metalation-deprotonation manifold,107-110 but can
better be rationalized in terms of a base-assisted internal
electrophilic-type substitution (BIES).111-114 Reactions con-
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Scheme 6. Mass Spectrometric Analysis.
Computational Mechanistic Studies
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Thereafter, we explored the mechanism of the electrochemi-
cal cobalt-catalyzed C–H activation by computational studies
at
the
PW6B95-D3BJ/def2-TZVP-SMD(TFE)//PBE0-
D3BJ/def2-SVP level of theory.117-125 Thus, the regio-control of
the key migratory insertion was found to place the aryl group
proximal to the heteroatom, thus reflecting the experimen-
tally observed selectivities. Notably, the regio-selectivity126
was largely governed by secondary attractive dispersion π-π
interactions between the (hetero)aryl motifs of the pyridine
and the arylacetylene moieties (Figure 3).
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As to the catalyst’s electrochemical mode of action, detailed
cyclovoltammetric studies unraveled the formation of a co-
balt(III) species by anodic oxidation (Figure 2). Furthermore,
the alkyne 7a (blue) did not show significant oxidation up to
a potential of 1.55 VSCE, while substrate 1a was oxidized with-
in several waves with an onset potential of 0.8 VSCE, and the
most notable peak at 1.61 VSCE (red). A mixture of Co(OAc)2
and NaOPiv in MeOH (pink) featured an oxidation potential
of 1.31 VSCE for the oxidation of cobalt(II) to cobalt(III). How-
ever, a mixture of Co(OAc)2, NaOPiv and 1a in MeOH
(green) highlighted a new broad oxidation wave with an
onset potential of 0.52 VSCE and a current maximum at 0.99
VSCE. These observations are indicative of an oxidation of
cobalt(II) to cobalt(III) in the presence of the substrate at
significantly lower potential. The addition of the alkyne 7a to
this mixture (blue) did not lead to a significant quenching.105
Figure 3. Computed Gibbs free energies (ΔG298.15) in kcal
mol˗1 for the regio-selectivity of the migratory alkyne inser-
tion within the electro-chemcial cobalt-catalyzed C–H/N–H
activation. [Co] = Co(OPiv). In the computed transition-state
structures non-participating H atoms were omitted for clari-
ty.105
Moreover, computation provided further support for the
observed (Scheme 3) preferential π-π interaction between the
electron-deficient pyridyl group and the more electron-rich
aryl motif in C–H/N–H activation with unsymmetrical alkyne
2k (Figure 4).
Figure 2. Cyclic voltammogram at 100 mV/s in MeOH. N-
Bu4NPF6 (0.1 M in MeOH), Alkyne = 7a, [Co] = Co(OAc)2.105
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Proposed Catalytic Cycle for Electro-Oxidative C–H/N–H
Activation
1
2
3
4
5
6
7
8
9
Based on our detailed experimental and computational
mechanistic studies, we propose a plausible catalytic cycle to
be initiated by the electro-oxidative formation of the catalyt-
ically competent cobalt(III)carboxylate species 10 by means
of anodic oxidation (Scheme 7). Thereafter, facile carbox-
ylate-assisted C–H activation provides intermediate 11, while
subsequent migratory insertion gives rise to the seven-
membered cobalta(III)cycle 9. Then, reductive elimination
delivers the desired product 3 and forms the cobalt(I) species
12. Finally, the catalytically active cobalt(III) carboxylate
complex 10 is regenerated by anodic oxidation, overall avoid-
ing the use of toxic and expensive metals as sacrificial stoi-
chiometric oxidants, instead generating H2 as the sole by-
product.
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Figure 4. Computed Gibbs free energies (ΔG298.15) in kcal
mol˗1 for the regio-selectivity of the migratory insertion of
alkyne 2k. [Co] = Co(OPiv). In the computed transition-state
structures non-participating H atoms were omitted for clari-
ty.105
Scheme 7. Plausible Catalytic Cycle.
Thereby, the migratory insertion delivers the seven-
membered cobalta(III)cycle 9 (Figure 5), which we observed
by electrospray mass spectrometry (vide supra). Thereafter,
facile reductive elimination occurs on the triplet surface
without any indication for spin-crossover behavior. Hence,
the cobalt(I) species is formed which sets the stage for the
anodic oxidation to regenerate the catalytically competent
species. Weak dispersion127 interactions were found to stabi-
lize the crucial transition states,105 as was primarily deduced
from the comparison of calculations with and without
Grimme’s D3 correction.
