Catalyst- and Reagent-Free Electrochemical Azole C?H Amination

Article abstract of DOI:10.1002/chem.201802832

Catalyst- and chemical oxidant-free electrochemical azole C?H aminations were accomplished via cross-dehydrogenative C?H/N?H functionalization. The catalyst-free electrochemical C?H amination proved feasible on azoles with high levels of efficacy and selectivity, avoiding the use of stoichiometric oxidants under ambient conditions. Likewise, the C(sp³)?H nitrogenation proved viable under otherwise identical conditions. The dehydrogenative C?H amination featured ample scope, including cyclic and acyclic aliphatic amines as well as anilines, and employed sustainable electricity as the sole oxidant.

Full text of DOI:10.1002/chem.201802832

A Journal of
Accepted Article
Title: Catalyst- and Reagent-free Electrochemical Azole C-H Amination
Authors: Youai Qiu, Julia Struwe, Tjark H. Meyer, Joao Carlos
Agostinho Carlos Agostinho Oliveira, and Lutz Ackermann
This manuscript has been accepted after peer review and appears as an
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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
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To be cited as: Chem. Eur. J. 10.1002/chem.201802832
Link to VoR: http://dx.doi.org/10.1002/chem.201802832
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Catalyst- and Reagent-free Electrochemical Azole C–H Amination
Youai Qiu,+ Julia Struwe,+ Tjark H. Meyer, João C. A. Oliveira, and Lutz Ackermann*[a]
Abstract: Catalyst-, and chemical oxidant-free electrochemical
azole C–H aminations were accomplished via cross-
dehydrogenative C–H/N–H functionalization. The catalyst-free
electrochemical C−H amination proved feasible on azoles with high
levels of efficacy and selectivity, avoiding the use of stoichiometric
oxidants under ambient conditions. Likewise, the C(sp3)–H
nitrogenation proved viable under otherwise identical conditions. The
dehydrogenative C–H amination featured ample scope, including
cyclic and acyclic aliphatic amines as well as anilines, and employed
sustainable electricity as the sole oxidant.
aminations, (ii) effective azole nitrogenation being devoid of
(photo)redox or metal catalyst,[5,12] (iii) exceedingly mild reaction
conditions, and (iv) selective C(sp3)–H nitrogenations with
electricity as the sole oxidant (Figure 2b).
Nitrogen-containing compounds have attracted considerable
attention due to their prevalence as key structural motifs in
biologically relevant compounds, drugs,[1] and natural products
(Figure 1).[2] Thus, efficient methods for the facile construction of
C−N bonds continue to be in high demand.[3] Among these
strategies, the direct nitrogenation by dehydrogenative
functionalization of C–H[4] and N–H bonds represents one of the
most attractive strategies[5] for the assembly of substituted
amines.[6]
Figure 2. Catalyst- and reagent-free electrochemical C–H amination.
Our studies were originally initiated by exploring
electrosynthsis for cobalt-catalyzed[12] nitrogenations of readily
accessible benzoxazole (1a) in a simple undivided cell set-up
with a platinum plate cathode and reticulated vitreous carbon
(RVC) anode, employing NaOPiv as the electrolyte and AcOH
as the additive in CH3CN at a room temperature of 23 °C
(Scheme 1). To our delight, the envisioned product 3aa was thus
obtained in 88% yield.
Figure 1. Selected medicinally-relevant aminated azoles.
In recent years, electrocatalysis has been established as an
increasingly powerful tool for molecular synthesis,[7] with
considerable
advances
in
metal-catalyzed
C–H
functionalizations.[8] In this context, we have very recently
devised reaction condition for unprecedented cobalt-catalyzed
electrooxidative C–H activation.[9] In continuation of our studies
directed towards sustainable C–H functionalizations,[10] we have
now identified robust reaction conditions for catalyst- and
reagent-free[11] C–H aminations in a dehydrogenative manner,
on which we wish to report herein (Figure 2). In contrast to the
previously disclosed methods (Figure 2a),[5] our strategy is
characterized by (i) reagent-free electrochemical C–H
Scheme 1. Preliminary electrochemical C–H amination.
[a]
Dr. Y. Qiu, J. Struwe, T. H. Meyer, Dr. J. C. A. Oliveira, 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
Homepage: http://www.org.chemie.uni-goettingen.de/ackermann/
These authors contributed equally to this work.
[+]
Supporting information for this article is given via a link at the end of
the document.
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Based on our preliminary findings, we further interrogated the
electrochemical C–H/N–H functionalization regime (Table 1).
