Electrooxidative amination of sp2 C-H bonds: Coupling of amines with aryl amides via copper catalysis

Article abstract of DOI:10.1021/acs.orglett.9b00003

Metal-catalyzed cross-coupling reactions are among the most important transformations in organic synthesis. However, the use of C-H activation for sp² C-N bond formation remains one of the major challenges in the field of cross-coupling chemistry. Described herein is the first example of the synergistic combination of copper catalysis and electrocatalysis for aryl C-H amination under mild reaction conditions in an atom-and step-economical manner with the liberation of H₂ as the sole and benign byproduct.

Full text of DOI:10.1021/acs.orglett.9b00003

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Electrooxidative Amination of sp2 C−H Bonds: Coupling of Amines
with Aryl Amides via Copper Catalysis
Subban Kathiravan,* Subramanian Suriyanarayanan, and Ian A. Nicholls*
Bioorganic & Biophysical Chemistry Laboratory, Department of Chemistry & Biomedical Sciences and Linnaeus University Centre
for Biomaterials Chemistry, Linnaeus University, SE-391 82 Kalmar, Sweden
S
* Supporting Information
ABSTRACT: Metal-catalyzed cross-coupling reactions are among the most important transformations in organic synthesis.
However, the use of C−H activation for sp2 C−N bond formation remains one of the major challenges in the field of cross-
coupling chemistry. Described herein is the first example of the synergistic combination of copper catalysis and electrocatalysis
for aryl C−H amination under mild reaction conditions in an atom-and step-economical manner with the liberation of H2 as the
sole and benign byproduct.
he efficient construction of C−N bonds is important in
Scheme 1. Transition-Metal-Catalyzed C−H Amination
Reactions: (a) Ullmann-Type C−N Bond Formation
Reactions; (b) Direct Oxidative C−H/N−H Coupling; (c)
External Oxidant-Free Metalloelectrocatalysis for C−H/N-
H coupling
T
organic chemistry due to the presence of nitrogen-
containing motifs in a wide range of natural products,
pharmaceuticals, and functional materials.1−4 There are a
number of notable routes to the formation of sp2 C−N bonds,
including the Buchwald−Hartwig reaction, Ullmann coupling,
and Chan−Lam amination that use prefunctionalized organo-
metallic reagents, organic halides, or pseudohalides as coupling
partners (Scheme 1a).5−16
From step- and atom-economy standpoints, approaches to
functionalized aromatic amine derivatives that make use of
otherwise unreactive C−H bonds in direct amination is most
desirable, especially if avoiding the use of prefunctionalized
coupling partners.17−21 Recent years have seen tremendous
effort being focused on the direct C−H/N−H cross-coupling.
To date, CuII, NiII, CoIII, IrIII, and RhIII catalysts have been
used to facilitate C−H amination reactions with both primary
and secondary and primary amines (Scheme 1b).22−39 Despite
these undisputable advances, direct C−H aminations largely
require sacrificial terminal oxidants, which lead to undesired
metal byproducts. For example, the first copper-promoted
directed amination of C(sp2)−H bonds was realized by Yu
using O2 as a terminal oxidant.40 Later, Chen reported copper-
catalyzed carboxamide directed ortho-amination of anilines
with alkylamines using PhI(OAc)2 as the oxidant.41 Daugulis
subsequently described a method for copper-catalyzed, direct
amination of sp2 C−H bonds of benzoic acid derivatives.42,43
This reaction employed a Cu(OAc)2 catalyst in conjunction
with Ag2CO3 as a cocatalyst and O2 as a co-oxidant. In spite of
the above excellent developments, the establishment of
efficient strategies for direct C−H aminations, ideally with
mild external oxidant-free catalyst systems, is highly desirable.
The synergistic merger of electrocatalysis and transition
metal catalysis (metalloelectro catalysis) has gained significant
momentum in synthetic organic chemistry and has even been
employed in the development of C−H activation reac-
Received: January 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00003
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Organic Letters
Letter
tions.44−51 We perceived that metalloelectrocatalysis might
provide an opportunity to realize transition-metal-catalyzed
oxidative C−H amination under external oxidant-free con-
ditions based upon results from a range of other metal-
loelectrocatalysis studies.52−58 For example, Jutand and co-
workers described a Pd-catalyzed electrochemical dehydrogen-
ative Heck reaction.59 Later, Kakiuchi and co-workers
developed a Pd-catalyzed aromatic C−H halogenation via
anodic oxidation.60 Mei and co-workers reported a Pd-
catalyzed direct electrochemical oxygenation.61 More recently,
Ackermann and Lei independently developed very interesting
cobalt(II)-catalyzed electrooxidative C−H amination.62,63
However, copper-catalyzed electrooxidative C(sp2)−H/N−H
cross-coupling has not yet been achieved.64 Herein, we
demonstrate the potential of copper(II) catalysis in electro-
oxidative C−H/N−H cross-coupling between amides and
various secondary amines including pharmaceutically active
compounds (Scheme 1c).