Electro-Reductive Catalytic Removal of Hydrazides
Finally, we envisioned the, to the best of our knowledge, first
128
electro-catalytic removal3,
of a directing group in C–H
activation chemistry. Specifically, we tested the cleavage of
the hydrazide motif in isoquinolone 3cc by means of samari-
um-catalyzed cathodic electro-reduction, again with a user-
friendly undivided cell set-up. First, we explored various
electrolytes and solvents for the electro-reductive hydrazide
removal on isoquinolone 3cc at ambient temperature (Table
2), with DMF emerging as the solvent of choice (entries 1-3).
Among various electrolytes, an equimolar combination of n-
Bu4NPF6 and NaI proved optimal, particularly when employ-
ing a sacrificial magnesium anode (entries 4-6). Thereby, the
effective use of catalytic quantities SmI2 proved viable, deliv-
ering the desired product 13cc in 90% yield in a sustainable
manner at a room temperature of 23 °C (entry 6).
Figure 5. Computed Gibbs free energies (ΔG298.15) in kcal
mol˗1 for the reaction profile for the cobalt-catalyzed C–H/N–
H [4+2] alkyne annulation. All values include dispersion
corrections. In the computed transition-state structures
non-participating H atoms were omitted for clarity.105
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Table 2. Electro-Reductive Hydrazide Removal[a]
3. CONCLUSIONS
1
2
In summary, we have reported on the first electrochemical
cobalt-catalyzed C–H/N–H activation for [4+2] annulations
that is applicable to internal alkynes. Thus, a versatile cobalt
catalyst enabled C–H activations on benzhydrazides with
high levels of chemo-, position- and regio-control. The elec-
tro-oxidative cobalt catalysis was conducted in an operation-
ally simple undivided cell set-up under exceedingly mild
conditions at room temperature.129 Detailed mechanistic
studies by competition experiments, isotopic labeling, head-
space analysis, mass spectrometry, cyclovoltametry and DFT
calculations provided strong support for a facile C–H activa-
tion by a catalytically competent cobalt(III) species. The use
of electrical energy overall prevents stoichiometric amounts
of toxic and costly transition metals as oxidants in C–H acti-
vations, being enabled by an earth-abundant, water-stable
cobalt catalyst under ambient conditions. It also noteworthy,
that we have provided the proof of concept for electro-
reductive directing group removal. Hence, the electro-
chemical samarium-catalyzed amino removal was chemo-
selectively accomplished in an undivided cell at room tem-
perature.
3
4
5
6
7
8
9
entry
anode
Al
cathode
Ni
electrolyte
Yield (%)
37[b]
44[c]
50
1
2
3
4
5
6
n-Bu4NPF6, NaI
n-Bu4NPF6, NaI
n-Bu4NPF6, NaI
n-Bu4NPF6, n-Bu4NI
n-Bu4NI
10
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Al
Ni
Al
Ni
Al
Pt
48
Al
Pt
37
Mg
Pt
n-Bu4NPF6, NaI
90
[a]
Reaction conditions: Undivided cell, 3cc (0.15 mmol),
overall electrolyte (0.20 M), DMF (3.0 mL), 5.0 mA, 5 h, an-
ode (1.0 × 1.5 cm), cathode (1.0 × 1.5 cm), 23 °C, 5.0 h, under
N2. [b] THF as the solvent. [c] CH3CN as the solvent.
ASSOCIATED CONTENT
Supporting Information
With the optimized conditions for the electro-catalytic N–N
cleavage in hand, we explored its scope for a variety of iso-
quinolones 3/8 (Scheme 8). Hence, the electro-reductive
hydrazide removal was found to be generally applicable,
highlighting the power of electrosynthesis by dialing in an
appropriate potential. Thereby, N-aminoisoquinolones 3 and
8 derived from both internal and terminal alkyl and aryl
alkynes were efficiently converted into the desired products
13 and 14, respectively by means of samarium electrocatalysis.
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details, detailed mechanistic and cyclovoltam-
mogrammic experiments and compound characterization
data (1H-/13C-NMR, IR, Mass) (PDF).
AUTHOR INFORMATION
Corresponding Author
Scheme 8. Electro-Reductive Amine Removal. Ratio of Re-
gio-isomers in parenthesis.
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Author Contributions
+These authors contributed equally.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
Generous support by the CaSuS PhD Program (Scholarship
to N.S.) the CSC (Scholarship to R.M.) and the DFG (Gott-
fried-Wilhelm-Leibniz award) is most gratefully acknowl-
edged. We also thank Mr. Lucas A. Paul and Prof. Dr. Inke
Siewert (Göttingen University) for assistance with the head-
space GC analysis.
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