Thus, the cobalt catalyst loading could be significantly reduced
(Table 1, entries 1-5), while typical manganese or copper
catalyst led to significantly diminished efficacy (Table 1, entries
4-5). Notably, an additional electrolyte was not required for the
electrosynthesis of the desired product 3aa (Table 1, entry 7),
and control experiments further unraveled that a transition metal
catalyst was not mandatory (Table 1, entry 9). Instead, the acid
additive proved to be the key to success (Table 1, entries 8 and
10-11). The C–H nitrogenation was not viable in the absence of
electricity (Table 1, entry 12). To the best of our knowledge,
these findings represent the first efficient electrochemical
synthesis of aminoazoles by catalyst-free C–H amination.
performance. While indole 1n failed to give the desired product,
oxadiazole 1o proved to be a viable substrate for the C–H
amination.
Table 1. Optimization of the electrochemical C–H amination.[a]
Entry
Catalyst (mol %)
Electrolyte
Additive
3aa [%][b]
1
Co(OAc)2 (20)
Co(OAc)2 (10)
Co(OAc)2 (2.0)
Mn(OAc)2 (2.0)
Cu(OAc)2 (2.0)
Co(OAc)2 (2.0)
Co(OAc)2 (2.0)
Co(OAc)2 (2.0)
---
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
---
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
---
88
2
90
3
91
4
66
Scheme 2. Catalyst-free electrochemical amination of azoles 1. [a] 1 (0.5
mmol), 2a (2.0 equiv), AcOH (2.4 equiv), Zn(OAc)2 (20 mol %) in CH3CN at
60 °C for 48 h. [b] 80 °C.
5
64
6
trace[c]
92
7
Thereafter, we probed the scope of viable amines
2
(Scheme 3). Here, a wealth of secondary cyclic and acyclic
amines 2 was smoothly transformed into the desired products 3.
It is noteworthy that important functional groups, including
reactive carbamates or alkenes,[13] were well accepted with
excellent levels of chemo-selectivity, setting the stage for further
diversification of the thus obtained products 3. Moreover, the
robust C–H nitrogenation was not restricted to alkyl-substituted
amines. Indeed, anilines were also suitable substrates,[14]
provided that the C–H functionalization was conducted at a
slightly elevated reaction temperature (3as).
8
---
17
9
---
AcOH
AcOH
PhCO2H
AcOH
94
10
11
12
---
---
65[d]
85
---
---
---
---
trace[c]
[a] Reaction conditions: Undivided cell, RVC anode, Pt cathode, constant
current = 4 mA, 1a (0.5 mmol), 2a (2.0 equiv), catalyst (20 mol %), NaOPiv
(2.0 equiv), AcOH (2.4 equiv), CH3CN (10 mL), 23 oC, 18 h. [b] Yield of isolated
product. [c] No electricity. [d] AcOH (1.2 equiv).
With the optimized electrochemical C–H nitrogenation in
hand, we explored its robustness with a representative set of
substituted heteroarenes 1 (Scheme 2). Hence, the C–H
amination was amenable to diversely decorated benzoxazoles 1
featuring both electron-donating as well as electron-withdrawing
substituents. Thereby,
a
variety of synthetically useful
electrophilic functional groups, such as chloro, bromo and nitro
substituents, were fully tolerated, which should prove invaluable
for further late-stage manipulation. The C–H nitrogenation of
benzothiazoles 1l was realized upon addition of catalytic
quantities of Zn(OAc)2, albeit with somewhat reduced
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Given the remarkable performance of the catalyst-free C–H
electrooxidation, we became intrigued to delineating its mode of
action. To this end, we first conducted intermolecular
competition experiments (Scheme 5a). Here, the electron-rich
substrates 1a outperformed the more electron-deficient azole 1i.
Second, the C–H amination was suppressed upon the addition
of the typical radical scavenger BHT (5, 2,4-di-tert-butyl-4-
methylphenol), being suggestive of a single-electron-transfer
(SET) process. Here, the amination product 6 was obtained
instead (Scheme 5b). Third, kinetic isotope effect studies were
subsequently performed (Scheme 5c). Thus, parallel kinetic
experiments using the substrate 1a and its isotopically labeled
analog [D]1-1a showed no kinetic isotope effect KIE of kH/kD
≈
1.0, being indicative of the C–H scission not being rate-
determining . Further, it is noteworthy that we did not observe an
H/D exchange of substrate 1a when using D3CCO2D as the
additive. These findings indicate that the C–H cleavage is not
kinetically relevant. Forth, headspace analysis by gas
chromatography unambiguously confirmed the formation of
molecular hydrogen by cathodic reduction of protons.[15]
Scheme 3. Electrochemical C–H amination with amines 2. [a] 60 °C. [b] 80 °C.