With the optimized copper(II) catalyst for the electro-
oxidative C−H/N−H functionalizations in hand, we examined
the scope of benzamides (1a−1s) ammenable to reaction with
morpholine 2a (Scheme 2). Gladly, the reaction tolerated a
Scheme 2. Scope of Amides
We initiated our studies by probing various reaction
conditions for the envisioned copper-catalyzed electrochemical
C−H amination (Table 1). Preliminary experiments identified
a
Table 1. Optimization Studies
b
entry
solvent
additive
T (°C)
yield (%)
1
2
3
4
5
6
7
8
DMF
DMSO
DCE
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
NaOPiv
KOAc
NaOAc
NaOAc
NaOAc
−
80
80
80
80
80
80
80
60
60
60
60
60
15
−
−
HFIP
−
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
68
11
50
79
79
range of substrate substituents, affording the corresponding
products in moderate to good yields (55−80%), relative to the
unsubstituted benzamide 1a, which afforded the desired
product in good yield (79%). Generally, the reactivity of
electron-deficient substrates (1k−1t) were lower than in the
case of electron-rich substrates (1b−1h). It was notable that,
in each case, only monoaminated products were observed.
Moreover, in the case of the meta-substituted benzamides (1c,
1i, 1l, and 1n), C−H functionalization was observed to take
place exclusively at the less hindered position, highlighting the
reaction’s good regioselectivity. Gratifyingly, 1- and 2-
napthamide (1g−1h) were also applicable under the standard
conditions, yielding the desired products (3g−3h) in good
yield. This transformation also tolerates halogenated sub-
stituents, notably the bromo and fluoro groups, which are
otherwise apt to participate in nucleophilic amination
reactions.66,67 In addition, we were pleased to find that the
heterocyclic thiophene amide 1s was also aminated (3s) in
moderate yields (61%).
To further explore the scope of this copper(II) catalyzed
electrooxidative amination reaction, a series of secondary
amines were tested. As seen in Scheme 3, the reaction of
substrate 1f with a range of cyclic six-membered ring secondary
amines was explored with piperidine and a series of its
derivatives containing either electron-withdrawing or -donating
substituents using the optimized electrooxidative conditions,
which yielded the aminated products in 55−88% yield (4b−
4k), highlighting the broad functional group compatibility of
c
d
9
e
10
11
12
−
−
−
f
g
NaOAc
a
Reaction conditions: undivided cell, 1a (0.4 mmol), 2a (1.2 mmol),
Cu(OAc)2 (20 mol %), base (4.0 equiv), solvent (13 mL), 60 °C, 2
mA, 12 h, RVC electrode (1.0 × 1.5 cm), Pt-plate electrode (1.5 cm ×
b
c
d
1.5 cm). Isolated yield. Cu(OAc)2 (10 mol %). Under air.
e
f
g
Without electricity. Without additive. Without copper catalyst.
RVC = reticulated vitreous carbon.
Cu(OAc)2 as an effective catalyst for the C−H amination of
the amide 1a derived from 8-aminoquinoline.65 From a series
of representative solvents (entries 1−5), acetonitrile was found
to provide the most optimal results (entry 5). It is noteworthy
that, to the best of our knowledge, this constitutes the first
example of the use of copper catalysis in conjunction with an
electrochemical C−H activation with secondary amines.
NaOAc proved to be the ideal additive (entries 6−7). The
observed comparable efficacy under an atmosphere of ambient
air (entries 8 and 9) confirmed the robustness of the
electrocatalysis. Control experiments were used to verify the
critical roles of the electricity, the copper catalyst, and the
additive (entries 10−12).
B
DOI: 10.1021/acs.orglett.9b00003
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Organic Letters
Letter
Scheme 3. Scope of Amines
Scheme 4. Synthetic Utility
Based on the observed reactivities and previous reports on
transition-metal-directed C−H activations and oxidative
functionalizations with hydrogen evolution without the use
of external chemical oxidants for recycling the catalysts, we
propose an electrooxidative C−H amination that proceeds
through a CuII/CuIII catalytic cycle (Scheme 5),62−64,68,69
the reaction. Moreover, the coupling of 1f with tetrahydro-
isoquinoline also gave the corresponding aminated product 4l
in 70% yield. Medicinally privileged protected piperizine
derivatives could also be used in the reaction, as is evidenced
throught the formation of 4m and 4n. Notably, the coupling of
thiomorpholine under metalloelectrocatalysis conditions was
successful and furnished the aminated product 4o in 63% yield.