The synthetic utility of the catalyst-free, electrooxidative C–H
amination was highlighted by the efficient synthesis of coumarin
4, which was shown to display highly potent anti-HIV and anti-
tumor activities.[5j] The desired product 4 was hence obtained
from commercial substrates under metal-free conditions
(Scheme 4), which obviates residual trace metal removal for
drug syntheses by the practitioner.
Scheme 5. Summary of mechanistic findings.
It is worth noting, that in addition to C(sp2)−H of benzoxazole,
the benzylic C(sp3)−H bond in substrate 5 was also efficiently
aminated by our strategy, selectively delivering the desired
product 6 in high yields (Scheme 6).
Scheme 6. Catalyst-free electrochemical C(sp3)–H amination.
Furthermore,
voltammetric
into
analysis
the electrochemical
revealed
key
C–H
mechanistic insights
Scheme 4. Synthesis of anti-HIV and antitumor piperazine
electrochemical C–H nitrogenation.
4
via
transformation (Figure 3).[15] The oxidation potential of substrate
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1a (Eox,1 = 2.02 VSCE, Eox,2 = 2.22 VSCE) was approximately 800
mV higher as compared with the oxidation potential of the amine
as well as of the operating current, which, for instance, could be
rationalized by a rate-determining cathodic reduction.
2a (1.19 VSCE), which renders
a direct oxidation of the
benzoxazole unlikely to be operative. The voltammogram of the
mixture of substrate 1a and amine 2a indicated that direct
radical transfer is preferential instead. Notably, the peak current
of amine 2a was significantly reduced, being consistent with a
fast subsequent chemical transformation of the thus formed
aminyl radical. Cyclic voltammetric studies in the presence of
KOAc provided strong support for the initial oxidation of amine
2a, which was further substantiated by DFT computational
analysis
on
the
B3PW91-D3BJ/def2-
QZVP+SMD(MeCN)//PBE0-D3BJ/def2TZVP+SMD(MeCN)[16]
level of theory.[15]
a)
b)
Figure 4. In-operando kinetic ReactIR studies.
Based on our studies, a plausible mechanistic scenario was
proposed for the electrochemical, external oxidant-free C–H
amination in Scheme 7. The anodic oxidation and deprotonation
of amine 2 give the aminyl radical I. We suggest that the AcOH
additive initially protonates the benzoxazole 1 to form the salt II,
which facilitates the subsequent attack of the aminyl radical as
suggested by DFT studies.[15] Finally, stepwise proton-coupled
electron transfer (PCET) of intermediate III generates the final
product 3. In contrast, the amination of substrate 5 is proposed
to proceed by its initial anodic oxidation.[17]
Figure 3. (a) Cyclic voltammograms at 100 mV s-1: n-Bu4NPF6 (0.1 M in
MeCN), concentration of substrates 4 mM. (b) Cyclic voltammograms at 100
mV s-1 : Influence of AcOH and KOAc.
Finally, we conducted detailed kinetic studies by means of
in-operando infrared spectroscopy (Figure 4).[15] Hence, ReactIR
analysis revealed a zeroth order in the concentration of the
substrates 1 and 2. In contrast, the reaction rate was solely
depending on the concentration of HOAc with saturation kinetics
Scheme 7. Proposed mechanism for catalyst-free C−H amination.
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In conclusion, we have developed an efficient method for
user-friendly, electrochemical C−H aminations of azoles via
cross-dehydrogenative C−H/N−H functionalization under
catalyst-, electrolyte- and chemical oxidant-free conditions. The
robust catalyst-free C−H nitrogenation proved broadly applicable
to cyclic and acyclic alkyl amines as well as anilines under mild
reaction conditions.[18] Detailed mechanistic studies gave strong
support for a SET-based reaction manifold. We believe that our
findings should provide guidance for the future evaluation and
development of catalyzed C−H aminations by means of
electrosynthesis.
Acknowledgements
Generous support by the DFG (Gottfried-Wilhelm-Leibniz award)
is gratefully acknowledged.
Keywords: Electrochemistry • C−H amination • catalyst-free •
oxidant-free • mild C−H functionalization
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10.1002/chem.201802832
Chemistry - A European Journal
COMMUNICATION
COMMUNICATION
Youai Qiu, Julia Struwe, Tjark H. Meyer,
João C. A. Oliveira, and Lutz
Ackermann*
Page No. – Page No.
Catalyst-free Electrochemical Azole
C–H Amination
Set them free: Catalyst-free electrochemical C–H aminations were accomplished
by oxidative C–H/N–H functionalizations with electricity as the sole oxidant.
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