Finally, pyrrolidine and piperidine could be cross-coupled,
furnishing products 4p−4q in moderate yields.
Scheme 5. Possible Mechanisms
We anticipate that this copper(II) catalyzed electrooxidation
should find wide application in medicinal chemistry, and
accordingly wanted to demonstrate that coupling fragments of
established significance could be performed (Scheme 4). The
examples presented in Scheme 4 consist of a series of amines
containing active pharmaceutical ingredients (APIs), or closely
related derivatives thereof, that can be effectively used in this
reaction. For example, reaction with the series of complex
substituted piperidine derivatives (5a−5e) proceeded well,
leading to the incorporation of amine fragments belonging to
the antidepressant Paroxetine (6a), Loratidine (antihistamine,
6b), Clopidogrel (antiplatelet agent, 6c), and Haloperidol
(antipsychotic/antimotility, 6c). Piperazines that feature in the
anti-Parkinsonian compound Piribedal (6d), and atypical
antipsychotics Perospirone and Ziprasidone (6e) all performed
well, as was also the case for the piperazine moiety that
constitutes the API in the antidepressant Amoxapine, 6f. We
were also able to employ the acylic N-methylamine containing
the API of the antidepressant Fluoxetine 6g. Notably, the use
of N-alkyl amines is reported to have limited compatibility in
reported C−H amination reactions.62,63 However, this elegant
copper(II)−metalloelectrocatalysis strategy provides a method
to incorporate N-alkylamines under mild reaction conditions
using electricity as a green oxidant.
where Cu(II) was oxidized to Cu(III) at the anode which then
reacts with amide 1 in the presence of NaOAc to form
intermediate A. Subsequent coordination of amine 2 to
intermediate A affords B. A subsequent reductive elimination
of the intermediate B delivers the final product 3, which is
followed by anodic oxidation to complete the catalytic cycle,
thus avoiding the use of expensive terminal oxidants (Path A).
Alternatively, the amide 1 could react with Cu(II) to form D,
C
DOI: 10.1021/acs.orglett.9b00003
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which on further oxidation at the anode yields complex A
(Path B).
In summary, copper-catalyzed coupling of synthetically
versatile aryl amides with various aliphatic amines has been
enabled under mild conditions in the absence of an external
oxidant. This has been achieved through a synergistic merging
of electrocatalysis with copper(II) organometallic chemistry
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hydrogen as the sole byproduct. The newly developed
methodology is tolerant of variation in both reaction partners
and proceeds in the presence of basic heteroatoms and several
heterocyclic scaffolds. They potential for using this method-
ology in late-stage functionalization in drug development is
highlighted by its use in the derivatization of a number of
pharmaceutically active compounds. Finally, we anticipate that
this new cross-dehydrogenative cross-coupling strategy will
provide a useful, complementary approach to C−N bond-
forming reactions while also expanding upon the repertoire of
transformations mediated by base metal catalysis.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00003.
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1
Experimental procedures, characterization data, and H
and 13C NMR spectra for all products (PDF)
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AUTHOR INFORMATION
■
Corresponding Authors
(17) Louillat, M.-L.; Patureau, F. W. Oxidative C-H amination
reactions. Chem. Soc. Rev. 2014, 43, 901−910.
*E-mail: suppan.kathiravan@lnu.se.
*E-mail: ian.nicholls@lnu.se.
ORCID
(18) Thirunavukkarasu, V. S.; Kozhushkov, S. I.; Ackermann, L. C-H
nitrogenation and oxygenation by ruthenium catalysis. Chem.
Commun. 2014, 50, 29−39.
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arenes: Expanding the scope of base-metal-catalyzed C-H function-
alization. ChemCatChem 2015, 7, 732−734.
Subban Kathiravan: 0000-0003-0774-2528
Ian A. Nicholls: 0000-0002-0407-6542
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Linnaeus University and Swedish Research Council
(Vetenskapsrådet, Grant 2014-4573) and the KK-Foundation
(Grant 20170059) for financial support. We thank the SGL
Carbon Company (Wiesbaden, Germany) for the generous
donation of RVC electrodes. We also thank Prasad Anaspure
(Linnaeus University) for the triplicate reproduction of the
synthesis of 3a.
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DOI: 10.1021/acs.orglett.9b00003
Org. Lett. XXXX, XXX, XXX−XXX